A Phase 1, Double Blind, Sponsor Open, Randomized, Placebo And Active Comparator Controlled, Dose Escalation Study To Investigate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Multiple Escalating Doses Of Pf-05251749 In Healthy Adult And Elderly Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Biogen
- 入组人数
- 97
- 试验地点
- 2
- 主要终点
- Change From Baseline for Bond and Lader Visual Analogue Scale (BL-VAS) on Days 1, 4, 7, 10, 14, 15 and 16 - Alertness
研究概览
简要总结
This is the first clinical trial to evaluate ascending multiple oral doses in healthy adult and healthy elderly subjects to characterize the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of BIIB118
详细描述
This study was previously posted by Pfizer. In March, 2020, sponsorship of the trial was transferred to Biogen.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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 male and/or female subjects of non-childbearing potential between the ages of 18 and 55 years (Parts A and B) or 65 and 85 years (Part C), inclusive (Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG and clinical laboratory tests).
- •Female subjects of non-childbearing potential must meet at least one of the following criteria:
- •Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle-stimulating hormone (FSH) level confirming the post-menopausal state;
- •Have undergone a documented hysterectomy and/or bilateral oophorectomy;
- •Have medically confirmed ovarian failure. All other female subjects (including females with tubal ligations and females that do NOT have a documented hysterectomy, bilateral oophorectomy and/or ovarian failure) will be considered to be of childbearing potential.
- •Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs).
- •Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
- •Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
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 time of dosing).
- •Treatment with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study medication (whichever is longer).
- •Screening supine blood pressure >= 140 mm Hg (systolic) or >=90 mm Hg (diastolic), following at least 5 minutes of rest. If BP is >=140 mm Hg (systolic) or >=90 mm Hg (diastolic), repeat per local standard operating procedures (SOP). If orthostatic changes are present and deemed to be clinically significant by the investigator, Subject can be excluded.
研究组 & 干预措施
Multiple Doses - Part A
Multiple ascending doses administered in the morning to healthy adult subjects in a parallel study design
干预措施: BIIB118 (Drug)
Multiple Doses - Part A
Multiple ascending doses administered in the morning to healthy adult subjects in a parallel study design
干预措施: Melatonin (Drug)
Multiple Dose - Part B
Multiple ascending doses administered in the evening to healthy adult subjects in a parallel study design
干预措施: BIIB118 (Drug)
Multiple Doses - Elderly
Multiple ascending doses administered to elderly subjects
干预措施: BIIB118 (Drug)
结局指标
主要结局
Change From Baseline for Bond and Lader Visual Analogue Scale (BL-VAS) on Days 1, 4, 7, 10, 14, 15 and 16 - Alertness
时间窗: Baseline (0h on Day 1), Day 1 (2h), Day 4 (1.5h), Day 7 (0h, 2h), Day 10 (1.5h), Day 14 (0h, 2h), Day 15 (0h) and Day 16 (0h).
The Bond and Lader Visual Analogue Scales (VAS) monitored the subjective mood of each participant on 16 mood scales. Participants were asked to indicate on the VAS scale ranging from 0 to 100 mm about how they felt at the moment the scale was administered (example, alert/drowsy; calm/excited; content/tensed). The individual responses from the 16 mood scales were then combined to make three affective dimensions/subscales a) alertness (average of 9 items \[total range 0 to 100, where each item is ordered so that higher scores indicated more alertness\]), b) mood (average of 2 items \[total range 0 to 100, where higher scores indicated elevated mood\]), and c) calmness (average of 5 items \[total range 0 to 100, where higher scores indicated more calmness\]). Baseline is defined as the last available recording prior to dosing on Day 1.
Change From Baseline for Bond and Lader Visual Analogue Scale (BL-VAS) on Days 1, 4, 7, 10, 14, 15 and 16 - Calmness
时间窗: Baseline (0h on Day 1), Day 1 (2h), Day 4 (1.5h), Day 7 (0h, 2h), Day 10 (1.5h), Day 14 (0h, 2h), Day 15 (0h) and Day 16 (0h).
The Bond and Lader Visual Analogue Scales (VAS) monitored the subjective mood of each participant on 16 mood scales. Participants were asked to indicate on the VAS scale ranging from 0 to 100 mm about how they felt at the moment the scale was administered (example, alert/drowsy; calm/excited; content/tensed). The individual responses from the 16 mood scales were then combined to make three affective dimensions/subscales a) alertness (average of 9 items \[total range 0 to 100, where each item is ordered so that higher scores indicated more alertness\]), b) mood (average of 2 items \[total range 0 to 100, where higher scores indicated elevated mood\]), and c) calmness (average of 5 items \[total range 0 to 100, where higher scores indicated more calmness\]). Baseline is defined as the last available recording prior to dosing on Day 1.
Change From Baseline for Bond and Lader Visual Analogue Scale (BL-VAS) on Days 1, 4, 7, 10, 14, 15 and 16- Mood
时间窗: Baseline (0h on Day 1), Day 1 (2h), Day 4 (1.5h), Day 7 (0h, 2h), Day 10 (1.5h), Day 14 (0h, 2h), Day 15 (0h) and Day 16 (0h).
The Bond and Lader Visual Analogue Scales (VAS) monitored the subjective mood of each participant on 16 mood scales. Participants were asked to indicate on the VAS scale ranging from 0 to 100 mm about how they felt at the moment the scale was administered (example, alert/drowsy; calm/excited; content/tensed). The individual responses from the 16 mood scales were then combined to make three affective dimensions/subscales a) alertness (average of 9 items \[total range 0 to 100, where each item is ordered so that higher scores indicated more alertness\]), b) mood (average of 2 items \[total range 0 to 100, where higher scores indicated elevated mood\]), and c) calmness (average of 5 items \[total range 0 to 100, where higher scores indicated more calmness\]). Baseline is defined as the last available recording prior to dosing on Day 1.
Number of Participants With Vital Signs Data Meeting Categorical Criteria (Decrease From Baseline)
时间窗: Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14).
Number of participants with vital signs data of increase from baseline meeting the following criteria was reported: Criterion A: maximum decrease from baseline in supine systolic BP \>= 30 mmHg; Criterion B: maximum decrease from baseline in supine diastolic BP \>= 20 mmHg. Baseline was defined as the last available recording prior to dosing.
Number of Participants With New Onset and Worsening of Post-baseline Suicidality for Columbia Suicide Severity Rating Scale (C-SSRS)
时间窗: Days 0, 7, 14, 16, and follow-up visit (28 calender days after the last dose of investigational product on Day 14).
The C-SSRS was an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced any of the following 1: completed suicide, 2: suicide attempt (response of "yes" on "actual attempt"), 3: preparatory acts toward imminent suicidal behavior ("yes" on "aborted attempt", "interrupted attempt", "preparatory acts or behavior"), 4: any suicidal behavior or ideation, 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"), 7: self-injurious behavior, no suicidal intent ("yes" on "has participant engaged in non-suicidal self-injurious behavior"). The new onset and worsening of post-baseline suicidality for C-SSRS was reported.
Number of Participants With Treatment-Emergent Adverse Events (AEs) (All Causalities)
时间窗: Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14).
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage.
Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Criteria (Absolute Values)
时间窗: Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14).
Number of participants with ECG data of absolute values meeting categorical criteria was reported as following: Criterion A: maximum PR interval (time from the beginning of P wave to the start of QRS complex, corresponding to the end of atrial depolarization and onset of ventricular depolarization) \>= 300 msec; Criterion B: maximum QRS complex (time from Q wave to the end of S wave, corresponding to ventricle depolarization)\>= 140 msec; Criterion C: Maximum QT interval (time from the beginning of Q wave to the end of T wave corresponding to electrical systole)\>= 500 msec; Criterion D: maximum QTC interval (QT interval corrected for heart rate) 450-\<480 msec; Criterion E: maximum QTC interval 480-\<500 msec; Criterion F: maximum QTC interval \>=500 msec; Criterion G: maximum QTCF interval (QT interval corrected for heart rate using Fridericia's formula) 450 -\< 480 msec; Criterion H: maximum QTCF interval 480 -\< 500 msec; Criterion I: maximum QTCF interval \>=500 msec.
Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Criteria (Increase From Baseline)
时间窗: Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14).
Number of participants with ECG Data of increase from baseline meeting the following criteria was reported: Criterion A: maximum PR interval increase from baseline percentage change (PctChg)\>=25/50%; Criterion B: maximum QRS complex increase from baseline PctChg \>=50%; Criterion C: maximum QTC interval (time from the beginning of Q wave to the end of T wave corresponding to electrical systole, corrected for heart rate) increase from baseline 30\<=change\<60 msec; Criterion D: maximum QTC interval increase from baseline change \>=60 msec; Criterion E: maximum QTCF (Fridericia's correction) interval increase from baseline 30\<=change\<60; Criterion F: maximum QTCF interval increase from baseline change \>=60 msec. Baseline was defined as the average of the triplicate measurements prior to dosing on Day 1.
Number of Participants With New/Intensified Neurological Examination Findings
时间窗: Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14).
The number of participants with new-intensified neurological examination findings were reported.
Number of Participants With Vital Signs Data Meeting Categorical Criteria (Increases From Baseline)
时间窗: Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14).
Number of participants with vital signs data of increase from baseline meeting the following criteria was reported: Criterion A: maximum increase from baseline in supine systolic BP \>= 30 mmHg; Criterion B: maximum increase from baseline in supine diastolic BP \>= 20 mmHg. Baseline was defined as the last available recording prior to dosing.
Number of Participants With Treatment-Emergent Adverse Events (AEs) (Treatment Related)
时间窗: Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14).
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; The event has a causal relationship with the treatment or usage.
Number of Participants With New/Intensified Physical Examination Findings
时间窗: Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14).
Physical examination included examination of ears, eyes, gastrointestinal, head, heart, lungs, lymph nodes, mouth, musculoskeletal, nose, skin. The number of participants with new-intensified physical examination findings were reported.
Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)
时间窗: Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14).
The laboratory test included: hematology (hemoglobin, hematocrit, red blood cell count, MCV, MCH, MCHC, platelets, white blood cell count, absolute lymphocytes, absolute total neutrophils, absolute basophils, absolute eosinophils and absolute monocytes), coagulation (PPT, prothrombin, PT international, ratio and fibrinogen, liver function(total bilirubin, direct bilirubin, aspartate, AST, Alanine, ALT, gamma GT, alkaline phosphatase, total protein and albumin), renal function (blood urea nitrogen, creatinine, HDL cholesterol, LDL cholesterol, triglycerides), Electrolytes (sodium, potassium, chloride, calcium, phosphate, venous bicarbonate), clinical chemistry (glucose, creatinine kinase), urinalysis dipstick (urine PH, urine glucose, urine ketones, urine protein, urine blood, urine urobilinogen, urine nitrite, urine leukocyte, esterase), urinalysis microscopy (urine RBC, urine WBC, urine casts, urine bacteria), miscellaneous (absolute lymphocyte marker CD4, CD8, CD19)
Number of Participants With Vital Signs Data Meeting Categorical Criteria (Absolute Values)
时间窗: Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14).
Number of participants with vital signs data of absolute values meeting categorical criteria was reported as following: (1) Supine systolic BP \< 90 mmHg; (2) Supine Diastolic BP \< 50 mmHg; (3) Supine Pulse Rate \< 40 BPM ; (4) Supine Pulse Rate \> 120 BPM.
次要结局
- Maximum Plasma Concentration (Cmax) of PF-05251749 - Days 1, 7 and 14(Days 1 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 48h), 7 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24h) and 14 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 48h).)
- Area Under the Concentration-Time Profile From Time 0 to Tau (AUCtau) of PF-05251749 - Days 1, 7 and 14.(Days 1 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 48h), 7 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24h) and 14 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 48h).)
- Terminal Half-Life (t1/2) of PF-05251749 - Day 14(Day 14 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 48h).)
- Cumulative Amount of Drug Recovered Unchanged in Urine Over Dosing Interval Tau (Aetau) of PF-05251749 - Day 14(Day 14 (0, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 12, 16, 20, 24, 48h).)
- Apparent Clearance (CL/F) of PF-05251749 - Days 7 and 14(Days 7 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24h) and 14 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 48h).)
- Time at Which Cmax Occurred (Tmax) of PF-05251749 - Days 1, 7 and 14(Days 1 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 48h), 7 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24h) and 14 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 48h).)
- Minimum Concentration Observed (Cmin) of PF-05251749 - Days 7 and 14(Days 7 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24h) and 14 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 48h).)
- Plasma Peak-to-trough Ratio (PTR) (Cmax/Cmin) of PF-05251749 - Days 7 and 14(Days 7 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24h) and 14 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 48h).)
- Observed Accumulation Ratio (Rac) of PF-05251749 -Days 7 and 14(Days 7 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24h) and 14 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 48h).)
- Observed Accumulation Ratio for Cmax (Rac,Cmax) of PF-05251749 - Days 7 and 14(Days 7 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24h) and 14 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 48h).)
- Apparent Volume of Distribution (Vz/F) of PF-05251749 - Day 14(Day 14 (0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 48h).)
- Percentage of Dose Recovered Unchanged in Urine Over Dosing Interval Tau (Aetau%) of PF-05251749 - Day 14(Day 14 (0, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 12, 16, 20, 24, 48h).)
- Renal Clearance (CLr) of PF-05251749 - Day 14(Day 14 (0, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 12, 16, 20, 24, 48h).)
- Change From Baseline for Dim Light Melatonin Onset (DLMO) Time - Day 6(Day 0 (Baseline) and Day 6.)
- Change From Baseline for Dim Light Melatonin Onset (DLMO) Time - Day 15(Day 0 (Baseline) and Day 15)