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

Healthy Volunteers Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05532358
• Other study ID #: anle138b-P1-03
• Secondary ID: 2022-002467-30
• Status: Completed
• Phase: Phase 1
• Start date: September 12, 2022
• Est. completion date: February 10, 2023

Study information

• Verified date: March 2023
• Source: MODAG GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: February 10, 2023
• Est. primary completion date: January 28, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy Volunteers

Intervention

Drug:
• anle138b (TEV-56286)
Anle138b (TEV-56286) as perpetrator
• Fluvoxamine 100 mg QD for 5 days
Anle138b (TEV-56286) as victim

Locations

Country	Name	City	State
United Kingdom	Quotient Sciences	Nottingham

Sponsors (4)

Lead Sponsor	Collaborator
MODAG GmbH	Aptuit, Quotient Sciences, Teva Pharmaceutical Industries, Ltd.

Country where clinical trial is conducted

United Kingdom, 

References & Publications (4)

Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry. US Food and Drug Administration. 07 Jul 2020. Available online: https://www.fda.gov/regulatoryinformation/search-fda-guidance-documents/clinical-drug-interaction-studiescytochrome-p450-enzyme-and-transporter-mediated-drug-interactions (accessed 23 Jun 2022).

Drug Interaction Studies M12. ICH Harmonised Guideline. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Draft version endorsed on 24 May 2022.

Levin J, Sing N, Melbourne S, Morgan A, Mariner C, Spillantini MG, Wegrzynowicz M, Dalley JW, Langer S, Ryazanov S, Leonov A, Griesinger C, Schmidt F, Weckbecker D, Prager K, Matthias T, Giese A. Safety, tolerability and pharmacokinetics of the oligomer modulator anle138b with exposure levels sufficient for therapeutic efficacy in a murine Parkinson model: A randomised, double-blind, placebo-controlled phase 1a trial. EBioMedicine. 2022 Jun;80:104021. doi: 10.1016/j.ebiom.2022.104021. Epub 2022 Apr 29. — View Citation

Wagner J, Ryazanov S, Leonov A, Levin J, Shi S, Schmidt F, Prix C, Pan-Montojo F, Bertsch U, Mitteregger-Kretzschmar G, Geissen M, Eiden M, Leidel F, Hirschberger T, Deeg AA, Krauth JJ, Zinth W, Tavan P, Pilger J, Zweckstetter M, Frank T, Bahr M, Weishaupt JH, Uhr M, Urlaub H, Teichmann U, Samwer M, Botzel K, Groschup M, Kretzschmar H, Griesinger C, Giese A. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease. Acta Neuropathol. 2013 Jun;125(6):795-813. doi: 10.1007/s00401-013-1114-9. Epub 2013 Apr 19. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	Oral pharmacokinetics (PK) of substrates caffeine and midazolam	PK parameter: Tmax	Day 1, Day 3, Day 18
Secondary	Oral pharmacokinetics (PK) of substrates caffeine and midazolam	PK parameter: Tlag	Day 1, Day 3, Day 18
Secondary	Oral pharmacokinetics (PK) of substrates caffeine and midazolam	PK parameter: lambda-z	Day 1, Day 3, Day 18
Secondary	Oral pharmacokinetics (PK) of substrates caffeine and midazolam	PK parameter: T1/2	Day 1, Day 3, Day 18
Secondary	Oral pharmacokinetics (PK) of substrates caffeine and midazolam	PK parameter: CL/F	Day 1, Day 3, Day 18
Secondary	Oral pharmacokinetics (PK) of substrates caffeine and midazolam	PK parameter: Vz/F	Day 1, Day 3, Day 18
Secondary	Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine	PK parameter: Tmax	Day 19
Secondary	Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine	PK parameter: lambda-z	Day 19
Secondary	Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine	PK parameter: T1/2	Day 19
Secondary	Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine	PK parameter: CL/F	Day 19
Secondary	Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine	PK parameter: Vz/F	Day 19
Secondary	Oral pharmacokinetics (PK) of TEV-56286 as perpetrator drug after co-administration with caffeine and midazolam	PK parameter: Tmax	Day 3
Secondary	Oral pharmacokinetics (PK) of TEV-56286 as perpetrator drug after co-administration with caffeine and midazolam	PK parameter: Cmax	Day 3
Secondary	Oral pharmacokinetics (PK) of TEV-56286 as perpetrator drug after co-administration with caffeine and midazolam	PK parameter: AUC (0-last)	Day 3
Secondary	Oral pharmacokinetics (PK) of TEV-56286	PK parameter: Trough concentration for TEV-56286	Day 3-18
Secondary	Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam	PK parameter: Tmax	Day 18
Secondary	Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam	PK parameter: Cmax	Day 18
Secondary	Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam	PK parameter: Cmin	Day 18
Secondary	Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam	PK parameter: Cavg	Day 18
Secondary	Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam	PK parameter: AUC (0-tau)	Day 18
Secondary	Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam	PK parameter: AUC (0-last)	Day 18
Secondary	Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286	PK parameter: Tmax	Day 19
Secondary	Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286	PK parameter: Cmax	Day 19
Secondary	Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286	PK parameter: Cmin	Day 19
Secondary	Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286	PK parameter: Cavg	Day 19
Secondary	Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286	PK parameter: AUC (0-tau)	Day 19
Secondary	Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286	PK parameter: AUC (0-last)	Day 19
Secondary	Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286	PK parameter: Trough concentration for fluvoxamine	Day 15-19
Secondary	Oral pharmacokinetics (PK) of TEV-56286 after first dose administered as part of repeated administration	PK parameter: Tlag for TEV-56286	Day 1
Secondary	Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose	PK parameter: Tmax	Day 1, Day 14
Secondary	Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose	PK parameter: Cmax	Day 1, Day 14
Secondary	Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose	PK parameter: AUC (0-tau)	Day 1, Day 14
Secondary	Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose	PK parameter: lambda-z	Day 1, Day 14
Secondary	Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose	PK parameter: T1/2	Day 1, Day 14
Secondary	Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose	PK parameter: CL/F	Day 1, Day 14
Secondary	Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose	PK parameter: Vz/F	Day 1, Day 14
Secondary	Oral pharmacokinetics (PK) of TEV-56286 following multiple dose	PK parameter: AUC (0-last)	Day 14
Secondary	Oral pharmacokinetics (PK) of TEV-56286 following multiple dose	PK parameter: Cmin	Day 14
Secondary	Oral pharmacokinetics (PK) of TEV-56286 following multiple dose	PK parameter: Cavg	Day 14
Secondary	Oral pharmacokinetics (PK) of TEV-56286 following multiple dose	PK parameter: Accumulation ratio	Day 14
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	Columbia-Suicide Severity Rating Scale (C-SSRS) total score	Columbia-Suicide Severity Rating Scale (C-SSRS) total score	Day 3 to day 21

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