A double-blind, randomized-withdrawal, placebo-controlled study to evaluate the efficacy and safety of human plasma-derived C1-esterase inhibitor as add-on to standard of care for the treatment of refractory antibody mediated rejection in adult renal transplant recipients
- Conditions
- antibody-mediated kidney transplant rejection'kidney graft rejection after renal transplant' and 'kidney not working properly after kidney transplant and not responsive to standard therapy'10027665
- Registration Number
- NL-OMON50633
- Lead Sponsor
- CSL Behring LLC
- Brief Summary
Trial ended prematurely
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 4
1. Provide written informed consent and willing and able to adhere to all
protocol requirements.
2. At least 18 years of age at the time of providing written informed consent.
3. Evidence of at least one DSA (to HLA class I and/or class II)
4. Recipient of a kidney transplant from an ABO compatible or ABO incompatible
donor, living or deceased.
5. At least one of the following if clinical data are available:
a. Achieved a steady-state, post-transplant eGFR * 40 mL/min/1.73 m2 (as
determined by local practice) within 60 days post-transplant, , OR
b. A 50% increase in urine output with a 50% decrease in serum creatinine over
the first 7 days post-transplant in subjects with slow or delayed graft
function.
6. Acute AMR defined per Banff 2015 criteria [Loupy et al, 2017] on pre
enrollment kidney biopsy (performed within 90 days of enrollment, as the
following:
a. Histologic evidence of acute tissue inflammation with presence of
neutrophils and/or monocytes (g > 0, v > 0, and/or ptc > 0), AND
b. C4d positive or, if C4d negative, then g + ptc * 2.
NOTE: Subjects who have mixed cellular rejection with AMR are eligible for
participation.
7. Acute AMR that is unresponsive (ie, no improvement in renal function as
determined by the treating physician) after standard of care treatment:
a. If standard of care treatment is * 100 mg/kg IVIg and plasmapheresis - with
or without rituximab -: * 7 days since the current AMR diagnosisat the Day 1
Visit, OR
b. If standard of care treatment is * 1 gram/kg IVIg without plasmapheresis -
with or without rituximab: * 45 days since the current AMR diagnosis.
8. Subject must be willing and able to comply with the requirements of the
study protocol.
9. Investigator believes that the subject understands the nature, scope and
possible consequences of the study.
1. Recipient of an en bloc kidney transplant
2. Ongoing dialysis > 2 weeks at Screening.
3. Hepatobiliary disease as indicated by 1 of the following:
a. Viral hepatitis ie, positive for HCV or HBV confirmed by nucleic acid
testing (if positive, subjects
must be receiving or have received antiviral therapy and have no history
of cirrhosis), OR
b. Alanine aminotransferase > 3 times upper limit of normal, OR
c. Total bilirubin > 1.5 times upper limit of normal.
4. History of human immunodeficiency virus with acquired immunodeficiency
syndrome
at Screening.
5. Active bacterial or fungal infection that is clinically significant in the
opinion of the investigator.
6. Not otherwise explained thrombotic microangiopathy on pre-enrollment kidney
biopsy.
7. Known congenital bleeding or coagulopathy disorder.
8. Evidence of non-catheter or non dialysis access-related deep vein
thrombosis, stroke, myocardial infarction, or arterial embolus within the 3
months before the Day 1 Visit; catheter-related thrombosis or history of
clotting a dialysis access is NOT exclusionary, unless a hereditary
coagulopathy has been diagnosed..
9. Treatment with a complement inhibitor (eg, Soliris [eculizumab], Berinert
[C1-INH], Cinryze [C1-INH]), or experimental therapies for the treatment of AMR
other than IVIg or rituximab (eg, bortezomib) within 14 days before
administration of C1-INH at the Day 1 Visit.
10. Current cancer or a history of cancer within 2 years before providing
informed consent, with the exception of successfully treated non-metastatic
basal or squamous cell carcinoma of the skin, in situ breast or other in situ
lesions considered cured by therapy
11. Any medical condition that, in the opinion of the investigator, might
interfere with the subject participation in the study, poses an added risk to
the subject, or confounds the assessment of the subject.
12. Female subjects who are pregnant (as evidenced by a positive serum
pregnancy test for choriogonadotropin beta at Screening) or breast feeding.
13. Female subject of childbearing potential or male subject not using or not
willing to use a medically reliable method of contraception from the first dose
of investigational product in any treatment period until 1 month after the last
dose of investigational product in the same treatment period.
NOTE: Childbearing potential and the acceptable methods of contraception are
defined in Section 7.4.
14. Participation in another interventional clinical study for AMR at
Screening; subject may have been withdrawn from an AMR study at any time before
Screening.
15. Known or suspected hypersensitivity to the investigational product (ie,
C1-INH or placebo), to any excipients of the investigational product, or to any
other C1-esterase inhibitor preparation (eg, Berinert) or albumin preparation.
16. Involved in the planning and/or conduct of the study (applies to CSL staff,
staff at the study site, and third-party vendors).
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Proportion of subjects with loss-of-response at the End-of-<br /><br>TP2.<br /><br>Loss-of-response at the End-of-TP2 is defined as any 1 of the<br /><br>following 3 conditions:<br /><br>* End-of-TP2 eGFR (mean of Week 36 and Week 38 eGFR)<br /><br>that is not stable, defined as:<br /><br>o End-of-TP2 eGFR that is < 90% of the End-of-TP1<br /><br>eGFR for subjects whose End-of-TP1 eGFR (mean of<br /><br>Week 11 and Week 12 eGFR) is * 100% of baseline;<br /><br>o End-of-TP2 eGFR that is < 90% of baseline for<br /><br>subjects whose end-of- TP1 eGFR is * 90% of baseline<br /><br>and < 100% of baseline<br /><br>* Allograft failure (defined by allograft nephrectomy, or<br /><br>institution of permanent dialysis, or return to the transplant<br /><br>waitlist for renal transplant, whichever occurs first)<br /><br>* Subject death by any cause</p><br>
- Secondary Outcome Measures
Name Time Method