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This Study evaluates the Effect of St. John's Wort dry Extract Ze 117 on Several Cytochrome P450 Enzymes and on Transporter P-Glycoprotein in Healthy Volunteers.
Current data indicate that St. John's wort preparations may induce hepatic cytochrome P450 enzymes and transport proteins. This can result in drug interactions.
The study design is standard for DDI studies and is based on the regulatory guidance of the Food and Drug Administration (FDA) and of the European Medicines Agency (EMA).
A cocktail approach involving the administration of multiple cytochrome P450 (CYP)- or P-glycoprotein (P-gp)-specific probe drugs is used to simultaneously assess the activities of these enzymes and the transporter P-gp.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Probe drug cocktail / Ze 117 | Experimental | One-sequence, Probe drug cocktail alone and in combination with Ze 117. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ze 117 | Drug | Subjects will be hospitalized to receive a probe drug cocktail alone and in combination with Ze 117. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Ratio AUC0-t, Day 17 (Probe Drug Cocktail Plus Ze117 [Only at Day 17]) vs. Day 1 (Probe Drug Cocktail Alone) | The "number" as provided in the tables is the ratio (in %) of geometric LS means of AUC of day 17 dosing samples (probe drug cocktail plus Ze117) vs. Day 1 dosing samples (probe drug cocktail alone). A one-way ANOVA model (with terms for subject and treatment) was applied to analyze the effect of Ze117 on the respective probe drug. Log transformed (base e) parameters were used within the model. The estimated treatment difference between day 17 and day 1 was transformed back to original scale and presented as the ratio between treatments including the corresponding 90% confidence interval. Effect limits were predefined as follows: (1) Mild effect limits (50-200%), extended bioequivalence limits (70-143%), bioequivalence limits (80-125%). | PK samples: pre-dose, and 10, 20, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours after each cocktail administration (at day 1 and day 17) |
| Measure | Description | Time Frame |
|---|---|---|
| Ratio AUC0-t, Day 8 (Probe Drug Cocktail Plus Ze117 [Daily Throughout pk Sampling Period]) vs. Day 1 (Probe Drug Cocktail Alone) | The "number" as provided in the tables is the ratio (in %) of geometric LS means of AUC of day 8 dosing samples (probe drug cocktail plus Ze117) vs. Day 1 dosing samples (probe drug cocktail alone). A one-way ANOVA model (with terms for subject and treatment) was applied to analyze the effect of Ze117 on the respective probe drug. Log transformed (base e) parameters were used within the model. The estimated treatment difference between day 8 and day 1 was transformed back to original scale and presented as the ratio between treatments including the corresponding 90% confidence interval. Effect limits were predefined as follows: (1) Mild effect limits (50-200%), extended bioequivalence limits (70-143%), bioequivalence limits (80-125%). |
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Inclusion Criteria:
Exclusion Criteria:
Caucasian
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| Name | Affiliation | Role |
|---|---|---|
| Michael Lissy | Neu-Ulm | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Nuvisan GmbH | Neu-Ulm | Germany |
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Healthy volunteers
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| ID | Title | Description |
|---|---|---|
| FG000 | Healthy Volunteers | 20 healthy volunteers receiving in in a single sequence the probe drug cocktail alone (day 1), then two times the probe drug cocktail and the test drug Ze117 (day 8 and day 17) |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | Healthy Volunteers | 20 healthy volunteers receiving in in a single sequence the probe drug cocktail alone (day 1), then two times the probe drug cocktail and the test drug Ze117 (day 8 and day 17) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Ratio AUC0-t, Day 17 (Probe Drug Cocktail Plus Ze117 [Only at Day 17]) vs. Day 1 (Probe Drug Cocktail Alone) | The "number" as provided in the tables is the ratio (in %) of geometric LS means of AUC of day 17 dosing samples (probe drug cocktail plus Ze117) vs. Day 1 dosing samples (probe drug cocktail alone). A one-way ANOVA model (with terms for subject and treatment) was applied to analyze the effect of Ze117 on the respective probe drug. Log transformed (base e) parameters were used within the model. The estimated treatment difference between day 17 and day 1 was transformed back to original scale and presented as the ratio between treatments including the corresponding 90% confidence interval. Effect limits were predefined as follows: (1) Mild effect limits (50-200%), extended bioequivalence limits (70-143%), bioequivalence limits (80-125%). | Posted | Number | 90% Confidence Interval | Percentage | PK samples: pre-dose, and 10, 20, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours after each cocktail administration (at day 1 and day 17) |
|
AEs have been measured from screening Day -1 until end of study visit Day 18. In case of ongoing AEs at the end of study or if participants terminated the study prematurely a follow up visit was performed within the next 30 days to control whether AE/SAE has been resolved.
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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 | One-sequence, Drug Cocktail and Test Product | 20 healthy volunteers entered the study, one participant dropped out on day5 due to an adverse Event (Tonsillitis) |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Dr. Veronika Butterweck | Max Zeller Söhne AG | 0041714660447 | veronika.butterweck@zellerag.ch |
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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 | Jan 15, 2018 | Jun 27, 2019 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 13, 2018 | Jun 27, 2019 | SAP_001.pdf |
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| ID | Term |
|---|---|
| C446503 | ZE 117 |
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open-label, non-randomized, single-sequence study
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| Probe drug cocktail | Drug | Subjects will be hospitalized to receive a probe drug cocktail alone and in combination with Ze 117. |
|
| PK samples: pre-dose, and 10, 20, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours after each cocktail administration (at day 1 and day 8) |
| Ratio Cmax, Day 17 (Probe Drug Cocktail Plus Ze117 [Only at Day 17]) vs. Day 1 (Probe Drug Cocktail Alone) | The "number" as provided in the tables is the ratio (in %) of geometric LS means of Cmax from day 17 dosing samples (probe drug cocktail plus Ze117) vs. Day 1 dosing samples (probe drug cocktail alone). A one-way ANOVA model (with terms for subject and treatment) was applied to analyze the effect of Ze117 on the respective probe drug. Log transformed (base e) parameters were used within the model. The estimated treatment difference between day 17 and day 1 was transformed back to original scale and presented as the ratio between treatments including the corresponding 90% confidence interval. Effect limits were predefined as follows: (1) Mild effect limits (50-200%), extended bioequivalence limits (70-143%), bioequivalence limits (80-125%). | PK samples: pre-dose, and 10, 20, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours after each cocktail administration (at day 1 and day 17) |
| Ratio Cmax, Day 8 (Probe Drug Cocktail Plus Ze117 [Daily Throughout pk Sampling Period]) vs. Day 1 (Probe Drug Cocktail Alone) | The "number" as provided in the tables is the ratio (in %) of geometric LS means of Cmax from day 8 dosing samples (probe drug cocktail plus Ze117) vs. Day 1 dosing samples (probe drug cocktail alone). A one-way ANOVA model (with terms for subject and treatment) was applied to analyze the effect of Ze117 on the respective probe drug. Log transformed (base e) parameters were used within the model. The estimated treatment difference between day 8 and day 1 was transformed back to original scale and presented as the ratio between treatments including the corresponding 90% confidence interval. Effect limits were predefined as follows: (1) Mild effect limits (50-200%), extended bioequivalence limits (70-143%), bioequivalence limits (80-125%). | PK samples: pre-dose, and 10, 20, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours after each cocktail administration (at day 1 and day 8) |
| Participants |
| No |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Caffeine |
Caffeine (CYP1A2) |
| OG001 | Bupropion | Bupropion (CYP2B6) |
| OG002 | Flurbiprofen | Flurbiprofen (CYP2C9) |
| OG003 | Omeprazole | Omeprazole (CYP2C19) |
| OG004 | Dextromethorphan | Dextromethorphan (CYP2D6) |
| OG005 | Midazolam | Midazolam (CYP3A4) |
| OG006 | Fexofenadine | Fexofenadine (P-gp) |
|
|
| Secondary | Ratio AUC0-t, Day 8 (Probe Drug Cocktail Plus Ze117 [Daily Throughout pk Sampling Period]) vs. Day 1 (Probe Drug Cocktail Alone) | The "number" as provided in the tables is the ratio (in %) of geometric LS means of AUC of day 8 dosing samples (probe drug cocktail plus Ze117) vs. Day 1 dosing samples (probe drug cocktail alone). A one-way ANOVA model (with terms for subject and treatment) was applied to analyze the effect of Ze117 on the respective probe drug. Log transformed (base e) parameters were used within the model. The estimated treatment difference between day 8 and day 1 was transformed back to original scale and presented as the ratio between treatments including the corresponding 90% confidence interval. Effect limits were predefined as follows: (1) Mild effect limits (50-200%), extended bioequivalence limits (70-143%), bioequivalence limits (80-125%). | Posted | Number | 90% Confidence Interval | Percentage | PK samples: pre-dose, and 10, 20, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours after each cocktail administration (at day 1 and day 8) |
|
|
|
| Secondary | Ratio Cmax, Day 17 (Probe Drug Cocktail Plus Ze117 [Only at Day 17]) vs. Day 1 (Probe Drug Cocktail Alone) | The "number" as provided in the tables is the ratio (in %) of geometric LS means of Cmax from day 17 dosing samples (probe drug cocktail plus Ze117) vs. Day 1 dosing samples (probe drug cocktail alone). A one-way ANOVA model (with terms for subject and treatment) was applied to analyze the effect of Ze117 on the respective probe drug. Log transformed (base e) parameters were used within the model. The estimated treatment difference between day 17 and day 1 was transformed back to original scale and presented as the ratio between treatments including the corresponding 90% confidence interval. Effect limits were predefined as follows: (1) Mild effect limits (50-200%), extended bioequivalence limits (70-143%), bioequivalence limits (80-125%). | Posted | Number | 90% Confidence Interval | Percentage | PK samples: pre-dose, and 10, 20, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours after each cocktail administration (at day 1 and day 17) |
|
|
|
| Secondary | Ratio Cmax, Day 8 (Probe Drug Cocktail Plus Ze117 [Daily Throughout pk Sampling Period]) vs. Day 1 (Probe Drug Cocktail Alone) | The "number" as provided in the tables is the ratio (in %) of geometric LS means of Cmax from day 8 dosing samples (probe drug cocktail plus Ze117) vs. Day 1 dosing samples (probe drug cocktail alone). A one-way ANOVA model (with terms for subject and treatment) was applied to analyze the effect of Ze117 on the respective probe drug. Log transformed (base e) parameters were used within the model. The estimated treatment difference between day 8 and day 1 was transformed back to original scale and presented as the ratio between treatments including the corresponding 90% confidence interval. Effect limits were predefined as follows: (1) Mild effect limits (50-200%), extended bioequivalence limits (70-143%), bioequivalence limits (80-125%). | Posted | Number | 90% Confidence Interval | Percentage | PK samples: pre-dose, and 10, 20, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours after each cocktail administration (at day 1 and day 8) |
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| 0 |
| 20 |
| 0 |
| 20 |
| 16 |
| 20 |
| Fatigue | General disorders | Systematic Assessment |
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| Feeling hot | General disorders | Systematic Assessment |
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| Pyrexia | General disorders | Systematic Assessment |
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| Abnormal feces | Gastrointestinal disorders | Systematic Assessment |
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| Dry mouth | Gastrointestinal disorders | Systematic Assessment |
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| Gastric hypertonia | Gastrointestinal disorders | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Epitaxis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Eye lid edema | Eye disorders | Systematic Assessment |
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| Photophobia | Eye disorders | Systematic Assessment |
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| Tonsillitis | Infections and infestations | Systematic Assessment |
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| Viral upper respiratory tract infection | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| ALT increased | Investigations | Systematic Assessment |
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| WBC descreased | Investigations | Systematic Assessment |
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| Insomnia | Psychiatric disorders | Systematic Assessment |
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| Restlessness | Psychiatric disorders | Systematic Assessment |
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| Ear pain | Ear and labyrinth disorders | Systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Hematoma | Vascular disorders | Systematic Assessment |
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