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

NCT02691702 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: B8001002MAD
• Study Type: interventional
• Target: 97
• Locations: 1 country
• Sites: 2

Brief Summary

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

Conditions

Healthy Adult Subjects; Healthy Elderly Subjects

Keywords

Multiple Ascending Dose Study; Safety and Tolerability; Pharmacokinetics; Pharmacodynamics; Melatonin; Plasma; Dim Light Melatonin Onset

Outcome Measures

Primary Outcomes (14)

• 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 Outcomes (15)

• 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).

• 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).

• 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).

• 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).

Study Arms (3)

Multiple Doses - Part A

EXPERIMENTAL

Multiple ascending doses administered in the morning to healthy adult subjects in a parallel study design

Drug: BIIB118; Drug: Melatonin

Multiple Dose - Part B

EXPERIMENTAL

Multiple ascending doses administered in the evening to healthy adult subjects in a parallel study design

Drug: BIIB118

Multiple Doses - Elderly

EXPERIMENTAL

Multiple ascending doses administered to elderly subjects

Drug: BIIB118

Interventions

BIIB118 DRUG

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

Also known as: PF-05251749

Multiple Dose - Part B; Multiple Doses - Elderly; Multiple Doses - Part A

Melatonin DRUG

Positive control used to assess the validity of DLMO as pharmacodynamic endpoint.

Multiple Doses - Part A

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Biogen: lead

Study Sites (2)

QPS-MRA, LLC (Miami Research Associates)

South Miami, Florida, 33143, United States

Location

Qps-Mra, Llc

South Miami, Florida, 33143, United States

Location

Related Publications (1)

• Lin J, Gaudreault F, Johnson N, Lin Z, Nouri P, Goosen TC, Sawant-Basak A. Investigation of CYP3A induction by PF-05251749 in early clinical development: comparison of linear slope physiologically based pharmacokinetic prediction and biomarker response. Clin Transl Sci. 2022 Sep;15(9):2184-2194. doi: 10.1111/cts.13352. Epub 2022 Jul 2.

  PMID: 35730131 DERIVED

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Interventions

Melatonin

Intervention Hierarchy (Ancestors)

Tryptamines; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Limitations and Caveats

From Parts A and B, it was deemed that safety, tolerability, PK and PD objectives were met, so Part C was not conducted. Because of limited saliva sampling duration (06:00 PM to 12:00 AM), DLMO observation(s) beyond midnight could not be quantified.

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Medical Director

  Biogen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 22, 2016
• First Posted: February 25, 2016
• Study Start: March 28, 2016
• Primary Completion: January 12, 2017
• Study Completion: January 12, 2017
• Last Updated: February 17, 2021
• Results First Posted: October 15, 2018

Record last verified: 2021-02

Locations

US (2)