Trial Outcomes & Findings for Study Evaluating TheSafety And Efficacy Of PF-05212377 Or Placebo In Subjects With Alzheimer's Disease With Existing Neuropsychiatric Symptoms On Donepezil (NCT NCT01712074)

NCT ID: NCT01712074

Last Updated: 2017-03-20

Results Overview

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.

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 186 participants
• Primary outcome timeframe: Baseline and Week 16
• Results posted on: 2017-03-20

Participant Flow

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.

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.

Participant milestones

Measure	Placebo Run-In Participants that received placebo during the 4-week single blind placebo run-in period	PF-05212377 30 mg: Double Blind Period All participants that received PF-05212377 30 mg during the 12-week double blind period	Placebo: Double Blind Period All participants that received placebo during the 12-week double blind period
Placebo Run-in Period STARTED	195	0	0
Placebo Run-in Period COMPLETED	185	0	0
Placebo Run-in Period NOT COMPLETED	10	0	0
Double Blind Period STARTED	0	91	94
Double Blind Period COMPLETED	0	77	86
Double Blind Period NOT COMPLETED	0	14	8

Reasons for withdrawal

Measure	Placebo Run-In Participants that received placebo during the 4-week single blind placebo run-in period	PF-05212377 30 mg: Double Blind Period All participants that received PF-05212377 30 mg during the 12-week double blind period	Placebo: Double Blind Period All participants that received placebo during the 12-week double blind period
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 Other	1	0	0
Placebo Run-in Period No longer willing to participate	1	0	0
Double Blind Period Adverse Event	0	2	1
Double Blind Period No longer willing to participate	0	2	4
Double Blind Period Death	0	1	0
Double Blind Period Lost to Follow-up	0	2	1
Double Blind Period Other	0	4	1
Double Blind Period Protocol Violation	0	0	1
Double Blind Period No longer met eligibility criteria	0	3	0

Baseline Characteristics

Study Evaluating TheSafety And Efficacy Of PF-05212377 Or Placebo In Subjects With Alzheimer's Disease With Existing Neuropsychiatric Symptoms On Donepezil

Baseline characteristics by cohort

Measure	Not Randomized n=9 Participants Participants who have been discontinued during the Placebo Run-In period	PF-05212377 30 mg: Double Blind Period n=92 Participants All participants entered the double blind period and received PF-05212377 30 mg	Placebo: Double Blind Period n=94 Participants All participants entered the double blind period and received placebo	Total n=195 Participants Total of all reporting groups
Age, Continuous	73.2 years STANDARD_DEVIATION 8.8 • n=5 Participants	76.0 years STANDARD_DEVIATION 8.0 • n=7 Participants	75.9 years STANDARD_DEVIATION 7.5 • n=5 Participants	76 years STANDARD_DEVIATION 7.7 • n=4 Participants
Sex: Female, Male FEMALE	7 Participants n=5 Participants	46 Participants n=7 Participants	55 Participants n=5 Participants	108 Participants n=4 Participants
Sex: Female, Male MALE	2 Participants n=5 Participants	46 Participants n=7 Participants	39 Participants n=5 Participants	87 Participants n=4 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	PF-05212377 30 mg n=78 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=86 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Change From Baseline in ADAS-cog13 Total Score at Week 16	0.111 scores on a scale Standard Error 0.6290	-0.584 scores on a scale Standard Error 0.5995	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	PF-05212377 30 mg n=78 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=87 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
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	-6.184 scores on a scale Standard Error 1.1801	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 4 to Week 18

Population: All participants who received any treatment during double blind period

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

Outcome measures

Measure	PF-05212377 30 mg n=91 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=94 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) Leading to Discontinuation	3.3 Percentage of Participants	0 Percentage of Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 4 to Week 16

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)

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).

Outcome measures

Measure	PF-05212377 30 mg n=91 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=94 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Proportion of Participants With Laboratory Abnormalities of Potential Clinical Concern During Double Blind Period	36.0 Percentage of Participants	52.0 Percentage of Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 6

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (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).

Outcome measures

Measure	PF-05212377 30 mg n=85 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=89 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Selected ECG Change From Baseline - PR Interval at Week 6 (Visit 3)	-2.8 milliseconds (msec) Interval -52.0 to 24.0	-3.6 milliseconds (msec) Interval -82.0 to 35.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 10

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (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).

Outcome measures

Measure	PF-05212377 30 mg n=79 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=87 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Selected ECG Change From Baseline - PR Interval at Week 10 (Visit 4)	-0.1 msec Interval -42.0 to 23.0	-1.3 msec Interval -61.0 to 61.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 16/Early Termination

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (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).

Outcome measures

Measure	PF-05212377 30 mg n=82 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=85 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Selected ECG Change From Baseline - PR Interval at Week 16/Early Termination (Visit 5)	-2.5 msec Interval -69.0 to 24.0	-1.6 msec Interval -49.0 to 33.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 4 to Week 16

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)

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.

Outcome measures

Measure	PF-05212377 30 mg n=86 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=90 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Percentage of Participant With PR Interval Abnormalities of Potential Clinical Concern Post-Baseline Maximum Absolute Value >=300 msec	0 Percentage of Participants	4.4 Percentage of Participants	—
Percentage of Participant With PR Interval Abnormalities of Potential Clinical Concern Post-Baseline Maximum Increase >=25/50%	0 Percentage of Participants	0 Percentage of Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 6

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)

The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization.

Outcome measures

Measure	PF-05212377 30 mg n=88 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=92 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Selected ECG Change From Baseline - QRS Complex at Week 6 (Visit 3)	-0.3 msec Interval -22.0 to 43.0	-0.8 msec Interval -14.0 to 10.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 10

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)

The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization.

Outcome measures

Measure	PF-05212377 30 mg n=81 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=90 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Selected ECG Change From Baseline - QRS Complex at Week 10 (Visit 4)	-0.1 msec Interval -13.0 to 45.0	0.1 msec Interval -15.0 to 22.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 16/Early Termination

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)

The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization.

Outcome measures

Measure	PF-05212377 30 mg n=85 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=89 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Selected ECG Change From Baseline - QRS Complex at Week 16/Early Termination (Visit 5)	0.1 msec Interval -14.0 to 18.0	-0.3 msec Interval -21.0 to 14.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 4 to Week 16

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)

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.

Outcome measures

Measure	PF-05212377 30 mg n=91 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=93 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Proportion of Participants With QRS Complex Abnormalities of Potential Clinical Concern Post-Baseline Maximum Absolute Value >=200 msec	0 Percentage of participants	0 Percentage of participants	—
Proportion of Participants With QRS Complex Abnormalities of Potential Clinical Concern Post-Baseline Maximum Increase >=25/50%	0 Percentage of participants	0 Percentage of participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 6

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (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.

Outcome measures

Measure	PF-05212377 30 mg n=88 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=92 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Selected ECG Change From Baseline - QTcF Interval at Week 6 (Visit 3)	-3.0 msec Interval -31.0 to 37.0	-4.9 msec Interval -35.0 to 35.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 10

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (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.

Outcome measures

Measure	PF-05212377 30 mg n=81 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=90 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Selected ECG Change From Baseline - QTcF Interval at Week 10 (Visit 4)	-0.2 msec Interval -38.0 to 47.0	-5.5 msec Interval -40.0 to 48.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 16/Early Termination

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (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.

Outcome measures

Measure	PF-05212377 30 mg n=85 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=89 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Selected ECG Change From Baseline - QTcF Interval at Week 16/Early Termination (Visit 5)	0.8 msec Interval -31.0 to 34.0	-2.2 msec Interval -62.0 to 30.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 4 to Week 16

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)

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.

Outcome measures

Measure	PF-05212377 30 mg n=91 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=93 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Proportion of Participants With QTcF Interval Abnormalities of Potential Clinical Concern Post-Baseline Absolute Value of 450-<480 msec	15.4 Percentage of Participants	14.0 Percentage of Participants	—
Proportion of Participants With QTcF Interval Abnormalities of Potential Clinical Concern Post-Baseline Absolute Value of 480-<500 msec	4.4 Percentage of Participants	1.1 Percentage of Participants	—
Proportion of Participants With QTcF Interval Abnormalities of Potential Clinical Concern Change from Baseline of 30 -<60 msec	6.6 Percentage of Participants	3.2 Percentage of Participants	—
Proportion of Participants With QTcF Interval Abnormalities of Potential Clinical Concern Change from Baseline >=60 msec	0 Percentage of Participants	0 Percentage of Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 6

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)

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.

Outcome measures

Measure	PF-05212377 30 mg n=89 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=93 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Blood Pressure (BP) Changes From Baseline - Week 6 (Visit 3) Supine Systolic BP	-3.6 millimeters of mercury (mm Hg) Interval -38.0 to 19.0	-3.9 millimeters of mercury (mm Hg) Interval -52.0 to 30.0	—
Blood Pressure (BP) Changes From Baseline - Week 6 (Visit 3) Standing Systolic BP	-4.1 millimeters of mercury (mm Hg) Interval -49.0 to 20.0	-3.0 millimeters of mercury (mm Hg) Interval -38.0 to 22.0	—
Blood Pressure (BP) Changes From Baseline - Week 6 (Visit 3) Supine Diastolic BP	-2.2 millimeters of mercury (mm Hg) Interval -37.0 to 26.0	-1.8 millimeters of mercury (mm Hg) Interval -33.0 to 20.0	—
Blood Pressure (BP) Changes From Baseline - Week 6 (Visit 3) Standing Diastolic BP	-1.1 millimeters of mercury (mm Hg) Interval -23.0 to 17.0	-1.0 millimeters of mercury (mm Hg) Interval -23.0 to 21.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 6

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)

The pulse rate changes from baseline at Week 6 (Visit 3) including supine pulse rate, and standing pulse rate.

Outcome measures

Measure	PF-05212377 30 mg n=89 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=93 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Pulse Rate Changes From Baseline - Week 6 (Visit 3) Supine Pulse Rate	-1.4 beats per minute (bpm) Interval -30.0 to 30.0	1.4 beats per minute (bpm) Interval -21.0 to 20.0	—
Pulse Rate Changes From Baseline - Week 6 (Visit 3) Standing Pulse Rate	-0.3 beats per minute (bpm) Interval -20.0 to 30.0	1.3 beats per minute (bpm) Interval -12.0 to 27.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 10

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)

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.

Outcome measures

Measure	PF-05212377 30 mg n=81 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=91 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
BP Changes From Baseline - Week 10 (Visit 4) Supine Systolic BP	-3.4 mmHg Interval -36.0 to 20.0	-0.3 mmHg Interval -68.0 to 34.0	—
BP Changes From Baseline - Week 10 (Visit 4) Standing Systolic BP	-3.8 mmHg Interval -33.0 to 32.0	0.8 mmHg Interval -49.0 to 49.0	—
BP Changes From Baseline - Week 10 (Visit 4) Supine Diastolic BP	-2.4 mmHg Interval -32.0 to 20.0	-0.7 mmHg Interval -39.0 to 25.0	—
BP Changes From Baseline - Week 10 (Visit 4) Standing Diastolic BP	-1.2 mmHg Interval -20.0 to 20.0	0.3 mmHg Interval -26.0 to 39.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 10

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)

The pulse rate changes from baseline at Week 10 (Visit 4) including supine pulse rate, and standing pulse rate.

Outcome measures

Measure	PF-05212377 30 mg n=81 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=91 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Pulse Rate Changes From Baseline - Week 10 (Visit 4) Supine Pulse Rate	-0.4 bpm Interval -26.0 to 22.0	0.5 bpm Interval -24.0 to 17.0	—
Pulse Rate Changes From Baseline - Week 10 (Visit 4) Standing Pulse Rate	-0.7 bpm Interval -20.0 to 24.0	1.8 bpm Interval -19.0 to 21.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 16/Early Termination

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (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.

Outcome measures

Measure	PF-05212377 30 mg n=85 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=90 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
BP Changes From Baseline - Week 16/Early Termination (Visit 5) Supine Systolic BP	-1.4 mmHg Interval -30.0 to 27.0	-1.1 mmHg Interval -30.0 to 72.0	—
BP Changes From Baseline - Week 16/Early Termination (Visit 5) Standing Systolic BP	-1.0 mmHg Interval -30.0 to 32.0	-1.1 mmHg Interval -26.0 to 66.0	—
BP Changes From Baseline - Week 16/Early Termination (Visit 5) Supine Diastolic BP	-2.1 mmHg Interval -39.0 to 22.0	-0.3 mmHg Interval -18.0 to 35.0	—
BP Changes From Baseline - Week 16/Early Termination (Visit 5) Standing Diastolic BP	-0.8 mmHg Interval -23.0 to 23.0	0.0 mmHg Interval -20.0 to 36.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 16/Early Termination

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)

The pulse rate changes from baseline at Week 16/Early Termination (Visit 5) including supine pulse rate, and standing pulse rate.

Outcome measures

Measure	PF-05212377 30 mg n=85 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=90 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Pulse Rate Changes From Baseline - Week 16/Early Termination (Visit 5) Supine Pulse Rate	-0.8 bpm Interval -29.0 to 31.0	0.6 bpm Interval -22.0 to 20.0	—
Pulse Rate Changes From Baseline - Week 16/Early Termination (Visit 5) Standing Pulse Rate	-1.9 bpm Interval -24.0 to 29.0	0.8 bpm Interval -17.0 to 17.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 4 to Week 16

Population: All participants who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5)

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.

Outcome measures

Measure	PF-05212377 30 mg n=91 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=94 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo All participants received placebo during double blind period
Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern Absolute Standing Pulse Rate <40 bpm	0 Percentage of Participants	0 Percentage of Participants	—
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	5.3 Percentage of Participants	—
Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern Absolute Supine Systolic BP<90 mmHg	0 Percentage of Participants	1.1 Percentage of Participants	—
Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern Absolute Standing Systolic BP<90 mmHg	0 Percentage of Participants	1.1 Percentage of Participants	—
Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern Absolute Supine Diastolic BP<50 mmHg	0 Percentage of Participants	2.1 Percentage of Participants	—
Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern Absolute Standing Diastolic BP <50 mmHg	0 Percentage of Participants	0 Percentage of Participants	—
Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern Absolute Supine Pulse Rate <40 bpm	0 Percentage of Participants	0 Percentage of Participants	—
Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern Absolute Supine Pulse Rate >120 bpm	0 Percentage of Participants	0 Percentage of Participants	—
Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern Absolute Standing Pulse Rate >140 bpm	0 Percentage of Participants	0 Percentage of Participants	—
Proportion of Participants With Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern Increase in Supine Systolic BP>=30 mmHg	0 Percentage of Participants	5.3 Percentage of Participants	—
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	3.2 Percentage of Participants	—
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	4.3 Percentage of Participants	—
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	5.3 Percentage of Participants	—
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	5.3 Percentage of Participants	—
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	5.3 Percentage of Participants	—
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	6.4 Percentage of Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From Screening to Week 18/Early Termination

Population: All participants screened and assigned

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.

Outcome measures

Measure	PF-05212377 30 mg n=195 Participants participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=91 Participants All participants who received placebo contributing to the analysis during the double blind period	Placebo n=94 Participants All participants received placebo during double blind period
Participants in Each Category of C-CASA Mapped From the C-SSRS Responses Week 16/Early Termination (Visit 5): <4>	0 Participants	1 Participants	0 Participants
Participants in Each Category of C-CASA Mapped From the C-SSRS Responses Week 4 (Visit 2): <7>	0 Participants	0 Participants	1 Participants
Participants in Each Category of C-CASA Mapped From the C-SSRS Responses Week 6 (Visit 3): <7>	0 Participants	1 Participants	0 Participants
Participants in Each Category of C-CASA Mapped From the C-SSRS Responses Week 4 (Visit 2): <4>	1 Participants	2 Participants	1 Participants
Participants in Each Category of C-CASA Mapped From the C-SSRS Responses Week 6 (Visit 3): <4>	0 Participants	0 Participants	1 Participants
Participants in Each Category of C-CASA Mapped From the C-SSRS Responses Week 10 (Visit 4): : <4>	0 Participants	2 Participants	0 Participants

Adverse Events

Placebo Run-In

Serious events: 1 serious events

Other events: 13 other events

Deaths: 0 deaths

PF-05212377 30 mg

Serious events: 5 serious events

Other events: 25 other events

Deaths: 0 deaths

Placebo

Serious events: 3 serious events

Other events: 20 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo Run-In n=195 participants at risk Participants received placebo during the single blind placebo run-in period	PF-05212377 30 mg n=91 participants at risk participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=94 participants at risk All participants receiving placebo during double blind period
Cardiac disorders Bradycardia	0.00% 0/195 • Baseline through Week 18 (Visit 16)	2.2% 2/91 • Number of events 2 • Baseline through Week 18 (Visit 16)	0.00% 0/94 • Baseline through Week 18 (Visit 16)
General disorders Accidental death	0.00% 0/195 • Baseline through Week 18 (Visit 16)	1.1% 1/91 • Number of events 1 • Baseline through Week 18 (Visit 16)	0.00% 0/94 • Baseline through Week 18 (Visit 16)
General disorders Asthenia	0.00% 0/195 • Baseline through Week 18 (Visit 16)	1.1% 1/91 • Number of events 1 • Baseline through Week 18 (Visit 16)	0.00% 0/94 • Baseline through Week 18 (Visit 16)
Hepatobiliary disorders Cholecystitis acute	0.00% 0/195 • Baseline through Week 18 (Visit 16)	1.1% 1/91 • Number of events 1 • Baseline through Week 18 (Visit 16)	0.00% 0/94 • Baseline through Week 18 (Visit 16)
Infections and infestations Pneumonia	0.00% 0/195 • Baseline through Week 18 (Visit 16)	0.00% 0/91 • Baseline through Week 18 (Visit 16)	1.1% 1/94 • Number of events 1 • Baseline through Week 18 (Visit 16)
Infections and infestations Urinary tract infection	0.00% 0/195 • Baseline through Week 18 (Visit 16)	1.1% 1/91 • Number of events 1 • Baseline through Week 18 (Visit 16)	0.00% 0/94 • Baseline through Week 18 (Visit 16)
Injury, poisoning and procedural complications Femoral neck fracture	0.51% 1/195 • Number of events 1 • Baseline through Week 18 (Visit 16)	0.00% 0/91 • Baseline through Week 18 (Visit 16)	0.00% 0/94 • Baseline through Week 18 (Visit 16)
Injury, poisoning and procedural complications Foreign body	0.00% 0/195 • Baseline through Week 18 (Visit 16)	0.00% 0/91 • Baseline through Week 18 (Visit 16)	1.1% 1/94 • Number of events 1 • Baseline through Week 18 (Visit 16)
Psychiatric disorders Delirium	0.00% 0/195 • Baseline through Week 18 (Visit 16)	0.00% 0/91 • Baseline through Week 18 (Visit 16)	1.1% 1/94 • Number of events 1 • Baseline through Week 18 (Visit 16)
Vascular disorders Orthostatic hypotension	0.00% 0/195 • Baseline through Week 18 (Visit 16)	1.1% 1/91 • Number of events 1 • Baseline through Week 18 (Visit 16)	0.00% 0/94 • Baseline through Week 18 (Visit 16)

Other adverse events

Measure	Placebo Run-In n=195 participants at risk Participants received placebo during the single blind placebo run-in period	PF-05212377 30 mg n=91 participants at risk participants who received PF-05212377 30 mg contributing to the analysis during double blind period	Placebo n=94 participants at risk All participants receiving placebo during double blind period
Gastrointestinal disorders Diarrhoea	3.1% 6/195 • Number of events 6 • Baseline through Week 18 (Visit 16)	8.8% 8/91 • Number of events 9 • Baseline through Week 18 (Visit 16)	3.2% 3/94 • Number of events 3 • Baseline through Week 18 (Visit 16)
Infections and infestations Urinary tract infection	0.00% 0/195 • Baseline through Week 18 (Visit 16)	5.5% 5/91 • Number of events 5 • Baseline through Week 18 (Visit 16)	4.3% 4/94 • Number of events 4 • Baseline through Week 18 (Visit 16)
General disorders Fatigue	0.00% 0/195 • Baseline through Week 18 (Visit 16)	2.2% 2/91 • Number of events 2 • Baseline through Week 18 (Visit 16)	2.1% 2/94 • Number of events 2 • Baseline through Week 18 (Visit 16)
Infections and infestations Bronchitis	0.00% 0/195 • Baseline through Week 18 (Visit 16)	2.2% 2/91 • Number of events 2 • Baseline through Week 18 (Visit 16)	1.1% 1/94 • Number of events 1 • Baseline through Week 18 (Visit 16)
Infections and infestations Nasopharyngitis	2.1% 4/195 • Number of events 4 • Baseline through Week 18 (Visit 16)	2.2% 2/91 • Number of events 2 • Baseline through Week 18 (Visit 16)	2.1% 2/94 • Number of events 2 • Baseline through Week 18 (Visit 16)
Infections and infestations Pneumonia	0.00% 0/195 • Baseline through Week 18 (Visit 16)	0.00% 0/91 • Baseline through Week 18 (Visit 16)	2.1% 2/94 • Number of events 2 • Baseline through Week 18 (Visit 16)
Infections and infestations Upper respiratory tract infection	0.00% 0/195 • Baseline through Week 18 (Visit 16)	2.2% 2/91 • Number of events 2 • Baseline through Week 18 (Visit 16)	1.1% 1/94 • Number of events 1 • Baseline through Week 18 (Visit 16)
Injury, poisoning and procedural complications Fall	1.0% 2/195 • Number of events 2 • Baseline through Week 18 (Visit 16)	3.3% 3/91 • Number of events 3 • Baseline through Week 18 (Visit 16)	3.2% 3/94 • Number of events 3 • Baseline through Week 18 (Visit 16)
Investigations Weight decreased	0.51% 1/195 • Number of events 1 • Baseline through Week 18 (Visit 16)	0.00% 0/91 • Baseline through Week 18 (Visit 16)	2.1% 2/94 • Number of events 2 • Baseline through Week 18 (Visit 16)
Nervous system disorders Headache	0.00% 0/195 • Baseline through Week 18 (Visit 16)	2.2% 2/91 • Number of events 2 • Baseline through Week 18 (Visit 16)	1.1% 1/94 • Number of events 1 • Baseline through Week 18 (Visit 16)
Psychiatric disorders Hallucination	0.00% 0/195 • Baseline through Week 18 (Visit 16)	0.00% 0/91 • Baseline through Week 18 (Visit 16)	2.1% 2/94 • Number of events 2 • Baseline through Week 18 (Visit 16)
Psychiatric disorders Insomnia	0.00% 0/195 • Baseline through Week 18 (Visit 16)	1.1% 1/91 • Number of events 1 • Baseline through Week 18 (Visit 16)	2.1% 2/94 • Number of events 3 • Baseline through Week 18 (Visit 16)

Additional Information

Pfizer

Pfizer

Phone: 1-8007181021

Email: ClinicalTrials.gov_Inquiries@pfizer.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER