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This is a single-centre, open-label, fixed-sequence trial to evaluate the impact of C21 on the exposure of CYP1A2, CYP2C9, CYP3A4 and P-gp substrates in healthy volunteers.
This is a single-centre, open-label, fixed-sequence trial to evaluate the influence of C21 on the exposure of CYP1A2, CYP2C9, CYP3A4 and P-gp substrates in healthy male and female volunteers.
The trial consists of a screening phase (Day -28 to Day -1), an open-label intervention phase (Day -1 to Day 19), and a follow-up phase (Day 20 to Day 25 [±2 days]). Subjects will remain at the trial site from the afternoon of Day -1 to the morning of Day 6, and again from the afternoon of Day 16 to the morning of Day 19.
The intervention phase consists of 3 periods: in period 1 (Day -1 to Day 3), the pharmacokinetics (PK) of all substrates will be evaluated in the absence of C21, in period 2 (Day 4 to Day 6), a potential inhibitory effect of C21 on the substrates be evaluated, and in period 3 (Day 17 to Day 19), the net effect of potential C21-mediated induction and inhibition on the substrates will be evaluated.
Subjects will be expected to attend a total of 4 visits to the trial site, including a screening visit (Visit 1), 2 intervention visits (Visits 2 and 3) and a follow-up visit (Visit 4).
Each subject is expected to participate in the trial for approximately 55 days, including an up to 28-day screening period, 19-day intervention period and a 4- to 8-day follow-up period.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental: C21 | Experimental | C21, single dose, oral administration twice daily, for 15 days |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Drug Drug Interaction | Drug | The intervention phase consists of 3 periods: in period 1, the pharmacokinetics (PK) of all substrates will be evaluated in the absence of C21, in period 2, a potential inhibitory effect of C21 on the substrates be evaluated, and in period 3, the net effect of potential C21-mediated induction and inhibition on the substrates will be evaluated |
| Measure | Description | Time Frame |
|---|---|---|
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (Cmax) | Maximum observed concentration (Cmax) for caffeine and its metabolite paraxanthine. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (Tmax) | Time of occurrence of Cmax (Tmax) for caffeine and its metabolite paraxanthine. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (AUC0-last) | Area under the plasma concentration vs. time curve from 0 to time of last measurable plasma concentration (AUC0-last) for caffeine and its metabolite paraxanthine. | Day 2 to day 19 |
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (AUC0-inf) | Area under the plasma concentration vs. time curve from 0 to infinity (AUC0-inf) for caffeine and its metabolite paraxanthine. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (Cmax) | Maximum observed concentration (Cmax) for Tolbutamide and its metabolites 4-hydroxy-tolbutamide and carboxy-tolbutamide. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
| Measure | Description | Time Frame |
|---|---|---|
| To Evaluate the Pharmacokinetics (PK) of C21 and M1 (Cmax) | Maximum observed concentration (Cmax) of C21 and its main metabolite M1. | Day 17 |
| To Evaluate the Pharmacokinetics (PK) of C21 and M1 (Tmax) |
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Inclusion Criteria:
Exclusion Criteria:
History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the trial, or influence the results or the subject's ability to participate in the trial.
Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP.
Malignancy within the past 5 years, with the exception of in situ removal of basal cell carcinoma.
Any planned major surgery within the duration of the trial.
Subjects who are pregnant, currently breastfeeding, or intend to become pregnant during the course of the trial.
Any positive result at the screening visit for serum hepatitis B surface antigen, hepatitis C antibodies and/or human immunodeficiency virus (HIV).
After 10 minutes supine rest at the screening visit, any vital signs values outside the following ranges:
Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant abnormalities in the resting ECG at the screening visit, as judged by the Investigator.
CYP2C9 genotype hetero- or homozygous for CYP2C9*2 (Arg144Cys) and/or CYP2C9*3 (Ile359Leu) variant alleles associated with altered CYP2C9 activity and tolbutamide metabolism [14], sampled at the screening visit.
History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to any of the IMPs.
Regular use of any prescribed or non-prescribed medications, including antacids, analgesics, herbal remedies, e.g. St. John's wort, vitamins and minerals, within 2 weeks prior to the first administration of IMP, except occasional intake of paracetamol (maximum 2000 mg/day and not exceeding 3000 mg/week), as well as nasal decongestants without cortisone, antihistamine or anticholinergics for a maximum of 10 days, at the discretion of the Investigator.
Planned treatment or treatment with another investigational drug within 3 months prior to Day -1. Subjects consented and screened but not dosed in previous phase 1 studies are not to be excluded.
Regular current smokers or users of nicotine products. Irregular use of nicotine (e.g., smoking, snuffing, chewing tobacco) less than 3 times/week is allowed before the screening visit.
Positive screening result for drugs of abuse or alcohol at the screening visit or on admission to the trial site prior to the first administration of the IMP.
History of alcohol abuse or excessive intake of alcohol, as judged by the Investigator.
Presence or history of drug abuse, as judged by the Investigator.
History of, or current use of anabolic steroids, as judged by the Investigator.
Excessive caffeine consumption defined by a daily intake of > 5 cups (1 cup = approximately 240 mL) of caffeine containing beverages, as judged by the Investigator.
Plasma donation within one month of screening or blood donation (or corresponding blood loss) during the last three months prior to screening.
The Investigator considers the subject unlikely to comply with trial procedures, restrictions and requirements.
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| Name | Affiliation | Role |
|---|---|---|
| Björn Schultze, MD | CTC Clinical Trial Consultants AB | Principal Investigator |
| MÃ¥ns Jergil, PhD | CTC Clinical Trial Consultants AB | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CTC Clinical Trial Consultants AB | Uppsala | SE-752 37 | Sweden |
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In total, 36 prospective trial subjects were screened for inclusion. Of these, 14 subjects were screening failures (ineligible), 2 subjects withdrew consent, and 1 subject met the eligibility criteria but was not needed. Nineteen (19) subjects were included in the trial. Of the 19 included subjects, 18 subjects were fully evaluable, i.e., completed the trial up until at least the end of Day 19.
Subjects were recruited from CTC's database of volunteers and from strategic marketing campaigns (including social media).
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| ID | Title | Description |
|---|---|---|
| FG000 | Experimental: C21 | C21, single dose, oral administration twice daily, for 15 days Drug Drug Interaction: The intervention phase consists of 3 periods: in period 1, the pharmacokinetics (PK) of all substrates will be evaluated in the absence of C21, in period 2, a potential inhibitory effect of C21 on the substrates be evaluated, and in period 3, the net effect of potential C21-mediated induction and inhibition on the substrates will be evaluated |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Experimental: C21 | C21, single dose, oral administration twice daily, for 15 days Drug Drug Interaction: The intervention phase consists of 3 periods: in period 1, the pharmacokinetics (PK) of all substrates will be evaluated in the absence of C21, in period 2, a potential inhibitory effect of C21 on the substrates be evaluated, and in period 3, the net effect of potential C21-mediated induction and inhibition on the substrates will be evaluated |
| 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 | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (Cmax) | Maximum observed concentration (Cmax) for caffeine and its metabolite paraxanthine. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
|
From signing ICF to Day 25
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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 | Period 1 - Without C21 | In period 1 (Day 1 to Day 3), the pharmacokinetics (PK) of all substrates were evaluated in the absence of C21. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | MedDRA 25.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Cecilia Ganslandt, MD, MSc | Vicore Pharma AB | +46 31788 05 60 | info@vicorepharma.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 28, 2023 | Jul 11, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D004347 | Drug Interactions |
| D002110 | Caffeine |
| D014044 | Tolbutamide |
| D008874 | Midazolam |
| C530716 | nintedanib |
| ID | Term |
|---|---|
| D000069437 | Pharmacological Phenomena |
| D002620 | Pharmacological and Toxicological Phenomena |
| D010829 | Physiological Phenomena |
| D014970 | Xanthines |
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Open label, one group
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| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (Tmax) | Time of occurrence of Cmax (Tmax) for Tolbutamide and its metabolites 4-hydroxy-tolbutamide and carboxy-tolbutamide. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (AUC0-last) | Area under the plasma concentration vs. time curve from 0 to time of last measurable plasma concentration (AUC0-last) for Tolbutamide and its metabolites 4-hydroxy-tolbutamide and carboxy-tolbutamide. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (AUC0-inf) | Area under the plasma concentration vs. time curve from 0 to infinity (AUC0-inf) for Tolbutamide and its metabolites 4-hydroxy-tolbutamide and carboxy-tolbutamide. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (Cmax) | Maximum observed concentration (Cmax) for midazolam and its metabolite 1-hydroxy-midazolam. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (Tmax) | Time of occurrence of Cmax (Tmax) for midazolam and its metabolite 1-hydroxy-midazolam. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (AUC0-last) | Area under the plasma concentration vs. time curve from 0 to time of last measurable plasma concentration (AUC0-last) for midazolam and its metabolite 1-hydroxy-midazolam. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (AUC0-inf) | Area under the plasma concentration vs. time curve from 0 to to infinity (AUC0-inf) for midazolam and its metabolite 1-hydroxy-midazolam. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (Cmax) | Maximum observed concentration (Cmax) for nintedanib and its metabolite BIBF 1202. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours post dose at Day 1 (period 1), Day 4 (period 2) and Day 17 (period 3) |
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (Tmax) | Time of occurrence of Cmax (Tmax) for nintedanib and its metabolite BIBF 1202. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours post dose at Day 1 (period 1), Day 4 (period 2) and Day 17 (period 3) |
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (AUC0-last) | Area under the plasma concentration vs. time curve from 0 to time of last measurable plasma concentration (AUC0-last) for nintedanib and its metabolite BIBF 1202. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours post dose at Day 1 (period 1), Day 4 (period 2) and Day 17 (period 3) |
| To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (AUC0-inf) | Area under the plasma concentration vs. time curve from 0 to infinity (AUC0-inf) for nintedanib and its metabolite BIBF 1202. | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours post dose at Day 1 (period 1), Day 4 (period 2) and Day 17 (period 3) |
Time of occurrence of Cmax (Tmax) of C21 and its main metabolite M1.
| Day 17 |
| To Evaluate the Pharmacokinetics (PK) of C21 and M1 (AUC0-last) | Area under the plasma concentration vs. time curve from 0 to time of last measurable plasma concentration (AUC0-last) of C21 and its main metabolite M1. | Day 17 |
| To Evaluate the Pharmacokinetics (PK) of C21 and M1 (AUC0-tau) | Area under the plasma concentration vs. time curve from 0 to the end of the dosing interval (AUC0-tau) of C21 and its main metabolite M1. | Day 17 |
| To Evaluate the Safety of C21 (AEs) | Frequency, seriousness and intensity of adverse events (AEs). | From signing ICF to Day 25 |
| To Evaluate the Safety of C21 (Vital Signs) | Number of patients with clinically significant changes in vital signs (systolic and diastolic blood pressure and pulse) from baseline. Any vital signs outside of normal ranges were judged as clinically significant or not clinically significant | From screening to day 25 |
| To Evaluate the Safety of C21 (ECG) | Number of patients with clinically significant changes in electrocardiogram (ECG) from baseline. The resting heart rate (HR) and PQ/PR, QRS, QT and QTcF intervals were recorded. Any abnormalities were specified and documented as clinically significant or not clinically significant | From screening to day 25 |
| To Evaluate the Safety of C21 (Clinical Laboratory Measurements) | Number of patients with clinically significant changes in clinical laboratory measurements (haematology, clinical chemistry, coagulation) from baseline. Any laboratory values outside of normal ranges were specified and documented as normal, abnormal not clinically significant, or abnormal clinically significant. | From screening to day 25 |
| 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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| Region of Enrollment | Number | participants |
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| OG002 | Period 3 - With C21 | In period 3 (Day 17 to Day 19), the net effect of potential C21-mediated induction and inhibition on the substrates was evaluated. |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (Tmax) | Time of occurrence of Cmax (Tmax) for caffeine and its metabolite paraxanthine. | PK analysis set. | Posted | Median | Full Range | hours | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (AUC0-last) | Area under the plasma concentration vs. time curve from 0 to time of last measurable plasma concentration (AUC0-last) for caffeine and its metabolite paraxanthine. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Day 2 to day 19 |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (AUC0-inf) | Area under the plasma concentration vs. time curve from 0 to infinity (AUC0-inf) for caffeine and its metabolite paraxanthine. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (Cmax) | Maximum observed concentration (Cmax) for Tolbutamide and its metabolites 4-hydroxy-tolbutamide and carboxy-tolbutamide. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (Tmax) | Time of occurrence of Cmax (Tmax) for Tolbutamide and its metabolites 4-hydroxy-tolbutamide and carboxy-tolbutamide. | PK analysis set. | Posted | Median | Full Range | hours | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (AUC0-last) | Area under the plasma concentration vs. time curve from 0 to time of last measurable plasma concentration (AUC0-last) for Tolbutamide and its metabolites 4-hydroxy-tolbutamide and carboxy-tolbutamide. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (AUC0-inf) | Area under the plasma concentration vs. time curve from 0 to infinity (AUC0-inf) for Tolbutamide and its metabolites 4-hydroxy-tolbutamide and carboxy-tolbutamide. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (Cmax) | Maximum observed concentration (Cmax) for midazolam and its metabolite 1-hydroxy-midazolam. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (Tmax) | Time of occurrence of Cmax (Tmax) for midazolam and its metabolite 1-hydroxy-midazolam. | PK analysis set. | Posted | Median | Full Range | hours | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (AUC0-last) | Area under the plasma concentration vs. time curve from 0 to time of last measurable plasma concentration (AUC0-last) for midazolam and its metabolite 1-hydroxy-midazolam. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (AUC0-inf) | Area under the plasma concentration vs. time curve from 0 to to infinity (AUC0-inf) for midazolam and its metabolite 1-hydroxy-midazolam. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24 hours post dose at Day 2 (period 1), Day 5 (period 2) and Day 18 (period 3) |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (Cmax) | Maximum observed concentration (Cmax) for nintedanib and its metabolite BIBF 1202. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours post dose at Day 1 (period 1), Day 4 (period 2) and Day 17 (period 3) |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (Tmax) | Time of occurrence of Cmax (Tmax) for nintedanib and its metabolite BIBF 1202. | PK analysis set. | Posted | Median | Full Range | hours | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours post dose at Day 1 (period 1), Day 4 (period 2) and Day 17 (period 3) |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (AUC0-last) | Area under the plasma concentration vs. time curve from 0 to time of last measurable plasma concentration (AUC0-last) for nintedanib and its metabolite BIBF 1202. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours post dose at Day 1 (period 1), Day 4 (period 2) and Day 17 (period 3) |
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| Primary | To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (AUC0-inf) | Area under the plasma concentration vs. time curve from 0 to infinity (AUC0-inf) for nintedanib and its metabolite BIBF 1202. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose and 0:15, 0:30, 0:45, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours post dose at Day 1 (period 1), Day 4 (period 2) and Day 17 (period 3) |
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| Secondary | To Evaluate the Pharmacokinetics (PK) of C21 and M1 (Cmax) | Maximum observed concentration (Cmax) of C21 and its main metabolite M1. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Day 17 |
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| Secondary | To Evaluate the Pharmacokinetics (PK) of C21 and M1 (Tmax) | Time of occurrence of Cmax (Tmax) of C21 and its main metabolite M1. | PK analysis set. | Posted | Median | Full Range | hours | Day 17 |
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| Secondary | To Evaluate the Pharmacokinetics (PK) of C21 and M1 (AUC0-last) | Area under the plasma concentration vs. time curve from 0 to time of last measurable plasma concentration (AUC0-last) of C21 and its main metabolite M1. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Day 17 |
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| Secondary | To Evaluate the Pharmacokinetics (PK) of C21 and M1 (AUC0-tau) | Area under the plasma concentration vs. time curve from 0 to the end of the dosing interval (AUC0-tau) of C21 and its main metabolite M1. | PK analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Day 17 |
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|
|
| Secondary | To Evaluate the Safety of C21 (AEs) | Frequency, seriousness and intensity of adverse events (AEs). | Full analysis set. | Posted | Count of Participants | Participants | From signing ICF to Day 25 |
|
|
|
| Secondary | To Evaluate the Safety of C21 (Vital Signs) | Number of patients with clinically significant changes in vital signs (systolic and diastolic blood pressure and pulse) from baseline. Any vital signs outside of normal ranges were judged as clinically significant or not clinically significant | Full analysis set. | Posted | Count of Participants | Participants | From screening to day 25 |
|
|
|
| Secondary | To Evaluate the Safety of C21 (ECG) | Number of patients with clinically significant changes in electrocardiogram (ECG) from baseline. The resting heart rate (HR) and PQ/PR, QRS, QT and QTcF intervals were recorded. Any abnormalities were specified and documented as clinically significant or not clinically significant | Full analysis set. | Posted | Count of Participants | Participants | From screening to day 25 |
|
|
|
| Secondary | To Evaluate the Safety of C21 (Clinical Laboratory Measurements) | Number of patients with clinically significant changes in clinical laboratory measurements (haematology, clinical chemistry, coagulation) from baseline. Any laboratory values outside of normal ranges were specified and documented as normal, abnormal not clinically significant, or abnormal clinically significant. | Full analysis set. | Posted | Count of Participants | Participants | From screening to day 25 |
|
|
|
| 0 |
| 19 |
| 0 |
| 19 |
| 8 |
| 19 |
| EG001 | Period 2 - With C21 | In period 2 (Day 4 to Day 6), a potential inhibitory effect of C21 on the substrates was evaluated. | 0 | 18 | 0 | 18 | 10 | 18 |
| EG002 | Period 3 - With C21 | In period 3 (Day 17 to Day 19), the net effect of potential C21-mediated induction and inhibition on the substrates was evaluated. | 0 | 18 | 0 | 18 | 5 | 18 |
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 25.1 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 25.1 | Systematic Assessment |
|
| Faeces hard | Gastrointestinal disorders | MedDRA 25.1 | Systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | MedDRA 25.1 | Systematic Assessment |
|
| Gastritis | Gastrointestinal disorders | MedDRA 25.1 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 25.1 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 25.1 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 25.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 25.1 | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 25.1 | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 25.1 | Systematic Assessment |
|
| Lacrimation increased | Eye disorders | MedDRA 25.1 | Systematic Assessment |
|
| Rhinitis | Infections and infestations | MedDRA 25.1 | Systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA 25.1 | Systematic Assessment |
|
Not provided
Not provided
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D011688 | Purinones |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D000096926 | Benzenesulfonamides |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D013453 | Sulfonylurea Compounds |
| D014508 | Urea |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| Paraxanthine |
|
|
| Paraxanthine |
|
|
| Paraxanthine |
|
|
|
| Carboxy-Tolbutamide |
|
|
| Carboxy-Tolbutamide |
|
|
| Carboxy-Tolbutamide |
|
| 4-Hydroxy-Tolbutamide |
|
|
| Carboxy-Tolbutamide |
|
|
|
|
|
|
| BIBF 1202 |
|
|
| BIBF 1202 |
|
|
| BIBF 1202 |
|
|
| BIBF 1202 |
|
|
|
|
|
|
| Title | Measurements |
|---|---|
|
| Any AE leading to withdrawal from trial |
|
| Any AE leading to death |
|
| Causality - C21 - Related |
|
| Causality - C21 - Not Related |
|
| Causality - C21 - Not Applicable |
|
| Causality - Nintedanib - Related |
|
| Causality - Nintedanib - Not Related |
|
| Causality - Nintedanib - Not Applicable |
|
| Causality - Caffeine - Related |
|
| Causality - Caffeine - Not Related |
|
| Causality - Caffeine - Not Applicable |
|
| Causality - Tolbutamide - Related |
|
| Causality - Tolbutamide - Not Related |
|
| Causality - Tolbutamide - Not Applicable |
|
| Causality - Midazolam - Related |
|
| Causality - Midazolam - Not Related |
|
| Causality - Midazolam - Not Applicable |
|
| Severity - Mild |
|
| Severity - Moderate |
|
| Severity - Severe |
|
| Severity - Life-Threatening |
|
| Severity - Death |
|