Zesiewicz 2012.

Methods	Double‐blind, placebo‐controlled, randomised study
Participants	20 participants with a genetically confirmed diagnosis of SCA3 were recruited and 18 entered the first phase. The mean age of participants in the varenicline group (5 female, 4 male (1 additional participant omitted from analyses)) was 47.44 years (± 10.83 years). The mean disease duration was 14 years (± 9.82 years). The mean age of the placebo group (3 female, 7 male randomised) was 53.8 years (± 11.2 years)
Interventions	Participants received oral varenicline (1 mg twice daily) or placebo. The treatment phase lasted 56 days with a subsequent washout phase of 57 to 83 days for both placebo and varenicline. Participants were allowed to continue taking all concomitant medications for the duration of the study
Outcomes	Primary outcome measures were derived from changes in baseline to end point scores of the SARA. The SARA contains a subscale focusing on speech function. The study protocol also included a standardised scale of functional health and wellbeing, the SF‐36
Notes	No power calculations were made to determine the required number of participants to accurately determine drug efficacy. Only 5 participants completed the placebo arm and 8 completed the varenicline arm of the study. There was no correction for multiple comparisons due to small sample size. Clinical presentation at baseline assessment was statistically significantly worse for the placebo group on the 'sitting' subscale in SARA Varenicline and matching placebo were provided by Pfizer Inc., USA. The National Ataxia Foundation, USA, and the Bobby Allison Ataxia Research Center (BAARC), USA provided funding
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	A 1:1 randomisation schedule was generated with Statistical Analysis System (SAS) 9.2 using a block size of 10. Participants were randomly allocated to either placebo or varenicline; however, the small sample size and blocked randomisation may have prevented equal distribution between groups. The placebo group had higher clinical severity scores and appeared on average older than the varenicline group, possibly influencing their responsiveness to treatment (Filla 2012)
Allocation concealment (selection bias)	Low risk	Sealed envelopes containing the treatment assignment for each subject were held by a member of the study team who was not involved in study assessments. All envelopes remained sealed at the end of the study. Study personnel involved in participant assessments (investigators and co‐ordinators), participants and caregivers were blinded to the treatment assignment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants were blinded to treatment condition
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All individuals involved in the assessments, including the investigators and participants, were blinded to the treatment assignment
Selective reporting (reporting bias)	Unclear risk	The 2nd period of the experiment, which was to include a cross‐over component, was abandoned due to the high dropout rate observed in the initial period reported
Incomplete outcome data (attrition bias) All outcomes	High risk	Only 5 participants completed the placebo arm and 8 completed the varenicline arm of the study. Data were analysed for 9 participants in each group despite the large number of participant dropouts. The time points at which the participants withdrew from the study were not stated, neither was the time at which the final (end point) analyses were performed
Other bias	Low risk	None identified

ADL: activities of daily living

FARS: Friedreich Ataxia Rating Scale

ICA: idiopathic cerebellar ataxia

ICARS: International Cooperative Ataxia Rating Scale

ITT: intention‐to‐treat

L‐5HT: L‐hydroxytryptophan

rhuEPO: recombinant human erythropoietin

SARA: Scale for Assessment and Rating of Ataxia

SCA: spinocerebellar ataxia

SCD: spinocerebellar degeneration

SD: standard deviation

TRH‐T: thyrotropin‐releasing hormone tartrate

VAS: visual analogue scale