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

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

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.

Study Overview

• Status: Completed
• Conditions: Huntington's Disease
• Intervention / Treatment: Drug: PF-02545920; Drug: PF-02545920; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 272
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6T 2B5
      • The Centre for Huntington Disease
  • Ontario
    • Toronto, Ontario, Canada, M3B 2S7
      • Centre for Movement Disorders
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
      • CHUM-Notre-Dame Hospital
    • Montreal, Quebec, Canada, H4L 4M1
      • CHUM Notre Dame, Pharmacie
• Germany
  • Aachen, Germany, 52074
    • Uniklinik RWTH Aachen
  • Berlin, Germany, 10117
    • Charité - Universitätsmedizin Berlin
  • Bochum, Germany, 44791
    • Prof. Dr. Carsten Saft
  • Erlangen, Germany, 91054
    • Friedrich-Alexander-Universität
  • Freiburg, Germany, 79106
    • Prof. Dr. med. Stephan Klebe
  • Lubeck, Germany, 23562
    • Universität zu Lübeck
  • Marburg, Germany, 35043
    • Philipps Universität Marburg
  • Münster, Germany, 48149
    • George Huntington Institut
  • Taufkirchen, Germany, 84416
    • Kbo-Isar-Amper-Klinikum gGmbH
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm
  • Wuerzburg, Germany, 97080
    • Universitatsklinikum Wuerzburg
  • Bavaria
    • Munchen, Bavaria, Germany, 81675
      • Technische Universität München
• Poland
  • Gdansk, Poland, 80462
    • Copernicus Podmiot Leczniczy Sp. z o.o.
  • Krakow, Poland, 31505
    • Krakowska Akademia Neurologii Sp. z o.o.
  • Poznan, Poland, 60529
    • Solumed Centrum Medyczne
  • Warszawa, Poland, 02957
    • Instytut Psychiatrii i Neurologii
• United Kingdom
  • Cambridge, United Kingdom, CB2 0PY
    • John Van Geest Centre for Brain Repair
  • Cardiff, United Kingdom, CF14 4XW
    • University of Wales Hospital
  • Glasgow, United Kingdom, G51 4TF
    • NHS Greater Glasgow and Clyde
  • London, United Kingdom, WC1N 3BG
    • University College London Hospitals NHS Foundation Trust
  • London, United Kingdom, SE1 9RT
    • Clinical Research Facility
  • London, United Kingdom, WC1B 5EH
    • University College London Hospitals Huntington's Disease Research Centre
  • Manchester, United Kingdom, M13 9WL
    • Central Manchester University Hospitals NHS Foundation Trust
  • Manchester, United Kingdom, M13 9WL
    • The National Institute for Health Research/Wellcome Trust Clinical Research Facility
  • Newcastle Upon Tyne, United Kingdom, NE3 3XT
    • St Nicholas Hospital
  • Newcastle Upon Tyne, United Kingdom, NE4 5PL
    • Newcastle Magnetic Resonance Centre
  • Aberdeenshire
    • Aberdeen, Aberdeenshire, United Kingdom, AB25 2ZA
      • NHS Grampian, Clinical Genetics Centre
  • Hampshire
    • Southampton, Hampshire, United Kingdom, SO16 6YD
      • University Hospital Southampton NHS Foundation Trust
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 9DU
      • Oxford University Hospitals NHS Trust
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2JF
      • Sheffield Teaching Hospitals NHS Foundation Trust
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2FG
      • Birmingham & Solihull Mental Health NHS Foundation Trust
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
    • Birmingham, Alabama, United States, 35233
      • The University of Alabama at Birmingham
    • Birmingham, Alabama, United States, 35233
      • The Kirklin Clinic of Uab Hospital
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic Arizona
  • California
    • Irvine, California, United States, 92697
      • University of California, Irvine
    • Los Angeles, California, United States, 90095
      • UCLA Radiology
    • Los Angeles, California, United States, 90095
      • Ronald Regan UCLA Medical Center Drug Information Center
    • Los Angeles, California, United States, 90095
      • UCLA Neurology Clinic
  • Colorado
    • Englewood, Colorado, United States, 80113
      • Rocky Mountain Movement Disorders Center
  • Florida
    • Gainesville, Florida, United States, 32607
      • University of Florida Center for Movement Disorders and Neurorestoration
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Neuroscience Center
  • Massachusetts
    • Charlestown, Massachusetts, United States, 02129
      • Massachusetts General Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Medical Center - Dept. of Neurology
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation Hospital Pharmacy
    • Columbus, Ohio, United States, 43221
      • Wexner Medical Center at the Ohio State University
    • Columbus, Ohio, United States, 43210
      • Davis Medical Center
    • Columbus, Ohio, United States, 43221
      • The Wexner Medical Center at the Ohio State University
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 20 mg PF-02545920 BID	Drug: PF-02545920; 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.; Drug: PF-02545920; 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.
Experimental: 5 mg PF-02545920 BID	Drug: PF-02545920; 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.; Drug: PF-02545920; 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.
Placebo Comparator: Placebo BID; Matching placebo	Other: Placebo; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2014
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): October 1, 2016

Study Registration Dates

• First Submitted: July 16, 2014
• First Submitted That Met QC Criteria: July 18, 2014
• First Posted (Estimate): July 22, 2014

Study Record Updates

• Last Update Posted (Actual): November 17, 2017
• Last Update Submitted That Met QC Criteria: October 13, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Huntington; chorea; total motor score; CAG repeat: total functional capacity; motor cognitive and behavioral symptoms
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Dyskinesias; Heredodegenerative Disorders, Nervous System; Dementia; Cognition Disorders; Chorea; Huntington Disease
• Other Study ID Numbers: A8241021; 2014-001291-56 (EudraCT Number)