A Trial to Evaluate the Impact of C21 on the Exposure of 4 Substrates in Healthy Volunteers

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Drug Interaction

Intervention / Treatment
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* Drug: Drug Drug Interaction


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to give written informed consent for participation in the trial. Healthy male, or healthy female subject of non-childbearing potential, aged 18 to 60 years, inclusive. Body mass index ≥ 18.5 and ≤ 30.0 kg/m2 at the time of the screening visit. Medically healthy subject without abnormal clinically significant medical history, physical findings, vital signs, ECG and laboratory values at the time of the screening visit, as judged by the Investigator. Women of non-childbearing potential, i.e. pre-menopausal females who have undergone any of the following surgical procedures; hysterectomy, bilateral salpingectomy or bilateral oophorectomy, or who are post-menopausal defined as 12 months of amenorrhea (in questionable cases a blood sample with detection of follicle stimulating hormone [FSH] >25 IU/L is confirmatory). Male subjects who are vasectomised, who are willing to use condoms or to practice sexual abstinence from heterosexual intercourse (only allowed when this is the preferred and usual lifestyle of the subject) to prevent pregnancy and drug exposure of a partner. Male subjects must also refrain from donating sperm from the first administration of IMP until 3 months after the last administration of IMP. Any female partner of a non-vasectomised male subject who is of child-bearing potential must use contraceptive methods with a failure rate of < 1% (see inclusion criterion no. 5) to prevent pregnancy from at least 2 weeks prior to the first administration of IMP to 4 weeks after the last administration of IMP. 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: Systolic blood pressure: <90 or >140 mmHg, or Diastolic blood pressure <50 or >90 mmHg, or Pulse <40 or >90 bpm 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Open label, one group
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: C21<br>C21, single dose, oral administration twice daily, for 15 days | Drug: Drug Drug Interaction<br>* 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<br>* Other names: Nintedanib, Ofev;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the impact of C21 on the pharmacokinetics (PK) of nintedanib (Cmax) | PK variable Cmax for nintedanib. | Day 1 to day 19 | 
| To evaluate the impact of C21 on the pharmacokinetics (PK) of nintedanib (AUCinf) | PK variable AUCinf for nintedanib. | Day 1 to day 19 | 
| To evaluate the impact of C21 on the pharmacokinetics (PK) of tolbutamide (Cmax) | PK variable Cmax for tolbutamide. | Day 2 to day 19 | 
| To evaluate the impact of C21 on the pharmacokinetics (PK) of tolbutamide (AUCinf) | PK variable AUCinf for tolbutamide. | Day 2 to day 19 | 
| To evaluate the impact of C21 on the pharmacokinetics (PK) of midazolam (Cmax) | PK variable Cmax for midazolam. | Day 2 to day 19 | 
| To evaluate the impact of C21 on the pharmacokinetics (PK) of midazolam (AUCinf) | PK variable AUCinf for midazolam. | Day 2 to day 19 | 
| To evaluate the impact of C21 on the pharmacokinetics (PK) of caffeine (Cmax) | PK variable Cmax for caffeine. | Day 2 to day 19 | 
| To evaluate the impact of C21 on the pharmacokinetics (PK) of caffeine (AUCinf) | PK variable AUCinf for caffeine. | Day 2 to day 19 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the PK of C21 (Cmax) | Pharmacokinetic variable Cmax for C21. | Day 17 | 
| To evaluate the PK of C21 (AUCtau) | Pharmacokinetic variable AUCtau for C21. | Day 17 | 
| To evaluate the safety of C21. | Frequency, seriousness and intensity of adverse events (AEs). | From signing ICF to Day 25 |