Study to Evaluate Safety, PK and PD of Single and Multiple Ascending Doses of EP-7041 in Healthy Subjects

eXIthera Pharmaceuticals

Status and phase: Completed; Phase 1

Conditions: Arthroplasty, Replacement, Knee

Treatments: Drug: EP=7041; Drug: Placebo

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT02914353

EXI-111

Details and patient eligibility

About

This First-In-Human study will evaluate the safety and tolerability, pharmacokinetic profile, and pharmacodynamic effects of EP-7041, a novel Factor XIa inhibitor, following IV administration of single ascending doses in healthy normal volunteers, and following continuous IV infusions of multiple ascending doses in healthy normal volunteers.

Full description

This will be a single-center, Phase 1a/1b, placebo-controlled, randomized, double-blind, integrated sequential ascending dose / multiple ascending dose study.

The study will be divided into two parts: the single ascending dose evaluation in healthy normal volunteers will constitute Part A and the multiple ascending doses evaluation in healthy normal volunteers will constitute Part B. The two study parts will be performed sequentially with partial overlapping.

Part A will include up to 6 cohorts (1 cohort per dose level; 4 planned cohorts and 2 optional adaptive cohorts). Each cohort will include 8 subjects - 6 on active drug and 2 on placebo - resulting in a maximum number of 48 subjects in the study - 32 planned and 16 optional. Subjects in each cohort will receive a single IV slow bolus (50 mL over 5 minutes) administration of study medication or placebo. The dose of EP-7041 will be sequentially escalated cohort by cohort in Part A . A staggered dosing schedule will be used for each cohort of Part A: 2 sentinel subjects (1 active and 1 placebo) will be dosed first and the remaining 6 subjects will be dosed the next day (5 active and 1 placebo).

Part B will include up to 4 cohorts (1 cohort per dose level; 3 planned cohorts and 1 optional adaptive cohort). As in Part A, each cohort of Part B will include 6 subjects on active drug and 2 on placebo, for a total of 8 subjects per cohort. Part B will therefore involve, at maximum, 32 subjects, with 24 planned subjects an 8 optional subjects. Subjects in each cohort of Part B will receive a total of 5 sequential 24-hour IV infusions of EP-7041 or matching placebo.

Evaluation of safety and tolerability to EP-7041 will include adverse events (i.e., seriousness, severity, relationship to EP-7041), vital signs, ECG, clinical laboratory parameters, physical examination, local response to each injection, and body weight.

Pharmacokinetic analyses will be performed with measurements of EP-7041 plasma concentrations, following single and multiple IV doses.

Pharmacodynamic effects of EP-7041 will be evaluated through the measurement of aPTT and PT in all subjects at multiple times throughout the course of both studies.

Enrollment: 80 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Male or female, non-smoker (no use of tobacco products within 3 months prior to screening), ≥18 and ≤60 years of age, with Body Mass Index (BMI) > 18.5 and < 32.0 kg/m2 and a weight of at least 60 kg but not greater than 100 kg.

• Healthy as defined by:

  1. No history of abnormal bleeding episodes, e.g. nosebleeds, or abnormally heavy periods, or extensive bleeding after injury, surgery or dental work.
  2. A normal short physical examination and normal vital signs (heart rate (HR), blood pressure (BP) and tympanic body temperature).
  3. Normal laboratory tests (hematology, biochemistry, urinalysis, coagulation tests (aPTT and PT).
  4. the absence of clinically significant illness and surgery within 4 weeks prior to dosing.
  5. the absence of clinically significant history of neurological, endocrinal, cardiovascular, pulmonary, hematological, immunologic, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease.

Exclusion criteria

• Any clinically significant abnormality or abnormal laboratory test results found during medical screening which, at the investigator's discretion, warrants exclusion or positive test for hepatitis B, hepatitis C, or HIV.
• Use of any drugs known to induce or inhibit hepatic drug metabolism within 30 days prior to drug administration.
• Positive pregnancy test at screening or check-in (Day -1).
• Clinically significant ECG abnormalities or vital sign abnormalities (systolic blood pressure lower than 90 or over 160 mmHg, diastolic blood pressure lower than 50 or over 90 mmHg, or heart rate less than 40 or over 100 bpm) at screening or check-in (Day -1).
• Participation in a clinical trial involving the administration of an investigational or marketed drug within 30 days (90 days for biologics), or five (5) half-lives, whichever is longer, prior to the first dosing or concomitant participation in an investigational study involving no drug administration.
• Hemoglobin or hematocrit clinically significantly less than lower limits of normal at screening.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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80 participants in 2 patient groups, including a placebo group

Experimental - EP-7041

Experimental group

Description:

Single Ascending Dose: Single IV dose for each cohort; dose range 0.01 mg/kg to 1.0 mg/kg Multiple Ascending Dose: 0.01 mg/kg/h - 5 x 24 h continuous infusion up to 0.6 mg/kg/h - 5 x 24 h continuous infusion

Treatment:

Drug: EP=7041

Placebo - Sterile Saline

Placebo Comparator group

Description:

Single Ascending Dose: Single IV dose for each cohort; Multiple Ascending Dose: 5 x 24 h continuous infusion for each cohort

Treatment:

Drug: Placebo