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

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 < or = 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.

[1]  C. Tanner,et al.  Optimizing the ongoing search for new treatments for Parkinson disease , 2006, Neurology.

[2]  Yuko Y Palesch,et al.  A responsive outcome for Parkinson's disease neuroprotection futility studies , 2005, Annals of neurology.

[3]  C. Tanner,et al.  Levodopa and the progression of Parkinson's disease. , 2004, The New England journal of medicine.

[4]  Mark A. Wilson,et al.  The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[5]  R. Nussbaum,et al.  Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1 , 2004, Science.

[6]  S. Lorenzl,et al.  Minocycline enhances MPTP toxicity to dopaminergic neurons , 2003, Journal of neuroscience research.

[7]  G. Bates,et al.  Minocycline and doxycycline are not beneficial in a model of Huntington's disease , 2003, Annals of neurology.

[8]  E. Hirsch,et al.  The Role of Glial Reaction and Inflammation in Parkinson's Disease , 2003, Annals of the New York Academy of Sciences.

[9]  R. Albin,et al.  Neuroprotective agents for clinical trials in Parkinson’s disease , 2003, Neurology.

[10]  M. Tarnopolsky,et al.  Acute and moderate-term creatine monohydrate supplementation does not affect creatine transporter mRNA or protein content in either young or elderly humans , 2003, Molecular and Cellular Biochemistry.

[11]  Wenhua Zhang,et al.  Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS , 2003, Annals of neurology.

[12]  Patrizia Rizzu,et al.  Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism , 2002, Science.

[13]  Joel S Perlmutter,et al.  Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. , 2002, Archives of neurology.

[14]  J. Julien,et al.  Minocycline Slows Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis , 2002, Neurobiology of Disease.

[15]  Dong-Kug Choi,et al.  Blockade of Microglial Activation Is Neuroprotective in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson Disease , 2002, The Journal of Neuroscience.

[16]  S. Paul,et al.  Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  A. Persky,et al.  Clinical pharmacology of the dietary supplement creatine monohydrate. , 2001, Pharmacological reviews.

[18]  O. Andreassen,et al.  Creatine Increases Survival and Delays Motor Symptoms in a Transgenic Animal Model of Huntington's Disease , 2001, Neurobiology of Disease.

[19]  S. Hersch,et al.  Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease , 2000, Nature Medicine.

[20]  Ole A. Andreassen,et al.  Neuroprotective Effects of Creatine in a Transgenic Mouse Model of Huntington's Disease , 2000, The Journal of Neuroscience.

[21]  P. Lamey,et al.  Minocycline-induced staining of the adult permanent dentition: a review of the literature and report of a case. , 1999, Dental update.

[22]  Ole A. Andreassen,et al.  Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis , 1999, Nature Medicine.

[23]  M. Beal,et al.  Creatine and Cyclocreatine Attenuate MPTP Neurotoxicity , 1998, Experimental Neurology.

[24]  Stephanie Green,et al.  Clinical Trials in Oncology , 1997 .

[25]  R Kieburtz,et al.  Effect of lazabemide on the progression of disability in early Parkinson's disease , 1996, Annals of neurology.

[26]  Robert Hill,et al.  Low platelet mitochondrial complex I and complex II/III activity in early untreated parkinson's disease , 1995, Annals of neurology.

[27]  S. Pillemer,et al.  Minocycline in Rheumatoid Arthritis: A 48-Week, Double-Blind, Placebo-Controlled Trial , 1995, Annals of Internal Medicine.

[28]  I. Sora,et al.  The cloning and expression of a human creatine transporter. , 1994, Biochemical and biophysical research communications.

[29]  C. Marsden,et al.  Mitochondrial function in Parkinson's disease , 1992, Annals of neurology.

[30]  C. Marsden,et al.  Mitochondrial Complex I Deficiency in Parkinson's Disease , 1990, Lancet.

[31]  J. Parks,et al.  Abnormalities of the electron transport chain in idiopathic parkinson's disease , 1989, Annals of neurology.

[32]  W. Nicklas,et al.  Mitochondrial and metabolic toxicity of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine. , 1987, Journal of Pharmacology and Experimental Therapeutics.

[33]  Stephen L. George,et al.  Fundamentals of Clinical Trials. (2nd ed.). , 1987 .

[34]  S K Carter,et al.  Calibrated phase II clinical trials in oncology. , 1986, Statistics in medicine.

[35]  J. Herson,et al.  Predictive probability early termination plans for phase II clinical trials. , 1979, Biometrics.

[36]  S J Pocock,et al.  The combination of randomized and historical controls in clinical trials. , 1976, Journal of chronic diseases.

[37]  M. Beal,et al.  Additive neuroprotective effects of creatine and a cyclooxygenase 2 inhibitor against dopamine depletion in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease , 2007, Journal of Molecular Neuroscience.

[38]  H. O. Heymann,et al.  Dental and oral discolorations associated with minocycline and other tetracycline analogs. , 1999, Journal of esthetic dentistry.

[39]  Anthony E. Lang,et al.  Effect of deprenyl on the progression of disability in early Parkinson's disease. , 1989, The New England journal of medicine.

[40]  Gehan Ea.  Update on planning of phase II clinical trials. , 1986 .

[41]  D. DeMets,et al.  Fundamentals of Clinical Trials , 1982 .