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End Stage Renal DiseasePhase 1/2C1INHDGFNCT02134314

C1INH Inhibitor Preoperative and Post Kidney Transplant to Prevent DGF & IRI

A Phase 1/2 study testing C1 Esterase Inhibitor in people with End Stage Renal Disease and Kidney Failure, run by Cedars-Sinai Medical Center at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The use of C1INH (Berinert) in patients receiving deceased donor kidney transplants with high risk for delayed graft function (DGF) may show significant improvement in outcomes post transplant compared with patients that do not receive C1INH treatment. Read more about this study

Who is it for?
Ages 18 to 70 years
What is being tested?
C1 Esterase Inhibitor
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
70 participants
Where
1 siteUnited States
Study dates
Sep 2014to 13 Mar 2017
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 18-70 yrs of age; recipient of ECD/DCD/ECD\&DCD with risk index 3-8 for DGF based on specific criteria
  • recipient who are ABO compatible with donor allograft
  • pretransplant with meningococcal vaccination
  • understand and sign a written consent prior to any study specific procedure.
  • Risk index (minimum 3- maximum 8):
  • DGF scale: Donor Age (<40yr = 0, 41-49yr = 1, 50-54yr = 2, 55-59yr = 3, >60yr=6), Cold Ischemia Time (0-12= 0, 13-18=1, 19-24=2, 24-30=3, 31-36=4, >37=6; Recipient Race (nonblack = 0, black =1); Donor death due to Cerebrovascular Accident (CVA) (donor age <50yrs = 0, donor age >50yrs = 3).

Who cannot join

  • patients with known prothrombotic disorder (e.g. factor V leiden)
  • history of thrombosis or hypercoagulable state excluding access clotting
  • history of administration of C1INH containing products or recombinant C1INH within 15 days prior to study entry
  • patients with known contraindication to treatment with C1INH
  • patients with abnormal coagulation function (INR >2, partial thromboplastin time (PTT) > 50, platelets <80,000)
  • who are not on anti-coagulation
Show all 11Show fewer
  • patients with known active presence of malignancies
  • Polymerase chain reaction (PCR) positive for hep B/hep C/or HIV
  • preemptive kidney transplantation recipient
  • recipients of multi-organ transplants (kidney and any other organ)
  • recipients of kidney allograft from DD who: cold ischemia time (CIT) <18h, terminal serum creatinine </= 1mg/dl, recipient of kidney allograft that was on pump preservation for any period prior to transplantation, recipient of kidney allograft from a living donor, female subject who are pregnant or lactating.

Trial locations and contacts

1 site in 1 country.

United States1 site
  • Cedars-Sinai Medical Center

    Los Angeles, California, 90048

Other trials in United States

About this study

Official title: Assessing Safety and Efficacy of Preoperative and Post-Transplant C1 Inhibitor (Berinert®) vs. Placebo in Recipients of a Renal Allograft From Deceased High Risk Donors and Its Impact on DGF and IRI

The use of C1INH (Berinert) in patients receiving deceased donor kidney transplants with high risk for delayed graft function (DGF) may show significant improvement in outcomes post transplant compared with patients that do not receive C1INH treatment. Complement activation has been detected in animal models and human kidneys with ischemic reperfusion injury (IRI) and inflammatory cell infiltrates. By blocking complement activation the investigators hope to improve kidney graft function post transplant in these recipients.

Read the detailed description

Early graft function has a long-term effect on graft survival. Poor early graft function and delayed graft function (DGF) contributes to decreased short- and long-term patient and graft survival, increased incidence of acute rejection, prolonged hospitalization, and higher costs of transplantation. Although multiple factors contribute to the impaired graft function, ischemia-reperfusion injury (IRI) is the underlying pathophysiology leading to poor early graft function and DGF. A >35% incidence of DGF has remained constant over time despite significant improvements in immunosuppressive strategies and patient management. This may be due to increased use of kidneys from "extended-criteria" and/or non-heart-beating donors, where even greater rates (>60%) of DGF have been reported.

More than 96,680 people are currently waiting for a kidney transplant in the United States (United Network for Organ Sharing (UNOS); UNOS.org 3/22/13). Of the 15,092 kidney transplants performed in the US in 2011, ~11,000 (62%) were from deceased donors. Of these, approximately 17% were from expanded-criteria donors. The USRDS reports that more than 50% of patients on the waiting list are willing to accept a kidney from an expanded-criteria donor (ECD) or donors after cardiac death (DCD).

From the investigators previous studies with C1INH (Berinert®) for prevention of antibody mediated rejection (ABMR), the investigators noted that no patients developed ABMR during treatment with C1INH, the investigators also noted a near significant reduction in DGF due to IRI (ClinicalTrials.gov(NCT01134510), FDA Investigational New Drug (IND#): 14363). These findings suggest an important role for complement in the mediation of IRI and that inhibition of early complement activation using C1INH in patients receiving at risk kidneys for IRI should reduce this costly and often devastating complication of kidney transplantation. In addition, numerous other studies in animal models have shown dramatic improvements in IRI models with the use of C1INH. Complement activation is detectable in animal and in human kidneys models after IRI and experimental data suggests that use of C1INH prior to induction of IRI significantly reduces IRI as well as inflammatory cell infiltrates. Based on this, the investigators hypothesize that the use of C1INH in patients receiving deceased donor (DD) kidney transplants with high risk for DGF will show significant reductions in DGF and improved outcomes post-transplant compared with patients receiving DD transplants who do not receive C1INH treatment. Here, the investigators propose to investigate the application of pre-operative and post-transplant doses of C1INH (Berinert®) vs. placebo in adult subjects receiving a DD renal allograft considered at high-risk for IRI and DGF. The investigators hypothesize that C1INH treated patients will demonstrate improved function of the kidney allograft compared to placebo, with equivalence in safety. The primary objectives of this study are: Using a double blinded, placebo controlled format, the investigators will:

  1. Evaluate and compare the safety of C1INH (50 units/kilogram, round to the nearest 500 unit) administered pre-transplant and 24 hrs post-transplant in recipients of kidney allografts from high risk for IRI deceased donors.

The secondary objectives are to:

  1. On the basis of safety and efficacy, determine appropriate Berinert® study dose for Phase III investigation, and
  2. Determine appropriate endpoint choice for Phase III investigation.
Being tested
C1 Esterase Inhibitor, Placebo
Keywords
ESRD (End Stage Renal Disease), CKD (Chronic Kidney Disease), Kidney Transplant, ECD, delayed graft function, chronic kidney disease, expanded-criteria donor, end stage renal disease
Medical subject headings
Kidney Failure, Chronic, Renal Insufficiency, Delayed Graft Function, Renal Insufficiency, Chronic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • C1 Esterase InhibitorDrug

    Also called Berinert (C1INH)

    C1 Esterase Inhibitor 50 units per kilogram intravenous infusion administered on day of transplant, and another dose at 24 hours post-operatively. Total: 2 doses

  • PlaceboDrug

    Also called Normal Saline (0.9%NaCl)

    Placebo medication identical to study drug (C1 esterase inhibitor) volume will be administered on day of transplant, and another dose at 24 hours post-operatively. Total: 2 doses

Study groups in NCT02134314
Study groupRoleWhat they receive
C1-Inhibitor (Berinert) (Human) (C1INH)Experimental35 patients will receive C1 esterase inhibitor in addition to standard of care immunosuppressive therapy.
Receives: Drug: C1 Esterase Inhibitor
Normal SalinePlacebo comparator35 patients will receive placebo in addition to standard of care immunosuppressive therapy.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Patients Enrolled With Serum Creatinine >3mg/dL on Postoperative Day 5.

    Number of participants in the C1INH and placebo groups with serum creatinine >3mg/dL on postoperative day 5

    Measured: First 7 days post-transplant

  2. Number of Patients Enrolled Who Require at Least One Session of Dialysis in the First 7 Days Post Transplant.

    The proportion of patients enrolled who require at least one session of dialysis in the first 7 days post transplant (excluding those who are dialyzed for hyperkalemia).

    Measured: First 7 days post-transplant

  3. Number of Patients With Serum Creatinine Reduction Ratio of < 30% From 24 to 48 Hours Post-transplant.

    Number of patients in the C1INH and placebo groups with serum creatinine reduction of < 30% from 24 to 48 hours post-transplant.

    Measured: First 7 days post-transplant

  4. Number of Dialysis Sessions Per Patient in the First 7 Days Post Transplant.

    Mean quantity of dialysis sessions per patient in the first 7 days post transplant.

    Measured: First 7 days post-transplant

Secondary outcomes (5)
  1. Serum Creatinine

    Mean serum creatinine on day 90 in mg/dL

    Measured: Up to 90 days post-transplant

  2. Creatinine Clearance

    Creatinine clearance calculated based on serum creatinine, milliliters per minute.

    Measured: Up to 90 days post-transplant

  3. 24h Urine Output

    24 hour urine output post-transplantation measured in milliliters

    Measured: 24 hours post-transplant

  4. Mean Number of Patients on Dialysis

    Mean number of patients on dialysis at 15 to 30 days post-transplant

    Measured: 15 to 30 days post-transplantation

  5. Number of Patients With Delayed Graft Function (DGF) (Categorized by DGF Scale)

    DGF Scale:

    Grade 1 - immediate urine production and no need for dialysis with creatinine reduction ratio (CRR) between time 0 of transplantation and day 7 post-transplantation >70%

    Grade 2 - creatinine reduction ratio (CRR) between time 0 of transplantation and day 7 post-transplantation of >70% with need for dialysis

    Grade 3 - creatinine reduction ratio (CRR) between time 0 of transplantation and day 7 post-transplantation <70% with no need for dialysis

    Grade 4 - creatinine reduction ratio (CRR) between time 0 of transplantation and day 7 post-transplantation of <70% with need for dialysis.

    Measured: First 7 days post-transplant

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 May 2014 (estimated)
  2. Study startSep 2014
  3. Primary completion13 Mar 2017
  4. Study completion13 Mar 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
70 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02134314
Sponsor's protocol ID
C1INH (Berinert) for DGF
Other IDs
IND15806
Acronym
C1INHDGF
Status last verified
Jun 2018
First submitted
19 Feb 2014
Last updated
25 Jun 2018
Data monitoring committee
Yes

Publications

  • Dalle Lucca JJ, Li Y, Simovic M, Pusateri AE, Falabella M, Dubick MA, Tsokos GC. Effects of C1 inhibitor on tissue damage in a porcine model of controlled hemorrhage. Shock. 2012 Jul;38(1):82-91. doi: 10.1097/SHK.0b013e31825a3522.

    PubMed 22683724
  • Pascual J, Zamora J, Pirsch JD. A systematic review of kidney transplantation from expanded criteria donors. Am J Kidney Dis. 2008 Sep;52(3):553-86. doi: 10.1053/j.ajkd.2008.06.005.

    PubMed 18725015
  • Castellano G, Melchiorre R, Loverre A, Ditonno P, Montinaro V, Rossini M, Divella C, Battaglia M, Lucarelli G, Annunziata G, Palazzo S, Selvaggi FP, Staffieri F, Crovace A, Daha MR, Mannesse M, van Wetering S, Paolo Schena F, Grandaliano G. Therapeutic targeting of classical and lectin pathways of complement protects from ischemia-reperfusion-induced renal damage. Am J Pathol. 2010 Apr;176(4):1648-59. doi: 10.2353/ajpath.2010.090276. Epub 2010 Feb 11.

    PubMed 20150432
  • Giral-Classe M, Hourmant M, Cantarovich D, Dantal J, Blancho G, Daguin P, Ancelet D, Soulillou JP. Delayed graft function of more than six days strongly decreases long-term survival of transplanted kidneys. Kidney Int. 1998 Sep;54(3):972-8. doi: 10.1046/j.1523-1755.1998.00071.x.

    PubMed 9734625

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing C1 Esterase Inhibitor in people with End Stage Renal Disease and Kidney Failure, run by Cedars-Sinai Medical Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Jun 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 25 Jun 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Patients Enrolled With Serum Creatinine >3mg/dL on Postoperative Day 5. (time frame: First 7 days post-transplant). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02134314, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jun 2018.

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