Deutetrabenazine for Huntington's Disease
Recruiting in Palo Alto (17 mi)
Overseen byAmy E Brown, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2 & 3
Recruiting
Sponsor: Vanderbilt University Medical Center
Must not be taking: VMAT2 inhibitors
Disqualifiers: Severe depression, Suicidal ideation, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Approved in 3 Jurisdictions
Trial Summary
What is the purpose of this trial?Examine the effects of deutetrabenazine on functional speech and gait impairment
Will I have to stop taking my current medications?
The trial requires that you stop taking any current VMAT2 inhibitors (like tetrabenazine, deutetrabenazine, or valbenazine) before participating.
What data supports the effectiveness of the drug deutetrabenazine for Huntington's disease?
Deutetrabenazine has been shown to significantly improve chorea (involuntary movements) in patients with Huntington's disease compared to a placebo, as demonstrated in a 12-week clinical trial. It is also generally well-tolerated, with a side effect profile similar to placebo, except for some drowsiness.
12345Is deutetrabenazine safe for humans?
Deutetrabenazine is generally considered safe for humans, with most side effects being mild or moderate. Long-term studies have shown it to be safe for up to three years, and it does not have a significant effect on heart rhythm at recommended doses.
12367What makes the drug deutetrabenazine unique for treating Huntington's disease?
Deutetrabenazine is a modified form of tetrabenazine with a longer-lasting effect, allowing it to be taken twice daily, which can improve patient compliance. It has a lower peak concentration, potentially reducing some side effects, and unlike tetrabenazine, it does not affect the heart's QT interval.
12368Eligibility Criteria
This trial is for individuals with Huntington's Disease who can walk at least 10 meters, have a certain level of chorea (involuntary movements), and are cognitively able to participate. They must not be pregnant or breastfeeding, have severe depression or speech impairments, nor any serious medical conditions that could interfere with the study.Inclusion Criteria
I have completed at least 10th grade.
Willing and able to give written informed consent prior to performing any study procedures
My cognitive function score is 22 or higher.
+5 more
Exclusion Criteria
Concurrent participation in any other investigational drug trials
I do not have any serious or unstable health or mental conditions.
I have severe difficulty speaking or cannot speak at all.
+8 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive deutetrabenazine with dose titration to achieve optimal chorea control
Up to 10 weeks
Weekly visits for dose titration
Evaluation
Comprehensive evaluations of speech production, fine motor skills, gait, and balance using standardized assessments and 3D motion analysis
Up to 10 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial is testing Deutetrabenazine to see if it improves functional speech and walking in people with Huntington's Disease. Participants will receive this medication and their speech and gait dynamics will be monitored for changes.
1Treatment groups
Experimental Treatment
Group I: DeutetrabenazineExperimental Treatment1 Intervention
The mode of administration is oral. Subjects will be started on deutetrabenazine at a dose of 6mg/day. Dosing will be up-titrated in increments of 6mg/day per week to achieve optimal chorea control.
Deutetrabenazine is already approved in United States, China, Australia for the following indications:
πΊπΈ Approved in United States as Austedo for:
- Chorea associated with Huntington's disease
- Tardive dyskinesia in adults
π¨π³ Approved in China as Austedo for:
- Chorea associated with Huntington's disease
- Tardive dyskinesia in adults
π¦πΊ Approved in Australia as Austedo for:
- Chorea associated with Huntington's disease
- Tardive dyskinesia in adults
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Vanderbilt University Medical CenterNashville, TN
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Who Is Running the Clinical Trial?
Vanderbilt University Medical CenterLead Sponsor
Teva Branded Pharmaceutical Products R&D, Inc.Industry Sponsor
References
Pharmacokinetics of Deutetrabenazine and Tetrabenazine: Dose Proportionality and Food Effect. [2022]Deutetrabenazine (Austedo, Teva), an approved treatment of chorea in Huntington's disease and tardive dyskinesia in adult patients, is a rationally designed deuterated form of tetrabenazine. Two studies assessed the pharmacokinetics and safety of deutetrabenazine compared with tetrabenazine, and the effects of food on absorption of the deuterated active metabolites, α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). One study was an open-label 2-part study in healthy volunteers; the first part included a crossover single dose of two 15 mg candidate deutetrabenazine formulations in fed and fasted states compared with tetrabenazine 25 mg in the fasted state, and the second part included single and repeated dosing of the commercial formulation of deutetrabenazine (7.5, 15, and 22.5 mg) compared with tetrabenazine 25 mg. The second study was an open-label 5-way crossover study in healthy volunteers (n = 32) to evaluate relative bioavailability of 4 dose levels of the commercial formulation of deutetrabenazine (6, 12, 18, and 24 mg) with a standard meal and 18 mg with a high-fat meal. Both studies confirmed longer half-lives for active metabolites and lower peak-to-trough fluctuations for the sum of the metabolites (total [α+β]-HTBZ) following deutetrabenazine compared with tetrabenazine (3- to 4-fold and 11-fold, respectively) in steady-state conditions. Deutetrabenazine doses estimated to provide total (α+β)-HTBZ exposure comparable to tetrabenazine 25 mg were 11.4-13.2 mg. Food had no effect on exposure to total (α+β)-HTBZ, as measured by AUC. Although the total (α+β)-HTBZ Cmax of deutetrabenazine was increased by ≈50% in the presence of food, it remained lower than that of tetrabenazine.
Deutetrabenazine: A Review in Chorea Associated with Huntington's Disease. [2018]Oral deutetrabenazine (Austedoβ’), a reversible inhibitor of vesicular monoamine transporter type 2 (VMAT2) that is structurally related to tetrabenazine is approved for the treatment of chorea symptoms associated with Huntington's disease (HD). In the pivotal 12-week phase III FIRST-HD trial (n = 90), deutetrabenazine, at doses titrated for optimal chorea control and tolerability (maintenance dosage range 12-48 mg/day), was significantly more effective for controlling chorea in HD patients than placebo. In the ongoing phase III ARC-HD trial, a preliminary analysis demonstrated that deutetrabenazine treatment was associated with improvements in chorea control at 54 weeks in patients who had completed FIRST-HD (i.e. β€ 66 weeks' treatment; rollover cohort) or switched overnight from tetrabenazine to deutetrabenazine. The tolerability profile of deutetrabenazine is similar to that of placebo, with most treatment-emergent adverse events of mild or moderate severity. In both trials, with the exception of somnolence, individual neuropsychiatric adverse events typically occurred in
Tetrabenazine Versus Deutetrabenazine for Huntington's Disease: Twins or Distant Cousins? [2022]Tetrabenazine is the only US Food and Drug Administration-approved drug for Huntington's disease, and deutetrabenazine was recently tested against placebo. A switching-trial from tetrabenazine to deutetrabenazine is underway, but no head-to-head, blinded, randomized controlled trial is planned. Using meta-analytical methodology, the authors compared these molecules.
Tetrabenazine and movement disorders. [2022]Based on blind review of videotape recordings, we analyzed the ability of tetrabenazine to suppress abnormal movements. The recordings were done before treatment, after 3 weeks on a stable dose (up to 200 mg daily) of tetrabenazine, and then after 3 weeks on placebo. Among the patients who completed the trial, improvement occurred in 6 of 8 with Huntington disease, 6 of 10 with tardive dyskinesia, and 3 of 8 with dystonic disorders. The drug was usually tolerated well.
Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease. [2018]Deutetrabenazine was recently approved for the treatment of chorea in Huntington's disease (HD) and is the first deuterated medication that has been US Food and Drug Administration (FDA)-approved for therapeutic use. In this article, we review deutetrabenazine's drug design, pharmacokinetics, drug interactions, efficacy, adverse events, comparison with tetrabenazine, dosage, and administration. Deutetrabenazine is a deuterated form of tetrabenazine and is a vesicular monoamine transporter 2 (VMAT2) inhibitor. The substitution of deuterium for hydrogen at key positions in the tetrabenazine molecule allows a longer drug half-life and less frequent daily dosing. Deutetrabenazine is administered twice daily up to a maximum daily dose of 48 mg, which corresponds to a similar daily dose of 100 mg of tetrabenazine. In a Phase III clinical trial (First-HD), there was a statistically significant improvement of chorea in HD subjects, as well as improvements in global impression of change as assessed by both patients and clinicians. This improvement was seen without significant adverse effects as the overall tolerability profile of deutetrabenazine was similar to placebo. Somnolence was the most commonly reported symptom in the deutetrabenazine group. In a study where subjects converted from tetrabenazine to deutetrabenazine in an open-label fashion (ARC-HD) and indirect comparison studies between tetrabenazine and deutetrabenazine, there is a suggestion that while efficacy for chorea is similar, the data may slightly favor tetrabenazine, but adverse effects and tolerability strongly favor deutetrabenazine. These data have not been replicated in true head-to-head studies. Current evidence supports that deutetrabenazine is an effective therapeutic treatment option for chorea in HD and may provide a more favorable adverse effect profile than tetrabenazine. However, more data are needed, particularly in the form of head-to-head studies between deutetrabenazine and other treatment options as well as longer term clinical experience with deutetrabenazine.
Clinical Utility of Deutetrabenazine as a Treatment Option for Chorea Associated with Huntington's Disease and Tardive Dyskinesia. [2023]Deutetrabenazine (DTBZ) is used for the treatment of tardive dyskinesia (TD) and chorea in Huntington's Disease (HD). Four pivotal clinical trials showed the efficacy of DTBZ in these conditions. Long term follow-up studies confirmed evidence of overall safety and continued efficacy of this drug. Indirect comparisons revealed relative superiority of DTBZ over TBZ in terms of safety, but direct comparisons of safety and efficacy between the VMAT2 and dopamine blocking agents is lacking. Deutetrabenazine is safe and effective in the treatment of TD and chorea in HD in doses up to 72 mg daily and for up to three years in duration.
Evaluation of Deutetrabenazine's Potential to Delay Cardiac Repolarization Using Concentration-QTc Analysis. [2023]Deutetrabenazine (Austedo) is indicated in adults for chorea associated with Huntington disease and tardive dyskinesia. Escalating deutetrabenazine doses were administered to healthy volunteers who were cytochrome P450 2D6 extensive/intermediate metabolizers (EMs) or poor metabolizers (PMs) to determine pharmacokinetic exposure of parent drug and active metabolites (Ξ±-dihydrotetrabenazine [Ξ±-HTBZ] and Ξ²-dihydrotetrabenazine [Ξ²-HTBZ]), and collect corresponding electrocardiograms (ECGs) for evaluation of the cardiodynamic effect using concentration-QTc (C-QTc) modeling. Participants (12 EMs, 24 PMs) received placebo or single doses of deutetrabenazine (24, 48, and 72 mg) to achieve plasma concentrations exceeding therapeutic range in both cohorts. Pharmacokinetic samples were obtained over 72 hours after dosing and were time matched with 12-lead ECGs extracted from continuous ECG recordings. C-QTc analysis, using linear mixed-effects modeling and model selection procedure, characterized the relationship between plasma concentrations of deutetrabenazine, deuterated Ξ±-HTBZ and Ξ²-HTBZ, and the change from baseline in QT interval corrected using Fridericia's formula. Deutetrabenazine exhibited linear kinetics, and a C-QTc model with deuterated Ξ±-HTBZ and Ξ²-HTBZ was selected to best describe the C-QTc relationship in pooled EM and PM data. This model predicted a placebo-corrected Fridericia corrected QT interval prolongation higher than 10 milliseconds can be excluded at concentrations associated with the maximum recommended doses in both populations. Adverse events increased with higher exposure as reflected by the higher event number in the PM cohort receiving 48 and 72 mg doses. No subject discontinued due to cardiac-related adverse events and no clinically relevant ECG findings were reported. Thus, this study found that deutetrabenazine does not have a clinically relevant effect on QT prolongation at maximum recommended doses in either cytochrome P450 2D6 EMs or PMs.
Deutetrabenazine: Treatment of hyperkinetic aspects of Huntington's disease, tardive dyskinesia and Tourette syndrome. [2018]Deutetrabenazine is a derivative of tetrabenazine in which two trideuteromethoxy groups substitute two methoxy groups. The active metabolites of deutetrabenazine have a longer half-life than those of tetrabenazine, together with a greater overall absorption. However, the peak plasma concentrations are lower. Because of these pharmacokinetic differences, deutetrabenazine can be given twice daily, thus improving compliance. The lower peak concentrations may account for a lower incidence of some unwanted adverse effects. Unlike tetrabenazine, deutetrabenazine has no effect on the QT interval. Treatment with deutetrabenazine significantly improved chorea in Huntington's disease, the hyperkinetic features of tardive dyskinesia, and tics in Tourette syndrome. In all three conditions, deutetrabenazine produced an acceptable level of overall adverse effects without causing any severe adverse effects.