Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Salvi, 2015

Type of study:

RCT

Setting and country:

Funding and conflicts of interest:

Inclusion criteria:

- aged 18-75 yrs

- euthyroid for at least 6-8 weeks (based on normal free thyroid hormone concentrations)

- affected with active GO (CAS of 4 of 10, ≥3 of 7), moderate to severe degree (NOSPECS)

Exclusion criteria:

N total at baseline:

Intervention: 16

Control: 16

Important prognostic factors²:

Age ± SD:

I:51.9±13.1

C: 50.4±11.4

Sex:

I: 93% M

C: 75% M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Rituximab (RTX), initially infused 1000 mg twice at a 2-week interval, 10 placebo infusions. After 12 patients, a single dose of 500 mg RTX was used (and 11 placebo infusions)

Premedicated with oral paracetamol, chlorphenamine and 100 mg iv hydrocortisone

Describe control (treatment/procedure/test):

Iv methylprednisolone (ivMP): proton pump inhibitors (prevention of gastric bleeding), calcium and vitamin D supplementation and bisphosphonate administration (prevention of steroid-induced osteoporosis)

Length of follow-up:

52 weeks.

Primary endpoint was at 24 weeks.

Loss-to-follow-up:

Intervention:

N=1 (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

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

Quality of life

Improvement of at least 6 points:

I, 24 weeks: 33,7%

C, 24 weeks: 61.5%

I, 52 weeks: 76.9%

C, 52 weeks: 53.8%

CAS

Reduction of ≥2 points

I, 24 weeks: 100%

C, 24 weeks: 75%

P=NS

CAS<3

I, 24 weeks: 100%

C, 24 weeks: 68.7%

P=0.043

CAS at 24 weeks (mean±SD):

I: 0.6±0.3

C: 2.3±0.5

P<0.006

NOSPECS

Reduction of ≥2 NOSPECS classes.

I: 20% (3/15)

C: 18,8% (3/16)

Not significant

Adverse evens

I: 86.6% (13/15)

C: 62.5% (10/16)

The study was stopped based on interim analyses on 32 patients, as disease reactivation in the ivMP group was noted, but not in the RTX group.

Stan, 2015

Type of study:

Prospective, double-masked RCT

Setting and country:

Academic private practice in the USA

Funding and conflicts of interest:

No industry involved, authors had nothing to disclose

Inclusion criteria:

Age 18-80 yrs

- moderate-to-severe and active GO with clinical activity score (CAS)≥4/7

- euthyroid for at least 6 weeks

- evidence of disease progression during the previous 2 months or lack of improvement in the prior 6 months. Previous steroid treatment was acceptable if discontinued ≥4 weeks before enrolment.

Exclusion criteria:

Evidence of dysthyroid optic neuropathy (DON) or impending DON, contraindicatinos to therapy with RTX; prior arbitol radiotherapy or decompression surgery or recent improvement in the disease.

N total at baseline:

Intervention: 13

Control: 12

Important prognostic factors²:

Age ± SD:

I:57.6±12.7

C: 61.8±11.0

Sex:

I: 31% M

C: 33% M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Rituximab, 1000 mg intravenous administered at baseline and 2 weeks later, preceded by acetaminophen and 100 mg of methylprednisolone 1h before the infusion (standard premedication)

Describe control (treatment/procedure/test):

1 L of normal saline, acetaminophen and 100 cm3 normal saline on the same schedule.

Length of follow-up:

24 weeks intervention (primary endpoint); follow-up for 52 weeks

Loss-to-follow-up (primary endpoint):

Intervention:

N=2 (%)

Reasons: disease progression, adverse event

Control:

N=2 (%)

Reasons: disease progression, personal reasons

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

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

Clinical activity score

Change after 24 weeks

I: 1.2±2

C: 1.5±1.8

P=0.73

Response (≥2 points)

I: 31%

C: 25%

P=0.75

Quality of life (SF-12)

Did not differ between groups. Both groups improved.

NOSPECS

-

Adverse events

I: 11x (in 8/13 patients)

C: 4x (in 3/12 patients)

Savino, 2015

Type of study:

RCT

Setting and country:

Funding and conflicts of interest:

Inclusion criteria:

Moderately severe TAO in the active phase arisen in the preceding 6 months, primary disease, previous

therapies with thyrostatic and/or surgical thyroidectomy, or

radioiodine therapy

Exclusion criteria:

TAO in the chronic phase,

pregnancy, breast feeding, unstable heart disease, association with other therapies, bowel disease, previous i.v. GCs therapy, and oral GCs treatment in the preceding 3 months

N total at baseline:

Intervention: 10

Control: 10

Important prognostic factors²:

Age, median (range)

I: 56.2 (45-70)

C: 57.3 (39-78)

Sex:

I: 40% M

C: 30% M

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Rituximab, intraorbital injection (100 mg/10 ml) in both eyes at a dose of 10 mg,

once a week for one month (four injections/month).

In all the patients, 5 ml of solution was injected in the retrobulbar space, seven patients had the remaining

5 ml of solution injected in the superior pre and postseptal lid

space and three patients in the inferior pre and postseptal lid

space. Patients were then treated with levofloxacin ophthalmic

eye drops, which were applied four times daily for

7 days and bandaged.

Describe control (treatment/procedure/test):

Systemic glucocorticoids intravenous pulse therapy, consisting of 500 mg/week of methylprednisolone

for 6 weeks and 250 mg/week for 6 weeks.

Length of follow-up:

20 weeks follow-up

Loss-to-follow-up:

Intervention:

N =1 (10%)

Reasons: progressed to severe TAO

Control:

N=0 (0%)

Reasons: -

Incomplete outcome data:

See above

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

Clinical Activity Score (CAS)

(read from graphs, by approach)

I baseline: 6

I 20 weeks: 3

C baseline: 6.5

C 20 weeks: 3

NOSPECS

Comparison

between t0 and t3 of both groups was not significant.

Side effects:

I: minor side effectsL nausea and mild temperature elevation (n=2)

C: minor adverse reactions, including frequent skin flushes during infusion, mild cushingoid features (four patients), mild increase in blood pressure (not requiring therapy) (three

patients), mild gastric symptoms controlled by omeprazole (one patient), and mild weight gain (two patients). None of

the patients had relevant hepatotoxicity, defined as a fourfold

or greater increase in serum liver enzymes.

Kahaly, 2018

Type of study:

Observer-masked, open-label RCT

Setting and country:

Multicentre, Germany and Italy

Funding and conflicts of interest:

Funded by Novartis (industry)

Inclusion criteria:

- Aged 18–75 years

- Euthyroidism for at least 2 months with antithyroid

drugs or after thyroidectomy, or 6 months after

radioiodine administration

- had active, thyroid eye

disease (clinical activity score of 3–7) that was

moderate to severe (moderate-to-severe active soft tissue involvement (according to the EUGOGO colour atlas

evaluation), proptosis ≥22 mm, eye muscle involvement with mono-ocular ductions in any direction of gaze of less than 30° or evident dysmotility, or diplopia

(Gorman score of grade 1–3)).

- not have received previous immunosuppressive

treatment for Graves’ orbitopathy, or received corticosteroids or other immunosuppressive agents within the past 3 months for any reason.

Exclusion criteria:

Optic neuropathy, acute or chronic viral hepatitis, any relevant malignancy, or chronic renal failure

N total at baseline:

Intervention: 83

Control: 81

Important prognostic factors²:

Age ± SD:

I:52.1±10.1

C: 50.6±10.0

Sex:

I:27 % M

C: 21% M

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Mycophenolate, orally one tablet (360 mg) twice per day for 24 weeks, plus Methylprednisolone, intravenous, 500 mg per week for 6 weeks, followed by 250 mg per week for 6 weeks.

Describe control (treatment/procedure/test):

Methylprednisolon, intravenous, 500 mg per week for 6 weeks, followed by 250 mg per week for 6 weeks with a cumulative dose of 4·5 g.7.

Length of follow-up:

24 weeks

Loss-to-follow-up:

Intervention:

N=10 (12%)

Reasons: withdrew consent (n=4); lost to follow-up (n=5); Hyperthryoidism (n=1)

Control:

N=13 (8.4%)

Reasons: withdrew consent (n=7), thyroidectomy (n=1); lost to follow-up (n=3); CAS<3 (n=2)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N=13 (14.3%)

Reasons: see above

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

Quality of life (EUGOGO)

Adjusted mean between-group difference (95%CI)

12 weeks: -1.57 (-6.60, 3.45), p=0.54

24 weeks: -0.29 (-6.44, 5.86), p=0.93

36 weeks: 0.58 (-6.57, 7.73), p=0.87

Clinical activity score

Adjusted mean between-group difference (95%CI)

Right eye

12 weeks: 0.21 (-0.19, 0.60), p=0.30

24 weeks: -0.04 (-0.49, 0.40), p=0.84

36 weeks: 0.00 (-0.45, 0.45), p=1.0

Left eye

12 weeks: 0.43 (0.01, 0.85), p=0.047

24 weeks: 0.05 (-0.41, 0.50), p=0.84

36 weeks: 0.02 (-0.41, 0.45), p=0.93

Respons after 12 weeks

I: 64%

C: 49%

OR=1.76, 95%CI 0.92, 3.39, p=0.09).

Clinical severity score (NOSPECS)

Adjusted mean between-group difference (95%CI)

Right eye

12 weeks: -0.01 (-0.94, 0.92), p=0.98

24 weeks: -0.24 (-0.84, 0.37), p=0.44

36 weeks: -0.38 (-1.07, 0.32), p=0.29

Left eye

12 weeks: 0.41 (-0.22, 1.04), p=0.20

24 weeks: 0.014 (-0.63, 0.66), p=0.97

36 weeks: -0.03 (-0.82, 0.75), p=0.93

Complications

Adverse events

Complications

I: 25% patients; 39 side effects

C: 20%; 29 side effects

P=0.48

Gastrointestinal disorders: (I:10x, C: 5x)

Infections and infestations: I: 5x, C: 5x

Vascular disorders: I:2x; C: 5x

Ye, 2017

Type of study:

RCT

Setting and country:

Medical center in China

Funding and conflicts of interest:

Funded by the National Natural Science Foundation of China.

There are no conflicts of interests

Inclusion criteria:

Active moderate-to-severe GO

Age 16–70 years with

active GO (defined by a clinical activity score (CAS) of 4 of 10 or

greater15), of moderate-to-severe degree (as defined by the NOSPECS

score16), euthyroid for at least 6–8 weeks (defined by normal

free thyroid hormone levels), with evidence of disease

progression during the previous 8 weeks or lack of improvement

in the prior 24 weeks and normal heart, liver and kidney function.

Patients with previous steroid treatment who had been discontinued

for at least 12 weeks were included in the study

Exclusion criteria:

evidence of dysthyroid optic

neuropathy and impaired heart, liver and kidney function, contraindications

to therapy with MMF or GC, prior orbital radiotherapy

or decompression surgery, or recent improvement in the

disease. Patients who received any immunosuppressive therapy

or radiotherapy in the previous 12 weeks were also excluded.

N total at baseline:

Intervention: 87

Control: 87

Important prognostic factors²:

Age ± SD:

I: 40.7±14.5

C: 41.4±13.7

Sex:

I: 34% M

C: 32% M

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

Mycophenolate mofetil (MMF), administered orally twice a day 500 mg (1000 mg/day) for 24 weeks

Describe control (treatment/procedure/test):

Glucocorticoids therapy, consisting of intravenous infusions of methylprednisolone (iv.MP) 0,5 g daily for three consecutive days per week for 2 weeks, subsequent treatment with oral prednisone at 60 mg/day for 8 weeks, and then a gradual tapering schedule with a reduction of 5 mg/week for 14 weeks.

Length of follow-up:

24 weeks

Loss-to-follow-up:

Intervention:

N=7 (%)

Reasons: withdrew consent n=2), lost-to-follow-up (n=5)

Control:

N=9 (%)

Reasons: withdrew consent (n=3), lack of efficacy (n=1); lost to follow-up (n=5)

Incomplete outcome data:

See above

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

Clinical Activity Score

Change at 24 weeks from baseline

I baseline: 5.25±1.24

I 24 weeks: 1.91± 0.83

C baseline: 5.24±1.28

C 24 weeks: 2.45±1.40

P between groups: ?

Percentage improved at 24 weeks:

I: 92.5%

C: 70.5%

Quality of life

Not evaluated

Douglas, 2020

Type of study:

Phase 3 multicentre, double-blind, RCT

Setting and country:

USA

Funding and conflicts of interest:

Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017 -002763

-18.)

Inclusion criteria:

- patients were 18 to 80 years of age,

- diagnosed with Graves’ disease

- active, severe to moderate thyroid eye disease

- had ocular symptoms that began

within 9 months before the baseline assessment

- Clinical Activity Score of 4 or more

- euthyroid

Exclusion criteria:

- previous orbital

irradiation or surgery for thyroid eye disease

- decreasing visual acuity or a visual-field or color

vision defect from optic nerve involvement within

the previous 6 months, glucocorticoid use

(cumulative dose equivalent to ≥1 g of methylprednisolone

for the treatment of thyroid eye disease), and any previous treatment with rituximab

or tocilizumab.

N total at baseline:

Intervention: 41

Control: 42

Important prognostic factors²:

Age ± SD:

I:51.6±12.6

C: 48.9±13.0

Sex:

I: 29% M

C: 26% M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Teprotumumab, intravenous;

10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions, every 3 weeks, total of 8 infusions

Describe control (treatment/procedure/test):

Placebo, once every

3 weeks for 21 weeks

(total of 8 infusions)

Length of follow-up:

Intervention 21 weeks (primairy end points)

Follow-up: 24 weeks

Loss-to-follow-up:

Intervention:

N=2 (5%)

Reasons: adverse event (n=1), withdrew consent (n=1)

Control:

N=2 (5%)

Reasons: adverse event (n=1), withdrew consent (n=1)

Incomplete outcome data:

Intervention:

N=8 (%)

Reasons: not described

Control:

N=8 (%)

Reasons: -

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

Clinical Activity Score (CAS)

CAS score of 0 or 1 at 24 wks (%) (no./total no.)

I: 59% (24/41)

C: 21% (0/42)

Difference: 36 (95%CI 17, 55)

P<0.001

Quality of life

Mean change at 24 weeks from baseline

I: 13.8±2.1

C: 4.4±2.1

Difference=9,4 (95%CI 4,1, 14,6)

P<0.001

Adverse events >10% (% in intervention / % in placebo)

Muscle spasm (32 versus 10%)

Alopecia (20 versus 12%)

Nausea (15 versus 10)

Fatigue (12 versus 2%)

Diarrhea (10 versus 12%)

Headache (10 versus 10%

Dry skin (10 versus 0%)

Dysgeusia (10 versus 0%)

Any adverse event: 85 versus 69%

Any serious adverse event: 5 versus 2%

Smith, 2017

Type of study:

Multicentre, double-blind, RCT

Setting and country:

15 medical centers, USA

Funding and conflicts of interest:

Supported by River Vision development; a grant from the Office of Orphan Products Development, Food and Drug Administration; grants from the National Institutes of Health; a Center for Vision grant and a grant from the National Eye Institute; an unrestricted grant from Research to Prevent Blindness; a grant from the Bell Charitable Foundation; a grant from the Department of Health’s National Institute for Health Research Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and University College London Institute of Ophthalmology; an unrestricted grant from Research to Prevent Blindness to the Hamilton Eye Institute, University of Tennessee; and an unrestricted grant from Research to Prevent blindness.

Inclusion criteria:

- patients were 18 to 75 years of age,

- with ophthalmopathy that had been diagnosed no more than 9 months after the onset of symptoms

- Clinical Activity Score of 4 or more on a 7-point scale (with a score of ≥3 indicating active thyroid-associated ophthalmopathy) in the more severely

affected (study) eye,

- had not received surgical or medical treatment, with the exception of oral glucocorticoids (a cumulative dose of ≤1 g of methylprednisolone or equivalent, with

a 6-week washout period).

Exclusion criteria:

Patients with optic neuropathy, severe ocular surface damage, or an improved Clinical Activity Score of 2 points or more between screening and baseline visits were excluded

N total at baseline:

Intervention: 42

Control: 45

Important prognostic factors²:

Age ± SD:

I:51.6±10.6

C: 54.2±13.0

Sex:

I: 35% M

C: 18% M

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Teprotumumab, provided as freeze-dried powder.

Patients received 8 intravenous infusions, one every 3 weeks. Initial dose 10 mg /kg body weight. Remaining 7 infusions: 20 mg /kg body weight

Describe control (treatment/procedure/test):

Placebo was 0.9% sodium chloride solution

Length of follow-up:

Intervention 24 weeks (primary end points)

Follow-up: 48 weeks

Loss-to-follow-up:

Intervention:

N=6 (12%)

Reasons: adverse event (n=5), other reason (n=1)

Control:

N=6 (13%)

Reasons: adverse event (n=1), progression of thyroid-associated ophthalmopathy (n=3), other reason (n=2)

Incomplete outcome data:

Intervention:

N=1 (%)

Reasons: not described

Control:

N=0 (%)

Reasons: -

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

Clinical Activity Score (CAS)

Proportion of patients with a change from baseline – week 16 of ≥2 points

I: 69%

C: 20%

Adjusted OR: 8.86, p<0.001)

Change at 24 weeks from baseline

I: -3.43±0.18

C: -1.85±0.17

P<0.001

Quality of life

Change at 24 weeks from baseline

I: 17.7±2.4

C: 6.8±2.3

P<0.01

Adverse events >10%

Nauseas (I 19%; C 9%)

Muscle spasms (I 19%; 5%) Diarrhea (I 14%; C5%) Hyperglycemia (I 12%; C5%)

Any adverse event: I: 74%; C:73%

Any serious adverse event: I: 12%; C: 2%

Perez-Moreiras, 2018

Type of study:

Double-blind, parallel RCT

Setting and country:

9 medical centers in Spain

Funding and conflicts of interest:

Partially supported by a grant of the Ministerio de SANIDAD,SERVIcios

Sociales e Igualdad, Gobierno de Spain; and by Fundacio´n Ramo´n Domı´nguez (Hospital Clı´nico Universitario, Santiago, Spain).

Roche, Inc donated

the tocilizumab and supported the pharmacovigilance and the final monitoring of the study. The funding organizations had no role in the design or conduct

of this research. One author reported fees from Roche Spain

Inclusion criteria:

≥ 18 years of age and

enrolled regardless of current treatment.

Normal thyroid hormone levels and active GO (defined as clinical activity score (CAS) of at least 4 (10-point scale) with a severity grade of moderate-to-severe or sight-threatening GO according to European Group on Graves Orbitopathy (EUGOGO) classification).

Incomplete responders to corticosteroid pulses ((1) incomplete response (defined as a CAS

improvement < 2) to at least 3 doses of 500 mg of intravenous

methylprednisolone; or (2) recurrence of GO, defined

as an increase in CAS > 1 after treatment with corticosteroids

pulses.

Exclusion criteria:

The need for immediate

surgery for orbital decompression, thyroidectomy or radioactive iodine treatment, active smoking, chronic or active infection, history of intestinal ulceration or diverticulitis,

neutrophil count less than 0.5 3 109/liter, platelet count less than 50 3 103/liter, and aspartate transaminase

(AST) or alanine transaminase (ALT) levels exceeding

1.5-fold of the upper normal limit.

N total at baseline:

Intervention: 15

Control: 17

Important prognostic factors²:

Age, median (IQR):

I: 45.1 (38.9-50.5)

C: 47.5 (41.1-57.4)

Sex:

I: 27% M

C: 23% M

Groups comparable at baseline?

Almost; GOQoL was higher in the TCZ group (perceiving a higher disability)

Describe intervention (treatment/procedure/test):

Tocilizumab, 8 mg/kg body weight, administered intravenously at weeks 0. 4. 8 and 12

Describe control (treatment/procedure/test):

Placebo administered intravenously at weeks 0. 4. 8 and 12.

Sterile, pyrogen-free solution of 0.9% sodium chloride

Length of follow-up:

40 weeks; primary end points at 16 weeks

Loss-to-follow-up (week 16):

Intervention:

N=0 (0%)

Reasons (describe)

Control:

N=0 (0%)

Reasons (describe)

Loss-to-follow-up (week 40):

Intervention:

N=1 (7%)

Reasons: not described

Control:

N=3 (18%)

Reasons: 2 lost to follow-up, 1 withdrew the consent

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

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

Clinical Activity Score (CAS)

Proportion of patients with a change from baseline – week 16 of ≥2 points

I: 93,3% (95%CI 70,1-98,8(

C: 58.8 (95%CI 36-78,3%)

OR= 9.8 (95%CI 1.3-73.2), p=0.04

Proportion of patients with a change from baseline – week 40 of ≥2 points

I: 86,7% (95%CI)

C: 58.8 (95%CI

p>0.05

Proportion of patients with a CAS<3 at week 16

I: 86.7% (95%CI 62.1-96.2%)

C: 35.2% (95%CI 17.3-58.7%)

OR=11.9 (95%CI 2.1-63.1), p=0.005

Proportion of patients with a CAS<3 at week 16

I: 80.0% (CI 54.8%-92.9%)

C: 47.1% (CI 26.1%-69.0%

p>0.05

Composite score EUGOGO?

Quality of life (GOQoL)

Improvement of ≥8 points

I: 47%

C: 35%

NOSPECS

-

Adverse events

I:

C:

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)

Salvi, 2015

Block randomization with randomly selected block of four patients

Unclear

Unlikely

Unclear (‘treatment was blind to patient and ophthalmologist)

Unlikely

Unlikely

Unclear (study was stopped based on interim-analyses)

Unclear

Stan, 2015

SAS procedure PROC PLAN, using blocks of 6. Stratief by smonking status and substratified according to CAS.

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Savino, 2014

Not described

Unclear

Likely

Unclear

Unclear

Unclear

Unlikely

Unlikely

Ye, 2017

Computer-generated code with random, permuted blocks.

Unclear

Likely; different administration methods

Likely

Unlikely, ophthalmologist was blinded to the intervention

Unlikely

Unlikely

Unlikely

Kahaly, 2018

Centrally randomised. The randomisation schedule was

generated by an independent statistician before study activation and was stratified by site in blocks of sixteen

Unlikely

Likely; different administration methods

Likely

Unlikely

Unlikely

Unlikely

Unlikely

Douglas, 2020

1:1 ratio; randomization was performed with the use of an interactive Web-response system (Bioclinica eClinical Solutions, a contract research organization).

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Smith, 2017

1:1 ratio in blocks of 2, stratified within each clinical center according to smoking status, with the use of an interactive Web-response system.

Unclear

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Perez-Moreiras, 2018

Randomly assigned in a 1:1 ratio. Performed centrally by the Bio-statistics Department of the Spanish Consortium to Support Network Biomedical Research with an electronic application of the case report form using SAS software version 9.2 to automatically and randomly assign the treatment groups. The treatment assignments used a pseudo-random process to ensure that both groups were similarly sized.

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely