Evaluating the Efficacy of Dextromethorphan/Quinidine in Treating Irritability in Huntington's Disease

Study Overview
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Brief Summary
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The purpose of this study is to assess efficacy and safety of dextromethorphan/quinidine 20mg/10mg (DM/Q 20mg/10mg) in patients with irritability due to Huntington's disease.

Official Title
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Evaluating the Efficacy of Dextromethorphan/Quinidine in Treating Irritability in Huntington's Disease

Conditions
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Huntington Disease, Irritability

Intervention / Treatment
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* Drug: Dextromethorphan/quinidine 20mg/10mg (DM/Q 20mg/10mg)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Verified HD mutation carriers; Irritable as diagnosed by the Irritability Scale with a score > 14; Stable concomitant medication (no change of medication during last 30 days prior to inclusion); Written informed consent by prospective study participant before conduct of any trial-related procedure. Participant must be able to make an informed decision of whether or not to participate in the study. Exclusion Criteria: Hypersensitivity to dextromethorphan (e.g., rash, hives), quinine, mefloquine, quinidine, or dextromethorphan/quinidine with a history of thrombocytopenia, hepatitis, bone marrow depression or lupus-like syndrome induced by these drugs; Pregnant or nursing women; Active suicidality based on the answer yes in questions 4 and 5 of the Columbia-Suicide Severity Rating Scale (baseline version); Woman of childbearing potential, not using highly effective methods of contraception such as oral, topical or injected contraception, IUD, contraceptive vaginal ring, or double barrier method such as diaphragm and condom with spermicide) or not surgically sterile (via hysterectomy, ovarectomy or bilateral tubal ligation) or not at least one year post-menopausal; Male not using an acceptable barrier method for contraception; Presence of any medically not controllable disease (e.g. uncontrolled arterial hypertension or diabetes mellitus); Clinically significant renal (calculated creatinine clearance < 30 ml/min) or hepatic dysfunction; Patients with pre-existing hepatic disease; Individuals with a history or complete heart block, QTc prolongation or tornadoes de pointes, or at high risk of complete AV block; Family history of congenital QT prolongation; History of unexplained syncope within the past year; Use of drugs containing quinidine, quinine, or mefloquine; Individuals currently taking strong CYP3A4 inhibitors or tetrabenazine; Use of certain antidepressants--amitriptyline, clomipramine, desipramine, fluoxetine, paroxetine, sertraline, venlafaxine; Use of certain heart rhythm medications--amiodarone, flecainide, procainamide, propafenone; Use of certain medicines to treat psychiatric disorders--chlorpromazine, haloperidol, perphenazine, pimozide, quetiapine, risperidone, thioridazine. Use of tamoxifen; Presence or history of seizures or diagnosed epilepsy; Severe cognitive disorders defined as a score < 18 on the MOCA; Clinically relevant abnormal findings in the ECG, the vitals, in the physical examination or laboratory values at screening that could interfere with the objectives of the study or the safety of the subject as judged by the investigator; Participation in another investigative drug trial within 2 months; Subjects who are unlikely to be compliant and attend scheduled clinic visits as required as determined by the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dextromethorphan/quinidine 20mg/10mg (DM/Q 20mg/10mg), then Placebo<br>Dextromethorphan/quinidine (DM/Q) 20mg/10mg one capsule once daily for 1 week, followed by DM/Q 20mg /10 mg twice daily for subsequent 4 weeks, and finally DM/Q 20mg/10mg once daily for 7days. | Drug: Dextromethorphan/quinidine 20mg/10mg (DM/Q 20mg/10mg)<br>* DM/Q 20mg/10mg one capsule once daily for 1 week, followed by DM/Q 20mg /10 mg twice daily for subsequent 4 weeks, and finally DM/Q 20mg/10mg once daily for 7days.<br>* Other names: Nuedexta;Drug: Placebo<br>* Placebo once daily for 1 week, followed by placebo twice daily for subsequent 4 weeks, and finally placebo once daily for 7days.<br>|
| Placebo Comparator: Placebo, then Dextromethorphan/quinidine 20mg/10mg (DM/Q 20mg/10mg)<br>Placebo one capsule once daily for 1 week, followed by placebo twice daily for subsequent 4 weeks, and finally placebo once daily for 7days. | Drug: Dextromethorphan/quinidine 20mg/10mg (DM/Q 20mg/10mg)<br>* DM/Q 20mg/10mg one capsule once daily for 1 week, followed by DM/Q 20mg /10 mg twice daily for subsequent 4 weeks, and finally DM/Q 20mg/10mg once daily for 7days.<br>* Other names: Nuedexta;Drug: Placebo<br>* Placebo once daily for 1 week, followed by placebo twice daily for subsequent 4 weeks, and finally placebo once daily for 7days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Irritability as assessed by The Irritability Scale. | The Irritability Scale total score ranges from 0 to 42, with higher scores indicating greater irritability. | Baseline. | 
| Irritability as assessed by The Irritability Scale | The Irritability Scale total score ranges from 0 to 42, with higher scores indicating greater irritability. | Week 6. | 
| Irritability as assessed by The Irritability Scale. | The Irritability Scale total score ranges from 0 to 42, with higher scores indicating greater irritability. | Week 13. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive symptoms, as assessed by the Unified Huntington's Disease Rating Scale (UHDRS) - cognitive domain. | The UHDRS - cognitive assessment includes a phonetic verbal fluency test, the Symbol Digit Modalities Test, and the Stroop Interference Test. These tests do not have a predefined score range, but higher scores indicate better cognitive performance. | Baseline. | 
| Cognitive symptoms, as assessed by the Unified Huntington's Disease Rating Scale (UHDRS) - cognitive domain. | The UHDRS - cognitive function assessment a phonetic verbal fluency test, the Symbol Digit Modalities Test, and the Stroop Interference Test. These tests do not have a predefined score range, but higher scores indicate better cognitive performance. | Week 6. | 
| Cognitive symptoms, as assessed by the Unified Huntington's Disease Rating Scale (UHDRS) - cognitive domain. | The UHDRS - cognitive assessment includes a phonetic verbal fluency test, the Symbol Digit Modalities Test, and the Stroop Interference Test. These tests do not have a predefined score range, but higher scores indicate better cognitive performance. | Week 13. | 
| Behavioral symptoms, as assessed by the Hospital Anxiety and Depression Scale (HADS). | The HADS is a self-report, 14-item scale (7 items relate to anxiety and 7 relate to depression) used to determine the levels of anxiety and depression that a person is experiencing. The total score ranges from 0 to 42 (21 per subscale), with higher scores signifying worse symptoms. | Baseline. | 
| Behavioral symptoms, as assessed by the Hospital Anxiety and Depression Scale (HADS). | The HADS is a self-report, 14-item scale (7 items relate to anxiety and 7 relate to depression) used to determine the levels of anxiety and depression that a person is experiencing. The total score ranges from 0 to 42 (21 per subscale), with higher scores signifying worse symptoms. | Week 6. | 
| Behavioral symptoms, as assessed by the Hospital Anxiety and Depression Scale (HADS). | The HADS is a self-report, 14-item scale (7 items relate to anxiety and 7 relate to depression) used to determine the levels of anxiety and depression that a person is experiencing. The total score ranges from 0 to 42 (21 per subscale), with higher scores signifying worse symptoms. | Week 13. | 
| Behavioral symptoms, as assessed by the Neuropsychiatric Inventory-Questionnaire (NPI-Q) - severity score. | The NPI-Q is a 12-domain informant-based interview that assesses neuropsychiatric symptoms over the previous month.The total NPI-Q severity score ranges from 0 to 36, with higher scores indicate greater symptoms severity. | Baseline. | 
| Behavioral symptoms, as assessed by the Neuropsychiatric Inventory-Questionnaire (NPI-Q) - severity score. | The NPI-Q is a 12-domain informant-based interview that assesses neuropsychiatric symptoms over the previous month.The total NPI-Q severity score ranges from 0 to 36, with higher scores indicate greater symptoms severity. | Week 6. | 
| Behavioral symptoms, as assessed by the Neuropsychiatric Inventory-Questionnaire (NPI-Q) - severity score. | The NPI-Q is a 12-domain informant-based interview that assesses neuropsychiatric symptoms over the previous month.The total NPI-Q severity score ranges from 0 to 36, with higher scores indicate greater symptoms severity. | Week 13. | 
| Behavioral symptoms, as assessed by the Neuropsychiatric Inventory-Questionnaire (NPI-Q) - caregiver distress. | Caregiver distress associated with the symptom is rated on an anchored 0- to 5-point scale, which total sum ranges from 0 to 60. Higher scores indicate greater caregiver distress related to patient's neuropsychiatric symptoms. | Baseline. | 
| Behavioral symptoms, as assessed by the Neuropsychiatric Inventory-Questionnaire (NPI-Q) - caregiver distress. | Caregiver distress associated with the symptom is rated on an anchored 0- to 5-point scale, which total sum ranges from 0 to 60. Higher scores indicate greater caregiver distress related to patient's neuropsychiatric symptoms. | Week 6. | 
| Behavioral symptoms, as assessed by the Neuropsychiatric Inventory-Questionnaire (NPI-Q) - caregiver distress. | Caregiver distress associated with the symptom is rated on an anchored 0- to 5-point scale, which total sum ranges from 0 to 60. Higher scores indicate greater caregiver distress related to patient's neuropsychiatric symptoms. | Week 13. | 
| Behavioral symptoms, as assessed by the Problem Behaviors Assessment - short version (PBA-s). | The PBA-s is a semistructured interview to measure severity and frequency of behavioral problems in Huntington's disease.The PBA-s is an 11-item scale rating the frequency and severity of symptoms. The total score ranges from 0 to 176, with higher scores indicating greater behavioral symptoms severity. | Baseline. | 
| Behavioral symptoms, as assessed by the Problem Behaviors Assessment - short version (PBA-s). | The PBA-s is a semistructured interview to measure severity and frequency of behavioral problems in Huntington's disease.The PBA-s is an 11-item scale rating the frequency and severity of symptoms. The total score ranges from 0 to 176, with higher scores indicating greater behavioral symptoms severity. | Week 6. | 
| Behavioral symptoms, as assessed by the Problem Behaviors Assessment - short version (PBA-s). | The PBA-s is a semistructured interview to measure severity and frequency of behavioral problems in Huntington's disease.The PBA-s is an 11-item scale rating the frequency and severity of symptoms. The total score ranges from 0 to 176, with higher scores indicating greater behavioral symptoms severity. | Week 13. | 
| Motor symptoms, as assessed by the total motor score (TMS) from the UHDRS. | The TMS comprises the motor section of the UHDRS, a 31-item subscale that comprehensively evaluates motor aspects of HD. The overall 31 items are each rated from grade 0 (not affected) to grade 4 (most severely affected), resulting in a range of 0-124 points. | Baseline. | 
| Motor symptoms, as assessed by the total motor score (TMS) from the UHDRS. | The TMS comprises the motor section of the UHDRS, a 31-item subscale that comprehensively evaluates motor aspects of HD. The overall 31 items are each rated from grade 0 (not affected) to grade 4 (most severely affected), resulting in a range of 0-124 points. | Week 6. | 
| Motor symptoms, as assessed by the total motor score (TMS) from the UHDRS. | The TMS comprises the motor section of the UHDRS, a 31-item subscale that comprehensively evaluates motor aspects of HD. The overall 31 items are each rated from grade 0 (not affected) to grade 4 (most severely affected), resulting in a range of 0-124 points. | Week 13. | 
| Motor symptoms, as assessed by the total maximal chorea (TMC). | The TMC comprises 7 of the 31 items in the TMS, which are related to chorea symptoms. The total TMC score ranges from 0 to 28, with higher scores indicating greater chorea severity. | Baseline. | 
| Motor symptoms, as assessed by the total maximal chorea (TMC). | The TMC comprises 7 of the 31 items in the TMS, which are related to chorea symptoms. The total TMC score ranges from 0 to 28, with higher scores indicating greater chorea severity. | Week 6. | 
| Motor symptoms, as assessed by the total maximal chorea (TMC). | The TMC comprises 7 of the 31 items in the TMS, which are related to chorea symptoms. The total TMC score ranges from 0 to 28, with higher scores indicating greater chorea severity. | Week 13. | 
| Functional independence, as assessed by the UHDRS Total Functional Capacity Scale (TFC). | The TFC lists five stages of Huntington's Disease and five levels of function in the domains of workplace, finances, domestic chores, activities of daily living and requirements for unskilled or skilled care. The total TFC score ranges from 0 to 13, with higher scores signifying better functioning. | Baseline. | 
| Functional independence, as assessed by the UHDRS Total Functional Capacity Scale (TFC). | The TFC lists five stages of Huntington's Disease and five levels of function in the domains of workplace, finances, domestic chores, activities of daily living and requirements for unskilled or skilled care. The total TFC score ranges from 0 to 13, with higher scores signifying better functioning. | Week 6. | 
| Functional independence, as assessed by the UHDRS Total Functional Capacity Scale (TFC). | The TFC lists five stages of Huntington's Disease and five levels of function in the domains of workplace, finances, domestic chores, activities of daily living and requirements for unskilled or skilled care. The total TFC score ranges from 0 to 13, with higher scores signifying better functioning. | Week 13. | 
| Behavioral suicidal events, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) - Suicidal ideation. | The C-SSRS is a suicidal ideation and behavior rating scale with yes/no responses. The first part (Items 1-5) rates an individual's degree of suicidal ideation on a 0-5 scale, ranging from wish to be dead to active suicidal ideation with specific plan and intent and behaviors. The C-SSRS outcomes are categories and have binary responses (yes/no). Suicidal ideation is considered when the patient responds a yes answer at any time during treatment to any one of the five suicidal ideation questions (Categories 1-5) on the C-SSRS. The sum of the 5 intensity item scores create a total score (range 0 to 25) to represent the intensity rating (higher scores indicate more severe suicidal ideation). | Baseline. | 
| Behavioral suicidal events, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) - Suicidal ideation | The C-SSRS is a suicidal ideation and behavior rating scale with yes/no responses. The first part (Items 1-5) rates an individual's degree of suicidal ideation on a 0-5 scale, ranging from wish to be dead to active suicidal ideation with specific plan and intent and behaviors. The C-SSRS outcomes are categories and have binary responses (yes/no). Suicidal ideation is considered when the patient responds a yes answer at any time during treatment to any one of the five suicidal ideation questions (Categories 1-5) on the C-SSRS. The sum of the 5 intensity item scores create a total score (range 0 to 25) to represent the intensity rating (higher scores indicate more severe suicidal ideation). | Week 6. | 
| Behavioral suicidal events, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) - Suicidal Ideation. | The C-SSRS is a suicidal ideation and behavior rating scale with yes/no responses. The first part (Items 1-5) rates an individual's degree of suicidal ideation on a 0-5 scale, ranging from wish to be dead to active suicidal ideation with specific plan and intent and behaviors. The C-SSRS outcomes are categories and have binary responses (yes/no). Suicidal ideation is considered when the patient responds a yes answer at any time during treatment to any one of the five suicidal ideation questions (Categories 1-5) on the C-SSRS. The sum of the 5 intensity item scores create a total score (range 0 to 25) to represent the intensity rating (higher scores indicate more severe suicidal ideation). | Week 13. | 
| Behavioral suicidal events, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) - Suicidal Behavior. | The questions 6-10 of the C-SSRS are related to suicidal behavior, and the outcome is a simple yes/no response. Suicidal behavior occurs if the patient answers a yes at any time during treatment to any one of the five suicidal behavior questions (Categories 6-10) on the C-SSRS. | Baseline. | 
| Behavioral suicidal events, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS). | The questions 6-10 of the C-SSRS are related to suicidal behavior, and the outcome is a simple yes/no response. Suicidal behavior occurs if the patient answers a yes at any time during treatment to any one of the five suicidal behavior questions (Categories 6-10) on the C-SSRS. | Week 3. | 
| Behavioral suicidal events, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS). | The questions 6-10 of the C-SSRS are related to suicidal behavior, and the outcome is a simple yes/no response. Suicidal behavior occurs if the patient answers a yes at any time during treatment to any one of the five suicidal behavior questions (Categories 6-10) on the C-SSRS. | Week 6. | 
| Cognitive symptoms, as assessed by the The Montreal Cognitive Assessment (MoCA). | The MoCA is as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains with a total possible score of 0 to 30 points; a score of 26 or above is considered normal. | Baseline. | 
| Cognitive symptoms, as assessed by the The Montreal Cognitive Assessment (MoCA). | The MoCA is as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains with a total possible score of 0 to 30 points; a score of 26 or above is considered normal. | Week 6. | 
| Cognitive symptoms, as assessed by the The Montreal Cognitive Assessment (MoCA). | The MoCA is as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains with a total possible score of 0 to 30 points; a score of 26 or above is considered normal. | Week 13. | 
| Patient progress and treatment response over time, as assessed by the Clinical Global Impressions Scale (CGI). | The CGI is a stand-alone assessment of the clinician's view of the patient's global functioning prior to and after initiating a study medication. The CGI is a 3-item observer-rated scale that measures illness severity (CGI-S), global improvement or change (CGI-I) and therapeutic response. The scale ranges from 1-7, with higher scores indicating worse outcomes. | Baseline. | 
| Patient progress and treatment response over time, as assessed by the Clinical Global Impressions Scale (CGI). | The CGI is a stand-alone assessment of the clinician's view of the patient's global functioning prior to and after initiating a study medication. The CGI is a 3-item observer-rated scale that measures illness severity (CGI-S), global improvement or change (CGI-I) and therapeutic response. The scale ranges from 1-7, with higher scores indicating worse outcomes. | Week 6. | 
| Patient progress and treatment response over time, as assessed by the Clinical Global Impressions Scale (CGI). | The CGI is a stand-alone assessment of the clinician's view of the patient's global functioning prior to and after initiating a study medication. The CGI is a 3-item observer-rated scale that measures illness severity (CGI-S), global improvement or change (CGI-I) and therapeutic response. The scale ranges from 1-7, with higher scores indicating worse outcomes. | Week 13. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Irritability