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

• ClinicalTrials.gov Identifier: NCT01712074
• Recruitment Status: Terminated
• First Posted: October 23, 2012
• Results First Posted: March 20, 2017
• Last Update Posted: March 20, 2017
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: October 19, 2012
• First Posted Date: October 23, 2012
• Results First Submitted Date: August 26, 2016
• Results First Posted Date: March 20, 2017
• Last Update Posted Date: March 20, 2017
• Study Start Date: November 2012
• Actual Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 30, 2017)

Change From Baseline in ADAS-cog13 Total Score at Week 16 [ Time Frame: 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.

• Original Primary Outcome Measures (submitted: October 19, 2012): Change from Baseline (Week 4) to 12 weeks after the start of double-blind study medication on the ADAS-cog13 total score (Week 16) [ Time Frame: Week 16 ]
• Change History: Complete list of historical versions of study NCT01712074 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: January 30, 2017)

Change From Baseline in the Neuropsychiatric Inventory (NPI) Total Score at Week 16 (Visit 5) [ Time Frame: 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.

• Original Secondary Outcome Measures (submitted: October 19, 2012): Change from baseline (Week 4) to 12 weeks after the start of double-blind study medication on the NPI total score (Week 16). [ Time Frame: Week 16 ]

Current Other Pre-specified Outcome Measures (submitted: January 30, 2017)

• Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) Leading to Discontinuation [ Time Frame: 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 Laboratory Abnormalities of Potential Clinical Concern During Double Blind Period [ Time Frame: 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).
• Selected ECG Change From Baseline - PR Interval at Week 6 (Visit 3) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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.
• Selected ECG Change From Baseline - QTcF Interval at Week 16/Early Termination (Visit 5) [ Time Frame: 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 QTcF Interval Abnormalities of Potential Clinical Concern [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study Evaluating TheSafety And Efficacy Of PF-05212377 Or Placebo In Subjects With Alzheimer's Disease With Existing Neuropsychiatric Symptoms On Donepezil
• Official Title: A Randomized, 18-week, Placebo-controlled, Double-blind, Parallel Group Study Of The Safety And Efficacy Of Pf-05212377 (Sam-760) In Subjects With Mild-to-moderate Alzheimer's Disease With Existing Neuropsychiatric Symptoms On A Stable Daily Dose Of Donepezil
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Alzheimer's Disease

Intervention

• Drug: PF-05212377 (SAM-760)
  30 mg QD of PF-05212377 (SAM-760)
• Other: Placebo
  Placebo QD

Study Arms

• Experimental: 30 mg QD of PF-05212377
  Intervention: Drug: PF-05212377 (SAM-760)
• Placebo Comparator: Placebo
  Intervention: Other: Placebo

• Publications *: Fullerton T, Binneman B, David W, Delnomdedieu M, Kupiec J, Lockwood P, Mancuso J, Miceli J, Bell J. A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer's disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil. Alzheimers Res Ther. 2018 Apr 5;10(1):38. doi: 10.1186/s13195-018-0368-9.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 29, 2016): 186
• Original Estimated Enrollment (submitted: October 19, 2012): 342
• Actual Study Completion Date: September 2015
• Actual Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 60 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Chile, France, Germany, Spain, United Kingdom, United States
• Removed Location Countries: Australia

Administrative Information

• NCT Number: NCT01712074
• Other Study ID Numbers: B2081011; 2014-000830-42 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Pfizer
• Study Sponsor: Pfizer
• Collaborators: Not Provided

Investigators

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

• PRS Account: Pfizer
• Verification Date: January 2017