Disease Case Study

A 54-year-old male presents in follow-up to your suburban neurology practice for treatment of his progressively worsening chorea caused by Huntington's Disease (HD) diagnosed 17 years ago. The patient has been known to you for the past 5 years as you have managed his HD and associated symptoms. His medical history is significant for an onset of mild depression 4 years ago, chorea, and progressive cognitive decline. His recent medical history is also significant for weight loss secondary to dysphagia related to his HD.

He has no other significant medical history and the only medication he takes is citalopram 20mg 1 tab PO daily for his depression. Today his BMI is 21.5, down from 23.0 6 months ago. Notably, 9 months ago the decision was made at his request to discontinue his tetrabenazine, which was used to manage his chorea. The dosing of tetrabenazine (3 times daily) was prohibitively complicated for him to self-administer with his worsening cognitive decline.

The resultant frequently-missed doses required an algorithm for dose-adjustment that proved too difficult for him to follow.

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This burden, the patient decided, outweighed any benefit obtained from the medication. Your patient is insistent on maintaining his autonomy, lives alone, and declines any outside help (aside from your practice) in managing his disease. He presents today with reports of worsening chorea interfering significantly with his quality of life and safety; he describes, in addition to recent increasing gait and balance disturbances, two recent falls. You observe on physical examination significant worsening of his chorea and marked gait disturbance. You have heard of a new drug recently approved by the FDA, deutetrabenazine, which has reportedly been shown to reduce HD-related chorea with fewer daily doses required, but you wonder if the research supports its efficacy in safely reducing the symptom burden of chorea in HD.

Clinical Question

In patients with Huntington's Disease-related chorea, does deutetrabenazine reduce chorea compared to no medical intervention?

Search Criteria

The question falls under the category of therapy, and, as such, the search was limited to clinical or randomized controlled trials. The search was also limited to peer-reviewed journals published within the last 5 years in English. The search was conducted through PubMed and MEDLINE using the subject terms Huntington's Disease, chorea, and deutetrabenazine. A total of 24 articles were identified.

Search Results

Of the 24 search results, all but 3 were either

1. reviews,
2. examined deutetrabenazine in treating other movement disorders, or
3. examined deutetrabenazine in combination with other medications.

Of note, any article that included the effects of tetrabenazine as a primary outcome measure was excluded, as the therapeutic outcome of tetrabenazine was not part of the clinical question. This eliminated one of the three remaining articles, which examined switching patients from tetrabenazine to deutetrabenazine overnight. The other remaining article was also excluded for comparing tetrabenazine to deutetrabenazine. Further searches of other databases, such as EBSCO, failed to yield further results. The remaining study, published in 2016 in JAMA by the Huntington Study Group, was a multicenter, randomized clinical trial with a satisfactory sample size that investigated the effect of deutetrabenazine on HD-related chorea compared with placebo.1 This trial was used to answer the clinical question.

Evaluating the Evidence

This was a multicenter, randomized, double-blind placebo controlled clinical trial investigating the effectiveness of deutetrabenazine in treating chorea in HD. 90 ambulatory adults with HD, defined as having an expanded HTT CAG repeat of ?36 and characteristic motor features were enrolled in 34 Huntington Study Group investigational sites across the U.S. and Canada. Inclusion criteria included patients with a Unified Huntington's Disease Rating Scale (UHDRS) total maximal chorea score of ?8 and a UHDRS total functional capacity score of ?5. Exclusion criteria included serious untreated psychiatric illness, prolonged QTc interval, left bundle branch-block, hepatic and renal impairment, significant speech impairment, or a score of ?11 on the Swallowing Disturbance Questionnaire (SDQ). Initially, use of tetrabenazine was exclusionary, but a protocol amendment once the study was initiated allowed patients with prior tetrabenazine exposure to enroll to meet enrollment expectations. Allocation concealment assured that study participants, caregivers, study partners, investigators, site personnel, data management staff, and the steering committee were blinded to treatment. Patients were randomized 1:1 to deutetrabenazine or placebo. Patients were titrated to an optimal study dose over 8 weeks, followed by 4 weeks of maintenance therapy and a 1-week washout. The primary endpoint was the change in total maximal chorea score from baseline to maintenance therapy measured by the UHDRS. The study was powered for a treatment effect of -2.7 points on the UHDRS maximal chorea score. Four secondary end points were assessed hierarchically in the following order: treatment success in the Patient Global Impression of Change scale (PGIC), the Clinical Global Impression of Change (CGIC), the 36-Item Short Form Health Survey (SF-36) physical functional subscale, and the Berg Balance Test. A total of 90 patients were enrolled, none were lost to follow-up, and there was 1 adverse event in both the intervention and placebo groups. The primary outcome was met; patients in the deutetrabenazine group had an average improvement of maximal chorea of -4.4; the mean between-group difference was -2.5 (95% CI -3.7 to -1.3) (P