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

Arthroplasty, Replacement, Knee Clinical Trial

Official title:

A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate The Safety Tolerability, Pharmacokinetics, and Pharmacodynamcs of Single and Multiple Ascending Doses of EP-7041 in Hea;Thy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02914353
• Other study ID #: EXI-111
• Status: Completed
• Phase: Phase 1
• First received: September 19, 2016
• Last updated: May 30, 2017
• Start date: July 2016
• Est. completion date: May 2017

Study information

• Verified date: May 2017
• Source: eXIthera Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: May 2017
• Est. primary completion date: May 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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.

Related Conditions & MeSH terms

• Arthroplasty, Replacement, Knee

Intervention

Drug:
• EP=7041
Factor X!a Inhibitor
• Placebo
Normal Saline

Locations

Country	Name	City	State
Australia	IDT CMAX	Adelaide	South Australia

Sponsors (4)

Lead Sponsor	Collaborator
eXIthera Pharmaceuticals	CPR Pharma Services Pty Ltd, Australia, IDT CMAX Clinical Trials, INC Research

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 following a single IV bolus of EP-7041	Assessment of safety and tolerability to EP-7041, administered as a single IV bolus, will be based on adverse events. Each AE will be graded with respect to its relationship to treatment using five categories: not related, unlikely, possible, probable, and highly probable. Each AE will also be graded on a three-point severity scale: mild, moderate, and severe. Adverse events will be coded by body system and preferred term using the MedDRA (Medical Dictionary for Regulatory Activities) dictionary. Assessments as to the effect of EP-7041 on vital signs, 12-lead ECG, telemetry, clinical laboratory parameters, physical examination, and local response to each injection, and body weight will also be made.; The number and percentage of subjects experiencing adverse events will be tabulated for each treatment group by body system and preferred term. The number and percentage of subjects experiencing AEs will also be tabulated by relationship to drug treatment and by severity. If an AE is	Adverse events will be collected and documented during the course of the study. For a period of 30 days following the last study drug administration, adverse events will also be documented if reported.
Primary	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 following a continuous IV infusion of EP-7041 administered over 5 days	Assessment of safety and tolerability to EP-7041, administered as a continuous IV infusion over 5 days, will be based on adverse events. Each AE will be graded with respect to its relationship to treatment using five categories: not related, unlikely, possible, probable, and highly probable. Each AE will also be graded on a 3-point severity scale: mild, moderate, and severe. Adverse events will be coded by body system and preferred term using the Medical Dictionary for Regulatory Activities dictionary. Assessments as to the effect of EP-7041 on vital signs, 12-lead ECG, telemetry, clinical laboratory parameters, physical examination, and local response to each injection, and body weight will also be made. The number and percentage of subjects experiencing adverse events will be tabulated for each treatment group by body system and preferred term.; The number and percentage of subjects experiencing AEs will also be tabulated by relationship to drug treatment and by severity.	Adverse events will be collected and documented during the course of the study. For a period of 30 days following the last study drug administration, adverse events will also be documented if reported.
Secondary	Measurement of Maximum Plasma Concentration Achieved Following a Single IV Bolus of EP-7041	Maximum Plasma Concentration (Cmax)	24 hours
Secondary	Measurement of Time of Maximum Plasma Concentration Following a Single IV Bolus of EP-7041	Time of Maximum Plasma Concentration (Tmax)	24 hours
Secondary	Measurement of Plasma Half-Life Following a Single IV Bolus of EP-7041	Plasma Half-Life (T½)	24 hours
Secondary	Measurement of ClearanceFollowing a Single IV Bolus of EP-7041	Clearance (CL)	24 hours
Secondary	Measurement of the Area Under the Plasma Concentration versus Time Curve Following a Single IV Bolus of EP-7041	Area Under the Curve (AUC)	24 hours
Secondary	Measurement of the Elimination Rate Constant Following a Single IV Bolus of EP-7041	Elimination Rate Constant (Kel)	24 hours
Secondary	Measurement of the Apparent Volume of Distribution Following a Single IV Bolus of EP-7041	Apparent Volume of Distribution (Vd)	24 hours
Secondary	Measurement of the Steady-State Concentration with a the Initiation of Continuous IV 5-day Infusion of EP-7041	Concentration at Steady State (Css)	6 days
Secondary	Measurement of the Time to Reach a Steady-State Concentration Following a the Initiation of Continuous IV 5-day Infusion of EP-7041	Time to Reach Concentration at Steady State (Tss)	6 days
Secondary	Measurement of the Clearance During the Course of a Continuous IV 5-day Infusion of EP-7041	Clearance (CL)	6 days
Secondary	Measurement of the Plasma Half-Life Following the Discontinuation of Continuous IV 5-day Infusion of EP-7041	Plasma Half-Life (T½)	6 day
Secondary	Measurement of Clotting Biomarker Activated Partial Thromboplastin Time Following a Single IV Bolus of EP-7041	Activated Partial Thromboplastin Time (aPTT)	1 day
Secondary	Measurement of Clotting Biomarker Activated Partial Thromboplastin Time During the Course of a Continuous IV 5-day Infusion of EP-7041	Activated Partial Thromboplastin Time (aPTT)	6 days
Secondary	Measurement of Clotting Biomarker Prothrombin Following a Single IV Bolus of EP-7041	Prothrombin Time (PT)	1 day
Secondary	Measurement of Clotting Biomarker Prothrombin During the Course of a Continuous IV 5-day Infusion of EP-7041	Prothrombin Time (PT)	6 day
Secondary	Measurement of Clotting Biomarker International Normalized Ratio Following a Single IV Bolus of EP-7041	International Normalized Ratio (INR)	1 day
Secondary	Measurement of Clotting Biomarker International Normalized Ratio During the Course of a Continuous IV 5-day Infusion of EP-7041	International Normalized Ratio (INR)	6 days