A Drug-Drug Interaction Study to Assess the CYP1A2 and CYP3A4 Interaction Potential of TEV-56286 (anle138b)

Study Overview
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Brief Summary
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The purpose of this healthy volunteers drug-drug interaction study is to assess the CYP1A2 and CYP3A4 perpetrator interaction potential and CYP1A2 victim potential of TEV-56286 (anle138b).

Detailed Description
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This a 2-part DDI study that will assess the CYP1A2 and CYP3A4 perpetrator interaction potential of TEV-56286 single dose and multiple dose, using caffeine and midazolam as substrates and CYP1A2 victim potential of TEV-56286 (anle138b) at steady state induction using fluvoxamine as inhibitor [1,2].The estimated time from screening until the follow-up visit is approximately up to 8 weeks for each subjects.

Official Title
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An Open-Label, One-Sequence, Two-Part Drug-Drug Interaction Study in Healthy Volunteers to Assess the CYP1A2 and CYP3A4 Perpetrator Interaction Potential and CYP1A2 Victim Potential of TEV-56286 (anle138b)

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: anle138b (TEV-56286)
* Drug: Fluvoxamine 100 mg QD for 5 days


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males or healthy females of non-childbearing potential Must provide written informed consent for participation in the study and must be able to understand the study requirements Body mass index (BMI) 18.5 to 32.0 kg/m2. Must agree to adhere to the contraception requirements defined in the study protocol. Exclusion Criteria: Serious adverse reaction or serious hypersensitivity to any drug or formulation excipients e.g. fluvoxamine, caffeine, midazolam or benzodiazepines or any of its excipients, or a known drug hypersensitivity idiosyncratic reaction to TEV-56286, or one of its excipients History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, metabolic diseases or a history of any illness that, in the opinion of the investigator, might pose additional risk to the subject by participation in the study or confound the results of the study Acute infection and/or antibiotic treatment within 28 days of Day 1 Major trauma or surgery in the 2 months before screening or at any time between screening and Day 1, or surgery scheduled during the study or follow up period History of malignancy or treatment of malignancy in the last 5 years History of suicidal ideation with an intent and/or plan and behaviour based upon either clinical history or source documents Personal or family history of arrhythmia, sudden unexplained death at a young age (before 40 years) in a first-degree relative, or long QT syndrome, or a personal history of syncope or previous treatment for high blood pressure (BP). Abnormality of 12-lead ECG that may, in the opinion of the investigator, interfere with study participation Any procedure or disorder that may interfere with drug absorption, distribution, metabolism, or excretion Clinically significant abnormal clinical chemistry, haematology or urinalysis as judged by the investigator. Subjects who have received any IMP in a clinical research study within the 90 days prior to Day 1, or less than 5 elimination half-lives prior to Day 1, whichever is longer Subjects who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies in the 14 days before study medication administration or within 5 half-lives whichever is longer. Subjects who are taking, or have taken hormonal contraceptives (e.g., oral, patch, injectable or intrauterine device) hormone replacement therapy (HRT) or a long-acting injectable hormonal within 4 weeks prior to first dose of IMP Subjects who are taking, or have taken any inducer of CYP 1A2, CYP3A4 within 28 days prior to Day -2 History of any drug or alcohol abuse in the past 2 years Current smokers and those who have smoked within the last 12 months or has a positive urine cotinine test Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months Subjects with a previous history of difficulty in swallowing tablets or capsules, or an anticipated problem with swallowing a large number of capsules Subjects who have consumed grapefruit, grapefruit juice, Seville oranges, pomelo-containing products, vegetables from the mustard green family (e.g., kale, broccoli, watercress, collard greens, kohlrabi, brussel sprouts, and mustard) and charbroiled meats within the 14 days prior to Day -2 Subjects who are unwilling to comply with the restricted use of caffeinated beverages (e.g. coffee, tea, cola) during the study

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: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Drug drug interaction study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: anle138b (TEV-56286) as perpetrator (part I)<br>Drug: TEV-56286 300 mg QD (single dose and multiple dose for 14 days) Victim drugs: Caffeine 200 mg Midazolam 2 mg | Drug: anle138b (TEV-56286)<br>* Anle138b (TEV-56286) as perpetrator<br>* Other names: Fluvoxamine;|
| Experimental: anle138b (TEV-56286) as victim (part II)<br>Drug: fluvoxamine 100 mg QD for 5 days Victim drug: TEV-56286 150 mg QD for 14 days + 5 days of co-administation with fluvoxamine | Drug: Fluvoxamine 100 mg QD for 5 days<br>* Anle138b (TEV-56286) as victim<br>* Other names: TEV-56286 150 mg QD for 14 days + 5 days of co-administation with fluvoxamine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oral pharmacokinetics (PK) of caffeine administered without TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: Cmax for caffeine. | Day 1 | 
| Oral pharmacokinetics (PK) of caffeine administered without TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: AUC(0-inf) for caffeine. | Day 1 | 
| Oral pharmacokinetics (PK) of caffeine administered without TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: AUC (0-last) for caffeine. | Day 1 | 
| Oral pharmacokinetics (PK) of midazolam administered without TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: Cmax for midazolam. | Day 1 | 
| Oral pharmacokinetics (PK) of midazolam administered without TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: AUC(0-inf) for midazolam. | Day 1 | 
| Oral pharmacokinetics (PK) of midazolam administered without TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: AUC (0-last) for midazolam. | Day 1 | 
| Oral pharmacokinetics (PK) of caffeine after single co-administration with TEV-56286 in healthy volunteers in the fasted state (Part I). | Cmax for caffeine. | Day 3 | 
| Oral pharmacokinetics (PK) of caffeine after single co-administration with TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: AUC(0-inf) for caffeine. | Day 3 | 
| Oral pharmacokinetics (PK) of caffeine after single co-administration with TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: AUC (0-last) for caffeine. | Day 3 | 
| Oral pharmacokinetics (PK) of midazolam after single co-administration with TEV-56286 in healthy volunteers in the fasted state (Part I). | Cmax for midazolam | Day 3 | 
| Oral pharmacokinetics (PK) of midazolam after single co-administration with TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: AUC(0-inf) for midazolam. | Day 3 | 
| Oral pharmacokinetics (PK) of midazolam after single co-administration with TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: AUC (0-last) for midazolam. | Day 3 | 
| Oral pharmacokinetics (PK) of caffeine after repeated administration of TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: Cmax for caffeine. | Day 18 | 
| Oral pharmacokinetics (PK) of caffeine after repeated administration of TEV-56286 in healthy volunteers in the fasted state (Part I). | AUC(0-inf) for caffeine. | Day 18 | 
| Oral pharmacokinetics (PK) of caffeine after repeated administration of TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: AUC (0-last) for caffeine. | Day 18 | 
| Oral pharmacokinetics (PK) of midazolam after repeated administration of TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: Cmax for midazolam. | Day 18 | 
| Oral pharmacokinetics (PK) of midazolam after repeated administration of TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: AUC(0-inf) for midazolam. | Day 18 | 
| Oral pharmacokinetics (PK) of midazolam after repeated administration of TEV-56286 in healthy volunteers in the fasted state (Part I). | PK parameter: AUC (0-last) for midazolam. | Day 18 | 
| Oral pharmacokinetics (PK) of TEV-56286 without fluvoxamine in healthy volunteers after repeated administration in the fasted state (Part II). | PK parameter: Cmax for TEV-56286. | Day 14 | 
| Oral pharmacokinetics (PK) of TEV-56286 without fluvoxamine in healthy volunteers after repeated administration in the fasted state (Part II). | PK parameter: AUC(0-tau) for TEV-56286. | Day 14 | 
| Oral pharmacokinetics (PK) of TEV-56286 in healthy volunteers after repeated co-administration with fluvoxamine in the fasted state. | PK parameter: Cmax for TEV-56286 (Part II). | Day 19 | 
| Oral pharmacokinetics (PK) of TEV-56286 in healthy volunteers after repeated co-administration with fluvoxamine in the fasted state. | PK parameter: AUC(0-tau) for TEV-56286 (Part II). | Day 19 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oral pharmacokinetics (PK) of substrates caffeine and midazolam | PK parameter: Tmax | Day 1, Day 3, Day 18 | 
| Oral pharmacokinetics (PK) of substrates caffeine and midazolam | PK parameter: Tlag | Day 1, Day 3, Day 18 | 
| Oral pharmacokinetics (PK) of substrates caffeine and midazolam | PK parameter: lambda-z | Day 1, Day 3, Day 18 | 
| Oral pharmacokinetics (PK) of substrates caffeine and midazolam | PK parameter: T1/2 | Day 1, Day 3, Day 18 | 
| Oral pharmacokinetics (PK) of substrates caffeine and midazolam | PK parameter: CL/F | Day 1, Day 3, Day 18 | 
| Oral pharmacokinetics (PK) of substrates caffeine and midazolam | PK parameter: Vz/F | Day 1, Day 3, Day 18 | 
| Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine | PK parameter: Tmax | Day 19 | 
| Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine | PK parameter: lambda-z | Day 19 | 
| Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine | PK parameter: T1/2 | Day 19 | 
| Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine | PK parameter: CL/F | Day 19 | 
| Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine | PK parameter: Vz/F | Day 19 | 
| Oral pharmacokinetics (PK) of TEV-56286 as perpetrator drug after co-administration with caffeine and midazolam | PK parameter: Tmax | Day 3 | 
| Oral pharmacokinetics (PK) of TEV-56286 as perpetrator drug after co-administration with caffeine and midazolam | PK parameter: Cmax | Day 3 | 
| Oral pharmacokinetics (PK) of TEV-56286 as perpetrator drug after co-administration with caffeine and midazolam | PK parameter: AUC (0-last) | Day 3 | 
| Oral pharmacokinetics (PK) of TEV-56286 | PK parameter: Trough concentration for TEV-56286 | Day 3-18 | 
| Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam | PK parameter: Tmax | Day 18 | 
| Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam | PK parameter: Cmax | Day 18 | 
| Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam | PK parameter: Cmin | Day 18 | 
| Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam | PK parameter: Cavg | Day 18 | 
| Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam | PK parameter: AUC (0-tau) | Day 18 | 
| Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam | PK parameter: AUC (0-last) | Day 18 | 
| Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286 | PK parameter: Tmax | Day 19 | 
| Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286 | PK parameter: Cmax | Day 19 | 
| Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286 | PK parameter: Cmin | Day 19 | 
| Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286 | PK parameter: Cavg | Day 19 | 
| Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286 | PK parameter: AUC (0-tau) | Day 19 | 
| Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286 | PK parameter: AUC (0-last) | Day 19 | 
| Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286 | PK parameter: Trough concentration for fluvoxamine | Day 15-19 | 
| Oral pharmacokinetics (PK) of TEV-56286 after first dose administered as part of repeated administration | PK parameter: Tlag for TEV-56286 | Day 1 | 
| Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose | PK parameter: Tmax | Day 1, Day 14 | 
| Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose | PK parameter: Cmax | Day 1, Day 14 | 
| Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose | PK parameter: AUC (0-tau) | Day 1, Day 14 | 
| Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose | PK parameter: lambda-z | Day 1, Day 14 | 
| Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose | PK parameter: T1/2 | Day 1, Day 14 | 
| Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose | PK parameter: CL/F | Day 1, Day 14 | 
| Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose | PK parameter: Vz/F | Day 1, Day 14 | 
| Oral pharmacokinetics (PK) of TEV-56286 following multiple dose | PK parameter: AUC (0-last) | Day 14 | 
| Oral pharmacokinetics (PK) of TEV-56286 following multiple dose | PK parameter: Cmin | Day 14 | 
| Oral pharmacokinetics (PK) of TEV-56286 following multiple dose | PK parameter: Cavg | Day 14 | 
| Oral pharmacokinetics (PK) of TEV-56286 following multiple dose | PK parameter: Accumulation ratio | Day 14 | 
| Oral pharmacokinetics (PK) of metabolites paraxanthine and 1-hydroxy midazolam after single administration of caffeine and midazolam | PK parameter: Tmax | Day 1, Day 3, Day 18 | 
| Oral pharmacokinetics (PK) of metabolites paraxanthine and 1-hydroxy midazolam after single administration of caffeine and midazolam | PK parameter: Cmax | Day 1, Day 3, Day 18 | 
| Oral pharmacokinetics (PK) of metabolites paraxanthine and 1-hydroxy midazolam after single administration of caffeine and midazolam | PK parameter: AUC (0-last) | Day 1, Day 3, Day 18 | 
| Oral pharmacokinetics (PK) of metabolites paraxanthine and 1-hydroxy midazolam after single administration of caffeine and midazolam | PK parameter: AUC (0-inf) | Day 1, Day 3, Day 18 | 
| Oral pharmacokinetics (PK) of metabolites paraxanthine and 1-hydroxy midazolam after single administration of caffeine and midazolam | PK parameter: lambda-z | Day 1, Day 3, Day 18 | 
| Oral pharmacokinetics (PK) of metabolites paraxanthine and 1-hydroxy midazolam after single administration of caffeine and midazolam | PK parameter: T1/2 | Day 1, Day 3, Day 18 | 
| Oral pharmacokinetics (PK) of metabolites paraxanthine and 1-hydroxy midazolam after single administration of caffeine and midazolam | PK parameter: parent: metabolite ratio | Day 1, Day 3, Day 18 | 
| Incidence of treatment-emergent adverse events including clinically significant changes in vital signs, ECGs and safety labs | adverse events and clinically significant changes in vital signs, ECGs and safety labs | Day 1 up to follow up visit (5-11 days post last TEV-56286 dose) | 
| Number of participants reporting use of concomitant medications | Number of participants reporting use of concomitant medications | Day 1 up to follow up visit (5-11 days post last TEV-56286 dose) | 
| Columbia-Suicide Severity Rating Scale (C-SSRS) total score | Columbia-Suicide Severity Rating Scale (C-SSRS) total score | Day 3 to day 21 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anle138b (TEV-56286), alpha-Synuclein, Oligomer modulator, Multiple System Atrophy, Parkinson Disease, Alzheimer Disease, Neurodegenerative diseases, Tauopathies, Amyloid, Drug-drug interaction