Clinical trial NCT03963895: Safety and Efficacy Study of AB002 (E-WE Thrombin) in End Stage Renal Disease Patients on Chronic Hemodialysis
Official title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of a Single Dose of E-WE Thrombin, Administered During a Regular Hemodialysis Procedure, in Patients With End-Stage Renal Disease on Chronic Hemodialysis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: End Stage Renal Disease
Thrombosis
Keywords: Hemodialysis
Lead sponsor: Aronora, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Celerion
First posted: 2019-05-28
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

Primary outcomes:
measure: The Number of Subjects With Treatment-emergent Adverse Events (TEAEs) Related to Treatment Will be Summarized Using Frequency Counts (Safety and Tolerability)
timeFrame: 22 days
measure: The Number of TEAEs Related to Treatment Will be Summarized Using Frequency Counts (Safety and Tolerability).
timeFrame: 22 days
measure: The Number of Subjects With Bleeding at the Hemodialysis (HD) Vascular Access Site (Safety and Tolerability)
timeFrame: At each hemodialysis session (non-dose days: study day -7, -5, -2, and 3 and dose day: study day 1)
measure: The Number of Subjects With Abnormal Electrocardiogram That is Related to Treatment Will be Summarized Using Frequency Counts (Safety and Tolerability).
timeFrame: Study Days -8 (pre-treatment), Day 1, and 3 (post-treatment)
measure: The Number of Subjects That Develop Antibodies to Endogenous Thrombin Will be Summarized Using Frequency Counts (Safety and Tolerability).
timeFrame: Study day 1 pre-dose and study day 14
measure: The Number of Subjects With Clinically Significant Changes in Body Temperature in Relation to Treatment Will be Assessed.
timeFrame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Respiratory Rate and Relation to Treatment Will be Assessed.
timeFrame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Blood Pressure (Systolic and Diastolic) and Relation to Treatment Will be Assessed.
timeFrame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Heart Rate and Relation to Treatment Will be Assessed.
timeFrame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment)
measure: 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.
timeFrame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment)
measure: 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.
timeFrame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment)
measure: 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.
timeFrame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment)
measure: 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.
timeFrame: Study days -7, -5, -2 (pre-treatment), 1 and 3 (post-treatment).
measure: 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.
timeFrame: Study days -8 and 3
measure: 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.
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Aspartate Aminotransferase (AST) Levels and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Alanine Aminotransferase (ALT) Levels and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Lactate Dehydrogenase (LDH) Levels and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Albumin Levels and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Sodium Levels and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Potassium Levels and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study days -8 and 3.
measure: The Number of Subjects With Clinically Significant Changes in Chloride Levels and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Glucose Levels and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Creatinine Levels and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Hemoglobin Levels and Relation to Treatment Will be Assessed as Part of a Standard Hematology Panel.
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Hematocrit and Relation to Treatment Will be Assessed as Part of a Standard Hematology Panel.
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Total Leukocyte Counts and Relation to Treatment Will be Assessed as Part of a Standard Hematology Panel.
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Differential Leukocyte Counts and Relation to Treatment Will be Assessed as Part of a Standard Hematology Panel.
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Red Blood Cell Count and Relation to Treatment Will be Assessed as Part of a Standard Hematology Panel.
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Platelet Count and Relation to Treatment Will be Assessed as Part of a Standard Hematology Panel.
timeFrame: Study days -7, -5, -2, 1, and 3, pre- and post-dialysis.
measure: The Number of Subjects With Clinically Significant Changes in Urine pH and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Urine Specific Gravity and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Urine Protein Levels and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Urine Glucose Levels and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Urine Ketone Levels and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Urine Bilirubin Levels and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Urine Blood Levels and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Urine Nitrite Levels and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Urine Urobilinogen Levels and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day -8 and 3
measure: The Number of Subjects With Clinically Significant Changes in Urine Leukocyte Esterase Levels and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day -8 and 3
Secondary outcomes:
measure: Hemodialysis Efficiency as Measured by Frequency of Clotting on the Dialysis Filters and Circuit (Pharmacodynamic Outcome).
timeFrame: At each hemodialysis session (non-dose days: study day -7, -5, -2, and 3 and dose day: study day 1)
measure: Hemodialysis Efficiency as Measure by the Frequency of Clotting on the Dialysis Circuit: Venous Chamber (Pharmacodynamic Outcome)
timeFrame: At each hemodialysis session (non-dose days: study day -7, -5, -2, and 3 and dose day: study day 1)
measure: Hemodialysis Efficiency as Measured by Blood Urea Nitrogen (BUN) Levels, URR (Pharmacodynamic Outcome).
timeFrame: At each hemodialysis session (non-dose days: study day -7, -5, -2, and 3 and dose day: study day 1)
measure: Hemodialysis Efficiency as Measured by Blood Urea Nitrogen (BUN) Levels (Pharmacodynamic Outcome), KtV.
timeFrame: At each hemodialysis session (non-dose days: study day -7, -5, -2, and 3 and dose day: study day 1)
measure: Hemodialysis Efficiency as Measured by Blood Potassium Levels (Pharmacodynamic Outcome).
timeFrame: At each hemodialysis session (non-dose days: study day -7, -5, -2, and 3 and dose day: study day 1)
measure: The Effect of a Single Intravenous Dose of E-WE Thrombin on Plasma Activated Protein C-Protein C Inhibitor Complex (APC-PCI) Levels as a Surrogate for Drug Exposure.
timeFrame: Study day 1: (pre-dose, 0.167h, 0.5h, 1h, 2h, 4h, 6h, 24h post-dose)
measure: The Number of Subjects That Develop Anti-drug Antibodies Will be Summarized by Frequency Counts.
timeFrame: Study day 1 pre-dose and study day 14
Other outcomes:
Locations:
city: Orlando
country: United States
facility: Orlando Clinical Research Center
state: Florida
Study officials:
References:
citation: Tucker EI, Verbout NG, Markway BD, Wallisch M, Lorentz CU, Hinds MT, Shatzel JJ, Pelc LA, Wood DC, McCarty OJT, Di Cera E, Gruber A. The protein C activator AB002 rapidly interrupts thrombus development in baboons. Blood. 2020 Feb 27;135(9):689-699. doi: 10.1182/blood.2019002771.