Clinical trial NCT02793232: 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: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects
Keywords: Safety
Tolerability
Pharmacokinetics
Alzheimer's disease
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2016-06-08
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Part A: Baseline up to 36 days; Part B and C: Baseline up to 49 days
measure: Number of Participants With Abnormal Physical Examinations Findings
timeFrame: Part A: Baseline up to 36 days; Part B and C: Baseline up to 49 days
measure: Number of Participants With Abnormal Neurological Examinations Findings
timeFrame: Part A: Baseline up to 36 days; Part B and C: Baseline up to 49 days
measure: Part B and C: Number of Participants With Positive Response on the Columbia Suicide Severity Rating Scale (C-SSRS) at Baseline
timeFrame: Baseline
measure: Part B and C: Number of Participants With Positive Response on the Columbia Suicide Severity Rating Scale (C-SSRS) at Day 7
timeFrame: Day 7
measure: Part B and C: Number of Participants With Positive Response on the Columbia Suicide Severity Rating Scale (C-SSRS) at Day 14
timeFrame: Day 14
measure: Part B and C: Number of Participants With Positive Response on the Columbia Suicide Severity Rating Scale (C-SSRS) at Day 19
timeFrame: Day 19
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
timeFrame: Part A: Baseline up to 36 days; Part B and C: Baseline up to 49 days
measure: Part A: Number of Participants With Cardiac Rhythms of Potential Clinical Concern Assessed By Telemetry
timeFrame: Day 1
measure: Number of Participants With Vital Sign Abnormalities
timeFrame: Part A: Baseline up to 36 days; Part B and C: Baseline up to 49 days
measure: Number of Participants With Laboratory Abnormalities
timeFrame: Part A: Baseline up to 36 days; Part B and C: Baseline up to 49 days
Secondary outcomes:
measure: Part A: Maximum Observed Plasma Concentration (Cmax) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1
measure: Part A: Area Under the Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1
measure: Part A: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1
measure: Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1
measure: Part A: Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast[dn]) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1
measure: Part A: Dose Normalized Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time (AUCinf [dn]) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1
measure: Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1
measure: Part A: Plasma Decay Half-Life (t1/2) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1
measure: Part A: Apparent Clearance (CL/F) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1
measure: Part A: Apparent Volume of Distribution (Vz/F) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1
measure: Part B: Maximum Observed Plasma Concentration (Cmax) of PF-06751979
timeFrame: 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
measure: Part B: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06751979
timeFrame: 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
measure: Part B: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06751979
timeFrame: 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
measure: Part B: Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) of PF-06751979
timeFrame: 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
measure: Part B: Dose Normalized Area Under the Curve From Time Zero to End of Dosing Interval Tau (AUCtau[dn]) of PF-06751979
timeFrame: 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
measure: Part B: Apparent Clearance (CL/F) of PF-06751979
timeFrame: 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
measure: Part B: Minimum Observed Plasma Concentration (Cmin) of PF-06751979
timeFrame: 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
measure: Part B: Peak-to-Trough Ratio of PF-06751979
timeFrame: 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
measure: Part B: Observed Accumulation Ratio (Rac) for AUCtau of PF-06751979
timeFrame: 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
measure: Part B: Observed Accumulation Ratio for Maximum Observed Plasma Concentration (Rac Cmax) of PF-06751979
timeFrame: 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
measure: Part B: Plasma Decay Half-Life (t1/2) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14
measure: Part B: Apparent Volume of Distribution (Vz/F) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14
measure: Part C: Maximum Observed Plasma Concentration (Cmax) of PF-06751979
timeFrame: 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
measure: Part C: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06751979
timeFrame: 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
measure: Part C: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06751979
timeFrame: 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
measure: Part C: Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) of PF-06751979
timeFrame: 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
measure: Part C: Dose Normalized Area Under the Curve From Time Zero to End of Dosing Interval Tau (AUCtau[dn]) of PF-06751979
timeFrame: 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
measure: Part C: Apparent Oral Clearance (CL/F)
timeFrame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14
measure: Part C: Minimum Observed Plasma Concentration (Cmin) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14
measure: Part C: Peak-to-Trough Ratio of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14
measure: Part C: Observed Accumulation Ratio (Rac) for AUCtau of PF-06751979
timeFrame: 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
measure: Part C: Observed Accumulation Ratio for Maximum Observed Plasma Concentration (Rac Cmax) of PF-06751979
timeFrame: 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
measure: Part C: Plasma Decay Half-Life (t1/2) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14
measure: Part C: Apparent Volume of Distribution (Vz/F) of PF-06751979
timeFrame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14
measure: Part B: Amount of PF-06751979 Excreted Unchanged in Urine Over the Dosing Interval Tau (Aetau)
timeFrame: 0-24 hours on Day 14
measure: Part B: Percentage of Dose of PF-06751979 Excreted Unchanged in the Urine Over the Dosing Interval Tau (Aetau%)
timeFrame: 0-24 hours on Day 14
measure: Part B: Renal Clearance of PF-06751979
timeFrame: 0-24 hours on Day 14
measure: Part B: Percent Change From Baseline in Cerebrospinal Spinal Fluid (CSF) Amyloid Beta (ABeta) Fragments
timeFrame: Baseline, Day 14
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Pfizer Clinical Research Unit
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: