Derebery 2004.

Study characteristics
Methods	Parallel‐group, double‐blind randomised controlled trial with 10 days duration of treatment and a total of 6 months of follow‐up
Participants	Setting:  Single‐centre trial, conducted in the USA. Study dates are not reported.  Sample size: Number randomised: 24 participants Number completed: 23 participants Participant baseline characteristics Age:  Not reported separately for the groups; the mean age for all participants was 48.3 years (SD 12.0) Gender:  Not reported separately for the groups; 6 participants were male and 17 were female  Probable/definite Ménière's disease:  All definite disease (inclusion criterion) Duration of disease:  The average duration of symptoms prior to study inclusion was 3.4 years  Attack frequency at baseline:  Famciclovir group: 5.3 attacks per week (SD 11.1) Control group: 5.3 attacks per week (SD 7.6) All participants reported at least 2 disabling vertigo spells per month at enrolment  Hearing loss at baseline:  Reported for those with unilateral disease only  Famciclovir group: mean hearing threshold 52.2 dB (SD 20.8) Control group: mean hearing threshold 53.4 dB (SD 7.2) Measure of tinnitus at baseline:  Famciclovir group: mean 57.0 (SD 14.1) Control group: mean 68.7 (SD 21.4) Number of participants with bilateral disease: Famciclovir group: 3/12 Control group: 2/11 Inclusion criteria: A diagnosis of definite Ménière's disease according to the AAO‐HNS 1995 criteria. Unilateral or bilateral disease. Active disease, experiencing disabling vertigo spells at least 2 times per month (the need to cease an activity and lie down until the dizzy spell is over, lasting at least 20 minutes). "If the initial diagnosis of Ménière’s disease had been made in the past 3 months, the subject had to wait 3 more months to begin the trial." Exclusion criteria: Renal disease. Immunocompromise. Hypersensitivity to famciclovir or penciclovir cream. MR evidence of vestibular schwannoma or other retrocochlear disease. Positive fluorescent treponemal antibody absorption test. Concurrent use of probenecid. Diagnosis of Ménière's disease: Definite Ménière's disease according to the AAO‐HNS 1995 criteria
Interventions	Intervention (n = 13 randomised, n = 12 completed) Famciclovir 250 mg 3 times per day for 10 days, followed by 250 mg twice daily for 80 days (total 3‐month course)    Comparator (n = 11 randomised, n = 10 completed) Placebo; "250mg placebo pills" contents not specified. To be taken 3 times daily for 10 days, then twice daily for 80 days, as above.  Background interventions administered to all participants None reported
Outcomes	Primary outcomes relevant to this review: Improvement in vertigo Assessed as the proportion of participants in each treatment arm who demonstrated a 20% reduction in the number of disabling vertigo episodes at 3 months (as compared with baseline measures)  Change in vertigo Assessed with the number of dizzy spells 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 Assessed with the DHI at 3 months  Hearing Assessed with pure tone audiometry at 0.5 kHz, 1 kHz, 2 kHz and 3 kHz  Tinnitus  Assessed with the THI. An obvious typographical error in the data means that we are unable to include these results in the analysis. Other adverse effects Authors state that "The clinical coordinator also recorded any physiological reactions to the drug, assessing for headaches, gastro‐intestinal problems, fever, increased dizziness, rash, decreased or increased appetite, and cardiovascular changes" Other outcomes reported in the study: Global quality of life (SF‐36) AAO‐HNS FLS median score at baseline and 3 months  Mean duration of vertiginous episodes Speech discrimination scores
Funding sources	Quote: "Dr. Derebery received the Percy Award from the American Academy of Otolaryngology–Head and Neck Surgery to support this study. Novartis graciously supplied both active drug and placebo for this trial."
Declarations of interest	No declarations are made
Notes	Research integrity checklist: No retractions/expressions of concern were identified Trial registration was not applicable (published in 2004) Baseline characteristics of the groups do not appear to be excessively similar Reasons are given for the small loss to follow‐up The study was free from implausible results Similar numbers were allocated to each group, but blocked randomisation was reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Subjects were randomized within blocks of 10 subjects, such that for every 10 subjects, 5 subjects would be randomized to active treatment and 5 subjects would be randomized to placebo".  Comment: this is likely to have been achieved with computerised randomisation, but this is not clear from the text.
Allocation concealment (selection bias)	Unclear risk	Comment: no information is reported regarding concealment of allocation to groups.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: described as double‐blind. No further details were given to establish the efficacy of blinding, and study personnel are not specifically stated to be blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: the majority of outcome data are from participant‐reported outcomes (e.g. frequency of vertigo episodes, according to a diary, DHI, THI etc.). As participants were blinded, this can be considered low risk.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: few dropouts, and reasons balanced across groups ‐ 1 participant in each group required additional treatment. One further dropout was not fully reported (after taking only 1 day of medication) and was excluded from outcome measures. However, inclusion of this participant is unlikely to have impacted the results of this trial.
Selective reporting (reporting bias)	High risk	Comment: no protocol is available to compare. Methods state that follow‐up at 6 months (3 months after discontinuation of treatment) would take place, but no results are reported at this time. This may be because of the failure of efficacy at the primary outcome point.
Other bias	Low risk	Comment: no other concerns identified.