A Study to Examine the Effects of Entinostat on Midazolam in Healthy Adult Subjects

NCT03187015 | Completed Phase 1 FDA Drug

• 1 other identifier: SNDX-275-0160
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to evaluate the effect of Entinostat on the bioavailability of Midazolam. The primary objective is to evaluate the effect of a single oral dose of entinostat on the pharmacokinetics (PK) of a single oral dose of midazolam in healthy subjects. The secondary objective is to evaluate the safety and tolerability of combined administration of entinostat and midazolam in healthy subjects.

Conditions

Drug Interaction; Healthy Volunteer

Keywords

Healthy Volunteers; Entinostat; Histone Deacetylase Inhibitor; HDAC

Outcome Measures

Primary Outcomes (3)

• PK endpoint of AUC0-t (area under the concentration-time curve) for midazolam administered with and without entinostat.

  AUC0-t for midazolam and 1 OH midazolam will be computed.

  Pre-dose to 24 hours after dosing

• PK endpoint of AUC0-inf (area under the concentration-time curve, from time 0 extrapolated to infinity) for midazolam administered with and without entinostat.

  AUC0-inf for midazolam and 1 OH midazolam will be computed

  Pre-dose to 24 hours after dosing

• PK endpoint of Cmax (maximum observed concentration) for midazolam administered with and without entinostat.

  Cmax for midazolam and 1 OH midazolam will be computed

  Pre-dose to 24 hours after dosing

Secondary Outcomes (1)

• Incidence of Treatment Emergent Adverse Events (safety and tolerability) of combined administration of entinostat and midazolam in healthy subjects.

  Pre-dose to 14 days after last dose

Other Outcomes (5)

• PK endpoint of AUC%extrap (percent of AUC0-inf extrapolated) for midazolam administered with and without entinostat.

  Pre-dose to 24 hours after dosing

• PK endpoint of Tmax (time to reach maximum observed concentration) for midazolam administered with and without entinostat.

  Pre-dose to 24 hours after dosing

• PK endpoint of Kel (apparent terminal elimination rate constant) for midazolam administered with and without entinostat.

  Pre-dose to 24 hours after dosing

Study Arms (1)

Midazolam

OTHER

Treatment A: 2 mg of Midazolam administered - Period 1, Day 1 Treatment B: 2 mg of Midazolam with 5 mg Entinostat (after 14 day minimum washout from Period 1, Day 1) - Period 2, Day 1

Drug: Entinostat; Drug: Midazolam

Interventions

Entinostat DRUG

HDAC (histone deacetylase inhibitor)

Also known as: SNDX-275, MS-275

Midazolam

Midazolam DRUG

benzodiazepine central nervous system (CNS) depressant

Midazolam

Eligibility Criteria

• Age: 19 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• \. Healthy, adult, male or female (of non childbearing potential only), 19-55 years of age, inclusive, at screening.
• Continuous non smoker who has not used nicotine containing products for at least 3 months prior to the first dose and throughout the study.
• Body mass index (BMI) ≥ 18.5 and ≤ 32 kg/m2 at screening.
• For a female of non childbearing potential: must have undergone one of the following sterilization procedures, and have official documentation, at least 6 months prior to the first dose:
• hysteroscopic sterilization;
• bilateral tubal ligation or bilateral salpingectomy;
• hysterectomy;
• bilateral oophorectomy; or be postmenopausal with amenorrhea for at least 1 year prior to the first dose and follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status as per PI or designee judgment.
• A non vasectomized, male subject must agree to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days beyond the last dose of study drug. (No restrictions are required for a vasectomized male provided his vasectomy has been performed 4 months or more prior to first dose of study drug. A male who has been vasectomized less than 4 months prior to study first dose must follow the same restrictions as a non vasectomized male).
• If male, must agree not to donate sperm from the first dose until 90 days after the last dose of study drug.
• Understands the study procedures in the informed consent form (ICF), and be willing and able to comply with the protocol.

You may not qualify if:

• Subject is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study.
• History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the PI or designee.
• History of any illness that, in the opinion of the PI or designee, might confound the results of the study or poses an additional risk to the subject by their participation in the study.
• History or presence of alcoholism or drug abuse within the past 2 years prior to the first dose.
• History or presence of hypersensitivity or idiosyncratic reaction to entinostat or drugs with a benzamide structure (e.g., tiapride, remoxipride, clebropride), midazolam, related compounds, or inactive ingredients.
• History or presence of any of the following as deemed clinically significant in the opinion of the PI or designee:
• Cardiovascular disorders;
• Acute or chronic GI conditions (e.g., gastroesophageal reflux disease, peptic ulcer, colitis, gastric bypass or equivalent) that would interfere with drug tolerance or absorption.
• Respiratory disease.
• Evidence of active infection or febrile illness (e.g., GI, bronchopulmonary, or urinary) within 7 days prior to the first dose of study drug
• Clinically significant infection within 3 months prior to dosing as determined by the PI or designee.
• Positive urine drug or alcohol results at screening or check in.
• Positive urine cotinine at screening.
• Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV).
• Female subjects of childbearing potential.

Sponsors & Collaborators

• Syndax Pharmaceuticals: lead

Study Sites (1)

Celerion

Lincoln, Nebraska, 68502, United States

Location

MeSH Terms

Interventions

entinostat; Midazolam

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• James Carraher, MD

  Celerion

  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: April 14, 2017
• First Posted: June 14, 2017
• Study Start: May 23, 2017
• Primary Completion: June 4, 2017
• Study Completion: August 22, 2017
• Last Updated: August 16, 2018

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)