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Trial record 1 of 1 for:    NCT02793232
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Clinical Trial In Healthy Volunteers And Health Elderly Volunteers To Evaluate The Safety, Tolerability And Blood Concentration After Single And Multiple Escalating Oral Doses Of PF-06751979.

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ClinicalTrials.gov Identifier: NCT02793232
Recruitment Status : Completed
First Posted : June 8, 2016
Results First Posted : September 17, 2018
Last Update Posted : September 17, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE June 3, 2016
First Posted Date  ICMJE June 8, 2016
Results First Submitted Date  ICMJE December 22, 2017
Results First Posted Date  ICMJE September 17, 2018
Last Update Posted Date September 17, 2018
Actual Study Start Date  ICMJE June 13, 2016
Actual Primary Completion Date January 5, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 22, 2017)
  • Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Part A: Baseline up to 36 days; Part B and C: Baseline up to 49 days ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment emergent were events between first dose of study drug and up to the follow up visit (up to 36 days in Part A, 49 days in Part B and C), that were absent before treatment or that worsened relative to pretreatment state.
  • Number of Participants With Abnormal Physical Examinations Findings [ Time Frame: Part A: Baseline up to 36 days; Part B and C: Baseline up to 49 days ]
    Full physical examination included head, ears, eyes, nose, mouth, skin, heart, lung, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. Abnormality in physical examinations was based on investigator's discretion.
  • Number of Participants With Abnormal Neurological Examinations Findings [ Time Frame: Part A: Baseline up to 36 days; Part B and C: Baseline up to 49 days ]
    The neurological examination included the assessment of higher cortical function, the cranial nerves, motor function, deep tendon reflexes, sensory exam, and coordination and gait. Abnormality in neurological examinations was based on investigator's discretion.
  • Part B and C: Number of Participants With Positive Response on the Columbia Suicide Severity Rating Scale (C-SSRS) at Baseline [ Time Frame: Baseline ]
    C-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced following: completed suicide; suicide attempt (response of "Yes" on "actual attempt"); preparatory acts toward imminent suicidal behavior ("Yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent). In this outcome measure, number of participants with positive response (response of "yes") to suicidal behavior, ideation or any non-suicidal self-injurious behavior, at baseline were reported.
  • Part B and C: Number of Participants With Positive Response on the Columbia Suicide Severity Rating Scale (C-SSRS) at Day 7 [ Time Frame: Day 7 ]
    C-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced following: completed suicide; suicide attempt (response of "Yes" on "actual attempt"); preparatory acts toward imminent suicidal behavior ("Yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent). In this outcome measure, number of participants with positive response (response of "yes") to suicidal behavior, ideation or any non-suicidal self-injurious behavior, at Day 7 were reported.
  • Part B and C: Number of Participants With Positive Response on the Columbia Suicide Severity Rating Scale (C-SSRS) at Day 14 [ Time Frame: Day 14 ]
    C-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced following: completed suicide; suicide attempt (response of "Yes" on "actual attempt"); preparatory acts toward imminent suicidal behavior ("Yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent). In this outcome measure, number of participants with positive response (response of "yes") to suicidal behavior, ideation or any non-suicidal self-injurious behavior, at Day 14 were reported.
  • Part B and C: Number of Participants With Positive Response on the Columbia Suicide Severity Rating Scale (C-SSRS) at Day 19 [ Time Frame: Day 19 ]
    C-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced following: completed suicide; suicide attempt (response of "Yes" on "actual attempt"); preparatory acts toward imminent suicidal behavior ("Yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent). In this outcome measure, number of participants with positive response (response of "yes") to suicidal behavior, ideation or any non-suicidal self-injurious behavior, at Day 19 were reported.
  • Number of Participants With Abnormal Electrocardiogram (ECG) Findings [ Time Frame: Part A: Baseline up to 36 days; Part B and C: Baseline up to 49 days ]
    Criteria for abnormal values of ECG parameters: maximum pulse rate (PR) interval greater than or equal to (>=)300 milliseconds (msec); maximum PR interval increase from baseline (IFB): >=25 percent (%) when baseline was greater than (>)200 msec; or >=50 % when baseline was greater than (>)200 msec, maximum QRS interval >=140 msec and QRS interval IFB: >=50%. QT interval using Fridericia's correction (QTcF) ranges from 450 msec to maximum less than (<)480 msec, less than or equal to (<=) 480 msec to maximum <500 msec and maximum >=500 msec, maximum QTcF interval IFB range from <=30 to <60 msec and maximum >=60 msec. Only categories which included at least 1 participant with abnormality are reported in this outcome measure.
  • Part A: Number of Participants With Cardiac Rhythms of Potential Clinical Concern Assessed By Telemetry [ Time Frame: Day 1 ]
    In all Periods of Part A, continuous cardiac monitoring was maintained for 8 hours (or longer if considered clinically necessary by the investigator) following dose administration on Day 1. All abnormal cardiac rhythms were recorded and reviewed by the study physician for the presence of rhythms of potential clinical concern.
  • Number of Participants With Vital Sign Abnormalities [ Time Frame: Part A: Baseline up to 36 days; Part B and C: Baseline up to 49 days ]
    Criteria for vital signs abnormalities: systolic blood pressure (SBP) <90 millimeter of mercury (mmHg), diastolic blood pressure (DBP) <50 mmHg, supine pulse rate <40 beats per minute (bpm). Maximum IFB in Supine SBP >=30 mmHg, Maximum decrease from baseline (DFB) in Supine SBP >=30 mmHg, maximum DFB in Supine DBP >=20 mmHg.
  • Number of Participants With Laboratory Abnormalities [ Time Frame: Part A: Baseline up to 36 days; Part B and C: Baseline up to 49 days ]
    Abnormalities criteria:hematology(hemoglobin; hematocrit; RBC<0.8*lower limit of normal [LLN]; platelets<0.5*LLN,>1.75*upper limit of normal [ULN]; WBC<0.6*LLN,>1.5*ULN; lymphocytes; neutrophils; basophils; eosinophils; monocytes<0.8*LLN,>1.2*ULN; coagulation(prothrombin ratio>1.1*ULN), liver(bilirubin>1.5*ULN; aspartate aminotransferase; alanine aminotransferase; alkaline phosphatase; gamma GT>0.3*ULN; protein; albumin<0.8*LLN,>1.2*ULN); renal(blood urea nitrogen, creatinine>1.3*ULN; uric acid>1.2*ULN); electrolytes(sodium<0.95*LLN,>1.05*ULN; potassium; chloride; calcium; bicarbonate<0.9*LLN,>1.1*ULN), chemistry(glucose<0.6*LLN,>1.5* ULN); urinalysis(pH <4.5,>8; glucose, ketones, protein, blood, urobilinogen, nitrite, bilirubin, leukocyte, esterase>1; WBC; bacteria>=20, epithelial cells>=6; granular casts, hyaline casts, red cell casts, white cell casts>1; lipids(cholesterol[C], LDL-C>1.3*ULN; HDL-C<0.8*LLN, triglycerides>1.3*ULN); hormones(T4, T3, T4, TSH<0.8*LLN,>1.2*ULN).
Original Primary Outcome Measures  ICMJE
 (submitted: June 3, 2016)
  • Number of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs) [ Time Frame: Baseline (Day 1) up to 28 days after last dose of study medication ]
    Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to Y days after last dose that were absent before treatment or that worsened relative to pretreatment state. Relatedness to Drug X was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category.
  • Number of Participants with categorical scores on the Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Day -4 (Part B) ]
    C-SSRS assessed whether participant experienced following: completed suicide (1), suicide attempt (2) (response of "Yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior (3)("Yes" on "preparatory acts or behavior"), suicidal ideation (4) ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent), any suicidal behavior or ideation, self-injurious behavior (7)("Yes" on "Has subject engaged in non-suicidal self-injurious behavior"). Since last visit.
  • Number of Participants with categorical scores on the Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Day 7 (Part B) ]
    C-SSRS assessed whether participant experienced following: completed suicide (1), suicide attempt (2) (response of "Yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior (3)("Yes" on "preparatory acts or behavior"), suicidal ideation (4) ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent), any suicidal behavior or ideation, self-injurious behavior (7)("Yes" on "Has subject engaged in non-suicidal self-injurious behavior"). Since last visit.
  • Number of Participants with categorical scores on the Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Day 14 (Part B) ]
    C-SSRS assessed whether participant experienced following: completed suicide (1), suicide attempt (2) (response of "Yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior (3)("Yes" on "preparatory acts or behavior"), suicidal ideation (4) ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent), any suicidal behavior or ideation, self-injurious behavior (7)("Yes" on "Has subject engaged in non-suicidal self-injurious behavior"). Since last visit.
  • Number of Participants with categorical scores on the Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Day 19 (Part B) ]
    C-SSRS assessed whether participant experienced following: completed suicide (1), suicide attempt (2) (response of "Yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior (3)("Yes" on "preparatory acts or behavior"), suicidal ideation (4) ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent), any suicidal behavior or ideation, self-injurious behavior (7)("Yes" on "Has subject engaged in non-suicidal self-injurious behavior").
Change History Complete list of historical versions of study NCT02793232 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 22, 2017)
  • Part A: Maximum Observed Plasma Concentration (Cmax) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1 ]
  • Part A: Area Under the Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1 ]
    Area under the plasma concentration-time profile from time zero to the time of last measured concentration (AUClast).
  • Part A: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1 ]
    AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).
  • Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1 ]
    Cmax(dn) was obtained calculated by dividing Cmax by the exact dose of PF-06751979 (in milligram) administered to a participant.
  • Part A: Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast[dn]) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1 ]
    AUClast(dn) was calculated by dividing AUClast by the exact dose of PF-06751979 (in mg) administered to a participant. AUClast was area under the plasma concentration-time profile from time zero to the time of last measured concentration.
  • Part A: Dose Normalized Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time (AUCinf [dn]) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1 ]
    AUCinf (dn) was calculated by dividing AUCinf by the exact dose of PF-06751979 (in mg) administered to a participant. AUCinf was area under the plasma concentration-time profile from time zero extrapolated to infinite time (0-inf).
  • Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1 ]
  • Part A: Plasma Decay Half-Life (t1/2) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1 ]
    Plasma decay half-life is the time duration for the plasma concentration of PF-06751979 to decrease by one-half of its original concentration.
  • Part A: Apparent Clearance (CL/F) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1 ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
  • Part A: Apparent Volume of Distribution (Vz/F) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1 ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
  • Part B: Maximum Observed Plasma Concentration (Cmax) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 1; pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 7; pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
  • Part B: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 1; pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 7; pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 14 ]
    Area under the plasma concentration versus time-curve from time zero to end of dosing interval (AUCtau), where dosing interval was 24 hours.
  • Part B: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 1; pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 7; pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
  • Part B: Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 1; pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 7; pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
    Cmax(dn) was obtained calculated by dividing Cmax by the exact dose of PF-06751979 (in mg) administered to a participant.
  • Part B: Dose Normalized Area Under the Curve From Time Zero to End of Dosing Interval Tau (AUCtau[dn]) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 1; pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 7; pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 14 ]
    Area under the concentration curve from time zero to end of dosing interval (AUCtau), where dosing interval was 24 hours. AUCtau (dn) was calculated by dividing AUCtau by the exact dose of PF-06751979 (in mg) administered to a participant.
  • Part B: Apparent Clearance (CL/F) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 7; pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
  • Part B: Minimum Observed Plasma Concentration (Cmin) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 7; pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
  • Part B: Peak-to-Trough Ratio of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 7; pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
    Peak-to-trough ratio was calculated by dividing Cmax with Cmin of PF-06751979. Cmax was maximum plasma concentration during the dosing interval and Cmin was minimum observed plasma concentration during the dosing interval.
  • Part B: Observed Accumulation Ratio (Rac) for AUCtau of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 1; pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 7; pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 14 ]
    Rac for AUCtau for Day 7 was calculated as: AUCtau on Day 7 divided by AUCtau on Day 1. Rac for AUCtau for Day 14 was calculated as: AUCtau on Day 14 divided by AUCtau on Day 1.
  • Part B: Observed Accumulation Ratio for Maximum Observed Plasma Concentration (Rac Cmax) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 1; pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 7; pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
    Rac for Cmax on Day 7 was calculated as: Cmax on Day 7 divided by Cmax on Day 1 and Rac for Cmax on Day 14 was calculated as: Cmax on Day 14 divided by Cmax on Day 1, where Cmax was the maximum observed plasma concentration.
  • Part B: Plasma Decay Half-Life (t1/2) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
    Plasma decay half-life is the time duration for the plasma concentration of PF-06751979 to decrease by one-half of its original concentration.
  • Part B: Apparent Volume of Distribution (Vz/F) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
  • Part C: Maximum Observed Plasma Concentration (Cmax) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 1; pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
  • Part C: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 1; pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 14 ]
    Area under the plasma concentration versus time-curve from time zero to end of dosing interval (AUCtau), where dosing interval was 24 hours.
  • Part C: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 1; pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
  • Part C: Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 1; pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
    Cmax(dn) was obtained calculated by dividing Cmax by the exact dose of PF-06751979 (in mg) administered to a participant.
  • Part C: Dose Normalized Area Under the Curve From Time Zero to End of Dosing Interval Tau (AUCtau[dn]) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 1; pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 14 ]
    Area under the concentration curve from time zero to end of dosing interval (AUCtau), where dosing interval was 24 hours. AUCtau (dn) was calculated by dividing AUCtau by the exact dose of PF-06751979 (in mg) administered to a participant.
  • Part C: Apparent Oral Clearance (CL/F) [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
  • Part C: Minimum Observed Plasma Concentration (Cmin) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
    Minimum observed concentration during the dosing interval.
  • Part C: Peak-to-Trough Ratio of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
    Peak-to-trough ratio was calculated by dividing Cmax with Cmin of PF-06751979. Cmax was maximum plasma concentration during the dosing interval and Cmin was minimum observed plasma concentration during the dosing interval.
  • Part C: Observed Accumulation Ratio (Rac) for AUCtau of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 1; pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 14 ]
    Rac for AUCtau at Day 14 was calculated as: AUCtau on Day 14 divided by AUCtau on Day 1.
  • Part C: Observed Accumulation Ratio for Maximum Observed Plasma Concentration (Rac Cmax) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 1; pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
    Rac for Cmax on Day 14 was calculated as: Cmax on Day 14 divided by Cmax on Day 1, where Cmax was the maximum observed plasma concentration.
  • Part C: Plasma Decay Half-Life (t1/2) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
    Plasma decay half-life was the time duration for the plasma concentration to decrease by one-half of its original concentration.
  • Part C: Apparent Volume of Distribution (Vz/F) of PF-06751979 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14 ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
  • Part B: Amount of PF-06751979 Excreted Unchanged in Urine Over the Dosing Interval Tau (Aetau) [ Time Frame: 0-24 hours on Day 14 ]
    Aetau was the amount of drug excreted unchanged in urine during the dosing interval tau, where tau was 24 hours.
  • Part B: Percentage of Dose of PF-06751979 Excreted Unchanged in the Urine Over the Dosing Interval Tau (Aetau%) [ Time Frame: 0-24 hours on Day 14 ]
    Aetau% was calculated as: 100*Aetau/dose. Aetau was the amount of drug excreted unchanged in urine during the dosing interval tau, where tau was 24 hours.
  • Part B: Renal Clearance of PF-06751979 [ Time Frame: 0-24 hours on Day 14 ]
    Renal clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated in urine. It was calculated as amount of drug excreted unchanged in urine during the dosing interval tau (Aetau) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau), where dosing interval was 24 hours.
  • Part B: Percent Change From Baseline in Cerebrospinal Spinal Fluid (CSF) Amyloid Beta (ABeta) Fragments [ Time Frame: Baseline, Day 14 ]
    ABeta is the peptide fragment of the amyloid precursor protein. Percent change from baseline in CSF concentration of ABeta fragments (ABeta 1-38, ABeta 1-40, ABeta 1-42, ABeta total, ABeta x-38, ABeta x-40, ABeta x-42, soluble amyloid precursor protein alpha (sAPP-alpha), soluble amyloid precursor protein beta (sAPP-beta) at Day 14 was reported in this outcome measure.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 3, 2016)
  • Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hours following single dose administration ]
    Maximum observed plasma concentration (Cmax) following single dose administration.
  • Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hours following single dose administration ]
    Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)
  • Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hours following single dose administration ]
    AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).
  • Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hours following single dose administration ]
  • Plasma Decay Half-Life (t1/2) [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hours following single dose administration ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
  • Apparent Oral Clearance (CL/F) [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hours following multiple dose administration ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Calculated on Day 7 and 14.
  • Apparent Volume of Distribution (Vz/F) [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hours following single dose administration ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
  • Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours following multiple dose administration on Day 1, Day 7 and Day 14 ]
    Maximum observed plasma concentration (Cmax) following multiple dose administration. Day 1 and Day 7 timepoints up to 24 hours (pre-dose) only.
  • Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours following multiple dose administration on Day 1, Day 7 and Day 14 ]
    Area under the concentration curve from time 0 to end of dosing interval (AUCtau), where dosing interval was 24 hours. Day 1 and Day 7 timepoints up to 24 hours (pre-dose) only.
  • Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours following multiple dose administration, Days 1, 7 and 14 ]
    Day 1 and Day 7 timepoints up to 24 hours (pre-dose) only.
  • Apparent Oral Clearance (CL/F) [ Time Frame: Hour 0, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose on Day 7 and 14. ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Day 7 and 14 only.
  • Minimum Observed Plasma Trough Concentration (Cmin) [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12 and 24 hours following multiple dose administration. Days 7 and 14. ]
    Calculated on Day 7 and Day 14.
  • Accumulation Ratio (Rac) [ Time Frame: Hour 0 - 24, Day 7 and Day 14 ]
    Accumulation ratio is calculated as Rac obtained from Area Under the Concentration Time Curve (AUC) from time 0-24 (Day 7 or 14) divided by AUC from time 0-24 (Day 1).
  • Observed Accumulation Ratio for Cmax (Rac,Cmax) [ Time Frame: Hour 0 - 24, Day 7 and Day 14 ]
    Accumulation ratio based on maximum plasma concentration (Cmax) is calculated as: Rac,Cmax = Cmax at steady state (ss) divided by Cmax at first dose.
  • Plasma Decay Half-Life (t1/2) [ Time Frame: Day 14 - 19 ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
  • Apparent Volume of Distribution (Vz/F) [ Time Frame: Day 14 - 19 ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
  • Cumulative Amount of Drug Recovered Unchanged in Urine (Ae) [ Time Frame: Day 14 ]
    Ae is the cumulative amount of drug recovered unchanged in urine during the dosing interval, where the dosing interval is 24 hours. Cumulative amount is calculated as sum of urine drug concentration in sample volume for each collection interval. Sample volume = (urine weight in gram [g]/1.020), where 1.020 g/mL is the approximate specific gravity of urine.
  • Renal Clearance (CLr) [ Time Frame: Day 14 ]
    Renal clearance is calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau), where dosing interval is 24 hours.
  • Dose Normalized Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hours following single dose administration ]
    Dose normalized maximum observed plasma concentration (Cmax) following single dose administration.
  • Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hours following single dose administration ]
    Dose normalized area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)
  • Dose Normalized Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hours following single dose administration ]
    Dose normalized AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).
  • Dose Normalized Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours following multiple dose administration on Day 1, Day 7 and Day 14 ]
    Dose normalized maximum observed plasma concentration (Cmax) following multiple dose administration. Day 1 and Day 7 timepoints up to 24 hours (pre-dose) only.
  • Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) [ Time Frame: Samples are collected pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours following multiple dose administration on Day 1, Day 7 and Day 14 ]
    Dose normalized area under the concentration curve from time 0 to end of dosing interval (AUCtau), where dosing interval was 24 hours. Day 1 and Day 7 timepoints up to 24 hours (pre-dose) only.
  • Cerebrospinal fluid (CSF) A-beta fragments [ Time Frame: Baseline and change from baseline after 14 days of dosing ]
    CSF Abeta fragments including (but not limited to) the following, as possible: Abeta1-40, Abeta1-42, Abeta total, Abetax-40, Abetax 42, sAPPalpha, sAPPbeta
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Clinical Trial In Healthy Volunteers And Health Elderly Volunteers To Evaluate The Safety, Tolerability And Blood Concentration After Single And Multiple Escalating Oral Doses Of PF-06751979.
Official Title  ICMJE A 3-part Phase 1, Randomized, Double-blind, Sponsor-open, Placebo Controlled Trial To Evaluate The Safety, Tolerability, Food Effect, Pharmacokinetics And Pharmacodynamics Of Pf-06751979 After Oral Administration: Part A - Single Ascending Doses In Healthy Adults; Part B - Multiple Ascending Doses In Healthy Adults; And Part C - Multiple Doses To Older Subjects
Brief Summary This study will test the safety, tolerability and blood concentrations of single and multiple oral doses of PF-06751979 in health subjects and healthy elderly subjects. PF-06751979 is being developed for the treatment of Alzheimer's disease.
Detailed Description

The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics (PK) of PF-06751979 following oral doses in healthy adult and healthy elderly subjects at higher doses than previously administered. Such characteristics will enable the design of future clinical trials in patient population, in the effort to optimize the efficacy of PF-06751979, as well as to establish safety margins in humans. Inclusion of healthy elderly subjects will be optional, but can provide additional safety and tolerability information in the age range of the target population while confirming the PK of PF-06751979 in these subjects for future clinical trials in the Alzheimer's disease patient population.

The Primary Objective is to evaluate the safety and tolerability of single and multiple ascending oral doses of PF-06751979 in healthy adult subjects. Secondary Objectives are to characterize the pharmacokinetics of PF-06751979 in: plasma following single and multiple ascending oral dose administration in healthy adult subjects and urine following multiple ascending oral dose administration in healthy adult subjects. An additional secondary objective is to evaluate the effect of multiple oral doses of PF 06751979 on CSF A-beta fragments in healthy adult subjects.

This study is divided into three parts: Part A - Single ascending doses (SAD) healthy adult subjects (18-55 years); Part B - Multiple ascending doses (MAD) in healthy adult subjects (18-55 years); Part C - Multiple doses (MD) in healthy elderly subjects (60-85 years). Study Parts may be run in a staggered fashion; Part C of the study may commence after satisfactory review of relevant data from Parts A and B.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Condition  ICMJE Healthy Subjects
Intervention  ICMJE
  • Drug: PF-06751979 single dose
    PF-06751979 administered as a single dose suspension in cross-over fashion. Each subject may receive up to 4 study treatments (placebo and up to 3 doses of PF 06751979). The planned dose levels are 200 mg, 400 mg, 700 mg, 200 mg fed (these doses are subject to change based on emerging data).
  • Drug: Placebo single dose
    Matched Placebo suspension administered as single dose
  • Drug: PF-06751979 multiple ascending dose
    PF-06751979 suspension administered daily for 14 consecutive days to parallel cohorts. The planned dose levels are mg, 100 mg, 200 mg, 340 mg (these are subject to change based on emerging data).
  • Drug: Placebo multiple ascending dose
    Matched placebo suspension administered daily for 14 consecutive days.
  • Drug: PF-06751979 multiple dose
    PF-06751979 suspension administered daily for 14 consecutive days. The planned dose level is 340 mg (this is subject to change based on emerging data).
  • Drug: Placebo multiple elderly dose
    Multiple dose administration to Healthy Elderly Subjects (Placebo)
Study Arms  ICMJE
  • Experimental: Single Ascending Dose Crossover
    Single Ascending Dose in 4-way cross-over design (PF-06751979/Placebo).
    Interventions:
    • Drug: PF-06751979 single dose
    • Drug: Placebo single dose
  • Experimental: Multiple Ascending Dose
    Multiple dose administration to Healthy Subjects in parallel cohorts (PF-06751979).
    Interventions:
    • Drug: PF-06751979 multiple ascending dose
    • Drug: Placebo multiple ascending dose
  • Experimental: Multiple Dose Elderly
    Multiple dose administration to Healthy Elderly Subjects (PF-06751979). This cohort is optional.
    Interventions:
    • Drug: PF-06751979 multiple dose
    • Drug: Placebo multiple elderly dose
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 14, 2017)
46
Original Estimated Enrollment  ICMJE
 (submitted: June 3, 2016)
54
Actual Study Completion Date  ICMJE January 5, 2017
Actual Primary Completion Date January 5, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Healthy female subjects of non childbearing potential and male subjects.
  • Body Mass Index (BMI) of 17.5 to 30.5 kg/m2 (32 kg/m2 for healthy elderly); and a total body weight >50 kg (110 lbs) at Screening.
  • Evidence of a personally signed and dated informed consent document indicating that the subject or a legally acceptable representative has been informed of all pertinent aspects of the study.
  • Additional criterion for subjects of Japanese descent who may be enrolled in Part B (multiple ascending dose cohorts in healthy subjects): Japanese subjects who have four Japanese grandparents born in Japan.

Exclusion Criteria:

  • Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
  • Male subjects with partners currently pregnant; male subjects able to father children who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of investigational product.
  • Unwilling or unable to comply with the Lifestyle Guidelines described in the protocol.
  • Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the study.
  • Any severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02793232
Other Study ID Numbers  ICMJE B8271004
2016-000325-39 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date December 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP