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Cyclophosphamide Therapy for Refractory Antibody-Mediated Rejection (AMR) in Kidney Transplants

Phase 2
Terminated
Conditions
Antibody Mediated Rejection
Interventions
Registration Number
NCT01630538
Lead Sponsor
University of Manitoba
Brief Summary

The study hypothesis is that short-term low dose cyclophosphamide therapy will be effective in resolving inflammation in patients with late phase antibody-mediated rejection refractory to current standard of care treatment.

Detailed Description

There is no consensus on the optimal treatment of de novo donor specific antibody-mediated rejection. Optimizing baseline immunosuppression (calcineurin inhibitor (CNI), anti-proliferative agent, and anti-inflammatory) is considered foundational but is insufficient. Pulse steroids are routinely used. A number of immunosuppressive approaches have been tried in uncontrolled trials. The strongest evidence, at least for early antibody-mediated rejection (\< 6 months from transplant), exists for plasmapheresis, with or without low dose IVIg, or high dose IVIg alone. However, as noted in a recent FDA workshop, "while the literature suggests that \[these agents\] have evidence of efficacy for the management of acute antibody-mediated rejection, and could be considered as standard of care, treatment regimes have not been standardized or optimized." Moreover the evidence supporting efficacy of this approach in late, as opposed to early antibody-mediated rejection is distinctly lacking.

Recruitment & Eligibility

Status
TERMINATED
Sex
All
Target Recruitment
4
Inclusion Criteria
  • Patients with a living or deceased donor kidney transplant
  • Failed current standard of care for late antibody-mediated rejection
  • Persistent de novo donor specific antibody and a concurrent biopsy with histologic evidence of acute antibody-mediated inflammation
  • Adults with reproductive potential must agree to use approved methods of birth control while in the study
Exclusion Criteria
  • Leukopenia (WBC) < 3.0 x 109/L
  • Creatinine Clearance less than or equal to 25 ml/min/1.73m2
  • HCV or HBV positive
  • BKV or CMV viremia assessed by PCR
  • Any active infection
  • Use of other investigational drugs within 4 weeks of study
  • Pregnancy/breast feeding/unwilling or unable to take birth control
  • Active malignancy
  • de novo DSA occurring equal to or greater than15 years after kidney transplant
  • Screening biopsy with equal to or greater than cg2 on Banff criteria
  • Cumulative/lifetime dose of cyclophosphamide, including anticipated total study dose (calculated according to Creatinine Clearance and mg/kg/day) equal to or greater than 36 g.
  • Any condition that, in the opinion of the investigator, would pose risk to the subject's safe participation in the study

Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
CyclophosphamideCyclophosphamideCyclophosphamide 1.5 mg/kg orally daily for 180 days (26 weeks) adjusted for renal function.
Primary Outcome Measures
NameTimeMethod
Microvascular inflammationmonth 6

Histologic resolution of acute antibody-mediated inflammation in a 6 month post-treatment biopsy (Banff histology scores: g, v, ptc, C4d +ve)

Secondary Outcome Measures
NameTimeMethod
Patient Survivalmonth 6 and 12
Graft Survivalmonth 6 and 12
titre of donor specific antibody (DSA)6 and 12 months

Change in the level of de novo DSA between enrolment and at 6 and 12 months post-enrollment

antibody-mediated tissue injurymonth 6

Change in antibody-mediated tissue injury between the enrollment and post-treatment kidney transplant biopsy samples

Urine Albumin/Creatinine ratiosmonth 6 and 12

Change in urine albumin/creatinine ratio between enrolment and 6 and 12 month post-enrolment samples

Creatinine Clearance and estimated GFRmonth 6 and 12

Evaluation of Creatinine Clearance, and estimated GFR using the Chronic Kidney Disease Epidemiology (CKR-EPI) equation

Trial Locations

Locations (1)

Transplant Manitoba Adult Kidney Transplant Program, Health Sciences Centre

🇨🇦

Winnipeg, Manitoba, Canada

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