Duphar B.V. 77.054/M.

Study characteristics
Methods	Single‐centre, randomised, double‐blind, placebo‐controlled, 2‐arm, parallel‐group trial. Duration of treatment and follow‐up was 12 weeks.
Participants	Setting: recruited from the National Ear, Nose and Throat Hospital, based in the UK from 1979 to 1982 Sample size: Number randomised: 50 participants Number completed: 36 participants Participant baseline characteristics Reported for those who completed the study  Age:  Betahistine group: mean 42.9 years (SD not reported) Placebo group: mean 48.8 years (SD not reported) Gender:  Betahistine group: 12 males (63%); 7 females (37%) Placebo group: 10 males (59%); 7 females (41%) Probable/definite Ménière's disease:  Not reported Duration of disease:  Not reported Attack frequency at baseline: Betahistine group: mean 5.3 episodes in a 3‐week period Placebo group: mean 3 episodes in a 3‐week period Hearing loss at baseline:  Not reported Measure of tinnitus at baseline:  Not reported Number of participants with bilateral disease: Not reported Inclusion criteria: Vertigo, likely to be of peripheral origin, either: Ménière’s disease Labyrinthine ischaemia Other forms of peripheral vertigo with unclear pathology Fairly stable symptoms for at least 2 months prior to study entry. Frequency of attacks of at least 1 per month during the 2 months before the study. 33/36 participants were recruited due to a diagnosis of Ménière’s disease. As the majority of participants had Ménière's disease, we included this study in the review.  Exclusion criteria: Vertigo related to infection of middle ear or sinuses. Vertigo of ocular origin. Spontaneous vertigo with focal neurological symptoms (TIAs). Vertigo of central origin as observed in intracranial tumours, brain stem ischaemia, multiple sclerosis, trauma capitis, epilepsy. Vertigo due to central disorders. Serious cardiac disease, hypertension, orthostatic hypotension, anaemia, diabetes, thyroid disorders, intoxication, syphilis, vertigo of psychological origin, peptic ulcer, phaeochromocytoma or asthma, stroke or MI in the preceding 2 months and pregnant women. Diagnosis of Ménière's disease: no diagnostic criteria are stated
Interventions	Intervention (number randomised not reported, n = 19 completed): betahistine 12 mg tablet 3 times daily for 12 weeks (total 36 mg daily)  Comparator (number randomised not reported, n = 17 completed): placebo; 3 placebo tablets were administered per day for 12 weeks
Outcomes	Primary outcomes relevant to this review: Improvement in vertigo Not reported  Change in vertigo Reported as the number of 'real attacks of vertigo' over a 6‐week period  Serious adverse events Adverse events appear to have been systematically recorded, although a description of serious adverse events is not present Secondary outcomes relevant to this review: Disease‐specific health‐related quality of life Not reported  Hearing Assessed with pure‐tone audiometry, but only reported narratively. No data are presented that are suitable for meta‐analysis.  Tinnitus  Not reported using a validated instrument  Other adverse effects A table was presented that included adverse effects experienced by the participants. This included a description of gastrointestinal disturbance and headache.  Other outcomes reported in the study: Impact of dizziness on quality of life, as assessed by the investigator Investigator's opinion of treatment Vertigo, severity at week 12  Patient/investigator evaluation of treatment  Deafness severity rating
Funding sources	Funded by Duphar Laboratories
Declarations of interest	No declaration is made
Notes	Research integrity checklist: No retractions/expressions of concern were identified but this study remains unpublished Trial registration was not applicable (conducted in 1983) Baseline characteristics of the groups do not appear to be excessively similar, but there are very limited data to assess Plausible dropout is reported  The study was free from implausible results The number randomised to each group is not reported, therefore we are uncertain whether the same number were recruited to each group
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “patients were randomly allocated to treatment with either betahistine or placebo” Comment: no further details are provided regarding the methods used for randomisation.
Allocation concealment (selection bias)	Unclear risk	Comment: no information was provided on any methods used to conceal allocation.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: placebo was used to blind participants. It is unclear whether study personnel were also blinded to group allocations.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: outcomes are reported by (blinded) participants, therefore we consider these to be at low risk of detection bias.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: substantial dropout of 14/50 (28%) participants, and reasons may be related to treatment. Per protocol analysis is suggested to have occurred due to the exclusion of one participant who failed to take their tablets.
Selective reporting (reporting bias)	High risk	Comment: no protocol is available to assess against pre‐specified outcomes. Audiometry was reported in a way that precludes meta‐analysis.
Other bias	High risk	Comment: we had concerns over the measures used to assess vertigo – an unvalidated scoring system was used, and it was unclear how “real attacks of vertigo” were defined.