Safety and Tolerability Study of Phenylbutyrate in Huntington's Disease (PHEND-HD)

Huntington's disease (HD) is an autosomal dominant disorder resulting in selective loss of neurons in the striatum-an area of the brain that controls movement, balance, and walking-and other areas of the brain. The disease is characterized by progressive motor and cognitive decline. There is no cure or even plausible treatment to offset the fatal course of the disease. Therefore, any treatment that ameliorates the disease would be of enormous importance.

The purpose of this double-blind, placebo-controlled study-with open-label follow-up-is to determine the safety and tolerability of 15-grams daily of oral phenylbutyrate in people with HD. The study will enroll 60 individuals. Eligible participants will be initially randomized to receive either phenylbutyrate or the matching placebo for 4 weeks.

After the placebo-controlled phase, all participants will enter the open-label phase to receive phenylbutyrate for 12 weeks. Participants will be followed for one month off phenylbutyrate.

This combination of a short-term double-blind, placebo-controlled phase followed by a longer open-label phase will favor the primary goals of detecting toxicity and intolerability while facilitating recruitment and maximizing number of subjects on study drug.

Inclusion criteria

• Subjects with clinical diagnosis of HD and family history of HD or a CAG repeat expansion greater than or equal to 37
• Subjects in stage I or II of illness (TFC greater than or equal to 7)
• Subjects must be ambulatory and not requiring skilled nursing care
• Age of 18 years or older
• Women of childbearing potential (i.e., those not postmenopausal or 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, such as oral birth control pills plus a barrier method (i.e. condoms, diaphragm) or IUD during their participation in the study
• Subjects currently taking psychotropic medications (including antidepressants and neuroleptics) must be on stable dosages for at least 4 weeks prior to baseline visit and should be maintained on constant dosage throughout the study
• 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

Exclusion criteria

• Exposure to phenylbutyrate, valproic acid, probenecid, known HDAC inhibitors or other transcriptionally active compounds within 3 months (90 days) prior to the baseline visit
• History of known sensitivity or intolerability to phenylbutyrate, sodium butyrate or sodium acetate
• Existence of a known malignancy that might require treatment during the course of this study
• Exposure to any investigational drug within 30 days of the baseline visit
• Subjects with underlying hematologic, hepatic or renal disease; screening white blood cell (WBC) count less than 3,800/mm3, screening creatinine greater than 2.0 or alanine aminotransferase (ALT) greater than 2 times the upper limit of normal
• Clinical evidence of unstable medical illness in the investigator's judgment
• Clinical illness that requires use of warfarin (Coumadin)
• Unstable psychiatric illness defined as psychosis (hallucinations or delusions) untreated major depression or plan for suicide 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
• History of heart failure or other conditions that might be exacerbated by sodium loading