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

Primary Purpose

Kidney Transplantation

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
C1 Esterase Inhibitor
Placebos
Sponsored by
Stanley Jordan, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Kidney Transplantation focused on measuring Kidney transplantation

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Cedars-Sinai medical center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

C1 esterase inhibitor

Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Serum Creatinine
Serum creatinine will be checked 6 months post transplant to monitor allograft function.
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). Each DSA can have a score of 10 maximum. However, patients may have more than one DSA and points can add up to more than 10. this depends on how many DSAs [Class I and/or Class II] are present at the time of transplant and quarterly after transplant. Patients can have an infinite number of donor specific antibodies, this score can be higher than 10.
Donor Specific Antibodies [DSA] Class II
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). Each DSA can have a score of 10 maximum. However, patients may have more than one DSA and points can add up to more than 10. this depends on how many DSAs [Class I and/or Class II] are present at the time of transplant and quarterly after transplant. However, patients may have more than one DSA and points can add up to more than 10 this depends on how many DSAs [Class I and/or Class II] are present at the time of transplant and quarterly after transplant. Patients can have an infinite number of donor specific antibodies, this score can be higher than 10.

Full Information

First Posted
May 26, 2010
Last Updated
February 16, 2017
Sponsor
Stanley Jordan, MD
Collaborators
CSL Behring
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1. Study Identification

Unique Protocol Identification Number
NCT01134510
Brief Title
Safety & Tolerability of Berinert® (C1 Inhibitor) Therapy to Prevent Rejection
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"
Study Type
Interventional

2. Study Status

Record Verification Date
February 2017
Overall Recruitment Status
Completed
Study Start Date
August 2011 (undefined)
Primary Completion Date
November 2013 (Actual)
Study Completion Date
November 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Stanley Jordan, MD
Collaborators
CSL Behring

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Kidney Transplantation
Keywords
Kidney transplantation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
C1 esterase inhibitor
Arm Type
Experimental
Arm Description
10 subjects will receive C1 esterase inhibitor in addition to standard of care immunosuppressive therapy.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
10 subjects placebo [normal saline] in addition to standard of care immunosuppressive therapy.
Intervention Type
Drug
Intervention Name(s)
C1 Esterase Inhibitor
Other Intervention Name(s)
Berinert
Intervention Description
C1 Esterase Inhibitor 20 units/kg twice weekly x 4 weeks
Intervention Type
Drug
Intervention Name(s)
Placebos
Intervention Description
NS (comparable volume as intervention) twice weekly x 4wks
Primary Outcome Measure Information:
Title
Post-transplant Biopsy to Identify Rejection Episodes
Description
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.
Time Frame
6 month
Secondary Outcome Measure Information:
Title
Serum Creatinine
Description
Serum creatinine will be checked 6 months post transplant to monitor allograft function.
Time Frame
6 months
Title
Donor Specific Antibodies [DSA] Class I
Description
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). Each DSA can have a score of 10 maximum. However, patients may have more than one DSA and points can add up to more than 10. this depends on how many DSAs [Class I and/or Class II] are present at the time of transplant and quarterly after transplant. Patients can have an infinite number of donor specific antibodies, this score can be higher than 10.
Time Frame
6 months
Title
Donor Specific Antibodies [DSA] Class II
Description
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). Each DSA can have a score of 10 maximum. However, patients may have more than one DSA and points can add up to more than 10. this depends on how many DSAs [Class I and/or Class II] are present at the time of transplant and quarterly after transplant. However, patients may have more than one DSA and points can add up to more than 10 this depends on how many DSAs [Class I and/or Class II] are present at the time of transplant and quarterly after transplant. Patients can have an infinite number of donor specific antibodies, this score can be higher than 10.
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stanley C Jordan, MD
Organizational Affiliation
Cedars-Sinai Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Cedars-Sinai medical center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
18635429
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.
Results Reference
background
PubMed Identifier
15579530
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. doi: 10.1097/01.ASN.0000145878.92906.9F.
Results Reference
background
PubMed Identifier
20077121
Citation
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.
Results Reference
background
PubMed Identifier
17352710
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. doi: 10.1111/j.1600-6143.2006.01688.x.
Results Reference
background
PubMed Identifier
18635436
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. No abstract available.
Results Reference
background
PubMed Identifier
25606785
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. Transplantation. 2015 Feb;99(2):299-308. doi: 10.1097/TP.0000000000000592.
Results Reference
result

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

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