Alzheimer's Disease
Conditions
Keywords
Randomized, Double Blind, Safety and Efficacy
Brief summary
This study will evaluate safety and efficacy of PF-05212377 in subjects with mild-to-moderate Alzheimer's Disease with existing neuropsychiatric symptoms on a stable dose of Donepezil. The 4-week run-in will minimize placebo effect. The 12-week treatment period is considered the minimum length necessary to reliably evaluate the effect PF-05212377 on cognition and and neuropsychiatric symptoms in this population. The 2-week washout will allow to monitor re-emergence of neuropsychiatric and cognitive symptoms.
Interventions
30 mg QD of PF-05212377 (SAM-760)
OTHERPlacebo
Placebo QD
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of probable AD with supportive brain imaging documentation * Have existing neuropsychiatric symptoms as defined by a score equal or greater than 10 on the NPI at screening, arising from item scores equal or greater than 2 (frequency X severity) on at least 2 domains. * Has been on donepezil (stable dose of 5 mg or 10 mg) for at least four months, with no intent to change such for the duration of the study.
Exclusion criteria
* Demonstrate extreme agitation, physical aggression or violence to themselves, their caregiver, or others, and/or an inability to complete the ADAS-cog assessment at Screening. * Have major structural brain disease other than Alzheimer's Disease * Other severe acute or chronical medical or psychiatric condition or laboratory abnormality
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in ADAS-cog13 Total Score at Week 16 | Baseline and Week 16 | ADAS-cog13 (13-item ADAS cog) is a psychometric instrument that evaluates word recall, ability to follow commands, constructional praxis, naming, ideational praxis, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure of delayed word recall and concentration/ distractibility. The total score of the 13-item scale ranges from 0 to 85, with an increase in score indicating cognitive worsening. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Neuropsychiatric Inventory (NPI) Total Score at Week 16 (Visit 5) | Baseline and Week 16 | The NPI evaluates both frequency and severity of 12 neuropsychiatric disturbances including delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, as well as appetite/eating. The NPI total score (for 12 behavioral domains) is calculated as the product of frequency and severity for each domain, and ranges from 0 to 144. An increase in score indicates a worsening of symptoms. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Selected ECG Change From Baseline - PR Interval at Week 6 (Visit 3) | Baseline and Week 6 | The PR interval is the time from the onset of the P wave to the start of the QRS complex (the combination of the Q wave, R wave and S wave, representing ventricular depolarization). |
| Selected ECG Change From Baseline - PR Interval at Week 10 (Visit 4) | Baseline and Week 10 | The PR interval is the time from the onset of the P wave to the start of the QRS complex (the combination of the Q wave, R wave and S wave, representing ventricular depolarization). |
| Selected ECG Change From Baseline - PR Interval at Week 16/Early Termination (Visit 5) | Baseline and Week 16/Early Termination | The PR interval is the time from the onset of the P wave to the start of the QRS complex (the combination of the Q wave, R wave and S wave, representing ventricular depolarization). |
| Percentage of Participant With PR Interval Abnormalities of Potential Clinical Concern | Week 4 to Week 16 | Proportion (%) of participants with PR Interval abnormalities meeting categorical criteria over the 12 week double blind treatment period. The PR interval is the time from the onset of the P wave to the start of the QRS complex (the combination of the Q wave, R wave and S wave, representing ventricular depolarization). Participants with post-baseline PR absolute value\>=300 msec , a PR increase of \>=25% (for participants with a baseline value\>=200 msec), or with an increase \>=50% (for participants with a baseline value\<200 msec) were counted. |
| Selected ECG Change From Baseline - QRS Complex at Week 6 (Visit 3) | Baseline and Week 6 | The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization. |
| Selected ECG Change From Baseline - QRS Complex at Week 10 (Visit 4) | Baseline and Week 10 | The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization. |
| Selected ECG Change From Baseline - QRS Complex at Week 16/Early Termination (Visit 5) | Baseline and Week 16/Early Termination | The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization. |
| Proportion of Participants With QRS Complex Abnormalities of Potential Clinical Concern | Week 4 to Week 16 | Proportion (%) of participants with QRS Complex abnormalities meeting categorical criteria over the 12 week double blind treatment period. The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization). Participants with post-baseline QRS complex absolute value\>=100 msec , a QRS complex increase of \>=25% (for participants with a baseline value\>=100 msec), or with an increase \>=50% (for participants with a baseline value\<100 msec) were counted. |
| Selected ECG Change From Baseline - QTcF Interval at Week 6 (Visit 3) | Baseline and Week 6 | The QTcF interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, which is corrected for heart rate using Fridericia's formula. |
| Selected ECG Change From Baseline - QTcF Interval at Week 10 (Visit 4) | Baseline and Week 10 | The QTcF interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, which is corrected for heart rate using Fridericia's formula. |
| Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) Leading to Discontinuation | Week 4 to Week 18 | Proportion of participants with TEAEs leading to discontinuation over the 12-week double blind treatment period and washout. Adverse events (AEs) occurring following start of treatment or increasing in severity were counted as treatment emergent |
| Proportion of Participants With QTcF Interval Abnormalities of Potential Clinical Concern | Week 4 to Week 16 | Proportion (%) of participants with QTcF Interval abnormalities meeting categorical criteria over the 12-week double blind treatment period. The QTcF interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, which is corrected for heart rate using Fridericia's formula. Participants with a post-baseline QTcF absolute value of 450 - \<480, 480 - \<500, or \>=500 mec, or with a post-baseline QTcF increase of 30 - \<60 or \>=60 msec were counted. |
| Blood Pressure (BP) Changes From Baseline - Week 6 (Visit 3) | Baseline and Week 6 | The BP changes from baseline at Week 6 (Visit 3) including supine systolic BP, standing systolic BP, standing systolic BP, supine diastolic BP, standing diastolic BP. |
| Pulse Rate Changes From Baseline - Week 6 (Visit 3) | Baseline and Week 6 | The pulse rate changes from baseline at Week 6 (Visit 3) including supine pulse rate, and standing pulse rate. |
| BP Changes From Baseline - Week 10 (Visit 4) | Baseline and Week 10 | The BP changes from baseline at Week 10 (Visit 4) including supine systolic BP, standing systolic BP, standing systolic BP, supine diastolic BP, standing diastolic BP. |
| Pulse Rate Changes From Baseline - Week 10 (Visit 4) | Baseline and Week 10 | The pulse rate changes from baseline at Week 10 (Visit 4) including supine pulse rate, and standing pulse rate. |
| BP Changes From Baseline - Week 16/Early Termination (Visit 5) | Baseline and Week 16/Early Termination | The BP changes from baseline at Week 16/Early Termination (Visit 5) including supine systolic BP, standing systolic BP, standing systolic BP, supine diastolic BP, standing diastolic BP. |
| Pulse Rate Changes From Baseline - Week 16/Early Termination (Visit 5) | Baseline and Week 16/Early Termination | The pulse rate changes from baseline at Week 16/Early Termination (Visit 5) including supine pulse rate, and standing pulse rate. |
| Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Week 4 to Week 16 | Proportion (%) of participants with vital signs abnormalities (absolute and change from baseline) meeting categorical criteria over the 12-week double blind treatment period were counted. Vital signs data included blood pressure (BP) and pulse rate. |
| Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | From Screening to Week 18/Early Termination | Participants in each category of the Columbia Classification Algorithm of Suicide Assessment (C-CASA) mapped from the Columbia-Suicide Severity Rating Scale (C-SSRS) responses were reported. C-CASA Event Code: \<1\> Completed suicide; \<2\> Suicide attempt; \<3\> Preparatory acts towards imminent suicidal behavior; \<4\> Suicidal Ideation; \<7\> Self-injurious behavior, no suicidal intent. The suicidality assessments were performed at Screening, Week 0 (Visit 1), Week 4 (Visit 2), Week 6, (Visit 3), Week 10 (Visit 4), Week 16 (Visit 5), and Week 18 (Visit 6). Only participants falling any category of C-CASA events were listed below. |
| Selected ECG Change From Baseline - QTcF Interval at Week 16/Early Termination (Visit 5) | Baseline and Week 16/Early Termination | The QTcF interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, which is corrected for heart rate using Fridericia's formula. |
| Proportion of Participants With Laboratory Abnormalities of Potential Clinical Concern During Double Blind Period | Week 4 to Week 16 | Proportion (%) of participants with laboratory abnormalities (without regard to baseline abnormalities) of potential clinical concern over the 12-week double blind treatment period. The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase, alanine aminotransferase, 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 (only at screening or needed: urine drug screen, thyroid panel, Vitamin B12, methylmalonic acid, folate and Hemoglobin A1). |
Countries
Canada, Chile, France, Germany, Spain, United Kingdom, United States
Participant flow
Recruitment details
Before entering in the 12-week treatment period, participants were required to enter a 4-week placebo run-in period. 195 participants started the placebo run-in period, of which 186 were eligible for the treatment period. Among the 186 enrolled participants, 185 were treated with the double-blind study treatment, 1 was enrolled but not treated.
Pre-assignment details
This study was a multicenter Phase 2a, randomized, placebo controlled, safety and efficacy study of 18 weeks in duration in participants with mild-to-moderate Alzheimer's disease (AD) who were stable on treatment with 5 or 10 mg of donepezil and who had existing neuropsychiatric symptoms.
Participants by arm
| Arm | Count |
|---|---|
| Not Randomized Participants who have been discontinued during the Placebo Run-In period | 9 |
| PF-05212377 30 mg: Double Blind Period All participants entered the double blind period and received PF-05212377 30 mg | 92 |
| Placebo: Double Blind Period All participants entered the double blind period and received placebo | 94 |
| Total | 195 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double Blind Period | Adverse Event | 0 | 2 | 1 |
| Double Blind Period | Death | 0 | 1 | 0 |
| Double Blind Period | Lost to Follow-up | 0 | 2 | 1 |
| Double Blind Period | No longer met eligibility criteria | 0 | 3 | 0 |
| Double Blind Period | No longer willing to participate | 0 | 2 | 4 |
| Double Blind Period | Other | 0 | 4 | 1 |
| Double Blind Period | Protocol Violation | 0 | 0 | 1 |
| Placebo Run-in Period | Adverse Event | 2 | 0 | 0 |
| Placebo Run-in Period | Lost to Follow-up | 1 | 0 | 0 |
| Placebo Run-in Period | No longer meets eligibility criteria | 5 | 0 | 0 |
| Placebo Run-in Period | No longer willing to participate | 1 | 0 | 0 |
| Placebo Run-in Period | Other | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Not Randomized | PF-05212377 30 mg: Double Blind Period | Placebo: Double Blind Period | Total |
|---|---|---|---|---|
| Age, Continuous | 73.2 years STANDARD_DEVIATION 8.8 | 76.0 years STANDARD_DEVIATION 8 | 75.9 years STANDARD_DEVIATION 7.5 | 76 years STANDARD_DEVIATION 7.7 |
| Sex: Female, Male FEMALE | 7 Participants | 46 Participants | 55 Participants | 108 Participants |
| Sex: Female, Male MALE | 2 Participants | 46 Participants | 39 Participants | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 195 | 25 / 91 | 20 / 94 |
| serious Total, serious adverse events | 1 / 195 | 5 / 91 | 3 / 94 |
Outcome results
Primary
Change From Baseline in ADAS-cog13 Total Score at Week 16
ADAS-cog13 (13-item ADAS cog) is a psychometric instrument that evaluates word recall, ability to follow commands, constructional praxis, naming, ideational praxis, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure of delayed word recall and concentration/ distractibility. The total score of the 13-item scale ranges from 0 to 85, with an increase in score indicating cognitive worsening.
Time frame: Baseline and Week 16
Population: The Full Analysis Set (FAS) is defined as all participants who were randomized. The FAS was the primary analysis set for efficacy data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PF-05212377 30 mg | Change From Baseline in ADAS-cog13 Total Score at Week 16 | 0.111 scores on a scale | Standard Error 0.629 |
| Placebo | Change From Baseline in ADAS-cog13 Total Score at Week 16 | -0.584 scores on a scale | Standard Error 0.5995 |
p-value: 0.425680% CI: [-0.424, 1.814]Mixed Models Analysis
Secondary
Change From Baseline in the Neuropsychiatric Inventory (NPI) Total Score at Week 16 (Visit 5)
The NPI evaluates both frequency and severity of 12 neuropsychiatric disturbances including delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, as well as appetite/eating. The NPI total score (for 12 behavioral domains) is calculated as the product of frequency and severity for each domain, and ranges from 0 to 144. An increase in score indicates a worsening of symptoms.
Time frame: Baseline and Week 16
Population: The FAS is defined as all participants who are randomized. The FAS was the primary analysis set for efficacy data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PF-05212377 30 mg | Change From Baseline in the Neuropsychiatric Inventory (NPI) Total Score at Week 16 (Visit 5) | -3.990 scores on a scale | Standard Error 1.2441 |
| Placebo | Change From Baseline in the Neuropsychiatric Inventory (NPI) Total Score at Week 16 (Visit 5) | -6.184 scores on a scale | Standard Error 1.1801 |
p-value: 0.202780% CI: [-0.013, 4.401]Mixed Models Analysis
Other Pre-specified
Blood Pressure (BP) Changes From Baseline - Week 6 (Visit 3)
The BP changes from baseline at Week 6 (Visit 3) including supine systolic BP, standing systolic BP, standing systolic BP, supine diastolic BP, standing diastolic BP.
Time frame: Baseline and Week 6
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| PF-05212377 30 mg | Blood Pressure (BP) Changes From Baseline - Week 6 (Visit 3) | Supine Systolic BP | -3.6 millimeters of mercury (mm Hg) |
| PF-05212377 30 mg | Blood Pressure (BP) Changes From Baseline - Week 6 (Visit 3) | Standing Systolic BP | -4.1 millimeters of mercury (mm Hg) |
| PF-05212377 30 mg | Blood Pressure (BP) Changes From Baseline - Week 6 (Visit 3) | Supine Diastolic BP | -2.2 millimeters of mercury (mm Hg) |
| PF-05212377 30 mg | Blood Pressure (BP) Changes From Baseline - Week 6 (Visit 3) | Standing Diastolic BP | -1.1 millimeters of mercury (mm Hg) |
| Placebo | Blood Pressure (BP) Changes From Baseline - Week 6 (Visit 3) | Standing Diastolic BP | -1.0 millimeters of mercury (mm Hg) |
| Placebo | Blood Pressure (BP) Changes From Baseline - Week 6 (Visit 3) | Supine Systolic BP | -3.9 millimeters of mercury (mm Hg) |
| Placebo | Blood Pressure (BP) Changes From Baseline - Week 6 (Visit 3) | Supine Diastolic BP | -1.8 millimeters of mercury (mm Hg) |
| Placebo | Blood Pressure (BP) Changes From Baseline - Week 6 (Visit 3) | Standing Systolic BP | -3.0 millimeters of mercury (mm Hg) |
Other Pre-specified
BP Changes From Baseline - Week 10 (Visit 4)
The BP changes from baseline at Week 10 (Visit 4) including supine systolic BP, standing systolic BP, standing systolic BP, supine diastolic BP, standing diastolic BP.
Time frame: Baseline and Week 10
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| PF-05212377 30 mg | BP Changes From Baseline - Week 10 (Visit 4) | Supine Systolic BP | -3.4 mmHg |
| PF-05212377 30 mg | BP Changes From Baseline - Week 10 (Visit 4) | Standing Systolic BP | -3.8 mmHg |
| PF-05212377 30 mg | BP Changes From Baseline - Week 10 (Visit 4) | Supine Diastolic BP | -2.4 mmHg |
| PF-05212377 30 mg | BP Changes From Baseline - Week 10 (Visit 4) | Standing Diastolic BP | -1.2 mmHg |
| Placebo | BP Changes From Baseline - Week 10 (Visit 4) | Standing Diastolic BP | 0.3 mmHg |
| Placebo | BP Changes From Baseline - Week 10 (Visit 4) | Supine Systolic BP | -0.3 mmHg |
| Placebo | BP Changes From Baseline - Week 10 (Visit 4) | Supine Diastolic BP | -0.7 mmHg |
| Placebo | BP Changes From Baseline - Week 10 (Visit 4) | Standing Systolic BP | 0.8 mmHg |
Other Pre-specified
BP Changes From Baseline - Week 16/Early Termination (Visit 5)
The BP changes from baseline at Week 16/Early Termination (Visit 5) including supine systolic BP, standing systolic BP, standing systolic BP, supine diastolic BP, standing diastolic BP.
Time frame: Baseline and Week 16/Early Termination
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| PF-05212377 30 mg | BP Changes From Baseline - Week 16/Early Termination (Visit 5) | Standing Diastolic BP | -0.8 mmHg |
| PF-05212377 30 mg | BP Changes From Baseline - Week 16/Early Termination (Visit 5) | Standing Systolic BP | -1.0 mmHg |
| PF-05212377 30 mg | BP Changes From Baseline - Week 16/Early Termination (Visit 5) | Supine Systolic BP | -1.4 mmHg |
| PF-05212377 30 mg | BP Changes From Baseline - Week 16/Early Termination (Visit 5) | Supine Diastolic BP | -2.1 mmHg |
| Placebo | BP Changes From Baseline - Week 16/Early Termination (Visit 5) | Standing Diastolic BP | 0.0 mmHg |
| Placebo | BP Changes From Baseline - Week 16/Early Termination (Visit 5) | Supine Diastolic BP | -0.3 mmHg |
| Placebo | BP Changes From Baseline - Week 16/Early Termination (Visit 5) | Supine Systolic BP | -1.1 mmHg |
| Placebo | BP Changes From Baseline - Week 16/Early Termination (Visit 5) | Standing Systolic BP | -1.1 mmHg |
Other Pre-specified
Participants in Each Category of C-CASA Mapped From the C-SSRS Responses
Participants in each category of the Columbia Classification Algorithm of Suicide Assessment (C-CASA) mapped from the Columbia-Suicide Severity Rating Scale (C-SSRS) responses were reported. C-CASA Event Code: \<1\> Completed suicide; \<2\> Suicide attempt; \<3\> Preparatory acts towards imminent suicidal behavior; \<4\> Suicidal Ideation; \<7\> Self-injurious behavior, no suicidal intent. The suicidality assessments were performed at Screening, Week 0 (Visit 1), Week 4 (Visit 2), Week 6, (Visit 3), Week 10 (Visit 4), Week 16 (Visit 5), and Week 18 (Visit 6). Only participants falling any category of C-CASA events were listed below.
Time frame: From Screening to Week 18/Early Termination
Population: All participants screened and assigned
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-05212377 30 mg | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 6 (Visit 3): <4> | 0 Participants |
| PF-05212377 30 mg | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 6 (Visit 3): <7> | 0 Participants |
| PF-05212377 30 mg | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 4 (Visit 2): <7> | 0 Participants |
| PF-05212377 30 mg | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 4 (Visit 2): <4> | 1 Participants |
| PF-05212377 30 mg | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 16/Early Termination (Visit 5): <4> | 0 Participants |
| PF-05212377 30 mg | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 10 (Visit 4): : <4> | 0 Participants |
| Placebo | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 4 (Visit 2): <7> | 0 Participants |
| Placebo | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 4 (Visit 2): <4> | 2 Participants |
| Placebo | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 6 (Visit 3): <4> | 0 Participants |
| Placebo | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 16/Early Termination (Visit 5): <4> | 1 Participants |
| Placebo | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 6 (Visit 3): <7> | 1 Participants |
| Placebo | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 10 (Visit 4): : <4> | 2 Participants |
| Placebo | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 6 (Visit 3): <4> | 1 Participants |
| Placebo | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 6 (Visit 3): <7> | 0 Participants |
| Placebo | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 10 (Visit 4): : <4> | 0 Participants |
| Placebo | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 4 (Visit 2): <4> | 1 Participants |
| Placebo | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 16/Early Termination (Visit 5): <4> | 0 Participants |
| Placebo | Participants in Each Category of C-CASA Mapped From the C-SSRS Responses | Week 4 (Visit 2): <7> | 1 Participants |
Other Pre-specified
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) Leading to Discontinuation
Proportion of participants with TEAEs leading to discontinuation over the 12-week double blind treatment period and washout. Adverse events (AEs) occurring following start of treatment or increasing in severity were counted as treatment emergent
Time frame: Week 4 to Week 18
Population: All participants who received any treatment during double blind period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-05212377 30 mg | Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) Leading to Discontinuation | 3.3 Percentage of Participants |
| Placebo | Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) Leading to Discontinuation | 0 Percentage of Participants |
Other Pre-specified
Percentage of Participant With PR Interval Abnormalities of Potential Clinical Concern
Proportion (%) of participants with PR Interval abnormalities meeting categorical criteria over the 12 week double blind treatment period. The PR interval is the time from the onset of the P wave to the start of the QRS complex (the combination of the Q wave, R wave and S wave, representing ventricular depolarization). Participants with post-baseline PR absolute value\>=300 msec , a PR increase of \>=25% (for participants with a baseline value\>=200 msec), or with an increase \>=50% (for participants with a baseline value\<200 msec) were counted.
Time frame: Week 4 to Week 16
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-05212377 30 mg | Percentage of Participant With PR Interval Abnormalities of Potential Clinical Concern | Post-Baseline Maximum Increase >=25/50% | 0 Percentage of Participants |
| PF-05212377 30 mg | Percentage of Participant With PR Interval Abnormalities of Potential Clinical Concern | Post-Baseline Maximum Absolute Value >=300 msec | 0 Percentage of Participants |
| Placebo | Percentage of Participant With PR Interval Abnormalities of Potential Clinical Concern | Post-Baseline Maximum Absolute Value >=300 msec | 4.4 Percentage of Participants |
| Placebo | Percentage of Participant With PR Interval Abnormalities of Potential Clinical Concern | Post-Baseline Maximum Increase >=25/50% | 0 Percentage of Participants |
Other Pre-specified
Proportion of Participants With Laboratory Abnormalities of Potential Clinical Concern During Double Blind Period
Proportion (%) of participants with laboratory abnormalities (without regard to baseline abnormalities) of potential clinical concern over the 12-week double blind treatment period. The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase, alanine aminotransferase, 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 (only at screening or needed: urine drug screen, thyroid panel, Vitamin B12, methylmalonic acid, folate and Hemoglobin A1).
Time frame: Week 4 to Week 16
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-05212377 30 mg | Proportion of Participants With Laboratory Abnormalities of Potential Clinical Concern During Double Blind Period | 36.0 Percentage of Participants |
| Placebo | Proportion of Participants With Laboratory Abnormalities of Potential Clinical Concern During Double Blind Period | 52.0 Percentage of Participants |
Other Pre-specified
Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern
Proportion (%) of participants with vital signs abnormalities (absolute and change from baseline) meeting categorical criteria over the 12-week double blind treatment period were counted. Vital signs data included blood pressure (BP) and pulse rate.
Time frame: Week 4 to Week 16
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Standing Diastolic BP <50 mmHg | 0 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Supine Pulse Rate <40 bpm | 0 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Supine Pulse Rate >120 bpm | 0 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Standing Pulse Rate <40 bpm | 0 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Decrease in Supine Systolic BP>=30 mmHg | 5.5 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Decrease in Standing Systolic BP>=30 mmHg | 5.5 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Decrease in Supine Diastolic BP >=20 mmHg | 8.8 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Supine Systolic BP<90 mmHg | 0 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Standing Systolic BP<90 mmHg | 0 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Supine Diastolic BP<50 mmHg | 0 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Standing Pulse Rate >140 bpm | 0 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Increase in Supine Systolic BP>=30 mmHg | 0 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Increase in Standing Systolic BP>=30 mmHg | 2.2 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Increase in Supine Diastolic BP >=20 mmHg | 4.4 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Increase in Standing Diastolic BP >=20 mmHg | 3.3 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Decrease in Standing Diastolic BP >=20 mmHg | 4.4 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Increase in Standing Systolic BP>=30 mmHg | 3.2 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Standing Diastolic BP <50 mmHg | 0 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Standing Systolic BP<90 mmHg | 1.1 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Supine Pulse Rate <40 bpm | 0 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Decrease in Supine Diastolic BP >=20 mmHg | 5.3 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Supine Pulse Rate >120 bpm | 0 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Supine Diastolic BP<50 mmHg | 2.1 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Standing Pulse Rate <40 bpm | 0 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Standing Pulse Rate >140 bpm | 0 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Increase in Standing Diastolic BP >=20 mmHg | 5.3 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Increase in Supine Diastolic BP >=20 mmHg | 4.3 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Decrease in Supine Systolic BP>=30 mmHg | 5.3 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Decrease in Standing Diastolic BP >=20 mmHg | 6.4 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Increase in Supine Systolic BP>=30 mmHg | 5.3 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Decrease in Standing Systolic BP>=30 mmHg | 5.3 Percentage of Participants |
| Placebo | Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern | Absolute Supine Systolic BP<90 mmHg | 1.1 Percentage of Participants |
Other Pre-specified
Proportion of Participants With QRS Complex Abnormalities of Potential Clinical Concern
Proportion (%) of participants with QRS Complex abnormalities meeting categorical criteria over the 12 week double blind treatment period. The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization). Participants with post-baseline QRS complex absolute value\>=100 msec , a QRS complex increase of \>=25% (for participants with a baseline value\>=100 msec), or with an increase \>=50% (for participants with a baseline value\<100 msec) were counted.
Time frame: Week 4 to Week 16
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-05212377 30 mg | Proportion of Participants With QRS Complex Abnormalities of Potential Clinical Concern | Post-Baseline Maximum Increase >=25/50% | 0 Percentage of participants |
| PF-05212377 30 mg | Proportion of Participants With QRS Complex Abnormalities of Potential Clinical Concern | Post-Baseline Maximum Absolute Value >=200 msec | 0 Percentage of participants |
| Placebo | Proportion of Participants With QRS Complex Abnormalities of Potential Clinical Concern | Post-Baseline Maximum Absolute Value >=200 msec | 0 Percentage of participants |
| Placebo | Proportion of Participants With QRS Complex Abnormalities of Potential Clinical Concern | Post-Baseline Maximum Increase >=25/50% | 0 Percentage of participants |
Other Pre-specified
Proportion of Participants With QTcF Interval Abnormalities of Potential Clinical Concern
Proportion (%) of participants with QTcF Interval abnormalities meeting categorical criteria over the 12-week double blind treatment period. The QTcF interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, which is corrected for heart rate using Fridericia's formula. Participants with a post-baseline QTcF absolute value of 450 - \<480, 480 - \<500, or \>=500 mec, or with a post-baseline QTcF increase of 30 - \<60 or \>=60 msec were counted.
Time frame: Week 4 to Week 16
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-05212377 30 mg | Proportion of Participants With QTcF Interval Abnormalities of Potential Clinical Concern | Post-Baseline Absolute Value of 450-<480 msec | 15.4 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With QTcF Interval Abnormalities of Potential Clinical Concern | Post-Baseline Absolute Value of 480-<500 msec | 4.4 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With QTcF Interval Abnormalities of Potential Clinical Concern | Change from Baseline of 30 -<60 msec | 6.6 Percentage of Participants |
| PF-05212377 30 mg | Proportion of Participants With QTcF Interval Abnormalities of Potential Clinical Concern | Change from Baseline >=60 msec | 0 Percentage of Participants |
| Placebo | Proportion of Participants With QTcF Interval Abnormalities of Potential Clinical Concern | Change from Baseline >=60 msec | 0 Percentage of Participants |
| Placebo | Proportion of Participants With QTcF Interval Abnormalities of Potential Clinical Concern | Post-Baseline Absolute Value of 450-<480 msec | 14.0 Percentage of Participants |
| Placebo | Proportion of Participants With QTcF Interval Abnormalities of Potential Clinical Concern | Change from Baseline of 30 -<60 msec | 3.2 Percentage of Participants |
| Placebo | Proportion of Participants With QTcF Interval Abnormalities of Potential Clinical Concern | Post-Baseline Absolute Value of 480-<500 msec | 1.1 Percentage of Participants |
Other Pre-specified
Pulse Rate Changes From Baseline - Week 10 (Visit 4)
The pulse rate changes from baseline at Week 10 (Visit 4) including supine pulse rate, and standing pulse rate.
Time frame: Baseline and Week 10
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| PF-05212377 30 mg | Pulse Rate Changes From Baseline - Week 10 (Visit 4) | Supine Pulse Rate | -0.4 bpm |
| PF-05212377 30 mg | Pulse Rate Changes From Baseline - Week 10 (Visit 4) | Standing Pulse Rate | -0.7 bpm |
| Placebo | Pulse Rate Changes From Baseline - Week 10 (Visit 4) | Supine Pulse Rate | 0.5 bpm |
| Placebo | Pulse Rate Changes From Baseline - Week 10 (Visit 4) | Standing Pulse Rate | 1.8 bpm |
Other Pre-specified
Pulse Rate Changes From Baseline - Week 16/Early Termination (Visit 5)
The pulse rate changes from baseline at Week 16/Early Termination (Visit 5) including supine pulse rate, and standing pulse rate.
Time frame: Baseline and Week 16/Early Termination
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| PF-05212377 30 mg | Pulse Rate Changes From Baseline - Week 16/Early Termination (Visit 5) | Standing Pulse Rate | -1.9 bpm |
| PF-05212377 30 mg | Pulse Rate Changes From Baseline - Week 16/Early Termination (Visit 5) | Supine Pulse Rate | -0.8 bpm |
| Placebo | Pulse Rate Changes From Baseline - Week 16/Early Termination (Visit 5) | Standing Pulse Rate | 0.8 bpm |
| Placebo | Pulse Rate Changes From Baseline - Week 16/Early Termination (Visit 5) | Supine Pulse Rate | 0.6 bpm |
Other Pre-specified
Pulse Rate Changes From Baseline - Week 6 (Visit 3)
The pulse rate changes from baseline at Week 6 (Visit 3) including supine pulse rate, and standing pulse rate.
Time frame: Baseline and Week 6
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| PF-05212377 30 mg | Pulse Rate Changes From Baseline - Week 6 (Visit 3) | Supine Pulse Rate | -1.4 beats per minute (bpm) |
| PF-05212377 30 mg | Pulse Rate Changes From Baseline - Week 6 (Visit 3) | Standing Pulse Rate | -0.3 beats per minute (bpm) |
| Placebo | Pulse Rate Changes From Baseline - Week 6 (Visit 3) | Supine Pulse Rate | 1.4 beats per minute (bpm) |
| Placebo | Pulse Rate Changes From Baseline - Week 6 (Visit 3) | Standing Pulse Rate | 1.3 beats per minute (bpm) |
Other Pre-specified
Selected ECG Change From Baseline - PR Interval at Week 10 (Visit 4)
The PR interval is the time from the onset of the P wave to the start of the QRS complex (the combination of the Q wave, R wave and S wave, representing ventricular depolarization).
Time frame: Baseline and Week 10
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PF-05212377 30 mg | Selected ECG Change From Baseline - PR Interval at Week 10 (Visit 4) | -0.1 msec |
| Placebo | Selected ECG Change From Baseline - PR Interval at Week 10 (Visit 4) | -1.3 msec |
Other Pre-specified
Selected ECG Change From Baseline - PR Interval at Week 16/Early Termination (Visit 5)
The PR interval is the time from the onset of the P wave to the start of the QRS complex (the combination of the Q wave, R wave and S wave, representing ventricular depolarization).
Time frame: Baseline and Week 16/Early Termination
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PF-05212377 30 mg | Selected ECG Change From Baseline - PR Interval at Week 16/Early Termination (Visit 5) | -2.5 msec |
| Placebo | Selected ECG Change From Baseline - PR Interval at Week 16/Early Termination (Visit 5) | -1.6 msec |
Other Pre-specified
Selected ECG Change From Baseline - PR Interval at Week 6 (Visit 3)
The PR interval is the time from the onset of the P wave to the start of the QRS complex (the combination of the Q wave, R wave and S wave, representing ventricular depolarization).
Time frame: Baseline and Week 6
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PF-05212377 30 mg | Selected ECG Change From Baseline - PR Interval at Week 6 (Visit 3) | -2.8 milliseconds (msec) |
| Placebo | Selected ECG Change From Baseline - PR Interval at Week 6 (Visit 3) | -3.6 milliseconds (msec) |
Other Pre-specified
Selected ECG Change From Baseline - QRS Complex at Week 10 (Visit 4)
The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization.
Time frame: Baseline and Week 10
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PF-05212377 30 mg | Selected ECG Change From Baseline - QRS Complex at Week 10 (Visit 4) | -0.1 msec |
| Placebo | Selected ECG Change From Baseline - QRS Complex at Week 10 (Visit 4) | 0.1 msec |
Other Pre-specified
Selected ECG Change From Baseline - QRS Complex at Week 16/Early Termination (Visit 5)
The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization.
Time frame: Baseline and Week 16/Early Termination
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PF-05212377 30 mg | Selected ECG Change From Baseline - QRS Complex at Week 16/Early Termination (Visit 5) | 0.1 msec |
| Placebo | Selected ECG Change From Baseline - QRS Complex at Week 16/Early Termination (Visit 5) | -0.3 msec |
Other Pre-specified
Selected ECG Change From Baseline - QRS Complex at Week 6 (Visit 3)
The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization.
Time frame: Baseline and Week 6
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PF-05212377 30 mg | Selected ECG Change From Baseline - QRS Complex at Week 6 (Visit 3) | -0.3 msec |
| Placebo | Selected ECG Change From Baseline - QRS Complex at Week 6 (Visit 3) | -0.8 msec |
Other Pre-specified
Selected ECG Change From Baseline - QTcF Interval at Week 10 (Visit 4)
The QTcF interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, which is corrected for heart rate using Fridericia's formula.
Time frame: Baseline and Week 10
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PF-05212377 30 mg | Selected ECG Change From Baseline - QTcF Interval at Week 10 (Visit 4) | -0.2 msec |
| Placebo | Selected ECG Change From Baseline - QTcF Interval at Week 10 (Visit 4) | -5.5 msec |
Other Pre-specified
Selected ECG Change From Baseline - QTcF Interval at Week 16/Early Termination (Visit 5)
The QTcF interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, which is corrected for heart rate using Fridericia's formula.
Time frame: Baseline and Week 16/Early Termination
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PF-05212377 30 mg | Selected ECG Change From Baseline - QTcF Interval at Week 16/Early Termination (Visit 5) | 0.8 msec |
| Placebo | Selected ECG Change From Baseline - QTcF Interval at Week 16/Early Termination (Visit 5) | -2.2 msec |
Other Pre-specified
Selected ECG Change From Baseline - QTcF Interval at Week 6 (Visit 3)
The QTcF interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, which is corrected for heart rate using Fridericia's formula.
Time frame: Baseline and Week 6
Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PF-05212377 30 mg | Selected ECG Change From Baseline - QTcF Interval at Week 6 (Visit 3) | -3.0 msec |
| Placebo | Selected ECG Change From Baseline - QTcF Interval at Week 6 (Visit 3) | -4.9 msec |