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| ID | Type | Description | Link |
|---|---|---|---|
| 2021-003513-19 | EudraCT Number |
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The purpose of this study was to assess the effect of multiple doses of itraconazole on single dose tepotinib pharmacokinetics in healthy participants. Study details include:
Study Duration: up to 48 days Treatment Duration: single dose of tepotinib on Days 1 and 12, 11 days of treatment with itraconazole (Days 8 to 18) Visit Frequency: residence in the Clinical Research Unit from Days -1 to 4 and Days 11 to 15, ambulatory daily visits from Days 5 to 10 and 16 to 20
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tepotinib then Itraconazole | Experimental | Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day and Day 12 under fed condition followed by single oral dose of itraconazole 200 mg on Days 8 to 11 and Days 13 to 18. On Day 12, participants received a single dose of 200 mg itraconazole simultaneously with a single dose of 500 mg Tepotinib. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tepotinib (HydroChloride hydrate) | Drug | Participants received Tepotinib (Hydrochloride hydrate) Film-coated tablet with food on Day 1 and 12 in the morning. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib | The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda (λ)z determination. | Predose up to 168 hours post dose |
| Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib | The AUC from time zero (= dosing time) to time of the last quantifiable concentration (tlast). Calculated using the mixed log-linear trapezoidal rule (linear up, log down). | Predose up to 168 hours post dose |
| Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Metabolite | Cmax was obtained directly from the concentration versus time curve. | Predose up to 168 hours post dose |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3 | An adverse event (AE) was defined as any untoward medical occurrence in a participant. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a study intervention. A serious adverse event (SAE) was any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE's were those events with onset dates on or after the first administration of study intervention. Severity of abnormalities were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version [24.1]. grade 1 : mild grade 2 : moderate grade 3 : severe or medically significant but not immediately life-threatening grade 4 : life threatening or disabling grade 5 : death related to AE |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Nuvisan GmbH | Neu-Ulm | Germany |
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| Label | URL |
|---|---|
| Trial Awareness and Transparency website | View source |
| Medical Information Location Map - Med Info Contacts | View source |
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We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21
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A total of 44 participants were screened, out of which 18 participants received the study drug.
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| ID | Title | Description |
|---|---|---|
| FG000 | Tepotinib and Itraconazole | Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1 and Day 12 under fed condition followed by single oral dose of itraconazole 200 mg on Days 8 to 11 and Days 13 to 18. On Day 12, participants received a single dose of 200 mg itraconazole simultaneously with a single dose of 500 mg tepotinib. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The Safety Analysis Set (SAF) included all participants, who were administered any dose of any study intervention.
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| ID | Title | Description |
|---|---|---|
| BG000 | Tepotinib and Itraconazole | Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1 and Day 12 under fed condition followed by single oral dose of itraconazole 200 mg on Days 8 to 11 and Days 13 to 18. On Day 12, participants received a single dose of 200 mg itraconazole simultaneously with a single dose of 500 mg tepotinib. |
| Units | Counts |
|---|---|
| Participants |
|
| 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 the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib | The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda (λ)z determination. | Pharmacokinetic (PK) analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours* nanograms per milliliter(h*ng/mL) | Predose up to 168 hours post dose |
|
Baseline (Day 1) up to follow up (assessed up to 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 | Tepotinib and Itraconazole | Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1 and Day 12 under fed condition followed by single oral dose of itraconazole 200 mg on Days 8 to 11 and Days 13 to 18. On Day 12, participants received a single dose of 200 mg itraconazole simultaneously with a single dose of 500 mg tepotinib. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal discomfort | Gastrointestinal disorders | MedDRA 24.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Communication Center | Merck Healthcare KGaA, Darmstadt Germany, an affiliate of 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 | Sep 15, 2021 | Jul 3, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 18, 2022 | Jul 3, 2023 | SAP_001.pdf |
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| ID | Term |
|---|---|
| C000707607 | tepotinib |
| D017964 | Itraconazole |
| ID | Term |
|---|---|
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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This is a single sequence cross-over trial.
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| Itraconazole | Drug | Participants received Itraconazole Hard-gelatin capsule with food once daily at the same time in the morning from Day 8 to Day 18; on Day 12 itraconazole is administered concomitantly with tepotinib. |
|
| Baseline (Day 1) up to follow up (assessed up to Day 20) |
| Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values | Laboratory investigation included hematology, biochemistry and urinalysis. Clinically meaningful was decided by the investigator. Number of participants with clinically meaningful change from baseline in laboratory values were reported. | Baseline (Day 1) up to follow up (assessed up to Day 20) |
| Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula. Clinical Significance was decided by the investigator. Number of participants with clinically meaningful change from baseline in ECG parameters were reported. | Baseline (Day 1) up to follow up (assessed up to Day 20) |
| Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Clinical Significance was decided by the investigator. Number of participants with clinically significant change from baseline in vital signs. | Baseline (Day 1) up to follow up (assessed up to Day 20) |
| Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib | CL/f following oral administration was calculated as Dose/AUC0-inf, where AUC0-inf calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clastcalc/λz, where Clastcalc was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and λz was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. | Predose up to 168 hours post dose |
| Apparent Volume of Distribution (Vz/f) for Tepotinib | Vz/F was defined as the apparent volume of distribution during the terminal phase following extravascular administration. | Predose up to 168 hours post dose |
| Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib | The time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve. | Predose up to 168 hours post dose |
| Apparent Terminal Half-Life (t1/2) of Tepotinib in Plasma | t1/2 was defined as the time taken for the plasma concentration or the amount of drug in the body to be reduced by half. | Predose up to 168 hours post dose |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 |
| Tepotinib and Itraconazole |
Participants received 200 mg itraconazole with food once daily in the morning from Day 12 to Day 18 along with a single oral dose of Tepotinib 500 mg on Day 12. |
|
|
| Primary | Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib | The AUC from time zero (= dosing time) to time of the last quantifiable concentration (tlast). Calculated using the mixed log-linear trapezoidal rule (linear up, log down). | PK analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose up to 168 hours post dose |
|
|
|
| Primary | Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Metabolite | Cmax was obtained directly from the concentration versus time curve. | PK analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram per mililiter (ng/mL) | Predose up to 168 hours post dose |
|
|
|
| Secondary | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3 | An adverse event (AE) was defined as any untoward medical occurrence in a participant. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a study intervention. A serious adverse event (SAE) was any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE's were those events with onset dates on or after the first administration of study intervention. Severity of abnormalities were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version [24.1]. grade 1 : mild grade 2 : moderate grade 3 : severe or medically significant but not immediately life-threatening grade 4 : life threatening or disabling grade 5 : death related to AE | The Safety Analysis Set (SAF) included all participants, who were administered any dose of any study intervention. | Posted | Count of Participants | Participants | Baseline (Day 1) up to follow up (assessed up to Day 20) |
|
|
|
| Secondary | Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values | Laboratory investigation included hematology, biochemistry and urinalysis. Clinically meaningful was decided by the investigator. Number of participants with clinically meaningful change from baseline in laboratory values were reported. | SAF included all participants, who were administered any dose of any study intervention. | Posted | Count of Participants | Participants | Baseline (Day 1) up to follow up (assessed up to Day 20) |
|
|
|
| Secondary | Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula. Clinical Significance was decided by the investigator. Number of participants with clinically meaningful change from baseline in ECG parameters were reported. | SAF included all participants, who were administered any dose of any study intervention. | Posted | Count of Participants | Participants | Baseline (Day 1) up to follow up (assessed up to Day 20) |
|
|
|
| Secondary | Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Clinical Significance was decided by the investigator. Number of participants with clinically significant change from baseline in vital signs. | SAF included all participants, who were administered any dose of any study intervention. | Posted | Count of Participants | Participants | Baseline (Day 1) up to follow up (assessed up to Day 20) |
|
|
|
| Secondary | Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib | CL/f following oral administration was calculated as Dose/AUC0-inf, where AUC0-inf calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clastcalc/λz, where Clastcalc was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and λz was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. | PK analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. | Posted | Geometric Mean | Geometric Coefficient of Variation | liter/hour | Predose up to 168 hours post dose |
|
|
|
| Secondary | Apparent Volume of Distribution (Vz/f) for Tepotinib | Vz/F was defined as the apparent volume of distribution during the terminal phase following extravascular administration. | PK analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. | Posted | Geometric Mean | Geometric Coefficient of Variation | liters | Predose up to 168 hours post dose |
|
|
|
| Secondary | Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib | The time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve. | PK analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. | Posted | Median | Full Range | hours | Predose up to 168 hours post dose |
|
|
|
| Secondary | Apparent Terminal Half-Life (t1/2) of Tepotinib in Plasma | t1/2 was defined as the time taken for the plasma concentration or the amount of drug in the body to be reduced by half. | PK analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Predose up to 168 hours post dose |
|
|
|
| 0 |
| 18 |
| 0 |
| 18 |
| 14 |
| 18 |
| Abdominal distension | Gastrointestinal disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA 24.1 | Non-systematic Assessment |
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| Epigastric discomfort | Gastrointestinal disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Faeces hard | Gastrointestinal disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | MedDRA 24.1 | Non-systematic Assessment |
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| Gastrointestinal motility disorder | Gastrointestinal disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Rectal tenesmus | Gastrointestinal disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Toothache | Gastrointestinal disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Catheter site induration | General disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Chest discomfort | General disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Chest pain | General disorders | MedDRA 24.1 | Non-systematic Assessment |
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| Fatigue | General disorders | MedDRA 24.1 | Non-systematic Assessment |
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| Rhinitis | Infections and infestations | MedDRA 24.1 | Non-systematic Assessment |
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| Amylase increased | Investigations | MedDRA 24.1 | Non-systematic Assessment |
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| Lipase increased | Investigations | MedDRA 24.1 | Non-systematic Assessment |
|
| Flank pain | Musculoskeletal and connective tissue disorders | MedDRA 24.1 | Non-systematic Assessment |
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| Ataxia | Nervous system disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Clumsiness | Nervous system disorders | MedDRA 24.1 | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 24.1 | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 24.1 | Non-systematic Assessment |
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| Hypoaesthesia | Nervous system disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA 24.1 | Non-systematic Assessment |
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| Abnormal dreams | Psychiatric disorders | MedDRA 24.1 | Non-systematic Assessment |
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| Middle insomnia | Psychiatric disorders | MedDRA 24.1 | Non-systematic Assessment |
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| Nocturia | Renal and urinary disorders | MedDRA 24.1 | Non-systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 24.1 | Non-systematic Assessment |
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| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 24.1 | Non-systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA 24.1 | Non-systematic Assessment |
|
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| D010879 |
| Piperazines |
| Title | Measurements |
|---|---|
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| Title | Measurements |
|---|---|
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