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

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 impact of C21 on the exposure of CYP1A2, CYP2C9, CYP3A4 and P-gp substrates in healthy volunteers.

Study Overview

• Status: Completed
• Conditions: Drug Interaction
• Intervention / Treatment: Drug: Drug Drug Interaction

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Uppsala, Sweden, SE-752 37
    • CTC Clinical Trial Consultants AB

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Willing and able to give written informed consent for participation in the trial.
2. Healthy male, or healthy female subject of non-childbearing potential, aged 18 to 60 years, inclusive.
3. Body mass index ≥ 18.5 and ≤ 30.0 kg/m2 at the time of the screening visit.
4. 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.
5. 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).
6. 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:

1. 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.
2. Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP.
3. Malignancy within the past 5 years, with the exception of in situ removal of basal cell carcinoma.
4. Any planned major surgery within the duration of the trial.
5. Subjects who are pregnant, currently breastfeeding, or intend to become pregnant during the course of the trial.
6. Any positive result at the screening visit for serum hepatitis B surface antigen, hepatitis C antibodies and/or human immunodeficiency virus (HIV).

7. 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
8. Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant abnormalities in the resting ECG at the screening visit, as judged by the Investigator.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. History of alcohol abuse or excessive intake of alcohol, as judged by the Investigator.
16. Presence or history of drug abuse, as judged by the Investigator.
17. History of, or current use of anabolic steroids, as judged by the Investigator.
18. 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.
19. Plasma donation within one month of screening or blood donation (or corresponding blood loss) during the last three months prior to screening.
20. The Investigator considers the subject unlikely to comply with trial procedures, restrictions and requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Experimental: C21; C21, single dose, oral administration twice daily, for 15 days

Drug: 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; Other Names: Caffeine, Koffein Meda; Tolbutamide, Tolbutamide CF; Midazolam, Midazolam APL; Nintedanib, Ofev

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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)
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)

Secondary Outcome Measures

Outcome Measure	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)	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

Collaborators and Investigators

• Sponsor: Vicore Pharma AB
• Investigators: Principal Investigator: Björn Schultze, MD, CTC Clinical Trial Consultants AB; Study Director: Måns Jergil, PhD, CTC Clinical Trial Consultants AB

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2023
• Primary Completion (Actual): May 11, 2023
• Study Completion (Actual): May 11, 2023

Study Registration Dates

• First Submitted: March 24, 2023
• First Submitted That Met QC Criteria: April 13, 2023
• First Posted (Actual): April 26, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: November 13, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Enzyme Inhibitors; Anesthetics; Central Nervous System Depressants; Protein Kinase Inhibitors; Neurotransmitter Agents; Purinergic Antagonists; Purinergic Agents; Adjuvants, Anesthesia; Hypnotics and Sedatives; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; GABA Modulators; GABA Agents; Central Nervous System Stimulants; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Midazolam; Nintedanib; Caffeine; Tolbutamide
• Other Study ID Numbers: VP-C21-012

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No