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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03854019
Recruitment Status : Recruiting
First Posted : February 26, 2019
Last Update Posted : April 19, 2019
Sponsor:
Collaborator:
Cures Within Reach
Information provided by (Responsible Party):
Erin Furr Stimming, The University of Texas Health Science Center, Houston

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Huntington Disease Irritability Drug: Dextromethorphan/quinidine 20mg/10mg (DM/Q 20mg/10mg) Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Evaluating the Efficacy of Dextromethorphan/Quinidine in Treating Irritability in Huntington's Disease
Actual Study Start Date : April 1, 2019
Estimated Primary Completion Date : November 1, 2019
Estimated Study Completion Date : November 1, 2019


Arm Intervention/treatment
Experimental: Dextromethorphan/quinidine 20mg/10mg (DM/Q 20mg/10mg)
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)
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.
Other Name: Nuedexta

Placebo Comparator: Placebo
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: Placebo
Placebo once daily for 1 week, followed by placebo twice daily for subsequent 4 weeks, and finally placebo once daily for 7days.




Primary Outcome Measures :
  1. Irritability as assessed by The Irritability Scale. [ Time Frame: Baseline. ]
    The Irritability Scale total score ranges from 0 to 42, with higher scores indicating greater irritability.

  2. Irritability as assessed by The Irritability Scale [ Time Frame: Week 6. ]
    The Irritability Scale total score ranges from 0 to 42, with higher scores indicating greater irritability.

  3. Irritability as assessed by The Irritability Scale. [ Time Frame: Week 13. ]
    The Irritability Scale total score ranges from 0 to 42, with higher scores indicating greater irritability.


Secondary Outcome Measures :
  1. Cognitive symptoms, as assessed by the Unified Huntington's Disease Rating Scale (UHDRS) - cognitive domain. [ Time Frame: Baseline. ]
    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.

  2. Cognitive symptoms, as assessed by the Unified Huntington's Disease Rating Scale (UHDRS) - cognitive domain. [ Time Frame: Week 6. ]
    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.

  3. Cognitive symptoms, as assessed by the Unified Huntington's Disease Rating Scale (UHDRS) - cognitive domain. [ Time Frame: Week 13. ]
    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.

  4. Behavioral symptoms, as assessed by the Hospital Anxiety and Depression Scale (HADS). [ Time Frame: Baseline. ]
    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.

  5. Behavioral symptoms, as assessed by the Hospital Anxiety and Depression Scale (HADS). [ Time Frame: Week 6. ]
    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.

  6. Behavioral symptoms, as assessed by the Hospital Anxiety and Depression Scale (HADS). [ Time Frame: Week 13. ]
    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.

  7. Behavioral symptoms, as assessed by the Neuropsychiatric Inventory-Questionnaire (NPI-Q) - severity score. [ Time Frame: Baseline. ]
    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.

  8. Behavioral symptoms, as assessed by the Neuropsychiatric Inventory-Questionnaire (NPI-Q) - severity score. [ Time Frame: Week 6. ]
    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.

  9. Behavioral symptoms, as assessed by the Neuropsychiatric Inventory-Questionnaire (NPI-Q) - severity score. [ Time Frame: Week 13. ]
    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.

  10. Behavioral symptoms, as assessed by the Neuropsychiatric Inventory-Questionnaire (NPI-Q) - caregiver distress. [ Time Frame: Baseline. ]
    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.

  11. Behavioral symptoms, as assessed by the Neuropsychiatric Inventory-Questionnaire (NPI-Q) - caregiver distress. [ Time Frame: Week 6. ]
    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.

  12. Behavioral symptoms, as assessed by the Neuropsychiatric Inventory-Questionnaire (NPI-Q) - caregiver distress. [ Time Frame: Week 13. ]
    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.

  13. Behavioral symptoms, as assessed by the Problem Behaviors Assessment - short version (PBA-s). [ Time Frame: Baseline. ]
    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.

  14. Behavioral symptoms, as assessed by the Problem Behaviors Assessment - short version (PBA-s). [ Time Frame: Week 6. ]
    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.

  15. Behavioral symptoms, as assessed by the Problem Behaviors Assessment - short version (PBA-s). [ Time Frame: Week 13. ]
    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.

  16. Motor symptoms, as assessed by the total motor score (TMS) from the UHDRS. [ Time Frame: Baseline. ]
    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.

  17. Motor symptoms, as assessed by the total motor score (TMS) from the UHDRS. [ Time Frame: Week 6. ]
    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.

  18. Motor symptoms, as assessed by the total motor score (TMS) from the UHDRS. [ Time Frame: Week 13. ]
    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.

  19. Motor symptoms, as assessed by the total maximal chorea (TMC). [ Time Frame: Baseline. ]
    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.

  20. Motor symptoms, as assessed by the total maximal chorea (TMC). [ Time Frame: Week 6. ]
    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.

  21. Motor symptoms, as assessed by the total maximal chorea (TMC). [ Time Frame: Week 13. ]
    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.

  22. Functional independence, as assessed by the UHDRS Total Functional Capacity Scale (TFC). [ Time Frame: Baseline. ]
    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.

  23. Functional independence, as assessed by the UHDRS Total Functional Capacity Scale (TFC). [ Time Frame: Week 6. ]
    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.

  24. Functional independence, as assessed by the UHDRS Total Functional Capacity Scale (TFC). [ Time Frame: Week 13. ]
    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.

  25. Behavioral suicidal events, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) - Suicidal ideation. [ Time Frame: Baseline. ]
    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).

  26. Behavioral suicidal events, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) - Suicidal ideation [ Time Frame: Week 6. ]
    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).

  27. Behavioral suicidal events, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) - Suicidal Ideation. [ Time Frame: Week 13. ]
    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).

  28. Behavioral suicidal events, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) - Suicidal Behavior. [ Time Frame: Baseline. ]
    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.

  29. Behavioral suicidal events, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS). [ Time Frame: Week 3. ]
    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.

  30. Behavioral suicidal events, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS). [ Time Frame: Week 6. ]
    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.

  31. Cognitive symptoms, as assessed by the The Montreal Cognitive Assessment (MoCA). [ Time Frame: Baseline. ]
    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.

  32. Cognitive symptoms, as assessed by the The Montreal Cognitive Assessment (MoCA). [ Time Frame: Week 6. ]
    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.

  33. Cognitive symptoms, as assessed by the The Montreal Cognitive Assessment (MoCA). [ Time Frame: Week 13. ]
    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.

  34. Patient progress and treatment response over time, as assessed by the Clinical Global Impressions Scale (CGI). [ Time Frame: Baseline. ]
    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.

  35. Patient progress and treatment response over time, as assessed by the Clinical Global Impressions Scale (CGI). [ Time Frame: Week 6. ]
    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.

  36. Patient progress and treatment response over time, as assessed by the Clinical Global Impressions Scale (CGI). [ Time Frame: Week 13. ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03854019


Contacts
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Contact: Erin Furr Stimming, MD (713) 500-7033 Erin.E.Furr@uth.tmc.edu

Locations
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United States, Texas
The University of Texas Health Science Center at Houston Recruiting
Houston, Texas, United States, 77030
Contact: Erin Furr Stimming, MD    713-500-7033    Erin.E.Furr@uth.tmc.edu   
Sponsors and Collaborators
The University of Texas Health Science Center, Houston
Cures Within Reach
Investigators
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Principal Investigator: Erin L Furr Stimming, MD The University of Texas Health Science Center, Houston

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Responsible Party: Erin Furr Stimming, Associate Professor, The University of Texas Health Science Center, Houston
ClinicalTrials.gov Identifier: NCT03854019     History of Changes
Other Study ID Numbers: HSC-MS-18-1049
First Posted: February 26, 2019    Key Record Dates
Last Update Posted: April 19, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Erin Furr Stimming, The University of Texas Health Science Center, Houston:
Irritability
Additional relevant MeSH terms:
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Huntington Disease
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Dementia
Chorea
Dyskinesias
Quinidine
Quinidine gluconate
Dextromethorphan
Antitussive Agents
Respiratory System Agents
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Anti-Arrhythmia Agents
Antimalarials