Clinical trial NCT00212316: Safety and Tolerability Study of Phenylbutyrate in Huntington's Disease (PHEND-HD)
Official title: Phenylbutyrate Development for Huntington's Disease (PHEND-HD): A Multi-Center, Double-Blind, Placebo-Controlled Study With Open-Label Follow-Up to Determine the Safety and Tolerability of Phenylbutyrate in Subjects With Huntington's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Huntington's Disease
Keywords: Huntington's Disease
phenylbutyrate
HDAC inhibitors
transcription
Lead sponsor: University of Rochester
Sponsor class: OTHER
Collaborators: name: HP Therapeutics Foundation
name: Massachusetts General Hospital
name: Columbia University
name: University of Iowa
name: University of California, San Diego
name: University of Kansas
name: University of Alabama at Birmingham
name: Johns Hopkins University
First posted: 2005-09-21
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety, tolerability and clinical impact of 15-grams daily of sodium phenylbutyrate (phenylbutyrate) in Huntington's disease and to lay the groundwork for possible subsequent trials designed to specifically address its ability to slow or halt the progression of the disease.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of subjects able to complete treatment (Week 16)
Secondary outcomes:
measure: Secondary safety and tolerability outcomes at Weeks 1, 4, 5, 10, 16, & 20 include:
measure: adverse events,
measure: changes in vital signs,
measure: and clinical lab assessments.
measure: Secondary clinical measures at Weeks 4, 10, 16, and 20 include components of the UHDRS:
measure: total motor,
measure: Stroop,
measure: independence,
measure: & total functional capacity.
measure: Secondary biological indicators of treatment affects at Weeks 4, 10, 16, & 20 include:
measure: markers of neuroprotection (e.g. NAA) via MRS,
measure: histone acetylation (levels in WBC; fetal hemoglobin levels in blood),
measure: depletion of glutamine,
measure: gene expression analyses,
measure: and biochemical analyses for pharmacokinetics.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: San Diego
country: United States
facility: University of California-San Diego
state: California
city: Iowa City
country: United States
facility: University of Iowa Hospital and Clinics
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: Columbia University
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
Study officials:
affiliation: Co-Chair, Huntington Study Group, Massachusetts General Hospital
name: Steven M. Hersch, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Director, Clinical Trials Coordination Center, University of Rochester
name: Karl Kieburtz, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: