A Study to Evaluate the Effect of AG-881 on the Pharmacokinetics of a Single Dose of Lamotrigine in Healthy Adults

NCT04015687 | Completed Phase 1 FDA Drug

• 1 other identifier: AG881-C-006
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

The main purpose of this study is to examine the effect of multiple doses of AG-881 on the pharmacokinetics (PK) of a single dose of lamotrigine in healthy adults.

Conditions

Healthy Participants

Keywords

Pharmacokinetic study

Outcome Measures

Primary Outcomes (18)

• Area under the Concentration-time Curve from Time 0 to Infinity (AUC0-inf) for Lamotrigine Administered with Interacting Drug AG-881

  At multiple time points daily from Day 14 to Day 21 (or early discontinuation) in Period 2 (21-day period)

• Area under the Concentration-time Curve from Time 0 to Infinity (AUC0-inf) for Lamotrigine Administered without Interacting Drug AG-881

  At multiple time points daily from Day 1 to Day 8 in Period 1 (8-day period)

• Maximum Observed Plasma Concentration (Cmax) for Lamotrigine Administered with Interacting Drug AG-881

  At multiple time points daily from Day 14 to Day 21 (or early discontinuation) in Period 2 (21-day period)

• Maximum Observed Plasma Concentration (Cmax) for Lamotrigine Administered without Interacting Drug AG-881

  At multiple time points daily from Day 1 to Day 8 in Period 1 (8-day period)

• Area under the Concentration-time Curve, from Time 0 to the Last Observed Non-zero Concentration (t) (AUC0-t) for Lamotrigine Administered with Interacting Drug AG-881

  At multiple time points daily from Day 14 to Day 21 (or early discontinuation) in Period 2 (21-day period)

• Area under the Concentration-time Curve, from Time 0 to the Last Observed Non-zero Concentration (t) (AUC0-t) for Lamotrigine Administered without Interacting Drug AG-881

  At multiple time points daily from Day 1 to Day 8 in Period 1 (8-day period)

• Percent of AUC0-inf Extrapolated (AUC%extrap) for Lamotrigine Administered with Interacting Drug AG-881

  At multiple time points daily from Day 14 to Day 21 (or early discontinuation) in Period 2 (21-day period)

• Percent of AUC0-inf Extrapolated (AUC%extrap) for Lamotrigine Administered without Interacting Drug AG-881

  At multiple time points daily from Day 1 to Day 8 in Period 1 (8-day period)

• Time to Maximum Observed Plasma Concentration (Tmax) for Lamotrigine Administered with Interacting Drug AG-881

  At multiple time points daily from Day 14 to Day 21 (or early discontinuation) in Period 2 (21-day period)

• Time to Maximum Observed Plasma Concentration (Tmax) for Lamotrigine Administered without Interacting Drug AG-881

  At multiple time points daily from Day 1 to Day 8 in Period 1 (8-day period)

• Apparent Terminal Elimination Rate Constant (Kel) for Lamotrigine Administered with Interacting Drug AG-881

  At multiple time points daily from Day 14 to Day 21 (or early discontinuation) in Period 2 (21-day period)

• Apparent Terminal Elimination Rate Constant (Kel) for Lamotrigine Administered without Interacting Drug AG-881

  At multiple time points daily from Day 1 to Day 8 in Period 1 (8-day period)

• Apparent Terminal Elimination Half-life (t½) for Lamotrigine Administered with Interacting Drug AG-881

  At multiple time points daily from Day 14 to Day 21 (or early discontinuation) in Period 2 (21-day period)

• Apparent Terminal Elimination Half-life (t½) for Lamotrigine Administered without Interacting Drug AG-881

  At multiple time points daily from Day 1 to Day 8 in Period 1 (8-day period)

• Apparent Total Plasma Clearance after Oral (Extravascular) Administration (CL/F) for Lamotrigine Administered with Interacting Drug AG-881

  At multiple time points daily from Day 14 to Day 21 (or early discontinuation) in Period 2 (21-day period)

• Apparent Total Plasma Clearance after Oral (Extravascular) Administration (CL/F) for Lamotrigine Administered without Interacting Drug AG-881

  At multiple time points daily from Day 1 to Day 8 in Period 1 (8-day period)

• Apparent Volume of Distribution during the Terminal Elimination Phase after Oral (Extravascular) Administration (Vz/F) for Lamotrigine Administered with Interacting Drug AG-881

  At multiple time points daily from Day 14 to Day 21 (or early discontinuation) in Period 2 (21-day period)

• Apparent Volume of Distribution during the Terminal Elimination Phase after Oral (Extravascular) Administration (Vz/F) for Lamotrigine Administered without Interacting Drug AG-881

  At multiple time points daily from Day 1 to Day 8 in Period 1 (8-day period)

Secondary Outcomes (6)

• Percentage of Participants with Adverse Events (AEs)

  Up to approximately 4 weeks

• Columbia-suicide Severity Rating Scale (C-SSRS)

  Up to approximately 4 weeks

• Percentage of Participants with Abnormalities in 12-lead Electrocardiograms (ECGs)

  Up to approximately 4 weeks

• Percentage of Participants with Abnormalities in Vital Sign Measurements

  Up to approximately 4 weeks

• Percentage of Participants with Abnormalities in Clinical Laboratory Tests

  Up to approximately 4 weeks

Study Arms (3)

AG-881 (Group 1)

EXPERIMENTAL

On Day 1 of Period 1, Group 1 participants will receive a single 50-milligram (mg) oral dose of lamotrigine at Hour 0. In Period 2, they will receive 50-mg oral doses of AG-881 once daily (QD) for 15 consecutive days (Days 1 to 15), with a single 50-mg oral dose of lamotrigine coadministered at Hour 0 on Day 14.

Drug: AG-881; Drug: Lamotrigine

AG-881 (Group 2)

EXPERIMENTAL

Following a safety and tolerability review of the data from at least 7 days of AG-881 dosing of Group 1 participants in Period 2, Group 2 participants will receive a single 50-mg oral dose of lamotrigine at Hour 0 in Period 1, and 50-mg oral doses of AG-881 QD for 15 consecutive days (Days 1 to 15), with a single 50-mg oral dose of lamotrigine coadministered at Hour 0 on Day 14 in Period 2.

Drug: AG-881; Drug: Lamotrigine

AG-881 (Group 3)

EXPERIMENTAL

Following a safety and tolerability review of the data from Group 1 participants, and from at least 7 days of AG-881 dosing of Group 2 participants in Period 2, Group 3 participants will receive a single 50-mg oral dose of lamotrigine at Hour 0 in Period 1; and 50-mg oral doses of AG-881 QD for 15 consecutive days (Days 1 to 15) with a single 50-mg oral dose of lamotrigine coadministered at Hour 0 on Day 14 in Period 2.

Drug: AG-881; Drug: Lamotrigine

Interventions

AG-881 DRUG

Supplied as uncoated tablets.

AG-881 (Group 1); AG-881 (Group 2); AG-881 (Group 3)

Lamotrigine DRUG

Supplied as tablets of LAMICTAL® or generic equivalent.

Also known as: LAMICTAL®

AG-881 (Group 1); AG-881 (Group 2); AG-881 (Group 3)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy, adult, male or female participants, 18-55 years of age, inclusive, at screening;
• Continuous non-smoker who has not used nicotine-containing products for at least 3 months prior to the first dosing and throughout the study, based on participant self-reporting;
• Body mass index (BMI) ≥ 18.0 and ≤ 32.0 kilograms per square meter (kg/m\^2) at screening;
• Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs or electrocardiograms (ECG), as deemed by the principal investigator or designee;
• Liver function tests (serum alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], alkaline phosphatase \[ALP\], and bilirubin \[total and direct\]) must be ≤ the upper limit of normal;
• Female participants must be of non-childbearing potential defined as a female who has undergone one of the following sterilization procedures at least 6 months prior to the first dosing:
• hysteroscopic sterilization;
• bilateral tubal ligation or bilateral salpingectomy;
• hysterectomy;
• bilateral oophorectomy;
• or is postmenopausal with amenorrhea for at least 1 year prior to the first dosing and follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status;
• A non-vasectomized, male participant must agree to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days after the last dosing. (No restrictions are required for a vasectomized male provided his vasectomy has been performed 4 months or more prior to the first dosing of study drug. A male who has been vasectomized less than 4 months prior to study first dosing must follow the same restrictions as a non-vasectomized male);
• If a male participant, must agree not to donate sperm from the first dosing until 90 days after the last dosing;
• Understands the study procedures in the informed consent form (ICF), and be willing and able to comply with the protocol.

You may not qualify if:

• Participant is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study;
• History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the principal investigator or designee;
• History of any illness that, in the opinion of the principal investigator or designee, might confound the results of the study or pose an additional risk to the participant (e.g., history or presence of rashes) by their participation in the study;
• History or presence of ventricular dysfunction or risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, cardiomyopathy, family history of Long QT Syndrome), in the opinion of the principal investigator or designee;
• History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing;
• History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds;
• Known medical history of progressive multifocal leukoencephalopathy;
• Presence of an active skin rash;
• Any positive responses on the Columbia-suicide severity rating scale (C-SSRS);
• Female participants of childbearing potential;
• Female participants with a positive pregnancy test or who are lactating;
• Positive urine drug or alcohol results at screening or first check-in;
• Positive results at screening for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies;
• Corrected QT interval by Fridericia (QTcF) is \>450 milliseconds (msec), or Q wave, R wave, and S wave complex (QRS) interval \>110 msec, or P wave to the start of the QRS complex (PR interval) \>220 msec or participants who have ECG findings deemed abnormal with clinical significance by the principal investigator or designee at screening;
• Estimated creatinine clearance \<90 millimeters per minute (mL/min) at screening;

Sponsors & Collaborators

• Agios Pharmaceuticals, Inc.: lead

Study Sites (1)

Celerion, Inc

Tempe, Arizona, 85283, United States

Location

MeSH Terms

Interventions

Lamotrigine

Intervention Hierarchy (Ancestors)

Triazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Medical Affairs

  Agios Pharmaceuticals, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 3, 2019
• First Posted: July 11, 2019
• Study Start: July 15, 2019
• Primary Completion: October 9, 2019
• Study Completion: October 9, 2019
• Last Updated: October 14, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)