Safety and Efficacy Study of AB002 (E-WE Thrombin) in End Stage Renal Disease Patients on Chronic Hemodialysis
Condition: End Stage Renal Disease; Thrombosis
MeSH terms: Kidney Diseases; Kidney Failure, Chronic; Thrombosis
Intervention: AB002 Dose 1; AB002 Dose 2; placebo
Intervention description: AB002 (E-WE thrombin) 1.5 mcg/kg administered on Day 1 as a single intravenous infusion; AB002 (E-WE thrombin) 3.0 mcg/kg administered on Day 1 as a single intravenous infusion; placebo administered on Day 1 as a single intravenous infusion
Intervention MeSH terms: Thrombin
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 40.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Hemodialysis

Summary:

      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).
    

Eligibility criteria:

        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.