Randomized, Placebo Controlled Study Of The Efficacy And Safety Of PF-02545920 In Subjects With Huntington's Disease

Study Overview
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Brief Summary
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This study is a 26 week, randomized, parallel group, double blind comparison of PF-02545920 5 mg, PF-02545920 20 mg, and placebo dosed BID in the treatment of motor impairment of subjects with Huntington's Disease. A total of approximately 260 subjects are planned to be randomized in the study. Primary endpoint is the change from baseline in the Total Motor Score (TMS) assessment of the Unified Huntington Disease Rating Scale (UHDRS) after 26 weeks of treatment. secondary endpoints will include change from baseline in the Total Maximum Chorea (TMC) score of the UHDRS after 13 and 26 weeks of treatment and Clinical Global Impression-Improvement score after 13 and 26 weeks of treatment.

Official Title
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A Phase 2, Randomized, Placebo Controlled, Double Blind Proof-of-concept Study Of The Efficacy And Safety Of Pf-02545920 In Subjects With Huntington's Disease

Conditions
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Huntington's Disease

Intervention / Treatment
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* Drug: PF-02545920
* Drug: PF-02545920
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CAG repeat equal or greater than 36; Total motor score equal or greater than 10; Total functional capacity equal or greater than 7. Exclusion Criteria: Clinically significant neurologic disorder other than Huntington's disease; Other severe acute psychiatric conditions, mania and/or psychosis; History of neutropenia, and myeloproliferative disorders;

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 20 mg PF-02545920 BID<br>20 mg PF-02545920 BID | Drug: PF-02545920<br>* 20 mg twice a day (BID) for 26 weeks. Each 20 mg dose will be taken as 4 tablets of 5 mg. The 20mg dose will be titrated as follow: 5mg BID for 7 days, 10mg BID for 7 days, 15 mg BID for 7 days and 20 mg BID to week 26. Study drug will be provided in weekly blister cards.<br>|
| Experimental: 5 mg PF-02545920 BID<br>5 mg PF-02545920 BID | Drug: PF-02545920<br>* 5 mg twice a day (BID) for 26 weeks. Each 5 mg dose will be taken as 4 tablets: one tablet of 5 mg and 3 tablets of matching placebo. The 5mg dose will not be titrated. Study drug will be provided in weekly blister cards.<br>|
| Placebo Comparator: Placebo BID<br>Matching placebo | Other: Placebo<br>* Matching Placebo twice a day (BID) for 26 weeks. Each placebo dose will be taken as 4 tablets of matching Placebo. The placebo dose will not be titrated. Matching placebo will be provided in weekly blister cards.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Total Motor Score (TMS) Assessment of the Unified Huntington Disease Rating Scale (UHDRS) After 26 Weeks of Treatment. | The UHDRS was a clinical rating scale which has been developed by the Huntington Disease Study Group (HSG) to provide a uniform assessment of the clinical features and course of Huntington's Disease (HD). The components of the full UHDRS assess motor function, cognition, behavior and functional abilities. The total motor score (TMS) assessed motor features of HD with standardized ratings of oculomotor function, dysarthria, chorea, dystonia, gait, and postural stability. Some items (such as chorea and dystonia) required grading each extremity (face, bucco-oral-lingual, and trunk) separately. Eye movements require both horizontal and vertical grades. The total motor impairment scores was the sum of all the individual 31 motor sub-items (each rated from 0 to 4), with higher scores indicating more severe motor impairment than lower scores. The range of TMS is 0-124. | Baseline, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Met White Blood Count (WBC) and Absolute Neutrophil Count (ANC) Stopping Criteria | The criteria for temporary study suspension was as follow: Criterion A: WBC count <=3000 cells/mm3 but >= 2000 cells/mm3 or ANC <= 1500 cells/mm3 but >= 1000 cells/mm3; Criterion B: WBC <= 2000 cells/mm3 or ANC <= 1000 cells/mm3; Criterion C: participants who are discontinued or permanently suspended due to WBC or ANC findings; Criterion D: ANC <= 500 cells/mm3 | Screening, Day 1, 7, 14, 28, 56, 91, 133, 182 and follow-up visits (from Day 189 to 192) | 
| Number of Participants With Adverse Events | Adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. | Day 1, 7, 14, 28, 56, 91, 133, 182 and follow-up visits (from Day 189 to 192) | 
| Number of Participants With Serious Adverse Events | Adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability or incapacity, congenital anomaly. | Day 1, 7, 14, 28, 56, 91, 133, 182 and follow-up visits (from Day 189 to 192) | 
| Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormalities) | Following parameters were analyzed for laboratory examination: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes);coagulation (PT international ratio); liver function (total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma GT, LDH, alkaline phosphatase, total protein, albumin); renal function (blood urea nitrogen, creatinine, uric acid); electrolytes (calcium, sodium, potassium, chloride, total bicarbonate, magnesium, phosphate); clinical chemistry (glucose, glycosylated, hemoglobin, human chorionic gonadotropin, creatine kinase); urinalysis (decimal logarithm of reciprocal of hydrogen ion activity [pH], urine specific gravity, glucose, protein, blood, ketones, nitrite). | Screening, Day 1, 7, 14, 28, 56, 91, 133, 182 and follow-up visits (from Day 189 to 192) | 
| Number of Participants With Laboratory Test Abnormalities (With Normal Baseline) | Following parameters were analyzed for laboratory examination: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes);coagulation (PT international ratio); liver function (total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma GT, LDH, alkaline phosphatase, total protein, albumin); renal function (blood urea nitrogen, creatinine, uric acid); electrolytes (calcium, sodium, potassium, chloride, total bicarbonate, magnesium, phosphate); clinical chemistry (glucose, glycosylated, hemoglobin, human chorionic gonadotropin, creatine kinase); urinalysis (decimal logarithm of reciprocal of hydrogen ion activity [pH], urine specific gravity, glucose, protein, blood, ketones, nitrite). | Screening, Day 1, 7, 14, 28, 56, 91, 133, 182 and follow-up visits (from Day 189 to 192) | 
| Number of Participants With Vital Sign Data That Met Criteria for Potential Clinical Concern (Absolute Values) | Absolute values were analyzed for supine systolic blood pressure (SBP), standing SBP, supine diastolic blood pressure (DBP), standing DBP, supine pulse rate, and standing pulse rate. Number of participants with vital signs data meeting the following criteria was reported: Criterion A: supine SBP less than (<) 90 millimeter of mercury(mmHg); Criterion B: standing SBP < 90 mmHg; Criterion C: supine DBP <50 mmHg; Criterion D: standing DBP <50 mmHg; Criterion E: supine pulse rate < 40 beats per minute(BPM); Criterion F: supine pulse rate greater than (>)120 BPM; Criterion G: standing pulse rate < 40 beats per minute(BPM); Criterion H: standing pulse rate >120 BPM; | Screening, Day 1, 28, 91, and 182 | 
| Number of Participants With Vital Sign Data That Met Criteria for Potential Clinical Concern (Increase From Baseline) | The number of participants with vital signs data of maximum increase from baseline meeting the following criteria was reported: Criterion A: maximum increase from baseline in supine SBP greater than or equal to (>=) 30 mmHg; Criterion B: maximum increase from baseline in standing SBP >= 30 mmHg; Criterion C: maximum increase from baseline in supine DBP >=20 mmHg; Criterion D: maximum increase from baseline in standing DBP >=20 mmHg | Screening, Day 1, 28, 91, and 182 | 
| Number of Participants With Vital Sign Data That Met Criteria for Potential Clinical Concern (Decrease From Baseline) | The number of participants with vital signs data of maximum decrease from baseline meeting the following criteria was reported: Criterion A: maximum decrease from baseline in supine SBP >= 30 mmHg; Criterion B: maximum decrease from baseline in standing SBP >= 30 mmHg; Criterion C: maximum decrease from baseline in supine DBP >=20 mmHg; Criterion D: maximum decrease from baseline in standing DBP >=20 mmHg | Screening, Day 1, 28, 91, and 182 | 
| Number of Participants With Electrocardiogram (ECG) Data That Met Criteria for Potential Clinical Concern(Absolute Values) | The number of participants with ECG absolute values meeting the following criteria was reported: Criterion A: maximum PR interval (time from the beginning of P wave to the start of QRS complex, corresponding to the end of atrial depolarization and onset of ventricular depolarization) >=300 msec; Criterion B: maximum QRS complex(time from Q wave to the end of S wave, corresponding to ventricle depolarization) >=140 msec; Criterion C: maximum QTcF interval (time from the beginning of Q wave to the end of T wave corresponding to electrical systole, corrected for heart rate using Fridericia's formula) 450-<480 msec; Criterion D: maximum QTcF interval 480-<500 msec; Criterion E: maximum QTcF interval (Fridericia's correction) >=500 msec | Screening, Day 1, 28, 91, and 182 | 
| Number of Participants With Electrocardiogram (ECG) Data That Met Criteria for Potential Clinical Concern(Increase From Baseline) | Number of participants with ECG meeting the following criteria was reported: Criterion A: maximum PR interval increase from baseline percentage change (PctChg)>= 25/50%; Criterion B: maximum QRS complex increase from baseline PctChg >=50%; Criterion C: maximum QTcF interval (Fridericia's correction) increase from baseline 30<=change<60 msec; Criterion D: maximum QTcF interval (Fridericia's correction) increase from baseline change >=60 msec. | Screening, Day 1, 28, 91, and 182 | 
| Severity of Adverse Events Related to Extrapyramidal Symptoms (EPS) Including Dystonia and Akathisia | Adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to severity; mild (not causing any significant problem, dose adjustment not required), moderate (caused problem that does not interfere significantly with usual activities or the clinical status, dose adjustment needed due to adverse event) and severe (caused problem that interferes significantly with usual activities or the clinical status, study drug stopped due to adverse event). EPS were reported AEs of dystonia and akathisia. | Day 1, 7, 14, 28, 56, 91, 133, 182 and follow-up visits (from Day 189 to 192) | 
| Change From Baseline in the Total Maximum Chorea (TMC) Score of the UHDRS After 13 and 26 Weeks of Treatment. | The UHDRS was a clinical rating scale which has been developed by the Huntington Disease Study Group (HSG) to provide a uniform assessment of the clinical features and course of HD. The components of the full UHDRS assess motor function, cognition, behavior and functional abilities. The Total Maximum Chorea (TMC) was a subset of the TMS assessment. It was composed of the scoring of 7 chorea assessments (face, orobuccolingual, trunk, right and left upper extremities, right and left lower extremities). Each assessment was rated from 0 to 4 (absent to prolonged). TMC is obtained by adding up each of the separate scores, leading to max score of 28. The minimum score is 0. The higher the score, the worse the symptoms. n is the number of evaluable subjects in each visit. | Baseline, Week 13, Week 26 | 
| Number of Participants With Suicidal Ideation or Suicidal Behavior as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) From Baseline to Follow-up Visit | The C-SSRS captured the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. C-SSRS assessed whether participant experienced following: completed suicide; suicide attempt; preparatory acts towards imminent suicidal behavior; suicidal ideation; self-injurious behavior, no suicidal intent. The results presented are the number of participants with completed suicide or non-fatal suicide events or behaviors. Worsening of suicidal ideation was an increase in severity of suicidal ideation from baseline. | Day 1, 7, 14, 28, 56, 91, 133, 182 and follow-up visits (from Day 189 to 192) | 
| Clinical Global Impression of Improvement (CGI-I) Scale Score After 13 and 26 Weeks of Treatment. | CGI-I: 7-point clinician rated scale ranging from 1 (very much improved) to 7 (very much worse). Clinician responded to a question: Compared to your subject's condition at the beginning of treatment, how much has your subject changed?. Improvement was compared to baseline and was defined as a score of 1 (very much improved), 2 (much improved), or 3 (minimally improved) on the scale. Higher score = more affected. n is the number of evaluable participants in each visit. | Week 13 & Week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Huntington; chorea; total motor score; CAG repeat: total functional capacity; motor cognitive and behavioral symptoms