A Trial to Evaluate the Impact of C21 on the Exposure of 4 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.

• Drug Drug Interaction (Drug), also known as Caffeine, Koffein Meda, Tolbutamide, Tolbutamide CF, Midazolam, Midazolam APL, Nintedanib, Ofev: 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

Primary outcomes

• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (Cmax) [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)]: Maximum observed concentration (Cmax) for caffeine and its metabolite paraxanthine.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (Tmax) [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)]: Time of occurrence of Cmax (Tmax) for caffeine and its metabolite paraxanthine.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (AUC0-last) [Day 2 to day 19]: 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.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (AUC0-inf) [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)]: Area under the plasma concentration vs. time curve from 0 to infinity (AUC0-inf) for caffeine and its metabolite paraxanthine.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (Cmax) [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)]: Maximum observed concentration (Cmax) for Tolbutamide and its metabolites 4-hydroxy-tolbutamide and carboxy-tolbutamide.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (Tmax) [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)]: Time of occurrence of Cmax (Tmax) for Tolbutamide and its metabolites 4-hydroxy-tolbutamide and carboxy-tolbutamide.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (AUC0-last) [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)]: 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.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (AUC0-inf) [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)]: 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.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (Cmax) [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)]: Maximum observed concentration (Cmax) for midazolam and its metabolite 1-hydroxy-midazolam.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (Tmax) [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)]: Time of occurrence of Cmax (Tmax) for midazolam and its metabolite 1-hydroxy-midazolam.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (AUC0-last) [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)]: 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.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (AUC0-inf) [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)]: Area under the plasma concentration vs. time curve from 0 to to infinity (AUC0-inf) for midazolam and its metabolite 1-hydroxy-midazolam.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (Cmax) [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)]: Maximum observed concentration (Cmax) for nintedanib and its metabolite BIBF 1202.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (Tmax) [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) for nintedanib and its metabolite BIBF 1202.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (AUC0-last) [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)]: 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.
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (AUC0-inf) [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)]: Area under the plasma concentration vs. time curve from 0 to infinity (AUC0-inf) for nintedanib and its metabolite BIBF 1202.

Secondary outcomes

• To Evaluate the Pharmacokinetics (PK) of C21 and M1 (Cmax) [Day 17]: Maximum observed concentration (Cmax) of C21 and its main metabolite M1.
• To Evaluate the Pharmacokinetics (PK) of C21 and M1 (Tmax) [Day 17]: Time of occurrence of Cmax (Tmax) of C21 and its main metabolite M1.
• To Evaluate the Pharmacokinetics (PK) of C21 and M1 (AUC0-last) [Day 17]: 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.
• To Evaluate the Pharmacokinetics (PK) of C21 and M1 (AUC0-tau) [Day 17]: 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.
• To Evaluate the Safety of C21 (AEs) [From signing ICF to Day 25]: Frequency, seriousness and intensity of adverse events (AEs).
• To Evaluate the Safety of C21 (Vital Signs) [From screening to day 25]: 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
• To Evaluate the Safety of C21 (ECG) [From screening to day 25]: 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
• To Evaluate the Safety of C21 (Clinical Laboratory Measurements) [From screening to day 25]: 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.

Sex: All, ages: 18 Years to 60 Years, accepts healthy volunteers

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.

Participant flow

Outcome results

• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (Cmax) (Primary), Geometric mean, ng/mL: Period 1 - Without C21 2290 +/- 22.3; Period 2 - With C21 2871 +/- 18.7; Period 3 - With C21 2784 +/- 37.1
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (Tmax) (Primary), Median, hours: Period 1 - Without C21 0.6333 (0.500 to 1.00); Period 2 - With C21 0.7500 (0.250 to 2.00); Period 3 - With C21 0.5167 (0.250 to 4.00)
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (AUC0-last) (Primary), Geometric mean, h*ng/mL: Period 1 - Without C21 15760 +/- 39.8; Period 2 - With C21 47560 +/- 14.7; Period 3 - With C21 34690 +/- 46.0
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Caffeine and Paraxanthine (AUC0-inf) (Primary), Geometric mean, h*ng/mL: Period 1 - Without C21 16880 +/- 43.5; Period 2 - With C21 130500 +/- 37.8; Period 3 - With C21 50190 +/- 79.5
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (Cmax) (Primary), Geometric mean, ng/mL: Period 1 - Without C21 48390 +/- 9.75; Period 2 - With C21 61070 +/- 15.2; Period 3 - With C21 64130 +/- 15.4
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (Tmax) (Primary), Median, hours: Period 1 - Without C21 2.500 (1.50 to 4.10); Period 2 - With C21 4.000 (2.00 to 24.0); Period 3 - With C21 4.000 (1.50 to 8.02)
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (AUC0-last) (Primary), Geometric mean, h*ng/mL: Period 1 - Without C21 449800 +/- 15.8; Period 2 - With C21 1146000 +/- 16.3; Period 3 - With C21 1207000 +/- 18.8
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Tolbutamide and 4-hydroxy-tolbutamide and Carboxy-tolbutamide (AUC0-inf) (Primary), Geometric mean, h*ng/mL: Period 1 - Without C21 499100 +/- 19.3; Period 2 - With C21 9919000 +/- 71.2; Period 3 - With C21 6134000 +/- 69.2
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (Cmax) (Primary), Geometric mean, ng/mL: Period 1 - Without C21 10.89 +/- 33.1; Period 2 - With C21 14.32 +/- 36.4; Period 3 - With C21 12.69 +/- 25.8
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (Tmax) (Primary), Median, hours: Period 1 - Without C21 0.7500 (0.500 to 0.783); Period 2 - With C21 0.7500 (0.500 to 1.00); Period 3 - With C21 0.7500 (0.500 to 1.00)
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (AUC0-last) (Primary), Geometric mean, h*ng/mL: Period 1 - Without C21 29.17 +/- 39.6; Period 2 - With C21 42.06 +/- 35.4; Period 3 - With C21 35.09 +/- 28.9
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Midazolam and 1-hydroxy-midazolam (AUC0-inf) (Primary), Geometric mean, h*ng/mL: Period 1 - Without C21 30.41 +/- 39.7; Period 2 - With C21 43.77 +/- 35.8; Period 3 - With C21 36.58 +/- 28.9
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (Cmax) (Primary), Geometric mean, ng/mL: Period 1 - Without C21 10.10 +/- 80.4; Period 2 - With C21 13.87 +/- 79.0; Period 3 - With C21 13.72 +/- 61.3
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (Tmax) (Primary), Median, hours: Period 1 - Without C21 3.000 (1.00 to 6.07); Period 2 - With C21 3.000 (1.00 to 6.00); Period 3 - With C21 2.000 (0.767 to 6.00)
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (AUC0-last) (Primary), Geometric mean, h*ng/mL: Period 1 - Without C21 92.87 +/- 82.3; Period 2 - With C21 128.4 +/- 57.9; Period 3 - With C21 106.4 +/- 48.2
• To Evaluate the Impact of C21 on the Pharmacokinetics (PK) of Nintedanib and BIBF 1202 (AUC0-inf) (Primary), Geometric mean, h*ng/mL: Period 1 - Without C21 101.0 +/- 80.3; Period 2 - With C21 143.3 +/- 56.2; Period 3 - With C21 114.7 +/- 47.4
• To Evaluate the Pharmacokinetics (PK) of C21 and M1 (Cmax) (Secondary), Geometric mean, ng/mL: Experimental: C21 1433 +/- 55.7
• To Evaluate the Pharmacokinetics (PK) of C21 and M1 (Tmax) (Secondary), Median, hours: Experimental: C21 1.000 (0.500 to 2.00)
• To Evaluate the Pharmacokinetics (PK) of C21 and M1 (AUC0-last) (Secondary), Geometric mean, h*ng/mL: Experimental: C21 2041 +/- 30.4
• To Evaluate the Pharmacokinetics (PK) of C21 and M1 (AUC0-tau) (Secondary), Geometric mean, h*ng/mL: Experimental: C21 2049 +/- 30.3
• 4 more outcome measures not shown.

Adverse events

Time frame: From signing ICF to Day 25

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2023-02-28)

• Björn Schultze, MD, Principal investigator, CTC Clinical Trial Consultants AB
• Måns Jergil, PhD, Study director, CTC Clinical Trial Consultants AB