RUCONEST® as a Therapeutic Strategy to Reduce the Incidence of Delayed Graft Function

A Phase I/II,Single Center,Randomized,Double-Blind,Placebo-Controlled Study to Evaluate the Feasibility of Using Human Recombinant C1 Inhibitor(RUCONEST®) as a Therapeutic Strategy to Reduce the Incidence of Delayed Graft Function in Recipients of Kidneys From Donation After Cardio-Circulatory Death

An unmet medical need exists for therapeutic regimens in transplantation that allow immediate postoperative graft function, thereby improving graft survival. Delayed graft function (DGF) after transplantation is the most common complication affecting kidney allographs in the immediate transplant period. The specific aim of this study is to evaluate the effect of recombinant human C1-inhibitor (rhC1INH), as a kidney recipient intra- and post operative treatment strategy to decrease systemic inflammation and decrease the incidence of DGF from donation after cardiac death donors (DCD).

This is a randomized, single-center double blinded study.

The main objective of this study are to determine the ability of rhC1INH to reduce the incidence and severity of delayed graft function in comparison to placebo in recipients of kidneys after cardio-circulatory determination of death (DCD).

This trial has specifically been designed to evaluate the protective effect of rhC1INH treatment in patients at high risk of developing DGF. The selection of potential donors to be part of this study will be limited to the population of DCD donors which have historically shown a risk of developing DGF ranging between 40-55%. Participation in each group will be randomly assigned. Treatment will be administered by an intra-operative infusion of placebo or rhC1INH (100 Units/kg) IV followed by twice a day infusion of 50 Units/Kg IV for the following 48 hours.

A total of 20 subjects will be divided into 2 groups:

Group 1: Control group: standard recipient management + placebo (0.9% Sodium Chloride IV to equal volume of investigational arm: intraoperatively, and then every 12 hours x 2 = total of 3 doses). treatment (n=10) Group 2: Standard recipient management + 100 U/kg intraoperative followed by 50 U/kg every 12 hours x 2 = total of 3 doses (200 U/kg).

Max dose 8400 units for the initial dose and 4200 units maximum for the second and third doses.

Inclusion Criteria for Transplant Recipient:

Adult patients receiving a transplanted kidney should satisfy the following to be considered part of the study:

1. Has the ability to understand the requirements of the study, is able to provide written informed consent (including consent for the use and disclosure of research related health information).

2. Male or female at least 18 years of age.

3. Is to be a recipient of a transplant from a deceased donor (donation after cardio-circulatory determination of death criteria).

4. Is able to comply with standard of care induction therapy requirement, such as antibody induction therapy with rabbit polyclonal anti-thymocyte globulin,anti-CD25 (anti-IL2R), or Anti-CD52.

5. A female subject is eligible to enter the study if she is:

   1. Not pregnant or nursing
   2. Of non-childbearing potential (i.e., post-menopausal defined as having been amenorrheic for at least 1 year prior to screening, or has had a bilateral tubal ligation at least 6 months prior to administration of study drug or bilateral oophorectomy or complete hysterectomy).
   3. If of childbearing potential, must have a negative serum pregnancy test within 48 hours prior to transplant surgery and be using an effective means of contraception (per the site-specific guidelines or using 2 methods of birth control concurrently, whichever is more stringent) which will be continued until the Day 180 visit.

6. Male subjects with female partners of childbearing potential must agree to use an effective means of contraception (per the site-specific guidelines or use 2 methods of birth control concurrently, whichever is more stringent), which will be continued until the Day 180 visit. They will also agree not to donate sperm until 6 months after dosing.

7. Must be up-to-date on cancer screening according to site-specific guidelines and past medical history must be negative for biopsy-confirmed malignancy within 5 years of randomization, with the exception of adequately treated basal cell or squamous cell carcinoma in situ or carcinoma of the cervix in situ.

8. Must be willing to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations.

Exclusion Criteria for Transplant Recipients:

1. Use of an investigational drug in the 30 days before surgery.
2. Participation in any other research study (drug or non-drug) without prior approval from the sponsor investigator.
3. Recipient of a live donor kidney or a kidney from a brain death donor (DBD) donor.
4. Recipient of donor kidney preserved with normothermic machine perfusion.
5. Scheduled to undergo multiorgan transplantation.
6. Has a planned transplant of kidneys that are implanted en-bloc (dual kidney transplantation).
7. Has planned transplant of dual kidneys (from the same donor) transplanted not en-bloc.
8. Has lost first kidney transplant due to graft thrombosis.
9. Is scheduled for transplantation of a kidney from a donor who is known to have received an investigational therapy under another IND/CTA for ischemic/reperfusion injury immediately prior to organ recovery.
10. Known hypersensitivity to human monoclonal antibodies or any of the study drug excipients.
11. Previous hypersensitivity to basiliximab, Campath-1H or antithymocyte globulin (ATG).
12. History of malignancy within the last five years, except excised squamous or basal cell carcinoma of the skin, or cervical intraepithelial neoplasia.
13. HIV positive recipients.
14. Hepatitis B surface antigen positive kidney transplant recipients.
15. Hepatitis B core antibody positive kidney transplant recipients.
16. Hepatitis C virus positive (HCV+) patients who are either untreated or have failed to demonstrate sustained viral remission for more than 12 months after anti-viral treatment.
17. Presence of clinically significant infections requiring continued therapy.
18. Positive screening for active tuberculosis.
19. Existence of any surgical or medical condition, other than the current transplantation which, in the opinion of the investigator, might significantly alter the distribution, metabolism or excretion of study medication.
20. Has a positive T- or B-cell cross-match by NIH anti-globulin lymphocytotoxicity method or CDC crossmatch method, if performed.
21. Has a positive T- or B-cell flow cross-match (over 250 channel shift) AND donor specific anti-HLA antibody (DSA) detected by flow cytometry (Luminex®) based antigen-specific anti-HLA antibody testing (over 4000 MFI) or by similar methodology, if performed.
22. History or presence of a medical condition or disease that in the investigator's assessment would place the patient at an unacceptable risk for study participation.
23. Lactating or pregnant woman.
24. Patient institutionalized by administrative or court order.
25. HLA or ABO incompatible kidney defined as a positive cytotoxic crossmatch or positive flow cross match.
26. Patients with known prothrombotic disorder (e.g. homozygous factor V leiden)
27. History of thrombosis or hypercoagulable state excluding access clotting
28. History of administration of C1INH containing products or recombinant C1INH within 15 days prior to study entry.
29. Patient with an abnormal Thromboelastogram.- results must be reported out prior to dosing (Defined by Coagulation Index of >3.0)
30. Patients on warfarin or other anti-coagulants or anti-platelets, such as Plavix, low molecular weight heparin (Low-dose aspirin prophylaxis allowed) due to a history or thrombotic or embolic events, or at a significantly increased risk for thrombosis due to conditions such as carotid stenosis or prosthetic valves.
31. Patients with known contraindication to treatment with C1INH
32. Patients with elevated abnormal platelet function (PLT>500,000).
33. Known or suspected allergy to rabbits and rabbit-derived products. History of immediate hypersensitivity reactions, including anaphylaxis, to C1 esterase inhibitor preparations.
34. Patients belonging to vulnerable populations: refers to but not limited to children, minors, pregnant women, prisoners, terminally ill patients, comatose, physically and intellectually challenged individuals, institutionalized, visual or hearing impaired, refugees, international research, and educationally disabled healthy volunteers.
35. Diagnosis of reversible Acute Kidney Injury