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| ID | Type | Description | Link |
|---|---|---|---|
| 2017-005055-92 | EudraCT Number |
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The study investigated the effect of tepotinib on the pharmacokinetics (PK) of the Cytochrome P450 (CYP) 3A substrate midazolam determined from concentrations of midazolam and its main metabolite 1-hydroxymidazolam in healthy participants.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Midazolam (Reference Treatment) | Experimental | Participants received single oral dose of 7.5 milligrams (mg) midazolam tablet on Day 1 of treatment period 1. The washout period between midazolam administrations in Period 1 and Period 2 was 12 days. |
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| Tepotinib + Midazolam (Test Treatment) | Experimental | All participants who received 7.5 mg midazolam tablet in treatment period 1 received single oral dose of 500 mg tepotinib film-coated tablet from Day 1 to 11 along with 7.5 mg midazolam tablet on Day 11 in treatment period 2. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Midazolam | Drug | Participant received single oral dose of 7.5 mg midazolam tablet on Day 1 of treatment period 1 and Day 11 in treatment period 2. |
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| 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 Midazolam | AUC0-t a Pharmacokinetic (PK) parameter was calculated according to the mixed log linear trapezoidal rule. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
| Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Midazolam | 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, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
| Maximum Observed Plasma Concentration (Cmax) of Midazolam | Cmax was obtained directly from concentration versus time curve. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Reach Maximum Plasma Concentration (Tmax) of Midazolam and Midazolam Metabolite (1-Hydroxymidazolam) | Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
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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 25 participants were screened in this study. Out of which, 12 participants received Midazolam and Tepotinib + Midazolam treatment.
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| ID | Title | Description |
|---|---|---|
| FG000 | Midazolam (Reference Treatment) | Participants received single oral dose of 7.5 milligrams (mg) midazolam tablet on Day 1 of treatment period 1. The washout period between midazolam administrations in Period 1 and Period 2 was 12 days. |
| FG001 | Tepotinib + Midazolam (Test Treatment) | All participants who received 7.5 mg midazolam tablet in treatment period 1 received single oral dose of 500 mg tepotinib film-coated tablet from Day 1 to 11 along with 7.5 mg midazolam tablet on Day 11 in 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 single oral dose of 7.5 mg midazolam tablet on Day 1 of treatment period 1 and oral dose of 500 mg tepotinib film-coated tablet from Day 1 to 11 along with 7.5 mg midazolam tablet on Day 11 in treatment period 2. The washout period between midazolam administrations in Period 1 and Period 2 was 12 days. |
| 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 Midazolam | AUC0-t a Pharmacokinetic (PK) parameter was calculated according to the mixed log linear trapezoidal rule. | PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements. | Posted | Geometric Mean | Geometric Coefficient of Variation | hour*picogram per milliliter (h*pg/mL) | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
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Baseline (Day 1 of treatment period 1) up to the End of Trial visit (Day 20)
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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 | Midazolam (Reference Treatment) | Participants received single oral dose of 7.5 milligrams (mg) midazolam tablet on Day 1 of treatment period 1. The washout period between midazolam administrations in Period 1 and Period 2 was 12 days. |
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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 | Jun 12, 2018 | Sep 6, 2022 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Nov 14, 2018 | Sep 6, 2022 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D008874 | Midazolam |
| C000707607 | tepotinib |
| ID | Term |
|---|---|
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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This is a single sequence cross-over trial.
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| Tepotinib | Drug | Participants received single oral dose of 500 mg tepotinib film-coated tablet from Day 1 to 11 in treatment period 2. |
|
| Elimination Half Life (t1/2) of Midazolam and Midazolam Metabolite (1-Hydroxymidazolam) | 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, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of 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 Midazolam Metabolite (1-Hydroxymidazolam) | AUC0-t a Pharmacokinetic (PK) parameter was calculated according to the mixed log linear trapezoidal rule. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
| Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Midazolam Metabolite (1-Hydroxymidazolam) | 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, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
| Maximum Observed Plasma Concentration (Cmax) of Midazolam Metabolite (1-Hydroxymidazolam) | Cmax was obtained directly from concentration versus time curve. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
| Metabolic Ratio of Midazolam and Midazolam Metabolite (1-hydroxymidazolam) | Metabolic ratio was calculated as AUC 0-infinity of midazolam divided by AUC 0-infinity of 1-hydroxymidazolam. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | 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. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both serious TEAEs and non-serious TEAEs. | Baseline (Day 1 of treatment period 1) up to the End of Trial visit (Day 20) |
| Number of Participants With Clinically Significant Changes in Laboratory Values | Number of participants with clinically significant changes in laboratory values were reported. Clinical significance was decided by the investigator. Laboratory investigation included hematology and urinalysis. | From Screening up to the End of Trial visit (Day 20) |
| Number of Participants With Clinically Significant Changes in 12-Lead Electrocardiogram (ECG) | Number of participants with clinically significant changes in 12-lead ECG were reported. Clinical significance was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minute in supine position. | Day 1 (Treatment Period 1) up to the End of Trial visit (Day 20) |
| Number of Participants With Clinically Significant Changes in Vital Signs | Number of participants with clinically significant changes in vital signs were reported. Clinical significance was decided by Investigator. Vital signs included body temperature, blood pressure and pulse rate. | Day 1 (Treatment Period 1) up to the End of Trial visit (Day 20) |
| 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 |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| OG001 | Tepotinib + Midazolam (Test Treatment) | All participants who received 7.5 mg midazolam tablet in treatment period 1 received single oral dose of 500 mg tepotinib film-coated tablet from Day 1 to 11 along with 7.5 mg midazolam tablet on Day 11 in treatment period 2. |
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| Primary | Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Midazolam | 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 included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*pg/mL | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
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| Primary | Maximum Observed Plasma Concentration (Cmax) of Midazolam | Cmax was obtained directly from concentration versus time curve. | PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
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| Secondary | Time to Reach Maximum Plasma Concentration (Tmax) of Midazolam and Midazolam Metabolite (1-Hydroxymidazolam) | Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve. | PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements. | Posted | Median | Full Range | Hours | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
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| Secondary | Elimination Half Life (t1/2) of Midazolam and Midazolam Metabolite (1-Hydroxymidazolam) | 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 included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements. | Posted | Geometric Mean | Geometric Coefficient of Variation | Hours | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
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| Secondary | 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 Midazolam Metabolite (1-Hydroxymidazolam) | AUC0-t a Pharmacokinetic (PK) parameter was calculated according to the mixed log linear trapezoidal rule. | PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*pg/mL | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
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| Secondary | Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Midazolam Metabolite (1-Hydroxymidazolam) | 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 included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*pg/mL | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
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|
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| Secondary | Maximum Observed Plasma Concentration (Cmax) of Midazolam Metabolite (1-Hydroxymidazolam) | Cmax was obtained directly from concentration versus time curve. | PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
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| Secondary | Metabolic Ratio of Midazolam and Midazolam Metabolite (1-hydroxymidazolam) | Metabolic ratio was calculated as AUC 0-infinity of midazolam divided by AUC 0-infinity of 1-hydroxymidazolam. | PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements. | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2 |
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| Secondary | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | 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. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both serious TEAEs and non-serious TEAEs. | Safety Analysis Set included all participants who have received atleast 1 dose of planned investigational medicinal product (IMP). Participants was analyzed according to the actual treatment they receive. | Posted | Count of Participants | Participants | Baseline (Day 1 of treatment period 1) up to the End of Trial visit (Day 20) |
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| Secondary | Number of Participants With Clinically Significant Changes in Laboratory Values | Number of participants with clinically significant changes in laboratory values were reported. Clinical significance was decided by the investigator. Laboratory investigation included hematology and urinalysis. | Safety Analysis Set included all participants who have received atleast 1 dose of planned IMP. Participants was analyzed according to the actual treatment they receive. | Posted | Count of Participants | Participants | From Screening up to the End of Trial visit (Day 20) |
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| Secondary | Number of Participants With Clinically Significant Changes in 12-Lead Electrocardiogram (ECG) | Number of participants with clinically significant changes in 12-lead ECG were reported. Clinical significance was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minute in supine position. | Safety Analysis Set included all participants who have received atleast 1 dose of planned IMP. Participants was analyzed according to the actual treatment they receive. | Posted | Count of Participants | Participants | Day 1 (Treatment Period 1) up to the End of Trial visit (Day 20) |
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| Secondary | Number of Participants With Clinically Significant Changes in Vital Signs | Number of participants with clinically significant changes in vital signs were reported. Clinical significance was decided by Investigator. Vital signs included body temperature, blood pressure and pulse rate. | Safety Analysis Set included all participants who have received atleast 1 dose of planned IMP. Participants was analyzed according to the actual treatment they receive. | Posted | Count of Participants | Participants | Day 1 (Treatment Period 1) up to the End of Trial visit (Day 20) |
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| 0 |
| 12 |
| 0 |
| 12 |
| 1 |
| 12 |
| EG001 | Tepotinib + Midazolam (Test Treatment) | All participants who received 7.5 mg midazolam tablet in treatment period 1 received single oral dose of 500 mg tepotinib film-coated tablet from Day 1 to 11 along with 7.5 mg midazolam tablet on Day 11 in treatment period 2. | 0 | 12 | 0 | 12 | 10 | 12 |
| Abdominal pain | Gastrointestinal disorders | MedDRA version 21.0 | Non-systematic Assessment |
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| Abdominal pain lower | Gastrointestinal disorders | MedDRA version 21.0 | Non-systematic Assessment |
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| Abdominal pain upper | Gastrointestinal disorders | MedDRA version 21.0 | Non-systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | MedDRA version 21.0 | Non-systematic Assessment |
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| Gingival bleeding | 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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| Medical device site reaction | General 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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| D006571 | Heterocyclic Compounds |
| TEAEs Leading to Death |
|