Safety and Effectiveness of Valbenazine as Adjunct Therapy to Botulinum Toxin Injections in Cervical Dystonia

Overview

The most common form of idiopathic dystonia is adult-onset cervical dystonia (CD), a focal form of dystonia affecting the muscles of the neck. CD is often associated with pain and limited range of motion, and frequently leads to reduced quality of life and disability. Effective long-term treatment options are extremely limited. Recurring botulinum neurotoxin (BoNT) injections can ease the symptoms of CD, but they frequently provide only partial relief and can be associated with intolerable side effects. Deep brain stimulation can be used to treat more severe cases of CD, but this neurosurgical procedure is invasive, on average only about 50% effective and may lead to serious adverse effects. Novel treatment approaches for CD are desperately needed to alleviate symptoms and improve the quality of life for the many who suffer from this chronic and disabling neurological disorder.

Detailed description

The dopaminergic system has been implicated in the pathophysiology of hyperkinetic movement disorders including dystonia. For example, it is well established that acute and chronic dystonia syndromes can be caused by dopamine receptor-blocking drugs. Several animal and human imaging studies also support the presence of abnormal dopaminergic function in idiopathic forms of dystonia. Although historically dopamine receptor-blocking medications have been used to treat dystonia, early clinical trials have been limited and the results mixed. The atypical neuroleptic clozapine was found to be moderately effective in treating segmental and generalized dystonia, but its usefulness was limited by potential adverse effects. Another atypical neuroleptic risperidone has been reported to be effective in a 4-week trial of five patients with various forms of dystonia. Dopamine depleting medications such as the VMAT2 inhibitor tetrabenazine has also been found helpful in some patients with dystonia, particularly those with tardive dystonia, which has overlapping phenomenology with idiopathic dystonia. The more recently developed VMAT2 inhibitor valbenazine has demonstrated clear benefit in tardive dyskinesia, but their therapeutic benefit in idiopathic dystonia has not been evaluated in a placebo-controlled clinical trial. Off label uses and an open-label study of valbenazine suggest it could provide some benefit and be well tolerated in idiopathic CD patient populations.

Interventions

• Drug Valbenazine
  To assess if valbenazine 80mg daily improves motor symptoms in idiopathic CD patients with persistent symptoms despite current treated with botulinum toxin injections.
• Drug Placebo
  Placebo

Primary outcome measures

• Toronto Western Spasmodic Torticollis Rating Scale-2 (TWSTRS)-severity score change at 12 weeks of treatment [Time frame: baseline and 12 weeks of treatment]

Secondary outcome measures (9)

• Global Dystonia Severity Rating Scale (GDSRS) [Time frame: Visit 2 (Baseline, Week 1) and Visit 3 (Week 6)]
• Hospital Anxiety and Depression Scale (HADS) [Time frame: Visit 2 (Baseline, Week 1) and Visit 3 (Week 6)]
• Pittsburgh Sleep Quality Index (PSQI) [Time frame: Visit 2 (Baseline, Week 1) and Visit 3 (Week 6)]
• Epworth Sleepiness Scale (ESS) [Time frame: Visit 2 (Baseline, Week 1) and Visit 3 (Week 6)]
• Cervical Dystonia Impact Profile - 58 item (CDIP-58) [Time frame: Visit 2 (Baseline, Week 1) and Visit 3 (Week 6)]
• Clinical Global Impression of Severity scale (CGI-S) [Time frame: Visit 2 (Baseline, Week 1) and Visit 3 (Week 6)]
• Patient Global Impression of Severity scale (PGI-S) [Time frame: Visit 2 (Baseline, Week 1) and Visit 3 (Week 6)]
• Columbia Suicide Severity Rating Scale (C-SSRS) [Time frame: Visit 2 (Baseline, Week 1) and Visit 3 (Week 6)]
• Pain in Dystonia Scale (PIDS) [Time frame: Visit 2 (Baseline, Week 1) and Visit 3 (Week 6)]

Eligibility criteria

Inclusion criteria

• Idiopathic CD (neck musculature first and most prominently affected)
• 18-75 years old (participants excluded if their dystonia symptoms began before age 18 as childhood-onset dystonia typically represents a genetic and/or primary generalized form of dystonia)
• Onset of dystonia ≥18 years old, no known hyperkinetic movement disorder-related genetic mutation
• Dystonia severity more than minimal and not very severe as defined by Toronto Western Spasmodic Torticollis Rating Scale-2 Motor Severity (TWSTRS-2-Severity) score ≥ 5 and ≤ 20.
• Stable on botulinum toxin injections last 90 days (BoNT dose change <10% and patient reported stability of response over last two injection cycles)
• Stable on other neuroactive medications.

Exclusion criteria

• History of deep brain stimulation
• History of uncontrolled or untreated depression in the prior 3 months, suicidality, or history of suicide attempts
• History of uncontrolled liver disease or failure
• History of tardive dyskinesia or tardive dystonia
• Currently taking dopaminergic and/or anti-dopaminergic medications including VMAT2 inhibitors or other antipsychotic medications
• Exposure to dopaminergic and/or anti-dopaminergic medications including VMAT2 inhibitors or other antipsychotic medications in the last 30 days -Presence of parkinsonism or other movement disorder other than dystonia on exam -Receiving botulinum toxin injections at a planned frequency other than every 3 months or typically receive injections at intervals <11 weeks or >13 weeks -Known history of long QT syndrome or cardiac tachyarrhythmia or any clinically significant cardiac abnormality.
• Prolonged QTc as defined by > 450 msec for men and > 470 msec for women

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Virginia Commonwealth University — Richmond

Identifiers

NCT: NCT06771323 · HM20029848

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗