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

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ClinicalTrials.gov Identifier: NCT01630538
Recruitment Status : Active, not recruiting
First Posted : June 28, 2012
Last Update Posted : December 6, 2017
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Antibody Mediated Rejection Drug: Cyclophosphamide Phase 2

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Pilot Study of Cyclophosphamide Therapy for Refractory Antibody-Mediated Rejection in Kidney Transplantation
Study Start Date : June 2013
Estimated Primary Completion Date : April 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Cyclophosphamide
Cyclophosphamide 1.5 mg/kg orally daily for 180 days (26 weeks) adjusted for renal function.
Drug: Cyclophosphamide
Cyclophosphamide 1.5 mg/kg orally daily for 180 days adjusted for renal function
Other Name: Procytox

Primary Outcome Measures :
  1. Microvascular inflammation [ Time Frame: month 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 :
  1. titre of donor specific antibody (DSA) [ Time Frame: 6 and 12 months ]
    Change in the level of de novo DSA between enrolment and at 6 and 12 months post-enrollment

  2. antibody-mediated tissue injury [ Time Frame: month 6 ]
    Change in antibody-mediated tissue injury between the enrollment and post-treatment kidney transplant biopsy samples

  3. Urine Albumin/Creatinine ratios [ Time Frame: month 6 and 12 ]
    Change in urine albumin/creatinine ratio between enrolment and 6 and 12 month post-enrolment samples

  4. Creatinine Clearance and estimated GFR [ Time Frame: month 6 and 12 ]
    Evaluation of Creatinine Clearance, and estimated GFR using the Chronic Kidney Disease Epidemiology (CKR-EPI) equation

  5. Graft Survival [ Time Frame: month 6 and 12 ]
  6. Patient Survival [ Time Frame: month 6 and 12 ]

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01630538

Canada, Manitoba
Transplant Manitoba Adult Kidney Transplant Program, Health Sciences Centre
Winnipeg, Manitoba, Canada
Sponsors and Collaborators
University of Manitoba
Principal Investigator: Peter W Nickerson, MD University of Manitoba
Study Chair: David N Rush, MD University of Manitoba

Responsible Party: University of Manitoba
ClinicalTrials.gov Identifier: NCT01630538     History of Changes
Other Study ID Numbers: TMCT-01
First Posted: June 28, 2012    Key Record Dates
Last Update Posted: December 6, 2017
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by University of Manitoba:

Additional relevant MeSH terms:
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists