Study Evaluating The Safety, Tolerability And Brain Function Of 2 Doses Of PF-0254920 In Subjects With Early Huntington's Disease

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01806896
• Collaborator: (none)
• Enrollment: 37
• Location: 1
• Arms: 4
• Duration (Months): 16
• Patients Per Site Per Month: 2.3

Study Details

Study Description

Brief Summary

This study will evaluate the Safety, Tolerability and Brain Function of 2 doses of PF-0254920 in Subjects with Early Huntington's Disease.

Condition or Disease	Intervention/Treatment	Phase
Huntington's Disease	Drug: PF-02545920; Drug: Placebo; Drug: PF-02545920; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Double-blind Randomized, Sequential Treatment Group, Placebo-controlled Study To Evaluate The Safety, Tolerability And Brain Cortico-striatal Function Of 2 Doses Of Pf-02545920 In Subjects With Early Huntington's Disease
• Study Start Date: Sep 1, 2013
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Jan 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 20 mg Arm Cohort A	Drug: PF-02545920; Dose will be titrated up every 2 days by 5mg increments: 5mg Days 1-2, 10mg days 3-4, 15mg days 5-6, and reach 20 mg from Days 7 to Day28. Orally, approx. Q12H (range 10-14 hours), administered at least one hour prior to, or two hours after meals. Treatment for 28 days.
Placebo Comparator: Placebo Arm Cohort A	Drug: Placebo; - Orally, approx. Q12H (range 10-14 hours), administered at least one hour prior to, or two hours after meals. Dosing for 28 days.
Experimental: 5 mg Arm Cohort B	Drug: PF-02545920; 5mg dose Orally, approx. Q12H (range 10-14 hours), administered at least one hour prior to, or two hours after meals. Dosing for 28 days.
Placebo Comparator: Placebo Arm Cohort B	Drug: Placebo; Orally, approx. Q12H (range 10-14 hours), administered at least one hour prior to, or two hours after meals. Dosing for 28 days.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [Baseline up to Day 38]

   An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. An 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/incapacity; congenital anomaly. Treatment-emergent are events between first dose of treatment and up to the follow-up period that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-serious AEs.

2. Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern (Without Regard to Baseline Abnormality) [Baseline up to Day 38]

   The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell [RBC] count, platelet count, white blood cell [WBC] count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen [BUN], creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase [AST], alanine aminotransferase [ALT], total and direct bilirubin, alkaline phosphatase, uric acid, albumin, and total protein; urinalysis (pH, glucose, protein/albumin, hemoglobin/blood, ketones/acetone, nitrites, leukocyte esterase, microscopy [if urine dipstick was positive for blood, protein, nitrites or leukocyte esterase]); others (urine/serum pregnancy test, glycosylated hemoglobin [HbA1c, if diabetic]).

3. Number of Participants With Potentially Clinically Significant Vital Signs Findings [Baseline up to Day 38]

   Vital signs assessment included pulse rate and blood pressure. Criteria for vital sign values meeting potential clinical concern included: supine/sitting pulse rate less than (<)40 or greater than (>)120 beats per minute (bpm), standing pulse rate <40 or >140 bpm; systolic blood pressure (SBP) of greater than or equal to (>=)30 millimeters of mercury (mmHg) change from baseline or SBP <90 mmHg, diastolic blood pressure (DBP) >=20 mmHg change from baseline or DBP <50 mmHg.

4. Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings [Baseline up to Day 38]

   ECG parameters included PR interval, QRS complex, and corrected QT interval using Fridericia's formula (QTcF). Criteria for ECG changes meeting potential clinical concern included: PR interval ≥200 milliseconds (msec) or ≥25% increase when baseline is >100 msec; QRS interval ≥50% increase from baseline when baseline is less than or equal to (<=)200 msec; and QTcF ≥450 msec or ≥30 msec increase from baseline.

5. Number of Participants With Change From Baseline in Body Weight of >=7% [Baseline up to Day 38]

   Weight assessment was performed by a study physician or a trained study nurse and was included in the physical examination.

6. Categorical Summary of Participants Meeting Stopping Criteria [Baseline up to Day 38]

   Absolute neutrophil count (ANC) and WBC were monitored for safety. Participants with WBC <3000 but >=2000 cells/mm^3 or ANC <1500 but >=1000 cells/mm^3 were to have study treatment suspended. Participants with WBC <2000 or ANC <1000 cells/mm^3 were to be discontinued from study participation.

7. Change From Baseline in Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score at Day 28 [Baseline, Day 28]

   The UHDRS is a clinical rating scale to provide a uniform assessment of the clinical features and course of Huntington Disease. The Total Motor Score (TMS) is 1 of the 6 components of UHDRS, includes 31 items, and ranges from a scale of 0 to 124 (higher scores indicate more severe disease).

8. Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Baseline [Baseline (Day 1)]

   C-SSRS is a participant rated questionnaire to assess suicidal ideation, suicidal behavior, actual attempts (yes or no responses), and intensity of ideation (rated 1=low severity to 5=high severity). Yes/No responses are mapped to Columbia Classification Algorithm of Suicide Assessment (C-CASA) categories: completed suicide, suicide attempt, preparatory acts towards imminent suicidal behavior, suicidal ideation, and self-injurious behavior, or no suicidal intent. A participant could have a yes or no response in more than 1 category.

9. Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 7 [Day 7]

   C-SSRS is a participant rated questionnaire to assess suicidal ideation, suicidal behavior, actual attempts (yes or no responses), and intensity of ideation (rated 1=low severity to 5=high severity). Yes/No responses are mapped to Columbia Classification Algorithm of Suicide Assessment (C-CASA) categories: completed suicide, suicide attempt, preparatory acts toward imminent suicidal behavior, suicidal ideation, and self-injurious behavior, or no suicidal intent. A participant could have a yes or no response in more than 1 category.

10. Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 28 [Day 28]

    C-SSRS is a participant rated questionnaire to assess suicidal ideation, suicidal behavior, actual attempts (yes or no responses), and intensity of ideation (rated 1=low severity to 5=high severity). Yes/No responses are mapped to Columbia Classification Algorithm of Suicide Assessment (C-CASA) categories: completed suicide, suicide attempt, preparatory acts toward imminent suicidal behavior, suicidal ideation, and self-injurious behavior, or no suicidal intent. A participant could have a yes or no response in more than 1 category.

Secondary Outcome Measures

1. Change From Baseline in Functional Magnetic Resonance Imaging (fMRI) in Monetary Incentive Delay (MID) Task at Day 28 [Baseline (Day 1), Day 28]

   The monetary incentive delay (MID) task is established as a reliable method to elicit ventral striatal (VS) activity in relation to reward/punishment anticipation and tracked with dysfunctionalities across a range of conditions in which incentive motivation is thought to be abnormal (schizophrenia, depression, substance abuse, and pathological gambling). Pharmacological intervention has demonstrated reversal of observed deficit. The beta contrast value of 'REW' is for analysis of reward-related activity in VS within the task-related 'reward network' during the gain condition (relative to neutral) of the MID task. The changes in beta contrasts (fMRI) provided are changes in parameter estimates and do not have a unit of measure.

2. Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC) [Baseline, Day 28]

   This incentive force task was developed to independently dissociate the degree to which a participant responds to reward motivation versus emotional motivation. The task itself included 12 repetitions of 9 trial types, for a total of 108 trials, grouped in a single session lasting about 20 minutes. The trial types were generated according to a combination of 3 emotional categories (negative, neutral, and positive pictures presented) and to 3 monetary incentives (0.01, 0.1, and 1€). Emotional categories and monetary incentives were randomly distributed over the trials and the sequence was fixed such that all subjects were assessed on the exact same task. For each trial, the subject was first presented with an emotional picture displayed on screen for 3000 milliseconds (ms).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Must have a diagnosis of Huntington's Disease

• a CAG repeat expansion equal or great than 39

• a Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score equal or greater than 5 and less than 60

• a UHDRS Total Functional Capacity equal or greater than 9

Exclusion Criteria:

• Subjects with evidence or history of severe acute or chronic medical condition or laboratory abnormality, or significant neurological disorder other than HD.

• Treatment with any antipsychotic medication within 5 weeks of enrollment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Centre d'Investigation Clinique (CIC)/ Institut du Cerveau et de la Möelle Epinière (ICM)	Paris Cedex 13		France	75651

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01806896
• Other Study ID Numbers: A8241016; 2012-004432-31
• First Posted: Mar 7, 2013
• Last Update Posted: Dec 14, 2017
• Last Verified: May 1, 2017

• Additional relevant MeSH terms: Huntington Disease

Study Results

Participant Flow

Arm/Group Title	PF-02545920 20 mg Twice a Day	Placebo Twice a Day
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.	Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.
Period Title: Overall Study
STARTED	20	17
Received Treatment	19	17
COMPLETED	17	17
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	PF-02545920 20 mg Twice a Day	Placebo Twice a Day	Total
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.	Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.	Total of all reporting groups
Overall Participants	19	17	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.4 (12.1)	43.1 (11.8)	45.4 (12.0)
Sex: Female, Male (Count of Participants)
Female	8 42.1%	10 58.8%	18 50%
Male	11 57.9%	7 41.2%	18 50%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
Description	An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. An 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/incapacity; congenital anomaly. Treatment-emergent are events between first dose of treatment and up to the follow-up period that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-serious AEs.
Time Frame	Baseline up to Day 38

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received at least 1 dose of PF-02545920 or placebo.

Arm/Group Title	PF-02545920 20 mg Twice a Day	Placebo Twice a Day
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.	Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.
Measure Participants	19	17
AEs	18 94.7%	14 82.4%
SAEs	1 5.3%	1 5.9%

2. Primary Outcome

Title	Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern (Without Regard to Baseline Abnormality)
Description	The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell [RBC] count, platelet count, white blood cell [WBC] count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen [BUN], creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase [AST], alanine aminotransferase [ALT], total and direct bilirubin, alkaline phosphatase, uric acid, albumin, and total protein; urinalysis (pH, glucose, protein/albumin, hemoglobin/blood, ketones/acetone, nitrites, leukocyte esterase, microscopy [if urine dipstick was positive for blood, protein, nitrites or leukocyte esterase]); others (urine/serum pregnancy test, glycosylated hemoglobin [HbA1c, if diabetic]).
Time Frame	Baseline up to Day 38

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received at least 1 dose of PF-02545920 or placebo.

Arm/Group Title	PF-02545920 20 mg Twice a Day	Placebo Twice a Day
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.	Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.
Measure Participants	19	17
Number [participants]	8 42.1%	8 47.1%

3. Primary Outcome

Title	Number of Participants With Potentially Clinically Significant Vital Signs Findings
Description	Vital signs assessment included pulse rate and blood pressure. Criteria for vital sign values meeting potential clinical concern included: supine/sitting pulse rate less than (<)40 or greater than (>)120 beats per minute (bpm), standing pulse rate <40 or >140 bpm; systolic blood pressure (SBP) of greater than or equal to (>=)30 millimeters of mercury (mmHg) change from baseline or SBP <90 mmHg, diastolic blood pressure (DBP) >=20 mmHg change from baseline or DBP <50 mmHg.
Time Frame	Baseline up to Day 38

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received at least 1 dose of PF-02545920 or placebo.

Arm/Group Title	PF-02545920 20 mg Twice a Day	Placebo Twice a Day
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.	Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.
Measure Participants	19	17
Supine SBP <90 mmHg	0 0%	0 0%
Standing SBP <90 mmHg	1 5.3%	0 0%
Supine DBP <50 mmHg	2 10.5%	1 5.9%
Standing DBP <50 mmHg	1 5.3%	0 0%
Supine Pulse Rate <40 or >120 bpm	0 0%	0 0%
Standing Pulse Rate <40 or >140 bpm	1 5.3%	0 0%
Increase From Baseline in Supine SBP >=30 mmHg	1 5.3%	0 0%
Increase From Baseline in Standing SBP >=30 mmHg	2 10.5%	2 11.8%
Increase From Baseline in Supine DBP >=20 mmHg	1 5.3%	0 0%
Increase From Baseline in Standing DBP >=20 mmHg	1 5.3%	0 0%
Decrease From Baseline in Supine SBP >=30 mmHg	1 5.3%	0 0%
Decrease From Baseline in Standing SBP >=30 mmHg	1 5.3%	0 0%
Decrease From Baseline in Supine DBP >=20 mmHg	2 10.5%	1 5.9%
Decrease From Baseline in Standing DBP >=20 mmHg	3 15.8%	0 0%

4. Primary Outcome

Title	Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings
Description	ECG parameters included PR interval, QRS complex, and corrected QT interval using Fridericia's formula (QTcF). Criteria for ECG changes meeting potential clinical concern included: PR interval ≥200 milliseconds (msec) or ≥25% increase when baseline is >100 msec; QRS interval ≥50% increase from baseline when baseline is less than or equal to (<=)200 msec; and QTcF ≥450 msec or ≥30 msec increase from baseline.
Time Frame	Baseline up to Day 38

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received at least 1 dose of PF-02545920 or placebo.

Arm/Group Title	PF-02545920 20 mg Twice a Day	Placebo Twice a Day
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.	Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.
Measure Participants	19	17
PR Interval >=200 msec	1 5.3%	1 5.9%
PR Interval >=300 msec	0 0%	0 0%
QTcF Interval 450-<480 msec	2 10.5%	0 0%
QTcF Interval 480-<500 msec	0 0%	0 0%
QTcF Interval >=500 msec	0 0%	0 0%
PR Interval >=25% increase when baseline >100 msec	0 0%	0 0%
PR Interval >=25% increase when baseline >200 msec	0 0%	0 0%
QRS >=50% increase when baseline <=100 msec	0 0%	0 0%
QRS >=50% increase when baseline <=200 msec	0 0%	0 0%
QTcF Interval Increase 30-<60 msec	1 5.3%	0 0%
QTcF Interval Increase >=60 msec	0 0%	0 0%

5. Primary Outcome

Title	Number of Participants With Change From Baseline in Body Weight of >=7%
Description	Weight assessment was performed by a study physician or a trained study nurse and was included in the physical examination.
Time Frame	Baseline up to Day 38

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received at least 1 dose of PF-02545920 or placebo.

Arm/Group Title	PF-02545920 20 mg Twice a Day	Placebo Twice a Day
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.	Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.
Measure Participants	19	17
Number [participants]	0 0%	0 0%

6. Primary Outcome

Title	Categorical Summary of Participants Meeting Stopping Criteria
Description	Absolute neutrophil count (ANC) and WBC were monitored for safety. Participants with WBC <3000 but >=2000 cells/mm^3 or ANC <1500 but >=1000 cells/mm^3 were to have study treatment suspended. Participants with WBC <2000 or ANC <1000 cells/mm^3 were to be discontinued from study participation.
Time Frame	Baseline up to Day 38

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received at least 1 dose of PF-02545920 or placebo.

Arm/Group Title	PF-02545920 20 mg Twice a Day	Placebo Twice a Day
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.	Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.
Measure Participants	19	17
WBC 2000-3000 or ANC 1000-1500 cells/mm^3	0 0%	1 5.9%
WBC <2000 or ANC <1000 cells/mm^3	0 0%	0 0%
Discontinued/Suspended Due to WBC or ANC Findings	0 0%	0 0%
ANC<500 cells/mm^3	0 0%	0 0%

7. Primary Outcome

Title	Change From Baseline in Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score at Day 28
Description	The UHDRS is a clinical rating scale to provide a uniform assessment of the clinical features and course of Huntington Disease. The Total Motor Score (TMS) is 1 of the 6 components of UHDRS, includes 31 items, and ranges from a scale of 0 to 124 (higher scores indicate more severe disease).
Time Frame	Baseline, Day 28

Outcome Measure Data

Analysis Population Description

The full analysis population included all participants randomized and had taken at least 1 dose of PF-02545920 or placebo.

Arm/Group Title	PF-02545920 20 mg Twice a Day	Placebo Twice a Day
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.	Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.
Measure Participants	19	17
Least Squares Mean (90% Confidence Interval) [units on a scale]	0.19 (6.23)	0.90 (5.70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PF-02545920 20 mg Twice a Day, Placebo Twice a Day
	Comments	PF-02545920 versus Placebo (Day 28)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.68
	Comments	2-sided p-value
	Method	ANCOVA
	Comments	Treatment differences are based on a mixed effect model including treatment as fixed effects and baseline, age, gender and CAG repeats as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.71
	Confidence Interval	(2-Sided) 90%; -3.56 to 2.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.68
	Estimation Comments

8. Primary Outcome

Title	Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Baseline
Description	C-SSRS is a participant rated questionnaire to assess suicidal ideation, suicidal behavior, actual attempts (yes or no responses), and intensity of ideation (rated 1=low severity to 5=high severity). Yes/No responses are mapped to Columbia Classification Algorithm of Suicide Assessment (C-CASA) categories: completed suicide, suicide attempt, preparatory acts towards imminent suicidal behavior, suicidal ideation, and self-injurious behavior, or no suicidal intent. A participant could have a yes or no response in more than 1 category.
Time Frame	Baseline (Day 1)

Outcome Measure Data

Analysis Population Description

The full analysis population included all participants randomized and had taken at least 1 dose of PF-02545920 or placebo.

Arm/Group Title	PF-02545920 20 mg Twice a Day	Placebo Twice a Day
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.	Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.
Measure Participants	19	17
Completed Suicide	0 0%	0 0%
Suicide Attempt	0 0%	0 0%
Acts Towards Imminent Suicidal Behavior	0 0%	0 0%
Suicidal Ideation	1 5.3%	0 0%
Self-Injurious Behavior, No Suicidal Intent	0 0%	0 0%

9. Secondary Outcome

Title	Change From Baseline in Functional Magnetic Resonance Imaging (fMRI) in Monetary Incentive Delay (MID) Task at Day 28
Description	The monetary incentive delay (MID) task is established as a reliable method to elicit ventral striatal (VS) activity in relation to reward/punishment anticipation and tracked with dysfunctionalities across a range of conditions in which incentive motivation is thought to be abnormal (schizophrenia, depression, substance abuse, and pathological gambling). Pharmacological intervention has demonstrated reversal of observed deficit. The beta contrast value of 'REW' is for analysis of reward-related activity in VS within the task-related 'reward network' during the gain condition (relative to neutral) of the MID task. The changes in beta contrasts (fMRI) provided are changes in parameter estimates and do not have a unit of measure.
Time Frame	Baseline (Day 1), Day 28

Outcome Measure Data

Analysis Population Description

The analysis population included all participants randomized, who had taken at least 1 dose of PF-02545920 or placebo and who had valid data (thresholded by acceptable motion). n=number of participants analyzed in the respective arms. The per-protocol set (PPS) table was used, not the full analysis set (FAS) table.

Arm/Group Title	PF-02545920 20 mg Twice a Day	Placebo Twice a Day
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.	Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.
Measure Participants	10	12
Cue Rew>Neut Left VS	0.01 (1.15)	0.11 (1.13)
Cue Rew>Neut Right VS	-0.20 (1.11)	-0.05 (1.32)
Out_win_Rew>Out_win N Left VS	0.20 (2.33)	0.45 (1.13)
Out_win_Rew>Out_win N Right VS	0.36 (2.00)	0.89 (1.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PF-02545920 20 mg Twice a Day, Placebo Twice a Day
	Comments	PF-02545920 versus Placebo (Cue Rew>Neut Left VS)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.79
	Comments	2-sided p-value
	Method	ANCOVA
	Comments	Treatment differences are based on a mixed effect model including treatment as fixed effect and baseline, age, gender and CAG repeats as covariates.
Method of Estimation	Estimation Parameter	Least square mean
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 90%; -0.72 to 0.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.36
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PF-02545920 20 mg Twice a Day, Placebo Twice a Day
	Comments	PF-02545920 versus Placebo (Cue Rew>Neut Right VS)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.70
	Comments	2-sided p-value
	Method	ANCOVA
	Comments	Treatment differences are based on a mixed effect model including treatment as fixed effect and baseline, age, gender and CAG repeats as covariates.
Method of Estimation	Estimation Parameter	Least square mean
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 90%; -0.80 to 0.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.37
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	PF-02545920 20 mg Twice a Day, Placebo Twice a Day
	Comments	PF-02545920 versus Placebo (Out_win_Rew>Out_win N Left VS)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.51
	Comments	2-sided p-value
	Method	ANCOVA
	Comments	Treatment differences are based on a mixed effect model including treatment as fixed effect and baseline, age, gender and CAG repeats as covariates.
Method of Estimation	Estimation Parameter	Least square mean
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 90%; -0.89 to 0.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.37
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	PF-02545920 20 mg Twice a Day, Placebo Twice a Day
	Comments	PF-02545920 versus Placebo (Out_win_Rew>Out_win N Right VS)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments	2-sided p-value
	Method	ANCOVA
	Comments	Treatment differences are based on a mixed effect model including treatment as fixed effect and baseline, age, gender and CAG repeats as covariates.
Method of Estimation	Estimation Parameter	Least square mean
	Estimated Value	-0.53
	Confidence Interval	(2-Sided) 90%; -1.10 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.33
	Estimation Comments

10. Primary Outcome

Title	Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 7
Description	C-SSRS is a participant rated questionnaire to assess suicidal ideation, suicidal behavior, actual attempts (yes or no responses), and intensity of ideation (rated 1=low severity to 5=high severity). Yes/No responses are mapped to Columbia Classification Algorithm of Suicide Assessment (C-CASA) categories: completed suicide, suicide attempt, preparatory acts toward imminent suicidal behavior, suicidal ideation, and self-injurious behavior, or no suicidal intent. A participant could have a yes or no response in more than 1 category.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

The full analysis population included all participants randomized and had taken at least 1 dose of PF-02545920 or placebo.

Arm/Group Title	PF-02545920 20 mg Twice a Day	Placebo Twice a Day
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.	Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.
Measure Participants	19	17
Completed Suicide	0 0%	0 0%
Suicide Attempt	0 0%	0 0%
Acts Towards Imminent Suicidal Behavior	0 0%	0 0%
Suicidal Ideation	0 0%	0 0%
Self-Injurious Behavior, No Suicidal Intent	0 0%	0 0%

11. Primary Outcome

Title	Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 28
Description	C-SSRS is a participant rated questionnaire to assess suicidal ideation, suicidal behavior, actual attempts (yes or no responses), and intensity of ideation (rated 1=low severity to 5=high severity). Yes/No responses are mapped to Columbia Classification Algorithm of Suicide Assessment (C-CASA) categories: completed suicide, suicide attempt, preparatory acts toward imminent suicidal behavior, suicidal ideation, and self-injurious behavior, or no suicidal intent. A participant could have a yes or no response in more than 1 category.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

The full analysis population included all participants randomized and had taken at least 1 dose of PF-02545920 or placebo.

Arm/Group Title	PF-02545920 20 mg Twice a Day	Placebo Twice a Day
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.	Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.
Measure Participants	19	17
Completed Suicide	0 0%	0 0%
Suicide Attempt	0 0%	0 0%
Acts Towards Imminent Suicidal Behavior	0 0%	0 0%
Suicidal Ideation	2 10.5%	0 0%
Self-Injurious Behavior, No Suicidal Intent	0 0%	0 0%

12. Secondary Outcome

Title	Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC)
Description	This incentive force task was developed to independently dissociate the degree to which a participant responds to reward motivation versus emotional motivation. The task itself included 12 repetitions of 9 trial types, for a total of 108 trials, grouped in a single session lasting about 20 minutes. The trial types were generated according to a combination of 3 emotional categories (negative, neutral, and positive pictures presented) and to 3 monetary incentives (0.01, 0.1, and 1€). Emotional categories and monetary incentives were randomly distributed over the trials and the sequence was fixed such that all subjects were assessed on the exact same task. For each trial, the subject was first presented with an emotional picture displayed on screen for 3000 milliseconds (ms).
Time Frame	Baseline, Day 28

Outcome Measure Data

Analysis Population Description

The analysis population included all participants randomized, who had taken at least 1 dose of PF-02545920 or placebo and who had valid data (acceptable task engagement). n=number of participants analyzed in the respective arms. The PPS table was used, not the FAS table.

Arm/Group Title	PF-02545920 20 mg Twice a Day	Placebo Twice a Day
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.	Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.
Measure Participants	16	17
Neutral Emotional Incentive Day 28	0.93	-6.37
Positive Emotional Incentive Day 28	1.10	-6.47
Negative Emotional Incentive Day 28	0.18	-7.10
0.01 Euro Monetary Incentive Day 28	-13.47	-14.45
0.1 Euro Monetary Incentive Day 28	-1.19	-5.97
1 Euro Monetary Incentive Day 28	16.85	0.50

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PF-02545920 20 mg Twice a Day, Placebo Twice a Day
	Comments	PF-02545920 versus Placebo (Emotional Incentive-Neutral) Day 28
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments	2-sided p-value
	Method	ANCOVA
	Comments	Mixed effect model including treatment, incentive and treatment*incentive as fixed effects; baseline, age, gender and CAG repeats as covariates.
Method of Estimation	Estimation Parameter	Least square mean
	Estimated Value	7.30
	Confidence Interval	(2-Sided) 90%; 1.43 to 13.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.57
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PF-02545920 20 mg Twice a Day, Placebo Twice a Day
	Comments	PF-02545920 versus Placebo (Emotional Incentive-Positive) Day 28
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments	2-sided p-value
	Method	ANCOVA
	Comments	Mixed effect model including treatment, incentive and treatment*incentive as fixed effects; baseline, age, gender and CAG repeats as covariates.
Method of Estimation	Estimation Parameter	Least square mean
	Estimated Value	7.57
	Confidence Interval	(2-Sided) 90%; 1.69 to 13.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.57
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	PF-02545920 20 mg Twice a Day, Placebo Twice a Day
	Comments	PF-02545920 versus Placebo (Emotional Incentive-Negative) Day 28
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments	2-sided p-value
	Method	ANCOVA
	Comments	Mixed effect model including treatment, incentive and treatment*incentive as fixed effects; baseline, age, gender and CAG repeats as covariates.
Method of Estimation	Estimation Parameter	Least square mean
	Estimated Value	7.28
	Confidence Interval	(2-Sided) 90%; 1.41 to 13.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.56
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	PF-02545920 20 mg Twice a Day, Placebo Twice a Day
	Comments	PF-02545920 versus Placebo (Monetary Incentive-0.01 Euro) Day 28
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments	2-sided p-value
	Method	ANCOVA
	Comments	Mixed effect model including treatment, incentive and treatment*incentive as fixed effects; baseline, age, gender and CAG repeats as covariates.
Method of Estimation	Estimation Parameter	Least square mean
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 90%; -4.91 to 6.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.58
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	PF-02545920 20 mg Twice a Day, Placebo Twice a Day
	Comments	PF-02545920 versus Placebo (Monetary Incentive-0.1 Euro) Day 28
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments	2-sided p-value
	Method	ANCOVA
	Comments	Mixed effect model including treatment, incentive and treatment*incentive as fixed effects; baseline, age, gender and CAG repeats as covariates.
Method of Estimation	Estimation Parameter	Least square mean
	Estimated Value	4.78
	Confidence Interval	(2-Sided) 90%; -1.11 to 10.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.58
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	PF-02545920 20 mg Twice a Day, Placebo Twice a Day
	Comments	PF-02545920 versus Placebo (Monetary Incentive-1 Euro) Day 28
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments	2-sided p-value
	Method	ANCOVA
	Comments	Mixed effect model including treatment, incentive and treatment*incentive as fixed effects; baseline, age, gender and CAG repeats as covariates.
Method of Estimation	Estimation Parameter	Least square mean
	Estimated Value	16.35
	Confidence Interval	(2-Sided) 90%; 10.46 to 22.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.58
	Estimation Comments

Adverse Events

Time Frame	Baseline up to Day 38
Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Arm/Group Title	PF-02545920 20 mg Twice a Day		Placebo Twice a Day
Arm/Group Description	Participants received PF-02545920 orally every 12 hours according to a titration dosing scheme: 5 mg twice daily (BID) on Days 1-2, 10 mg BID on Days 3-4, 15 mg BID on Days 5-6, and 20 mg BID on Days 7-28; followed by a 7 to 10 day safety evaluation period.		Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period.
All Cause Mortality
	PF-02545920 20 mg Twice a Day		Placebo Twice a Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	PF-02545920 20 mg Twice a Day		Placebo Twice a Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		1/17 (5.9%)
Nervous system disorders
Chorea	1/19 (5.3%)		0/17 (0%)
Reproductive system and breast disorders
Ovarian cyst	0/19 (0%)		1/17 (5.9%)
Other (Not Including Serious) Adverse Events
	PF-02545920 20 mg Twice a Day		Placebo Twice a Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/19 (94.7%)		14/17 (82.4%)
Blood and lymphatic system disorders
Anaemia	0/19 (0%)		1/17 (5.9%)
Cardiac disorders
Palpitations	1/19 (5.3%)		0/17 (0%)
Ear and labyrinth disorders
Vertigo	0/19 (0%)		2/17 (11.8%)
Gastrointestinal disorders
Abdominal pain	2/19 (10.5%)		0/17 (0%)
Constipation	1/19 (5.3%)		0/17 (0%)
Diarrhoea	3/19 (15.8%)		2/17 (11.8%)
Dry mouth	4/19 (21.1%)		1/17 (5.9%)
Flatulence	0/19 (0%)		1/17 (5.9%)
Gastrointestinal disorder	1/19 (5.3%)		0/17 (0%)
Mouth ulceration	0/19 (0%)		1/17 (5.9%)
Nausea	5/19 (26.3%)		2/17 (11.8%)
Vomiting	2/19 (10.5%)		0/17 (0%)
General disorders
Asthenia	2/19 (10.5%)		1/17 (5.9%)
Fatigue	8/19 (42.1%)		4/17 (23.5%)
Feeling hot	1/19 (5.3%)		0/17 (0%)
Gait disturbance	0/19 (0%)		1/17 (5.9%)
Thirst	1/19 (5.3%)		1/17 (5.9%)
Infections and infestations
Nasopharyngitis	1/19 (5.3%)		0/17 (0%)
Pharyngitis	1/19 (5.3%)		0/17 (0%)
Rhinitis	0/19 (0%)		1/17 (5.9%)
Urinary tract infection	0/19 (0%)		1/17 (5.9%)
Investigations
Blood pressure increased	1/19 (5.3%)		0/17 (0%)
Blood urine present	1/19 (5.3%)		0/17 (0%)
Electrocardiogram QRS complex prolonged	0/19 (0%)		1/17 (5.9%)
Electrocardiogram QT prolonged	1/19 (5.3%)		1/17 (5.9%)
Neutrophil count decreased	0/19 (0%)		3/17 (17.6%)
Metabolism and nutrition disorders
Decreased appetite	1/19 (5.3%)		0/17 (0%)
Glucose tolerance impaired	0/19 (0%)		1/17 (5.9%)
Musculoskeletal and connective tissue disorders
Back pain	1/19 (5.3%)		0/17 (0%)
Muscle spasms	0/19 (0%)		1/17 (5.9%)
Musculoskeletal pain	1/19 (5.3%)		0/17 (0%)
Pain in extremity	0/19 (0%)		1/17 (5.9%)
Nervous system disorders
Akathisia	2/19 (10.5%)		0/17 (0%)
Chorea	4/19 (21.1%)		0/17 (0%)
Dysgeusia	1/19 (5.3%)		0/17 (0%)
Headache	5/19 (26.3%)		6/17 (35.3%)
Migraine	1/19 (5.3%)		1/17 (5.9%)
Oromandibular dystonia	1/19 (5.3%)		0/17 (0%)
Presyncope	1/19 (5.3%)		0/17 (0%)
Somnolence	3/19 (15.8%)		0/17 (0%)
Psychiatric disorders
Aggression	1/19 (5.3%)		0/17 (0%)
Bradyphrenia	1/19 (5.3%)		0/17 (0%)
Insomnia	2/19 (10.5%)		0/17 (0%)
Irritability	0/19 (0%)		1/17 (5.9%)
Libido decreased	1/19 (5.3%)		0/17 (0%)
Negative thoughts	1/19 (5.3%)		0/17 (0%)
Renal and urinary disorders
Pollakiuria	1/19 (5.3%)		0/17 (0%)
Reproductive system and breast disorders
Dysmenorrhoea	0/19 (0%)		1/17 (5.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/19 (5.3%)		0/17 (0%)
Nasal congestion	1/19 (5.3%)		0/17 (0%)
Skin and subcutaneous tissue disorders
Alopecia	0/19 (0%)		1/17 (5.9%)
Hyperhidrosis	4/19 (21.1%)		0/17 (0%)
Vascular disorders
Hot flush	2/19 (10.5%)		0/17 (0%)

Limitations/Caveats

The study was initially designed to include 20 mg BID and 5 mg BID. Interim analysis of 20 mg BID/placebo supported the development of PF-02545920, and therefore, 5 mg BID was not enrolled.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.