Title

A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease

Authors

Bernard Ravina, National Institute of Neurological Disorders and Stroke (NINDS)
Karl Kieburtz, University of Rochester
Barbara Tilley, Medical University of South Carolina
Kathleen Shannon, Rush University Medical Center
Kathleen Shannon, Rush University Medical Center
Caroline Tanner, Parkinson's Institute
G. Frederick Wooten, University of Virginia
Brad Racette, Washington University School of Medicine in St. Louis
Patricia Deppen, Washington University School of Medicine in St. Louis
Richard B. Dewey, UT Southwestern Medical School
Brigid Hayward, UT Southwestern Medical School
Burton Scott, Duke University
Joanne Field, Duke University
Julie Carter, Oregon Health & Science University
Matthew Brodsky, Oregon Health & Science University
Pamela Andrews, Oregon Health & Science University
Bala Manyam, Scott and White
Jacqueline Whetteckey, Scott and White
Jayaraman Rao, LSU Health Sciences Center - New Orleans
Maureen Cook, LSU Health Sciences Center - New Orleans
Michael J. Aminoff, University of California, San Francisco
Chadwick Christine, University of California, San Francisco
Jessie Roth, University of California, San Francisco
Martha Nance, Struthers Parkinson's Center
Sotirios Parashos, Struthers Parkinson's Center
Susan Peterson, Struthers Parkinson's Center
Jeana Jaglin, Rush University Medical Center
Carlos Singer, University of Miami
Marian A. Perez, University of Miami
Anita Blenke, University of Miami
Robert Hauser, University of South Florida, Tampa
Theresa McClain, University of South Florida, Tampa

Document Type

Article

Abstract

Background: Creatine and minocycline were prioritized for testing in Phase II clinical trials based on a systematic evaluation of potentially disease modifying compounds for Parkinson disease (PD). Objective: To test whether creatine and minocycline alter the course of early PD relative to a predetermined futility threshold for progression of PD in a randomized, double-blind, Phase II futility clinical trial. Agents that do not perform better than the futility threshold are rejected as futile and are not considered for further study. Methods: Participants had a diagnosis of PD within 5 years, but did not require medications for the management of symptoms. The primary outcome was the change in the total Unified Parkinson’s Disease Rating Scale (UPDRS) score from baseline to either the time when there was sufficient disability to warrant symptomatic therapy for PD or 12 months, whichever came first. Subjects were randomized 1:1:1 to receive creatine 10 g/day, minocycline 200 mg/day, or matching placebo. The futility threshold was set as a 30% reduction in UPDRS progression based on the placebo/tocopherol arm of the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) trial. p Values ≤ 0.1 indicate futility. Results: Two hundred subjects were randomized to the three groups. Neither creatine (p = 0.96) nor minocycline (p = 0.66) could be rejected as futile based on the DATATOP futility threshold. The rate of progression for the calibration placebo group fell outside the 95% CI for the DATATOP historical control. In a sensitivity analysis, based on the threshold derived from the calibration placebo group, again neither drug could be rejected as futile. Tolerability was 91% in the creatine group and 77% in the minocycline group. Common adverse events included upper respiratory symptoms (26%), joint pain (19%), and nausea (17%). Conclusions: Both creatine and minocycline should be considered for definitive Phase III trials to determine if they alter the long term progression of Parkinson disease (PD). Additional factors must be weighed before selecting agents for Phase III trials, including safety, tolerability, activity, cost, and availability of these two agents in comparison with other agents currently in development for PD.

Publication Date

1-1-2006

Publication Title

Neurology

ISSN

00283878

E-ISSN

1526632X

Volume

66

Issue

5

First Page

664

Last Page

671

PubMed ID

16481597

Digital Object Identifier (DOI)

10.1212/01.wnl.0000201252.57661.e1

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