Creatine Safety & Tolerability in Huntington's Disease

PRÉCIS Protocol Title Creatine Safety \& Tolerability in Huntington's Disease (CREST-X): A Single-Center, Open-Label, Long-Term Safety \& Tolerability Extension Study of Creatine in Subjects with HD

Study Phase Phase II Clinical Trial

Funding Departmental Funds

Drug Supply Provided By The Avicena Group, Inc (Palo Alto, CA)

Number of Subjects Up to 10 subjects enrolling from the creatine dose-finding study CREST-UP1 (PHRC Protocol: 2004-P-000925)

Number of Study Centers Single site

Study Period Approximately 306 weeks on study medication Approximately 310 weeks total including follow-up

Primary Objective To evaluate the long-term safety, tolerability and clinical impact of 30 grams per day of creatine.

Secondary Objective To serve as a basis for subsequent trials designed to specifically address creatine's ability to slow or halt the progression of HD

Primary Outcome Measure Primary purpose of this study is to estimate the proportion of subjects who find the drug intolerable.

Secondary Outcome Measures 1. Changes in UHDRS subscores

1. Biological indicators that creatine might affect neuroprotection (serum creatine levels, absolute brain creatine concentrations) Significance/Relevance Several studies in rat and transgenic mouse models of HD have suggested that creatine may be neuroprotective. Most data on safety and tolerability of creatine have been performed in healthy athletes. Significant side effects were not found in studies of 14 days duration or less, while significant improvements in motor function have been shown in some studies of athletes, but not in others. There has been little data on safety and tolerability of creatine in disease conditions. In a Phase II study with HD subjects, we have found that 8g/day creatine taken over 16 weeks has been safe \& well tolerated.

Study Population All subjects enrolled in CREST-UP1 who continue to meet inclusion criteria are eligible. These are men and women >18 years if age with a clinical diagnosis of HD will be considered. Sexually active women of childbearing potential may participate if they have a negative pregnancy test at screening and either use adequate birth control, are post-menopausal or are surgically sterile.

Study Design Open-label safety and tolerability study in subjects with HD enrolled at 1 site to receive creatine for approximately 306 weeks. All subjects enrolled in CREST-UP1 will be eligible to rollover into this study after the de-escalation phase; these subjects will receive 30 grams/day of creatine.

Eligibility Criteria Inclusion Criteria Subjects from CREST-UP1 eligible to continue on creatine in this extension study.

Subjects in Stage 1-3 of illness. Age of 18 years or older. Women of childbearing potential (i.e., those pre-menopausal or not surgically sterile) must confirm to the best of their knowledge that they are not pregnant or plan to get pregnant. Women of childbearing potential must have negative pregnancy test, be non-lactating and use adequate contraception methods. Adequate contraception methods include: oral birth control pills plus a barrier method (i.e. condoms, diaphragm), IUD or abstinence during the study. Abstinence will be considered an adequate contraception method on a case-to-case basis per site investigator's clinical assessment.

Subjects currently taking psychotropic medications (including antidepressants and neuroleptics) must be on stable dosages for at least 4 weeks prior to enrollment and should be maintained on constant dosage throughout the study. If clinical conditions mandate modifications of such medications, these changes will be systematically recorded and subject permitted to remain in the trial.

Subjects must be capable of providing informed consent and complying with trial procedures.

Subjects must be able to take oral medication. A person willing and able to serve as an informant and provide information about the daily dosing of study medication (if available).

Exclusion Criteria History of known sensitivity or intolerability to creatine. Subjects with underlying hematologic, hepatic or renal disease; screening white blood cell (WBC) count less than 3,800/mm3, screening creatinine greater than 2.25 or alanine aminotransferase (ALT) greater than 2 times the upper limit of normal.

Clinical evidence of unstable medical illness in the investigator's judgment. History of renal impairment (moderate to severe). Unstable psychiatric illness defined as psychosis (hallucinations or delusions), untreated major depression or suicidal ideation within 90 days of the Baseline visit.

Current or history of substance (alcohol or drug) abuse within 1 year of the Baseline visit.

Pregnant women, or women who are currently breast-feeding. Subjects who are unable to tolerate an MRI scan.

Study Procedures: Prior to taking part in the CREST-X trial, both subject and responsible informant (if available) will be provided with information about the study and will be given time to decide whether they wish to participate.

Eligible subjects from the CREST-UP1 study who wish to continue on creatine will be given the option of rolling into this study after the de-escalation phase; subjects who do not wish to continue on creatine in this study will follow Washout procedures according to the CREST-UP1 protocol.

At Baseline (Visit 1) informed consent will be obtained from each subject. All inclusion/exclusion criteria will be reviewed to determine continued eligibility for the extension study. Additional assessments will include: past/current medication, vital signs/body weight/EKG, pregnancy test (females), blood/urine samples for clinical safety/research labs.

All subjects will receive a dose of 30 grams/day; a 6-month supply of study drug will be dispensed.

Subjects will be contacted by telephone at Week 3 (Phone 1) to assess compliance with trial medication, document adverse events, and changes to concomitant medications.

During the on-study drug period, eligible subjects will return for in-person visits at Week 6 (Visit 2), Week 16 (Visit 3), Week 24 (Visit 4), Week 36 (Visit 5), Week 64 (Visit 6), Week 88 (Visit 7), Week 112 (Visit 8), Week 136 (Visit 9), as well as for Visits 10-15 (Weeks 25-170 post Visit 9), and/or withdrawal, for the following evaluations: general medical exam, vital signs/body weight/EKG, review of concomitant medication, study drug compliance, adverse events, and clinical safety/research labs. UHDRS will be completed at Week 24 (Visit 4), Week 64 (Visit 6), Week 88 (Visit 7), Week 112 (Visit 8), and Week 136 (Visit 9) and Visits 10-15. MRI will be completed at Week 24 (Visit 4), Week 64 (Visit 6), Week 88 (Visit 7), Week 112 (Visit 8), and Week 136 (Visit 9) and Visits 10-15. Subjects will receive a new supply of study drug approximately every three months as needed.

Intermittent assessments during the on-study drug period will be completed at Week 9 (Phone 2), Week 18 (Phone 3), Week 30 (Phone 4), Week 52 (Phone 5), Week 76 (Phone 6), Week 100 (Phone 7), and Week 124 (Phone 8) to primarily evaluate compliance with trial medication (during on-study period), document adverse events, and changes to concomitant medications.

Subjects who demonstrate unexpected long-term toxicity or who no longer wish to remain in the study will proceed to Washout and be followed for eight weeks off-study drug.

At Phone Washout 1 (approximately 172 weeks post-Visit 9 subjects will be contacted by telephone primarily to document any adverse events and changes in concomitant medication during the washout period.

At Visit Washout 1 (approximately 174 weeks post-Visit 9 subjects will return for the following evaluations: general medical exam, vital signs/body weight/EKG, UHDRS, review of concomitant medication, adverse events, and clinical safety/research labs, and MRI.