A pilot clinical trial of creatine and minocycline in early Parkinson disease: 18-month results

Abstract

Objective: To report an 18-month follow-up on creatine and minocycline futility study, the Neuroprotective Exploratory Trials in Parkinson Disease, Futility Study 1 (NET-PD FS-1).

Background: The NET-PD FS-1 futility study on creatine and minocycline found neither agent futile in slowing down the progression of disability in Parkinson disease (PD) at 12 months using the prespecified futility threshold. An additional 6 months of follow-up aimed to assess safety and potential interactions of the study interventions with antiparkinsonian therapy.

Methods: Additional 6 months of follow-up in randomized, blinded phase II trial of creatine (dosage, 10 g/d) and minocycline (dosage, 200 mg/d) in subjects with early PD.

Results: By 18 months, symptomatic treatment of PD symptoms was required in 61% of creatine, 62% of minocycline, and 60% of placebo-treated subjects. Study treatment was prematurely discontinued in 9%, 23%, and 6% of subjects in the creatine, minocycline, and placebo arms, respectively. Creatine and minocycline did not seem to adversely influence the response to symptomatic therapy nor increase adverse events.

Conclusions: Data from this small, 18-month phase II trial of creatine and minocycline do not demonstrate safety concerns that would preclude a large, phase III efficacy trial, although the decreased tolerability of minocycline is a concern.

FIGURE 1

Flow diagram from randomization to study completion (duration, 18 months). The number of subjects terminating the study before 18 months, the number of subjects completing the study, and the number of subjects requiring symptomatic therapy are indicated.

FIGURE 2

Kaplan-Meier estimate of time to need for symptomatic therapy.

FIGURE 3

Change in total UPDRS over time. Subject may be receiving symptomatic therapy at the time of visit. The UPDRS value just before initiating symptomatic therapy is not carried forward. The worst observation for the group is used to impute missing values. At 18 months, missing values were imputed for 2 creatine, 4 minocycline, and 4 placebo subjects. Bars represent SEM at 1, 3, 6, 9, 12, and 18 months.

FIGURE 4

Box-and-Whisker plot of improvement in total UPDRS after initiating symptomatic therapy. Before is the value at the need for symptomatic therapy visit. After is the value at the first visit after initiating symptomatic therapy. Only subjects requiring symptomatic therapy with a subsequent UPDRS evaluation are included (creatine, 35; minocycline, 33; placebo, 35). The length of the box represents the interquartile range. The plus sign represents the mean; the horizontal line in the box represents the median. Whiskers extend to minimum and maximum values.