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| ID | Type | Description | Link |
|---|---|---|---|
| 2017-004074-34 | EudraCT Number |
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This study investigated the effect of Tepotinib on the pharmacokinetics (PK) of the p-glycoprotein (P-gp) probe substrate Dabigatran etexilate.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dabigatran Etexilate | Experimental |
| |
| Tepotinib + Dabigatran | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dabigatran Etexilate | Drug | 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. |
| 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 | AUC0-t was calculated according to the mixed log linear trapezoidal rule. | 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 | 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 | Cmax was 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Reach Maximum Plasma Concentration (Tmax) of Total Dabigatran | 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 |
| Elimination Half Life (t1/2) of Total Dabigatran |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | Merck KGaA, Darmstadt, Germany | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Nuvisan GmbH | Neu-Ulm | 89231 | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37415001 | Derived | Yalkinoglu O, Becker A, Krebs-Brown A, Vetter C, Lupfert C, Perrin D, Heuer J, Biedert H, Hirt S, Bytyqi A, Bachmann A, Strotmann R. Assessment of the potential of the MET inhibitor tepotinib to affect the pharmacokinetics of CYP3A4 and P-gp substrates. Invest New Drugs. 2023 Aug;41(4):596-605. doi: 10.1007/s10637-023-01378-z. Epub 2023 Jul 6. |
| Label | URL |
|---|---|
| Trial Awareness and Transparency website | View source |
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Overall, 39 participants were screened in this study. Out of which, 20 participants received Dabigatran and Tepotinib + Dabigatran treatment.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment Period 1 |
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| Treatment Period 2 |
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| ID | Title | Description |
|---|---|---|
| BG000 | All 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. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | AUC0-t was calculated according to the mixed log linear trapezoidal rule. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram*hour per milliliter (ng*h/mL) | 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 |
|
Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal discomfort | Gastrointestinal disorders | MedDRA, Version 21.0 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Communication Center | Merck KGaA, Darmstadt, Germany | +49-6151-72-5200 | service@emdgroup.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 23, 2018 | Sep 6, 2022 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Aug 28, 2018 | Sep 6, 2022 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D002289 | Carcinoma, Non-Small-Cell Lung |
| ID | Term |
|---|---|
| D002283 | Carcinoma, Bronchogenic |
| D001984 | Bronchial Neoplasms |
| D008175 | Lung Neoplasms |
| D012142 | Respiratory Tract Neoplasms |
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| ID | Term |
|---|---|
| D000069604 | Dabigatran |
| C000707607 | tepotinib |
| ID | Term |
|---|---|
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D001562 | Benzimidazoles |
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| Tepotinib | Drug | Participants received single oral dose of Tepotinib for 8 days in Treatment period 2. |
|
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. |
| 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 |
| Apparent Clearance (CL/f) of Total Dabigatran | 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 |
| Apparent Volume of Distribution During Terminal Phase (Vz/f) of Total Dabigatran | 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. | 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 |
| Percentage of Area Under the Plasma Concentration-Time Curve From Time Tlast Extrapolated to Infinity (AUC0-inf) Obtained by Extrapolation (AUCextra%) of Total Dabigatran | The AUC from time tlast extrapolated to infinity given as percentage of AUC0-inf. AUCextra% = (AUCextra /AUC0-inf)*100. | 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 |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | 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. | Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2 |
| Number of Participants With Clinically Significant Changes in Laboratory Values | 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. | Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2 |
| Number of Participants With Clinically Significant Changes in 12-lead Electrocardiogram (ECG) Findings | 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. | Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2 |
| Number of Participants With Clinically Significant Changes in Vital Signs | 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. | Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2 |
| Medical Information Location Map - Med Info Contacts | View source |
| Redacted Clinical study report, redacted clinical study protocol and redacted statistical analysis plan for this study is also available at the HC-PRCI portal (Health Canada-Public release of clinical information) | View source |
| NOT COMPLETED |
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| Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| OG001 | 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. |
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| Primary | Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Total Dabigatran | 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). | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | 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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|
|
|
| Primary | Maximum Observed Plasma Concentration (Cmax) of Total Dabigatran | Cmax was obtained directly from the concentration versus time curve. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | Nanogram per milliliter (ng/mL) | 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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|
| Secondary | Time to Reach Maximum Plasma Concentration (Tmax) of Total Dabigatran | Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve. | 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. | Posted | Median | Full Range | Hour | 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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|
|
| Secondary | Elimination Half Life (t1/2) of Total Dabigatran | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | Hour | 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 | Apparent Clearance (CL/f) of Total Dabigatran | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter per hour (L/h) | 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 | Apparent Volume of Distribution During Terminal Phase (Vz/f) of Total Dabigatran | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter | 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 | Percentage of Area Under the Plasma Concentration-Time Curve From Time Tlast Extrapolated to Infinity (AUC0-inf) Obtained by Extrapolation (AUCextra%) of Total Dabigatran | The AUC from time tlast extrapolated to infinity given as percentage of AUC0-inf. AUCextra% = (AUCextra /AUC0-inf)*100. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | percentage of AUC0-inf | 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 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | 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. | The safety analysis set included all participants who received at least 1 dose of the planned investigational medicinal product (IMP). | Posted | Count of Participants | Participants | Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2 |
|
|
|
| Secondary | Number of Participants With Clinically Significant Changes in Laboratory Values | 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. | The safety analysis set included all participants who received at least 1 dose of the planned IMP. | Posted | Count of Participants | Participants | Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2 |
|
|
|
| Secondary | Number of Participants With Clinically Significant Changes in 12-lead Electrocardiogram (ECG) Findings | 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. | The safety analysis set included all participants who received at least 1 dose of the planned IMP. | Posted | Count of Participants | Participants | Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2 |
|
|
|
| Secondary | Number of Participants With Clinically Significant Changes in Vital Signs | 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. | The safety analysis set included all participants who received at least 1 dose of the planned IMP. | Posted | Count of Participants | Participants | Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2 |
|
|
|
| 0 |
| 20 |
| 0 |
| 20 |
| 4 |
| 20 |
| EG001 | 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. | 0 | 20 | 0 | 20 | 15 | 20 |
| Abdominal pain | Gastrointestinal disorders | MedDRA, Version 21.0 | Non-systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA, Version 21.0 | Non-systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA, Version 21.0 | Non-systematic Assessment |
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| Dyspepsia | Gastrointestinal disorders | MedDRA, Version 21.0 | Non-systematic Assessment |
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| Faeces hard | Gastrointestinal disorders | MedDRA, Version 21.0 | Non-systematic Assessment |
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| Faeces soft | Gastrointestinal disorders | MedDRA, Version 21.0 | Non-systematic Assessment |
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| Flatulence | Gastrointestinal disorders | MedDRA, Version 21.0 | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA, Version 21.0 | Non-systematic Assessment |
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| Tongue ulceration | Gastrointestinal disorders | MedDRA, Version 21.0 | Non-systematic Assessment |
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| Blood creatine phosphokinase increased | Investigations | MedDRA, Version 21.0 | Non-systematic Assessment |
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| Heart rate increased | Investigations | MedDRA, Version 21.0 | Non-systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA, Version 21.0 | Non-systematic Assessment |
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| Intervertebral disc protrusion | Musculoskeletal and connective tissue disorders | MedDRA, Version 21.0 | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA, Version 21.0 | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA, Version 21.0 | Non-systematic Assessment |
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| D013899 |
| Thoracic Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D006574 |
| Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |