Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities

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

The primary goal of this study is to investigate the efficacy of deutetrabenazine treatment of TD in this previously untreated patient population. Compare movement disorder deutetrabenazine treatment response in persons with IDD to response seen in patients without IDD treated with deutetrabenazine in other treatment settings (per literature review). Compare global deutetrabenazine treatment response with validated instruments.

In addition, we plan to:

• Assess the safety of deutetrabenazine in the treatment of TD in persons with IDD.
• Assess change in Activities of Daily Living (ADLs) in persons with IDD and TD treated with deutetrabenazine, utilizing a validated ADL instrument.
• Assess change in Quality of Life (QOL) in persons with IDD and TD treated with deutetrabenazine, utilizing a validated QOL instrument.
• Assess caregiver burden with a validated caregiver burden instrument.

In this study, 25 participants with IDD and TD will undergo Deutetrabenazine 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.

This study does not include a comparison group. Therefore, researchers will compare the response of the study participants to deutetrabenazine treatment with those from a previous reported work that resulted in the FDA approval of this medication. This will be an open-label, Phase 4 study.

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 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. Deutetrabenazine, 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 a treatment option for patients - as well as their caregivers and families - affected by 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 an 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 TD studies.

There is recent initial research attempting to identify and/or quantify the consequence of TD on activities of daily living (ADLs) and quality of life (QOL) of affected individuals; as well as the caregiver burden that may accompany TD for family and non-family caregivers of affected individuals. The Impact-TD scale was developed by TD clinician experts through a modified Delphi process, and produces subscale scores across four domains (social, psychological/psychiatric, physical, vocational/educational/recreational), resulting in a global Impact-TD score. The Impact-TD can utilize input from patients, families, caregivers and clinicians in arriving at subscale and global scores. The Tardive Dyskinesia Impact Scale (TDIS) evolved from a previous scale (the Tardive Dyskinesia Rating Scale) using input from patients and caregivers. The TDIS is an eleven-item questionnaire using a five-point Likert scale to produce a total scale score ranging from 0-44, with higher scores reflecting greater impact of TD on daily functioning. In a small sample of patients with TD, the TDIS appeared valid and reliable. Interestingly, in this sample, TDIS scores did not appear to correlate with AIMS score, indicating that the two scales seemed to capture different aspects of TD severity and consequence.

To date, neither the Impact-TD nor the TDIS have included subjects with IDD and TD. The subjects included in TD studies to date (both the treatment studies of the two VMAT2 inhibitors currently available, and the subsequent studies of the Impact-TD and TDIS) have had diagnoses of schizophrenia, schizoaffective disorder, and mood disorders. Although persons with IDD can and do suffer from these co-occurring psychiatric disorders, this group of individuals have mostly been excluded from TD studies.

The Waisman Activities of Daily Living Scale (W-ADL) is a 17 item instrument rated on a 3-point scale, which has been used in both snapshot and longitudinal studies, and has been shown to have construct validity and few floor or ceiling effects, as well as reliability over time. The World Health Organization Quality of Life Disability Scale (WHO-QOL-D) caregiver form has been used to measure QOL in adults with various disabilities, including intellectual disability. The Zarit Caregiver Burden Scale has been utilized to measure/monitor caregiver burden in individuals with dementia over time. Accordingly, these instruments will be administered pre-and-post treatment of a cohort of adults with ID and TD, in order to determine whether successful treatment of TD will mitigate ADLs and QOL in affected individuals, and caregiver burden in their family and non-family caregivers.

The primary end point of this clinical study is to measure the efficacy of deutetrabenazine in improving TD and reducing AIMS total score. Secondary objectives are to determine whether deutetrabenazine treatment will produce significant improvement in activities of daily living, quality of life; and reduce caregiver burden, in persons with IDD and TD.

Participant 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 deutetrabenazine, 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 of birth control throughout study duration.
• Subject able to comply with scheduled visits and assessments
• Consent of subject, or legally authorized representative to study protocol.

Caregiver Inclusion Criteria:

• Able to understand and answer questionnaires
• Able to comply with scheduled visits
• Ability to be primary Caregiver for 24 weeks of study

Participant 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 CYP2D6 inhibitor such as fluoxetine, paroxetine, quinidine, bupropion. Current treatment with strong anticholinergic agents, monoamine oxidase inhibitors, metoclopramide, dopamine agonists, L-DOPA, or stimulants within past 30 days, or botulinum toxin within the past 3 months.
• Any unstable medical condition in the 60 days prior to study entry.
• Pregnant or breast-feeding
• Current or recent hepatic impairment
• 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.
• Inability to take study medications

Caregiver Exclusion Criteria:

• Unable to complete questionnaires
• Unable to comply with scheduled visits
• Will not be a primary Caregiver for the 24 weeks of the study