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

Antibody Mediated Rejection Clinical Trial

Official title:

Phase II Pilot Study of Cyclophosphamide Therapy for Refractory Antibody-Mediated Rejection in Kidney Transplantation

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01630538
• Other study ID #: TMCT-01
• Status: Terminated
• Phase: Phase 2
• First received: June 25, 2012
• Last updated: April 17, 2018
• Start date: June 2013
• Est. completion date: January 18, 2018

Study information

• Verified date: April 2018
• Source: University of Manitoba
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 4
• Est. completion date: January 18, 2018
• Est. primary completion date: January 18, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Antibody Mediated Rejection

Intervention

Drug:
• Cyclophosphamide
Cyclophosphamide 1.5 mg/kg orally daily for 180 days adjusted for renal function

Locations

Country	Name	City	State
Canada	Transplant Manitoba Adult Kidney Transplant Program, Health Sciences Centre	Winnipeg	Manitoba

Sponsors (1)

Lead Sponsor	Collaborator
University of Manitoba

Country where clinical trial is conducted

Canada, 

References & Publications (2)

Archdeacon P, Chan M, Neuland C, Velidedeoglu E, Meyer J, Tracy L, Cavaille-Coll M, Bala S, Hernandez A, Albrecht R. Summary of FDA antibody-mediated rejection workshop. Am J Transplant. 2011 May;11(5):896-906. doi: 10.1111/j.1600-6143.2011.03525.x. — View Citation

Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ, Goldberg A, Birk PE, Rush DN, Nickerson PW. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012 May;12(5):1157-67. doi: 10.1111/j.1600-6143.2012.04013.x. Epub 2012 Mar 19. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Microvascular inflammation	Histologic resolution of acute antibody-mediated inflammation in a 6 month post-treatment biopsy (Banff histology scores: g, v, ptc, C4d +ve)	month 6
Secondary	titre of donor specific antibody (DSA)	Change in the level of de novo DSA between enrolment and at 6 and 12 months post-enrollment	6 and 12 months
Secondary	antibody-mediated tissue injury	Change in antibody-mediated tissue injury between the enrollment and post-treatment kidney transplant biopsy samples	month 6
Secondary	Urine Albumin/Creatinine ratios	Change in urine albumin/creatinine ratio between enrolment and 6 and 12 month post-enrolment samples	month 6 and 12
Secondary	Creatinine Clearance and estimated GFR	Evaluation of Creatinine Clearance, and estimated GFR using the Chronic Kidney Disease Epidemiology (CKR-EPI) equation	month 6 and 12
Secondary	Graft Survival		month 6 and 12
Secondary	Patient Survival		month 6 and 12