Clinical trial NCT04314024: Relative Bioavailability (rBA) of Evobrutinib Intended Commercial and Clinical Tablets, and Effect of Food on Intended Commercial Tablets
Official title: Phase I, Randomized, Open-Label, Single-Dose, Three Period, Six-Sequence Crossover Study to Determine the Relative Bioavailability of the Evobrutinib Intended Commercial Tablet Formulation (TF2) Compared to the Clinical Tablet Formulation (TF1) and Evaluate the Effect of Food on TF2 Bioavailability in Healthy Participants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Evobrutinib
Pharmacokinetics
Relative Bioavailability
Crossover
Lead sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2020-03-18
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: The study will evaluate the relative bioavailability (rBA) of the intended commercial tablet formulation (Test Treatment, TF2) of Evobrutinib compared to the clinical tablet formulation (Reference Treatment, TF1) of Evobrutinib and to assess the effect of food on the bioavailability of the intended commercial tablet formulation of Evobrutinib.


Eligibility criteria: Inclusion Criteria:

* Participants are overtly healthy as 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
* Male or female participants agree to be consistent with local regulations on contraception methods
* Female participants are not pregnant or breastfeeding, and at least one of the following condition applies:
* Not a WOCBP or
* If a WOCBP, use a highly effective contraceptive method (that is, with a failure rate of \<1 percent per year, preferably with low user dependency for the following time period:
* Before the first dose of the study intervention, if using hormonal contraception:
* Has completed at least one 4-week cycle of an oral contraception pill and either had or has begun her menses or
* Has used a depot contraceptive or extended-cycle oral contraceptive for least 28 days and has a documented negative pregnancy test using a highly sensitive assay and
* A barrier method
* During the intervention period
* After the study intervention period (that is after the last dose of study intervention is administered) for at least 90 days, plus 30 days (a menstrual cycle) after the last dose of study intervention and agree not to donate eggs (ova, oocytes) for reproduction during this period. The Investigator evaluates the effectiveness of the contraceptive method in relationship to the first dose of study intervention
* Females have a negative serum pregnancy test at the Screening Visit and within 24 hours before the first dose of study intervention
* The Investigator reviews the medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female with an early undetected pregnancy
* Participants are stable non-smokers for at least 3 months preceding screening
* 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.
* 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 alcoholism or drug abuse within 2 years prior to screening, or evidence of such abuse as indicated by the laboratory assays conducted during screening
* History of residential exposure to tuberculosis, or a positive QuantiFERON® test within 4 weeks prior to screening
* Administration of live vaccines or live-attenuated virus vaccines within 3 months prior to screening
* Any condition, including findings in the laboratory tests, medical history, or other screening assessments, that in the opinion of the Investigator constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study's objectives, conduct, or evaluation
* Other protocol defined exclusion criteria could apply.

Primary outcomes:
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Evobrutinib Under Fasted Conditions
timeFrame: Pre-dose up to 24 hours post-dose on Day 6
measure: Area Under the Plasma Concentration-Time Curve from Time Zero to Infinity (AUC0-inf) of Evobrutinib Under Fasted Conditions
timeFrame: Pre-dose up to 24 hours post-dose on Day 6
measure: Maximum Observed Plasma Concentration (Cmax) of Evobrutinib Under Fasted Conditions
timeFrame: Pre-dose up to 24 hours post-dose on Day 6
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Evobrutinib Under Fed Conditions
timeFrame: Pre-dose up to 24 hours post-dose on Day 6
measure: Area Under the Plasma Concentration-Time Curve from Time Zero to Infinity (AUC0-inf) of Evobrutinib Under Fed Conditions
timeFrame: Pre-dose up to 24 hours post-dose on Day 6
measure: Maximum Observed Plasma Concentration (Cmax) of Evobrutinib Under Fed Conditions
timeFrame: Pre-dose up to 24 hours post-dose on Day 6
Secondary outcomes:
measure: Number of Participants With Treatment -Emergent Adverse Events (TEAEs) Based on Severity Under Fasted Conditions
timeFrame: Day 1 up to Day 6
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs, Laboratory Parameters and Electrocardiogram Findings Under Fasted Conditions
timeFrame: Day 1 up to Day 6
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 24 Hours After Evobrutinib Administration (AUC0-24)
timeFrame: Pre-dose up to 24 hours post-dose on Day 6
measure: Area Under The Plasma Concentration-Time Curve From Time Zero to Time 12 Hours After Evobrutinib Administration (AUC0-12)
timeFrame: Pre-dose up to 12 hours post-dose on Day 6
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Evobrutinib
timeFrame: Pre-dose up to 24 hours post-dose on Day 6
measure: Time Prior to the First Measurable (non-zero) Concentration (t lag) of Evobrutinib
timeFrame: Pre-dose up to 24 hours post-dose on Day 6
measure: Terminal First Order (elimination) Rate Constant (λz) of Evobrutinib
timeFrame: Pre-dose up to 24 hours post-dose on Day 6
measure: Apparent Elimination Half Life (t1/2) of Evobrutinib
timeFrame: Pre-dose up to 24 hours post-dose on Day 6
measure: Apparent Total Body Clearance (CL/f) of Evobrutinib
timeFrame: Pre-dose up to 24 hours post-dose on Day 6
measure: Apparent Volume of Distribution During Terminal Phase (VZ/f) of Evobrutinib
timeFrame: Pre-dose up to 24 hours post-dose on Day 6
measure: Relative Bioavailability of Test Treatment in Relation to Reference Treatment (Frel)
timeFrame: Pre-dose up to 24 hours post-dose on Day 6
Other outcomes:
Locations:
city: Neu-Ulm
country: Germany
facility: Nuvisan GmbH
Study officials:
affiliation: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: