Objective: Revisit Phase II futility studies.

Background: Published results of a Phase III trial of creatine monohydrate for Parkinson’s disease (PD) in the presence of dopaminergic treatment did not show a benefit of creatine. Creatine was previously tested using a futility study. Because the Phase III trial failed to detect a benefit of creatine questions have been raised about the value of futility studies in PD.

Methods: Feasible PD futility studies require outcome measures ascertained in one year or less. Participants must be early enough in their disease to show an intervention effect. In PD, participants with early disease on dopaminergic therapy may exhibit few changes over one year. Thus futility studies are usually conducted in de novo participants. A Phase II futility design uses a one-sided test, inflated alpha (usually 0.15-0.20) representing the probability of rejecting a beneficial treatment, and power of 0.85 (1-the probability of carrying an ineffective treatment into Phase III). Current thinking requires a concurrent control group. However, futility designs still require a smaller sample size than a Phase III trial. Only treatments that cannot be shown to be futile proceed to Phase III.

Results: Futility studies in NET-PD de novo patients suggested minocycline, GPI-1485, and co-enzyme-Q were futile as compared to historical controls. Only creatine was not shown to be futile. A Phase III study in progress when NET-PD results for co-enzyme Q were known confirmed co-enzyme Q as futile. A recent futility study of pioglitazone (FS-ZONE) with concurrent placebo controls and a background of MAO-inhibitors in all patients provided evidence that pioglitazone was futile to take to Phase III.

Conclusions: When testing PD interventions in de novo patients the outcome is a surrogate for the primary outcome in a Phase III trial where participants are on background dopaminergic therapy. PD futility studies are as strong as the surrogate short term outcome. The FS-ZONE Phase II study, used a background of MAO-inhibitors. MAO-inhibitors slowed time to symptomatic therapy and may prove useful in future futility studies. By design, futility studies do not have power to assure positive results but can substantially reduce the cost of Phase III trials by eliminating therapies unlikely to be successful in Phase III. More research on short term outcome measures in PD with background therapy is required.

IBC Florence, 2015.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/are-parkinsons-disease-futility-studies-futile/