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INTRO-HD: INvestigation of Tolerability in a Randomized Trial of OPC-14117 in HD

Led by Ira Shoulson, MD, and sponsored by Otsuka America Pharmaceutical, Inc. (Rockville, MD) was the first HSG multicenter trial to examine the safety of the experimental antioxidant OPC-14117 in patients with manifest HD. INTRO-HD included a total of 64 research subjects who, during this 20-week trial, were administered tablets of OPC-14117 (at one of three dosages) or matching placebo. Participating sites included Columbia University in New York, Emory University in Atlanta, the University of California in San Diego, and the University of Rochester. Enrollment in the trial began in November 1994, and the follow-up was completed in September 1995. A full report of INTRO-HD was published in Neurology (vol. 50:1366-73, 1998).

Basic Science Investigations Based on INTRO-HD

Through the development of the INTRO-HD trial and the support from Otsuka America Pharmaceutical, Inc. the HSG carried out studies of OPC-14117 in experimental animals in the laboratories of J. Timothy Greenamyre, MD, PhD (Emory University), Roger Albin, MD (University of Michigan), and Flint Beal, MD (formerly at Massachusetts General Hospital).

Flint Beal, MD, and his co-workers at Massachusetts General Hospital also examined the cerebrospinal fluid (CSF), serum and urine of INTRO-HD subjects to identify possible in vivo markers of oxidative stress. High priorities of the HSG are to develop reliable neurological markers of HD onset and progression and to test promising experimental interventions in genetic animal models of HD.

CAG Laboratory Studies Based on INTRO-HD

The HSG obtained blood samples from participating subjects in the INTRO-HD trial to examine the relationship between DNA (CAG repeat lengths of the HD IT-15 gene) and the phenotypic features of HD. Analyses are in progress to help define the relationship between the CAG repeat length and clinical progression of HD.

In the INTRO-HD trial, we also examined possible CAG repeat length variability among four research laboratories at Emory University, Johns Hopkins, Massachusetts General Hospital and University of British Columbia to determine the reliability of these measures in our research studies. Our analyses (Neurology 1996; 46:A258) indicated a remarkable degree of inter-laboratory agreement in CAG repeat length measurements among these four research laboratories, but the clinician must still weigh all available evidence before confirming HD gene-carrier status. The findings from this analysis may also have practical implications for pre-symptomatic HD testing.

START-HD: Short Term Assessment of Remacemide Tolerability-HD

Under the leadership of Karl Kieburtz, MD and Andrew Feigin, MD and sponsored by Fisons Pharmaceuticals, was the first placebo-controlled study to evaluate the safety and tolerability of remacemide, a glutamate antagonist in patients with early Huntington's disease. There were 31 subjects enrolled at the University of Rochester who were randomized to receive either placebo or active remacemide. A full report of START-HD was published in Movement Disorders (vol. 11:273-277,1996).

CARE-HD: Co-enzyme Q10 And Remacemide Evaluation in Huntington's Disease

Under the leadership of Karl Kieburtz, MD (University of Rochester) and Walter Koroshetz, MD (Massachusetts General Hospital), the HSG's application for this multi-center study was funded in 1997 (NS 35284) by the National Institute of Neurologic Disorders and Stroke (NINDS) of the NIH. In preliminary studies conducted by HSG participants, co-enzyme Q10 and remacemide have been examined in HD patients. This study evaluated the naturally occurring substance CoQ10, which is important in the powerhouse of all cells (mitochondria) for normal energy transmission and remacemide that blocks glutamate receptors and may potentially have some value is slowing the progression of HD. Enrollment in the CARE-HD trial began in July 1997 and was completed in June 1998. Research participants were evaluated over a 2.5 year period and the last subject completed the trial in the fall of 2000. See the results of the CARE-HD trial.

RID-HD: RIluzole Dosing in HD

In September 1999, the HSG received funding from the US Food and Drug Administration's Orphan Products Division for a multicenter placebo controlled study of riluzole under the principal direction of Frederick Marshall, MD at the University of Rochester and Merit Cudkowicz, MD at Massachusetts General Hospital. The "Riluzole Dosing in HD" (RID-HD) study was designed to assess riluzole's short-term impact on motor, cognitive and behavioral symptoms of HD and to gather information on the safety and tolerability of riluzole. Enrollment in the RID-HD trial began in January 2000 and was completed in August 2000. The results of RID-HD trial were presented at the 19th International Meeting of the World Federation of Neurology Research Group on Huntington's Disease, August 25-28, 2001, Copenhagen, Denmark. A copy of the abstract is linked here. Another informational piece from Dr. Marshall about RID-HD is also available.

Creatine in Huntington's Disease

Under the direction of Karl Kieburtz, MD (University of Rochester) a pilot study was undertaken at the University of Rochester, Ohio State University and Westmead Hospital (Australia). This was an initial study to evaluate and obtain information on the safety and feasibility of creatine, which may have an effect on cellular energy and oxidative stress in neurons of the brain. A copy of the abstract is linked here.

Participating HSG research sites included Massachusetts General Hospital, University of Rochester, University of Iowa, University of Alberta, Mayo Clinic, and University of Maryland. 

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