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

The NINDS NET-PD Investigators

Research output: Contribution to journalArticle

291 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)664-671
Number of pages8
JournalNeurology
Volume66
Issue number5
DOIs
StatePublished - 2006

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Medical Futility
Minocycline
Creatine
Parkinson Disease
Clinical Trials
Tocopherols
Selegiline
Parkinsonian Disorders
Placebos
Phase II Clinical Trials
Calibration
Secondary Parkinson Disease
Arthralgia
Therapeutics
Nausea
Safety
Costs and Cost Analysis

ASJC Scopus subject areas

  • Clinical Neurology

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A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. / The NINDS NET-PD Investigators.

In: Neurology, Vol. 66, No. 5, 2006, p. 664-671.

Research output: Contribution to journalArticle

The NINDS NET-PD Investigators. / A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. In: Neurology. 2006 ; Vol. 66, No. 5. pp. 664-671.
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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.",
author = "{The NINDS NET-PD Investigators} and Bernard Ravina and Karl Kieburtz and Barbara Tilley and Kathleen Shannon and Caroline Tanner and {Frederick Wooten}, G. and Brad Racette and Patricia Deppen and Dewey, {Richard B.} and Brigid Hayward and Burton Scott and Joanne Field and Julie Carter and Matthew Brodsky and Pamela Andrews and Bala Manyam and Jacqueline Whetteckey and Jayaraman Rao and Maureen Cook and Aminoff, {Michael J.} and Chadwick Christine and Jessie Roth and Martha Nance and Sotirios Parashos and Susan Peterson and Kathleen Shannon and Jeana Jaglin and Carlos Singer and Perez, {Marian A.} and Anita Blenke and Robert Hauser and Theresa McClain and Summer Wolfrath and Ted Dawson and Becky Dunlop and Rajesh Pahwa and Kelly Lyons and Amy Parsons and Maureen Leehey and Jacci Bainbridge and Lisa Shulman and William Weiner and Katharine Pabst and Rodger Elble and Charlene Young and Kapil Sethi and Buff Dill and Wayne Martin and Germaine McInnes and Calabrese, {Vincent P.}",
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T1 - A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease

AU - The NINDS NET-PD Investigators

AU - Ravina, Bernard

AU - Kieburtz, Karl

AU - Tilley, Barbara

AU - Shannon, Kathleen

AU - Tanner, Caroline

AU - Frederick Wooten, G.

AU - Racette, Brad

AU - Deppen, Patricia

AU - Dewey, Richard B.

AU - Hayward, Brigid

AU - Scott, Burton

AU - Field, Joanne

AU - Carter, Julie

AU - Brodsky, Matthew

AU - Andrews, Pamela

AU - Manyam, Bala

AU - Whetteckey, Jacqueline

AU - Rao, Jayaraman

AU - Cook, Maureen

AU - Aminoff, Michael J.

AU - Christine, Chadwick

AU - Roth, Jessie

AU - Nance, Martha

AU - Parashos, Sotirios

AU - Peterson, Susan

AU - Shannon, Kathleen

AU - Jaglin, Jeana

AU - Singer, Carlos

AU - Perez, Marian A.

AU - Blenke, Anita

AU - Hauser, Robert

AU - McClain, Theresa

AU - Wolfrath, Summer

AU - Dawson, Ted

AU - Dunlop, Becky

AU - Pahwa, Rajesh

AU - Lyons, Kelly

AU - Parsons, Amy

AU - Leehey, Maureen

AU - Bainbridge, Jacci

AU - Shulman, Lisa

AU - Weiner, William

AU - Pabst, Katharine

AU - Elble, Rodger

AU - Young, Charlene

AU - Sethi, Kapil

AU - Dill, Buff

AU - Martin, Wayne

AU - McInnes, Germaine

AU - Calabrese, Vincent P.

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

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