Trial Outcomes & Findings for Effect of Tepotinib on the PK of the P-gp Substrate Dabigatran Etexilate (NCT NCT03492437)

NCT ID: NCT03492437

Last Updated: 2023-08-07

Results Overview

AUC0-t was calculated according to the mixed log linear trapezoidal rule.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 20 participants
• Primary outcome timeframe: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8
• Results posted on: 2023-08-07

Participant Flow

Overall, 39 participants were screened in this study. Out of which, 20 participants received Dabigatran and Tepotinib + Dabigatran treatment.

Participant milestones

Measure	Dabigatran Etexilate Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Treatment Period 1 STARTED	20	0
Treatment Period 1 COMPLETED	20	0
Treatment Period 1 NOT COMPLETED	0	0
Treatment Period 2 STARTED	0	20
Treatment Period 2 COMPLETED	0	19
Treatment Period 2 NOT COMPLETED	0	1

Reasons for withdrawal

Measure	Dabigatran Etexilate Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Treatment Period 2 Withdrawal by Subject	0	1

Baseline Characteristics

Effect of Tepotinib on the PK of the P-gp Substrate Dabigatran Etexilate

Baseline characteristics by cohort

Measure	All Participants n=20 Participants All participants who received a single oral dose of 75 mg dabigatran etexilate capsule in treatment period 1 and 500 mg tepotinib (500 mg) film coated tablet from Day 1 to 8 along with 75 mg dabigatran etexilate Capsule in treatment period 2 under fed state.
Age, Continuous	33 Years STANDARD_DEVIATION 8.1 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants
Sex: Female, Male Male	19 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	20 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	19 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8

Population: Pharmacokinetic (PK) analysis set: all participants who completed at least 1 period without any relevant protocol violations with respect to factors affecting comparability of PK results with adequate study drug compliance and evaluable dabigatran PK data. Here, "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

AUC0-t was calculated according to the mixed log linear trapezoidal rule.

Outcome measures

Measure	Dabigatran Etexilate n=20 Participants Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran n=19 Participants All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Area Under Plasma Concentration-time Curve From Time Zero to Last Sampling Time (Tlast) at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Total Dabigatran	461 nanogram*hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 74.9	709 nanogram*hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 64.6

PRIMARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8

Population: PK analysis set: all participants who completed at least 1 period without any relevant protocol violations with respect to factors affecting comparability of PK results with adequate study drug compliance and evaluable dabigatran PK data. Here, "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

AUC0-inf was calculated as AUC0-t plus (+) AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clastpred/Lambda z, where Clastpred is the predicted plasma concentration at the last sampling time point, calculated from the log-linear regression line for Lambda z determination at which the measured plasma concentration is at or above Lower limit of quantification (LLOQ).

Outcome measures

Measure	Dabigatran Etexilate n=19 Participants Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran n=19 Participants All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Total Dabigatran	544 ng*hr/mL Geometric Coefficient of Variation 32.8	730 ng*hr/mL Geometric Coefficient of Variation 61.8

PRIMARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8

Population: PK analysis set: all participants who completed at least 1 period without any relevant protocol violations with respect to factors affecting comparability of PK results with adequate study drug compliance and evaluable dabigatran PK data. Here, "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Cmax was obtained directly from the concentration versus time curve.

Outcome measures

Measure	Dabigatran Etexilate n=20 Participants Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran n=19 Participants All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Maximum Observed Plasma Concentration (Cmax) of Total Dabigatran	54.5 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 72.8	76.9 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 61.8

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8

Population: PK analysis set: all participants who completed at least 1 period without any relevant protocol violations with respect to factors affecting comparability of PK results with adequate study drug compliance and evaluable dabigatran PK data. Here, "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve.

Outcome measures

Measure	Dabigatran Etexilate n=20 Participants Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran n=19 Participants All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Time to Reach Maximum Plasma Concentration (Tmax) of Total Dabigatran	3.00 Hour Interval 1.5 to 6.0	4.00 Hour Interval 2.0 to 6.0

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8

Population: PK analysis set: all participants who completed at least 1 period without any relevant protocol violations with respect to factors affecting comparability of PK results with adequate study drug compliance and evaluable dabigatran PK data. Here, "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Elimination Half Life (t1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half.

Outcome measures

Measure	Dabigatran Etexilate n=19 Participants Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran n=19 Participants All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Elimination Half Life (t1/2) of Total Dabigatran	8.18 Hour Geometric Coefficient of Variation 12.9	7.81 Hour Geometric Coefficient of Variation 13.5

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8

Population: PK analysis set: all participants who completed at least 1 period without any relevant protocol violations with respect to factors affecting comparability of PK results with adequate study drug compliance and evaluable dabigatran PK data. Here, "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

Outcome measures

Measure	Dabigatran Etexilate n=19 Participants Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran n=19 Participants All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Apparent Clearance (CL/f) of Total Dabigatran	138 Liter per hour (L/h) Geometric Coefficient of Variation 32.8	103 Liter per hour (L/h) Geometric Coefficient of Variation 61.8

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8

Population: PK analysis set: all participants who completed at least 1 period without any relevant protocol violations with respect to factors affecting comparability of PK results with adequate study drug compliance and evaluable dabigatran PK data. Here, "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/f after oral dose was influenced by the fraction absorbed.

Outcome measures

Measure	Dabigatran Etexilate n=19 Participants Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran n=19 Participants All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Apparent Volume of Distribution During Terminal Phase (Vz/f) of Total Dabigatran	1627 Liter Geometric Coefficient of Variation 34.7	1157 Liter Geometric Coefficient of Variation 58.4

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8

Population: PK analysis set: all participants who completed at least 1 period without any relevant protocol violations with respect to factors affecting comparability of PK results with adequate study drug compliance and evaluable dabigatran PK data. Here, "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

The AUC from time tlast extrapolated to infinity given as percentage of AUC0-inf. AUCextra% = (AUCextra /AUC0-inf)*100.

Outcome measures

Measure	Dabigatran Etexilate n=20 Participants Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran n=19 Participants All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Percentage of Area Under the Plasma Concentration-Time Curve From Time Tlast Extrapolated to Infinity (AUC0-inf) Obtained by Extrapolation (AUCextra%) of Total Dabigatran	3.03216 percentage of AUC0-inf Geometric Coefficient of Variation 55.1249	2.3654 percentage of AUC0-inf Geometric Coefficient of Variation 63.8621

SECONDARY outcome

Timeframe: Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2

Population: The safety analysis set included all participants who received at least 1 dose of the planned investigational medicinal product (IMP).

Adverse event (AE) was defined as any untoward medical occurrence in participants which does not necessarily have causal relationship with treatment. AE was any unfavorable and unintended sign (including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. A serious adverse event (SAE) was AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both serious TEAEs and non-serious TEAEs.

Outcome measures

Measure	Dabigatran Etexilate n=20 Participants Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran n=20 Participants All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs Treatment-emergent Adverse Events (TEAEs)	4 Participants	15 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs Serious TEAEs	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2

Population: The safety analysis set included all participants who received at least 1 dose of the planned IMP.

Number of participants with clinically significant change in laboratory values were reported. Clinical significance was decided by the investigator. Laboratory investigation included hematology, biochemistry, virology, drugs of abuse, hormones, urinalysis, and coagulation.

Outcome measures

Measure	Dabigatran Etexilate n=20 Participants Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran n=20 Participants All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Number of Participants With Clinically Significant Changes in Laboratory Values	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2

Population: The safety analysis set included all participants who received at least 1 dose of the planned IMP.

Number of participants with clinically significant change in 12-lead ECG were reported. Clinical significance was decided by the investigator. The 12-lead ECGs were recorded after the participant have rested for at least 5 minutes in supine position.

Outcome measures

Measure	Dabigatran Etexilate n=20 Participants Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran n=20 Participants All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Number of Participants With Clinically Significant Changes in 12-lead Electrocardiogram (ECG) Findings	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2

Population: The safety analysis set included all participants who received at least 1 dose of the planned IMP.

Number of participants with clinically significant change in vital signs were reported. Clinical significance was decided by the investigator. Vital signs included body temperature, blood pressure, and pulse rate.

Outcome measures

Measure	Dabigatran Etexilate n=20 Participants Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran n=20 Participants All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Number of Participants With Clinically Significant Changes in Vital Signs	0 Participants	0 Participants

Adverse Events

Dabigatran Etexilate

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Tepotinib + Dabigatran

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Dabigatran Etexilate n=20 participants at risk Participants received a single oral dose of 75 milligrams (mg) dabigatran etexilate capsule on Day 1 under fed state in treatment period 1.	Tepotinib + Dabigatran n=20 participants at risk All participants who received 75 mg Dabigatran Etexilate in treatment period 1, received oral dose of 500 mg tepotinib film-coated tablets from Day 1 to 8 under fed state along with 75 mg dabigatran etexilate on Day 8 of treatment period 2.
Gastrointestinal disorders Abdominal discomfort	0.00% 0/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	5.0% 1/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Gastrointestinal disorders Abdominal pain	0.00% 0/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	10.0% 2/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Gastrointestinal disorders Abdominal pain upper	0.00% 0/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	35.0% 7/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Gastrointestinal disorders Diarrhoea	5.0% 1/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	55.0% 11/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Gastrointestinal disorders Dyspepsia	0.00% 0/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	5.0% 1/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Gastrointestinal disorders Faeces hard	0.00% 0/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	5.0% 1/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Gastrointestinal disorders Faeces soft	0.00% 0/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	10.0% 2/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Gastrointestinal disorders Flatulence	0.00% 0/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	15.0% 3/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Gastrointestinal disorders Nausea	0.00% 0/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	30.0% 6/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Gastrointestinal disorders Tongue ulceration	0.00% 0/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	5.0% 1/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Investigations Blood creatine phosphokinase increased	0.00% 0/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	10.0% 2/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Investigations Heart rate increased	0.00% 0/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	5.0% 1/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Musculoskeletal and connective tissue disorders Back pain	5.0% 1/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	0.00% 0/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	5.0% 1/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	0.00% 0/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Nervous system disorders Dizziness	5.0% 1/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	5.0% 1/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Nervous system disorders Headache	10.0% 2/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2	10.0% 2/20 • Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2

Additional Information

Communication Center

Merck KGaA, Darmstadt, Germany

Phone: +49-6151-72-5200

Email: service@emdgroup.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: OTHER