Safety and Efficacy Study of AB002 (E-WE Thrombin) in End Stage Renal Disease Patients on Chronic Hemodialysis

Aronora, Inc.40 enrolled

Overview

This study evaluates the safety and efficacy of AB002 (E-WE thrombin) in patients with end stage renal disease on chronic hemodialysis. Two dose levels will be evaluated in two cohorts. Within each cohort the patients will be randomized to receive either AB002 (E-WE thrombin) or placebo (at a ratio of 2:1 active: placebo).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Enrollment

Conditions

End Stage Renal Disease Thrombosis

Interventions

AB002 Dose 1DRUG

AB002 (E-WE thrombin) 1.5 mcg/kg administered on Day 1 as a single intravenous infusion

AB002 Dose 2DRUG

AB002 (E-WE thrombin) 3.0 mcg/kg administered on Day 1 as a single intravenous infusion

placeboDRUG

placebo administered on Day 1 as a single intravenous infusion

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. End Stage Renal Disease (ESRD) maintained on stable outpatient hemodialysis regimen, using an established (\> 3 months) and normally functioning, regular flow, uninfected mature AV fistula (or AV graft) and skin consistent with standard chronic hemodialysis access injuries, and hemodialysis stability defined as Kt/V ≥ 1.2 within 3 months prior to screening at a healthcare center for \> 3 months from screening. 2. On hemodialysis regimen at least 3 times per week for a minimum of 3 hours per dialysis session, using a complication-free well maintained AV fistula (or AV graft), expected and plan to continue this throughout and for at least 3 months beyond the study. 3. Is capable of understanding the written informed consent, provides signed and witnessed written informed consent and agrees to comply with protocol requirements and study related procedures. 4. Willing to be confined to the clinical research unit for the duration of the study, able to comply with all study-related requirements, and able to adhere to study restrictions and visit schedules. 5. Male or female, between 18 and 80 years of age (inclusive) at the time of screening. 6. Body Mass Index (BMI) of ≥ 18 at the time of screening. 7. Considered by the principle investigator (PI) to be clinically stable with respect to underlying ESRD, based on the medical evaluation that includes medical and surgical history, and a complete physical examination including vital sign measurements, electrocardiograms (ECGs), and clinical laboratory and coagulation test results at screening. Repeat assessments are permitted for any laboratory, coagulation, ECG, or vital sign parameter required for enrollment. 8. Female patients must be of non-childbearing potential and must have undergone one of the following sterilization procedures at least 6 months prior to dosing: * hysteroscopic sterilization; * bilateral tubal ligation or bilateral salpingectomy; * hysterectomy; * bilateral oophorectomy; or be postmenopausal with amenorrhea for at least 1 year prior to dosing and follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status as per PI or designee judgment. 9. Male patients must either be sterile (vasectomy with history of a negative sperm count following the procedure); practice total abstinence from sexual intercourse as the preferred lifestyle (periodic abstinence is not acceptable); use a male condom with any sexual activity; or agree to use a birth control method considered to be appropriate by the Investigator from the time of dosing until 90 days after study drug administration. Male patients must agree not to donate sperm for a period of 90 days after study drug administration. Exclusion Criteria: 1. Documented history of acute vasoocclusive thrombotic event (acute coronary syndrome, stroke or transient ischemic attack, venous thromboembolic event), or vascular access fistula or AV graft failure in the past 3 months. 2. With the exception of unfractionated heparin during HD that is allowed until study check-in, concomitant or prior use of anticoagulant/antiplatelet agents (e.g., low molecular weight heparins, warfarin, apixaban, bivalirudin, ticagrelor, edoxaban, dabigatran, rivaroxaban, clopidogrel, prasugrel, ticlopidine, eptifibatide, tirofiban, dipyridamole, diclofenac, and all other non steroidal antiinflammatory drugs) that may affect hemostasis for 2 weeks prior to check in on Day -8 and throughout the study. 3. Any clinically significant (CS) concomitant disease or condition (including treatment for such conditions) that, in the opinion of the PI, could either interfere with the study drug, compromise interpretation of study data, or pose an unacceptable risk to the patient. 4. Any other CS abnormalities in laboratory test results at screening or Day * 8 check-in that would, in the opinion of the PI, increase the patient's risk of participation, jeopardize complete participation in the study, or compromise interpretation of study data. 5. Pregnant (positive pregnancy test) at screening or check-in on Day -8. If serum human chorionic gonadotropin (hCG) pregnancy test results are indeterminate, follow-up testing should be performed to determine eligibility. All female patients will not be pregnant and will have a negative pregnancy test at screening and check-in on Day -8, with the following exception: females receiving dialysis with an indeterminate pregnancy test result or persistently low hCG resulting in a false positive pregnancy test may be included in the study at the discretion of the PI. Postmenopausal patients with a result outside the postmenopausal range or an indeterminate pregnancy test will undergo additional testing with FSH to confirm postmenopausal status prior to study enrollment. 6. Treatment with another investigational drug or participation in a device study within 30 days (or 5 half lives, whichever is longer) prior to check-in on Day -8. 7. Acute illness that is considered by the PI to be CS within 2 weeks of check-in on Day 8. 8. Surgery within the past 90 days prior to dosing which in the opinion of the PI or designee is clinically relevant. 9. Currently have established underlying inherited or acquired symptomatic bleeding disorders and/or are at risk for excessive bleeding per PI judgment or current active bleeding (e.g., gastrointestinal, intracranial), aside from minor bleeding from the puncture site on the AV fistula or AV graft, which would be expected to occur during the dialysis procedure, with the following values: * Platelet count \< 100,000 cells/mm3 (if \< 100,000 cells/mm3 but \> 75,000 cells/mm3, with permission of PI and medical monitor) at screening or check-in on Day -8. * INR \> 1.4 at screening or check-in on Day -8 * aPTT up to 1.2 x upper limit of normal (ULN) (if \> 1.2 x ULN and up to \< 1.5 x ULN, with permission of PI and medical monitor) at screening or check-in on Day -8 * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2 x ULN at screening or check-in on Day -8 * Total bilirubin \> 1.2 x ULN at screening or check-in on Day -8 * Hemoglobin concentration \< 10 g/dL at screening or check-in on Day * 8 10. Seated blood pressure \< 90/40 mmHg at screening and check-in on Day * 8\. 11. Exclusion criteria for ECG at screening and check-in on Day -8: Heart rate \< 45 and \> 110 bpm QTcF interval \> 500 msec bpm = beats per minute; msec = milliseconds; QTcF = QT interval corrected using Fridericia's formula * Any significant arrhythmia or conduction abnormality, (including but not specific to atrioventricular block \[2nd degree or higher\], Wolff Parkinson White syndrome \[unless curative radio ablation therapy\]), which, in the opinion of the PI and Medical Monitor, could interfere with the safety for the individual patient. * Non-sustained or sustained ventricular tachycardia (\> 2 consecutive ventricular ectopic beats at a rate of \> 1.7/second). 12. History of a CS allergy or a known sensitivity or idiosyncratic reaction to any compound known to be present in E-WE thrombin, its related compounds, or any compound listed as being present in the study formulation. 13. Hypersensitivity to ß-lactam / penicillin derivatives. 14. Participate in strenuous exercise from 72 hours prior to check-in on Day -8 and throughout the study. 15. Positive test for drugs of abuse and/or positive alcohol test at screening or check in on Day 8 if not accounted for by a prescription medication. Patients with a positive test based on a prescribed medication may be enrolled. 16. Positive test at screening for hepatitis B surface antigen (HBsAg) or human immunodeficiency virus (HIV). If a patient with ESRD has positive test results for hepatitis C virus (HCV) but liver function tests are otherwise not clinically significant, the patient may be included at the PI's discretion. 17. Receiving blood purification therapy other than HD. 18. Donation of blood or significant blood loss within 56 days prior to dosing. 19. Plasma donation within 7 days prior to dosing. 20. Presence of advanced malignant neoplasms of any organ or system that produces illness or symptoms that have been treated within 3 months with chemotherapy or whole body irradiation, or bone marrow irradiation, and may affect life expectancy in the following 6 months. 21. Any other reason that would render the patient unsuitable for study enrollment at the discretion of the PI.

Locations (1)

Orlando Clinical Research Center

Orlando, Florida, United States

Outcomes

Primary Outcomes

The Number of Subjects With Treatment-emergent Adverse Events (TEAEs) Related to Treatment Will be Summarized Using Frequency Counts (Safety and Tolerability)

TEAEs will be determined by physical examination that will include assessment of skin, head, ears, eyes, nose, throat, respiratory system, cardiovascular system, gastrointestinal system, neurological condition, blood and lymphatic systems, and the musculoskeletal system.

Time frame: 22 days

The Number of TEAEs Related to Treatment Will be Summarized Using Frequency Counts (Safety and Tolerability).

Time frame: 22 days

The Number of Subjects With Bleeding at the Hemodialysis (HD) Vascular Access Site (Safety and Tolerability)

The number of patients in which clinically relevant and non-major bleeding events occurred from the vascular access site. Bleeding from the access site was assessed immediately following decannulation. Pressure was placed on the access site for 10 min. After 10 minutes, the access site was checked for bleeding. If still bleeding, pressure was applied for another 5 minutes and checked again. This was repeated until hemostasis was achieved and the time to hemostasis was recorded. A time greater than 10 min was considered a non-major bleeding event.

Time frame: At each hemodialysis session (non-dose days: study day -7, -5, -2, and 3 and dose day: study day 1)

The Number of Subjects With Abnormal Electrocardiogram That is Related to Treatment Will be Summarized Using Frequency Counts (Safety and Tolerability).

12-lead electrocardiogram measurement. Abnormal electrocardiogram was determined by the study PI. The result was determined to be treatment related if the abnormal electrocardiogram occurred post-treatment and not pre-treatment. Data from the specified time points (Study Day 1 (0.5h post-dose) and Study Day 3) were combined by adding the number of participants on each Study Day that showed an abnormal electrocardiogram compared to pre-treatment (Study Day -8).

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Time frame: Study Days -8 (pre-treatment), Day 1, and 3 (post-treatment)

The Number of Subjects That Develop Antibodies to Endogenous Thrombin Will be Summarized Using Frequency Counts (Safety and Tolerability).

Immunogenicity measured by the presence of serum anti-thrombin antibodies in both an ADA screening assay and confirmatory assay.

Time frame: Study day 1 pre-dose and study day 14

The Number of Subjects With Clinically Significant Changes in Body Temperature in Relation to Treatment Will be Assessed.

Body temperature will be measured in degrees Celsius. Clinically significant changes in body temperature were determined by the study PI. The result was determined to be treatment related if the change in body temperature occurred post-treatment and not pre-treatment. Data from the specified time points (Study Day 1 (1h post-dose) and Study Day 3) were combined by adding the number of participants on each Study Day that showed a clinically significant change in body temperature compared to pre-treatment (Study Days -7, -5, -2, and 1 (pre-dose)).

Time frame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment)

The Number of Subjects With Clinically Significant Changes in Respiratory Rate and Relation to Treatment Will be Assessed.

Respiratory rate will be measured in breaths per minute. Clinically significant changes in respiratory rate were determined by the study PI. The result was determined to be treatment related if the clinically significant changes in respiratory rate occurred post-treatment compared to pre-treatment. Data from the specified time points (Study Day 1 (1h post-dose) and Study Day 3) were combined by adding the number of participants on each Study Day that showed a clinically significant change in respiratory rate compared to pre-treatment (Study Days -7. -5. -2 and 1 (pre-dose)).

Time frame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment)

The Number of Subjects With Clinically Significant Changes in Blood Pressure (Systolic and Diastolic) and Relation to Treatment Will be Assessed.

Systolic and diastolic blood pressure will be measured in mmHg. Clinically significant changes in blood pressure were determined by the study PI. The result was determined to be treatment related if the clinically significant changes in blood pressure occurred post-treatment compared to pre-treatment. Data from the specified time points (Study Day 1 (1h post-dose) and Study Day 3) were combined by adding the number of participants on each Study Day that showed a clinically significant change in blood pressure compared to pre-treatment (Study Days -7, -5, -2 and 1 (pre-dose)).

Time frame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment)

The Number of Subjects With Clinically Significant Changes in Heart Rate and Relation to Treatment Will be Assessed.

Heart rate will be measured in beats per minute. Clinically significant changes in heart rate were determined by the study PI. The result was determined to be treatment related if the clinically significant changes in heart rate occurred post-treatment compared to pre-treatment. Data from the specified time points (Study Day 1 (1h post-dose) and Study Day 3) were combined by adding the number of participants on each Study Day that showed a clinically significant change in heart rate compared to pre-treatment (Study Days -7, -5, -2 and 1 (pre-dose)).

Time frame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment)

The Number of Subjects With Clinically Significant Changes in Activated Partial Thromboplastin Time (aPTT) and Relation to Treatment Will be Assessed as Part of a Standard Coagulation Panel.

Plasma aPTT will be measured in seconds. Clinically significant changes in aPTT were determined by the study PI. The result was determined to be treatment related if the clinically significant changes in aPTT occurred post-treatment compared to pre-treatment. Data from the specified time points (Study Day 1 and Study Day 3) were combined by adding the number of participants on each Study Day that showed a clinically significant change in aPTT compared to pre-treatment (Study Days -7, -5, -2 and 1 (pre-dose)).

Time frame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment)

The Number of Subjects With Clinically Significant Changes in Prothrombin Time and Relation to Treatment Will be Assessed as Part of a Standard Coagulation Panel.

Prothrombin time will be measured in seconds. Clinically significant changes in prothrombin time were determined by the study PI. The result was determined to be treatment related if the clinically significant changes in prothrombin time occurred post-treatment compared to pre-treatment. Data from the specified time points (Study Day 1 and Study Day 3) were combined by adding the number of participants on each Study Day that showed a clinically significant change in prothrombin time compared to pre-treatment.

Time frame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment)

The Number of Subjects With Clinically Significant Changes in Plasma Fibrinogen and Relation to Treatment Will be Assessed as Part of a Standard Coagulation Panel.

Plasma fibrinogen will be measured in mg/dL. Clinically significant changes in fibrinogen were determined by the study PI. The result was determined to be treatment related if the clinically significant changes in fibrinogen occurred post-treatment compared to pre-treatment. Data from the specified time points (Study Day 1 and Study Day 3, before and after hemodialysis) were combined by adding the number of participants on each Study Day that showed a clinically significant change in fibrinogen compared to pre-treatment (Study Days -7. -5. -2).

Time frame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment)

The Number of Subjects With Clinically Significant Changes in Thrombin Time and Relation to Treatment Will be Assessed as Part of a Standard Coagulation Panel.

Thrombin time will be measured in seconds. Clinically significant changes in thrombin time were determined by the study PI. The result was determined to be treatment-related if the clinically significant changes in thrombin time occurred post-treatment compared to pre-treatment. Data from the post-treatment time points (Study Day 1 and Study Day 3, before and after hemodialysis) were combined by adding the number of participants on each Study Day that showed a clinically significant change in prothrombin time compared to pre-treatment.

Time frame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment).

The Number of Subjects With Clinically Significant Changes in Bilirubin (Total and Direct) Levels and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.

Bilirubin (total and direct) levels in the blood will be measured in mg/dL. Clinically significant changes in bilirubin were determined by the study PI. The result was determined to be treatment-related if the clinically significant changes in bilirubin occurred post-treatment compared to pre-treatment. Data from the post-treatment time point (Study Day 3) is presented as the number of participants that showed a clinically significant change in bilirubin compared to pre-treatment (Study Day -8).

Time frame: Study days -8 and 3

The Number of Subjects With Clinically Significant Changes in Alkaline Phosphatase Levels and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.

Alkaline phosphatase levels in the blood will be measured in U/L. Clinically significant changes in alkaline phosphatase were determined by the study PI. The result was determined to be treatment-related if the clinically significant changes in alkaline phosphatase occurred post-treatment compared to pre-treatment. Data from the post-treatment time point (Study Day 3) is presented as the number of participants that showed a clinically significant change in alkaline phosphatase compared to pre-treatment (Study Day -8).