Safety & Tolerability of Berinert® (C1 Inhibitor) Therapy to Prevent Rejection

Kidney Transplantation Clinical Trial

Official title:

A Phase I/II Trial to Evaluate the Safety & Tolerability of Berinert® (C1 Inhibitor) Therapy to Prevent Complement-Dependent, Antibody-Mediated Rejection Post-Transplant in Highly-HLA Sensitized Patients"

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01134510
• Other study ID #: C1INH001CSMC
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: May 26, 2010
• Last updated: July 28, 2015
• Start date: August 2011
• Est. completion date: November 2013

Study information

• Verified date: July 2015
• Source: Cedars-Sinai Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Organ transplantation offers the only hope for a normal life for patients with end-stage renal disease on dialysis (ESRD). For the highly-sensitized patient, patients with antibodies to human leukocyte antigens (HLA), transplantation is extremely difficult or impossible since pre-formed antibodies will cause severe rejection and loss of transplanted organs. Approximately 30% of the transplant list in the U.S. is considered sensitized (have detectable antibodies to HLA antigens). These anti-HLA (anti-Human Leukocyte Antigen antibodies) pose a significant barrier to transplantation that has recently been successfully addressed using desensitization therapies with IVIG, rituximab and/or plasmapheresis (PE). Despite the success of these therapies, post-transplant antibody mediated rejection (AMR) and chronic Antibody Mediated Rejection (CAMR) remain significant problems. Recent data suggests that addition of Berinert (C1 Inhibitor) to post-transplant treatment regimen may significantly reduce incidence of Antibody Mediation Rejection.

Twenty highly-sensitized patients who have undergone desensitization treatment and are awaiting kidney transplant will be enrolled in the study. Once transplanted these patients will be started on the standard of care post-transplant immunosuppressive protocol. In addition patients will receive Berinert 20 units/ kg daily x 3 days, then twice weekly x 3 weeks. At the end of Berinert treatment a kidney biopsy will be performed. Subjects will be followed for 6 months to assess safety and efficacy of the study protocol.

Description:

Single center, Phase I/II, randomized The trial will examine the safety and efficacy of human C1 INH given post-transplant to reduce or prevent complement-dependent, antibody-mediated rejection (AMR) in 20 subjects (adult) who are highly-HLA sensitized (HS),(Panel Reactive Antibodies >30% (PRA), have undergone desensitization with intravenous immunoglobin (IVIG) + rituximab and/or plasmapheresis and are awaiting Living donor (LD)/ Deceased Donor (DD) kidney transplant. Once transplant offers are entertained, a donor-specific crossmatch will be performed to detect anti-HLA antibodies and donor-specific anti-HLA antibodies (DSA) which are associated with acute rejection or graft loss. (These anti-HLA (anti-Human Leukocyte Antigen antibodies) antibodies may result naturally or from previous pregnancy, transfusions, or prior transplants.) If acceptable crossmatches and Donor Specific Antibody levels are seen after desensitization, the patients will proceed to Living Donor/Deceased Donor transplantation. Patients receiving transplants will have pre-transplant labs obtained for C1 INH levels, Complement 3 (C3) and Complement 4 (C4) at transplant. In addition to the standard post-transplant immunosuppressive protocol, participating patients will receive placebo or 20 Units/kg C1 INH twice weekly X 4 weeks. At the end of the treatment, a protocol biopsy will be performed to assess the allograft for evidence of Antibody Mediated Rejection, including C4d staining. Since ~25% of highly sensitized patients experience Antibody Mediated Rejection post-transplant and 85% of these Antibody Mediated Rejection episodes occur in the 1st post-transplant month, we feel the assessment of the potential impact of C1 INH therapy is best assessed in this time period. After completion of the C1 INH therapy, patients will be followed for an additional 6 month to assess allograft function and Antibody Mediated Rejection episodes as well as Donor Specific Antibodies.

The subjects will be followed to determine the proportion who develop evidence of Antibody Mediated Rejection within 6 month of completion of the study. In addition we will asses the transplanted patients to determine the number who sustain a viable and functioning kidney allograft for 6 months. All subjects will be evaluated on an intent-to-treat basis. The subject accrual rate will be limited to no more than five subjects per month in the initial three months to assure safety to all subjects. Repeat laboratories will be performed at the completion of C1 INH therapy to determine effect on levels and correlation with any potential events.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: November 2013
• Est. primary completion date: November 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• End-stage renal disease.

• No known contraindications for therapy with Immune Globuillin Intravenous 10%/Rituximab or C1 INH.

• Age 18-65 years at the time of screening.

• Panel Reactive Antibody [PRA] > 50% demonstrated on 3 consecutive samples, Patient highly-HLA (Human Leukocyte Antigen) sensitized and a candidate for Living Donor/Deceased Donor transplantation after desensitization at Cedars Sinai Medical Center.

• At transplant, patient must have Donor Specific Antibody /Cross match + non-HLA (Human Leukocyte Antigen) identical donor.

Subject/Parent/Guardian must be able to understand and provide informed consent.

Exclusion Criteria:

• Lactating or pregnant females.

• Women of child-bearing age who are not willing or able to practice Food and Drug Administration [FDA]-approved forms of contraception.

• HIV-positive subjects.

• Subjects who test positive for Hepatitis B Virus infection [positive Hepatitis B Virus surface Antigen, Hepatitis B Virus core Antigen, or Hepatitis B Virus e Antigen/DNA] or Hepatitis C Virus infection [positive Anti-Hepatitis C Virus (EIA) and confirmatory Hepatitis C Virus Recombinant ImmunoBlot Assay (RIBA)].

• Subjects with active Tuberculosis.

• Subjects with selective Immunoglobulin A deficiency, those who have known anti-Immunoglobulin A antibodies, and those with a history of anaphylaxis or severe systemic responses to any part of the clinical trial material.

• Subjects who have received or for whom multiple organ transplants are planned.

• Recent recipients of any licensed or investigational live attenuated vaccine(s) within two months of the screening visit (including but not limited to any of the following:

• Adenovirus [Adenovirus vaccine live oral type 7] Varicella [Varivax] Hepatitis A [VAQTA] Rotavirus [Rotashield] Yellow fever [Y-F-Vax] Measles and mumps [Measles and mumps virus vaccine live] Measles, mumps, and rubella vaccine [M-M-R-II] Sabin oral polio vaccine Rabies vaccines [IMOVAX Rabies I.D., RabAvert])

• A significantly abnormal general serum screening lab result defined as a White Blood Cell < .0 X 103/ml, a Hemoglobin < 8.0 g/dL, a platelet count < 100 X 103/ml, , an Serum Glutamic Oxaloacetic Transaminase [SGOT] > 5X upper limit of normal, and an Serum Glutamic Pyruvic Transaminase [SGPT] >5X upper limit of normal range.

• Individuals deemed unable to comply with the protocol.

• Subjects with active Cytomegalovirus or Epstein Barr Virus infection as defined by Cytomegalovirus-specific serology (Immunoglobulin G or Immunoglobulin M) and confirmed by quantitative Polymerase Chain Reaction with or without a compatible illness.

• Subjects with a known history of previous myocardial infarction within one year of screening.

• Subjects with a history of clinically significant thrombotic episodes, and subjects with active peripheral vascular disease.

• Use of investigational agents within 4 weeks of participation.

• Know allergy/sensitivity to C1 INH infusions

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Kidney Transplantation

Intervention

Drug:
• C1 Esterase Inhibitor
C1 Esterase Inhibitor 20 units/kg vs Placebo twice weekly x 4 weeks

Locations

Country	Name	City	State
United States	Cedars-Sinai medical center	Los Angeles	California

Sponsors (2)

Lead Sponsor	Collaborator
Stanley Jordan, MD	CSL Behring

Country where clinical trial is conducted

United States, 

References & Publications (6)

Jordan SC, Reinsmoen N, Peng A, Lai CH, Cao K, Villicana R, Toyoda M, Kahwaji J, Vo AA. Advances in diagnosing and managing antibody-mediated rejection. Pediatr Nephrol. 2010 Oct;25(10):2035-45; quiz 2045-8. doi: 10.1007/s00467-009-1386-4. Epub 2010 Jan 14. Review. — View Citation

Jordan SC, Tyan D, Stablein D, McIntosh M, Rose S, Vo A, Toyoda M, Davis C, Shapiro R, Adey D, Milliner D, Graff R, Steiner R, Ciancio G, Sahney S, Light J. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. J Am Soc Nephrol. 2004 Dec;15(12):3256-62. — View Citation

Shapiro R. Reducing antibody levels in patients undergoing transplantation. N Engl J Med. 2008 Jul 17;359(3):305-6. doi: 10.1056/NEJMe0804275. — View Citation

Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, Campbell PM, Cascalho M, Collins AB, Demetris AJ, Drachenberg CB, Gibson IW, Grimm PC, Haas M, Lerut E, Liapis H, Mannon RB, Marcus PB, Mengel M, Mihatsch MJ, Nankivell BJ, Nickeleit V, Papadimitriou JC, Platt JL, Randhawa P, Roberts I, Salinas-Madriga L, Salomon DR, Seron D, Sheaff M, Weening JJ. Banff '05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy ('CAN'). Am J Transplant. 2007 Mar;7(3):518-26. — View Citation

Vo AA, Lukovsky M, Toyoda M, Wang J, Reinsmoen NL, Lai CH, Peng A, Villicana R, Jordan SC. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med. 2008 Jul 17;359(3):242-51. doi: 10.1056/NEJMoa0707894. — View Citation

Vo AA, Zeevi A, Choi J, Cisneros K, Toyoda M, Kahwaji J, Peng A, Villicana R, Puliyanda D, Reinsmoen N, Haas M, Jordan SC. A phase I/II placebo-controlled trial of C1-inhibitor for prevention of antibody-mediated rejection in HLA sensitized patients. Tran — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Post-transplant Biopsy to Identify Rejection Episodes	Subjects will have a routine kidney biopsy 6 month after transplant to screen for episodes of acute rejection.; For purposes of this investigation, antibody-mediated rejection (AMR) is defined as follows: Deterioration of allograft function in a high-risk transplant recipient (i.e. sensitized patient with history of Donor Specific Antibodies) measured by serum Creatinine and estimated Glomerular Filtration Rate; Association with the presence of Donor Specific Antibody (usually increasing in strength) measured by luminex techniques.; Biopsy evidence of capillaritis, inflammation and C4d deposition.	6 month	No
Secondary	Serum Creatinine	Serum creatinine will be checked 6 months post transplant to monitor allograft function.	6 months	No
Secondary	Donor Specific Antibodies [DSA] Class I	Donor Specific Antibodies [DSAs] Class I will be checked 1, 3, and 6 months post transplant to monitor allograft function.; DSA will be measured using a relative intensity score (RIS) ranges from 0 points = No DSA; 2 points = <5000MFI (weak intensity); 5 points = 5000-10,000 MFI (moderate intensty); 10 points = >10,000MFI (strong intensity). Patients may have more than one DSA and points can add up to more than 10.	6 months	No
Secondary	Donor Specific Antibodies [DSA] Class II	Donor Specific Antibodies [DSAs] Class II will be checked 1, 3, and 6 months post transplant to monitor allograft function.; DSA will be measured using a relative intensity score (RIS) ranges from 0 points = No DSA; 2 points = <5000MFI (weak intensity); 5 points = 5000-10,000 MFI (moderate intensty); 10 points = >10,000MFI (strong intensity). Patients may have more than one DSA and points can add up to more than 10.	6 months	No