Clinical Trial to Assess Effect of Verapamil on Systemic Exposure of EP395 and Effect of EP395 on Systemic Exposure of Midazolam and Digoxin

NCT06118684 | Completed Phase 1 FDA Drug

• 1 other identifier: EP395-004
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of this trial is to assess the potential key drug-drug interactions with EP395 in the clinical setting.

Conditions

COPD; Chronic Obstructive Pulmonary Disease Exacerbation

Outcome Measures

Primary Outcomes (14)

• Part A: PK parameters of EP395 - AUC0-24

  Area under the plasma concentration vs. time curve from timepoint 0 to 24 hours of EP395.

  Days 1 to 6 and Day 14 to 19

• Part A: PK parameters of EP395 - AUC0-inf

  Area under the plasma concentration vs. time curve from timepoint 0 to infinity of EP395.

  Days 1 to 6 and Day 14 to 19

• Part A: PK parameters of EP395 - AUC%extrap

  Percent of AUCinf derived from extrapolation of the plasma concentration vs. time curve of EP395.

  Days 1 to 6 and Day 14 to 19

• Part A: PK parameters of EP395 - CL/F

  Apparent total body clearance following extravascular administration of EP395.

  Days 1 to 6 and Day 14 to 19

• Part A: PK parameters of EP395 - Cmax

  Maximum observed plasma concentration of EP395.

  Days 1 to 6 and Day 14 to 19

• Part A: PK parameters of EP395 - Tmax

  Time to occurrence of Cmax of EP395.

  Days 1 to 6 and Day 14 to 19

• Part A: PK parameters of EP395 - T1/2

  Terminal elimination half-life of EP395.

  Days 1 to 6 and Day 14 to 19

• Part A: PK parameters of EP395 - Vz/F

  Volume of distribution following extravascular administration of EP395.

  Days 1 to 6 and Day 14 to 19

• Part B: PK parameters of midazolam and digoxin - AUC0-24

  Area under the plasma concentration vs. time curve from timepoint 0 to 24 hours of midazolam and digoxin.

  Days 1 to 3/6 and Day 24 to 29

• Part B: PK parameters of midazolam and digoxin - AUC0-inf

  Area under the plasma concentration vs. time curve from timepoint 0 to infinity of midazolam and digoxin.

  Days 1 to 3/6 and Day 24 to 29

• Part B: PK parameters of midazolam and digoxin - AUC%extrap

  Percent of AUCinf derived from extrapolation of the plasma concentration vs. time curve of midazolam and digoxin.

  Days 1 to 3/6 and Day 24 to 29

• Part B: PK parameters of midazolam and digoxin - Cmax

  Maximum observed plasma concentration of midazolam and digoxin.

  Days 1 to 3/6 and Day 24 to 29

• Part B: PK parameters of midazolam and digoxin - Tmax

  Time to occurrence of Cmax of midazolam and digoxin.

  Days 1 to 3/6 and Day 24 to 29

• Part B: PK parameters of midazolam and digoxin - T1/2

  Terminal elimination half-life of midazolam and digoxin.

  Days 1 to 3/6 and Day 24 to 29

Secondary Outcomes (25)

• Part A: Assessment of adverse event occurrence

  From screening to Day 30.

• Part A: Absolute change from baseline in vital signs (Systolic and diastolic blood pressure)

  Screening (Day -28 to Day -1), Day 1, Day 10-19

• Part A: Absolute change from baseline in vital signs (Pulse)

  Screening (Day -28 to Day -1), Day 1, Day 10-19

• Part A: Absolute change from baseline in 12-lead Electrocardiogram (ECG) parameters (heart rate)

  Screening (Day -28 to Day -1), Day 1, Day 10-19

• Part A: Absolute change from baseline in 12-lead Electrocardiogram (ECG) parameters (PQ/PR interval)

  Screening (Day -28 to Day -1), Day 1, Day 10-19

Study Arms (2)

Part A - EP395 as a 'victim' of DDIs

EXPERIMENTAL

Part A will investigate EP395 as a 'victim' of DDIs. The impact of CYP3A4 and P-glycoprotein (Pgp) inhibition on the pharmacokinetics (PK) of EP395 will be assessed. Verapamil has been selected as a moderate inhibitor of CYP3A4 and an inhibitor of Pgp.

Drug: EP395 (Part A and B); Drug: Verapamil (Part A)

Part B - EP395 as a 'perpetrator' of DDIs

EXPERIMENTAL

Part B will investigate EP395 as a 'perpetrator' of DDIs. The impact of EP395 on the PK of a CYP3A4 substrate and a Pgp substrate will be assessed. Midazolam has been selected as the CYP3A4 substrate and digoxin as the Pgp substrate.

Drug: EP395 (Part A and B); Drug: Midazolam (Part B); Drug: Digoxin (Part B)

Interventions

EP395 (Part A and B) DRUG

EP395 (test product) oral capsule 125 mg. Part A: Dose: 1 capsule as a single dose on Day 1 and Day 14, total daily dose: 125 mg. Part B: Dose: 3 capsules once daily on Days 9 to 28, total daily dose: 375 mg.

Part A - EP395 as a 'victim' of DDIs; Part B - EP395 as a 'perpetrator' of DDIs

Verapamil (Part A) DRUG

Verapamil (CYP3A4/Pgp inhibitor), tablet 40 mg. Part A: Dose: 3 tablets twice daily Days 10 to 18, total daily dose: 240 mg.

Part A - EP395 as a 'victim' of DDIs

Midazolam (Part B) DRUG

Midazolam (CYP3A4 substrate) oral solution 1 mg/mL. Part B: Dose: 4 mL as a single dose on Day 1 and Day 24, total daily dose: 4 mg.

Part B - EP395 as a 'perpetrator' of DDIs

Digoxin (Part B) DRUG

Digoxin (Pgp substrate) tablet 0.25 mg. Part B: Dose: 1 tablet as a single dose on Day 1 and Day 24, total daily dose: 0.25 mg.

Part B - EP395 as a 'perpetrator' of DDIs

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Willing and able to understand the information on the nature, the scope, and the relevance of the trial, and to provide voluntary, written informed consent to participate in the trial before any trial-related procedures.
• Healthy male or female participant aged 18 to 55 years, inclusive.
• Body mass index ≥ 19.0 and ≤ 33.0 kg/m2 at the time of the screening visit.
• Medically healthy participant 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.
• Non-smoker, or former smoker with \<10 pack years who stopped smoking (including e-cigarettes) at least 6 months before the screening visit.
• Women of childbearing potential (WOCBP) must:
• have a negative pregnancy test (blood) at the screening visit and (urine) Day 1.
• agree to use, and be able to comply with, highly effective measures of contraceptive control (failure rate less than 1% per year when used consistently and correctly) without interruption, during trial participation and until 90 days after the last IMP intake.
• agree to abstain from breast feeding during the trial participation and for 90 days after the last IP intake.
• Women defined as of non-childbearing potential are postmenopausal (no menses for at least 1 year without alternative medical cause \[follicle stimulating hormone, FSH, measurement in serum may be done as additional confirmation at Investigator's discretion\]) or surgically sterile women (tubal ligation, hysterectomy, or bilateral oophorectomy).
• Men must agree to use a condom during sexual intercourse with WOCBP during treatment and for 90 days after the last IP intake and should not donate sperm during this time.

You may not qualify if:

• History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the participant at risk because of participation in the trial, or influence the results, or the participant'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.
• Presence or history of lung disease, e.g., asthma, chronic obstructive pulmonary disease.
• Presence or history of significant gastrointestinal medical condition that could lead to abnormal absorption.
• History of or active tuberculosis at the time of the screening visit based on participant anamnesis. Participants who have been living together with another person with active tuberculosis at any time over the past 10 years will also be excluded.
• Clinically significant abnormality on 12-lead ECG at the screening visit or Day 1 pre-dose, including prolonged QTcF (\>450 msec men or \>470 msec women) or PR interval \>210 msec.
• Abnormal renal function at the time of the screening visit:
• serum creatinine \>upper limit of normal (ULN); and/or
• estimated glomerular filtration rate \<60 mL/min according to the revised Lund-Malmö GFR estimating equation.
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>1.5 x ULN at the time of the screening visit.
• Use of prescription or non-prescription medications or herbal remedies within 28 days prior to Day 1, or unable to refrain from prescription or non-prescription medications or herbal remedies during the trial, with the following exceptions:
• hormone replacement therapy (HRT)
• contraception
• occasional use of paracetamol Note: other medications will be reviewed by the Medical Monitor and a participant may be included if both the Investigator and Medical Monitor agree that the medication will not interfere with the trial assessments or participant's safety.
• Live vaccine within 28 days or any other vaccine within 14 days prior to Day 1 until 28 days after the final dose (with the exception of COVID-19 vaccine boosters).

Sponsors & Collaborators

• EpiEndo Pharmaceuticals: lead
• CTC Clinical Trial Consultants AB: collaborator

Study Sites (1)

Clinical Trial Consultants AB

Uppsala, 75237, Sweden

Location

Related Publications (1)

• Singh D, Hanrott K, Breuer O, Bylund J, Schultze B, Norris V. Early clinical pharmacology evaluation of the novel anti-inflammatory macrolide, glasmacinal (EP395): tolerability, pharmacokinetics and drug interactions. Br J Clin Pharmacol. 2026 Mar 17. doi: 10.1002/bcp.70509. Online ahead of print.

  PMID: 41845869 RESULT

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

Verapamil; Midazolam; Digoxin

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenethylamines; Ethylamines; Amines; Organic Chemicals; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Glycosides; Carbohydrates

Study Officials

• Björn Schultze, MD

  CTC Clinical Trial Consultants AB

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a single centre, open label trial to assess the impact of CYP3A4 and Pgp inhibition on the PK of EP395 (Part A); and, to assess the impact of EP395 on the PK of a CYP3A4 substrate and a Pgp substrate (Part B). Parts A and B of the trial may be conducted concurrently.

Study Record Dates

• First Submitted: October 20, 2023
• First Posted: November 7, 2023
• Study Start: October 23, 2023
• Primary Completion: January 2, 2024
• Study Completion: January 2, 2024
• Last Updated: April 29, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

SE (1)