Study to Evaluate the Effect of UGT Inhibition by Valproic Acid on the Pharmacokinetics of BIIB074

A Phase 1, Open-label, Fixed-sequence Study to Evaluate the Effect of UGT Inhibition by Valproic Acid on the Pharmacokinetics of BIIB074 in Healthy Subjects

The primary objective of this study is to evaluate the effect of multiple doses of the UGT inhibitor valproic acid on the single-dose pharmacokinetics of BIIB074. The secondary objectives of this study are to evaluate the safety and tolerability of BIIB074 when administered alone and when coadministered with the UGT inhibitor valproic acid and to evaluate the effect of the UGT inhibitor valproic acid on the PK of the M13, M14, and M16 metabolites of BIIB074.

Study Overview

• Status: Completed
• Conditions: Drug Interaction
• Intervention / Treatment: Drug: BIIB074; Drug: Valproic Acid

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75247
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Must have a body mass index between 18 and 32 kg/m^2, inclusive.
• Must be male, postmenopausal female, or surgically sterile female
• Must be in good health as determined by the Investigator, based on medical history and screening evaluations.

Key Exclusion Criteria:

• History of any clinically significant cardiac, endocrine, gastrointestinal (GI), hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, or renal disease, or other major disease, as determined by the Investigator
• Clinically significant abnormal laboratory test values, as determined by the Investigator, at Screening or Day -1
• History of, or positive test result at Screening for, human immunodeficiency virus (HIV)
• Treatment with any prescription or over-the-counter oral medication (excluding acetaminophen) within 14 days prior to Day -1 and an unwillingness or inability to refrain from this treatment during study participation, unless specifically permitted elsewhere within this protocol.
• Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the subject unsuitable for enrollment.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BIIB074 150 mg and Valproic Acid 500 mg; Participants will receive BIIB074 in tablet form in 150 mg doses. BIIB074 will be taken once daily (QD) on Days 1-16 after an 8-hour fast. Valproic Acid will be given in capsule form in 500 mg doses on prescription (TID) every 8 hours on Days 8-22. The morning dose on Day 16 will be coadministered with BIIB074 following an 8-hour fast.	Drug: BIIB074; Administered as specified in the treatment arm; Drug: Valproic Acid; Administered as specified in the treatment arm; Other Names: Depakote, Depakene, Stavzor, and Valproic

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum Observed Concentration (Cmax) of BIIB074	Day 1 through Day 8, Day 16 through Day 23
Area Under the Concentration-Time Curve from Time 0 to Infinity (AUCinf) of BIIB074	Day 1 through Day 8, Day 16 through Day 23
Area Under the Concentration-Time Curve from Time Zero to Time of the Last Measurable Concentration (AUClast) of BIIB074	Day 1 through Day 8, Day 16 through Day 23
Time to Reach Maximum Observed Concentration (Tmax) for BIIB074	Day 1 through Day 8, Day 16 through Day 23
Time of Last Measured Serum Concentration (Tlast) of BIIB074	Day 1 through Day 8, Day 16 through Day 23
Elimination Half-Life (T 1/2) of BIIB074	Day 1 through Day 8, Day 16 through Day 23
Apparent Clearance (CL/F) of BIIB074	Day 1 through Day 8, Day 16 through Day 23
Apparent Volume of Distribution (V/F) of BIIB074	Day 1 through Day 8, Day 16 through Day 23

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment.	Up to Day 32
Number of Participants with Abnormal Change from Baseline of Electrocardiogram (ECG) up to Day 23		Day 1, 3, 8, 13, 16, 18, 23
Number of Participants with Abnormal Change from Baseline of Clinical Laboratory Parameters up to Day 23		Day 3, 8, 13, 16, 18, 23
Number of Participants with Abnormal Change from Baseline of Vital Signs up to Day 23		Day 1, 3, 8, 13, 16, 18, 23
Cmax of BIIB074 Metabolites M13, M14, and M16		Day 1 through Day 8, Day 16 through Day 23
AUCinf of BIIB074 Metabolites M13, M14, and M16		Day 1 through Day 8, Day 16 through Day 23
AUClast of BIIB074 Metabolites M13, M14, and M16		Day 1 through Day 8, Day 16 through Day 23
Tmax of BIIB074 Metabolites M13, M14, and M16		Day 1 through Day 8, Day 16 through Day 23
Tlast of BIIB074 Metabolites M13, M14, and M16		Day 1 through Day 8, Day 16 through Day 23
T1/2 of BIIB074 Metabolites M13, M14, and M16		Day 1 through Day 8, Day 16 through Day 23
Metabolite-to-Parent Ratio in AUC (MRauc) of BIIB074 Metabolites M13, M14, and M16		Day 1 through Day 8, Day 16 through Day 23
Number of Participants with Abnormal Change from Baseline in Columbia Suicide Severity Rating (C-SSRS) scale	C-SSRS is a suicidal ideation rating used to evaluate suicidality in children ages 12 and up. It rates an individual's degree of suicidal ideation on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent	Day 8, 23, and once between Day 29-32

Collaborators and Investigators

• Sponsor: Biogen

Publications and helpful links

General Publications

• Zhao Y, Kotecha M, Finnigan H, Serenko M, Naik H. Evaluation of the Effect of Uridine Diphosphate-Glucuronosyltransferases (UGT) Inhibition by Valproic Acid on Vixotrigine Pharmacokinetics in Healthy Volunteers. Clin Drug Investig. 2022 Oct;42(10):829-837. doi: 10.1007/s40261-022-01194-y. Epub 2022 Aug 31.

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2017
• Primary Completion (Actual): October 13, 2017
• Study Completion (Actual): October 13, 2017

Study Registration Dates

• First Submitted: October 13, 2017
• First Submitted That Met QC Criteria: December 27, 2017
• First Posted (Actual): December 28, 2017

Study Record Updates

• Last Update Posted (Actual): April 20, 2018
• Last Update Submitted That Met QC Criteria: April 18, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Healthy Volunteer
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid
• Other Study ID Numbers: 802HV109

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes