Creatine in Huntington's Disease (HD) (CREST-E)

This is a multi-center, randomized, double-blind, placebo-controlled trial of creatine monohydrate involving 553 ambulatory subjects with HD who are not requiring skilled care or institutionalization. Eligible subjects were randomized to receive up to 40 grams daily of creatine monohydrate or matching placebo. Randomization will be followed by a Titration Phase, a Maintenance Phase, an Optional Extended Maintenance Phase, and Washout. During the Titration Phase, which may last up to six months, study drug will be initially escalated in 5-gram increments starting at 5 g/day until the 40 g/day target dose is reached. Should subjects be unable to reach or stay at the maximum dose during the Titration Phase, they will remain on the highest tolerated dose (HTD) for which they have no significant side effects. During the Maintenance Phase, subjects will be followed prospectively and systematically. Subjects completing 36 months of follow-up on study drug will be eligible to continue in the study for an additional twelve months of follow-up in the Extended Maintenance Phase. The primary measure of efficacy is the annualized rate of change in TFC. The primary hypothesis of the study is that chronic treatment of early-stage HD subjects with creatine monohydrate will slow the progressive functional decline of HD. ]]> CREST-E SCREENING/DEMOGRAPHICSCREST-E CONSENT/WITHDRAWAL OF CONSENT FOR FUTURE PROCEDURESCREST-E INCLUSION/EXCLUSIONCREST-E INCLUSION/EXCLUSION (CANADIAN SITES ONLY)CREST-E SOCIO-ECONOMICSCREST-E ETHNICITY/RACECREST-E ETHNICITY/RACE (NZ)CREST-E VITAL SIGNSCREST-E ELECTROCARDIOGRAMCREST-E MEDICAL HISTORY CAMCREST-E MEDICAL HISTORY (GENERAL)CREST-E MEDICAL HISTORY (HD)CREST-E MEDICAL HISTORY (HD DIAGNOSTIC)CREST-E GENERAL PHYSICAL EXAMCREST-E GENERAL NEUROLOGICAL EXAMCREST-E UNIFIED HUNTINGTON'S DISEASE RATING SCALE '99 (MOTOR)CREST-E UNIFIED HUNTINGTON'S DISEASE RATING SCALE '99 (COGNITIVE)CREST-E UNIFIED HUNTINGTON'S DISEASE RATING SCALE '99 (BEHAVIORAL) (CLARIFIED VERSION 2005)CREST-E UNIFIED HUNTINGTON'S DISEASE RATING SCALE '99 (FUNCTIONAL)CREST-E UNIFIED HUNTINGTON'S DISEASE RATING SCALE '99 (INDEPENDENCE)CREST-E UNIFIED HUNTINGTON'S DISEASE RATING SCALE '99 (TFC)CREST-E UNIFIED HUNTINGTON'S DISEASE RATING SCALE '99 (SUMMARY)CREST-E PREDOMINANT SYMPTOM QUESTIONNAIRECREST-E NEUROPSYCHOLOGICAL TESTING (HOPKINS VERBAL LEARNING TEST - REVISED)CREST-E NEUROPSYCHOLOGICAL TESTING (DIGIT SPAN)CREST-E NEUROPSYCHOLOGICAL TESTING (LINE ORIENTATION)CREST-E BLINDEDNESS QUESTIONNAIRECREST-E HD CAREGIVER ASSESSMENTCREST-E HD CAREGIVER BURDEN INTERVIEWCREST-E BIOMARKER LABS DOSE INFORMATIONCREST-E SAFETY LABSCREST-E PREGNANCY FORMCREST-E TRANSCRIPTOMIC LABORATORY PROCEDURESCREST-E UNSCHEDULED CREATININE LABCREST-E DNA BLOOD SAMPLE PROCEDURESCREST-E MAGNETIC RESONANCE IMAGING SCANCREST-E TELEPHONE FOLLOW-UPCREST-E SIGNATURE FORMCREST-E CONCOMITANT MEDICATION LOGCREST-E ADVERSE EVENT LOG, PRIMARY OUTCOME DEFINITIONSCREST-E DOSE MANAGEMENT LOGCREST-E DRUG RETURN AND ACCOUNTABILITY LOGCREST-E END OF STUDY DRUG TREATMENTCREST-E CONSENT FOR REFERRAL TO IMAGING CENTERCREST-E HIGHEST TOLERATED DOSECREST-E SUBJECT SITE TRANSFER FORMCREST-E CONCLUSION OF STUDY PARTICIPATIONCREST-E ADVERSE EVENT FOLLOW-UP LOGCREST-E CONSENT FOR EXTENDED MAINTENANCE PHASECLINICAL GLOBAL IMPRESSION SCALEInclusion Criteria To be eligible for enrollment into this study, subjects must meet the following eligibility criteria within 28 days prior to randomization: Male or female age 18 or older. Subjects must have clinical features of HD and a confirmatory family history of HD; OR CAG repeat expansion greater or equal to 36. Subjects in Stage I or II of illness (TFC greater or equal to 7). Subjects must be ambulatory and not requiring skilled nursing care at the time of enrollment. Women of childbearing potential (i.e., those not postmenopausal or surgically sterile) must have a negative pregnancy test, be non-lactating and use adequate contraception methods during the study. Adequate birth control includes: abstinence; oral, implanted or injected contraceptives, e.g., birth control pills; intra-uterine device; barrier (e.g., vaginal ring or diaphragm/cervical cap with spermicide; transdermal patch and/or partner vasectomy). Reliable contraception must have been in use 30 days prior to the Baseline Visit. Subjects currently taking psychotropic medications (including anti-depressants and neuroleptics) must be on stable dosages for at least 30 days prior to randomization. Subjects must be capable of providing informed consent and complying with trial procedures. Subjects must be able to take oral medication. Exclusion Criteria History of known sensitivity or intolerability to creatine monohydrate. Exposure to any investigational drug within 30 days of randomization (Baseline visit). Use of supplemental creatine at a dose greater than 10 grams within 90 days of randomization (Baseline visit). Use of supplemental Coenzyme Q10 at a dose greater than 600 milligrams daily within 90 days of randomization (Baseline visit). CoQ10 supplements totaling greater than 300mg daily are not allowed during the study but may be taken prior to the baseline visit. Screening creatinine greater than 2.0 mg/dL. Screening white blood cell count less than 3800/mm3. Screening alanine aminotransferase greater than 2 times the upper limit of normal. Screening laboratory abnormalities that in the judgment of the investigator would jeopardize safe conduct of study. Current or history of substance (alcohol or drug) abuse within one year of randomization (Baseline visit). Clinical evidence of unstable medical illness in the investigator's judgment. Clinical evidence of unstable psychiatric illness defined as psychosis (hallucinations or delusions), untreated major depression or suicidal ideation within 90 days of the Baseline visit. Additional Exclusion Criteria for Imaging Sites: Previously obtained MRI scans with evidence of infection, infarction or other focal lesions. Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or body or any other known contra-indication to MRI. ]]> Phase Completion Date Activity Planing 7/9/2008 Project award granted Implementation 9/2/2009 Begin screening 9/29/2009 First enrollment 10/2/2014 Completion of enrollment 12/9/2014 Completion of follow-up of subjects 2/4/2015 Secure database Analysis/Publication 6/8/2015 Lock database ]]>