Huntington's Disease
Conditions
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.
Interventions
DRUGPF-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.
DRUGPlacebo
\- Orally, approx. Q12H (range 10-14 hours), administered at least one hour prior to, or two hours after meals. Dosing for 28 days.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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 \[HbA1c, if diabetic\]). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PF-02545920 20 mg Twice a Day 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. | 19 |
| Placebo Twice a Day Participants received placebo matched to PF-02545920 orally every 12 hours for 28 days, followed by a 7 to 10 day safety evaluation period. | 17 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Other | 1 | 0 |
Baseline characteristics
| Characteristic | PF-02545920 20 mg Twice a Day | Placebo Twice a Day | Total |
|---|---|---|---|
| Age, Continuous | 47.4 years STANDARD_DEVIATION 12.1 | 43.1 years STANDARD_DEVIATION 11.8 | 45.4 years STANDARD_DEVIATION 12 |
| Sex: Female, Male Female | 8 Participants | 10 Participants | 18 Participants |
| Sex: Female, Male Male | 11 Participants | 7 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 18 / 19 | 14 / 17 |
| serious Total, serious adverse events | 1 / 19 | 1 / 17 |
Outcome results
Primary
Categorical Summary of Participants Meeting Stopping Criteria
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
Population: The safety analysis population included all participants who received at least 1 dose of PF-02545920 or placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-02545920 20 mg Twice a Day | Categorical Summary of Participants Meeting Stopping Criteria | WBC 2000-3000 or ANC 1000-1500 cells/mm^3 | 0 participants |
| PF-02545920 20 mg Twice a Day | Categorical Summary of Participants Meeting Stopping Criteria | WBC <2000 or ANC <1000 cells/mm^3 | 0 participants |
| PF-02545920 20 mg Twice a Day | Categorical Summary of Participants Meeting Stopping Criteria | Discontinued/Suspended Due to WBC or ANC Findings | 0 participants |
| PF-02545920 20 mg Twice a Day | Categorical Summary of Participants Meeting Stopping Criteria | ANC<500 cells/mm^3 | 0 participants |
| Placebo Twice a Day | Categorical Summary of Participants Meeting Stopping Criteria | ANC<500 cells/mm^3 | 0 participants |
| Placebo Twice a Day | Categorical Summary of Participants Meeting Stopping Criteria | WBC 2000-3000 or ANC 1000-1500 cells/mm^3 | 1 participants |
| Placebo Twice a Day | Categorical Summary of Participants Meeting Stopping Criteria | Discontinued/Suspended Due to WBC or ANC Findings | 0 participants |
| Placebo Twice a Day | Categorical Summary of Participants Meeting Stopping Criteria | WBC <2000 or ANC <1000 cells/mm^3 | 0 participants |
Primary
Change From Baseline in Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score at 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).
Time frame: Baseline, Day 28
Population: The full analysis population included all participants randomized and had taken at least 1 dose of PF-02545920 or placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PF-02545920 20 mg Twice a Day | Change From Baseline in Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score at Day 28 | 0.19 units on a scale | 90% Confidence Interval 6.23 |
| Placebo Twice a Day | Change From Baseline in Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score at Day 28 | 0.90 units on a scale | 90% Confidence Interval 5.7 |
Comparison: PF-02545920 versus Placebo (Day 28)p-value: 0.6890% CI: [-3.56, 2.15]ANCOVA
Primary
Number of Participants With Change From Baseline in Body Weight of >=7%
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
Population: The safety analysis population included all participants who received at least 1 dose of PF-02545920 or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-02545920 20 mg Twice a Day | Number of Participants With Change From Baseline in Body Weight of >=7% | 0 participants |
| Placebo Twice a Day | Number of Participants With Change From Baseline in Body Weight of >=7% | 0 participants |
Primary
Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern (Without Regard to Baseline Abnormality)
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
Population: The safety analysis population included all participants who received at least 1 dose of PF-02545920 or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-02545920 20 mg Twice a Day | Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern (Without Regard to Baseline Abnormality) | 8 participants |
| Placebo Twice a Day | Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern (Without Regard to Baseline Abnormality) | 8 participants |
Primary
Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings
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
Population: The safety analysis population included all participants who received at least 1 dose of PF-02545920 or placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=25% increase when baseline >200 msec | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 450-<480 msec | 2 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=25% increase when baseline >100 msec | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 480-<500 msec | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS >=50% increase when baseline <=100 msec | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS >=50% increase when baseline <=200 msec | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=200 msec | 1 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval Increase 30-<60 msec | 1 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval >=500 msec | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval Increase >=60 msec | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=300 msec | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval Increase >=60 msec | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval >=500 msec | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=25% increase when baseline >100 msec | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=25% increase when baseline >200 msec | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=200 msec | 1 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=300 msec | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 450-<480 msec | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS >=50% increase when baseline <=100 msec | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS >=50% increase when baseline <=200 msec | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval Increase 30-<60 msec | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 480-<500 msec | 0 participants |
Primary
Number of Participants With Potentially Clinically Significant Vital Signs Findings
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
Population: The safety analysis population included all participants who received at least 1 dose of PF-02545920 or placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP <90 mmHg | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing SBP <90 mmHg | 1 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP <50 mmHg | 2 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing DBP <50 mmHg | 1 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine Pulse Rate <40 or >120 bpm | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing Pulse Rate <40 or >140 bpm | 1 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Increase From Baseline in Supine SBP >=30 mmHg | 1 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Increase From Baseline in Standing SBP >=30 mmHg | 2 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Increase From Baseline in Supine DBP >=20 mmHg | 1 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Increase From Baseline in Standing DBP >=20 mmHg | 1 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Decrease From Baseline in Supine SBP >=30 mmHg | 1 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Decrease From Baseline in Standing SBP >=30 mmHg | 1 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Decrease From Baseline in Supine DBP >=20 mmHg | 2 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Decrease From Baseline in Standing DBP >=20 mmHg | 3 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Decrease From Baseline in Supine SBP >=30 mmHg | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP <90 mmHg | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Increase From Baseline in Standing SBP >=30 mmHg | 2 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing SBP <90 mmHg | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Decrease From Baseline in Supine DBP >=20 mmHg | 1 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP <50 mmHg | 1 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Increase From Baseline in Supine DBP >=20 mmHg | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing DBP <50 mmHg | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Decrease From Baseline in Standing SBP >=30 mmHg | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine Pulse Rate <40 or >120 bpm | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Increase From Baseline in Standing DBP >=20 mmHg | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing Pulse Rate <40 or >140 bpm | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Decrease From Baseline in Standing DBP >=20 mmHg | 0 participants |
| Placebo Twice a Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Increase From Baseline in Supine SBP >=30 mmHg | 0 participants |
Primary
Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Baseline
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)
Population: The full analysis population included all participants randomized and had taken at least 1 dose of PF-02545920 or placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Baseline | Completed Suicide | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Baseline | Suicide Attempt | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Baseline | Acts Towards Imminent Suicidal Behavior | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Baseline | Suicidal Ideation | 1 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Baseline | Self-Injurious Behavior, No Suicidal Intent | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Baseline | Acts Towards Imminent Suicidal Behavior | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Baseline | Completed Suicide | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Baseline | Self-Injurious Behavior, No Suicidal Intent | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Baseline | Suicide Attempt | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Baseline | Suicidal Ideation | 0 participants |
Primary
Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at 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.
Time frame: Day 28
Population: The full analysis population included all participants randomized and had taken at least 1 dose of PF-02545920 or placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 28 | Completed Suicide | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 28 | Suicidal Ideation | 2 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 28 | Acts Towards Imminent Suicidal Behavior | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 28 | Self-Injurious Behavior, No Suicidal Intent | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 28 | Suicide Attempt | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 28 | Self-Injurious Behavior, No Suicidal Intent | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 28 | Completed Suicide | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 28 | Suicide Attempt | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 28 | Acts Towards Imminent Suicidal Behavior | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 28 | Suicidal Ideation | 0 participants |
Primary
Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at 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.
Time frame: Day 7
Population: The full analysis population included all participants randomized and had taken at least 1 dose of PF-02545920 or placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 7 | Acts Towards Imminent Suicidal Behavior | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 7 | Completed Suicide | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 7 | Suicidal Ideation | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 7 | Self-Injurious Behavior, No Suicidal Intent | 0 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 7 | Suicide Attempt | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 7 | Self-Injurious Behavior, No Suicidal Intent | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 7 | Suicidal Ideation | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 7 | Completed Suicide | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 7 | Acts Towards Imminent Suicidal Behavior | 0 participants |
| Placebo Twice a Day | Number of Participants With Suicidal Tendencies (C-SSRS Mapped to C-CASA) at Day 7 | Suicide Attempt | 0 participants |
Primary
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
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
Population: The safety analysis population included all participants who received at least 1 dose of PF-02545920 or placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-02545920 20 mg Twice a Day | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 18 participants |
| PF-02545920 20 mg Twice a Day | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 1 participants |
| Placebo Twice a Day | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 14 participants |
| Placebo Twice a Day | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 1 participants |
Secondary
Change From Baseline in Functional Magnetic Resonance Imaging (fMRI) in Monetary Incentive Delay (MID) Task at 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.
Time frame: Baseline (Day 1), Day 28
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| PF-02545920 20 mg Twice a Day | Change From Baseline in Functional Magnetic Resonance Imaging (fMRI) in Monetary Incentive Delay (MID) Task at Day 28 | Out_win_Rew>Out_win N Right VS | 0.36 beta contrasts | 90% Confidence Interval 2 |
| PF-02545920 20 mg Twice a Day | Change From Baseline in Functional Magnetic Resonance Imaging (fMRI) in Monetary Incentive Delay (MID) Task at Day 28 | Cue Rew>Neut Left VS | 0.01 beta contrasts | 90% Confidence Interval 1.15 |
| PF-02545920 20 mg Twice a Day | Change From Baseline in Functional Magnetic Resonance Imaging (fMRI) in Monetary Incentive Delay (MID) Task at Day 28 | Cue Rew>Neut Right VS | -0.20 beta contrasts | 90% Confidence Interval 1.11 |
| PF-02545920 20 mg Twice a Day | Change From Baseline in Functional Magnetic Resonance Imaging (fMRI) in Monetary Incentive Delay (MID) Task at Day 28 | Out_win_Rew>Out_win N Left VS | 0.20 beta contrasts | 90% Confidence Interval 2.33 |
| Placebo Twice a Day | Change From Baseline in Functional Magnetic Resonance Imaging (fMRI) in Monetary Incentive Delay (MID) Task at Day 28 | Out_win_Rew>Out_win N Left VS | 0.45 beta contrasts | 90% Confidence Interval 1.13 |
| Placebo Twice a Day | Change From Baseline in Functional Magnetic Resonance Imaging (fMRI) in Monetary Incentive Delay (MID) Task at Day 28 | Out_win_Rew>Out_win N Right VS | 0.89 beta contrasts | 90% Confidence Interval 1.14 |
| Placebo Twice a Day | Change From Baseline in Functional Magnetic Resonance Imaging (fMRI) in Monetary Incentive Delay (MID) Task at Day 28 | Cue Rew>Neut Right VS | -0.05 beta contrasts | 90% Confidence Interval 1.32 |
| Placebo Twice a Day | Change From Baseline in Functional Magnetic Resonance Imaging (fMRI) in Monetary Incentive Delay (MID) Task at Day 28 | Cue Rew>Neut Left VS | 0.11 beta contrasts | 90% Confidence Interval 1.13 |
Comparison: PF-02545920 versus Placebo (Cue Rew\>Neut Left VS)p-value: 0.7990% CI: [-0.72, 0.52]ANCOVA
Comparison: PF-02545920 versus Placebo (Cue Rew\>Neut Right VS)p-value: 0.790% CI: [-0.8, 0.51]ANCOVA
Comparison: PF-02545920 versus Placebo (Out\_win\_Rew\>Out\_win N Left VS)p-value: 0.5190% CI: [-0.89, 0.4]ANCOVA
Comparison: PF-02545920 versus Placebo (Out\_win\_Rew\>Out\_win N Right VS)p-value: 0.1390% CI: [-1.1, 0.04]ANCOVA
Secondary
Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC)
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| PF-02545920 20 mg Twice a Day | Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC) | Neutral Emotional Incentive Day 28 | 0.93 percentage of MVC |
| PF-02545920 20 mg Twice a Day | Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC) | Positive Emotional Incentive Day 28 | 1.10 percentage of MVC |
| PF-02545920 20 mg Twice a Day | Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC) | Negative Emotional Incentive Day 28 | 0.18 percentage of MVC |
| PF-02545920 20 mg Twice a Day | Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC) | 0.01 Euro Monetary Incentive Day 28 | -13.47 percentage of MVC |
| PF-02545920 20 mg Twice a Day | Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC) | 0.1 Euro Monetary Incentive Day 28 | -1.19 percentage of MVC |
| PF-02545920 20 mg Twice a Day | Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC) | 1 Euro Monetary Incentive Day 28 | 16.85 percentage of MVC |
| Placebo Twice a Day | Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC) | 0.1 Euro Monetary Incentive Day 28 | -5.97 percentage of MVC |
| Placebo Twice a Day | Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC) | Neutral Emotional Incentive Day 28 | -6.37 percentage of MVC |
| Placebo Twice a Day | Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC) | 0.01 Euro Monetary Incentive Day 28 | -14.45 percentage of MVC |
| Placebo Twice a Day | Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC) | Positive Emotional Incentive Day 28 | -6.47 percentage of MVC |
| Placebo Twice a Day | Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC) | 1 Euro Monetary Incentive Day 28 | 0.50 percentage of MVC |
| Placebo Twice a Day | Change From Baseline in Grip Strength Incentive Motivation Task at Day 28: Percent of Maximum Voluntary Contraction (MVC) | Negative Emotional Incentive Day 28 | -7.10 percentage of MVC |
Comparison: PF-02545920 versus Placebo (Emotional Incentive-Neutral) Day 28p-value: 0.0490% CI: [1.43, 13.18]ANCOVA
Comparison: PF-02545920 versus Placebo (Emotional Incentive-Positive) Day 28p-value: 0.0390% CI: [1.69, 13.45]ANCOVA
Comparison: PF-02545920 versus Placebo (Emotional Incentive-Negative) Day 28p-value: 0.0490% CI: [1.41, 13.15]ANCOVA
Comparison: PF-02545920 versus Placebo (Monetary Incentive-0.01 Euro) Day 28p-value: 0.7890% CI: [-4.91, 6.87]ANCOVA
Comparison: PF-02545920 versus Placebo (Monetary Incentive-0.1 Euro) Day 28p-value: 0.1890% CI: [-1.11, 10.67]ANCOVA
Comparison: PF-02545920 versus Placebo (Monetary Incentive-1 Euro) Day 28p-value: <0.0190% CI: [10.46, 22.24]ANCOVA