Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Carrr, 2012

SR and meta-analysis of RCTs (MP4002 (NCT00651118), MP4004 (NCT00740792), and MP4006 (NCT00883168))

Literature search up to (month/year)

A: Hampel, 2010

B: Meltzer, 2012

C: Meltzer, 2013

Study design: RCTs parallel

Setting and Country:

Multicentre, outpatient study in USA, Germany, Belgium and UK

Source of funding and conflicts of interest:

funded by Meda Pharmaceuticals, Inc

Inclusion criteria SR: Subjects (>12 years old) with a minimum 2-year history of SAR, significant current clinical rhinitis symptomatology, and a positive skin prick test response to relevant pollen were randomized. All subjects had moderate-to-severe SARdefined by a reflective total nasal symptom score (rTNSS) of at least 8 of 12, with a congestion score of 2 or 3 during screening. Inclusion criteria for the duration of symptoms for the 3 studies were slightly different.

Exclusion criteria SR: erosion, ulceration, or septal perforation or another disease (eg, sinusitis, rhinitis medicamentosa, polyposis, respiratory tract infection (within 14 days of screening), asthma (except intermittent asthma)), significant pulmonary disease, or symptomatic cardiac conditions or were taking concomitant medication that could interfere with the interpretation of study results

Important patient characteristics at baseline:

N total at baseline:

Intervention: 207+193+448=848

Control: 208+194+445=847

Sex:

I: 36% M

C: 36% M

Age ± SD:

I: 36.7 (14.3)

C: 35.9 (14.1)

Groups comparable at baseline? yes

Describe intervention:

 MP29-02 nasal spray (novel

formulation of 137 mg of azelastine/50 mg of FP

Describe control:

corticosteroid (FP)

Placebo spray comprised exactly the same vehicle/

formulation as the active treatments without any active agent

End-point of follow-up:

A: 14 days

B: 14 days

C: 14 days

For how many participants were no complete outcome data available?

Loss-to follow-up:

(intervention/control)

A: Intervention

Control

B: Intervention

Control

C: Intervention

Control

Outcome measures and effect size (include 95%CI and p-value if available):

Total symptom score (reduction from baseline):

Baseline Change

A I: 18.3 (3.0) -5.5 (5.2) n=207

C: 18.2 (3.2) -5.0 (4.7) n=207

B I: 18.2 (3.3) -5.6 (5.2) N=193

C: 18.2 (3.1) -5.0 (5.2)

N=189

C I: 19.4 (2.4) -5.6 (5.2) N=448

C: 19.5 (2.4) -5.1 (4.7) N=450

Pooled

I: -5.7 (SD 5.3)

C: -4.4 (SD 4.8)

Quality of life:

A: I:

C:

B: I:

C:

C: I:

C:

Baseline

I: -1.6 (SD 1.3)

C: -1.4 (SD 1.3)

Adverse events:

A I: 4 (2 %)

C: 1 (0.5 %)

B I: 3 (1.5 %)

C: 1 (0.5 %)

C I: 3(0.7 %)

C: 4 (0.9 %)

Sick leave:

Not reported

MP29-02 nasal spray (novel formulation of 137 mg of azelastine/50 mg of FP

MP 4002

MP 4004 beschreven in Meltzer, 2012

MP 4006

Facultative:

Brief description of author’s conclusion

Personal remarks on study quality, conclusions, and other issues (potentially) relevant to the research question

Level of evidence: GRADE (per comparison and outcome measure) including reasons for down/upgrading

Sensitivity analyses (excluding small studies; excluding studies with short follow-up; excluding low quality studies; relevant subgroup-analyses); mention only analyses which are of potential importance to the research question

Heterogeneity: clinical and statistical heterogeneity; explained versus unexplained (subgroup analysis)

Berger, 2014

EudraCT no. 2011-001368-23

Price, 2013

Type of study: open-label RCT

Setting and country: India

Funding and conflicts of interest: W. E. Berger has received honoraria, consulted for, and received research support from MEDA and Alcon; has consulted for and received speaker fees from Sunovian and TEVA; has received speaker fees from Astra- Zeneca; and has received speaker fees and served as an adviser for Allergan. S. Shah has consulted and received research grants from MEDA and given lectures for TEVA, Alcon, and AstraZeneca. P. Lieberman is an adviser for the Allergy Foundation of America and Baxter and has given lectures for MEDA, Genentech, Ista, and TEVA. J. Hadley has consulted and served as an adviser for MEDA, Merck, and TEVA. D. Price has received consultancy and speaker fees from Merck, Mundipharma, Novartis, Medapharma, Kyorin, and TEVA; has received consultancy fees from GlaxoSmithKline, Almirall, and Chiese; has received consultancy fees and grants from Pfizer and AstraZeneca; has received consultancy fees and grants from Boehringer Ingelheim; has received speaker fees and grants from Aerocrine; has received grants from the UK National Health Service, Nycomed, and Medapharma; is director of research in Real Life LTD; is a guideline group member for Allergic Rhinitis and its Impact on Asthma and European Position Paper on Rhinosinusitis and Nasal Polyps; and has shares in AKL Ltd. U. Munzel is an employee of Medapharma. S. Bhatia has received research grants and consulted for MED

Inclusion criteria:

Male and female subjects 12 to 80 years of age with an established history (>=1 year) of chronic rhinitis due to perennial allergies or nonallergic triggers were eligible for the study. Subjects with a seasonal allergic component were included, provided that they had significant symptoms outside the allergy seasons. The diagnosis of rhinitis, whether allergic or nonallergic, was made on the basis of a thorough evaluation. This evaluation included medical history, physical examination, rhinitis symptoms, and skin testing, or validated in vitro tests for allergen-specific Ig E. All the subjects were symptomatic at study entry, with nasal symptoms of rhinitis for at least 2 days during the screening period. Subjects who received subcutaneous immunotherapy (antigen desensitization) were on a stable maintenance regimen for at least 30 days before the first study visit.

Exclusion criteria:

If on nasal examination, they had any nasal ulceration (grade 3) or nasal septal perforation (grade 4); recent nasal or sinus surgery; chronic sinusitis; recent acute sinusitis; nasal disease(s), such as rhinitis medicamentosa, clinically significant nasal polyposis, or nasal structural abnormalities. Women who were pregnant or nursing and women of childbearing potential who were not using an acceptable method of contraception were not permitted to enroll. Subjects also were excluded if they had a history of asthma (with the exception of mild intermittent asthma), significant pulmonary disease, posterior subcapsular cataracts or glaucoma, clinically significant arrhythmia or prolonged corrected QT interval, a history of drug or alcohol abuse within the past 2 years, or a hypersensitivity to AZ or FP. Recent use of any investigational drug, systemic corticosteroids or omalizumab, inhaled corticosteroids or combination inhaled corticosteroids and/or long-acting b-agonists (within 30 days), or sublingual immunotherapy (within 6 months) was not permitted.

N total at baseline:

Intervention: 388

Control: 199

Important prognostic factors²:

Age ± SD:

I: 32.8 ± 11.5

C: 35.3 ± 11.5

Sex:

I: 59% M

C: 52% M

Symptom score:

I: 3.81 ± 2.49

C: 3.90 ± 2.32

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

MP29-02 a Novel Intranasal Formulation of Azelastine Hydrochloride and Fluticasone Propionate in an Advanced Delivery System

administered at a dosage of 1 spray per nostril twice daily (AM and PM); each metered spray delivered 137 mcg of AZ and 50 mcg of FP per actuation, for a total daily dose of 548 mcg and 200 mcg for AZ and FP, respectively.

Describe control (treatment/procedure/test):

Fluticasone Propionate FP nasal spray (commercially available generic fluticasone; Boehringer Ingelheim/Roxane Laboratories, Columbus, Ohio) was administered at a dosage of 2 sprays per nostril once daily (AM), each metered spray 50 mcg, for a total daily dose of 200 mcg.

Length of follow-up:

Baseline evaluations were performed, with additional

outpatient evaluations at months 1, 3, 6, 9, and 12.

Loss-to-follow-up:

Intervention:

N (%) 88 (23%)

Reasons (describe):

Adverse Event n = 11

Abnormal Test Result n = 2

Treatment Failure n = 0

Noncompliance n = 5

Withdrew Consent n = 12

Lost to follow-up n = 38

Administrative problems n = 15

Protocol Violation n = 3

Other n = 2

Control:

N (%) 51 (26%)

Reasons (describe):

Adverse Event n = 6

Abnormal Test Result n = 0

Treatment Failure n = 2

Noncompliance n = 3

Withdrew Consent n = 8

Lost to follow-up n = 20

Administrative problems n = 6

Protocol Violation n = 3

Other n = 3

Outcome measures and effect size (include 95%CI and p-value if available):

Total symptom score (rTNSS) (after 52 weeks)

I: -2.98

C: -2.71

Diff: -0.27; 95% CI; -0.56, 0.02; P=.0642

Quality of life:

Not reported

Quality of life:

Not reported

Adverse events:

I: 9.4%

C: 11.1%

The most common TRAEs were dysgeusia (2.5%) in the MP29-02 group and headache (4.3%) in the FP group

Sick leave:

Not reported

Two publications Price 2013 symptoms; adverse events Berger 2014

Study conducted at 37 investigational sites in India during 2008 and 2009

Hampel, 2010

NCT00660517

Type of study: randomized, double-blind, placebo-controlled, parallelgroup study conducted at 6 investigational sites

Setting and country: Texas

Funding and conflicts of interest: Funding for this study was provided by MedPointe Pharmaceuticals, Somerset, New Jersey. Dr Wheeler is the director of medical communications at Meda Pharmaceuticals. Dr Sacks is the chief medical officer of Meda Pharmaceuticals.

Inclusion criteria:

a minimum 2-year history of allergy to Texas mountain cedar pollen (J ashei), as confirmed by a positive prick-puncture skin test result to mountain cedar pollen within the past 12 months

At screening, eligible patients had to have a 12-hour reflective total nasal symptom score (TNSS) of at least 8 of a possible 12 and a congestion score of 2 or 3; Patients were also required to be in general ood health and free of any disease or concomitant treatment

that could interfere with the interpretation of the study results as determined by the study investigator.

Exclusion criteria:

(1) the presence of any nasal mucosal erosion, nasal ulceration, or nasal septal perforation (grade 1b-4) at either screening or randomization; (2) other nasal disease(s) likely to affect deposition of intranasal medication, such as sinusitis, rhinitis medicamentosa, clinically significant polyposis, or nasal structural abnormalities; (3) nasal surgery or sinus surgery within the previous year; or (4) more than 3 episodes per year of chronic sinusitis

N total at baseline:

Intervention: 153

Control: 151

Important prognostic factors²:

age ± SD:

I: 39.5 (12-73)

C:38.1 (12-74)

Sex:

I: 36,6% M

C: 33,8% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Azelastine/fluticasone

Combination azelastine 0.1% and fluticasone, 1 spray per nostril twice daily (each metered spray of azelastine-fluticasone delivers 137microgram of azelastine hydrochloride and 50 [1]g of fluticasone propionate; therefore, a dosage of 1 spray per nostril twice daily delivers 548 microgram of azelastine hydrochloride and 200 microgram of fluticasone propionate)

Describe control (treatment/procedure/test):

1 spray per nostril twice daily (each metered spray of Flonase delivers 50 microgram of fluticasone propionate; therefore, a dosage of 1 spray per nostril twice daily delivers 200 [1]g of fluticasone);

Length of follow-up: 14 days

Loss-to-follow-up:

33 (5%) discontinued participation in the study. Completion rates were similar in all treatment groups. One patient in the combination group, 3 in the azelastine group, 1 in the fluticasone group, and 1 in the placebo group discontinued participation in the study because of an adverse event. The most common reason for study withdrawal was noncompliance, followed by “other,” withdrawal of consent, and adverse events.

Outcome measures and effect size (include 95%CI and p-value if available):

Total symptom score

TNSS baseline

I: 18,8 (9-24) (SD 61.3)

C: 18,3 (8-24) (SD 28.6)

TNSS end

I: -5.31 (5.08)

C:-3.84 (4.76)

Quality of life (RQLQ):

I: 1.60

C: 1.43

Adverse events:

I:

Dysgeusia (bitter taste) 11 (7.2)

Epistaxis 6 (3.9)

Headache 4 (2.6)

Pharyngolaryngeal pain 2 (1.3)

Nasal discomfort 2 (1.3)

Nausea 1 (0.7)

Mucosal erosion 1 (0.7)

Somnolence 1 (0.7)

C:

Dysgeusia (bitter taste) 3 (2.0)

Epistaxis 4 (2.6)

Headache 2 (1.3)

Pharyngolaryngeal pain 1 (0.7)

Nasal discomfort 0 (0.0)

Nausea 2 (1.3)

Mucosal erosion 1 (0.7)

Somnolence 0 (0%)

Sick Leave:

Not reported

Berger, 2018

NCT01794741

Type of study: parallel-group, open-label design

Setting and country: outpatient study, California USA

Funding and conflicts of interest: Research and medical writing support was funded by Mylan, Inc. (Canonsburg, PA) E. Sher is a national speaker for Mylan, Inc. and ALK Pharmaceuticals. S. Gawchik has served on the Advisory Board for Meda. The remaining authors have no conflicts of interest pertaining to this article

Inclusion criteria: Male and female children 4–11 years old with a history of AR (SAR or PAR) who, in the opinion of the study center investigators, could benefit from treatment with MP-AzeFlu were eligible for inclusion. Children were required to be in generally good health, without concomitant disease or medical treatment that could interfere with interpretation of study results

Exclusion criteria:

se of concomitant medication was discouraged; however, medications considered necessary and that did not interfere with the evaluation of study medications were allowed at investigator discretion. (See the Online Supplement Text for a list of prohibited medications.)

N total at baseline:

Intervention: 304

Control: 100

Important prognostic factors²:

age ± SD:

I: 8.1 ± 2.1

C: 8.1 ± 1.9

Sex:

I: 60% M

C: 51% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

MP-AzeFlu (137microgram AZE and 50 microgram FP per spray)

Treatments were administered as one spray per nostril twice daily, morning and evening, which provided total daily doses of 548 microgram for MP-AzeFlu and 200microgram for FP

Describe control (treatment/procedure/test):

FP nasal spray (50

Treatments were administered as one spray per nostril twice daily, morning and evening, which provided total daily doses of 548microgram for MP-AzeFlu and 200 microgram for FP

Length of follow-up: 3 months

Loss-to-follow-up:

Intervention:

N (%) 19 (6%):

Reasons (describe)

adverse events (6), treatment failure (1), protocol violation (1), noncompliance (2), withdrawal by subject (4), lost to follow-up (3), other (2)

Control: 9 (9%)

N (%)

Reasons (describe): adverse events (4), protocol violation (1), withdrawal by subject (1), lost to follow-up (2)

other (1)

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Total symptom score

Not reported

Quality of life:

Not reported

Adverse events:

Treatment emergent adverse events

I: 124 (41%)

C: 37 (37)

Treatment related adverse events:

I: 49 (16%)

C: 12 (12%)

Sick leave:

Not reported

children

Study reference

(first author, publication year)

Describe method of randomisation

Bias due to inadequate concealment of allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?

(unlikely/likely/unclear)

Bias due to loss to follow-up?

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?

(unlikely/likely/unclear)

Berger, 2014

An interactive voice response

system was used to sequentially assign the next available

randomization number from a central randomization schedule.

unlikely

not blinded, unclear

not blinded, unclear

not blinded, unclear

unclear

unclear

unlikely

Berger, 2018

centralized, age-group stratified, block randomization scheme using Proc Plan (SAS, Cary, NC) was used to assign subjects to treatment (3:1 ratio). An interactive Web response system ensured proper stratification

unlikely

not blinded, unclear

not blinded, unclear

not blinded, unclear

unclear

unclear

unlikely

Carr, 2012

Patients were randomized and balanced by study site in blocks of 4. Eligible subjects received the study site’s next available randomization number in sequence

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

Hampel, 2010

randomized by a computer-generated randomization schedule

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Weiner, 1998

SR and meta-analysis of (RCTs / cohort / case-control studies)

Literature search up to 1997

A: Bunnag, 1992

B: Schoenwetter, 1995

C: Bernstein, 1995

D: Brooks, 1996

E: Gehanno, 1997

F: Vervloet, 1997

Study design: RCTs

Setting and Country:

Department of

Medicine, Monash

University,

Melbourne,

Victoria, 3181,

Australia

Source of funding and conflicts of interest:

Funding: Astra Pharmaceuticals (Australia) provided library and research assistance and support for presentation at a scientific meeting. Astra did not provide any other direct financial support.

Conflict of interest: Each of the authors is involved in clinical practice and prescribes both intranasal corticosteroids and oral antihistamines for patients. While the support of Astra Pharmaceuticals (manufacturers of budesonide brand nasal spray) is acknowledged, the authors produced this review independently and it was not subject to any editorial review or changes by Astra. The authors believe that no conflict of interest arose during the production of this paper.

Inclusion criteria SR: randomised controlled trials of topical corticosteroids and rhinitis published between 1966 and 1997. At least one of the following clinical outcomes had to be reported: nasal symptoms (including total nasal symptom scores), eye symptoms, global symptoms, drug requirements for treating the rhinitis, nasal function (including measurements of nasal resistance), and assessment of quality of life.

Exclusion criteria SR: studies that reported only nasal challenge with specific allergens or non­clinical outcomes, such as in vitro results of inflammatory mediators.

16 studies included

Important patient characteristics at baseline:

N, mean age

A: 69, 30yrs

B: 298, 40

C: 239, 36

D: 60, not reported

E: 114, 39

F: 238, 29

Describe intervention:

A: Astemizole 10 mg

B: Loratadine 10 mg

C: Astemizole 10 mg

D: Loratadine 10 mg

E: Loratadine 10 mg

F: Cetirizine 10 mg

Describe control:

A: Budesonide, 200 µg

B: Triamcinolone 220 µg

C: Triamcinolone 220 µg

D: Beclamethasone 336 µg

E: Fluticasone 200 µg

F: Fluticasone 200 µg

End-point of follow-up:

Not specified in SR

For how many participants were no complete outcome data available?

(intervention/control)

Not specified in SR

Outcome measure-1

Total nasal symptom score

SMD (95% CI):

B: -0.606 (-0.848 to -0.364)

C: -0.427 (-0.701 to -0.152)

E: -0.677 (-1.055 to -0.299)

F: -0.062 (-0.317 to 0.193)

Pooled effect (fixed effects model):

-0.423 (-0.531 to -0.315) favoring steroid treatment

χ²=26.82, df=8, P<0.001

Outcome measure-2

Ocular symptom score

SMD (95% CI):

A: -0.216 (-0.696 to 0.265)

B: -0.149 (-0.386 to 0.088)

C: 0.000 (-0.271 to 0.271)

D: -0.382 (-1.008 to 0.244)

Pooled effect (fixed effects model):

-0.043 (-0.157 to 0.072)

favoring steroid treatment

χ²=32.4, df=10, P<0.0005

Study

First author, year

Appropriate and clearly focused question?¹

Yes/no/unclear

Comprehensive and systematic literature search?²

Yes/no/unclear

Description of included and excluded studies?³

Yes/no/unclear

Description of relevant characteristics of included studies?⁴

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?⁵

Yes/no/unclear/notapplicable

Assessment of scientific quality of included studies?⁶

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?⁷

Yes/no/unclear

Potential risk of publication bias taken into account?⁸

Yes/no/unclear

Potential conflicts of interest reported?⁹

Yes/no/unclear

Weiner, 1998

Yes

Yes

Yes

Yes

Not applicable, only RCTs

Yes

Yes

No

Yes

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size ⁴

Comments

Frølund, 1991

Type of study:

RCT, randomized, double-blind, double-dummy comparative study

Setting and country: Single-center study in Copenhagen, Denmark.

Funding and conflicts of interest:

Not reported.

Inclusion criteria:

Unequivocal history of seasonal allergic rhinitis for the previous two seasons. The diagnosis was confirmed by a positive skin prick test.

Exclusion criteria:

Any concurrent disease that would interfere with the study results or require treatment or if pregnant or lactating, nasal polyps, deviated septa or any structural defect which might cause nasal obstruction or interfere with clinical evaluation, pre-seasonal or co-seasonal immunotherapy with antigen extracts started within the 12 months prior to the study or any maintenance doses of these preparations during the 12 months before entering the study; therapy with loratadine within 3 months, systemic or topical corticosteroids, sodium cromoglycate within 2 weeks prior to the study, decongestants within 24 h, astemizole within 4 weeks, and antihistamines other than astemizole 4 days prior to the study.

N total at baseline: 60

Intervention: 30

Control: 30

18 to 65 years, 61.7% male. No difference was seen between random allocation of patients or treatments.

Loratadine 10 mg once daily for 3 weeks

beclomethasone dipropionate (BDP) nasal spray 100 µg into each nostril twice daily for 3 weeks

Length of follow-up:

Duration of the treatment

Loss-to-follow-up:

6 patients in the LOR group and 3 patients in the BDP group discontinued because of treatment failure. 6

patients in the LOR group discontinued due to other reasons not related to treatment failure.

Incomplete outcome data:

N.A.

Both treatments reduced total symptom score compared to baseline, with no differences between the groups. This was true for both the medical visits and self-reported scores.

On day 5, self-reported nasal symptoms score more improved in the BDP group (change from baseline -3.97) compared with LOR (-2.29). On the other hand, during the first 6 days, self-reported eye symptoms score was significantly lower in the LOR group. Ocular score was similar after both treatment (-1.73 with BDP, -1.8 with LOR).

One patient in the LOR group compared with 4 patients in the BDP group had to have a prescription for rescue medication (antihistamine- vasoconstrictor eye drops), whereas 1 patient in the BDP group used α-adrenic nasal spray. The rescue medication was not used continuously at any time during the study.

Charpin, 1994

Type of study:

RCT, randomized, double-blind, double-dummy comparative trial.

Setting and country: Multicenter study performed in 13 centers in France.

Funding and conflicts of interest:

Not reported.

Inclusion criteria:

Patients aged 12 years and older with a moderate to severe seasonal allergic rhinitis diagnosed by a positive (2+) skin test reaction to grass pollen.

Exclusion criteria: Not described.

N total at baseline: 237

Intervention: 118

Control: 119

Patient characteristics were not provided. Groups were comparable at baseline.

1. Cetirizine tablet, 10 mg once daily for 3 weeks.

(2. Loratadine tablet, 10 mg once daily for 4 weeks.

3. Terfenadine tablet, 60 mg twice daily for 2 weeks.

4. Astemizole tablet, 10 mg once daily for 2 weeks.)

Fluticasone propionate (FP) aqueous nasal spray, 200 µg once daily.

Length of follow-up:

Duration of the treatment

Loss-to-follow-up:

None

Incomplete outcome data:

N.A.

FP-treated patients showed a significantly greater decrease in mean total symptom score at the end of the treatment (p=0.001) and a higher number of symptom-free days for each nasal symptom (P<0.001) compared to the CTZ-treated group. No values were provided.

% symptom-free days per symptom:

Nasal obstruction night: FP 57% CTZ 30%

Nasal obstruction day: FP 53% CTZ 31%

Sneezing: FP 46% CTZ 32%

Nasal itching: FP 58% CTZ 42%

Nasal discharge: FP 50% CTZ 33%. (P<0.001 for all symptoms)

Fewer events were reported in the FP group. In particular, no drowsiness was reported with FP treatment. No values reported.

Jordana, 1996

Type of study:

RCT, double-blind, randomized, parallel- group study.

Setting and country: Multicenter study performed in 5 allergy clinics in southern Ontario, Canada.

Funding and conflicts of interest:

Supported by Glaxo Canada. Conflict of interest not declared.

Inclusion criteria:

History of moderate to severe ragweed-induced seasonal allergic rhinitis.

Exclusion criteria: Concurrent perennial rhinitis, use of long-acting histamine antagonists within the past 6 weeks; inhaled, intranasal, or systemic corticosteroids or inhaled sodium cromoglycate within the past 4 weeks; or loratadine or another over-the-counter antihistamine within the last week. Other rhinitis therapy or clinical evidence of infection of the paranasal sinuses and/or of the upper or lower respiratory tract. Nasal surgery within the past year, structural nasal abnormalities or concurrent disease that could interfere with the validity of the study results, nursing/pregnant/ possibly pregnant

N total at baseline: 257

Intent to treat: 240

Intervention: 119

Control: 121

12-17 years of age. 56% male. Groups were comparable at baseline.

Loratadine tablets, 10 mg daily for 4 weeks

Fluticasone propionate aqueous nasal spray, 50 µg per actuation, 200 µg daily for 4 weeks

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

Six patients were withdrawn from the study because of violation of inclusion/exclusion criteria, and nine were withdrawn before randomization. Two patients elected not

to participate in the trial just before the study

medications were issued.

4 subjects were withdrawn because of suspected adverse events: 3 from the LOR group (infectious mononucleosis, angioedema, sinus headache), 1 from the FP group, (asthma exacerbation). 3 subjects discontinued from the FP group (failure to return, broken spray bottle, violation of exclusion criteria). 4 subjects in the LOR group and 1 in the FP group elected to withdraw because of ineffectiveness of study medication.

Incomplete outcome data:

All but 3 subjects recorded valid data for at least 28 days.

FP improved symptom-free days significantly compared to LOR for blockage (day), blockage (waking), sneezing, and nasal itching, but not for runny nose and eye irritation. In accordance, mean symptom scores were significantly lower in FP compared to LOR for all symptoms except eye irritation. There were no statistically significant differences between the groups for percentage of rescue-free days or use of rescue eye drops/ bronchodilator. No SD provided.

The most common adverse events in both treatment

groups were headache and pharyngitis (42% and 16%, respectively, in the FP group and 25% and 10% in the LOR group, respectively). Headaches occurred in 50 subjects in the FP group and 27 subjects in the LOR group. Headaches were classified in as severe in nine and six subjects in FP and LOR groups, respectively (not significant), moderate in 29 and 14 subjects (p = 0.002), and mild in 66 and 29 subjects (p < 0.001). The event most frequently reported by the investigator as "drug-related" was epistaxis (7% and 4%, respectively).

Gawchik, 1997

Type of study:

RCT, double-blind, randomized, placebo-controlled parallel- group study.

Setting and country: Multicenter study performed in 10(?) centers throughout the USA.

Funding and conflicts of interest:

The study was sponsored and supported by Rhône-Poulenc Rorer Pharmaceuticals.

Inclusion criteria:

Medical history of at least 2 consecutive seasons of allergic rhinitis characterized by rhinorrhea, sneezing, nasal stuffiness, nasal itch, and postnasal drip, with or without ocular symptoms.

Exclusion criteria:

Lactating, (possible) pregnancy, long-acting steroid use, recent immunotherapy, medication that could affect study outcome, habitual abuse of nasal decongestants, a history of hypersensitivity or nonresponse to topical steroids/ antihistaminics, sinusitis, concomitant illness.

N total at baseline: 305

Intervention: 153

Control: 152

Mean age 33.1 years (12-68), 43% male.

Loratadine 10 mg, for 4 weeks

Triamcinolone acetonide (TAA) nasal aerosole inhaler, 55 µg/spray, 2 sprays/nostril, once daily, for 4 weeks

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

89% completed the study in the intervention group, 92% in the control group.

Incomplete outcome data:

Outcome for 1 patient in the LORA group was missing.

All rhinitis and ocular symptoms improved significantly in both study groups, with no differences between the groups at week 1. During week 2, TAA patients showed significantly greater improvement than LOR in total nasal score (46 versus 36%), nasal itch (51 versus 41%), nasal stuffiness (40 versus 29%) and sneezing (54 versus 41%). Differences between the groups in postnasal drip, rhinorrhea, and ocular symptoms were not significant. During week 3 and 4, TAA treatment resulted in significantly greater improvement in total nasal score, nasal itch, nasal stuffiness, rhinorrhea, sneezing and ocular symptoms compared to LOR treatment. 3 patients from the LOR group were discontinued for lack of effectiveness.

Patient scores for the physician global evaluation at week 4 indicate a significantly (P<0.002) greater proportion of patients in the TAA group (68.4%) experienced moderate to complete relief of rhinitis symptoms than did the LOR group (59.2%)

8 subjects in either group were withdrawn due to adverse effects. Adverse events were reported in 41% of patients in TAA group, versus 37% in the LOR group. Headache was the most commonly described adverse effect in both groups. The only other drug-related adverse effect in more than 2% was increased rhinitis in the LOR group. 2 patients in the TAA group discontinued treatment, 1 due to moderate nervousness and the other due to mild epistaxis. In the LOR group, 1 patient discontinued due to moderate conjunctivitis and a moderate lacrimation disorder plus increased rhinitis symptoms.

D’Ambrosio, 1998

Type of study:

Placebo-controlled comparative trial.

Setting and country:

Single-center study in Messina, Italy.

Funding and conflicts of interest:

Not described.

Inclusion criteria:

>14 years old, clinical history of allergic rhinitis or rhino-conjunctivitis, positive allergy test for Parietaria Judaica, total initial symptom score of 6 at the end of run-in.

Exclusion criteria:

Pathologies that may alter the treatment results, use of drugs that may interfere with the treatment results.

N total at baseline: 60 patients in 3 groups.

CTZ: 18 patients, age 28.1 ± 10.4 years, 50% male.

FP: 19 patients, age 30.0 ± 9.4 years, 42% male.

No differences between groups in age, sex and initial symptoms.

Cetirizine tablet, 10 mg once daily for 60 days

Fluticasone propionate 100 mg (not µg?) per nostril once daily by aerosol for 60 days.

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

6 patients interrupted the treatment for personal reasons.

Incomplete outcome data:

N.A.

CTZ significantly reduced rhinorrhea, sneezing and nasal itching symptom scores compared to baseline. FP only improved nasal obstruction. Total symptom score decreased from 7.4 to 2.9 (=4.5) in the CTZ group, and from 7.2 to 4.8 in the FP group (=2.4, P<0.05 between groups). Symptom scores between days 20, 40 and 60 were limited for all symptoms.

EPC in nasal secretion decreased significantly in both groups (CTZ from 258.9 ±192.8 ng/ml to 74.6 ± 49.8 ng/ml; FP from 248.8 ± 238.7 ng/ml to 68.9 ± 75.9 ng/ml), with no difference between the interventions.

4 patients in the CTZ group reported dizziness, 1 gastric disorders and 1 visual problems. 2 patients in the FP group experienced dryness of the nasal mucosa and 1 reported a burning sensation of the nasal-throat mucosa. All adverse effects were light and temporary.

Ratner, 1998

Type of study:

RCT, double-blind, randomized, placebo-controlled parallel- group comparative trial.

Setting and country:

Multicenter study in 5 sites across Texas, USA

Funding and conflicts of interest:

The study was supported by a grant from Glaxo welcome Inc.

Inclusion criteria:

Male/female >12 years old, positive skin test to Juniperus ashei, appearance of the nasal mucosa consistent with allergic rhinitis, a history of seasonal onset and offset of symptoms for at least 2 previous mountain ceder pollen seasons, moderate to severe symptoms of rhinitis.

Exclusion criteria:

Recent treatment with loratadine, astemizole, cromolyn sodium, nasal decongestants or systemic corticosteroids; septal deviation, nasal polyp, a history of nasal surgery or nasal septal perforation; candical inflation, pregnancy, lactating, any impairment that might affect completion of the study.

N total at baseline: 300

Intervention: 150, 40.1 (15-70) years old, 46% male

Control: 150, 40.7 (13-80) years old, 45% male.

No differences in demographic characteristics and compliance between groups

Loratadine tablet, 10 mg once daily for 14 days

Fluticasone propionate (FP) aqueous nasal spray, 2 50-µg sprays per nostril once daily for 14 days

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

95% completed the study. In the LOR group, 5% of patients were withdrawn, 1% due to adverse events, 2% due to lack of efficacy and 2 for other reasons. In the FP group, also 5% was withdrawn, 2% due to adverse events, and 3% due to lack of efficacy.

Incomplete outcome data:

N.A.

Both after 7 and 14 days, clinician-rated total nasal symptoms (expressed as change from baseline) were significantly lower in the FP (187 on a scale of 400) than in the LOR group (102). This was also true for all individual nasal symptoms, i.e. blockage, discharge, itching and sneezing.

Both clinicians’ and patients’ overall evaluation (% of clinicians/patients scoring improvement on a 6 point scale) were significantly higher in FP than in LOR.

Improvements in mean global and individual RQLQ scores at day 14 were significantly higher in FP (2.2) than in LOR (1.3).

No significant differences in adverse events between the groups. 5-8% of patients experienced an adverse event possibly related to the medication. The most frequently reported drug-related adverse events were blood in the nasal mucus (1-2%), epistaxis (≤1%) and xerostomia (≤2%) for all treatments.

Condemi, 2000

Type of study:

RCT, double-blind, dummy-controlled randomized, parallel group study.

Setting and country:

Multi-center study at 11 sites throughout the USA.

Funding and conflicts of interest:

This study was funded by Rhône-Poulenc

Rorer Pharmaceuticals Inc.

Inclusion criteria:

A 2-year consecutive history of allergic rhinitis symptoms verified by a positive skin prick test to grass pollens indigenous to the area; a combined rhinitis symptom score of 24 points or greater on 4 of the 5 baseline days according to a 4-point scale for the five symptoms evaluated

Exclusion criteria:

Clinically significant abnormalities on physical examination or in urinalysis, hematology, or serum chemistry test results; nasal candidiasis, acute or chronic sinusitis, significant nasal polyposis or septum deviation; or rhinitis medicamentosa. Women who were pregnant, lactating, or of childbearing potential and not practicing an approved method of contraception; Recent or regular use of any of the following medications: topical corticosteroids, intranasal cromolyn, topical decongestants, systemic steroids, long-acting antihistamines, or investigational drugs; a history of habitual abuse of nasal decongestants; used medication for another indication that might affect the symptoms of seasonal allergic rhinitis; or had a history of hypersensitivity or nonresponse to topical steroids or antihistamines.

N total at baseline: 351

Intervention: 176

Control: 175

Mean age 32 (12-69) years, 55% male, 90% caucasian.

The 2 treatment groups were comparable at baseline

Loratadine (10 mg) once daily, given as a single capsule, for 4 weeks.

Triamcinolone acetonide (TAA) aqueous nasal spray 220 µg once daily, given as 2 sprays (55 µg/spray in each nostril) , for 4 weeks.

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

Control group: 15 patients (9%) withdrew from study for protocol deviations (6); adverse clinical events (4); treatment failure (4); and lost to follow-up (1).

Intervention: 19 patients withdrew from the study for protocol deviations (9), adverse clinical events (3), treatment failure (5), and lost to follow-up (2).

Incomplete outcome data:

N.A.

Mean change in total nasal score was significantly stronger in TAA (-4.4 ± 2.9) than in LORA (-3.6 ± 3.2). Individual symptoms in which the change was also significant were nasal congestion (TAA -1.1 ± 0.9 versus -0.8 ± 1.0), sneezing (TAA -1.2 ± 0.9 versus -0.9 ± 0.9), and nasal itch (-1.1 ± 0.8 versus -0.9 ± 0.9). No differences between groups for rhinorrhea and ocular symptoms. Both treatment groups had improvement in symptoms as early as day 1, but the greatest improvement occurred over the first 3 days of treatment.

Physician global evaluation showed high relief levels in both groups. A similar number of patients in each group (4 TAA and 5 LOR) withdrew from the study early due to lack of efficacy.

Overall RQLQ was better in the TAA group both at 2 (TAA 1.79 ± 1.27 versus 2.13 ± 1.18) and 4 weeks (TAA 1.48 ± 1.24 versus 1.82 ± 1.29). In addition, At week 2, TAA-treated patients had significantly better QoL than LOR-treated patients in the dimensions of activity, emotions, nasal symptoms, and practical problems. At week 4, patients in the TAA group had better QoL in the dimensions of activity, nasal symptoms, and practical problems,

Headache was the most frequently reported adverse event with 25 TAA patients (14.3%) and 27 LOR patients (15.3%). Seven patients discontinued the study due to adverse events. The 4 TAA patients who discontinued study reported 6 adverse events; three of these events (headache, rhinitis, and chest pain) were possibly/probably related to study drug and occurred in one patient. The 3 LOR patients reported one adverse event each, none of which were related to study drug.

Kaszuba, 2001

Type of study:

Randomized, open-label, parallel-group study

Setting and country:

Single-center study in Chicago

Funding and conflicts of interest:

This study was supported in part by a grant from Glaxo Wellcome Inc, Research Triangle Park, NC; and grant AI 45583 from the National Institutes of Health, Bethesda, Md.

Inclusion criteria:

A history of rhinitis during at least the last 2 ragweed seasons in Chicago, Ill, and a positive puncture skin test result to ragweed antigen extract.

Exclusion criteria:

Symptoms or physical signs suggestive of renal, hepatic, or cardiovascular disease; nasal polyps; a displaced septum; or perennial rhinitis, recent use of topical or systemic corticosteroids, antihistamines, decongestants, cromolyn sodium; pregnant or lactating women

N total at baseline: 88

Intervention: 44, mean age 30.0 (19-44) years, 57% male

Control: 44, mean age 27.5 (18-48) years, 48% male

The groups were matched for age, sex, race, and skin test sensitivity

Loratadine tablet (10 mg/d) if needed, for 4 weeks

Fluticasone propionate nasal spray (100 µg/d per nostril) if needed, for 4 weeks

Length of follow-up:

Duration of the treatment.

Loss of follow-up:

Two patients from each treatment group dropped out before completing the protocol. One patient moved away and 3 were noncompliant with respect to returning for their appointments.

Incomplete outcome data:

N.A.

Compared to LOR, the fluticasone group had significantly better scores on overall RQLQ and in the activity, sleep, practical, and nasal domains after 2 and 4 weeks.

Mean symptom scores were significantly better in the FP (improvement from baseline 5.2) than in the LOR (worsening of 0.99) group throughout the study period, with 4.0 with FP versus 7.0 at day 28. No SD reported.

Both total eosinophils and ECP levels were markedly and significantly lower in FP compared to LOR, after 2 and 4 weeks. The ECP levels followed the same pattern, with significant decreases in the intranasal corticosteroid–treated group and significant increases in the H1 receptor antagonist–treated group. No values described, only graphs.

Adverse events were not described.

Rinne, 2002

Type of study:

Double-blind, double-dummy, randomized, parallel-group design

Setting and country:

Single-center study at the Skin and Allergy Hospital of the University of Helsinki,

Finland

Funding and conflicts of interest:

Supported by AstraZeneca R&D, Lund, Sweden, and Helsinki University

Central Hospital grant 9303

Inclusion criteria:

16 to 68 years of age; symptoms of perennial rhinitis for 1 to 3 years; Rhinitis symptoms were required to be present for at least 1 hour on most days. Patients had to have eosinophils present in nasal smear (score ≥1), a positive skin prick test response for at least one perennial allergen, or both.

Exclusion criteria:

Severe seasonal rhinitis symptoms; upper respiratory infection during the 4 weeks before randomization; concomitant illness or medication that might interfere with the study; previous steroid treatment >3 months at any time or within 1 month before randomization; systemic steroid therapy within 3 months or cutaneous application of steroids; immunotherapy for seasonal or perennial rhinitis within the past 3 years; women who were pregnant or lactating. Antihistamines, if used, were discontinued 48 hours before randomization (2 months before randomization in the case of astemizole), and intranasal cromoglycate was discontinued 14 days before randomization. Women of childbearing age were required to use adequate contraception.

N total at baseline: 143 patients entered the study.

Budenoside 71 patients, CTZ 72 patients.

Oral cetirizine

(Zyrtec) 10 mg, once daily for 1 year

Intranasal budesonide (Rhinocort Turbuhaler), 400 μg, (equivalent to a delivered dose of 280 μg) once daily for 1 year

Length of follow-up:

2 years

Loss-to-follow-up:

88% continued

until the end of the 1-year treatment.

Incomplete outcome data:

N.A.

Reductions in total and individual nasal symptom scores during the first year were significantly greater with budesonide than with CTZ, except for the score for blocked nose at 12 months. For total nasal symptoms, budesonide was significantly more effective than cetirizine. At 28 days, total nasal symptom score improvement was greater with budesonide (2.69) than with CTZ (1.71).

The percentage of rhinitis-free days was significantly higher in the budesonide group (45.1%) compared with that in the CTZ group (25.9%). There was no significant difference between the groups in eye symptoms. Patients in the CTZ group used significantly more phenylpropanolamine tablets as rescue medication than patients in the budesonide group (P=0.002). Budesonide was significantly more effective in controlling rhinitis symptoms than CTZ. Substantial or total control of symptoms was achieved in 74% of budesonide-treated patients compared with in 50% of those receiving cetirizine (P=0.0023).

Nasal peak expiratory flow (nPEF) increased from a mean of 236 to 257 L/min (8.9%) in the budesonide

group and from 231 to 241 L/min (4.3%) in the cetirizine (P<0.05). Nasal smear eosinophilia decreased to a greater extent in patients treated with budesonide (from 0.79 to 0.16) than in those treated with CTZ (from 0.85 to 0.54 (P<0.01)

Adverse events occurred in 65 budesonide-treated patients and 68 patients receiving CTZ. The most common adverse events in each group were viral upper respiratory tract infections, which occurred in 48 budesonide-treated patients and 52 CTZ treated patients, blood in nasal secretion (ranging from blood-tinged mucus to nasal bleeding; 19 and 9 patients, resp.), conjunctivitis (8 and 5 patients, respectively), and headache (6 and 1 patients, respectively). Sinusitis was observed in 2 budesonide- treated patients and in one CTZ-treated patient. Most adverse events were mild or moderate in intensity. 3 budesonide-treated patients withdrew from the study at 6 months because of crusting of the nasal mucosa, bleeding, or both, and one CTZ-treated patient withdrew because of drowsiness.

Spangler, 2003

Type of study:

Randomized, double-blinded study

Setting and country:

Single-center study

Funding and conflicts of interest:

This study was supported by an unrestricted grant from Alcon Laboratories, Inc.,

Fort Worth, Texas. The authors have no proprietary interest in the products studied.

Inclusion criteria:

Positive history of allergic rhinoconjunctivitis, a positive skin test result within 2 years.

Exclusion criteria:

Not specified

N total at baseline: 73

mean age 45.3 (21-73) years, 42.5% male.

Group size per treatment not specified.

fexofenadine

hydrochloride 180-mg tablets, once daily for 1 week

Mometasone furoate monohydrate

50-µg nasal spray, once daily for 1 week

Length of follow-up:

Duration of the treatment.

Two subjects did not complete the study: 1 was lost to follow-up at visit 3 and 1 took a disallowed medication

Incomplete outcome data:

N.A.

Mean ocular itching score and mean total nasal score not different between treatments conjunctival allergen challenge. Mean total nasal symptom scores after nasal allergen challenge were lower in the mometasone group than in the fexofenadine group.

Focus on conjunctival versus nasal challenge, limited data on medication differences.

Fokkens, 2004

Type of study:

Double-blind, double-dummy placebo-controlled RCT.

Setting and country:

Dual-center study at the UK and the Netherlands.

Funding and conflicts of interest:

This study was funded by GlaxoSmithKline R&D, UK. Potential conflict of interest was not specified.

Inclusion criteria:

Perennial rhinitis for more than 2 weeks, age 2-4 years, parental consent.

Exclusion criteria:

Requirements for inhaled or intranasal corticosteroids, sodium cromoglycate or antihistamines, use of systemic corticosteroids, presence of nasal polyps or other anatomical deformations, presence of other severe illness, e.g. cleft palate, concurrent nasal infections or contraindications to steroids.

N total at baseline: 26

Age 2-4 years,

62% male.

Oral ketotifen 1 mg once daily plus intranasal placebo, for 6 weeks.

Fluticasone propionate aqueous nasal spray 100 µg once daily plus oral placebo, for 6 weeks

Length of follow-up:

Duration of the treatment.

Incomplete outcome data:

3 subjects could not be evaluated. No reason was provided.

Patients treated with FPANS had a significant reduction in the total night-time rhinitis symptom assessment for weeks 4–6 (FPANS 4.2, ketotifen 6.5, no SD reported), and a significantly reduced total daytime rhinitis symptom score over the same period (FPANS 3.6, ketotifen 5.5, no SD). The corresponding measurements over weeks 1–3 for both total daytime and total night-times symptom scores were reduced in the fluticasone group but this difference was not statistically significant

Bernstein, 2004

FNM 30033

Type of study:

Double-blind, double-dummy placebo-controlled RCT.

Setting and country:

Multi-center study at 14 investigative sites in the US

Funding and conflicts of interest:

This study was funded by GlaxoSmithKline Inc., Research

Triangle Park, NC.

Inclusion criteria:

At least 12 years of age with a history of allergic rhinitis for ≥2 years and a positive skin test to at least one allergen relevant to the spring pollen season and geographic region

Exclusion criteria:

Not described

N total at baseline: 471, 80% between 18 and 64 years old, 42-38% male in each group, 80-90% Caucasian.

FP: n=158

LOR: n=158

(Placebo: 155)

Encapsulated loratadine 10mg, once daily for 4 weeks

Fluticasone propionate aqueous nasal spray, 200 µg (2 sprays of 50 µg per nostril) once daily for 4 weeks

(Placebo group not considered)

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

87% of the LOR group, and 94% of the FP group completed the 28-day treatment period

The most common reasons for premature discontinuation were adverse events (4% in the LOR group and 3% in the FP group) and lack of efficacy (4% in the LOR group and 0% in the FP group).

Incomplete outcome data:

N.A.

Total ocular symptom score change was significantly greater in FP (-88.7 ± 5.3) than in LOR (-72.5 ± 5.4), as well as all separate symptoms itching, redness, and tearing. Nasal congestion improvement was also greater in FP (-35.3 ± 1.9) than in LOR (-25.0 ± 1.9).

Patients’ overall assessment of the effectiveness of the treatment on a seven-point categorical scale was significantly different between groups. 82% of patients in the FP group reported (significant/ moderate/mild) improvement against 64% in the LOR group.

The incidence of adverse events was similar among the treatment groups, with 42% of the LOR group, and 44% of the FP group reporting at least 1 adverse event during the study. The most common event was headache, 18% with LOR and 17% with FP.

Andrews, 2009

Type of study:

RCT, double-blind, randomized, placebo-controlled parallel- group study.

Setting and country:

Funding and conflicts of interest:

GlaxoSmithKline funded the research (FFU109045 and FFU109047) described in this article; GlaxoSmithKline funded Dr. Saiers’ work. H Kaiser, D Mohar, R Jacobs, and B Martin are all research sponsors for GlaxoSmithKline; H Kaiser and M Vandewalker are speakers for GlaxoSmithKline; L Lee, W Toler, B Prillaman, E Philpot, and A Dalal are employees of GlaxoSmithKline

Inclusion criteria:

At least 12 years old, with a diagnosis of seasonal allergic rhinitis as defined by a clinical history of nasal allergy symptoms during each of the last two respective allergy seasons and a positive skin test to mountain cedar allergen (study 1) or ragweed allergen (study 2) within 12 months of screening

Exclusion criteria:

Plans to travel outside the region for >48 hours of the study, (attempt at) pregnancy, severe physical obstruction of the nose (e.g., deviated septum or nasal polyp); recent nasal septal surgery or perforation; asthma, unless it was mild intermittent asthma; rhinitis medicamentosa; ocular or upper respiratory bacterial or viral infection; chronic use of medications that could affect allergic rhinitis or assessments of efficacy of study medication; current tobacco use: recent use of subcutaneous omalizumab, corticosteroids short-acting prescription or over-the-counter antihistamines, oral or intranasal decongestants, anticholinergics, long-acting β-agonists, or oral antileukotrienes; long-acting antihistamines and intranasal antihistamines or intranasal or ocular cromolyn.

N total at baseline: Study 1: 936

FFNS, n=312 mean age 37.8 years, 33% male.

Fex, n=311, mean age 39.6 years, 36% male.

Study 2: 680

FFNS, n=224, mean age 34.0 years, 41% male.

FEX, n=227, mean age 34.8 years, 39% male.

Fexofenadine (FEX), 180 mg oral tablet once daily for 2 weeks

Fluticasone furoate nasal spray (FFNS) 110 µg once daily for 2 weeks

(placebo group not considered)

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

In study 1, premature withdrawal was 4% in the fluticasone furoate group and 8% in the fexofenadine group. The most common reason for premature withdrawal was protocol violation. In study 2, the incidence of premature withdrawal was 7% in the fluticasone furoate group and 6% in the fexofenadine group.

Incomplete outcome data:

N.A.

FFNS was significantly (p < 0.001) more effective than fexofenadine with respect to the mean change from baseline in the nighttime symptoms score in both studies. FFNS also showed greater improvement to all three individual components of the nighttime symptoms score—nasal congestion on awakening, nighttime awakenings due to nasal symptoms, and difficulty going to sleep because of nasal symptoms.

FFNS was significantly (p < 0.001) more effective than FEX in both studies with respect to the mean change from baseline in the nighttime reflective TNSS. FFNS was significantly more effective than FEX in nighttime reflective total ocular symptom score in study 2, but not in study 1. FFNS was significantly (p <

0.001) more effective than fexofenadine and placebo

with respect to the mean changes from baseline in

morning peak nasal inspiratory flow. FFNS was significantly (p <0.001) more effective in both studies than FEX with respect to the mean changes from baseline in the daytime rTNSSs and evening peak nasal inspiratory flow measurements. FFNS was significantly more effective with respect to the mean change from baseline in the daytime reflective total ocular symptom score in study 2, but not in study 1.

FFNS was significantly (p < 0.001) more effective than FEX in both studies with respect to the mean change from baseline in the overall nocturnal RQLQ total score.

The percentage of patients with at least 1 adverse event was similar among groups in study 1 (16% in the FFNS group, 18% in the FEX group). The only adverse events reported in >1% of patients in a treatment group and reported more often with active treatment than placebo was pharyngo-laryngeal pain (2% FFNS, <1% FEX). The number of patients who prematurely withdrew from the study because of adverse events was 2 in the FFNS group (one each with sinusitis and influenza), 5 in the FEX group (one each with cholecystitis, hypersensitivity, cough, upper respiratory infection, and sinusitis). Three adverse events in the FEX group (cholecystitis, upper respiratory infection, and sinusitis), but none of the other adverse events leading to premature withdrawal, were designated by the investigator as having possibly been caused by study treatment.

The percentage of patients in study 2 with at least 1 adverse event was also similar among groups (14%

in the FFNS group, 16% in the FEX group). The only adverse event reported in >1% of patients in a treatment group and reported more often with active treatment than placebo was epistaxis (no reports with FFNS, 2% FEX). The number of patients who prematurely withdrew from the study because of adverse events was two in the FFNS group (upper respiratory infection and urticaria), one in the FEX group (lymph gland infection). The adverse event of urticaria in the FFNS group was the only event considered by the investigator as possibly caused by study treatment.

Kulapaditha-rom, 2010

Type of study:

RCT, randomized, parallel-group

study.

Setting and country:

Single-center study in Ramathibodi Hospital, Bangkok, Thailand

Funding and conflicts of interest:

Faculty of Medicine, Ramathibodi Hospital,

Mahidol University partially supported this study and played no role in study execution.

Inclusion criteria:

At least 18 years of age, a documented history of allergic rhinitis of more than 1 year.

Exclusion criteria:

Allergic bronchial asthma, non-allergic rhinitis (infection or drug-induced, etc), structural abnormality of the nose (deviation of nasal septum, obstructive nasal polyps), known cardiac disease, renal or hepatic dysfunction and pregnant or breastfeeding women. Excluded medications were other antihistamines and corticosteroids, leukotriene inhibitors, decongestants and immunotherapies in the last 6 weeks

N total at baseline: 100

Levocetirizine 50, Budenoside 50

26% male, aged 35.72 ± 10.96,

no significant differences

between the two treatment groups.

Levocetirizine 5 mg daily for 4 weeks

Budesonide nasal spray 256 mg daily (two spays into each nostril, 64 mg per

spray) for 4 weeks

Length of follow-up:

29-56 days

Loss-to-follow-up:

xx% completed the study in the intervention group, xx% in the control group.

Incomplete outcome data:

Not described

Fractional reduction of TSS compared to baseline: Budesonide 0.19, Levocetirizine 0.33. No SD reported for these values.

Highly indirect presentation of TSS scores and response time (time for the drop in TSS to a value of ≤4) by calculating area under curve for fractional change, and separating high TSS and low TSS at baseline.

Adverse events were not described.

Bhatia, 2005

Type of study:

RCT, double-blind, randomized, placebo-controlled parallel- group study.

Setting and country:

Single-center study in Chicago, USA

Funding and conflicts of interest:

This study was supported by a grant from the Investigator Sponsored Studies Program of AstraZeneca, Westborough, Mass.

Inclusion criteria:

Age 18 to 45 years, a clinical history of sensitivity to tree or grass pollens, positive skin test result and symptoms during the spring season for the past 2 years.

Exclusion criteria:

Use of systemic corticosteroids in the previous 30 days, oral antihistamines or decongestants in the past 7 days, and topical antihistamines or decongestants in the past 24 hours, long-term antiasthma medications, immunotherapy in the previous 2 years; pregnancy or nursing

N total at baseline:

61

Desloratadine n=31, 39% male, mean age 26.4 ± 7.41;

Budesonide n=30, 53% male, mean age 25.6 ± 5.97;

No differences between groups.

Desloratadine, 5 mg once daily for 2 weeks

Budesonide, 32-μg per nostril once daily, for 2 weeks

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

xx% completed the study in the intervention group, xx% in the control group.

Incomplete outcome data:

Not reported

The primary outcome variable was nasal peak inspiratory flow (NPIF). Comparing the total NPIF between budesonide and desloratadine showed a significant difference on all of the treatment days except days 5 and 6, with budesonide providing more improvement in nasal airflow than desloratadine. The total change over the baseline showed a significantly greater improvement for budesonide (493.1, no SD reported) than for desloratadine (248.5, P=0.01).

RQLQ at the end of treatment was similar with Desloratadine 1.30 ± 0.17 versus Budesonide 1.08 ± 0.92., with no difference in improvement from baseline between the groups (DES 1.56, BUD 2.05)

Total symptom score (sneezing, runny nose, stuffy nose, itchy eyes/nose) improved with 7.35 points in the Budesonide group, and 5.47 in the Desloratadine group. No SD reported.

No adverse events reported.

Ford, 2015

Type of study:

RCT, double-blind, randomized, placebo-controlled parallel- group study.

Setting and country:

Multicenter at 32 investigative sites across the USA.

Funding and conflicts of interest:

The study was funded by GSK (study 200165)

L.B. Ford has received support from GSK to conduct this study and her institution has received research grants from Teva, F. Hoffmann-La Roche, Novartis, AstraZeneca, Merck, Sanofi, Circassia, Forest, Johnson and Johnson, Amgen, Mylan, Aquinox, Perrigo, Oriel, Pfizer, Roxanne, and Biota. J. Matz has received support from GSK to conduct this study, has served as a consultant for Biota, has received payment for the development of educational programs from Novartis, and his institution has received research grants or has grants pending from Teva, Perrigo, Merck, Shionogi, and Greer. T. Hankinson, B. Prillaman, and G. Georges were employees of GSK and held stock in GSK at the time of study conduct and during the writing of this manuscript

Inclusion criteria:

Previous diagnosis with SAR or a positive skin-prick test result to a prevalent seasonal allergen; allergy treatable on an outpatient basis; at least 18 years of age.

Exclusion criteria:

Significant medical conditions, use of study protocol–prohibited concurrent medications, or hypersensitivity to any excipient of the study treatments.

N total at baseline: 682

170 patients FP

170 patients CTZ

And 2 placebo groups

The mean age was similar among the four treatment groups, with 98% to 99% of the subjects 18 to 64 years old. 36-44% male in all treatment groups. The majority of subjects in all groups (78–84%) reported having SAR for at least 10 years.

Cetirizine 10 mg once daily for 2 weeks

Fluticasone propionate (FP) nasal spray 200 µg once daily for 2 weeks

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

One subject in the FPNS group withdrew due to an adverse event. One patient in the CTZ group was withdrawn as a result of protocol deviation.

Incomplete outcome data:

Not mentioned.

The primary efficacy measurement defined for this study was the change in the rTNSS from baseline over the 2-week treatment period. FP -2.2 ± 0.19, CTZ -1.9 ± 0.18. Instantaneous ocular TSS change FP -1.9 ± 0.18, CTZ -1.3 ± 0.17. Change in nocturnal RQLQ for FP was -1.0 ± 0.10, versus -0.6 ± 0.09 with CTZ.

“All treatments (…) were well tolerated, with comparable rates of adverse events and no serious adverse events.”

Kim, 2015

NCT 01430260

Type of study:

RCT, open-label, 3-arm, parallel-group randomized study

Setting and country:

Multicenter study at 13 sites

Funding and conflicts of interest:

“There are no financial or other issues that might lead to conflict of interest.”

Funding was provided by Handok Inc. and Takeda Pharmaceutical Co. (Clinical

trial registry URL and registration number: www.clinicaltrials.gov

/ct2/show/

NCT01430260).

Inclusion criteria:

At least 18 years, signs and symptoms of AR for longer than 1 year. In accordance with ARIA guidelines, only subjects with moderate to severe SAR or PAR were included. All subjects tested were positive for skin allergy tests (skin prick test) or serological allergy tests, including for multiple allergen simultaneous tests (MAST), to 1 or more specified allergens less than 1 year prior to screening.

Exclusion criteria:

active asthma requiring treatment with inhaled or systemic corticosteroids and/or routine use of beta-agonists or any other medications; nasal pathologies, including nasal polyps or bronchial anomalies; chronic obstructive pulmonary disease; clinically significant renal disease, liver disease within 2 months before the screening visit; intranasal biopsy revealing ulcers, trauma, surgery, atrophic rhinitis or drug-derived rhinitis within 2 months before screening; respiratory infections within 2 weeks before or during screening; usage of systemic steroids within 2 months of screening or local steroids (hydrocortisone >1%) within 4 weeks of screening or antibiotic treatment within 2 weeks of screening; a possibility of receiving medications like systemic corticosteroids or high-dose steroids, beta-agonists or other investigational drugs that were not permitted in the protocol during the study period; known or suspected hypersensitivity to ciclesonide or hydroxyzine; and genetic disorders such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

N total at baseline: 260

Ciclesonide n=88, age 32.9 ± 11.3, 43.2% male

Levocetirizine n=89, age 32.9 ± 10.2, 54.5% male

levocetirizine 5 mg once daily for 2 weeks

Ciclesonide nasal spray 200 μg once daily for 2 weeks

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

1 patient from the levocetirizine group

was unable to locate their patient diary.

Incomplete outcome data: Two subjects were excluded from efficacy analysis but included for safety analysis.

levocetirizine group experienced a randomization error and was inadvertently dosed with ciclesonide. This subject’s data were analyzed as belonging to the levocetirizine group when assessing efficacy, but as the ciclesonide group when assessing safety.

The primary endpoint was the change from baseline in the mean value of patient-reported rTNSS (morning and evening) averaged over the 2-week treatment period. rTNSS (rhinorrhea, nasal itching, nasal congestion, and sneezing) changed in Cicle group -3.9 ± 2.2, versus-3.0 ± 2.1 with Levo. rTOSS (itchy eyes, red

eyes, and watery eyes) in cicle group -1.4 ± 1.6 versus -0.9 ± 1.4 with Levo. Physician-assessed overall nasal signs (discoloration, swelling, discharge, and postnasal drip) and symptoms (rhinorrhea, itching, nasal congestion, and sneezing) severity improvement was 1.1 ± 0.7 with Cicle versus 0.8 ± 0.6 in the Levo group. Mean RQLQ decreased with 1.4 ± 1.0 with Cicle and 1.1 ± 1.0 in the Levo group.

Adverse events:

One (1.1%)patient with Cicle: nasal pain.

Six (6.8%) patients with 8 symptoms in the Levo group: dry mouth, sleepiness, dizziness, dry nose, headache, epistaxis

Wartna, 2017

Dutch Trial Register No. 3429

Type of study:

Single-blinded RCT

Setting and country:

Multicenter study in 61 GP practices and 2 paediatric outpatient clinics in the South-West of the Netherlands

Funding and conflicts of interest:

Mrs Wartna, Dr. Elshout, Dr. Bohnen and Dr. Bindels report grants from Lung Foundation Netherlands and Stichting Astma Bestrijding , during the conduct of the study; Mr. Pols and Dr. Pijnenburg have nothing to disclose; Dr. Gerth van Wijk reports personal fees from MSD, HAL, Crucell, ALK-Abello, Novartis, and Emerade, grants from NWO, STW, Novartis, Biomay, and DBV, personal fees from Allergopharma, Thermo Fisher, Chiesi, de Tijdstroom, and Bohn, Stafleu, van Loghum, outside the submitted work.

Supported by The Lung Foundation Netherlands (Longfonds) (grant number 3.4.11.049); Stichting Astma Bestrijding (grant number 2013/036). Both funders had no influence in the study design, in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Inclusion criteria:

Aged between 6 and 18 years; recruitment by a GP on ICPC R97 or prescription of AR-related medication in the previous season; sensitization to grass pollen; a minimum retrospective (previous year) AR symptom score of 7/21, written informed consent

Exclusion criteria:

Recent use of antihistamines or intranasal corticosteroids, being pregnant or breastfeeding, not being able to speak Dutch sufficiently, contraindications, not having internet access.

N total at baseline: 150

48 patients antihistamines on demand;

50 patients INCS daily;

52 INCS on demand

Mean age 11.6 years, 52% male. No differences between groups.

Levocetirizine dihydrochloride tablet, 5 mg/day on demand for 3 months

Fluticasone propionate nasal spray, for 3 months.

Dose: aged <12 years 100 µg/day, aged ≥12 years 200 µg/day

1) daily

2) on demand

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

132 patients were suitable for the ITT analysis (45 patients in the INCS daily group, 46 in the INCS on demand group, and 41 in the antihistamine group

18 patients were excluded due to insufficient data: 7 patients dropped out (stopped using study medication and without any measurement) and 11 patients neglected to fill in their diary.

8 patients discontinued using their study medication; but continued to fill out the diary and questionnaires, and had an end visit

The INCS on demand group had the highest percentage of symptom free days (30%), followed by the INCS daily group (22%) and the antihistamine group (15%)

The clinical relevant difference in symptom free days was set at 10%-point. The difference between INCS on the demand and INCS daily use was 8% more symptom free days in favour of on demand use, with a confidence interval of -5 to +21%.

There was no difference between INCS and antihistamines for symptom free days.

Comparison between antihistamine on demand and INCS daily use showed that INCS daily use resulted in a higher percentage of nose symptom-free days than antihistamine use, with sneezing-free days showing a significant difference (57% versus 38%, p=0.017). Also, antihistamine use resulted in more eye symptom-free days than INCS daily use; this difference was significant for itching eye-free days (43 versus 52, p=0.022). Comparing antihistamine use with INCS daily use, antihistamine use had a higher symptom score (3.90 95% CI 3.03-4.76) than INCS (4.63, 95% CI 3.81-5.46) on the combined symptoms and, more specifically, on nose symptoms (CS 3.20, 95% CI 2.69-3.71; AH 4.14, CI

3.63-4.66), but none of the differences were significant. No change in symptom scores could be calculated without baseline data.

Patients in the antihistamine group used on average 43 tablets on average for 91 days. in the INCS daily group, on average 23.1 ml fluticasone was used (± 257 sprays), and the INCS on demand group used on average 9.1 ml fluticasone (± 102 sprays) (p<0.0001). On average, patients used rescue medication on 12% of the days; there was no significant difference between the three groups.

Malizia, 2018

ID:

NCT02646904

Type of study:

Open-label RCT

Setting and country:

Single-center study in Palermo, Italy

Funding and conflicts of interest:

The study was supported by CHIESI Farmaceutici S.p.A., Parma, Italy (Unrestricted Grant N. 3774/2015).

The authors declare that they have no conflicts of interest.

Inclusion criteria:

Age 6-14 years; clinical history of perennial allergic rhinitis in the previous year, positive skin prick test response to Dermatophagoides pteronyssinus; Total 5-Symptom Score (T5SS) ≥5 (rhinorrhea, nasal obstruction,

nasal itching, sneezing, eye itching)

Exclusion criteria:

positive skin prick test result to seasonal allergens and other perennial allergens; medical diagnosis of nasal anatomic defects or nasal polyp disease; medical diagnosis of asthma; upper or lower respiratory tract infection in the previous 2 weeks; use of oral antihistamines, decongestants, leukotriene antagonists, systemic/topical antibiotics or corticosteroids in the previous 4 weeks; ongoing allergen immunotherapy; active smoking; adherence <80%.

N total at baseline: 68

Intervention: 34 children, mean age 9.47 ± 2.36, 68% male

Control: 34 children, mean age 10.06 ± 2.35, 62% male

No differences in demographic characteristics between groups.

Cetirizine 10-mg tablet once daily, for 21 days

Beclomethasone dipropionate nasal spray suspension (nBDP), 100 μg per nostril twice daily, for 21 days

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

1 consent withdrawal in the CTZ group, 2 lost to follow up (change of residence). No dropouts in the nBDP group.

Incomplete outcome data:

Not specified

Nasal volume values increased significantly after 21 days in the nBDP group (P=.033), while the change was not significant in the CTZ group (P=.900). Minimal cross sectional area values

increased significantly in the nBDP group (P=.045), while

the change was not significant in the CTZ group (P=.840). After adjusting for confounders, nBDP was found to improve nasal volume more than CTZ (LSmc, 2.21 cm³ versus 0.20 cm³; P=.013). Similarly, nBDP improved MCA more than CTZ (LSmc, 0.63 cm² versus 0.13 cm²; P=0.002).

In the nBDP group, with respect to the CTZ group, a more pronounced improvement was observed in eosinophil classes (LSmc, –1.10 versus –0.40, P=0.031) and neutrophil classes (LSmc, –0.97 versus –0.17; P=.010), T5SS total score (LSmc, –5.63 versus –3.54; P=.008), PSQI total score (LSmc, –1.30 versus –0.19; P=.025), and PRQLQ total score (LSmc, –1.15 versus –0.69;

P=.031).

No adverse events were observed.

Study reference

(first author, publication year)

Describe method of randomisation

Bias due to inadequate concealment of allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?

(unlikely/likely/unclear)

Bias due to loss to follow-up?

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?

(unlikely/likely/unclear)

Frølund, 1991

Patients were assigned a treatment group according to a computer-generated randomization code.

Unlikely, a double-blind, double-dummy technique was

Used, in which test medication was provided as identical, opaque capsules, supplied in strips labelled with Patient No., Week No., and Prescribed Time of Administration, and as identically labelled pressurized canisters.

Unlikely

Unlikely

Unlikely

Unlikely, outcomes presented in Results are consistent with outcomes described in Methods.

Likely, loss to follow-up is considerable and dissimilar between treatment groups.

Unclear

Charpin, 1994

Not described

Unlikely, double-blind, double-dummy

Unlikely

Unlikely

Unlikely

Unclear

Unlikely

Unclear, not described

Jordana, 1996

“Subjects were randomized as a cohort”

Unlikely, double-blind, double-dummy

Unlikely

Unlikely

Unlikely

Unlikely, outcomes presented in Results are consistent with outcomes described in Methods.

Unlikely

Unlikely, intention to treat analysis was performed.

Gawchik, 1997

Not described

Unlikely, study was double blind and placebo-controlled.

Unlikely

Unlikely

Unlikely

Unlikely, all outcome measures described in the methods are quantified in the results.

Unlikely, loss to follow up was limited and similar between groups.

Unclear

D’Ambrosio, 1998

Randomization not certain: “patients were divided into three homogeneous groups, according to age and symptom score”

Unlikely, the study was placebo-controlled.

Unlikely

Unclear

Unclear

Unlikely

Unclear

Unclear

Ratner, 1998

Not specified

Unlikely, the study was placebo-controlled

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely, loss to follow up was limited

Unclear

Condemi, 2000

Not specified

Unlikely, the study was placebo-controlled

Unlikely

Unlikely

Unclear

Unlikely

Unlikely, loss to follow up was limited and similar between groups.

Unclear

Kaszuba, 2001

subjects were randomized in balanced blocks of 4

Likely, patients were not blinded

Likely

Likely

Unclear

Unlikely

Unlikely, loss to follow up was limited

Unclear

Rinne, 2002

Not described

Unlikely, the study was placebo-controlled

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Unlikely, data were analyzed on an intention-to-treat basis

Spangler, 2003

Not described

Unlikely, the study was placebo-controlled

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Fokkens, 2004

Not described

Unlikely, the study was placebo-controlled

Unlikely

Unlikely

Unlikely

Unlikely

Likely, 3 out of 26 were lost, and reasons and distribution between the groups was not specified.

Unlikely, data were analyzed on an intention-to-treat basis

Bernstein, 2004

randomly assigned in a 1 : 1 : 1 ratio

Unlikely, the study was placebo-controlled

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely, loss to follow up was limited

Unclear

Bhatia, 2005

randomization was assigned by a code in blocks of 4,

Unlikely, the study was placebo-controlled

Unlikely

Unlikely

Unlikely

Unclear

Unclear

Unclear

Andrews, 2009

Patients were randomized 1:1:1

Unlikely, the study was placebo-controlled

Unlikely

Unlikely

Unlikely

Unclear

Unlikely, loss to follow up was limited

Unlikely, ITT analysis was specified

Ford, 2015

subjects were randomized with equal allocation to one of the treatment groups:

Unlikely, the study was placebo-controlled

Unlikely

Unlikely

Unlikely

Likely, a seemingly subjective cut-off value was used to separate the group in high versus low allergy when describing results.

Unclear

Unlikely, ITT analysis was specified

Kim, 2015

Block randomization at each study center (2 block sizes were combined for randomization), with random numbers generated using the SAS® Software Package

Likely, patients were not blinded

Likely

Likely

Unclear

Unlikely

Unlikely

Unlikely

Wartna, 2017

computerized block-randomization

Likely, patients were not blinded

Likely, patients were not blinded

Likely, care providers were not blinded

Unlikely, outcome assessors were blinded

Unlikely

Unclear

Unlikely, ITT analysis was specified

Malizia, 2018

computer-generated randomization sequence (1:1 allocation) unknown to the physicians

Likely, patients were not blinded

Likely

Unlikely

Unclear

Unlikely

Unlikely, loss to follow up was limited

Unlikely, ITT analysis was specified

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Gambardella, 1993

Type of study:

Randomized, double-blind, double-dummy, parallel-group comparative study.

Setting and country: Single-center study in Copenhagen, Denmark.

Funding and conflicts of interest:

Not reported.

Inclusion criteria:

30 patients (25 males) with a history of seasonal allergic rhinitis of between 2 and 31 years. The median age of the patients enrolled was 31 years (range 18 - 55 years) and the duration of the current episode of seasonal rhinitis ranged from 2 to 30 days.

Oral formulation of loratadine (LOR), given one 10-mg tablet once daily for 6 weeks. N=15

Azelastine hydrochloride nasal spray 0.14 mg/nostril twice daily for 6 weeks. N=15

Length of follow-up:

Patients were assessed at week 0 (baseline), at weeks 2, 4 and 6 (end of medication), and 7.

Loss to follow-up:

1 patient in the intervention group withdrew from the study due to nasal congestion and 2 in the control group due to side effects of the treatment (1 sleepiness, 1 epigastralgia and urticaria).

Incomplete outcome data:

N.A.

Symptoms evaluated were sneezing, nose and/or eye itching, lacrimation, rhinorrhoea, photophobia, nasal occlusion, throat irritation, smell loss, nasal mucosa swelling, conjunctivitis, and pharyngeal mucosa reddening. The severity of each symptom was evaluated by the investigator using a four-point scale; a total symptom score was calculated from the sum of the individual symptom scores. Compared with baseline, mean total symptom scores for both groups were significantly (P < 0.05) reduced at each of the assessments during treatment. All patients had improved symptoms during treatment and no significant differences were observed between the 2 groups.

Each of the individual symptoms assessed, showed significant (P < 0.05) reduction from baseline scores in both treatment groups. No significant differences were detected between the two treatment groups for any symptom. Values are only presented in graphs without SD.

Conde Hernández, 1995

Type of study:

Open, randomized, parallel comparative study.

Setting and country: Single-center study in Sevilla, Spain.

Funding and conflicts of interest:

Not reported.

Inclusion criteria:

A history of seasonal allergic rhinitis and positive skin test to pollen.

Exclusion criteria:

Not described.

N total at baseline: 63

Intervention: 32

Control: 31

43% male, mean age 26.5 years (18-59)

The use of antihistaminics, ketotifen, disodium cromoglycate and topical or inhaled corticosteroids was not permitted two weeks prior to the study.

Ebastine oral tablet 10 mg once daily for 2 weeks.

Azelastine nasal spray 0.14 mg/nostril twice daily for 2 weeks.

Length of follow-up:

Duration of the treatment.

Loss to follow-up:

5 patients did not complete the study.

3 in the intervention group, 2 due to lack of efficacy and 1 dropout.

2 in the control group, 1 did not attend the last visit and 1 dropout for practical reasons.

Incomplete outcome data:

N.A.

Primary endpoint was the difference in the total of all symptom scores. Symptoms were rated from 0 (absent) to 3 (severe). Total score decreased in both groups, with no significant differences between the groups (EBA 6.6 ± 5.3, 51.5%; AZE 5.6 ± 4.4, 53.2%). No differences between sums of ocular (EBA 2.1 ± 1.9; AZE 1.6 ± 1.8), nasal (EBA 3.5 ± 3.2; AZE 3.3 ± 2.6) and pharyngeal symptoms (EBA 0.9 ± 1.3; AZE 0.7 ± 1.0) or between individual symptoms were found between groups. 65.5% of AZE patients were considered responders (>50% symptom improvement) against 58% with EBA. No differences between groups in active rhinomanometry.

13 out of 62 patients reported 16 adverse events. In the AZE group, bitter taste (4), pharyngeal pruritis (2), nasal pruritis, facial paresthesia, mild in severity and probably related to the treatment. In the EBA group, sedation (1x mild, 1x moderate), headache (2), somnolence, weakness, epigastralia, increased appetite. These were probably related to the treatment. In both groups, tolerance was very good in most patients and good in some.

Charpin, 1995

Type of study:

Randomized, double-blind, placebo-controlled comparative study.

Setting and country: Multicenter study performed in 3 hospitals in France.

Funding and conflicts of interest:

Not reported.

Inclusion criteria:

Between the ages of 12 and 60 years, experiencing

At least 1 year of seasonal allergic rhinitis associated with watery rhinorrhea,

bouts of sneezing and incomplete or unilateral nasal stuffiness, a response diameter of greater

than 3 mm to a prick test and positive serum immunoglobulin E results.

Exclusion criteria:

History of non-allergic or

perennial rhinitis, asthma, atopic eczema or sinusitis; a mechanical cause for nasal obstruction, any respiratory tract infection,

or a known drug allergy; overt cardiac, renal and/or hepatic disorders; pregnancy or post-partum breast feeding, concurrent

treatment with non-steroidal anti-inflammatory drugs or

glucocorticoids, desensitization treatment within the 3 months before

the study or any treatment for rhinitis within the preceding

month.

N total at baseline: 129

CTZ: 62

AZE: 62 (totals do not correspond)

Median age 30 years. No baseline differences.

Cetirizine once daily as

a 10 mg capsule, for 2 weeks.

Azelastine nasal spray 0.14

mg/activation, one spray in each nostril twice daily, for 2 weeks.

Length of follow-up:

Duration of the treatment

Loss-to-follow-up:

In the CTZ group, 6 patients withdrew, 4 for ineffectiveness, 1 for poor tolerance, and 1 for poor compliance. Eight withdrew from the AZE group, 6 for ineffectiveness, 1 for poor tolerance, and 1 for poor tolerance and ineffectiveness.

Incomplete outcome data:

N.A.

The primary efficacy variable used was the total symptom score of the investigator (TSSI). Both treatment groups had significant improvements in symptoms. At day 14 the decrease in total symptom score from baseline was 61% in the azelastine group and that in the CTZ group was 67%, P=0.66. Nasal scores at day 14 were decreased by 60.2% from baseline in the AZE group and 63.3% in the CTZ group, P=0.7. Ocular scores (i.e., the sum of eye lacrimation, erythema, irritation and swelling) showed a 65% decrease in the AZE group and 60.8% in the CTZ group, P=0.7 by t14.

Analysis of the regression of the VAS with time for the population of patients included in the efficacy analysis revealed significant differences in the slope coefficient between treatment groups for the two variables of nasal stuffiness (AZE -13.97 ± 1.15; CTZ -9.38 ± 0.94; P=0.002) and rhinorrhea (AZE -14.71 ± 0.79; CTZ -11.74 ± 1.25; P = 0.044). No significant differences were seen for any of the other symptom scores.

Twelve patients in the AZE-treated group developed 16 adverse events, with 6 of these events related to the medications used. Treatment was stopped for 2 of these patients, 1 of whom reported severe nausea, vomiting and dizziness while the other had a mild increase in nasal pruritis. Twenty patients in the CTZ-treated group developed 27 adverse events, and a relationship to the study medication was confirmed for 19 of these. Treatment was stopped completely for 1 of the patients, who reported drowsiness, and for 2 days for 1 patient who reported nausea and vomiting. The only frequently occurring adverse event was drowsiness, which occurred in 9 CTZ-treated patients and 2 AZE-treated patients (P=0.03).

Berger, 2003

Type of study:

Randomized, double-blind, placebo-controlled, parallel-group trial.

Setting and country: Multicenter study at 21 investigational sites across the USA.

Funding and conflicts of interest:

Supported by a grant from Medpointe Pharmaceuticals, Somerset, New Jersey.

Inclusion criteria:

12 years of age and older, a minimum 2-year history of seasonal allergic rhinitis, a documented positive allergy skin test result during the previous year.

Exclusion criteria:

use of medications that could affect the evaluation of efficacy; any medical or surgical condition that could affect the metabolism of the study medications; having clinically significant nasal disease other than seasonal allergic rhinitis or significant nasal structural abnormalities; having respiratory infection or other infection requiring antibiotic therapy within 2 weeks of beginning the baseline screening period; having significant pulmonary disease and/or active asthma requiring daily medication; and history of or current alcohol or drug abuse; (potentially) pregnant or nursing.

N total at baseline: 440 (in 4 groups)

AZE: 108, 39.8% male, age 35.9 (12-70) years

DES: 111, 37% male, age 35.4 (15-59) years

No baseline differences.

Desloratadine 5 mg in capsules, once daily, for 2 weeks

Azelastine nasal spray, 2 sprays per nostril twice daily, for 2 weeks

(not considered:

azelastine nasal spray plus loratadine group and placebo group)

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

428 of the 440 randomized patients completed the treatment period. Of the 12 patients who did not complete the study, 4 discontinued due to an adverse event and 8 discontinued for administrative or other reasons.

Incomplete outcome data:

N.A.

The primary efficacy variable was the change from baseline to day 14 in the TNSS, as measured by symptom scores recorded twice daily. Mean % change from baseline in the overall TNSS was 21.9% with AZE and 17.5% with DES. Statistical analysis only performed with placebo.

Bitter taste was the most commonly reported adverse experience among patients treated with azelastine nasal spray (11%). Headache (3%) and pharyngitis (4%) were the most commonly reported adverse events with desloratadine. Somnolence was reported by 2% of the patients treated with azelastine nasal spray compared with 1% with desloratadine. Two patients treated with azelastine nasal spray discontinued the study due to an adverse event: one patient had moderate chest pain and the other experienced lightheaded-ness. One patient in the desloratadine group (headache and nausea) also discontinued due to an adverse event. None of these were considered serious.

Corren, 2005

ACT I

Type of study:

Randomized, double-blind, parallel-group, 2-week comparative trial.

Setting and country: Multicenter study at 20 investigational research centers throughout the USA.

Funding and conflicts of interest:

No conflict reported, but co-authors were employed by MedPointe Pharmaceuticals, Somerset, New Jersey, manufacturer of Azelastine nasal spray.

Inclusion criteria:

Male and female patients aged ≥12 years with at least a 2-year history of SAR and a documented positive allergy skin test, either intraderreal or epicutaneous, during the previous year.

Exclusion criteria:

use of concomitant medication(s) that could affect the assessment of efficacy of study treatment; any medical or surgical condition that could affect the metabolism of study medications; clinically significant nasal disease (other than SAR) or significant nasal structural abnormalities; respiratory infection or other infection requiring antibiotic therapy within 2 weeks of the single-blind placebo lead-in period; past or current alcohol or drug abuse; and significant pulmonary disease, including persistent asthma requiring use of controller medication; (potentially) pregnant or nursing women.

N total at baseline: 307

AZE: 151

CTZ: 155

Age 12 to 74 years, mean 35; 37.1% male. No baseline differences.

Cetirizine 10-mg tablets once daily, for 2 weeks

Azelastine nasal spray, 2 sprays per nostril twice daily, for 2 weeks

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

8 patients did not complete the treatment.

4 patients in the AZE group and 2 in the CTZ group discontinued due to an adverse event, and 1 patient in each group was excluded because of a protocol violation. 1 patient had no postbaseline data and was excluded.

Incomplete outcome data:

N.A.

Primary efficacy variables were change from baseline to day 14 in the severity of rhinitis symptoms based on the combined morning and evening 12-hour reflective TNSS, and onset of action. Mean TNSS improvement was larger in AZE group with 5.56 (29.3%) versus 4.32 (23.0%) with CTZ, P=0.015. The improvement in daily symptom scores was significant for AZE compared with CTZ on study days 8, 9, 10, 12, 13, and 14 (all, P < 0.05). There was a statistically significant improvement in runny nose with AZE (29.8%) compared with CTZ (19.6%, P=0.003).

Onset: The difference in onset between treatment groups significantly favored AZE at 60 and 240 minutes (both, P = 0.040) but not at the other 8 time points.

RQLQ mean change from baseline was higher in AZE with 1.41 ± 1.25 versus 1.11 ± 1.18 in CTZ, P=0.049. There were no statistically significant differences between groups on any of the individual RQLQ domains.

The most common adverse events with AZE were bitter taste (3.3%), headache (2.6%), epistaxis (2.0%), somnolence ( 1.3%), and nasal discomfort (1.3%). The most common adverse event with CTZ was somnolence (2.6%). All other adverse events were reported in <1% of patients. Four patients in the azelastine group discontinued the study due to adverse events (1 each, sleeplessness, sinus infection, nausea, and allergy exacerbation). One patient in the CTZ group discontinued the study due to somnolence and 1 discontinued due to a skin rash.

Berger 2006

ACT II

Type of study:

Randomized, double-blind, parallel-group comparative trial.

Setting and country: Multicenter study at 24 investigational research centers across the USA.

Funding and conflicts of interest:

Funding for this study was provided by MedPointe Pharmaceuticals.

Inclusion criteria:

Males and females 12 years and older with at least a 2-year history of SAR and a documented positive skin test reaction to ambient pollen aeroallergen during the previous year.

Exclusion criteria:

Use of concomitant medication(s) that could affect the evaluation of efficacy; any medical or surgical condition that could affect the metabolism of the study medications; clinically significant nasal disease (other than SAR) or significant nasal structural abnormalities; respiratory tract infection or other infection requiring antibiotic drug therapy within 2 weeks of beginning the baseline screening period; a history of or current alcohol or other drug abuse; or significant pulmonary disease, including persistent asthma requiring daily controller medication; (potentially) pregnant or nursing women.

N total at baseline: 360

CTZ: 175

AZE: 179

The patients ranged in age from 12 to 74 years (mean age 35); No baseline differences.

Cetirizine 10-mg tablets once daily for 2 weeks.

Azelastine nasal spray, 2 sprays per nostril twice daily for 2 weeks.

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

Nine patients discontinued before completing the 2-week treatment period: 7 in the azelastine group (4 experienced adverse events, 1 was lost to follow-up, and 2 for administrative reasons) and 2 in the cetirizine group (1 had an adverse event and 1 was lost to follow-up). Three patients completed the 2-week protocol but were not considered evaluable due to protocol violations.

Incomplete outcome data:

Postbaseline observations were missing for 6 patients. Therefore, data from 354 patients were included in the primary analysis of the ITT population.

The primary efficacy variable was the change from baseline to day 14 in rhinitis symptom severity based on the combined morning and evening 12-hour reflective TNSS. In the primary analysis of the ITT population, the mean improvement from baseline TNSS was 4.6 ± 4.2 with AZE and 3.9 ± 4.3 with CTZ (P<0.14). The % change was 23.9% with AZE and 19.6% with CTZ (P.08).

Secondary efficacy variables were (1) change from baseline to day 14 in total RQLQ and (2) change from baseline to day 14 in individual symptoms. AZE significantly improved each domain of the RQLQ, including the nasal symptoms domain (P<0.05), and the overall RQLQ score (P<0.002) compared with CTZ (no values given, only graphs). For individual symptoms, statistically significant improvements in favor of AZE over CTZ were observed for nasal congestion (P<0.049) and sneezing (P<0.01).

The most common adverse event with AZE was bitter taste (7.7%). All other adverse events in both treatment groups, including somnolence, headache, epistaxis, and pharyngolaryngeal pain, occurred with an incidence of less than 2%. Four patients in the AZE group discontinued the study because of adverse events (headache and fatigue, unexpected pregnancy, elevated blood pressure, and cough). One patient in the CTZ group discontinued because of vomiting and gastrointestinal distress.

Ellis, 2013

Type of study:

Randomized, four-way, double-blind, placebo controlled crossover phase IV trial.

Setting and country: Single-center study in Ontario, Canada.

Funding and conflicts of interest:

This study was funded by Bayer, Inc.

Dr Ellis has received speaking honoraria from Pfizer, Merck and Sanofi, has served on an Advisory Board for Sanofi, and has received research grants from Circassia Ltd, Adiga Life Sciences, and GlaxoSmithKline in the last 12 months. All other authors declare that have no competing interests.

Inclusion criteria:

Healthy male and female volunteers between the ages of 18 and 65 with a history of SAR to ragweed for the preceding two consecutive pollen seasons.

Exclusion criteria:

A history of hypersensitivity or non-response to AZE, LORA, or CTZ; relevant concomitant disease (chronic sinusitis) or nasal structural abnormalities causing greater than 50% obstruction; presence of an acute illness that could have interfered with the conduct of the study within 7 days of any pollen exposure; asthma requiring more than occasional use (<3 times per week) of inhaled short-acting β-2 agonists; recent restricted medications; clinically significant histories of hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, or neurologic malignancies within the last 5 years; alcoholism or drug abuse within 2 years prior to the screening visit; regular use within 6 months of any type of tobacco product(s) or any smoking cessation nicotine-containing product; participation in any other trials involving investigational or marketed products within 30 days prior to the screening visit; and history of a positive test for HIV, TB (not due to vaccination), hepatitis B (not due to vaccination), or hepatitis C; women who were pregnant, lactating or had the intention of becoming pregnant

N total at baseline: 70

Mean age 35 (21-63) years.

All groups were equal (crossover study).

Loratadine, 10 mg tablet

or

Cetirizine, 10 mg tablet

Taken after 2 hours during an 8-hour allergen challenge in an Environmental Exposure Unit

Azelastine nasal spray, 1 spray per nostril

Taken after 2 hours into an 8-hour allergen challenge in an Environmental Exposure Unit

Length of follow-up:

Duration of the treatment.

Loss-to-follow-up:

4 participants were excluded from the PP population for failing to complete all four dosing periods or for lacking the required symptom score.

Incomplete outcome data:

N.A.

The primary efficacy parameter was the onset of action measured by the change from baseline in TNSS. AZE was more effective than CTZ at each time point from 15 to 60 minutes post-dose (95%CI ≤ -0.2) and more effective than LORA at each time point from 15 minutes to 5 hours post dose (95%CI ≤ -0.1). The raw mean changes from baseline in TNSS ranged from -0.8 (at 15 minutes) to -3.8 (at 2.5, 3.5, and 4 hours) for CTZ, from -0.7 (at 15 minutes) to -3.4 (at 2.5 hours) for LORA, and from -1.5 (at 15 minutes) to -4.3 (at 120 minutes) for AZE.

The secondary efficacy parameter was measured by four components: change from baseline for the individual components of the symptoms constituting the TNSS (sneezing, itchy nose, and runny nose); the average TNSS change from baseline over the last 2 hours of the allergen challenge; the relief of nasal obstruction, teary eyes, itchy eyes; and the overall participant assessment of efficacy. AZE was more effective than CTZ at each time point from 15 to 45 minutes post-dose and more effective than LORA at each time point from 15 to 60 minutes and 105 to 120 minutes post dose for the sneezing score. It was also more effective than CTZ at each time point from 30 to 60 minutes post-dose and more effective than LORA at each time point from 15 minutes to 5 hours post dose with the exception of the 3 hour time point for the itchy nose score. AZE was more effective than CTZ at each time point from 15 to 60 minutes post-dose and more effective than LORA at each time point from 30 minutes to 6 hours post dose with the exception of 4.5 hours for the runny nose score.

AZE, CTZ and LORA were well tolerated, and few adverse events were reported. For AZE, all except 1 of the adverse events were mild or moderate in intensity, and all except 2 adverse events were considered not possibly related to the study medication. The severe adverse event was sinus headache, and the 2 possibly related adverse events were moderate somnolence and mild dysgeusia. The most commonly reported adverse event was myalgia (3 subjects), followed by headache (2 subjects), diarrhea (2 subjects), and nasal congestion (2 subjects). For CTZ, all except 1 of the adverse events were mild or moderate in intensity, and all adverse events were considered not possibly related to the study medication by the investigator. The severe adverse event was abdominal pain. No adverse event was reported by more than 1 subject. For loratadine, all adverse events were mild or moderate in intensity, and all except 1 adverse event were considered not possibly related to the study medication. The possibly related adverse event was mild urticaria. The only adverse event reported by more than 1 subject was upper respiratory tract infection.

Study reference

(first author, publication year)

Describe method of randomisation¹

Bias due to inadequate concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

Gambardella, 1993

Not described

Unclear, not described

Unlikely.

Unlikely, the study is double-blind, double-dummy.

Unlikely, the study is double-blind.

Unlikely, all outcome measures described in the methods are reported in the results. However, it is unclear why from 1 patient the global assessments at 7 weeks were not reported.

Unlikely, 1 patient in the intervention group withdrew from the study due to a congested nose and 2 in the control group due to side effects of the treatment.

Unclear.

Conde Hernández, 1995

“The patients were included in either group on the basis of the randomization scheme previously established.”

Unclear, not described

Likely, the study was not blinded and treatment allocation was obvious.

Likely, the study was not blinded and treatment allocation was obvious.

Likely, the study was not blinded and treatment allocation was obvious.

Unlikely, all outcome measures described in the methods are quantified in the results.

Unlikely, loss to follow up is limited and similar between groups.

Unlikely.

Charpin, 1995

Not described

Unclear, not described

Unlikely, the study is double-blind, double-dummy.

Unlikely, the study is double-blind.

Unlikely, the study is double-blind.

Likely, some outcome measures presented in the results were not specified in the Methods. Extra analysis “for the population of patients included in the efficacy analysis” was not described.

Likely, the number of analysed/excluded patients differs between outcome measures.

Unclear.

Berger, 2003

Not described

Unlikely, the study was double-blind and placebo controlled

Unlikely, the study was double-blind and placebo controlled

Unlikely, the study was double-blind and placebo controlled

Unlikely, the study was double-blind and placebo controlled

Unlikely, all outcome measures described in the methods are quantified in the results.

Unlikely, loss to follow up was limited and similar between groups.

Unlikely, primary analysis was an intent-to-treat analysis.

Corren, 2005

“A computer-generated randomization schedule was used to assign eligible patients to the 2 treatment groups in blocks of 4.”

Unlikely, “blinding of the study was preserved at each study site until all patients had completed the study and the database was locked.”

Unlikely, the study was double-blind and placebo controlled

Unlikely, the study was double-blind and placebo controlled

Unlikely, the study was double-blind and placebo controlled

Unlikely, all outcome measures described in the methods are quantified in the results.

Unlikely, loss to follow up was limited and similar between groups.

Unlikely, “the primary analysis was an intent-to-treat analysis”.

Berger 2006

“Patients who met the inclusion and exclusion criteria were randomized to treatment groups by means of a computergenerated randomization schedule”

Unlikely, “access to the random code was confidential and accessible only to authorized persons who were not involved in the study. Blinding of the study was preserved at each study site until all the patients completed the study and the database was locked.”

Unlikely

Unlikely

Unlikely

Unlikely, all outcome measures described in the methods are quantified in the results.

Unlikely, loss to follow up is limited and similar between groups.

Unlikely, the authors clearly indicate the group was analysed with intention-to-treat. However, additional analysis was performed were statistical significance was not obtained with the ITT population.

Ellis, 2013

“Randomization occurred in a 1:1:1:1 ratio”

Unlikely, study was double blind and placebo-controlled.

Unlikely

Unlikely

Unlikely

Unlikely, all outcome measures described in the methods are quantified in the results.

Unlikely

Unlikely

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Wei, 2016

SR and meta-analysis of RCTs

Literature search up to March 2016

A: Meltzer, 2000

B: Philip, 2002

C: Adelsberg, 2003a

D: Adelsberg, 2003b

E: Lu, 2009a

F: Lu, 2009b

G: Nayak, 2002

H: van Cauwenberge, 2000

I: Philip, 2004

J: Holmberg, 2009

K: Bachert, 2009

L: Bousquet, 2010

M: Jauregui, 2011

N: Pradalier, 2007

O: Patel, 2005

P: Demoly: 2009

Study design: RCT

Setting and Country:

Source of funding and conflicts of interest:

(commercial / non-commercial / industrial co-authorship)

Inclusion criteria SR:

1) randomised controlled trail (RCT) design;

2) patients with SAR or PAR.

3) with specific endpoint evaluation

standards;

4) provision of efficacy or safety information;

5) comparing SAHs with Montelukast or placebo, or Montelukast

with placebo or combination therapy;

6) data present as (mean +/- SD) or data to estimate them.

Exclusion criteria SR:

1) reviews, systematic reviews or Meta-analysis;

2) duplicate reports or reports on same subjects; 3) if providing

insufficient data;

4) if focused on patient with asthma;

5) if combined therapy contained interventions other than SAHs and

Montelukast.

8 studies included

Important patient characteristics at baseline:

N, mean age

A: 278, 34 yrs

B: 1312, 36 yrs

C: 1079, 36 yrs

D: 1295, 36 yrs

E: 285, 35 yrs

F: 281, 35 yrs

G: 605, 37 yrs

O: 1992, 36 yrs

Groups comparable at baseline?

Describe intervention:

A: Montelukast 10 mg;

B: Montelukast 10 mg;

C: Montelukast 10 mg;

D: Montelukast 10 mg;

E: Montelukast 10 mg;

F: Montelukast 10 mg;

G: Montelukast 10 mg;

O: Montelukast 10 mg;

Describe control:

A: Loratadine 10 mg/placebo;

B: Loratadine 10 mg/placebo;

C: Loratadine 10 mg/placebo;

D: Loratadine 10 mg/placebo;

E: Loratadine 10 mg/placebo;

F: Loratadine 10 mg/placebo;

G: Loratadine 10 mg/placebo;

O: Placebo

End-point of follow-up:

A: 2 weeks

B: 2 weeks

C: 4 weeks

D: 2 weeks

E: 2 weeks

F: 2 weeks

G: 2 weeks

H: 2 weeks

I: 2 weeks

J: 3 weeks

K: 2 weeks

L: 4 weeks

M: 2 weeks

N: 2 weeks

O: 2 weeks

P: 2 weeks

For how many participants were no complete outcome data available?

(intervention/control)

A: -

B: -

C: -

D: -

E: -

F: -

G: -

O:-

1. Montelukast versus placebo

Outcome measure-1

CSS (composite symptoms score)

Defined as mean DNSS and NNSS (4 point scale 0-3)

Pooled effect (fixed effects model):

-0.11 (95% CI -0.15 to -0.06) favoring Montelukast

Heterogeneity (I²): 0%

Outcome measure-2

RQLQ (rhino conjunctivitis quality of life questionnaire)

Pooled effect (fixed effects model):

-0.20 (95% CI -0.26 to -0.13) favoring Montelukast

Heterogeneity (I2): 5%

2. Montelukast versus SAH

Outcome measure-1

CSS (composite symptoms score)

Defined as mean DNSS and NNSS (4 point scale 0-3)

Pooled effect (random effects model / fixed effects model):

-0.03 (95% CI -0.01 o 0.07)

Heterogeneity (I²): 0|%

Outcome measure-2

RQLQ (rhino conjunctivitis quality of life questionnaire)

Pooled effect (fixed effects model):

0.09 (95% CI 0.02 to 0.15)

Heterogeneity (I2):0%

Facultative:

Brief description of author’s conclusion

Personal remarks on study quality, conclusions, and other issues (potentially) relevant to the research question

Level of evidence: GRADE (per comparison and outcome measure) including reasons for down/upgrading

Study

First author, year

Appropriate and clearly focused question?¹

Yes/no/unclear

Comprehensive and systematic literature search?²

Yes/no/unclear

Description of included and excluded studies?³

Yes/no/unclear

Description of relevant characteristics of included studies?⁴

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?⁵

Yes/no/unclear/notapplicable

Assessment of scientific quality of included studies?⁶

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?⁷

Yes/no/unclear

Potential risk of publication bias taken into account?⁸

Yes/no/unclear

Potential conflicts of interest reported?⁹

Yes/no/unclear

Wei, 2016

Yes

Yes

Yes

Yes

NA

Yes, however incomplete?

Yes

Yes

No

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Rajashekar, 2018

Type of study: RCT

Setting and country:

polyclinic in a district place of Southern

India

Funding and conflicts of interest:

‘Source of Support: Nil, Conflict of Interest: None declared.’

Inclusion Criteria

-age18-65 yr

-diagnosed with persistent mild-to-moderate AR.

Exclusion Criteria

-Patients of intermittent AR, severe PAR, non-AR, associated bronchial asthma, and atopic dermatitis patients.

-Patients with deviated nasal septum, nasal polyps, atrophic rhinitis, and any nasal mass.

-Patients who are allergic and intolerant to medications used in the study.

-Patients who are on immunotherapy/herbal therapy or corticosteroid therapy either presently or in the recent past.

-Chronic smokers, chronic alcoholics, drug addicts and psychiatry patients, pregnant and lactating mothers.

-a history of any significant systemic disorders.

N total at baseline:

A: n=35

B: n=35

C: n=35

Groups comparable at baseline?

Yes

Group A: Ebastine 10 mg,

Group B: Montelukast 10 mg,

Group C: Ebastine 10 mg + Montelukast 10 mg.

Length of follow-up:

4 weeks

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Symptoms

total nasal symptom score

AM symptom score

PM symptom score

total five nasal symptom scoring (T5NSS) system,

5 parameters: sneezing, rhinorrhea, itching, congestion, and eye symptoms (itching, lacrimation, and congestion), scored on a severity scale 0 to 3 (0 = none, 1 = mild, 2 = moderate, and 3 = severe) max score of 15,

patients were requested to record their symptoms twice daily for 4 weeks.

mean ± standard

error mean

Montelukast

Baseline 161.72 ± 1.5

4 weeks: 145.66 ± 1.3

Ebastine

Baseline: 157.89 ± 1.6

4 weeks: 142.53±1.6

Persitant AR

Kaur, 2017

Type of study:

RCT

Setting and country:

Tertiary care hospital, India

Funding and conflicts of interest:

‘Source of support: Nil, Conflict of interest: none’

Inclusion criteria:

-10-55 yr

-clinically diagnosed as suffering from allergic rhinitis based on the characteristic history, corroborative physical findings, and blood eosinophilia

Exclusion criteria:

-History of asthma

-treatment with topical or -systemic corticosteroids < 1 month

-Study drugs or decongestants < 1 week

N total at baseline:

N= 125 (n=25/group)

Group 1: Montelukast

Group 2: Levocitrizine 5 mg

Group 3: Fexofenadine 180 mg

Group 4: Desloratidine 5 mg

Group 5: Chlorpheniramine maleate 4 mg

Important prognostic factors:

For example

age ± SD:

I:

<20: 5

21-30: 5

31-40: 8

41-50: 5

51- 60: 2

C:

<20: 5

21-30: 10

31-40: 6

41-50: 2

51- 60: 2

Sex:

Total 58 % M

I: 72 % M

C: 60% M

Groups comparable at baseline?

Yes

Montelukast 10 mg once a day (OD) in group I,

tablet Levocetirizine 5 mg OD in group II,

tablet Fexofenadine 180 mg OD in group III,

tablet Desloratadine 5 mg OD in group IV,

tablet Chlorpheniramine maleate 4 mg three times a day (TDS) in group V.

Length of follow-up:

6 weeks

Loss-to-follow-up:

Group 5: N=4, reason not reported

Incomplete outcome data:

-

Symptoms

Total symptoms score sneezing

Montelukast

Baseline:

1: 4 (16%)

2: 12 (48%)

3: 9 (36%)

6wk:

0: 16 (64%)

1: 9 (36%)

Levocetrizine

Baseline:

1: 4 (16%)

2: 12 (48%)

3: 9 (36%)

6 wk:

0: 14 (56%)

1: 11 (44%)

(…)

Total symptoms score nasal congestion/obstruction

Andhale, 2016

Type of study:

RCT?

Setting and country:

ENT out-patient department of Goa

Medical College, India

Funding and conflicts of interest:

Inclusion criteria:

-perennial allergic rhinitis on the basis of Allergic Rhinitis and its Impact on Asthma (ARIA) classification

Exclusion criteria:

-asthma

N total at baseline:

I: n=28

C: n=22

Important prognostic factors²:

age ± SD:

No data reported

Sex:

Seventy-five (37 males and 38 females). No data reported for the groups separately

Groups comparable at baseline?

No data reported

Montelukast

in a dosage of 10mg

for two weeks at bed-time

Levocetrizine

in a dosage of 5mg,

for two weeks at bed-time

Length of follow-up:

2 weeks

Loss-to-follow-up:

-

Incomplete outcome data:

-

Visual analogue score (VAS) for nasal and eye symptoms

during the day-time and night-time.

Daytime symptoms

Nasal blockage

Intervention

Pre 5.5±2.7

Post 2.0±2.3*

Control

Pre 6.2±2.7

Post: 3.9±2.5*

Nasal irritation

Intervention

Pre 3.9±3.5*

Post 1.5±2.2

Control

Pre: 4.3±3.6*

Post 2.1±2.2

Nasal discharge

Intervention

Pre 6.7±2.5

Post 2.1±2.6*

Control

Pre: 7.2±2.4

Post: 4.1±2.9*

Sneezing

Intervention

Pre 6.0±2.3

Post 1.9±2.1*

Control

6.5±2.3

2.9±2.7

Night-time Symptoms

Mouth breathing

Post-nasal drip

Sleep disturbance

Eye Symptoms

Redness and itching

3 groups, unclear if patients were randomized.

Ciebada, 2011

Type of study:

RCT, cross-over design

Setting and country:

Poland

Funding and conflict of interest:

“This article was self-funded

The authors have nothing to declare pertaining to this article”

Inclusion criteria:

-age 18–65 yr

>= 2 yr history of persistent AR

-nasal congestion score of at least 2 on a 4-point scale

-with sensitization to perennial

allergens relevant for Central Europe (house-dust mites, cats, and dogs) confirmed by a positive skin-prick test

-Women of childbearing age were required to have a negative

urine pregnancy test

Exclusion criteria

-Sensitized to seasonal allergens (grass, tree, and weed pollen),

-bronchial asthma,

-current smokers.

-Patients with upper respiratory tract infection within 6 weeks preceding the study

N total at baseline:

N=20

Important prognostic factors²:

Sex F/M

14: 6

16: 4

Mean age (yr, sd) 23.65, 2.1

Groups comparable at baseline?

Yes

montelukast (10-mg

tablet once daily in the evening)

levocetirizine (5-mg tablet once daily in the evening)

placebo

Length of follow-up:

4*6 + 2 weeks

Loss-to-follow-up:

-

Incomplete outcome data

-

Congestion symptoms

estimated using nasal symptom scores, with a 4-point scale (0: none, 1: mild (noticeable but not bothersome), 2: moderate (noticeable and some of the time bothersome), and 3: severe (bothersome most of the time/very bothersome some of the

time)) assessed by subjects in daily diary cards

Placebo

Day of Treatment

0: 2.55 (0.24)

42: 1.55 (0.25)

Montelukast

Day of Treatment

0: 2.55 (0.24)

42: 1.05 (0.18)

Levocetrizine

Day of Treatment

0: 2.55 (0.24)

42: 0.9 (0.23)

Bisgaard, 2009

Type of study:

Randomized, double-blind, placebo controlled

study

Setting and country:

Multicentre USA

Funding and conflicts of interest:

-

Inclusion criteria:

Patients enrolled in the study demonstrated a positive skin test (wheal diameter at least 3 mm greater than saline

control to one of the allergens active during the study season) and a Daytime Rhinitis Symptom Score >2

each day during the 3- to 5-day placebo run-in period.

Exclusion criteria:

-

N total at baseline: 413

I: n= 280

C: n= 133

Important prognostic factors²:

Age:

2-14 yr

Sex:

I: 157/123

C: 77/56

Groups comparable at baseline?

I: Montelukast

Patients <=5 received 4=mg chewable tablet

Patients >= 6 yr old received 5-mg chewable tablet

C: placebo

Matching image placebo

Length of follow-up:

2 weeks

Loss-to-follow-up:

Study discontinuation due to AE (N %)

I: n=5 (1.8%)

C: n=1(0.8%)

Incomplete outcome data:

Not reported

No. of children (%)

Adverse experiences

Overall

I: 73 (26.1)

C: 35 (26.3)

Headache

I: 9 (3.2)

C: 2 (1.5)

Pharyngitis

I: 9 (3.2)

C: 2 (1.5)

Fever

I: 7 (2.5)

C: 4 (3.0)

URI

I: 6 (2.1)

C: 2 (1.5)

Otitis media

I: 6 (2.1)

C: 2 (1.5)

Study discontinuation due to AE (N %)

I: n=5 (1.8%)

C: n=1(0.8%)

Two of these discontinuations (one in each treatment group) were due to worsening asthma; others included upper respiratory infection, viral infection, otitis media, and ophthalmic infection.

Unpublished data

The fifth short-term double-blind study (referred to as

the allergic rhinitis study) was a multicenter (31 sites in the United States), randomized, double-blind, placebocontrolled

study conducted over a 2-week period during

spring pollen season in 413 children 2–14 years of

age with seasonal allergic rhinitis.

The safety profile

of montelukast, along with exploratory evaluations of

allergic rhinitis efficacy end points and validation of

measurement characteristics of new allergic rhinitis

symptom scales, was assessed in this study.

Okubo, 2008

Type of study: RCT

Setting and country: Multicenter, Japan

Funding and conflicts of interest: not reported

Inclusion criteria:

(1) quantitative analysis of specific

IgE antibody (UniCAP-RAST) revealed scores =

2 points (containing antibodies against pollen scattered

between February and April, 2003);

-history of typical seasonal allergic rhinitis at least for the past two years;

-age: between 15 and 65 years

(male or female),

-the following two criteria fulfilled

for symptoms: (1) total scores of daytime nasal symptoms (sneezing attacks, nasal discharge and

nasal congestion during the day) = 4 points per day, as an average (total = 12 points) and (2) total scores of nighttime nasal symptoms (difficulties in falling into sleep, nasal congestion at night, and degree of wakening at night) = 2 points per day, as an average (total = 6 points)) The study was performed

when the patients fulfilled these two inclusion criteria.

Exclusion criteria:

-The patients with nasal disorders that might interfere with the efficacy assessment, or those using drugs that might interfere with the efficacy assessment

were excluded from the study.

-Patients who used any drug that might affect efficacy assessment

in the study within 2 weeks before the run-in period

-Bronchial asthma patients with uncontrolled mild to moderate symptoms and patients with severe bronchial asthma were excluded from the study.

N total at baseline:

N=945

Placebo: n=314

Montelukast 5 mg: n=318

Montelukast 10 mg: n=310

Important prognostic factors²:

Male (%M)

Placebo: 35.7

Montelukast 5mg: 34.3

Montelukast 10 mg: 36.8

Age (Years), Mean (SD)

Placebo: 36.3 (9.5)

Montelukast 5mg: 37.2 (9.7)

Montelukast 10mg: 36.4 (9.8)

Groups comparable at baseline?

Yes

Placebo

Montelukast 5 mg

Montelukast 10 mg

Montelukast sodium 5-mg and 10-mg tablets and the

matching placebo tablets (Banyu Pharmaceutical Co.,

Ltd.) were orally administered once daily at bedtime for two weeks.

Length of follow-up:

2 weeks

Loss-to-follow-up:

N=28 (%) discontinued the study

Placebo: n=9,

Montelukast 5mg: n=12

Montelukast 10mg: n=7

Incomplete outcome data:

-

composite

nasal symptom scores (

CNSS) (average of nasal

symptom scores during the daytime and the night

time) over a 2 week treatment period

baseline

placebo: 1.53±0.45

M5: 1.54±0.46

M10: 1.52±0.43

Mean change from baseline:

Placebo: −0.37

M5: −0.47

M10: −0.47

(P = 0.001 for both groups compared to placebo, M5 versus M10: ns).

No sd or 95%CI reported

Adverse Events

Drug related:

The incidences of drugrelated

AE were

4.1%,

4.7% and

4.2% for clinical AE

and

3.2%,

1.9%

and 5.8% for laboratory AE in the placebo,

.

There were no serious AE and no fatalities.

“Headache”, “constipation”, “thirst” and “somnolence”

were common drug-related AE occurring in

more than 2 cases (approximately 1%) in any of the three groups.

All drug-related clinical AE were mild or moderate. In addition, one patient terminated the

study due to the drug-related AE, severe “pruritus”

and “nausea”, in the montelukast 5 mg group. The patient recovered thereafter.

“Blood bilirubin increased”, “blood triglycerides increased”,

“urinary occult blood positive” and “protein

urine present” were drug-related laboratory AE occurring in more than 2 cases (approximately 1%) assigned to at least one of the three groups. All drugrelated laboratory AE were transient in the

montelukast-treated groups, and all of them recovered

or improved without any treatment.

Chen, 2006

Type of study:

RCT

Setting and country:

Taiwan

Funding and conflicts of interest:

This study did not receive

any support from the pharmaceutical industry.

Inclusion criteria:

-Age 2-6 yr

-Patients were recruited

based on a documented clinical history of perennial allergic rhinitis (PAR) of at least half

a year, a positive prick-test for house dust-mite and a positive mite-specific IgE.

Exclusion criteria:

-Patients were excluded if they had taken the following drugs:

corticosteroids or sodium cromoglycate within the past 4 wk, or H1-antagonist and/or decongestant within the past 7 days.

N total = 60

Cetirizine

(n = 20)

Montelukast

(n = 20)

Placebo

(n = 20)

Important prognostic factors²:

M/F ratio

12/8

11/9

9/11

Age (yr, sd)

4.53 ( 0.91)

4.49 (1.09)

4.36 (0.87)

Groups comparable at baseline

Yes

i) Cetirizine

(UCB FARCHIM S.A., Brussels, Belgium)

5 mg p.o. daily at bedtime, (ii) Montelukast

(Merck & Co, Inc., Whitehouse Station, NJ,

USA) 4 mg p.o. daily at bedtime, (iii) Placebo

(glucose) 5 mg p.o. daily at bedtime.

Length of follow-up:

12 wk

Loss-to-follow-up:

-

Incomplete outcome data:

-

QoL

PRQLQ

Change from baseline (sd)

Cetrizine -31.15 (23.36)

Montelukast -19.15 (20.71)

Placebo -3.85 (5.56)

Montlukast versus placebo

(p = 0.028)

The Total Symptom Score (TSS)

Symptoms included four nasal symptoms

(nasal itching, sneezing, rhinorrhea and nasal

congestion) and four non-nasal symptoms

(throat itching, conjunctival itching, conjunctival

hyperemia and eye tearing).

TSS was the mean of eight

symptoms, ranged from 0 to 3. The baseline TSS

was calculated as the mean of the daily during

the baseline study period of 7 days. Subsequently

TSS was based on the scores for the previous

28 days at 4, 8, and 12 wk after treatment.

Table 2

Change from baseline (sd)

Cetrizine -0.60 (0.25)

Montelukast -0.43 (0.23)

Placebo -0.11 (0.12)

Montelukast versus placebo (p < 0.001)

Fig. 1. Change from baseline in TSS. Significant change

compared with placebo (*p < 0.05, **p < 0.001), cetirizine

compared with montelukast (#p < 0.05).

TSS (0, none, not noticeable; 1,

mild, noticeable but not bothersome; 2, moderate,

noticeable and bothersome some of the time;

3, severe, bothersome most of the time and/or

very bothersome some of the time.)

The PRQLQ features 23 items corresponding to

five separate survey domains (nose symptoms,

eye symptoms, practical problems, other symptoms,

and activities) (18). Questionnaire respondents

provided their response according to a

seven-point scale.

Ciebada, 2006

Type of study:

RCT

Setting and country:

Poland

Funding and conflicts of interest:

Not reported

Inclusion criteria:

The following inclusion criteria were used to select

individuals for the study: age 18 to 65 years, persistent AR

for at least 2 years, a nasal congestion score of at least 2 using a 4-point scale (0

to perennial allergens relevant to Central Europe (house dust

mite, cat, and dog) confirmed by a positive skin prick test

result.

Exclusion criteria:

The exclusion criteria were concomitant sensitization

to seasonal allergens (grass, trees, and weed pollen), bronchial

asthma, current smoking, respiratory tract infection

during the 6 weeks preceding the study, pregnancy, breastfeeding,

severe illnesses, nasal septal deviation, nasal polyps,

acute or chronic rhinosinusitis, and any other abnormality

that might affect nasal breathing or nocturnal sleep patterns.

Patients were not allowed to use any antiallergic medications

during the study except the study medication. No participant

underwent allergen-specific immunotherapy.

N total at baseline:

Important prognostic factors²:

Forty patients (age range, 18–65 years; mean [1] SD age,

28.9 [1] 2.7 years; 30 women and 10 men) with persistent AR

were included in this study.

Groups comparable at baseline?

Yes

Montelukast sodium (Singulair; Merck & Co Inc,

Whitehouse Station, NJ) (10-mg daily dose),

desloratadine (Aerius; Schering Canada Inc, Pointe-Claire, Quebec) (5-mg

daily dose),

levocetirizine (Xyzal; UCB, Brussels, Belgium)

(5-mg daily dose),

or placebo were used as daily treatment during the study. Medications were prepared by the hospital pharmacy staff, who placed the pills in identical white capsules.

The medication was administered once daily before sleep.

Length of follow-up:

7 months

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Levocetrizine (n=20)

Total daytime nasal symptoms score (mean (SEM))

Baseline 7.95 (0.68)

6 weeks:

Placebo 4.99 (0.76)

Antihistamine 3.02 (0.64)

Montelukast 3.44 (0.55)

Montelukast versus placebo(p<0.001)

Montelukast versus levocetrizine (NS )

Daytime eye symptom

score

Baseline 3.15 (0.73)

6 weeks:

Placebo 1.71 (0.62) Antihistamine 0.48 (0.26)

Montelukast 1.13 (0.38)

Montelukast versus placebo(p<0.001)

Montelukast versus levocetrizine (NS)

Persistant AR

The primary end point was the daytime nasal symptom score, (SUM

Sneezing Discharge Itching Congestion

Symptom scores and drug use. Individual nasal symptom scores, daytime nasal symptom scores, and daytime eye symptom scores were recorded. Symptom scores were noted by each patient before treatment (baseline) and then every day during the first week and on days 14, 21, 28, 35, and 42 of the treatment period.

Symptom scores were graded according to the following 4-point severity scale: 0, none; 1, mild (noticeable but not bothersome); 2, moderate (noticeable and some of the time bothersome); and 3, severe (bothersome

most of the time/very bothersome some of the time).

Allergic rhinitis was defined

according to Allergic Rhinitis and Its Impact on Asthma

guidelines, where persistent means that the symptoms are

present “more than 4 days a week and for more than 4

weeks.”16

Lombardo, 2006

Type of study:

RCT

Setting and country:

Italy

Funding and conflicts of interest:

Not reported

Inclusion criteria:

>=18 yr

-SAR

-Patients with asthma, using only short-acting B-antagonist bronchodilators.

Exclusion criteria:

-persistent rhinitis,

-Non-allergic rhinitis

-rhinitis medicamentosa

-structural nasal obstruction

-Upper respiratory tract infection

-Acute or chronic pulmonary disorder

-Pregnancy

-Medication for allergic rhinitis not allowed during the study

-Patients who had begun immunotherapy < 6 months

N total at baseline:

N= 388

Levocetricine: n = 96

Montelukast: n= 104

Combi: n=134

Placebo: n=54

Important prognostic factors²:

Age

1: 42 (13)

2:

3:

4: 39 (12)

Sex (%M)

1: 58

2: 59

3: 68

4: 30

Groups comparable at baseline?

Yes

Group1: levicocetrizine (5mg/d)

Group 2: Montelukast (10mg/d)

Group 3: combined Levico + Montelukast

Group 4: placebo

1/day 4 weeks

Length of follow-up:

4 wk

Discontinuation

1: 3 (3%)

2: 7 (7%)

3: 9 (7%)

4: 3 (6%)

(lack of effectiveness, protocol deviation, lost to follow-up, other)

Loss to follow-up

1:1 (1%)

2:1 (1%)

3:2 (1%)

4:0 (0%)

Symptoms (4-point scale)

0 = none – 3 = severe

Daytime nasal symptoms

(average of individual symptoms of nasal congestion, rhinorrea, pruritus and sneezing)

Mean change (95%CI)

1: 0.43 (0.47-0.28)

2: 0.34 (0.39-0.18)

3: 0.70 (0.73-0.52)

4: -

P < 0.01 (compared to placebo)

Night-time nasal symptoms

1: 0.37 (0.39-0.2) (ns)

2: 0.27 (0.31-0.15) (ns)

3: 0.48 (0.57-0.25)

4:-

Significant improvement 3 versus placebo

Daytime eye symptoms

1: 0.38 (0.45-0.19) (ns)

2: 0.22 (0.25-0.10) (ns)

3: 0.45 (0.48-0.28)

4:-

Significant improvement 3 versus placebo

Clinical adverse experience

1: n=0

2: n=0

3: n=1

4: n=1

QoL: RQLQ (scale 0-6)

Change:

1: 0.8

2: 0.6

3: 1.1

4: 0.4

P<0.05 compared to placebo

Patel, 2005

Type of study:

RCT

Setting and country:

122 medical centers in the United States and Europe.

Funding and conflicts of interest:

-

Inclusion criteria:

Patients were 15 to 85 years old and had at least a 2-year

clinical history of PAR and at least a mild-to-moderate level

of daytime nasal symptoms (defined in the “End Points”

subsection) during the placebo run-in period. Eligible patients

had to demonstrate a positive skin test reaction (wheal diameter

[1]3 mm greater than the control) to 2 or more perennial

allergens. The antigens tested were extracts of dust mites

Dermatophagoides pteronyssinus and Dermatophagoides

farinae, cat antigen (pelt), dog antigen (epithelium), a mixed

extract of German and American cockroaches, and a mixed

extract of perennial fungi (Penicillium species and Aspergillus

species). Asthmatic patients requiring only as-needed

inhaled, short-acting B-agonists were allowed to participate

in the study.

Exclusion criteria:

Patients with other respiratory and ocular disorders

were not permitted to participate. Additional therapy

for asthma, including corticosteroids and long-acting

and the use of other confounding medications (including

antihistamines and decongestants) were not permitted.

N total at baseline:

Montelukast group

(n [1] 1,002)

Placebo group

(n [1] 990)

Important prognostic factors²:

Age, mean  SD (range), y

36.3  13.6 (15–81)

36.6  13.1 (15–79)

Female sex, No. (%)

644 (64.3)

632 (63.8)

Groups comparable at baseline?

Yes

10 mg of montelukast daily at bedtime during the 6-weeks

placebo daily at bedtime during the 6-weeks

Length of follow-up:

6 wk

Loss to follow-up

I: N= 89 (8.9%)

C: N= 84 (8.5%)

Reasons

I: clinical adverse experience (n=32), lack of efficacy (n=14), lost to follow-up (n=3) patient discontinued for other reasons (n=5), patient withdrew consent (n=10), protocol deviation (n=25)

C: clinical adverse experience (n=35), lack of efficacy (n=142, lost to follow-up (n=4) patient discontinued for other reasons (n=6), patient withdrew consent (n=4), protocol deviation (n=23)

 Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

The primary end point of daytime nasal symptoms

score (average of the nasal congestion, rhinorrhea, and sneezing

scores)

mean change from baseline

Primary end point

Daytime nasal symptoms score

Secondary end points

RQLQ score

throughout the entire 6 weeks of treatment.

Montelukast improved rhinitis-specific quality of life compared

with placebo: the difference between treatments in

mean change from baseline in the RQLQ score was

(95% CI,

Safety/adverse events

There were no clinically meaningful differences between the montelukast and placebo groups in the incidence of clinical

adverse experiences. Discontinuations due to adverse experiences

(I: n= 32 versus C: n=35)

Perennial AR

= Patel 2008 in SR Wei

Philip, 2005

Type of study:

RCT

Setting and country:

Multicenter (52 centers), US and Europe

Funding and conflicts of interest:

Supported by a grant from Merck Research

Laboratories, Rahway, NJ, USA.

Inclusion criteria:

-age 15 years–85 years old,

- ≥ 1-year clinical history of active asthma (including dyspnea, wheezing, chest tightness, cough)

and a ≥ 2-year clinical history of seasonal allergic rhinitis

(rhinitis symptoms exacerbating during allergy season).

Daily Rhinitis Symptoms at least mild-to-moderate in severity during the placebo run-in period.

positive skin test (wheal diameter

≥ 3 mm greater than control) to ≥ 3 allergens active during the study season.

Patients also had to meet ≥ 1 of

4 criteria for active asthma: asthma symptoms ≥ once

weekly, on average, during the 4 weeks before the first

visit; reversible airway obstruction (≥ 12% increase in

forced expiratory volume in 1 s (FEV1) after inhaled

short-acting β-agonist); history of methacholine hyperresponsiveness;

≥ 1-year history of exercise-induced

bronchoconstriction.

Patients on a stable dose of inhaled corticosteroid and/or inhaled long-acting β-agonist were

eligible.

Exclusion criteria:

Other confounding disorders, and medications for allergic rhinitis, conjunctivitis, ocular and other nasal symptoms, and other medications for asthma were not

allowed: these included antihistamines and decongestants;

oral, parenteral, nasal, and ophthalmic corticosteroids;

cromolyn sodium, nedocromil, theophylline, and inhaled anticholinergics; antileukotrienes such as zafirlukast and zileuton; and oral β-adrenergic agonists.

N total at baseline:

Montelukast: n = 415

Placebo: n = 416

Important prognostic factors²:

Age, years (range)

I: 33.0 ± 13.2 (15–78)

C: 33.6 ± 13.7 (15–80)

Sex, n (%) Female

I: 265 (63.9)

C: 269 (64.7)

Groups comparable at baseline?

Yes

oral montelukast 10 mg (n = 415) daily at bedtime during the 2-week active-treatment period

placebo (n = 416) daily at bedtime during the 2-week

active-treatment period

Length of follow-up:

2 wk

Loss to follow-up:

Montelukast

Discontinued

N = 15 (3.6%)

Clinical adverse

experience n=2 (0.5%)

Lost to follow-up

1 (0.2%)

Protocol deviation

4 (1.0%)

Lack of efficacy

3 (0.7%)

Other

5 (1.2%)

Placebo

Discontinued

N = 17 (4.1%)

Clinical adverse

experience

4 (1.0%)

Lost to follow-up

2 (0.5%)

Protocol deviation

6 (1.4%)

Lack of efficacy

3 (0.7%)

Other

2 (0.4%)

Incomplete outcome data:

-

Daily Rhinitis Symptoms score, defined as the mean of two components (DNSS, NSS)

Daytime Nasal Symptoms score

(average of nasal congestion, rhinorrhea, sneezing, and

itching, each rated on a 0–3 scale)

Nighttime Symptoms score (average of nasal congestion upon

awakening, difficulty going to sleep, and nighttime

awakenings, each rated on a 0–3 scale).

Daytime Eye Symptoms score (average of the individual symptoms of tearing, itching, red and puffy eyes).

Baseline efficacy measures

Daily rhinitis symptoms score

1.75 (0.42)

1.77 (0.42)

Daytime nasal symptoms score

2.07 (0.44)

2.07 (0.44)

Nighttime symptoms score

1.44 (0.55)

1.48 (0.56)

Daytime eye symptoms score

1.44 (0.75)

1.51 (0.78)

Rhinoconjunctivitis quality-of-life score

2.87(1.10)

2.95 (1.07)

Change from baseline (mean ± SD) Treatment difference (LS mean, 95% CI)

Montelukast

Placebo

Montelukast minus placebo

Primary endpoint

Daily rhinitis symptoms score

–0.35 ± 0.48

–0.24 ± 0.46

–0.12 (–0.18, –0.06)***

P<0.001

Components of primary endpoint

Daytime nasal symptoms score

–0.42 ± 0.58

–0.29 ± 0.53

–0.14 (–0.21, –0.07)***

P<0.001

Nighttime symptoms score –0.28 ± 0.47

 –0.20 ± 0.50

 –0.10 (–0.16, –0.04)***

P<0.001

Other endpoints

Daytime eye symptoms score

–0.29 ± 0.58

–0.24 ± 0.54

–0.08 (–0.15, –0.01)*

P<0.05

RQLQ

Change from baseline (mean ,sd)

Montelukast

–0.73 (1.14)

Placebo

–0.55 (1.10)

Treatment difference (LS mean, 95% CI)

Montelukast minus placebo

–0.22 (–0.36, –0.08)**

P<0.01

Adverse events

I: 49 (11.8%) and

C: 54 (13.0%)

The most frequently

reported adverse experiences (>1% incidence) were: in the montelukast treatment group – rash, 5 (1.2%) and headache, 4 (1.0%); in the placebo treatment group –

headache, 8 (1.9%); sinusitis, 5 (1.2%); nasopharyngitis,

5 (1.2%); and dry mouth, 4 (1.0%). There were no

clinically meaningful differences and no statistically significant differences between treatment groups in the incidence of clinical adverse experiences.

Subgroup allergic rhinitis and asthma

Trend > treatment effect in level of asthma (ns)

Hsieh, 2004

Type of study:

RCT

Setting and country:

Taiwan

Funding and conflicts of interest:

Not reported

Inclusion criteria:

-Age 6-12 yr

-known history of moderate to severe perennial allergic rhinitis for at least the previous 1 year.

Exclusion criteria:

-A positive response to any other allergen (other than allergy to house dust mite) was considered an exclusion criterion.

-Other exclusion criteria included any nasal abnormality,

concurrent purulent nasal infection, or any other significant medical condition. For all study participants, any current medication, which may have been perceived to affect any allergy symptoms, were discontinued as appropriate.

N total at baseline:

N= 65

N= 21 patients to the cetirizine group (10 mg daily),

N= 21 patients to the montelukast group (5 mg daily)

N= 22 patients to the placebo group.

Important prognostic factors²:

Sex (%M)

Cetrizine: 60%

Montelukast: 65%

Placebo: 55%

Age, year (sd)

Cetrizine: 8.05 (2.39)

Montelukast 8.20 (1.96)

Placebo 8.05 (1.82)

Groups comparable at baseline?

Yes

cetirizine group (10 mg daily),

montelukast group (5 mg daily)

placebo group.

Length of follow-up:

12 wk

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Of 65 patients entered into the study, 60 patients completed the study fully, 20 patients for each group.

Four of the original 65 patients were excluded from the study because their TSS recordings had not been performed during their treatment period (one from the cetirizine, one from the montelukast, and two from the placebo group). One patient from the placebo group failed to continue with the trial due to a lack of

medication efficacy.

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

TSS

Cetirizine and montelukast significantly reduced the mean TSS scores compared with the placebo group. Cetirizine appeared to be more efficacious than montelukast (Fig. 1).

Montelukast versus placebo (p<0.01)

Montelukast versus Cetrizine

(p<0.01)

C:

Baseline: 8.8

12 wk: 3.3

M:

Baseline: 8.9

12 wk: 6.2

P:

Baseline: 8.5

12 wk: 8.3

Pediatric Rhinoconjunctivitis

Quality of Life Questionnaires (PRQLQ).

23 items corresponding to five separate survey domains (nose symptoms,

eye symptoms, practical problems, other symptoms, and activities).

Data not reported?

PRQLQ: Cetirizine and montelukast significantly reduced the mean PRQLQ values compared with the

placebo group after 3 months of treatment (p , 0.01).

Adverse events

Cetrizine: n= 1 (sedation)

Montelukast: n=1 (headache)

Daily diary of nasal symptom score: Patients recorded their specific symptoms themselves every day, including four nasal symptoms (rhinorrhea, nasal stuffiness/congestion, nasal itching, and sneezing) and four nonnasal symptoms (eye itching/burning, eye tearing/watering, eye redness, itching of ears/or

palate).

Each symptom was scored on a four-point scale ranging from 0 to 3 as follows: 0, none (symptom

not noticeable); 1, mild (symptom noticeable but not bothersome); 2, moderate (symptom noticeable

and bothersome some of the time); and 3, severe (symptom bothersome most of the time and/or

very bothersome some of the time).

The total symptom score (TSS) was the sum including nasal and nonnasal symptom scores. The average baseline TSS and each symptom score were calculated as the

mean of the daily score during the baseline study period of 7 days. Subsequent to the baseline study period, the mean TSS and individual symptom scores were based upon diary scores for the previous 28 days at weeks 4, 8, and 12.

PRQLQ: The PRQLQ features 23 items corresponding to five separate survey domains (nose symptoms,

eye symptoms, practical problems, other symptoms, and activities). Questionnaire respondents provided

their response according to a seven-point scale, the children typically completing the questionnaire within

5 minutes.

Kurowski, 2004

Type of study:

RCT

Setting and country:

Poland

Funding and conflicts of interest:

‘This study was supported by a grant from the Medical University of

Łodz´ .

Inclusion criteria

Patients of both sexes aged 18–35 years

-history of seasonal AR symptoms for 2 years or more and positive skin prick test to a mixture of grasses or grasses/cereals allergens.

Exclusion criteria:

Patients diagnosed with bronchial asthma,

having polyvalent pollen allergy, suffering from rhinitis outside the pollen season,

using specific immunotherapy, or participating in another drug efficacy trial during 4-week period preceding the study were not considered eligible for inclusion.

N total at baseline: n=60

Group A: n=11

Group B: n=11

Group C: n=19

Group D: n=19

Important prognostic factors²:

Age (years), mean (SD):

Group A (placebo): 24.15 (5.41)

Group B (MNT): 25.45 (4.30)

Group C (CET): 23.68 (4.68)

Group D (MNT + CET): 25.40 (5.34)

Sex: M/F

Group A (placebo): 8/3

Group B (MNT): 8/3

Group C (CET): 15/4

Group D (MNT + CET): 15/4

Groups comparable at baseline? Yes

group A, placebo for both cetirizine and montelukast before the expected beginning of grass pollen season (i.e. before May 15)

and active cetirizine 10mg/day plus active montelukast 10mg/day

after May 15;

group B, active montelukast 10mg/day plus placebo

for cetirizine;

group C, active cetirizine 10mg/day plus placebo for

montelukast;

group D, active cetirizine 10mg/day plus active montelukast 10mg/day throughout the study period

Length of follow-up:

12 wk

Loss to follow-up:

A: n=2

B: n=2

C: n=5

D: n=3

Reasons for discontinuation

Group A:

Exacerbation of symptoms n=2

Group B:

Exacerbation of symptoms n=1, Lost to follow-up n=1

Group C:

Violation of protocol n=1, Lost to follow-up n=4

Group D:

Exacerbation of symptoms n=1, Lost to follow-up n=2

Incomplete outcome data:

Overall? NO sign dif, A<B<C

Fig. 4 all-symptom score

= mean Symptom scores (mean ± SEM) Rhinorrhea , Sneezing, Nose itching, Eye itching, Lacrimation

Fig. 3

Nose itching p<0.05 B versus A

Sneezing p < 0.05 C versus A

effects of 6-week pretreatment

of seasonal allergic rhinitis (AR)

New criteria part of the study population would be classified as having persistent AR

Study reference

(first author, publication year)

Describe method of randomisation¹

Bias due to inadequate concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

Rajashekar, 2018

‘The enrolled subjects

were randomly divided into three groups and were received

following oral treatment for 3 weeks, once daily post cibum

at 8:00 PM.’

Unclear

Unlikely,

Drug treatment was double-blinded for both investigators and

patients.

Unlikely

Unlikely,

Drug treatment was double-blinded for both investigators and

patients.

unclear

Unclear

unclear

Kaur, 2017

‘All the patients were randomly divided into five groups of 25 each’

Unclear

unclear

unclear

unclear

unlikely

unlikely

unlikely

Andhale, 2016

‘Randomly studied’

Unclear

Likely

Likely

Likely

Unlikely

Unclear

Unlikely

Ciebada, 2011

‘Each patient received medications in crossover, blinded fashion.’

Unclear

Unlikely

Unlikely

Unlikely

Unclear

Unclear

Unlikely

Bisgaard, 2009

unclear

unclear

unlikely

unlikely

unlikely

Unclear

unclear

unclear

Okubo, 2008

‘The patients were randomized in a 1 : 1 : 1 ratio to receive

either montelukast 5 mg, 10 mg, or placebo groups.’

Unclear

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Likely

Chen, 2006

‘A randomized, double-blind, placebo-controlled, parallel-group study design was used. Patients were divided into three groups, 20 for each group, (…)‘

Unclear

unlikely

unlikely

unlikely

unlikely

unlikely

Unlikely

Ciebada, 2006

‘Eligible patients were randomly assigned to the group receiving montelukast alone, desloratadine

alone, both agents, or placebo (20 patients) or to the group receiving montelukast alone, levocetirizine alone, both agents, or placebo (20 patients). The sequence of treatment

was randomly assigned.’

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

Lombardo, 2006

Not described.

Unclear

unlikely

unlikely

unlikely

unlikely

Unlikely

unclear (Itt, however excluded patients from analysis: lack of efficacy and protocol deviation, small number of patients, all study arms)

Patel, 2005

“After a single-blind, placebo run-in period of 5 to 7 days, patients

were randomized (using a computer-generated schedule)

Unlikely

unlikely

unlikely

Unlikely

Unlikely

Unlikely

Unlikely (stopped lack of efficacy in both groups)

Philip, 2005

‘Following a singleblind

placebo run-in period of 3 days–5 days, patients were randomized (using a computer-generated

schedule) to oral montelukast 10 mg (n = 415) or placebo (n = 416) daily at bedtime during the 2-week

active-treatment period.’

Unlikely

Unlikely, double-blind, double-dummy study

Unlikely, double-blind, double dummy study

Unlikely, double blind, double dummy study

Unlikely

Unlikely

Unclear (excluded patients from analysis: lack of efficacy and protocol deviation, however small number of patients, all study arms)

Hsieh, 2004

‘By means of a computer-generated randomization code, survey-qualifying patients were assigned to one of the three treatment groups’

Unlikely

Unlikely, double-blinded, parallel-group, placebo-controlled design

Unlikely, double-blinded, parallel-group, placebo-controlled design

Unlikely, double-blinded, parallel-group, placebo-controlled design

Unlikely

Unclear

Unlikely

Kurowski, 2004

‘Patients were randomly assigned to one of the following treatments:group A, placebo for both cetirizine and montelukast before

the expected beginning of grass pollen season (i.e. before May 15)

and active cetirizine 10mg/day plus active montelukast 10mg/day after May 15; group B, active montelukast 10mg/day plus placebo for cetirizine; group C, active cetirizine 10mg/day plus placebo for

montelukast; and group D, active cetirizine 10mg/day plus active montelukast 10mg/day throughout the study period.’

unclear

Unlikely, double blind, parallel-group, placebo-controlled

study

Unlikely, double blind, parallel-group, placebo-controlled

study

Unlikely, double blind, parallel-group, placebo-controlled

study

unlikely

Likely, reasons for study discontinuation : exacerbation of symptoms, violation of protocol, Lost to follow-up

Unlikely