Clinical trial NCT03612856: Safety and Efficacy Study of AB023 (Xisomab 3G3) in End Stage Renal Disease Patients on Chronic Hemodialysis
Official title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy/Potency of a Single Dose of Xisomab 3G3, Administered at the Beginning of 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
First posted: 2018-08-02
Enrollment: 27
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 AB023 (xisomab 3G3) 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 AB023 (xisomab 3G3) or placebo (at a ratio of 2:1 active: placebo).


Eligibility criteria: Inclusion Criteria:

Patients must fulfill all of the following inclusion criteria to be eligible for participation in the study:

1. ESRD maintained on stable outpatient HD regimen, using an established (\> 3 months) and normally functioning, regular flow, uninfected first mature AV fistula (or AV graft) and skin consistent with standard chronic HD access injuries, and HD stability defined as Kt/V ≥ 1.2 within 3 months prior to screening at a healthcare center for \> 3 months from screening.
2. On HD 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 CRU 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. BMI of ≥ 18 at the time of screening.
7. Considered by the PI to be clinically stable with respect to underlying ESRD, based on medical evaluation that includes medical and surgical history, and a complete physical examination including vital signs, ECG, and clinical laboratory test results at screening. Repeat assessments are permitted for any laboratory, 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 (such as one of the methods identified above for female patients) from the time of screening 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:

Patients must not be enrolled in the study if they meet any of the following 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, 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 NSAIDs) that may affect hemostasis for 2 weeks prior to check-in on Day -8 and throughout the study.
3. Use of unfractionated heparin for HD sessions from check-in on Day -8 and throughout the study.
4. 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.
5. Any other CS abnormalities in laboratory test results at screening 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.
6. 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.
7. Treatment with another investigational drug or device study within 30 days (or 5 half lives, whichever is longer) prior to check-in on Day -8.
8. Acute illness that is considered by the PI to be CS within 2 weeks of check-in on Day 8.
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 but \> 75,000 cells/mm3, with permission of PI and medical monitor) at screening
   * INR \> 1.4 at screening
   * aPTT up to 1.2 x ULN (if \>1.2x ULN up to \< 1.5 x ULN, with permission of PI and medical monitor) at screening
   * ALT or AST \> 2 x ULN at screening
   * Total bilirubin \> 1.2 ULN at screening
   * Hemoglobin concentration \< 10 g/dL at screening
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 to recombinant biologic drug, rodents, or a known sensitivity or idiosyncratic reaction to any compound present in xisomab 3G3, its related compounds, or any compound listed as being present in the study formulation.
13. Participate in strenuous exercise from 48 hours prior to check-in on Day -8 and throughout the study.
14. 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.
15. 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.
16. Receiving blood purification therapy other than HD.
17. 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-related Adverse Events (TEAEs) and the Number of TEAEs Will be Summarized Using Frequency Counts (Safety and Tolerability)
timeFrame: 21 days
measure: Incidence of Bleeding at the HD Vascular Access Site (Safety and Tolerability)
timeFrame: Study Days -7, -5, -3 (pre-dose) 1, 3, and 5 (post-dose)
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 and 1, pre-dose (pre-treatment) and Study Days 6 and 12 (post-treatment)
measure: The Number of Subjects That Develop Treatment-related Immunogenicity Will be Summarized Using Frequency Counts (Safety and Tolerability).
timeFrame: Study day 1 (predose) and Study Day 12
measure: The Number of Subjects With Clinically Significant Changes in Body Temperature, Frequency, and Relation to Treatment Will be Assessed.
timeFrame: Study days -7, -5, -3, and 1 (pre-treatment) and study days 1 (1h post-dose), 3, 5, 6, 8, 10, and 12 (post-treatment).
measure: The Number of Subjects With Clinically Significant Changes in Respiratory Rate, Frequency, and Relation to Treatment Will be Assessed.
timeFrame: Study days -7, -5, -3, and 1 (pre-treatment) and study days 1 (1h post-dose), 3, 5, 6, 8, 10, and 12 (post-treatment).
measure: The Number of Subjects With Clinically Significant Changes in Blood Pressure (Systolic and Diastolic), Frequency, and Relation to Treatment Will be Assessed.
timeFrame: Study days -7, -5, -3, and 1 (pre-treatment) and study days 1 (1h post-dose), 3, 5, 6, 8, 10, and 12 (post-treatment).
measure: The Number of Subjects With Clinically Significant Changes in Heart Rate, Frequency, and Relation to Treatment Will be Assessed.
timeFrame: Study days -7, -5, -3, and 1 (pre-treatment) and study days 1 (1h post-dose), 3, 5, 6, 8, 10, and 12 (post-treatment).
measure: The Number of Subjects With Clinically Significant Changes in Activated Partial Thromboplastin Time (aPTT), Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Coagulation Panel.
timeFrame: Study days -7, -5, -3, and 1 (pre-treatment) and study days 1 (3h post-dose), 3, 5, 6, and 12 (post-treatment).
measure: The Number of Subjects With Clinically Significant Changes in Prothrombin Time, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Coagulation Panel.
timeFrame: Study days -7, -5, -3, and 1 (pre-treatment) and study days 1 (3h post-dose), 3, 5, 6, and 12 (post-treatment).
measure: The Number of Subjects With Clinically Significant Changes in Bilirubin (Total and Direct) Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Alkaline Phosphatase Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Aspartate Aminotransferase (AST) Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Alanine Aminotransferase (ALT) Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Lactate Dehydrogenase (LDH) Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Albumin Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Sodium Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Potassium Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Chloride Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Glucose Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Creatinine Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Serum Chemistry Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Hemoglobin Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Hematology Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Hematocrit Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Hematology Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Total Leukocyte Counts, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Hematology Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Differential Leukocyte Counts, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Hematology Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Red Blood Cell Count, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Hematology Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Platelet Count, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Hematology Panel.
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Urine pH, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Urine Specific Gravity, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Urine Protein Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Urine Glucose Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Urine Ketone Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Urine Bilirubin Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Urine Blood Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Urine Nitrite Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Urine Urobilinogen Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
measure: The Number of Subjects With Clinically Significant Changes in Urine Leukocyte Esterase Levels, Frequency, and Relation to Treatment Will be Assessed as Part of a Standard Urinalysis Panel (Unless Patient is Anuric).
timeFrame: Study day 1 (pre-treatment), and study days 6 and 12 (post-treatment)
Secondary outcomes:
measure: Hemodialysis Efficiency as Measured by Frequency of Clotting on the Dialysis Filters and Circuit (Pharmacodynamic Outcome).
timeFrame: At each hemodialysis session (pre-dose days: study day -7, -5, -3, and post-dose dose days: study day 1, 3, and 5)
measure: Hemodialysis Efficiency as Measured by Blood Urea Nitrogen (BUN) Levels (Pharmacodynamic Outcome).
timeFrame: 21 days
measure: Hemodialysis Efficiency as Measured by Blood Urea Nitrogen (BUN) Levels (Pharmacodynamic Outcome), KtV.
timeFrame: 21 days
measure: Hemodialysis Efficiency as Measured by Blood Potassium Levels (Pharmacodynamic Outcome).
timeFrame: 21 days
measure: Hemodialysis Efficiency as Measured by Length of the Hemodialysis Session (Pharmacodynamic Outcome).
timeFrame: 21 days
measure: The Effect of a Single Intravenous Dose of Xisomab 3G3 on the Activated Partial Thromboplastin Time (aPTT) (Pharmacodynamic Outcome).
timeFrame: Study day 1 predose and 0.167, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 96, 120, 168, 216, and 264 hours after dosing
measure: The Maximum Plasma Concentration (Cmax) of Xisomab 3G3 After a Single Injection Will be Measured in Each Patient (Pharmacokinetic Outcome).
timeFrame: 14 days
measure: The Time to Reach Maximum Plasma Concentrations of Xisomab 3G3 (Tmax) After a Single Injection Will be Measured in Each Patient (Pharmacokinetic Outcome).
timeFrame: 14 days
measure: The Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Non-zero Concentration (AUC0-t) After a Single Injection of Xisomab 3G3 Will be Calculated for Each Patient (Pharmacokinetic Outcome)
timeFrame: 14 days
measure: The Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) After a Single Injection of Xisomab 3G3 Will be Calculated for Each Patient (Pharmacokinetic Outcome).
timeFrame: 14 days
measure: The Percent of AUC0-inf Extrapolated (AUC%Extrap) After a Single Injection of Xisomab 3G3 Will be Calculated for Each Patient (Pharmacokinetic Outcome).
timeFrame: 14 days
measure: The Apparent First Order Terminal Elimination Rate Constant (Kel) of Xisomab 3G3 After a Single Intravenous Injection Will be Calculated for Each Subject (Pharmacokinetic Outcome).
timeFrame: 14 days
measure: The Apparent First Order Terminal Elimination Half-life (T1/2) of Xisomab 3G3 After a Single Intravenous Injection Will be Calculated for Each Patient (Pharmacokinetic Outcome).
timeFrame: 14 days
measure: The Apparent Total Plasma Clearance (CL) of Xisomab 3G3 After a Single Intravenous Injection Will be Calculated for Each Patient (Pharmacokinetic Outcome).
timeFrame: 14 days
measure: The Total Apparent Volume of Distribution (Vss) of Xisomab 3G3 After a Single Intravenous Injection Will be Calculated for Each Patient (Pharmacokinetic Outcome).
timeFrame: 14 days
Other outcomes:
Locations:
city: Orlando
country: United States
facility: Orlando Clinical Research Center
state: Florida
Study officials:
References:
citation: Lorentz CU, Tucker EI, Verbout NG, Shatzel JJ, Olson SR, Markway BD, Wallisch M, Ralle M, Hinds MT, McCarty OJT, Gailani D, Weitz JI, Gruber A. The contact activation inhibitor AB023 in heparin-free hemodialysis: results of a randomized phase 2 clinical trial. Blood. 2021 Dec 2;138(22):2173-2184. doi: 10.1182/blood.2021011725.