Study Comparing Pharmacokinetics of Different Formulations of Evobrutinib in Healthy Participants

NCT05245396 | Completed Phase 1

• 2 other identifiers: MS200527_00912021-005056-11
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy

Keywords

Bruton's tyrosine kinase; delayed release; multiparticulate

Outcome Measures

Primary Outcomes (2)

• 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

• 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 Outcomes (2)

• 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

• Pharmacokinetic Plasma Concentration of Evobrutinib Formulations

  Pre-dose up to 72 hours post-dose on Day 4

Study Arms (14)

Part A: Evobrutinib: Treatment Sequence 1

EXPERIMENTAL

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); Drug: Evobrutinib MR-T1; Drug: Evobrutinib MR-T2

Part A: Evobrutinib: Treatment Sequence 2

EXPERIMENTAL

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); Drug: Evobrutinib MR-T1; Drug: Evobrutinib MR-T2

Part A: Evobrutinib: Treatment Sequence 3

EXPERIMENTAL

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); Drug: Evobrutinib MR-T1; Drug: Evobrutinib MR-T2

Part A: Evobrutinib: Treatment Sequence 4

EXPERIMENTAL

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); Drug: Evobrutinib MR-T3; Drug: Evobrutinib MR-T4

Part A: Evobrutinib: Treatment Sequence 5

EXPERIMENTAL

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); Drug: Evobrutinib MR-T3; Drug: Evobrutinib MR-T4

Part A: Evobrutinib: Treatment Sequence 6

EXPERIMENTAL

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); Drug: Evobrutinib MR-T3; Drug: Evobrutinib MR-T4

Part B: Evobrutinib: Treatment Sequence 1

EXPERIMENTAL

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); Drug: Evobrutinib MUPS-C1; Drug: Evobrutinib MUPS-C2

Part B: Evobrutinib: Treatment Sequence 2

EXPERIMENTAL

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); Drug: Evobrutinib MUPS-C1; Drug: Evobrutinib MUPS-C2

Part B: Evobrutinib: Treatment Sequence 3

EXPERIMENTAL

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); Drug: Evobrutinib MUPS-C1; Drug: Evobrutinib MUPS-C2

Part C: Evobrutinib: Treatment Sequence 4

EXPERIMENTAL

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); Drug: Evobrutinib MUPS-C3; Drug: Evobrutinib MUPS-C4

Part C: Evobrutinib: Treatment Sequence 5

EXPERIMENTAL

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); Drug: Evobrutinib MUPS-C3; Drug: Evobrutinib MUPS-C4

Part C: Evobrutinib: Treatment Sequence 6

EXPERIMENTAL

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); Drug: Evobrutinib MUPS-C3; Drug: Evobrutinib MUPS-C4

Part D: Evobrutinib: Treatment Sequence 1

EXPERIMENTAL

Participants will receive single oral dose of MR-T adapted on Day 1 of treatment period 1, followed by two single oral doses of Ref (TF2) on Day 1 in treatment period 2, followed by 1 sequential period 3. There will be 72 hours washout period between Periods 1 and 2 and 28 days between Period 2 and 3.

Drug: Ref (TF2); Drug: Evobrutinib MR-T1; Drug: Evobrutinib MR-T adapated

Part D: Evobrutinib: Treatment Sequence 2

EXPERIMENTAL

Participants will receive two single oral doses of Ref (TF2) on Day 1 of treatment period 1, followed by single oral dose of MR-T adapted on Day 1 in treatment period 2, followed by 1 sequential period 3. There will be 72 hours washout period between Periods 1 and 2 and 28 days between Period 2 and 3.

Drug: Ref (TF2); Drug: Evobrutinib MR-T1; Drug: Evobrutinib MR-T adapated

Interventions

Ref (TF2) DRUG

Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.

Also known as: M2951

Part A: Evobrutinib: Treatment Sequence 1; Part A: Evobrutinib: Treatment Sequence 2; Part A: Evobrutinib: Treatment Sequence 3; Part A: Evobrutinib: Treatment Sequence 4; Part A: Evobrutinib: Treatment Sequence 5; Part A: Evobrutinib: Treatment Sequence 6; Part B: Evobrutinib: Treatment Sequence 1; Part B: Evobrutinib: Treatment Sequence 2; Part B: Evobrutinib: Treatment Sequence 3; Part C: Evobrutinib: Treatment Sequence 4; Part C: Evobrutinib: Treatment Sequence 5; Part C: Evobrutinib: Treatment Sequence 6; Part D: Evobrutinib: Treatment Sequence 1; Part D: Evobrutinib: Treatment Sequence 2

Evobrutinib MR-T1 DRUG

Participants will receive single oral dose of MR-T1 on Day 1 in treatment period 1, 2, and 3 of Part A.

Also known as: M2951

Part A: Evobrutinib: Treatment Sequence 1; Part A: Evobrutinib: Treatment Sequence 2; Part A: Evobrutinib: Treatment Sequence 3; Part D: Evobrutinib: Treatment Sequence 1; Part D: Evobrutinib: Treatment Sequence 2

Evobrutinib MR-T2 DRUG

Participants will receive single oral dose of MR-T2 on Day 1 in treatment period 1, 2, and 3 of Part A.

Also known as: M2951

Part A: Evobrutinib: Treatment Sequence 1; Part A: Evobrutinib: Treatment Sequence 2; Part A: Evobrutinib: Treatment Sequence 3

Evobrutinib MR-T3 DRUG

Participants will receive single oral dose of MR-T3 on Day 1 in treatment period 1, 2, and 3 of Part A.

Also known as: M2951

Part A: Evobrutinib: Treatment Sequence 4; Part A: Evobrutinib: Treatment Sequence 5; Part A: Evobrutinib: Treatment Sequence 6

Evobrutinib MR-T4 DRUG

Participants will receive single oral dose of MR-T4 on Day 1 in treatment period 1, 2, and 3 of Part A.

Also known as: M2951

Part A: Evobrutinib: Treatment Sequence 4; Part A: Evobrutinib: Treatment Sequence 5; Part A: Evobrutinib: Treatment Sequence 6

Evobrutinib MUPS-C1 DRUG

Participants will receive single oral dose of MUPS-C1 on Day 1 in treatment period 1, 2, and 3 of Part B.

Also known as: M2951

Part B: Evobrutinib: Treatment Sequence 1; Part B: Evobrutinib: Treatment Sequence 2; Part B: Evobrutinib: Treatment Sequence 3

Evobrutinib MUPS-C2 DRUG

Participants will receive single oral dose of MUPS-C2 on Day 1 in treatment period 1, 2, and 3 of Part B.

Also known as: M2951

Part B: Evobrutinib: Treatment Sequence 1; Part B: Evobrutinib: Treatment Sequence 2; Part B: Evobrutinib: Treatment Sequence 3

Evobrutinib MUPS-C3 DRUG

Participants will receive single oral dose of MUPS-C3 on Day 1 in treatment period 1, 2, and 3 of Part C.

Also known as: M2951

Part C: Evobrutinib: Treatment Sequence 4; Part C: Evobrutinib: Treatment Sequence 5; Part C: Evobrutinib: Treatment Sequence 6

Evobrutinib MUPS-C4 DRUG

Participants will receive single oral dose of MUPS-C4 on Day 1 in treatment period 1, 2, and 3 of Part C.

Also known as: M2951

Part C: Evobrutinib: Treatment Sequence 4; Part C: Evobrutinib: Treatment Sequence 5; Part C: Evobrutinib: Treatment Sequence 6

Evobrutinib MR-T adapated DRUG

Participants will receive single oral dose of MR-T adapted on Day 1 in treatment period 1, 2, and 3 of Part D.

Also known as: M2951

Part D: Evobrutinib: Treatment Sequence 1; Part D: Evobrutinib: Treatment Sequence 2

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany: lead
• Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (1)

Quotient Clinical Ltd

Nottingham, NG11, United Kingdom

Location

Related Links

• Trial Awareness and Transparency website
• Medical Information Location Map - Med Info Contacts

Study Officials

• Medical Responsible

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

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part A, B and C, periods 1 to 3 will be an incomplete cross-over; Part A, B and C, periods 4 and 5 are sequential. Part D, periods 1 and 2 will be 2-sequence cross-over design with 2 treatment sequences; Part D, period 3 is optional.

Study Record Dates

• First Submitted: January 24, 2022
• First Posted: February 18, 2022
• Study Start: February 2, 2022
• Primary Completion: February 14, 2023
• Study Completion: February 14, 2023
• Last Updated: March 22, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)