Study of Potential for Drug Interactions Mediated by CYP3A4 Inhibition With Aramchol in Healthy Volunteers

NCT03760848 | Completed Phase 1

• 1 other identifier: Aramchol 016
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

The trial is an open-label, 2-period, single-sequence assessment of CYP3A4 inhibition by aramchol using the probe substrates midazolam and atorvastatin to assess CYP3A4 activity.

Conditions

Healthy

Outcome Measures

Primary Outcomes (20)

• Midazolam - cmax

  Maximum plasma concentration

  Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.

• Atorvastatin - cmax

  Maximum plasma concentration

  Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.

• Midazolam - tmax

  Time of maximum plasma concentration

  Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.

• Atorvastatin - tmax

  Time of maximum plasma concentration

  Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.

• Midazolam - Area under the concentration-time curve to last measurable concentration (AUClast)

  Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.

• Atorvastatin - Area under the concentration-time curve to last measurable concentration (AUClast)

  Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.

• Midazolam - Area under the concentration-time curve extrapolated to infinite time (AUCinf)

  Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.

• Atorvastatin - Area under the concentration-time curve extrapolated to infinite time (AUCinf)

  Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.

• Midazolam - %AUCextrapinf

  Percentage of AUC that was extrapolated

  Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.

• Atorvastatin - %AUCextrapinf

  Percentage of AUC that was extrapolated

  Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.

• Midazolam - t½

  Terminal elimination half-life

  Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.

• Atorvastatin - t½

  Terminal elimination half-life

  Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.

• Midazolam - CL/F

  Clearance/fraction of dose absorbed

  Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.

• Atorvastatin - CL/F

  Clearance/fraction of dose absorbed

  Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.

• Midazolam - VZ/F

  Volume of distribution/fraction of dose absorbed

  Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.

• Atorvastatin - VZ/F

  Volume of distribution/fraction of dose absorbed

  Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.

• Midazolam - MRT

  Mean residence time

  Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.

• Atorvastatin - MRT

  Mean residence time

  Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.

• Midazolam - λz

  Terminal rate constant

  Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.

• Atorvastatin - λz

  Terminal rate constant

  Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.

Study Arms (1)

Midazolam, Atorvastatin / Aramchol, Midazolam, Atorvastatin

OTHER

Midazolam 2 mg -atorvastatin 40 mg /Aramchol 600mg -midazolam 2 mg-atorvastatin 40 mg (MA/MAA)

Drug: Aramchol; Drug: Midazolam; Drug: Atorvastatin

Interventions

Aramchol DRUG

Aramchol 600 mg

Midazolam, Atorvastatin / Aramchol, Midazolam, Atorvastatin

Midazolam DRUG

Midazolam 2 mg

Midazolam, Atorvastatin / Aramchol, Midazolam, Atorvastatin

Atorvastatin DRUG

atorvastatin 40 mg

Midazolam, Atorvastatin / Aramchol, Midazolam, Atorvastatin

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male healthy volunteers.
• Aged 18-45 years at time of consent.
• A body mass index (BMI; Quetelet index) in the range 18.0-30.9.
• Ability to understand the nature of the trial and any hazards of participating in it. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of the entire trial.
• Willingness to give written consent to participate after reading and understanding the information and consent form, and after having the opportunity to discuss the trial with the investigator or his delegate.
• Agree to use effective contraception as described in section 9.
• Agree not to donate blood or blood products during the study and for up to 3 months after the administration of the trial medication.
• Willingness to give written consent to have data entered into The Overvolunteering Prevention System (TOPS).

You may not qualify if:

• Volunteers of East Asian descent including, but not limited to, Chinese, Japanese, Korean, Mongolian, and/or Vietnamese
• Be a smoker, or have smoked cigarettes or other tobacco or nicotine products in the last 12 months.
• Clinically relevant abnormal history, physical findings, ECG, or laboratory values at the pre-trial screening assessment that could interfere with the objectives of the trial or the safety of the volunteer.
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (AP) \> Upper Limit of Normal (ULN) at the screening visit. A repeat is allowed on one occasion for determination of eligibility.
• Presence of acute or chronic illness or history of chronic illness sufficient to invalidate the volunteer's participation in the trial or make it unnecessarily hazardous,
• Presence or history of obstructive sleep apnoea.
• History or presence of any disease or condition known to interfere with the absorption, distribution, metabolism or excretion of drugs including gastrointestinal disorder or of oesophageal, gastric, biliary or intestinal surgery (excluding herniotomy and appendectomy).
• Use of anticholinergic or other drugs known to affect gastrointestinal motility during the 7 days before the first dose of trial medication.
• Impaired endocrine, thyroid, hepatic, respiratory or renal function, diabetes mellitus, coronary heart disease, or history of any psychotic mental illness.
• Surgery (eg stomach bypass) or medical condition that might affect absorption of medicines.
• Presence or history of severe adverse reaction to any drug or a history of sensitivity to aramchol, midazolam or atorvastatin, or any excipients in the tablets.
• Use of a prescription medicine or any other medicine or herbal remedy (such as St John's wort) during the 28 days before the first dose of trial medication or use of any other over-the-counter medicine, with the exception of acetaminophen (paracetamol), during the 7 days before the first dose of trial medication.
• Receipt of an investigational product (including prescription medicines) as part of another clinical trial within the 3 months before first admission to this study; in the follow-up period of another clinical trial at the time of screening for this study.
• Presence or history of drug or alcohol abuse, or intake of more than 14 units of alcohol weekly.
• Blood pressure and heart rate in supine position at the screening examination outside the ranges: blood pressure 100-140 mm Hg systolic, 50-90 mm Hg diastolic; heart rate 45\_90 beats/min, unless judged not clinically significant.

Sponsors & Collaborators

• Galmed Pharmaceuticals Ltd: lead
• Hammersmith Medicines Research: collaborator
• Analyst Research Laboratories: collaborator
• Alderley Analytical Ltd.: collaborator
• Diamond Pharma Services Regulatory Affairs Consultancy: collaborator

Study Sites (1)

Hammersmith Medicines Research (HMR)

London, NW10 7EW, United Kingdom

Location

MeSH Terms

Interventions

aramchol; Midazolam; Atorvastatin

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heptanoic Acids; Fatty Acids; Lipids

Study Officials

• Adeep Puri, M.D.

  HMR

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 22, 2018
• First Posted: November 30, 2018
• Study Start: November 12, 2018
• Primary Completion: February 2, 2019
• Study Completion: February 2, 2019
• Last Updated: August 22, 2019

Record last verified: 2019-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)