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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 46
- 试验地点
- 1
- 主要终点
- Part B and C: Number of Participants With Positive Response on the Columbia Suicide Severity Rating Scale (C-SSRS) at Day 14
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Single Ascending Dose Crossover
Single Ascending Dose in 4-way cross-over design (PF-06751979/Placebo).
干预措施: PF-06751979 single dose (Drug)
Single Ascending Dose Crossover
Single Ascending Dose in 4-way cross-over design (PF-06751979/Placebo).
干预措施: Placebo single dose (Drug)
Multiple Ascending Dose
Multiple dose administration to Healthy Subjects in parallel cohorts (PF-06751979).
干预措施: PF-06751979 multiple ascending dose (Drug)
Multiple Ascending Dose
Multiple dose administration to Healthy Subjects in parallel cohorts (PF-06751979).
干预措施: Placebo multiple ascending dose (Drug)
Multiple Dose Elderly
Multiple dose administration to Healthy Elderly Subjects (PF-06751979). This cohort is optional.
干预措施: PF-06751979 multiple dose (Drug)
Multiple Dose Elderly
Multiple dose administration to Healthy Elderly Subjects (PF-06751979). This cohort is optional.
干预措施: Placebo multiple elderly dose (Drug)
结局指标
主要结局
Part B and C: Number of Participants With Positive Response on the Columbia Suicide Severity Rating Scale (C-SSRS) at Day 14
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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).
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- Part A: Maximum Observed Plasma Concentration (Cmax) of PF-06751979(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(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 Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06751979(pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1)
- Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) of PF-06751979(pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1)
- Part A: Apparent Volume of Distribution (Vz/F) of PF-06751979(pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1)
- Part B: Maximum Observed Plasma Concentration (Cmax) of PF-06751979(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(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)
- Part A: Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast[dn]) of PF-06751979(pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1)
- Part A: Apparent Clearance (CL/F) of PF-06751979(pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1)
- Part A: Dose Normalized Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time (AUCinf [dn]) of PF-06751979(pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1)
- Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06751979(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(pre-dose, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose on Day 1)
- Part B: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06751979(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 Area Under the Curve From Time Zero to End of Dosing Interval Tau (AUCtau[dn]) of PF-06751979(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)
- Part B: Observed Accumulation Ratio (Rac) for AUCtau of PF-06751979(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)
- Part B: Plasma Decay Half-Life (t1/2) of PF-06751979(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(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 C: Maximum Observed Plasma Concentration (Cmax) of PF-06751979(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 B: Apparent Clearance (CL/F) of PF-06751979(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: Minimum Observed Plasma Concentration (Cmin) of PF-06751979(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(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: Apparent Volume of Distribution (Vz/F) of PF-06751979(pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14)
- Part B: Observed Accumulation Ratio for Maximum Observed Plasma Concentration (Rac Cmax) of PF-06751979(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 C: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06751979(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)
- Part C: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06751979(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(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 Area Under the Curve From Time Zero to End of Dosing Interval Tau (AUCtau[dn]) of PF-06751979(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)
- Part C: Apparent Oral Clearance (CL/F)(pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14)
- Part C: Minimum Observed Plasma Concentration (Cmin) of PF-06751979(pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14)
- Part C: Peak-to-Trough Ratio of PF-06751979(pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14)
- Part C: Observed Accumulation Ratio (Rac) for AUCtau of PF-06751979(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)
- Part C: Observed Accumulation Ratio for Maximum Observed Plasma Concentration (Rac Cmax) of PF-06751979(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: Plasma Decay Half-Life (t1/2) of PF-06751979(pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14)
- Part C: Apparent Volume of Distribution (Vz/F) of PF-06751979(pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post dose on Day 14)
- Part B: Amount of PF-06751979 Excreted Unchanged in Urine Over the Dosing Interval Tau (Aetau)(0-24 hours on Day 14)
- Part B: Percentage of Dose of PF-06751979 Excreted Unchanged in the Urine Over the Dosing Interval Tau (Aetau%)(0-24 hours on Day 14)
- Part B: Renal Clearance of PF-06751979(0-24 hours on Day 14)
- Part B: Percent Change From Baseline in Cerebrospinal Spinal Fluid (CSF) Amyloid Beta (ABeta) Fragments(Baseline, Day 14)