Clinical trial NCT05121714: Evaluation of the Potential CYP1A2-mediated Drug Drug Interaction Safety, and Tolerability of ABX464
Official title: A Two Part, Fixed-sequence, Open-label Crossover Study to Evaluate Potential CYP1A2-mediated Drug-drug Interactions of ABX464 in Healthy Subjects Using Caffeine and Fluvoxamine as Probe Drugs
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Abivax S.A.
Sponsor class: INDUSTRY
First posted: 2021-11-16
Enrollment: 59
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is a Phase 1, 2 part, fixed-sequence open-label, crossover study to evaluate the potential CYP1A2-mediated drug-drug interactions (DDI), safety, and tolerability of ABX464 combined with a known CYP1A2 substrate (caffeine) and a known CYP1A2 inhibitor (fluvoxamine). Sixty (60) healthy adult male and female subjects 18 to 55 years of age are planned to participate in the study. Separate cohorts of subjects will be enrolled for Part A (24 subjects) and Part B (36 subjects).
Primary purpose: PREVENTION

Brief summary: A two part, fixed-sequence, open-label crossover study to evaluate potential CYP1A2-mediated drug-drug interactions of ABX464 in healthy subjects using caffeine and fluvoxamine as probe drugs

Detailed description: This is a Phase 1, 2 part, fixed-sequence open-label, crossover study to evaluate the potential CYP1A2-mediated drug-drug interactions (DDI), safety, and tolerability of ABX464 combined with a known CYP1A2 substrate (caffeine) and a known CYP1A2 inhibitor (fluvoxamine). Sixty (60) healthy adult male and female subjects 18 to 55 years of age are planned to participate in the study. Separate cohorts of subjects will be enrolled for Part A (24 subjects) and Part B (36 subjects).

Eligibility criteria: Inclusion Criteria:

1. Healthy, male or female subject, between 18 and 55 years of age, inclusive.
2. Women of childbearing potential (WOCBP) and men receiving the study treatment and their partners must agree to use a highly effective contraceptive method during the study and for 6 months (180 days) after end of study or early termination.
3. Subject with a body mass index (BMI) of 18.5-30 kilogrammes per square metre (kg/m²).
4. No clinically significant history of previous allergy / sensitivity to ABX464 or any of the excipients within the IMP.
5. No clinically significant history of previous allergy / sensitivity to caffeine (for Part A) or fluvoxamine (for Part B), or any of the excipients contained within the Non-Investigational Medicinal Product (NIMP).
6. No clinically significant abnormal test results for serum biochemistry, haematology and/or urine analyses within 28 days before the first dose administration of the Investigational Medicinal Product (IMP)/NIMP.
7. Subject with a negative urinary drugs of abuse (DOA) screen (including alcohol and cotinine) test results, determined within 28 days before the first dose administration of the IMP (N.B.: A positive result may be repeated at the Investigator's discretion).
8. Subject with negative human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HBsAg)) and hepatitis C virus antibody (HCV Ab) results at Screening.
9. No known history of hypertension or abnormal vital signs at screening defined as supine systolic blood pressure (SBP) \< 90 or \> 140 millimetres of mercury (mmHg), and pulse rate \< 40 or \> 90 beats per minute (bpm).
10. No clinically significant abnormalities in 12-lead electrocardiogram (ECG) determined within 28 days before first dose of IMP including PR \> 220 milliseconds (ms) and QT interval corrected using Fridericia formula (QTcF) \>450 ms in males or \>470 ms in females, or evidence of clinically significant dysrhythmias (long QT features on ECG, left bundle branch block, or ventricular arrhythmia), atrial fibrillation or history of familial long QT syndromes (Note: partial right bundle branch block is acceptable).
11. Subject must be available to complete the study (including all follow up visits/phone call).
12. Subject must satisfy an Investigator about their fitness to participate in the study.
13. Subject must provide written informed consent to participate in the study

Exclusion Criteria:

1. Female subject who is pregnant, currently lactating or breastfeeding.
2. A clinically significant history of gastrointestinal disorder likely to influence IMP absorption.
3. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements, or any product known to interact with CYP1A2 within 28 days or 5 half-lives (whichever is longer) prior to the first dose of IMP.
4. Subject who has, or who have a relevant history of any clinically significant: neurological, gastrointestinal, renal, hepatic, cardiovascular, vascular, psychiatric, respiratory, metabolic, endocrine, or haematological conditions and/or other significant medical conditions including, without limitation, those pertaining to coronavirus disease 2019 (COVID-19) that, in the opinion of the Investigator or their appropriately qualified designee, would jeopardise the safety of the subject, safety of anyone involved in the study or impact on the validity of the study results.
5. A clinically significant history of drug or alcohol abuse (defined as the consumption of more than 14 units for male and female subjects) of alcohol a week) within the past two years.
6. Inability to communicate well with the Investigators (i.e., language problem, poor mental development or impaired cerebral function).
7. Participation in a New Chemical Entity (NCE) clinical study within 3 months or five half-lives, whichever is longer, or a marketed drug clinical study within 30 days or five half-lives, whichever is longer, before the first dose of IMP (Washout period between studies is defined as the period of time elapsed between the last dose of the previous study and the first dose of the next study).
8. Donation of 450 millilitres (mL) or more blood within the 3 months before the first dose of IMP.
9. Users of nicotine products i.e., current smokers or ex-smokers who have smoked within 6 months prior to first dose administration with the study medication or users of cigarette replacements (i.e., e-cigarettes, nicotine patches or gums).
10. Total serum bilirubin, alkaline phosphatase (ALP), aspartate transaminase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) and alanine transaminase (ALT) / Serum glutamic pyruvic transaminase (SGPT) \> 1.5 x upper limit of normal (ULN).
11. Experiences regular headaches (i.e., experiences headaches more than weekly).

    Part B Only:
12. Meets Diagnostic and Statistical Manual of Mental Disorders (5th Edition) criteria for moderate or severe substance use disorder within 6 months before Screening.
13. Reports having experienced suicidal ideation (Type 4 or 5 on the Columbia-Suicide Severity Rating Scale \[C-SSRS\]) within 30 days prior to Screening, any suicidal behaviour within 2 years prior to Screening (Any "Yes" answers on Suicidal Behaviour section of C-SSRS), and/or the Investigator assesses the subject to be a safety risk to him/herself or others;
14. Clinically significant history of depression or anxiety.

Primary outcomes:
measure: Part A Evaluate the potential for inhibition and/or induction of CYP1A2 in vivo based on the Peak Plasma Concentration (Cmax) of caffeine (a known CYP1A2 substrate) in the presence and absence of ABX464.
timeFrame: Day 1, Day 4 and Day 17
measure: Part A Evaluate the potential for inhibition and/or induction of CYP1A2 in vivo based on the Area under the plasma concentration versus time curve (AUC) of caffeine (a known CYP1A2 substrate) in the presence and absence of ABX464.
timeFrame: Day 1, Day 4 and Day 17
measure: Part B Evaluate whether ABX464 is a substrate for CYP1A2 in vivo based on Peak Plasma Concentration (Cmax) in the presence and absence of fluvoxamine.
timeFrame: Day 1 and Day11
measure: Part B Evaluate whether ABX464 is a substrate for CYP1A2 in vivo based on Area under the plasma concentration versus time curve (AUC) in the presence and absence of fluvoxamine.
timeFrame: Day 1 and Day 11
Secondary outcomes:
measure: Parts A & B • Evaluate the safety and tolerability of ABX464 alone and in the presence of caffeine or fluvoxamine
timeFrame: from baseline up to Day 25
Other outcomes:
Locations:
city: Merthyr Tydfil
country: United Kingdom
facility: Simbec-Orion
Study officials:
affiliation: Abivax S.A.
name: Paul Gineste
role: STUDY_DIRECTOR
References: