Drug-Drug Interaction Study of Evobrutinib and Transporter Substrates

Sponsor
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany (Industry)
Overall Status
Recruiting
CT.gov ID
NCT05064488
Collaborator
(none)
40
Enrollment
1
Location
2
Arms
1.5
Anticipated Duration (Months)
26.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study consists of 2 parts: Part 1 and 2. The purpose of this study is to evaluate the pharmacokinetic, safety and tolerability of multiple doses of evobrutinib on single doses of digoxin, metformin and rosuvastatin in Part-1 and sumatriptan in Part-2 of the study.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
40 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I, Open-Label, Two-Part Study of the Effect of Multiple-Dose Evobrutinib on Transporter Substrates Digoxin, Metformin, Rosuvastatin, and Sumatriptan Pharmacokinetics in Healthy Participants
Actual Study Start Date :
Oct 4, 2021
Anticipated Primary Completion Date :
Nov 19, 2021
Anticipated Study Completion Date :
Nov 19, 2021

Arms and Interventions

ArmIntervention/Treatment
Experimental: Part-1: Evobrutinib + Digoxin + Metformin + Rosuvastatin

Drug: Evobrutinib
Participants will receive evobrutinib film-coated tablet, twice daily under fed conditions from Days 4 to 12 in Part 1 and from Days 2 to 8 in Part 2 of the study.
Other Names:
  • M2951
  • Drug: Digoxin
    Participants will receive digoxin tablet under fed conditions, once a day on Day 1 and Day 10 in Part 1.

    Drug: Metformin
    Participants will receive metformin oral solution under fed conditions, once a day on Day 1 and Day 10 in Part 1.

    Drug: Rosuvastatin
    Participants will receive rosuvastatin tablet under fed conditions, once a day on Day 1 and Day 10 in Part 1.

    Experimental: Part-2: Evobrutinib + Sumatriptan

    Drug: Evobrutinib
    Participants will receive evobrutinib film-coated tablet, twice daily under fed conditions from Days 4 to 12 in Part 1 and from Days 2 to 8 in Part 2 of the study.
    Other Names:
  • M2951
  • Drug: Sumatriptan
    Participants will receive sumatriptan tablet under fed conditions, once a day on Day 1 and Day 8 in Part 2.

    Outcome Measures

    Primary Outcome Measures

    1. Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Transporter Cocktail [Pre-dose through 16 hours post-dose on Days 1 and 10; 24, 36 hours post-dose on Day 2 and Day 11; 48, 60 hours post-dose on Day 3 and Day 12; 72 hours post-dose on Day 4 and Day 13]

      The transporter cocktail includes digoxin, metformin, and rosuvastatin.

    2. Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Evobrutinib [Day 10, 11 and 12: 1 hours post-dose]

    3. Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Sumatriptan [Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9]

    4. Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Evobrutinib [Day 6, 7 and 8: 1 hours post-dose]

    5. Part 1: Maximum Observed Plasma Concentration (Cmax) of Transporter Cocktail [Pre-dose through 16 hours post-dose on Days 1 and 10; 24, 36 hours post-dose on Day 2 and Day 11; 48, 60 hours post-dose on Day 3 and Day 12; 72 hours post-dose on Day 4 and Day 13]

    6. Part 1: Maximum Observed Plasma Concentration (Cmax) of Evobrutinib [Day 10, 11 and 12: 1 hours post-dose]

    7. Part 2: Maximum Observed Plasma Concentration (Cmax) of Sumatriptan [Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9]

    8. Part 2: Maximum Observed Plasma Concentration (Cmax) of Evobrutinib [Day 6, 7 and 8: 1 hours post-dose]

    Secondary Outcome Measures

    1. Part 1 and Part 2: Number of Participants with Treatment Emergent Adverse Events (TEAEs) [Part 1: Up to Day 13; Part 2: Up to Day 9]

    2. Part 1 and Part 2: Number of Participants with Treatment Emergent Adverse Events (TEAEs) by Severity [Part 1: Up to Day 13; Part 2: Up to Day 9]

    3. Part 1 and Part 2: Number of Participants With Abnormal Changes From Baseline in Laboratory Parameters, Vital Signs and 12-Lead Electrocardiogram (ECG) Findings [Part 1: Baseline up to Day 13; Part 2: Baseline up to Day 9]

      Number of participants with abnormal changes from baseline in laboratory parameters, vital signs and 12-Lead electrocardiogram (ECG) findings will be reported.

    4. Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Transporter Cocktail [Pre-dose through 16 hours post-dose on Days 1 and 10; 24, 36 hours post-dose on Day 2 and Day 11; 48, 60 hours post-dose on Day 3 and Day 12; 72 hours post-dose on Day 4 and Day 13]

    5. Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Evobrutinib [Day 10, 11 and 12: 1 hours post-dose]

    6. Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of Sumatriptan [Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9]

    7. Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of Evobrutinib [Day 6, 7 and 8: 1 hours post-dose]

    8. Part 1: Apparent Terminal Half-Life (t1/2) of Transporter Cocktail [Pre-dose through 16 hours post-dose on Days 1 and 10; 24, 36 hours post-dose on Day 2 and Day 11; 48, 60 hours post-dose on Day 3 and Day 12; 72 hours post-dose on Day 4 and Day 13]

    9. Part 1: Apparent Terminal Half-Life (t1/2) of Evobrutinib [Day 10, 11 and 12: 1 hours post-dose]

    10. Part 2: Apparent Terminal Half-Life (t1/2) of Sumatriptan [Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9]

    11. Part 2: Apparent Terminal Half-Life (t1/2) of Evobrutinib [Day 6, 7 and 8: 1 hours post-dose]

    12. Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Transporter Cocktail [Pre-dose through 16 hours post-dose on Days 1 and 10; 24, 36 hours post-dose on Day 2 and Day 11; 48, 60 hours post-dose on Day 3 and Day 12; 72 hours post-dose on Day 4 and Day 13]

    13. Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Evobrutinib [Day 10, 11 and 12: 1 hours post-dose]

    14. Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Sumatriptan [Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9]

    15. Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Evobrutinib [Day 6, 7 and 8: 1 hours post-dose]

    16. Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Transporter Cocktail [Pre-dose through 16 hours post-dose on Days 1 and 10; 24, 36 hours post-dose on Day 2 and Day 11; 48, 60 hours post-dose on Day 3 and Day 12; 72 hours post-dose on Day 4 and Day 13]

    17. Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Evobrutinib [Day 10, 11 and 12: 1 hours post-dose]

    18. Part 2: Apparent Total Body Clearance From Plasma (CL/F) of Sumatriptan [Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9]

    19. Part 2: Apparent Total Body Clearance From Plasma (CL/F) of Evobrutinib [Day 6, 7 and 8: 1 hours post-dose]

    20. Part 1: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Transporter Cocktail [Pre-dose through 16 hours post-dose on Days 1 and 10; 24, 36 hours post-dose on Day 2 and Day 11; 48, 60 hours post-dose on Day 3 and Day 12; 72 hours post-dose on Day 4 and Day 13]

    21. Part 1: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Evobrutinib [Day 10, 11 and 12: 1 hours post-dose]

    22. Part 2: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Sumatriptan [Pre-dose through 16 hours post-dose on Days 1 and Day 8; 24 hours post-dose on Day 2 and Day 9]

    23. Part 2: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Evobrutinib [Day 6, 7 and 8: 1 hours post-dose]

    24. Part 1: Cumulative Amount Excreted From Time Zero to the End of the Collection Interval After Dosing Dosing (Ae0-36) of Merformin [Pre-dose, 0 to 4, 4 to 8, 8 to 12 hours post-dose on Day 1 and Day 10; 12 to 24, 24 to 36 hours post-dose on Day 2 and Day 11]

    25. Part 1: Renal Clearance (CLR) of Metformin [Pre-dose, 0 to 4, 4 to 8, 8 to 12 hours post-dose on Day 1 and Day 10; 12 to 24, 24 to 36 hours post-dose on Day 2 and Day 11]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 55 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:
    • Participants are overtly healthy as determined by medical evaluation, including no clinically significant abnormality identified on physical examination or laboratory evaluation and no active clinically significant disorder, condition, infection or disease that would pose a risk to participant safety or interfere with the study evaluation, procedures, or completion

    • Participants have a body weight within 50.0 and 100.0 kilograms [kg] (inclusive) and body mass index within the range of 19.0 and 30.0 kilograms per square meter [kg/m^2] (inclusive)

    • Other protocol defined inclusion criteria could apply

    Exclusion Criteria:
    • History or presence of clinically relevant respiratory, gastrointestinal, renal, hepatic, hematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, connective tissue diseases or disorders, as determined by medical evaluation

    • Individuals with diagnosis of hemochromatosis, Wilson´s disease, alpha 1 antitrypsin deficiency, or any other chronic liver disease including Gilbert's disease will be excluded from the study

    • Prior history of cholecystectomy or splenectomy, and any clinically relevant surgery within 6 months prior to Screening

    • History of any malignancy

    • History of chronic or recurrent acute infection or any bacterial, viral, parasitic or fungal infections within 30 days prior to Screening and at any time between Screening and admission, or hospitalization due to infection within 6 months prior to Screening

    • History of shingles within 12 months prior to Screening

    • History of drug hypersensitivity, ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or formulation ingredients; history of serious allergic reactions leading to hospitalization or any other hypersensitivity reaction in general, which may affect the safety of the participant and/or outcome of the study per the Investigator's discretion

    • History of alcoholism or drug abuse within 2 years prior to Screening, or positive for drugs of abuse, nicotine/cotinine or alcohol by the laboratory assays conducted during Screening and Day -1

    • History of residential exposure to tuberculosis, or a positive QuantiFERON® test within 4 weeks prior to or at the time of Screening

    • Administration of live vaccines or live-attenuated virus vaccines within 3 months prior to Screening

    • Moderate or strong inhibitors or inducers of Cytochrome P450, family 3, subfamily A (CYP3A4/5) within 4 weeks prior to the first administration of study intervention

    • Other protocol defined exclusion criteria could apply

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Nuvisan GmbHNeu-UlmGermany89231

    Sponsors and Collaborators

    • Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

    Investigators

    • Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
    ClinicalTrials.gov Identifier:
    NCT05064488
    Other Study ID Numbers:
    • MS200527_0078
    • 2021-001923-42
    First Posted:
    Oct 1, 2021
    Last Update Posted:
    Nov 18, 2021
    Last Verified:
    Nov 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Nov 18, 2021