RID-HD Abstract Riluzole Dosing in Huntington's Disease (RID-HD): Results of an 8-Week Double-Blind, Placebo-Controlled, Multi-Center Study by the Huntington Study Group
Presenter:
Frederick J. Marshall, M.D. (University of Rochester)
Background:
Riluzole reduces striatal lesion size and improves abnormal movements in pharmacological animal models of Huntington's disease (HD) using quinolinate, malonate, or 3-nitropropionate. Riluzole was well tolerated and improved chorea in a 6-week open-label study of 8 HD patients.
Methods:
We conducted an 8-week double blind study of riluzole in sixty-three subjects (32F, 31M) with HD (total functional capacity mean 9.9, SD 1.9) enrolled at 9 North American Huntington Study Group (HSG) centers. Subjects were required to be medically and psychiatrically stable at baseline, and were allowed to be on stable dosages of concomitant neuroleptic. Subjects were randomized to receive placebo (22), riluzole 100 mg/d (18), or riluzole 200 mg/d (23). The primary outcome variable was the change from baseline to week-8 in the total maximal chorea score of the Unified Huntington's Disease Rating Scale (version 1999) (UHDRS-99). Secondary outcomes included motor, cognitive, behavioral, and functional components of the UHDRS-99 as well as safety and tolerability.
Results:
The treatment groups were comparable with regard to demographics and disease parameters at baseline, except that more subjects in the riluzole 200 mg/d group were on stable dosages of concomitant neuroleptic. There was significant improvement in chorea at 8 weeks in the riluzole 200mg/d group (mean -2.2, SD 3.3) vs. placebo (mean +0.7, SD 3.4) (p = 0.01). Riluzole 100mg/d also improved chorea (mean -0.2, SD 2.9), but this result did not reach significance vs. placebo. The UHDRS-99 total motor score improved in the high-dose group (mean -4.0, SD 7.1) vs. placebo (mean 1.6, SD 7.4) (p = 0.03), but this was attributable to the improvement in chorea. Seven subjects failed to complete the study (placebo 2, riluzole 100mg/d 2, riluzole 200mg/d 3). There was a dosage related trend toward elevation of serum alanine aminotransferase (ALT) >2x upper limit of normal (placebo 0, riluzole 100mg/d 3, riluzole 200mg/d 5) (p = 0.01). There were no significant differences in the occurrence of other adverse events or in other motor, cognitive, behavioral or functional endpoints.
Conclusions:
Riluzole was safe and well tolerated by HD subjects at the highest dosage explored in the current study (200mg/d), although ALT must be monitored per guidelines. Riluzole improves chorea in HD, without favorably or adversely impacting other clinical features of the illness over the course of 8 weeks. It is unclear whether riluzole's impact on chorea represents a direct effect of the drug or an adjunctive effect in the setting of concomitant neuroleptic treatment.
Supported primarily by a grant from the Food and Drug Administration Office of Orphan Products Development (FD-R-001671-01), and by grants from the Huntington Disease Society of America. Study-drug and matching placebo were provided free-of-charge by Aventis Pharmaceuticals.
