Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Lohia,

2012

(individual study characteristics deduced from (1st author,

year of publication

))

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of RCTs

Literature search:

- PubMed (1950 to May 2012) and

- Cochrane Library (May 2012)

- MEDLINE database (January 1966 to May 2012)

A: Agondi, 2008

B: Baiardini, 2001

C: Corren, 1992

D: Dahl, 2005

E: Henriksen, 1984

F: Katial, 2010

G: Kersten, 2012

H: Nair, 2010

I: Nathan, 2005

J: Pedersen, 1990

K: Pedersen, 1998

L: Pedroletti, 2008

M: Reed, 1998

N: Sandrini, 2003

O: Scichilone, 2010

P: Stelmach, 2005

Q: Thio, 2000

R: Watson, 1993

Study design:

RCT parallel: R, H, J, K. cross-over: A – G, I, L - Q

Setting and Country:

Not reported

Source of funding and conflicts of interest:

Review has no source of funding or conflicts of interest. Source of funding or support was not indicated for each of the included studies.

Inclusion criteria SR:

- Randomized controlled trials (RCTs)

- evaluating the efficacy of INCS medications

- on adults or children

- if studies assessed at least one asthma-specific clinical outcome

measure, to include pulmonary function, bronchial reactivity,

asthma symptom scores, asthma-specific quality of life, or use of rescue medications.

- Single and double-blind studies were both included, as were appropriate crossover trials.

- clear diagnostic criteria for AR and asthma. The diagnosis of AR was established based on typical symptoms plus a positive skin prick test or serumspecific IgE to at least one inhalant allergen. Diagnosis of

asthma was established by clinical symptoms and physiologic features, the Global Initiative for Asthma (GINA) criteria,

or the American Thoracic Society (ATS) criteria.

- interventions: INCS spray versus placebo, INCS spray plus asthma-specific medications versus

placebo nasal spray plus asthma-specific medications and

nasally inhaled corticosteroid versus placebo.

- Standard asthma

medications could include short and long acting beta-agonists,

orally inhaled corticosteroids, systemic corticosteroids (oral or parenteral), leukotriene receptor antagonists, 5-lipoxygenase inhibitors, ipratropium bromide, sodium cromoglycate,

and theophylline.

- To isolate the impact of nasal therapies, studies were included only if asthma medications

remained constant throughout the study and the only variable

that changed was the nasal therapy

Exclusion criteria SR:

If studies assessed the efficacy of two or more treatments simultaneously, had a washout period <1 week between treatments, or did not have a placebo control group.

18 studies included

Important patient characteristics at baseline:

N, mean age

Not reported, studies included children, adults or a mixed group

A: 30, mixed

B: 51, adults

C: 18, adults

D: 236, mixed

E: 36, children

F: 366, adults

G: 25, children

H: 25, adults

I: 509, adults

J: 30, adults

K: 24, children

L: 40, children

M: 74, mixed

N: 16, adults

O: 17, adults

P: 54, adults

Q: 93, adults

R: 42, children

Sex:

Not reported

Groups comparable at baseline?

yes

Describe intervention:

BDP, beclomethasone dipropionate;

MMF, mometasone furoate;

FP, fluticasone propionate;

FF, fluticasone furoate; TA, triamcinolone acetonide;

A: BDP nasal spray

B: MMF nasal spray

C: BDP nasal spray

D: 1. FP nasal spray

2. FP nasal spray, orally inhaled FP

E: BPD nasal spray

F: FP nasal spray, orally inhaled FP/salmeterol

G: FF nasal spray

H: FP nasal spray, orally inhaled

I: FP nasal spray

J: Nasally inhaled budesonide

K: Nasally inhaled budesonide

L: MMF nasal spray

M: 1. Flunisolide nasal spray

2. Beclomethasone nasal spray

N: TA nasal spray

O: Budesonide nasal spray

P: 1. BDP nasal spray; placebo inhaler

2. BDP nasal spray; orally inhaled BDP

Q: 1. FP nasal spray

2. FP nasal spray

3. BDP nasal spray

R: BDP nasal spray

Describe control:

All studies included one control arm with administration of a placebo nasal spray unless noted otherwise

H: Placebo nasal spray, orally inhaled FP

P: 3. Placebo nasal spray; placebo inhaler

4. Placebo nasal spray; orally inhaled BPD

End-point of follow-up:

A: 125 days

B: 4 weeks

C: 7 weeks

D: 6 weeks

E: 4 weeks

F: 4 weeks

G: 22 ± 3 days

H: 12 weeks

I: 4 weeks

J: 2 weeks

K: 1 weeks

L: 4 weeks

M: 4 weeks

N: 4 weeks

O: 2 weeks

P: 16 weeks

Q: 6 weeks

R: 4 weeks

For how many participants were no complete outcome data available?

Studies included a total of 2162 patients, of which 1659 completed the full study and 503 withdrew or dropped out.

FEV1

Defined as Forced Expiratory Volume in 1 s

INCS spray to placebo

Effect measure: standardized mean difference. Pooled effect (random effects model): 0.21 (95% CI -0.05 to 0.47) favoring INCS spray

Heterogeneity (I²): 0%

INCS spray in addition to baseline administration of orally inhaled corticosteroids

Effect measure: standardized mean difference. Pooled effect (random effects model): 0.04 (95% CI -0.15 to 0.22) not favoring any treatment group

Heterogeneity (I²): 0%

Asthma symptom scores

INCS spray to placebo

Effect measure: standardized mean difference. Pooled effect (random effects model): 0.61 (95% CI 0.02 to 1.20) favoring INCS spray

Heterogeneity (I²): 71%

INCS spray in addition to baseline administration of orally inhaled corticosteroids

Effect measure: standardized mean difference. Pooled effect (random effects model): 0.04 (95% CI -0.15 to 0.22) not favoring any treatment group

Heterogeneity (I²): 0%

Nasal inhalation versus placebo (mean± SD)

Nasal inhalation

Trial 1 2,67 ± 0,31

Trial 2 2,08 ± 0,42

Placebo

Trial 1 3,27 ± 0,24

Trial 2 1,09 ± 0,42

Rescue medication use

INCS spray to placebo

Effect measure: standardized mean difference. Pooled effect (random effects model): 0.29 (95% CI 0.01 to 0.58) favoring INCS spray

Heterogeneity (I²): 73%

INCS spray in addition to baseline administration of orally inhaled corticosteroids

Effect measure: standardized mean difference. Pooled effect (random effects model): 0.00 (95% CI -0.14 to 0.15) not favoring any treatment group

Heterogeneity (I²): 0%

Facultative:

The results of this meta-analysis demonstrated that intranasal corticosteroid medications significantly improve some asthma-specific outcome measures in patients

suffering from both AR and asthma. This effect was most pronounced with INCS

sprays when patients were not on orally inhaled corticosteroids, or when corticosteroid medications were inhaled through the nose into the lungs. Overall, intranasal corticosteroid medications improve some asthma-specific outcome measures in patients with both AR and asthma. Further research is needed to clarify the role of INCS sprays as asthma-specific therapy, as well as the role of the nasal

inhalation technique as a monotherapy in patients suffering from both asthma

and AR.

Study

First author, year

Appropriate and clearly focused question?

Yes/no/unclear

Comprehensive and systematic literature search?

Yes/no/unclear

Description of included and excluded studies?

Yes/no/unclear

Description of relevant characteristics of included studies?

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?

Yes/no/unclear/not applicable

Assessment of scientific quality of included studies?

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?

Yes/no/unclear

Potential risk of publication bias taken into account?

Yes/no/unclear

Potential conflicts of interest reported?

Lohia, 2012

Yes, the objective of this study was to perform an updated systematic review with meta-analysis assessing the impact of

INCS medications upon asthma outcomes in patients with AR and comorbid asthma.

yes

Yes

yes

Not applicable

Yes, Risk of bias for each study was evaluated using the Cochrane ‘Risk of bias’ tool, including selection bias

(random sequence generation and allocation concealment),

performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessment), attrition bias

(incomplete outcome data), and reporting bias (selective reporting)

yes

Yes, publication bias could not be assessed because there were fewer than 10 included studies per outcome measure.

No, source of funding or support was not indicated for each of the included studies.

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Aaronson, 1996

Type of study:

double-blind, randomized,

parallel, placebo-controlled

trial

Setting and country:

Aaronson Asthma and Allergy Associates, USA.

Funding and conflicts of interest:

Not reported

Inclusion criteria:

- Patients from 12 to 65 years old and had positive skin tests for allergens that correlated clinically with their disease.

- At study entry, each patient had to have a history of perennial bronchial asthma without significant seasonal exacerbation for at least the last 2 years, and a forced expiratory volume in one second (FEV1) of at least 50% predicted normal that improved by at least 15% within 15 minutes after inhaling albuterol.

Exclusion criteria:

- Females who were pregnant, lactating,

or not using reliable contraceptive

measures.

- Patients with a concomitant illness that might interfere with the evaluation of the clinical response, such as acute sinusitis, nasal polyposis, otitis media, upper respiratory infection, or underlying systemic illness

- Patients with an FEV1 less than 50% predicted at baseline;

- Patients with a history of intolerance to antihistamines or bronchodilators.

- Patients who had taken inhaled or intranasal steroids or cromolyn sodium during the 2 weeks prior to the study;

- those who had taken antihistamines during the 48 hours prior to the study and astemizole for 6 weeks prior to the

study;

- those who had taken oral corticosteroids during the week prior to the study. All of these medications were also withheld throughout the study; however, two 5-day prednisone bursts were allowed for the management of infection-related asthma flares or acute asthma exacerbations.

N total at baseline: 28

Intervention: not described

Control: not described

Important prognostic factors²:

Mean age (range):

29.7 years (13.3 to 59.1)

Sex:

46 % M

Author did only describe age and sex of all patients

Groups comparable at baseline?

Not described

Describe intervention (treatment/procedure/test)

20 mg of cetirizine each evening after the peak flow measurement

Describe control (treatment/procedure/test):

Placebo, no details described

Length of follow-up:

26 weeks

Loss-to-follow-up:

Intervention:

N (%) 4

Reasons: not described

Control:

N (%) 6

Reasons:

Two patients discontinued due to lack of efficacy. Other reasons not described.

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

Results were derived from figures, since the authors did not report them separately.

10-point descriptive scale in which 0 was none and 9 was unbearable.

Mean daily total rhinitis symptom scores (MDRT)

The determination of MDRT included an assessment of sneezing, nasal congestion,

itching of eyes, itching of nose,

postnasal drip, runny nose, and watery eyes, each rated on a simple 10-point descriptive scale in which 0 was none and 9 was unbearable.

Although not statistically significant, the reduction in total rhinitis scores including (Fig 3A) nasal congestion, was greater at most time points for patients treated with cetirizine (5 points at end study) than for patients given Placebo (11 points at end study).

Asthmatic symptoms

Symptoms of asthma were evaluated on a 10-point scale twice daily by each patient.

These symptoms included chest tightness, wheezing, shortness of breath, cough, sputum production, and nocturnal asthma. Statistically significant differences between cetirizine and placebo were observed in the assessment of chest tightness at visits 7, 10, 12, 13 and 14; in the assessment of wheezing at visits 10, 11, and 14; and in the assessment of shortness of breath at visits 7 and 10 through 14 (Fig 4A–C). Cetirizine was judged by patients to be effective

throughout the day, as very little difference was observed between the mean morning and evening scores for these three symptoms. In addition,

the mean scores for nocturnal asthma were lower at each visit for patients receiving cetirizine than for patients

receiving placebo, and a statistically significant difference was observed

between the treatment groups at visit 7 (Fig 4D). No significant treatment effect was seen for the symptoms of

cough and sputum production (Fig 5A and B).

FEV1

No statistically significant differences were seen between the cetirizine group

and the placebo group for FEV1 at any evaluation point of the study.

Albuterol puffs

At all visits, patients in the cetirizine group reported a lower mean number of albuterol puffs (Fig 6A), but these differences were not statistically significant. Mean number of albuterol puffs were significantly higher in the evening (both treatment groups). There was no time or treatment effect for pseudoephedrine use.

Adverse events

Adverse events were reported by four patients (28,6%) after taking placebo and by two patients (14,3%) after taking cetirizine (RR: 0,50; 95% CI: 0,11 – 2,30).

Only one event, drowsiness, of moderate severity, was considered to be related to cetirizine use.

Berger, 2002

Type of study:

multicenter, parallel-group, double-blind study

Setting and country:

United States

Funding and conflicts of interest:

Not described

Inclusion criteria:

15 years of age or older with a minimum 2-year history of SAR and increased asthma signs or symptoms in conjunction with

fall/winter allergy season.

- Clinically

symptomatic at screening, with moderate nasal rhinorrhea, a total nasal symptom score of at least 6, a total nonnasal score of at least 5, and mild seasonal allergic asthma exacerbations

(see Evaluation Criteria and Table 1). Subjects were also

required to have had a forced expiratory volume in 1 second

(FEV1) ≥70% of predicted value and a total frequency of

asthma score and/or bronchodilator use of a least 2 at the

screening visit, and to have demonstrated reversibility with an inhaled bronchodilator within the past 2 years. Reversibility was defined as an increase in absolute FEV1 ≥12% over the baseline value and an absolute volume increase of ≥200 mL after administration of an inhaled bronchodilator. Forced expiratory flow rate between 25 and 75% of vital capacity.

All subjects had a positive immunoglobulin E-mediated skin test response to a relevant allergen (wheal

diameters of 3 mm (skin prick) or 7 mm (intradermal) larger

than control) within 24 months of screening. All subjects

were in general good health as determined by clinical evaluation

and laboratory tests.

Exclusion criteria:

Exclusion criteria included the use of chronic inhaled or

systemic corticosteroids, current or frequent clinically significant

upper airway disease, structural nasal abnormalities, and

an FEV1 of 70% or less of predicted normal value. Use of nasal, oral, or ocular decongestants, nasal topical antihistamines,

and corticosteroids was prohibited.

Immunotherapy

(vaccination) was permitted if it was given on a regular

schedule and was maintained throughout the trial. The use of

bronchodilators was restricted to inhaled albuterol as a rescue

treatment to control asthma symptoms.

N total at baseline:

Intervention: 168

Control: 163

Important prognostic factors²:

Age (range):

I: 32.5 (15-75)

C: 32.0 (15-73)

Sex:

I: 38% M

C: 30% M

Mean SAR duration, years (range)

I: 21.2 (2–73)

C: 19.4 (2–66)

Mean asthma duration, years (range)

I: 16.7 (1–73)

C: 16.0 (<1–66)

Groups comparable at baseline?

yes

Describe intervention (treatment/procedure/test):

Desloratadine 5-mg tablets administered orally once daily in the morning for 4 weeks

Describe control (treatment/procedure/test):

Identical placebo tablets administered orally once daily in the morning for 4 weeks.

Length of follow-up:

29 days

Loss-to-follow-up:

Intervention:

N (%) 2 (1.2%)

Reasons: not described

Control:

N (%) 3 (1.8%)

Reasons: not described

Incomplete outcome data:

Intervention:

N (%) 47 (9%)

Control:

N (%) 32 (20%)

Reasons: authors only stated that reasons for discontinuation were similar, except that more subjects receiving placebo (n = 14) failed treatment compared

with those receiving desloratadine (n = 6).

General reasons for discontinuation were: patients were noncompliant or experienced an exacerbation

of SAR, significant AEs, or significant laboratory

abnormalities.

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

Subjects completed diary cards (with assistance from the

parent/guardian, if needed) twice daily: upon arising (AM) and approximately 12 hours later (PM). Subjects scored the severity of individual SAR and asthma signs and symptoms at that moment (instantaneous) and for the previous 12 hours (reflective) on a 4-point scale (Table 1). The morning scores were recorded before taking the medication. Severity graded as 0 = none; 1 = mild (clearly present but minimal awareness, easily tolerated), 2 = moderate (definite awareness, bothersome but tolerable), or 3 = severe (hard to tolerate, may have interfered with activities of daily living and/or sleeping).

Mean AM/PM reflective total symptom score (TSS), expressed as the change from baseline for the averages of days 1 to 15, with additional analyses at days 1 to 29.

Desloratadine significantly reduced the primary efficacy variable, the mean AM/PM reflective TSS, over days 1 to 15

(-4.90) compared with placebo (-2.98; P < 0.001; Fig 1).

These reductions appeared on day 1 and continued over the

entire 4-week treatment period.

AM instantaneous TSS

Desloratadine significantly reduced the mean AM instantaneous TSS at the first study timepoint (-2.57 versus -0.85, respectively; P < 0.001) and throughout the whole study, day 2-29 (-4.54 versus -2.99, respectively; P = 0.002) (Table 5).

AM/PM reflective total asthma symptom score

Desloratadine reduced the mean AM/PM reflective total

asthma symptom score over days 1 to 15 (-1.35) compared

with placebo (-0.94; P < 0.023; Fig 4). Compared with placebo, total asthma symptom scores improved over the

entire treatment period: -1.18 (control) versus -1.54 (desloratadine) (P = 0.055).

Number of uses of β-agonist rescue medication

Desloratadine also reduced the number of times β-agonist inhalers were used for days 1 to 15 (P = 0.031), and the reduction in inhaler use approached statistical significance for days 1 to 29 (P = 0.087)

Adverse events (Any adverse clinical change experienced during the study, irrespective of its relationship to study drug(s), was considered an AE.)

Desloratadine was safe and well tolerated. The number and

type of treatment-related AEs were similar among the treatment groups: 26 (15.5%) subjects treated with desloratadine and 23 (14.1%) subjects receiving placebo reported AEs (RR: 1,10; 95CI: 0,65 – 1,84).

Among desloratadine-treated subjects, the most frequently reported treatment-related AEs were headache (3.0%) and fatigue (2.4%); nausea or dry mouth occurred in 1.2% of patients. Among patients in the placebo group, headache (3.7%), dry mouth (2.5%), and nausea (2.5%) were most commonly reported. Fatigue occurred in <1% of patients taking placebo. Most treatment-related AEs were mild or moderate in severity. There were no cardiovascular AEs, heart rate/rhythm disorders, or ECG changes, including QTc interval changes, reported in desloratadine-treated subjects. One subject receiving placebo developed palpitations unrelated to treatment.

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)

Aaronson, 1995

Not described

Unclear, method of randomisation not described

Unlikely, both investigators and patients were blinded to the treatment regimen

Unlikely, both investigators and patients were blinded to the treatment regimen

Unlikely, both investigators and patients were blinded to the treatment regimen

Unlikely, authors all outcomes that were reported at method section were described

Unclear, 10 of 28 patients were lost to follow-up. Two patients discontinued due to lack of efficacy. Other reasons were not described.

Unlikely. Authors reported that study data were analyzed based on the intent-to-treat principle. However exact numbers of patients participating in intervention or control group are missing.

Berger, 2001

Not described

Unclear, method of randomisation not described

Unlikely, authors state this is a double blinded study, but no more information is given

Unlikely, authors state this is a double blinded study, but no more information is given

Unclear, authors state this is a double blinded study, but no more information is given

Unlikely, authors all outcomes that were reported at method section were described

Unlikely, loss-to-follow-up for intervention group was: 2 (1.2%) and the control group: 3 (1.8%)

However reasons were not described.

Unlikely, patients were analyzed in the intervention groups to which they were randomized.