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Study Comparing Pharmacokinetics of Different Formulations of Evobrutinib in Healthy Participants

Sponsor
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany (Industry)
Overall Status
Recruiting
CT.gov ID
NCT05245396
Collaborator
Merck KGaA, Darmstadt, Germany (Industry)
48
Enrollment
1
Location
12
Arms
5.9
Anticipated Duration (Months)
8.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety and tolerability of evobrutinib after oral administration of immediate release (IR) and modified release (MR) formulations in healthy participants.

Condition or Disease Intervention/Treatment Phase
  • Drug: Ref (TF2)
  • Drug: Evobrutinib MR-T1
  • Drug: Evobrutinib MR-T2
  • Drug: Evobrutinib MR-T3
  • Drug: Evobrutinib MR-T4
  • Drug: Evobrutinib MUPS-C1
  • Drug: Evobrutinib MUPS-C2
  • Drug: Evobrutinib MUPS-C3
  • Drug: Evobrutinib MUPS-C4
 Phase 1

Study Design

Study Type:
Interventional
Anticipated Enrollment :
48 participants
Allocation:
Randomized
Intervention Model:
Sequential Assignment
Intervention Model Description:
Part A and B, periods 1 to 3 are incomplete cross-over; Part A and B, periods 4 and 5 are sequential.Part A and B, periods 1 to 3 are incomplete cross-over; Part A and B, periods 4 and 5 are sequential.
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I, Single-site, Open-label, Partially Randomized Study to Evaluate the Relative Bioavailability and Pharmacokinetics of Evobrutinib Following Administration of Different Formulations in Healthy Participants
Actual Study Start Date :
Feb 2, 2022
Anticipated Primary Completion Date :
Aug 2, 2022
Anticipated Study Completion Date :
Aug 2, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Part A: Evobrutinib: Treatment Sequence 1

Participants will receive single oral dose of modified release evobrutinib tablet-1 (MR-T1) on Day 1 in treatment period 1, followed by single oral dose of modified release tablet-2 (MR-T2) on Day 1 in treatment period 2, followed by two single oral doses of immediate release (IR) oral tablet [Ref (TF2)] on Day 1 in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or multiparticulate system capsules (MUPS-C) formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5.

Drug: Ref (TF2)
Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, and 3 of Part A and B.
Other Names:
  • M2951

    • Drug: Evobrutinib MR-T1
    Participants will receive single oral dose of MR-T1 on Day 1 in treatment period 1, 2, and 3 of Part A.
    Other Names:
  • M2951

    • Drug: Evobrutinib MR-T2
    Participants will receive single oral dose of MR-T2 on Day 1 in treatment period 1, 2, and 3 of Part A.
    Other Names:
  • M2951

    		•
    Experimental: Part A: Evobrutinib: Treatment Sequence 2

    Participants will receive single oral dose of MR-T2 on Day 1 in treatment period 1, followed by two single oral doses of Ref (TF2) on Day 1 in treatment period 2, followed by single oral dose of MR-T1 on Day 1 in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5.

    Drug: Ref (TF2)
    Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, and 3 of Part A and B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MR-T1
    Participants will receive single oral dose of MR-T1 on Day 1 in treatment period 1, 2, and 3 of Part A.
    Other Names:
  • M2951

    • Drug: Evobrutinib MR-T2
    Participants will receive single oral dose of MR-T2 on Day 1 in treatment period 1, 2, and 3 of Part A.
    Other Names:
  • M2951

    		•
    Experimental: Part A: Evobrutinib: Treatment Sequence 3

    Participants will receive two single oral doses of Ref (TF2) on Day 1 in treatment period 1, followed by single oral dose of MR-T1 on Day 1 in treatment period 2, followed by single oral dose of MR-T2 on Day 1 in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5.

    Drug: Ref (TF2)
    Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, and 3 of Part A and B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MR-T1
    Participants will receive single oral dose of MR-T1 on Day 1 in treatment period 1, 2, and 3 of Part A.
    Other Names:
  • M2951

    • Drug: Evobrutinib MR-T2
    Participants will receive single oral dose of MR-T2 on Day 1 in treatment period 1, 2, and 3 of Part A.
    Other Names:
  • M2951

    		•
    Experimental: Part A: Evobrutinib: Treatment Sequence 4

    Participants will receive single oral dose of modified release evobrutinib tablet-3 (MR-T3) on Day 1 in treatment period 1, followed by single oral dose of modified release tablet-4 (MR-T4) on Day 1 in treatment period 2, followed by two single oral doses of immediate release (IR) oral tablet [Ref (TF2)] on Day 1 in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or multiparticulate system capsules (MUPS-C) formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5.

    Drug: Ref (TF2)
    Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, and 3 of Part A and B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MR-T3
    Participants will receive single oral dose of MR-T3 on Day 1 in treatment period 1, 2, and 3 of Part A.
    Other Names:
  • M2951

    • Drug: Evobrutinib MR-T4
    Participants will receive single oral dose of MR-T4 on Day 1 in treatment period 1, 2, and 3 of Part A.
    Other Names:
  • M2951

    		•
    Experimental: Part A: Evobrutinib: Treatment Sequence 5

    Participants will receive single oral dose of MR-T4 on Day 1 in treatment period 1, followed by two single oral doses of Ref (TF2) on Day 1 in treatment period 2, followed by single oral dose of MR-T3 on Day 1 in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5.

    Drug: Ref (TF2)
    Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, and 3 of Part A and B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MR-T3
    Participants will receive single oral dose of MR-T3 on Day 1 in treatment period 1, 2, and 3 of Part A.
    Other Names:
  • M2951

    • Drug: Evobrutinib MR-T4
    Participants will receive single oral dose of MR-T4 on Day 1 in treatment period 1, 2, and 3 of Part A.
    Other Names:
  • M2951

    		•
    Experimental: Part A: Evobrutinib: Treatment Sequence 6

    Participants will receive two single oral doses of Ref (TF2) on Day 1 in treatment period 1, followed by single oral dose of MR-T3 on Day 1 in treatment period 2, followed by single oral dose of MR-T4 on Day 1 in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5.

    Drug: Ref (TF2)
    Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, and 3 of Part A and B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MR-T3
    Participants will receive single oral dose of MR-T3 on Day 1 in treatment period 1, 2, and 3 of Part A.
    Other Names:
  • M2951

    • Drug: Evobrutinib MR-T4
    Participants will receive single oral dose of MR-T4 on Day 1 in treatment period 1, 2, and 3 of Part A.
    Other Names:
  • M2951

    		•
    Experimental: Part B: Evobrutinib: Treatment Sequence 1

    Participants will receive single oral dose of MUPS-C1 evobrutinib on Day 1 in treatment period 1, followed by single oral dose of MUPS-C2 on Day 1 in treatment period 2, followed by two single oral doses of Ref (TF2) on Day 1 of in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5.

    Drug: Ref (TF2)
    Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, and 3 of Part A and B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MUPS-C1
    Participants will receive single oral dose of MUPS-C1 on Day 1 in treatment period 1, 2, and 3 of Part B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MUPS-C2
    Participants will receive single oral dose of MUPS-C2 on Day 1 in treatment period 1, 2, and 3 of Part B.
    Other Names:
  • M2951

    		•
    Experimental: Part B: Evobrutinib: Treatment Sequence 2

    Participants will receive single oral dose of MUPS-C2 evobrutinib on Day 1 in treatment period 1, followed by two single oral doses of Ref (TF2) on Day 1 in treatment period 2, followed by single oral dose of MUPS-C2 on Day 1 of in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5.

    Drug: Ref (TF2)
    Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, and 3 of Part A and B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MUPS-C1
    Participants will receive single oral dose of MUPS-C1 on Day 1 in treatment period 1, 2, and 3 of Part B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MUPS-C2
    Participants will receive single oral dose of MUPS-C2 on Day 1 in treatment period 1, 2, and 3 of Part B.
    Other Names:
  • M2951

    		•
    Experimental: Part B: Evobrutinib: Treatment Sequence 3

    Participants will receive two single oral doses of Ref (TF2) evobrutinib on Day 1 in treatment period 1, followed by single oral dose of MUPS-C1 on Day 1 in treatment period 2, followed by single oral dose of MUPS-C2 on Day 1 of in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5.

    Drug: Ref (TF2)
    Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, and 3 of Part A and B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MUPS-C1
    Participants will receive single oral dose of MUPS-C1 on Day 1 in treatment period 1, 2, and 3 of Part B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MUPS-C2
    Participants will receive single oral dose of MUPS-C2 on Day 1 in treatment period 1, 2, and 3 of Part B.
    Other Names:
  • M2951

    		•
    Experimental: Part B: Evobrutinib: Treatment Sequence 4

    Participants will receive single oral dose of MUPS-C3 evobrutinib on Day 1 in treatment period 1, followed by single oral dose of MUPS-C4 on Day 1 in treatment period 2, followed by two single oral doses of Ref (TF2) on Day 1 of in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5.

    Drug: Ref (TF2)
    Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, and 3 of Part A and B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MUPS-C3
    Participants will receive single oral dose of MUPS-C3 on Day 1 in treatment period 1, 2, and 3 of Part B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MUPS-C4
    Participants will receive single oral dose of MUPS-C4 on Day 1 in treatment period 1, 2, and 3 of Part B.
    Other Names:
  • M2951

    		•
    Experimental: Part B: Evobrutinib: Treatment Sequence 5

    Participants will receive single oral dose of MUPS-C4 evobrutinib on Day 1 in treatment period 1, followed by two single oral doses of Ref (TF2) on Day 1 in treatment period 2, followed by single oral dose of MUPS-C3 on Day 1 of in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5.

    Drug: Ref (TF2)
    Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, and 3 of Part A and B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MUPS-C3
    Participants will receive single oral dose of MUPS-C3 on Day 1 in treatment period 1, 2, and 3 of Part B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MUPS-C4
    Participants will receive single oral dose of MUPS-C4 on Day 1 in treatment period 1, 2, and 3 of Part B.
    Other Names:
  • M2951

    		•
    Experimental: Part B: Evobrutinib: Treatment Sequence 6

    Participants will receive two single oral doses of Ref (TF2) evobrutinib on Day 1 in treatment period 1, followed by single oral dose of MUPS-C3 on Day 1 in treatment period 2, followed by single oral dose of MUPS-C4 on Day 1 of in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5.

    Drug: Ref (TF2)
    Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, and 3 of Part A and B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MUPS-C3
    Participants will receive single oral dose of MUPS-C3 on Day 1 in treatment period 1, 2, and 3 of Part B.
    Other Names:
  • M2951

    • Drug: Evobrutinib MUPS-C4
    Participants will receive single oral dose of MUPS-C4 on Day 1 in treatment period 1, 2, and 3 of Part B.
    Other Names:
  • M2951

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Relative Bioavailability Based on Area Under the Plasma Concentration Curve From Time Zero to 24 Hours Post Dose [Frel(AUC0-24)] of Evobrutinib Modified-Release Formulation Compared to Immediate-Release Evobrutinib Reference Formulation [Pre-dose up to 72 hours post-dose on Day 4]

    2. Relative Bioavailability Based on Area Under the Plasma Concentration Curve From Time Zero to Infinity [Frel(AUC0-inf)] of Evobrutinib Modified-Release Formulation Compared to Immediate-Release Evobrutinib Reference Formulation [Pre-dose up to 72 hours post-dose on Day 4]

    Secondary Outcome Measures

    1. Number of Participants with Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), Abnormal Laboratory Test Results, Abnormal Vital Signs and Abnormal Electrocardiogram (ECG) Measurements [Up to Day 123]

    2. Pharmacokinetic Plasma Concentration of Evobrutinib Formulations [Pre-dose up to 72 hours post-dose on Day 4]

    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 comprehensive clinical assessment (detailed medical history and a complete physical examination), ECG, and laboratory investigations (hematology and biochemistry)

    • Participants have a body weight within 50.0 to 100.0 kilogram (kg) and body mass index (BMI) within the range 19 to 32 kilogram per meter square (kg/m^2) (inclusive)

    • Other protocol defined inclusion criteria could apply

    Exclusion Criteria:

    • Participants with history or presence of clinically relevant respiratory, gastrointestinal, renal, hepatic, metabolic, hematological, lymphatic, neurological (including epilepsy), cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, connective tissue diseases or disorders, as determined by medical evaluation

    • Participants with history of any malignancy

    • Administration of live vaccines or live-attenuated virus vaccines within 3 months prior to Screening. Administration of other types of vaccines (e.g. SARS-CoV-2 vaccines) is allowed until 2 weeks before the admission to the CRU

    • Medical history and physical examination results that include any ongoing clinically relevant findings as judged by the Investigator

    • Moderate or strong inhibitors or inducers of CYP3A4/5 or Pgp within 4 weeks prior to the first administration of study intervention

    • Other protocol-defined exclusion criteria could apply

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Quotient Clinical Ltd Nottingham United Kingdom NG11

    Sponsors and Collaborators

    • Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
    • 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:
    NCT05245396
    Other Study ID Numbers:
    • MS200527_0091
    • 2021-005056-11
    First Posted:
    Feb 18, 2022
    Last Update Posted:
    Jul 12, 2022
    Last Verified:
    Jul 1, 2022
    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
    Bruton's tyrosine kinase
    delayed release
    multiparticulate

    Study Results

    No Results Posted as of Jul 12, 2022