Multiple Dose Study Of BIIB118 (PF-05251749) In Healthy Volunteers

Study Overview
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Brief Summary
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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

Detailed Description
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This study was previously posted by Pfizer. In March, 2020, sponsorship of the trial was transferred to Biogen.

Official Title
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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

Conditions
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Healthy Adult Subjects, Healthy Elderly Subjects

Intervention / Treatment
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* Drug: BIIB118
* Drug: Melatonin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Multiple Doses - Part A<br>Multiple ascending doses administered in the morning to healthy adult subjects in a parallel study design | Drug: BIIB118<br>* Multiple ascending doses of BIIB118 (50 mg, 150 mg, 450 mg and 900 mg) as extemporaneously prepared solution/suspension administered once daily over 2 weeks<br>* Other names: PF-05251749;Drug: Melatonin<br>* Positive control used to assess the validity of DLMO as pharmacodynamic endpoint.<br>|
| Experimental: Multiple Dose - Part B<br>Multiple ascending doses administered in the evening to healthy adult subjects in a parallel study design | Drug: BIIB118<br>* Multiple ascending doses of BIIB118 (50 mg, 150 mg, 450 mg and 900 mg) as extemporaneously prepared solution/suspension administered once daily over 2 weeks<br>* Other names: PF-05251749;|
| Experimental: Multiple Doses - Elderly<br>Multiple ascending doses administered to elderly subjects | Drug: BIIB118<br>* Multiple ascending doses of BIIB118 (50 mg, 150 mg, 450 mg and 900 mg) as extemporaneously prepared solution/suspension administered once daily over 2 weeks<br>* Other names: PF-05251749;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline for Bond and Lader Visual Analogue Scale (BL-VAS) on Days 1, 4, 7, 10, 14, 15 and 16 - Alertness | 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. | 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). | 
| Change From Baseline for Bond and Lader Visual Analogue Scale (BL-VAS) on Days 1, 4, 7, 10, 14, 15 and 16 - Calmness | 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. | 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). | 
| Change From Baseline for Bond and Lader Visual Analogue Scale (BL-VAS) on Days 1, 4, 7, 10, 14, 15 and 16- Mood | 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. | 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). | 
| Number of Participants With New Onset and Worsening of Post-baseline Suicidality for Columbia Suicide Severity Rating Scale (C-SSRS) | 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. | Days 0, 7, 14, 16, and follow-up visit (28 calender days after the last dose of investigational product on Day 14). | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) (All Causalities) | 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. | Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14). | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) (Treatment Related) | 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. | Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14). | 
| Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality) | 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) | 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 Meeting Categorical Criteria (Absolute Values) | 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. | 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 Meeting Categorical Criteria (Increases From Baseline) | 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. | 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 Meeting Categorical Criteria (Decrease From Baseline) | 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. | Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14). | 
| Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Criteria (Absolute Values) | 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. | Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14). | 
| Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Criteria (Increase From Baseline) | 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. | Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14). | 
| Number of Participants With New/Intensified Physical Examination Findings | 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. | Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14). | 
| Number of Participants With New/Intensified Neurological Examination Findings | The number of participants with new-intensified neurological examination findings were reported. | Day 1 to follow-up visit (28 calendar days after the last dose of investigational product on Day 14). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of PF-05251749 - Days 1, 7 and 14 | Maximum plasma concentration (Cmax) of PF-05251749 was observed directly from data on 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. | AUCtau referred to the area under the curve from time 0 to time tau, the dosing interval, where tau equaled to 24 hours on 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). | 
| Time at Which Cmax Occurred (Tmax) of PF-05251749 - Days 1, 7 and 14 | Tmax of PF-05251749 was observed directly from data on Days 1, 7 and 14, as time of first occurrence. | 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). | 
| Apparent Clearance (CL/F) of PF-05251749 - Days 7 and 14 | Apparent clearance was influenced by the fraction of the dose absorbed, which was measured by Dose/AUCtau. | 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). | 
| Minimum Concentration Observed (Cmin) of PF-05251749 - Days 7 and 14 | Minimum concentration observed (Cmin) of PF-05251749 was observed directly from data on 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 | Peak-to-through ratio (PTR) was the ratio of Cmax to Cmin, which was measured on 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 | Observed accumulation ratio (Rac) was calculated as AUCtau (Days 7 or 14) divided by AUCtau (Day 1). | 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 | Observed accumulation ratio for Cmax (Rac,Cmax) was calculated as: Cmax on Day 7 or 14 divided by Cmax on Day 1. | 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). | 
| Terminal Half-Life (t1/2) of PF-05251749 - Day 14 | Terminal half-life (t1/2) was calculated as Loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve. | Day 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 | Apparent volume of distribution (Vz/F) was calculated by Dose/(AUCtau × kel) on 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 | Aetau was the cumulative amount of drug recovered unchanged in urine from time 0 to end of the dosing interval, which was calculated by sum of (urine concentration × volume of urine). | Day 14 (0, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 12, 16, 20, 24, 48h). | 
| Percentage of Dose Recovered Unchanged in Urine Over Dosing Interval Tau (Aetau%) of PF-05251749 - Day 14 | Aetau% was the percentage of dose recovered unchanged into urine from 0 to end of the dosing interval, which was calculated by 100 × Aetau/Dose. | 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 | Renal clearance was 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), Aetau/AUCtau. | 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 | Dim Light Melatonin Onset (DLMO) was defined as point in time when the smooth melatonin curve exceeds the threshold. The threshold for each melatonin profile was calculated as the mean of three low consecutive daytime values (raw data points) plus twice the standard deviation of these points. | Day 0 (Baseline) and Day 6. | 
| Change From Baseline for Dim Light Melatonin Onset (DLMO) Time - Day 15 | DLMO was defined as point in time when the smooth melatonin curve exceeds the threshold. The threshold for each melatonin profile was calculated as the mean of three low consecutive daytime values (raw data points) plus twice the standard deviation of these points. | Day 0 (Baseline) and Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Ascending Dose Study, Safety and Tolerability, Pharmacokinetics, Pharmacodynamics, Melatonin, Plasma, Dim Light Melatonin Onset