- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03492437
Effect of Tepotinib on the PK of the P-gp Substrate Dabigatran Etexilate
August 3, 2023 updated by: Merck KGaA, Darmstadt, Germany
Phase I, Open-label, Single Sequence, Two-Period Study to Evaluate the Effect of Tepotinib on P-gp by Investigating the PK of the P-gp Probe Substrate Dabigatran Etexilate in Healthy Subjects
This study investigated the effect of Tepotinib on the pharmacokinetics (PK) of the p-glycoprotein (P-gp) probe substrate Dabigatran etexilate.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Study Type
Interventional
Enrollment (Actual)
20
Phase
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
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Neu-Ulm, Germany, 89231
- Nuvisan GmbH
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-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 44 years (Adult)
Accepts Healthy Volunteers
Yes
Description
Inclusion Criteria:
- Healthy participants of non-child bearing potential
- Body weight between 50 to 100 kilogram (kg)
- Body mass index (BMI) between 18.5 and 29.9 kilogram per meter square (kg/m^2)
- A male participant must agree to use and to have his female partner of childbearing potential to use highly effective method of contraception
- Participant must have given written informed consent before any study-related activities
- All values for hematology, coagulation, and biochemistry tests of blood and urinalysis are within the normal range. Minor (solitary) non-clinically relevant deviation(s) are allowed as judged by the Investigator
- Other protocol defined inclusion criteria could apply
Exclusion Criteria:
- Participation in a clinical study within 60 days prior to first drug administration
- Whole blood donation or loss of > 450 milliliter (mL) within 60 days prior to first drug administration
- Any surgical or medical condition, or any other significant disease that could interfere with the study objectives, conduct, or evaluation
- Supine systolic blood pressure (SBP) greater than (>) 140 millimeter of mercury (mmHg) or less than (<) 90 mmHg, diastolic blood pressure (DBP) > 90 or < 50 mmHg, and pulse rate > 90 or <50 beats per minute (bpm) at Screening and at admission on Day-1.
- 12-Lead electrocardiograms (ECG) showing a corrected QT interval per Fridericia's formula (QTcF) > 450 milliseconds (ms), PR > 215 ms, or QRS > 120 ms (at Screening)
- Creatinine clearance estimated glomerular filtration rate (eGFR) < 90 milliliter per minute (mL/min) (at Screening)
- Participants with gall bladder removal or other relevant surgery of gastrointestinal tract
- History of any malignancy
- History of epilepsy
- Ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or excipients
- Participants who in the Investigator's judgment were perceived as having an increased risk of bleeding
- Positive screen for alcohol or drugs of abuse (at Screening and Day -1)
- Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV), and human immunodeficiency virus 1 and 2 antibodies (HIV1/HIV2 antibodies) (at Screening)
- Excessive consumption of xanthine-containing food or beverages before study drug administration until collection of last pharmacokinetic (PK) sample in each period (at Screening and Day -1)
- Receipt of any prescription or nonprescription medication within 14 days or 5 half-lives, before study drug administration
- Smoker or former smoker who stopped smoking less than 6 months before the time of the Screening Visit
- Intake of grapefruit, Seville orange, cranberry or juices of these 3 fruits, or St. John's Wort, from 14 days prior to Day -1
- Inability to communicate or cooperate with the Investigator
- Other factors, which in the opinion of the Investigator may interfere with study conduct (at Screening and Day -1 of first Period only)
- Legal incapacity or limited legal capacity
- Participants kept in detention
- Other protocol defined exclusion criteria could apply
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Other
- Allocation: N/A
- Interventional Model: Crossover Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Dabigatran Etexilate
|
Participants received single oral dose of Dabigatran etexilate on Day 1 of Treatment period 1 and co-administration of Dabigatran with Tepotinib on Day 8 of Treatment period 2.
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Experimental: Tepotinib + Dabigatran
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Participants received single oral dose of Dabigatran etexilate on Day 1 of Treatment period 1 and co-administration of Dabigatran with Tepotinib on Day 8 of Treatment period 2.
Participants received single oral dose of Tepotinib for 8 days in Treatment period 2.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
Time Frame: 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
|
AUC0-t was calculated according to the mixed log linear trapezoidal rule.
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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
|
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Total Dabigatran
Time Frame: 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
|
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).
|
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
|
Maximum Observed Plasma Concentration (Cmax) of Total Dabigatran
Time Frame: 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
|
Cmax was obtained directly from the concentration versus time curve.
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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
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Time to Reach Maximum Plasma Concentration (Tmax) of Total Dabigatran
Time Frame: 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
|
Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve.
|
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
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Elimination Half Life (t1/2) of Total Dabigatran
Time Frame: 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
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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.
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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
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Apparent Clearance (CL/f) of Total Dabigatran
Time Frame: 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
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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.
|
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
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Apparent Volume of Distribution During Terminal Phase (Vz/f) of Total Dabigatran
Time Frame: 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
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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.
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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
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Percentage of Area Under the Plasma Concentration-Time Curve From Time Tlast Extrapolated to Infinity (AUC0-inf) Obtained by Extrapolation (AUCextra%) of Total Dabigatran
Time Frame: 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
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The AUC from time tlast extrapolated to infinity given as percentage of AUC0-inf.
AUCextra% = (AUCextra /AUC0-inf)*100.
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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
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Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
Time Frame: Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
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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.
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Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
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Number of Participants With Clinically Significant Changes in Laboratory Values
Time Frame: Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
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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.
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Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
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Number of Participants With Clinically Significant Changes in 12-lead Electrocardiogram (ECG) Findings
Time Frame: Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
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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.
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Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
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Number of Participants With Clinically Significant Changes in Vital Signs
Time Frame: Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
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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.
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Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- Study Director: Medical Responsible, Merck KGaA, Darmstadt, Germany
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
May 17, 2018
Primary Completion (Actual)
August 27, 2018
Study Completion (Actual)
August 27, 2018
Study Registration Dates
First Submitted
April 3, 2018
First Submitted That Met QC Criteria
April 3, 2018
First Posted (Actual)
April 10, 2018
Study Record Updates
Last Update Posted (Actual)
August 7, 2023
Last Update Submitted That Met QC Criteria
August 3, 2023
Last Verified
August 1, 2023
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- MS200095_0032
- 2017-004074-34 (EudraCT Number)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
No
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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