DDI Study of Single Oral Dose of Acoziborole With Sequential Co-administration of Midazolam and Dextromethorphan

NCT05947604 | Completed Phase 1

• 1 other identifier: DNDi-OXA-07-HAT
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

To assess Drug drug interactions between Acoziborole and Dextromethorphan and Midazolam in healthy male volunteers.

Conditions

Trypanosomiasis, African

Outcome Measures

Primary Outcomes (6)

• To assess the effect of single dose of acoziborole on pharmacokinetics (PK) parameters (Cmax) of midazolam as a probe substrate for CYP3A4 (induction)

  Midazolam Cmax, plasma concentration

  Up to 72 hours post drug administration

• To assess the effect of single dose of acoziborole on pharmacokinetics (PK) parameters (Cmax) of dextromethorphan as a probe substrate for CYP2D6 (inhibition).

  Dextromethorphan Cmax, plasma concentration

  Up to 72 hours post drug administration

• To assess the effect of single dose of acoziborole on pharmacokinetics (PK) parameters ( AUC0-t) of midazolam as a probe substrate for CYP3A4 (induction)

  Midazolam AUC0-t (plasma concentration) of Period 1 and Period 2.

  Up to 72 hours post drug administration

• To assess the effect of single dose of acoziborole on pharmacokinetics (PK) parameters ( AUC0-t) of dextromethorphan as a probe substrate for CYP2D6 (inhibition).

  Dextromethorphan AUC0-t (plasma concentration) of Period 1 and Period 2.

  Up to 72 hours post drug administration

• To assess the effect of single dose of acoziborole on pharmacokinetics (PK) parameters (AUC0-24) of midazolam as a probe substrate for CYP3A4 (induction)

  Midazolam AUC0-24 (plasma concentration) of Period 1 and Period 2

  Up to 72 hours post drug administration

• To assess the effect of single dose of acoziborole on pharmacokinetics (PK) parameters (AUC0-24) of dextromethorphan as a probe substrate for CYP2D6 (inhibition).

  Dextromethorphan AUC0-24 of Period 1 and Period 2.

  Up to 72 hours post drug administration

Secondary Outcomes (63)

• To evaluate the clinical and laboratory safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.

  Up to End of Study Visit, Day 31

• To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: Height

  Baseline

• To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: weight

  Baseline and End of Study (Day 28 to Day 31)

• To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: Sistolic and Diastolic BP

  Up to End of Study (Day 28 to Day 31)

• To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: respiratory rate

  Up to End of Study (Day 28 to Day 31)

Study Arms (2)

Dextromethorphan and Midazolam

OTHER

Drug drug interaction Dextromethorphan and Midazolam administrations * Dextromethorphan 15 mg syrup in fasted condition Period 1: Single oral dose of 15 mg administered on Day 1 * Midazolam 5 mg syrup in fasted condition Period 1: Single oral dose of 5 mg administered on Day 8

Drug: Midazolam; Drug: Dextromethorphan

Acoziborole, Dextromethorphan and Midazolam

OTHER

Drug drug interaction Acoziborole, Dextromethorphan and Midazolam administrations * Acoziborole 960 mg (three tablets of 320 mg) for oral route in fasted condition Period 2: single oral administration on Day 12 * Dextromethorphan 15 mg syrup in fasted condition Period 2: Single oral dose of 15 mg administered on Day 14 * Midazolam 5 mg syrup in fasted condition Period 2: Single oral dose of 5 mg administered on Day 21

Drug: Acoziborole; Drug: Midazolam; Drug: Dextromethorphan

Interventions

Acoziborole DRUG

Acoziborole 960 mg (three tablets of 320 mg) for oral route in fasted condition Period 2: single oral administration on Day 12

Acoziborole, Dextromethorphan and Midazolam

Midazolam DRUG

• Midazolam 5 mg syrup in fasted condition Period 1: Single oral dose of 5 mg administered on Day 8 Period 2: Single oral dose of 5 mg administered on Day 21

Acoziborole, Dextromethorphan and Midazolam; Dextromethorphan and Midazolam

Dextromethorphan DRUG

• Dextromethorphan 15 mg syrup in fasted condition Period 1: Single oral dose of 15 mg administered on Day 1 Period 2: Single oral dose of 15 mg administered on Day 14

Acoziborole, Dextromethorphan and Midazolam; Dextromethorphan and Midazolam

Eligibility Criteria

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

You may qualify if:

• Healthy males.
• Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures..
• Age 18 to 55 (inclusive) years of age at the time of signing informed consent.
• Body mass index (BMI) of 18.0 to 30.0 kg/m2 as measured at screening.
• Body weight not less than 50 kg.
• Non-smokers (defined as has not used nicotine-containing products including e-cigarette for at least 3 months prior to the first dose as confirmed by cotinine test).
• Must be willing and able to communicate and participate in the whole study.
• Normal blood pressure (BP): Systolic BP (SBP) between 90 and 140 mmHg (inclusive), diastolic BP (DBP) between 45 and 90 mmHg (inclusive), measured after 10 min rest in supine position at screening and first admission (Day -1).
• A resting heart rate (HR) between 45 and 90 bpm (inclusive), measured after 10 min rest in supine position at screening and first admission (Day -1).
• ECG recording without clinically significant abnormality, including Fridericia's corrected interval between Q and T waves (QTcF) measure of ≤450 msec at screening and first admission (Day -1).
• Participants must be able to swallow multiple capsules.

You may not qualify if:

• Have participated in an investigational trial involving administration of any investigational compound within 90 days prior to the study dosing or 5-times the half-life of the drug tested in the previous clinical trial, whichever is longer (time calculated relative to the last dose in the previous clinical trial).
• History of any drug or alcohol abuse in the past 2 years.
• Regular alcohol consumption \>14 units per week and (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on type) as confirmed by a positive alcohol breath test at screening or any on admission to the CRW.
• Participants who do not have suitable veins for multiple venepunctures/cannulations as assessed by the Investigator or delegate at screening.
• Clinically significant abnormal clinical chemistry, haematology, urinalysis, or clinically significant abnormal physical examination findings as judged by the Investigator.
• Abnormal renal function (estimate glomerular filtration rate \[eGFR\] \<90 mL/min).
• Confirmed positive drugs of abuse urine test result (including but not limited to, amphetamines, tetrahydrocannabinol, morphine, methamphetamine, ketamine and benzodiazepines) and at any time during the study.
• Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results.
• Positive COVID test at screening and at admission of hospitalisation.
• COVID-19 full vaccination to be received less than 21 days before Day 1, or start of vaccination, or second dose or booster of vaccination planned during the study period.
• Clinically significant medical condition and/or abnormal laboratory results that could, in the opinion of the Investigator, jeopardize the participant's safety or participation in the study.
• Known serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients in the past.
• Presence or history of clinically significant allergy requiring treatment (including asthma, urticaria, clinically significant allergic rash or other severe allergic diathesis), as judged by the Investigator. Hay fever is allowed unless it is active.
• Donation or loss of greater than 400 mL of blood within the previous 3 months or more than 100 mL within 30 days before signing informed consent form (ICF) to this trial.
• Participants who are taking any prescribed drug in the 30 days before screening or require regular use of any prescription medication during the study.

Sponsors & Collaborators

• Drugs for Neglected Diseases: lead

Study Sites (1)

Clinical Research Center (CRC) Ampang Hospital

Kuala Lumpur, Malaysia

Location

MeSH Terms

Conditions

Trypanosomiasis, African

Interventions

Midazolam; Dextromethorphan

Condition Hierarchy (Ancestors)

Trypanosomiasis; Euglenozoa Infections; Protozoan Infections; Parasitic Diseases; Infections; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Study Officials

• Sharon Ng Shi Min

  Clinical Research Center (CRC) Ampang Hospital

  PRINCIPAL INVESTIGATOR

Study Design

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

Model Details: On Period 1, participants will receive: A single oral dose of Dextromethorphan on Day and of midazolam on Day 8. On Period 2, participants will receive: A single oral dose of acoziborole on Day 12, of dextromethorphan on Day 14, and of midazolam on Day 21. The study duration will be approximately 8 weeks: Screening period before the first study drug administration, Period 1 with a hospitalisation period from the day before the first dose of dextromethorphan until 24 h after the first dose of midazolam, Wash-out period: 3 days, Period 2 with a hospitalisation period from the day before the single administration of acoziborole until 24 h after the last dose of midazolam . End of study (EoS) visit between 7-10 days after last dose of midazolam on Period 2

Study Record Dates

• First Submitted: March 5, 2023
• First Posted: July 17, 2023
• Study Start: February 9, 2023
• Primary Completion: May 3, 2023
• Study Completion: May 3, 2023
• Last Updated: July 17, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

MY (1)