Safety, Tolerability and Pharmacokinetics of BIIB118 (PF-05251749)

Study Overview
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Brief Summary
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This is a First in human (FIH) single ascending dose study to evaluate the safety, tolerability and pharmacokinetics (PKs) of BIIB118 following single oral doses in healthy human subjects

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, Randomized, Double Blind, Placebo Controlled Study To Investigate The Safety, Tolerability, Pharmacokinetics And Relative Bioavailability Of Single Escalating Oral Doses Of Pf-05251749 In Healthy Adult Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: BIIB118
* Drug: BIIB118
* Drug: BIIB118


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, 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: 55 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Ascending Dose-1 (Part A)<br>Single ascending doses of BIIB118 administered to healthy volunteers in a cross over study design | Drug: BIIB118<br>* Single ascending doses of BIIB118 as extemporaneously prepared solution/suspension, once every 2 week in a cross over study: 3 mg, 30 mg, 200 mg, 800 mg and placebo<br>* Other names: PF-05251749;|
| Experimental: Single Ascending Dose-2 (Part A)<br>Single ascending doses of BIIB118 administered to healthy volunteers in a cross over study design | Drug: BIIB118<br>* Single ascending doses of BIIB118 as extemporaneously prepared solution/suspension, once every 2 week in a cross over study: 10 mg, 100 mg, 400 mg, and placebo<br>* Other names: PF-05251749;|
| Experimental: Single Dose Cerebrospinal Fluid (Part B)<br>Single maximum dose from Part A of BIIB118 administered to healthy volunteers to assess the PK of BIIB118 in CSF | Drug: BIIB118<br>* Single dose (Maximum Tolerated Dose) of BIIB118 as extemporaneously prepared solution/suspension<br>* Other names: PF-05251749;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. A 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. | For Cohort 1 and 2: Baseline up to Week 8, Cohort 3: Baseline up to Week 2, Cohort 4: Baseline up to Week 3 | 
| Number of Participants With Laboratory Abnormalities | Hemoglobin(Hgb),hematocrit,red blood cell(RBC):less than(<)0.8*lower limit of normal(LLN), MCV,MCH,MCHC,MPV:<0.9*LLN or >1.1*upper limit of normal(ULN), platelet:<0.5*LLN or >1.75*ULN, white blood cell(WBC):<0.6*LLNor>1.5*ULN, lymphocyte,neutrophil,total neutrophil:<0.8*LLN or >1.2*ULN,basophil,eosinophil,monocyte:>1.2*ULN; PTT, PT:>1.1*ULN,Fibrinogen<0.75*ULNor>1.25ULN; total, direct, indirect bilirubin >1.5*ULN,aspartate aminotransferase,alanine aminotransferase,gamma-glutamyl transferase,alkaline phosphatase:> 3.0*ULN,total protein,albumin:<0.8*LLN or >1.2*ULN;blood urea nitrogen,creatinine:>1.3*ULN,uric acid>1.2*ULN;sodium:<0.95*LLN or>1.05*ULN,potassium,chloride, calcium,magnesium,bicarbonate:<0.9*LLN or >1.1*ULN, phosphate<0.8*LLN or >1.2*ULN; glucose <0.6*LLN or >1.5*ULN,creatine kinase>2.0*ULN;urine(specific gravity<1.003or>1.030,pH <4.5or>8,glucose,ketone,protein,blood/Hgb,bilirubin,leukocyte esterase,crystals>=1,RBC,WBC >=20*ULN,bacteria>20);CSF (WBC>=6,RBC>0,Albumin>35). | Cohort 1 and 2: Baseline up to Week 8, Cohort 3: Baseline up to Week 2, Cohort 4: Baseline up to Week 3 | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | Criteria for clinically significant change from baseline in vital signs: supine systolic blood pressure (SBP) <90 millimeter of mercury (mmHg), supine diastolic BP (DBP) <50 mmHg, supine pulse rate <40 beats per minute (bpm) or >120 bpm. Maximum increase or decrease from baseline in supine SBP greater than or equal to (>=)30 mmHg and maximum increase or decrease from baseline in supine DBP >=20 mmHg. | Cohort 1 and 2: Baseline up to Week 8, Cohort 3: Baseline up to Week 2, Cohort 4: Baseline up to Week 3 | 
| Number of Participants With Abnormal 12-Lead Electrocardiogram (ECG) Findings | ECG parameters included maximum pulse rate (PR) interval, QRS interval, and corrected QT interval using Fridericia's formula (QTcF). Criteria for abnormal ECG: Maximum PR interval >=300 milliseconds (msec) or >=25 percent increase when baseline is >200 msec and >=50 percent increase when baseline is less than or equal to (=<) 200 msec; QRS interval >=140 msec or >=50 percent increase from baseline (IFB); and QTcF 30<=change<60 or change>=60 msec increase. The number of participants with abnormal ECG findings are reported. | Cohort 1 and 2: Baseline up to Week 8, Cohort 3: Baseline up to Week 2, Cohort 4: Baseline up to Week 3 | 
| Change From Baseline in Bond and Lader Visual Analogue Scale (BL-VAS) at 2 Hours Post Dose in Cohorts 1 and 2 | The BL-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) contentment (average of 2 items [total range 0 to 100, where higher scores indicated more contentment]), 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 of the first Period. | Baseline, Day 1: 2 hours post dose | 
| Change From Baseline in Bond and Lader Visual Analogue Scale (BL-VAS) at 6 Hours Post Dose in Cohorts 1 and 2 | The BL-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) contentment (average of 2 items [total range 0 to 100, where higher scores indicated more contentment]), 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 of the first Period. | Baseline, Day 1: 6 hours post dose | 
| Change From Baseline in Bond and Lader Visual Analogue Scale (BL-VAS) at 48 Hours Post Dose in Cohorts 1 and 2 | The BL-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) contentment (average of 2 items [total range 0 to 100, where higher scores indicated more contentment]), 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 of the first Period. | Baseline, Day 3: 48 hours post dose | 
| Change From Baseline in Extrapyramidal Symptom Rating Scale (ESRS) at 2 Hours Post Dose in Cohorts 1 and 2 | ESRS is a clinician rated scale to assess parkinsonism,dystonia,dyskinesia,akathisia.The ESRS consists of 4 subscales and 4 clinicians global impressions-severity scales(CGI-S scales):I)a questionnaire of extrapyramidal symptoms or drug-induced movement disorders(a series of 4-point Likert scale questions with 0=Absent and 3=Severe);II)an examination of Parkinsonism and akathisia(7-point Likert scale with 0=Absent,6=extremely severe);III)an examination of dystonia(7-point Likert scale with 0=Absent,6=extremely severe);IV)an examination of dyskinesia(7-point Likert scale with 0=normal,6=most severe);V)toVIII)CGI-S scales(9-point Likert scale with 0=Absent,8=extremely severe)of tardive dyskinesia,parkinsonism,dystonia,akathisia.ESRS-Parkinsonism:total score range:0 to 14 where higher scores indicates greater severity;ESRS-dystonia:total score range:0 to 14 where higher scores indicates greater severity.Change from baseline was only observed in examination of parkinsonism and dystonia. | Baseline, Day 1: 2 hours post dose | 
| Change From Baseline in Extrapyramidal Symptom Rating Scale (ESRS) at 48 Hours Post Dose in Cohorts 1 and 2 | ESRS is a clinician rated scale to assess parkinsonism,dystonia,dyskinesia,akathisia.The ESRS consists of 4 subscales and 4 clinicians global impressions-severity scales(CGI-S scales):I)a questionnaire of extrapyramidal symptoms or drug-induced movement disorders(a series of 4-point Likert scale questions with 0=Absent and 3=Severe);II)an examination of Parkinsonism and akathisia(7-point Likert scale with 0=Absent,6=extremely severe);III)an examination of dystonia(7-point Likert scale with 0=Absent,6=extremely severe);IV)an examination of dyskinesia(7-point Likert scale with 0=normal,6=most severe);V)toVIII)CGI-S scales(9-point Likert scale with 0=Absent,8=extremely severe)of tardive dyskinesia,parkinsonism,dystonia,akathisia.ESRS-Parkinsonism:total score range:0 to 14 where higher scores indicates greater severity;ESRS-dystonia:total score range:0 to 14 where higher scores indicates greater severity.Change from baseline was only observed in examination of parkinsonism and dystonia. | Baseline, Day 1: 48 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of PF-05251749 |  | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post dose | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05251749 | Area under the plasma concentration-time profile from time zero to the time of last quantifiable concentration (Clast ). | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post dose | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of PF-05251749 | AUC (0 -∞) = Area under the plasma concentration- time profile from time zero extrapolated to infinite time. It was calculated as AUC last + (C last*/k el), where C last* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis. | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05251749 |  | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post dose | 
| Plasma Decay Half-Life (t1/2) of PF-05251749 | Terminal elimination half-life (t1/2). It was calculated as dividing the natural logarithm to the base e (Log e)*2/k el, where k el is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post dose | 
| Apparent Oral Clearance (CL/F) of PF-05251749 | 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. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post dose | 
| Apparent Volume of Distribution (Vz/F) of PF-05251749 | 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. | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post dose | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Milled and Unmilled PF-05251749: Cohort 4 | Area under the plasma concentration-time profile from time zero to the time of last quantifiable concentration (Clast). | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post dose | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of Milled and Unmilled PF-05251749: Cohort 4 | AUC (0 -∞) = Area under the plasma concentration- time profile from time zero extrapolated to infinite time. It was calculated as AUC last + (C last*/k el), where C last* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis. | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post dose | 
| Maximum Observed Plasma Concentration (Cmax) of Milled and Unmilled PF-05251749: Cohort 4 |  | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Milled and Unmilled PF-05251749: Cohort 4 |  | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post dose | 
| Area Under the Curve From Time Zero to Last Quantifiable Cerebrospinal Fluid (CSF) Concentration (AUClast) of PF-05251749 | Area under the CSF concentration-time profile from time zero to the time of last quantifiable concentration (Clast). | Predose, 1.5, 2.5, 4, and 8 hours post dose | 
| Area Under the Curve From Time Zero to Extrapolated Cerebrospinal Fluid (CSF) Infinite Time [AUC (0 - ∞)] of PF-05251749 | AUC (0 -∞) = Area under the CSF concentration- time profile from time zero extrapolated to infinite time. It was calculated as AUC last + (C last*/k el), where C last* was the predicted CSF concentration at the last quantifiable time point estimated from the log-linear regression analysis. | Predose, 1.5, 2.5, 4, and 8 hours post dose | 
| Maximum Observed Cerebrospinal Fluid (CSF) Concentration (Cmax) of PF-05251749 |  | Predose, 1.5, 2.5, 4, and 8 hours post dose | 
| Time to Reach Maximum Observed Cerebrospinal Fluid (CSF) Concentration (Tmax) of PF-05251749 |  | Predose, 1.5, 2.5, 4, and 8 hours post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Plasma, First in human, Single Ascending Dose Study, Safety and Tolerability, Pharmacokinetics, Cerebrospinal Fluid