TD-AIDD: Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities

Sponsor

Stephen Ruedrich (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06107829

Collaborator

Neurocrine Biosciences (Industry)

Enrollment

Location

Arm

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The goal of this open-label clinical trial is to test the safety and efficacy of valbenazine treatment in patients with Intellectual/Developmental Disability (IDD) who have a diagnosis of Tardive dyskinesia (TD). The main questions this study aims to answer are:

Does valbenazine treatment of TD in the previously untreated patient population of adults with IDD produce comparable amelioration of signs of movement disorder as what has historically been reported in adults without IDD?
Is valbenazine treatment of TD in persons with IDD as safe as what has historically been reported in adults without IDD?
Does valbenazine treatment improve Quality of Life (QOL) in persons with IDD and TD treated with valbenazine?
Does valbenazine treatment produce positive change in Activities of Daily Living (ADLs) in persons with IDD and TD?
Does valbenazine treatment of TD in persons with IDD reduce caregiver burden?

This study does not include a comparison group. Therefore, researchers will compare the response of the study participants to valbenazine treatment with those from a previous reported work that resulted in the FDA approval of this medication.

Condition or Disease	Intervention/Treatment	Phase
Tardive Dyskinesia Intellectual Disability Developmental Disabilities	Drug: Valbenazine Oral Capsule	Phase 4

Detailed Description

Tardive dyskinesia (TD) is recognized as a common and often debilitating movement disorder, associated with treatment of a variety of illnesses with dopamine receptor-blocking medications (also commonly known as antipsychotic medications. In addition to the distressing and disfiguring movements of TD, there is now also evidence of a reduced quality of life in patients with TD compared to peers with similar psychiatric disorders without TD.

When originally described, TD had been thought to be primarily associated with use of First-Generation Antipsychotics (FGA's, also known as typical antipsychotics), but there are now good studies to suggest that TD is also frequently a result of exposure to Second Generation Antipsychotics (SGA's) as well. Valbenazine, a selective vesicular monoamine transporter 2 inhibitor, is now available to treat the symptoms of TD, with a favorable efficacy and safety profile. This medication offers, for the first time, a treatment option for patients - as well as their caregivers and families - suffering with TD.

Individuals with intellectual and developmental disabilities (IDD) commonly suffer from co-occurring psychiatric and/or behavioral disorders (informally known as a "dual diagnosis"). Such individuals are commonly prescribed antipsychotic medications to treat these co-occurring disorders. Several authors have noted that antipsychotic medications have frequently been over-prescribed for individuals with IDD, often in the absence of an identified psychotic illness. Some studies have shown that up to 20-30% of adults with IDD are prescribed antipsychotic medications across a variety of residential settings.

Surrounding this frequent use of antipsychotic medications in persons with IDD, it is now well-established that persons and that having intellectual disability is a recognized risk factor for developing TD when treated with antipsychotic medications. Finally, recent research has confirmed the long-suspected belief that persons with IDD are MORE susceptible to movement disorder side effects when treated with antipsychotic medications when compared to persons without IDD.

Based on their increased exposure to antipsychotics, and increased susceptibility to movement disorders including TD, it would seem that persons with IDD who have TD are a group who could benefit most from treatment with a novel agent which can address this movement disorder.

Before TD can be treated, it must be clinically identified and formally diagnosed. Once diagnosed, patients and families must be educated on the availability of treatment options, outcomes when no treatment is undertaken, and the potential benefits (and risks) of treatment itself.

Movement disorders such as TD have been diagnosed on the basis of clinical examination, often using formal assessment tools to identify and quantify the movement abnormalities seen. One such instrument is the Abnormal Involuntary Movement Scale (AIMS). The AIMS has been used for many years as the gold standard for this purpose. In addition, there have been recent attempts to quantify the amount of improvement (change in movement intensity, and reduction in AIMS scores) that are considered clinically significant in rating improvement. Additionally, a number of authors have noted the difficulty in using the AIMS in persons with IDD who cannot cooperate fully in the examination process. For this reason, some have suggested using videotaped AIMS exams as a methodology for more accurately quantifying change. Videotaping of exams pre- and post-treatment for blind rating of improvement has been a methodology utilized in a number of recent studies of valbenazine.

In this study, 25 participants with IDD and TD will undergo valbenazine treatment for 24 weeks. The participants will be seen for a total of 5 visits: at baseline, and at follow up visits at 3 weeks, 6 weeks, 12 weeks, and 24 weeks. Consented participants will have an AIMS administered and videotaped at each visit, initially to identify and quantify TD, and subsequently to measure possible response to valbenazine. Subjects' TD response to valbenazine will also be assessed using the Clinical Global Impression of Change (CGI-C) scale (by investigator) and Caregiver Global Impression Scale (by proxy caregiver). Subjects' quality of life will be assessed with the World Health Organization Quality of Life Scale- For Persons with Disability (WHOQOL-DIS), a proxy-reported instrument designed for individuals with IDD, before and after valbenazine treatment. Participants' behavior will be assessed with the Aberrant Behavior Checklist-Irritability Subscale, before and after valbenazine treatment. Subjects' Activities of Daily Living (ADL's) will be assessed with the Waisman Activities of Daily Living Scale (W-ADL), a proxy-reported instrument designed for individuals with IDD and other disabilities, before and after valbenazine treatment. Caregiver burden will be assessed with the Zarit Burden Inventory, short version, before and after valbenazine treatment.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

25 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Identification, Assessment, and Treatment of Tardive Dyskinesia With Valbenazine in Adults With Intellectual/Developmental Disabilities and Co-occurring Psychiatric and/or Behavioral Disorders

Anticipated Study Start Date :

Mar 1, 2024

Anticipated Primary Completion Date :

Mar 1, 2026

Anticipated Study Completion Date :

Mar 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Valbenazine This an open-label study in which all participants will have their valbenazine dose titrated from 40 mg to 80 mg per day, which will remain the valbenazine dose through end of study, unless interrupted by adverse events. Participants taking valbenazine who are concurrently taking strong CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion, duloxetine) will continue their valbenazine dose at 40 mg per day through end of study. Participants taking valbenazine who are concurrently taking strong CYP3A4 inhibitors (ketoconazole, fluconazole, cimetidine, verapamil) will continue their valbenazine dose at 40 mg per day through end of study.	Drug: Valbenazine Oral Capsule Open-label twenty-four-week treatment with valbenazine oral capsules (up to 80 mg/day) to test the safety and effectiveness of this medication in ameliorating the signs of tardive dyskinesia in persons with intellectual disability. Other Names: Ingrezza

Arm

Intervention/Treatment

Experimental: Valbenazine

This an open-label study in which all participants will have their valbenazine dose titrated from 40 mg to 80 mg per day, which will remain the valbenazine dose through end of study, unless interrupted by adverse events. Participants taking valbenazine who are concurrently taking strong CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion, duloxetine) will continue their valbenazine dose at 40 mg per day through end of study. Participants taking valbenazine who are concurrently taking strong CYP3A4 inhibitors (ketoconazole, fluconazole, cimetidine, verapamil) will continue their valbenazine dose at 40 mg per day through end of study.

Drug: Valbenazine Oral Capsule

Open-label twenty-four-week treatment with valbenazine oral capsules (up to 80 mg/day) to test the safety and effectiveness of this medication in ameliorating the signs of tardive dyskinesia in persons with intellectual disability.

Other Names:

Ingrezza

Outcome Measures

Primary Outcome Measures

Change in AIMS total scores of items 1-7 [Baseline and 24 weeks from start of treatment]
The Abnormal Involuntary Movement Scale (AIMS) has been used for many years as the gold standard for this purpose and the amount of improvement (change in movement intensity, and reduction in AIMS scores) have been assessed clinical significance in rating improvement. A number of authors have noted the difficulty in using the AIMS in persons with IDD who cannot cooperate fully in the examination process. For this reason, some have suggested using videotaped AIMS exams as a methodology for more accurately quantifying change. Videotaping of exams pre- and post-treatment for blind rating of improvement has been a methodology utilized in a number of recent studies of valbenazine. The minimum value of the AIMS total score of items 1-7 is 0 and the maximum value is 49. Higher total AIMS scores mean worse outcomes.

Secondary Outcome Measures

Change in AIMS item 8 scores [Baseline and 24 weeks from start of treatment]
Item 8 of the AIMS represents an overall index of severity of abnormal involuntary movements. The minimum value of the AIMS total score of items 1-7 is 0 and the maximum value is 4; Higher total scores mean worse outcomes.
CGI-C [Baseline and 24 weeks from start of treatment]
Clinical Global Impression of Change (CGI-C), as the names indicates, denotes the clinician's impression of change between baseline and after the treatment in which -3 will be marked worsening, -2 moderate worsening, -1 mild worsening, 0 no change, +1 will be marked for mild improvement, +2 moderate improvement, and +3 marked improvement.
CaGI-C [Baseline and 24 weeks from start of treatment]
Caregiver Global Impression of Change (CaGI-C). This is similar to the CGI-C, except that this is the impression of the participant's caregiver, -3 will be marked worsening, -2 moderate worsening, -1 mild worsening, 0 no change, +1 will be marked for mild improvement, +2 moderate improvement, and +3 marked improvement.
Change in ABC-I score [Baseline and 24 weeks from start of treatment]
The Aberrant Behavioral Checklist, Irritability Subscale (ABC-I) is commonly used in clinical trials. It consists of 15 items, which are scored on a 4-point Likert scale of severity, ranging from "not at all a problem" to "the problem is severe in degree."
Change in W-ADL score [Baseline and 24 weeks from start of treatment]
The Waisman Activities of Daily Living (W-ADL) Scale for adolescents and adults with developmental disabilities, is a validated scale that consists of 17 items in the final version of the W-ADL pertain to the current or expected performance of the target individual at the time when the survey was given. The target adult's performance of each activity is rated on a 3-point scale (0 = "does not do at all", 1 = "does with help", 2 = "independent"), and item scores are summed to produce an overall score. Therefore, this means that the scores can range from a minimum of 0 to a maximum value of 51. Higher total W-ADL scores mean better outcomes.
Change in Zarit Burden Interview (short version) score [Baseline and 24 weeks from start of treatment]
The short version of the Zarit Burden Interview is suitable across diagnostic groups of cognitively impaired older adults, and can be used in cross-sectional, longitudinal, and intervention studies. It consists of 12 items, which are answered by a caregiver and measures the change over time, resulting from the progression of (or therapeutic effect of an intervention on) the care recipient's condition. Each item is scored on a 5-point Likert scale, with higher scores indicating greater burden, i.e., worse outcome.

Other Outcome Measures

Change Simpson-Angus Scale for EPS [Baseline and 24 weeks from start of treatment]
The Simpson-Angus Scale is a tool used to assess the severity of extrapyramidal symptoms (EPS), which are side effects of antipsychotic medications. The scale consists of ten items that assess five domains: gait, arm dropping, shoulder shaking, elbow rigidity, and wrist rigidity or fixation of position. Each item is rated on a 5-point scale of severity (0 = normal; 4 = most severe; NR = not rated). The total score ranges from 0 to 40, with higher scores indicating more severe EPS outcome.
Change in Barnes Akathisia Scale [Baseline and 24 weeks from start of treatment]
The Barnes Akathisia Scale is a rating scale used to assess the severity of drug-induced akathisia (a syndrome of motor restlessness). It is the most widely used rating scale for akathisia. The scale consists of four items that rate the observable, restless movements that characterize the condition, the subjective awareness of restlessness, and any distress associated with the akathisia. The scale is scored on a 4-point scale from 0-3 and is summed yielding a total score ranging from 0 to 9. The higher the score, the more severe the akathisia, i.e., the worse the outcome.
Assessment of electrocardiogram (EKG)-derived QT/QTc intervals [Baseline and 24 weeks from start of treatment]
QTc intervals have clinical importance as a biomarker of potential drug toxicity. QTc intervals ≥ 450 ms are generally considered long, and drug-induced QTc interval prolongations ≥ 60 ms are generally considered clinically relevant.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of IDD (IQ < 70; social/adaptive dysfunction, onset < age 22) as per DSM-5
Clinical diagnosis of Tardive Dyskinesia (TD) per DSM-5 for at least 3 months before study inclusion (presence of movement disorder for at least 3 months, in absence of previous formal diagnosis of TD).
Eligible to receive valbenazine according to current product labeling.
Stable doses of all psychotropic medications for minimum of three months before study inclusion.
Willing to remain on stable doses of all psychotropics for 24 weeks of study. If female of childbearing age, practicing acceptable form for birth control throughout study duration.
Subject able to comply with scheduled visits and assessments.
Consent of subject, or legally authorized representative to study protocol.

Exclusion Criteria:

Previous treatment with a VMAT2 inhibitor (tetrabenazine, valbenazine, or deutetrabenazine).
Treatment with any investigational drug in the 30 days prior to study entry.
Currently taking a strong CYP3A4 inducer such as carbamazepine, phenobarbital, diphenylhydantoin, or primidone.
Any unstable medical condition in the 60 days prior to study entry.
Pregnant or breast-feeding.
Inability to take study medication.
History of neuroleptic malignant syndrome.
History of long QTc on electrocardiogram, bundle branch block (BBB), atrioventricular block, serious cardiac arrhythmia, or heart failure.
QTc on EKG > 450 msec (Fredericia formula) on EKG within 3 months prior to study entry.
History of substance abuse or dependence in the 3 months prior to study entry.
Significant risk of suicide or dangerous aggression to others at time of or 3 months prior to study entry.