A randomized, double blind, futility clinical trial of creatine and minocycline in early Parkinson disease
NINDS NET-PD Investigators;
Commented by , 28 Apr 2006
Background
Creatine and minocycline were prioritized for clinical testing in Parkinson disease (PD) based on a systematic review of potentially neuroprotective compounds (ref. 1). Creatine monohydrate is a dietary supplement, which plays an important role in mitochondrial energy production.
Minocycline is a semi-synthetic tetracycline, which exerts anti-inflammatory effects. PD has been associated with mitochondrial dysfunction as well as inflammatory responses in substantial nigra. Both substances were found to be neuroprotective in preclinical models of PD.
Aim
The aim of this study was 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.
Methods
Patients 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 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/tocepherol arm of the previously conducted large DATATOP trial (ref. 2); p values < 0.1 were accepted to indicate futility.
Results
Two hundred patients 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 were upper respiratory symptoms, joint pain and nausea. The authors concluded that both creatine and minocycline should be considered for definitive Phase III trials to determine if they alter the long term progression of PD.
Professor Emre's comments
We need both novel compounds as well as novel approaches to research in order to advance our knowledge and improve the way we treat our patients. As funds and participants in clinical trials are not infinite, novel approaches become particularly important to predict the potential value of treatment strategies which can only be properly assessed in large samples and over a long durations, such as disease modifying agents for PD.
Futility designs (ref. 3) may prove to be useful in eliminating substances which have low potential for success. These are a type of Phase II clinical trials which have been successfully used in cancer research. They are intended to eliminate substances that show low potential for further development.
Those substances which do not perform better than a pre-determined futility threshold are rejected as futile and would not be considered for further clinical trials. Those which are not found to be futile are further considered for testing based on the overall profile including safety, tolerability and activity. In other words the objective of the futility trials is not to prove the efficacy of a compound, it is rather to demonstrate futility in order to better allocate resources.
This study is a successful example of how futility designs may be employed to test compounds with a potential to modify disease progression in PD. As PD is a slowly progessive disorder with a variable rate of progression over time across the patients, lenghty trials with large sample sizes are required to reliably demonstrate efficacy.
Both minocycline and creatine performed better than the futility threshold in this trial. Thus, they have passed the first hurdle. It remains now to be determined which of the two compounds should be advanved to large scale Phase III trials and ultimate efficacy needs to be demonstrated.
References
1. Ravina BM, Fagan SC, Hart RG, et al. Neuroprotective agents for clinical trials in Parkinson’s disease: a systematic assessment. Neurology 2003; 60; 1234-1240.
2. The Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson's disease. New England Journal of Medicine 1989; 321; 1364-1371
3. Tilley BC, Palesch YY, Kieburtz K, et al. Optimizing the ongoing search for new treatments for Parkinson disease: using futility designs. Neurology 2006; 66; 628-633