Evaluation of Vamorolone CYP3A4 Induction on Midazolam (a Sensitive CYP 3A4 Substrate) Pharmacokinetics

An Open-label, Single-arm Study to Evaluate the CYP3A4 Induction Potential of Vamorolone on the Pharmacokinetics of Midazolam (a Sensitive CYP3A4 Probe) in Healthy Subjects.

The purpose of this study was to investigate how vamorolone affects the CYP3A4 enzyme in humans by measuring the pharmacokinetics of midazolam and its metabolite, 1'-hydroxymidazolam, in healthy subjects. The pharmacokinetics of midazolam were measured on Day 1 and then on Day 14 to investigate the potential interaction between the two compounds.

The safety and the tolerability was also investigated.

Study Overview

• Status: Completed
• Conditions: Drug Interaction
• Intervention / Treatment: Drug: Vamorolone; Drug: Midazolam

Detailed Description

This was a non-randomized, single-center, open-label, single-sequence, single-arm Phase I study.

• Day 1: Participants received a single dose of 2.5 mg midazolam in fasted state in the morning.
• Day 2: Wash-out period.
• Days 3 to 13: Participants received daily doses of 6 mg/kg vamorolone in the morning within 30 minutes after start of a standard breakfast.
• Day 14: Participants received single doses of 2.5 mg midazolam and 6 mg/kg vamorolone in fasted state in the morning.
• Safety and tolerability parameters were collected during the entire study phase from screening to follow-up.
• Blood samples for PK assessment of midazolam and 1'-hydroxymidazolam were collected from predose through 10 hours following the midazolam doses on Days 1 and 14.
• Blood samples for PK assessment of vamorolone were collected throughout the vamorolone dosing period.
• Blood and urine biomarkers samples for CYP3A4 induction assessment were collected throughout the treatment period.
• On Day 28, a follow-up safety phone call was done

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Neu-Ulm, Germany, 89231
    • Nuvisan GmBH

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age of 18 to 55 years inclusive, at the time of signing the informed consent.
2. Subject is overtly healthy as determined by medical evaluation including medical history, physical examination, vital signs, laboratory tests, and ECG.
3. Body weight ≥ 50 kg and a BMI ≥ 18 kg/m2 and ≤ 29.9 kg/m2 at screening.

4. Male and female. Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

   Male subjects:

   • If the subject is a sexually active man and not surgically sterilized, he must be willing to:

   • Abstain from sexual intercourse or
   • Use a condom plus another form of contraception, (e.g., spermicide, IUD, birth control pills taken by female partner) if engaging in sexual intercourse with a woman who could become pregnant.
   • Use a condom during sexual intercourse with pregnant or lactating women.
   • Must not father a child and must refrain from donating sperm from administration of the first dose and up to 3 months after the last dose of study treatment.

   Female subjects:

   All women (regardless of their status, i.e. WOCBP and WONCBP; for definitions see Section 10.4.1) must have a negative serum β-hCG pregnancy test prior to the initiation of the study treatments. FSH levels of suspected postmenopausal females must be > 30 mIU/mL.

   Vamorolone has the potential to induce CYP3A4, which may result in a reduction in the effectiveness of contraceptives that are metabolized by CYP3A4 such as hormonal contraceptives when co-administered with vamorolone. Therefore, hormonal contraceptives by any route of administration are contraindicated.

   Women participating in the study must be either:

   • WONCBP or

   • WOCBP using, during the length of the study and for at least 3 months after the stop of the study treatments, 1 of the following contraceptive methods plus a condom:

     • IUD during the study and up to 3 months after the last administration of the study treatments
     • Any IUD with published data showing that the lowest expected failure rate is less than 1% per year (not all IUDs meet this criteria)
     • Any other methods with published data showing that the lowest expected failure rate for birth control is less than 1% per year, or
     • Abstinent from intercourse for 2 weeks before exposure to the study treatments, throughout the clinical trial until 3 months following discontinuation of the study treatments, or
     • Have a male partner who is sterile prior to the woman's entry into the study and is the sole sexual partner for that woman during the study period.

   The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

5. Subject is a non-smoker for at least 3 months prior exposure to the study treatments. Subject must also have abstained from use of other nicotine containing products (e.g., nicotine patch, chewing gum or e-cigarettes) for at least 3 months before exposure to the study treatments.
6. Capable of giving signed informed consent as described in Section 10.1, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol prior to any clinical study specific procedure.
7. Supine systolic blood pressure ≥ 90 mmHg and ≤ 140 mmHg; diastolic blood pressure ≥ 50 mmHg and ≤ 90 mmHg and pulse rate ≥ 45 bpm and ≤ 90 bpm, and tympanic body temperature ≥ 35.0 °C and ≤ 37.5 °C at screening.
8. Subjects must be able to communicate well with the Investigator and comply with the protocol requirements, instructions, and protocol related restrictions (e.g. dietary, fluid and lifestyle restrictions from screening to study completion; Section 5.3).

9. Subjects must be able to swallow the study treatments as per protocol.

   Exclusion Criteria:

10. A past medical history of clinically significant abnormalities or a history/family history of long QT interval syndrome, structural cardiac abnormalities (including but not limited to hypertrophic cardiomyopathy, valvulopathy, and congenital defects), or cardiogenic syncope.

11. An abnormal ECG, defined as:

    • PR > 215 msec and < 100 msec, QRS complex > 120 msec; QTcF > 450 msec by automated reading
    • Any clinically significant ST/T wave abnormalities
    • Any atrial or ventricular arrhythmias
12. A past medical history of myocardial infarction, angina pectoris, atherosclerosis or other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension).
13. A past medical history of peptic ulcers, diverticulitis, and non-specific ulcerative colitis.
14. History of complaints of frequent dizziness and /or vomiting spells or lightheadedness ("frequent" defined as incidence occurs more than once every week) or history of/or present sleep apnea.
15. Any history or evidence of any clinically relevant, gastrointestinal, respiratory, hepatic, renal, endocrinologic, hematologic, immunologic, metabolic, genitourinary, pulmonary, neurologic, dermatologic, musculoskeletal, and/or other major disease or malignancy as determined by medical evaluation (including physical examination) capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatments; or interfering with the interpretation of data.
16. Known Gilbert's syndrome.
17. Any clinically relevant history of allergic conditions requiring hospitalization or prolonged systemic treatment (including drug allergies, allergic asthma, eczema, allergies requiring therapy with corticosteroids or anaphylactic reactions); but excluding untreated, asymptomatic, seasonal allergies at time of dosing or allergic contact sensitizations (e.g., nickel allergy).
18. Known or suspected hypersensitivity or contraindications to vamorolone and/or midazolam or any components of the formulation used.
19. Relevant current acute or chronic/recurrent viral, bacterial, fungal, or parasitic infections (e.g., pulmonary/upper respiratory, gastrointestinal, urinary, skin, or ENT infections) at screening or within 28 days prior to administration of the study treatments.

20. Use of any concomitant medication or any drugs / medicines (including dietary supplements, natural and herbal remedies, and hormone replacement therapy) within 2 weeks or 5 times the half-life of the respective drug, whichever is longer, prior to the first administration of the study treatments.

    Occasional use of paracetamol up to 2 g/day or ibuprofen up to 1.2 g/day (medicinal products in their original packaging, approved and marketed in Germany) is permitted.

    Oral, injectable, and implantable contraceptives as outlined in Section 5.1 are permitted.

21. Previous exposure to vamorolone.
22. Any use of corticoids within 6 months prior to the first administration of the study treatments.
23. Administration of live, attenuated, replication-competent vaccines within 6 weeks prior to the first administration of the study treatments until 2 weeks after the follow-up visit. Administration of vector-based or mRNA COVID-19 vaccines within 2 weeks prior to the first administration of the study treatments until 2 weeks after the follow-up visit.
24. Treatment with biologic agents (such as monoclonal antibodies including marketed drugs) within 3 months or 5 half-lives (whichever is longer) prior to the first administration of the study treatments.
25. Use of any investigational drug or participation in any clinical study within 30 days or 5 half-lives (whichever is longer) prior to the expected date of first administration of study treatments or planning to take other investigational drugs during the study.
26. Positive results for HBsAg, anti-HCV, anti-HIV 1 and 2, and HIV 1-p24 antigen at screening.
27. Positive screen for alcohol, drugs of abuse and cotinine at screening.
28. Elevations in ALT > 1.1 x ULN, AST > 1.2 x ULN, serum bilirubin > 1.2 x ULN, creatinine > 1.1 x ULN and and HbA1c > ULN at screening. A case-by-case decision for any abnormality must be discussed with the Sponsor before inclusion.
29. TSH outside of normal ranges.
30. eGFR based on the CKD-EPI (details for calculation see Section 10.2) of < 90 mL/min at screening.
31. Potassium or magnesium blood concentration below the lower limit of normal at screening.
32. Subjects who are unwilling to adhere to contraceptive requirements.
33. Higher than low-risk alcohol consumption i.e., consumption of an average weekly alcohol intake of > 21 units/week for men and > 14 units/week for women. 1 unit (12 g) corresponds to 0.3 L of beer/day or 0.12 L of wine/day or 1 glass (at 2 cL) of spirits/day.
34. Excessive consumption of caffeine- or xanthine-containing food or beverages (> 5 cups of coffee a day or equivalent) or inability to stop consuming from 48 hours prior to first planned administration of study treatments.
35. Consumption of alcohol from 48 hours prior to admission.
36. Consumption of high dose resveratrol-containing products or products with enzyme-inducing or enzyme-inhibiting properties (for details refer to Section 5.3.1) 14 days prior to first administration of study treatment.
37. Regular consumption of poppy seed containing food prior to first administration of study treatment.
38. Any use of drugs-of-abuse or alcohol abuse within 1 month prior to dosing.
39. Subject with vegetarian, vegan, or restricted diet (e.g., gluten-free) or not willing or able to eat the complete standard meals.
40. Female subject who has been pregnant within 6 months prior to screening or breastfeeding or lactating within 3 months prior to screening or plans to become pregnant during the clinical study period and for 3 months after final study treatment administration.
41. Donation or loss of more than 400 mL of blood or received a transfusion of any blood or blood products within 30 days, or donated plasma within 30 days prior to first administration of study treatment.
42. Strenuous physical activity within 72 h to admission.
43. Employee of the Sponsor, the Nuvisan Group, or other Contract Research Organization involved in the clinical study.
44. Legal incapacity or limited legal capacity, or incarceration and vulnerable subjects.
45. Inability to understand or communicate reliably with the Investigator or considered by the Investigator to be unable to or unlikely to co-operate with the protocol requirements, instructions, and study-related restrictions.
46. History of non-compliance to medical regimens and subjects who are considered potentially unreliable (e.g., refuse to comply with study regulations).
47. Any other conditions or factors which in the opinion of the Investigator may interfere with study conduct.
48. Changes in medical conditions compared to screening, as judged by the Investigator.
49. Body weight < 50 kg.
50. Changes in prior/concomitant therapy compared to screening, as judged by the Investigator.
51. Positive screen for alcohol, drugs of abuse and cotinine test upon admission.
52. Changes in other exclusion criteria compared to screening, as judged by the Investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• 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: Midazolam/Vamorolone; Single oral dose midazolam 2.5mg on day 1 Single oral suspension vamorolone 6mg/kg on day 3 to day 13 Single oral dose midazolam 2.5mg + Single oral suspension vamorolone 6mg/kg on day 14	Drug: Vamorolone; Days 3 to 14: 6 mg/kg vamorolone once daily.; Other Names: Test Drug; Drug: Midazolam; Day 1 and 14: Single oral doses of 2.5 mg midazolam; Other Names: Reference Drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC0-tlast of Midazolam	Area under the plasma concentration-time curve from 0 to the time of the last observed concentration (h*pg/mL) on day 1 and day 14. The timepoints at which the data were collected to create the curve are as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours postdose.	Day 1 and Day 14
AUC0-inf of Midazolam	Area under the plasma concentration-time curve from zero to infinite time on day 1 and day 14. The timepoints at which the data were collected to create the curve are as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours postdose and extrapolation to infinity.	Day 1 and Day 14
Cmax of Midazolam	maximum measured concentration of midazolam after administration of midazolam until the last collection time, i.e., 10 hours after dosing on day 1 and day 14	Day 1 and Day 14
AUC0-tlast of 1'-Hydroxymidazolam	Area under the plasma concentration-time curve from 0 to the time of the last observed concentration (h*pg/mL) on day 1 and day 14. The timepoints at which the data were collected to create the curve are as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours postdose.	Day 1 and Day 14
AUC-inf of 1'-Hydroxymidazolam	Area under the plasma concentration-time curve from 0 to the infinite time (h*pg/mL) on day 1 and Day 14. The timepoints at which the data were collected to create the curve are as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours postdose and extrapolation to infinity.	Day 1 and Day 14
Cmax of 1'-Hydroxymidazolam	maximum measured concentration of 1'-Hydroxymidazolam after administration of midazolam until the last collection time, i.e., 10 hours after dosing	Day 1 and Day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tmax of Midazolam	Time to reach observed maximal concentration of midazolam after administration of midazolam until the last collection time, i.e., 10 hours after administration on day 1 and day 14	Day 1 and Day 14
CL/F of Midazolam	The apparent clearance measures how quickly a drug leaves the body, considering how much reaches it after being taken orally. It was calculated using the formula: Dose/AUCinf on day 1 and day 14. The timepoints used were as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 hours on day 1 and day 14	Day 1 and Day 14
Vz/F of Midazolam	Vz/F is the ratio of the volume of distribution of a drug to its bioavailability. It describes how widely the drug is distributed in the body after oral administration. It was calculated based on the terminal phase (ℷz)using the formula: Dose /ℷz.AUCinf on day 1 and day 14. The timepoints were as follows: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 hours.	Day 1 and Day 14
t1/2 of Midazolam	Elimination half-life is the amount of time it takes for the concentration of the drug (midazolam) in the body to decrease by half after administration on day 1 and day 14. The collection times were predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 hours.	Day 1 and Day 14
Tmax of 1'-Hydroxymidazolam	Time to reach observed maximal concentration of 1'-Hydroxymidazolam after administration of midazolam until the last collection time, i.e., 10 hours after dosing on day 1 and day 14	Day 1 and Day 14
t1/2 of 1'-Hydroxymidazolam	Elimination half-life is the amount of time it takes for the concentration of the drug (1'-Hydroxymidazolam) in the body to decrease by half on day 1 and day 14. The collection times were predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 hours.	Day 1 and Day 14
Predose Concentration (Ctrough) of Vamorolone	Concentration measurements taken just before the first administration of vamorolone on day 3, and at the end of each vamorolone dosing interval before the next dose on days 4, 7, 11, 13, and 14.	Day 3, Day 4, Day 7, Day 11, Day 13, Day 14
Urinary 6β-hydroxycortisol to Cortisol Ratio	Urinary 6β-hydroxycortisol to cortisol ratio is used as in vivo biomarkers for CYP3A4 activity. The impact of vamorlone on adrenal suppression could result in alterations in urinary cortisol and 6-β-hydroxycortisol levels.. Thus, the 6-β-hydroxycortisol to cortisol ratio is an unreliable measure of vamorolone's CYP3A4 induction potential.	Day 1, Day 3, Day 4, Day 7, Day 11, Day 14, Day 15
Plasma 4β-hydroxycholesterol Level	The plasma concentration of 4-β-hydroxycholesterol is used as an in vivo marker to assess CYP3A4 induction activity	Day 1, Day 3, Day 4, Day 7, Day 11, Day 14, Day 15

Collaborators and Investigators

• Sponsor: Santhera Pharmaceuticals
• Investigators: Principal Investigator: Michael Lissy, MD, Nuvisan GmBH

Study record dates

Study Major Dates

• Study Start (Actual): August 13, 2024
• Primary Completion (Actual): September 24, 2024
• Study Completion (Actual): October 16, 2024

Study Registration Dates

• First Submitted: September 5, 2024
• First Submitted That Met QC Criteria: November 13, 2024
• First Posted (Actual): November 14, 2024

Study Record Updates

• Last Update Posted (Actual): December 15, 2025
• Last Update Submitted That Met QC Criteria: December 12, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Drug-Drug-Interaction Study
• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Benzazepines; Benzodiazepines; Evaluation Studies as Topic; Drug Development; Midazolam; VBP15 compound; Drug Evaluation
• Other Study ID Numbers: SNT-I-VAM-025; 2024-513845-36-00 (Ctis)

Drug and device information, study documents

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