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

NCT01134510 | Completed Phase 1 Results

• 1 other identifier: C1INH001CSMC
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Kidney Transplantation

Keywords

Kidney transplantation

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (3)

• Serum Creatinine

  6 months

• Donor Specific Antibodies [DSA] Class I

  6 months

• Donor Specific Antibodies [DSA] Class II

  6 months

Study Arms (2)

C1 esterase inhibitor

EXPERIMENTAL

10 subjects will receive C1 esterase inhibitor in addition to standard of care immunosuppressive therapy.

Drug: C1 Esterase Inhibitor

Placebo

PLACEBO COMPARATOR

10 subjects placebo \[normal saline\] in addition to standard of care immunosuppressive therapy.

Drug: Placebos

Interventions

C1 Esterase Inhibitor DRUG

C1 Esterase Inhibitor 20 units/kg twice weekly x 4 weeks

Also known as: Berinert

C1 esterase inhibitor

Placebos DRUG

NS (comparable volume as intervention) twice weekly x 4wks

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Stanley Jordan, MD: lead
• CSL Behring: collaborator

Study Sites (1)

Cedars-Sinai medical center

Los Angeles, California, 90048, United States

Location

Related Publications (6)

• 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.

  PMID: 18635429 BACKGROUND

• 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. doi: 10.1097/01.ASN.0000145878.92906.9F.

  PMID: 15579530 BACKGROUND

• 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.

  PMID: 20077121 BACKGROUND

• 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. doi: 10.1111/j.1600-6143.2006.01688.x.

  PMID: 17352710 BACKGROUND

• Shapiro R. Reducing antibody levels in patients undergoing transplantation. N Engl J Med. 2008 Jul 17;359(3):305-6. doi: 10.1056/NEJMe0804275. No abstract available.

  PMID: 18635436 BACKGROUND

• 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. Transplantation. 2015 Feb;99(2):299-308. doi: 10.1097/TP.0000000000000592.

  PMID: 25606785 RESULT

MeSH Terms

Interventions

Complement C1 Inhibitor Protein

Intervention Hierarchy (Ancestors)

Glycoproteins; Glycoconjugates; Carbohydrates; Complement C1 Inactivator Proteins; Serpins; Peptides; Amino Acids, Peptides, and Proteins; Complement Inactivator Proteins; Complement System Proteins; Immunoproteins; Blood Proteins; Proteins

Results Point of Contact

• Title: Stanely Jordan, MD
• Organization: Cedars-Sinai Medical Center

stan.jordan@cshs.org

310-428-8186

Study Officials

• Stanley C Jordan, MD

  Cedars-Sinai Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Medical Director, Medical Director, Renal Transplantation & Transplant Immunotherpay

Study Record Dates

• First Submitted: May 26, 2010
• First Posted: June 2, 2010
• Study Start: August 1, 2011
• Primary Completion: November 1, 2013
• Study Completion: November 1, 2013
• Last Updated: March 21, 2017
• Results First Posted: August 3, 2015

Record last verified: 2017-02

Locations

US (1)