PRI-VENT FSGS: Preemptive Rituximab to Prevent Recurrent Focal Segmental Glomerulosclerosis Post-Transplant
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|ClinicalTrials.gov Identifier: NCT03763643|
Recruitment Status : Recruiting
First Posted : December 4, 2018
Last Update Posted : February 8, 2023
|First Submitted Date ICMJE||August 7, 2018|
|First Posted Date ICMJE||December 4, 2018|
|Last Update Posted Date||February 8, 2023|
|Actual Study Start Date ICMJE||July 1, 2019|
|Estimated Primary Completion Date||August 31, 2023 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Feasibility assessment [ Time Frame: through study completion, an average of 1 year ]
quantifying the number and proportion of patients who can undergo the steps of recruitment, informed consent, enrollment, randomization, and follow-ups within the time frame of interest.
|Original Primary Outcome Measures ICMJE
||Recurrent FSGS at 1 year post-transplant. [ Time Frame: through study completion, an average of 1 year ]|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||PRI-VENT FSGS: Preemptive Rituximab to Prevent Recurrent Focal Segmental Glomerulosclerosis Post-Transplant|
|Official Title ICMJE||PRI-VENT FSGS: Preemptive Rituximab to Prevent Recurrent Focal Segmental Glomerulosclerosis Post-Transplant|
|Brief Summary||This is a pilot/feasibility, multicenter, randomized, open label, clinical trial to test that hypothesis that plasmapheresis plus rituximab prior to or at the time of kidney transplantation can prevent recurrent FSGS in children and adults.|
Recurrent FSGS is a risk factor for graft lost: Recurrence of FSGS can occur rapidly, within minutes of transplantation, and can lead to immediate onset of proteinuria and graft dysfunction. Recurrent FSGS is definitively diagnosed with a kidney biopsy. Early kidney biopsies in recurrent FSGS often demonstrate only extensive foot process effacement with the classic focal sclerosis appearing only after months of proteinuria. Recurrent FSGS is the single most important cause of graft failure in patients with FSGS. Patients with recurrent FSGS have significantly decreased graft survival compared to patients without recurrence and often require multiple kidney transplants in their lifetime. A number of clinical risk factors for recurrent FSGS have been identified including prior recurrence, Caucasian race, rapid progression of primary FSGS to ESRD within 3 years, mesangial hypercellularity on primary biopsy and living donor transplant, however these findings are inconsistent among various small studies. 3 A recent study from Europe identified late steroid resistant FSGS (nephrotic syndrome that is initially responsive to steroids, then later resistant) as a strong risk factor for recurrence. These findings have been replicated in our recent retrospective study of a North American cohort from the Midwest Pediatric Nephrology Consortium (N=116) that showed risk of recurrent FSGS was 70.6% in children with late steroid resistant FSGS compared to 35.8% risk in children with initial steroid resistant FSGS (manuscript in preparation). Genetic risk factors for late steroid resistant FSGS are unknown. In the same study Investigators identified native kidney biopsy findings that may predict risk of recurrence. Unfortunately, an individual's risk of recurrent disease cannot be predicted accurately prior to transplant. Thus, patients with FSGS have a high risk of recurrent disease post-transplant that is difficult to predict and patients have poor kidney transplant outcomes.
Plasmapheresis is utilized as a treatment for recurrent FSGS once it occurs: Several therapies for recurrent FSGS have been attempted with varying degrees of success but there remains no proven treatment for recurrent FSGS post-transplant. 7-10 The demonstration of a possible causative circulating factor by Savin et. al. 11 galvanized the field to attempt plasmapheresis to remove 'the permeability factor' as a therapy for recurrent FSGS. Therefore, recurrent FSGS is most often treated with plasmapheresis to remove the circulating factor and this is effective in a subset of patients. The results of uncontrolled single center case reports and series suggest a benefit from plasmapheresis 12-14 although graft loss from recurrent disease remains unacceptably high. Patients who do not respond to plasmapheresis have rapidly progressive chronic kidney disease. These patients have been treated with alternate agents such as rituximab, abatacept, or high dose cyclosporine with variable responses.15-17 Ideally, therapies will be identified to prevent recurrent FSGS before it occurs. Prevention of recurrent FSGS will lead to longer kidney transplant survival and reduced health care costs.
No treatments are available to prevent the recurrence of FSGS after transplant: Since 2005, there have been 3 published studies that have utilized a variety of protocols of plasmapheresis for the prevention of recurrent FSGS with inconsistent results. 18-20 The University of Minnesota pediatric transplant program has utilized pre-emptive plasmapheresis in children at risk for recurrent FSGS since 2006. In a recent review of our data, the incidence of recurrent FSGS post-transplant was not significantly different in patients who had undergone pre-emptive prophylactic plasmapheresis versus historic controls who had not (31% vs. 23%, p 0.5) (manuscript in press). Although this is a retrospective study, the data seems to suggest that plasmapheresis alone is not effective for preventing recurrence of FSGS. In addition, as stated above, the benefit of plasmapheresis in the treatment of recurrence is reported. 12-14 Thus, plasmapheresis with additional preemptive strategies to prevent recurrent FSGS are needed.
Rituximab has been used to treat recurrent FSGS and is a promising novel therapy to prevent recurrent disease. Rituximab is a chimeric monoclonal antibody against CD20 on B cells that leads to B cell depletion that has been used successfully for the treatment of primary steroid sensitive nephrotic syndrome as well as steroid sensitive and resistant FSGS. 21,22 Rituximab may act in FSGS via alterations in B-cell/T-cell interactions leading to changes in cytokine secretion or co-stimulation. Alternately, rituximab may have a direct effect on podocyte structure and function as it has been found to bind directly to the sphingomyelin phosphodiesterase acid-like 3b protein on the surface of podocytes. 23 Recent systematic reviews on the use of rituximab in the treatment of post-transplant FSGS (either with or without plasmapheresis) demonstrate partial or complete remission in ~60% of treated patients.15,24 The use of preemptive rituximab has been reported to be effective in preventing recurrent FSGS in 4 patients at very high risk due to prior graft loss from recurrent disease, however randomized controlled trials have not been performed. 25 Given the effectiveness of rituximab in the treatment of some patients with both primary and recurrent FSGS and the report of successful preemptive use of rituximab in high risk transplant patients, treatment with Rituximab in patients with FSGS prior to kidney transplant is a promising novel therapy to prevent recurrent disease. Preventing recurrent FSGS, rather than treating it once it has already occurred, is likely to minimize graft injury and prolong graft life, therefore preemptive strategies are needed.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Early Phase 1|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Control group and treatment/intervention groupMasking: None (Open Label)
Primary Purpose: Prevention
|Condition ICMJE||Focal Segmental Glomerulosclerosis|
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Estimated Study Completion Date ICMJE||December 31, 2024|
|Estimated Primary Completion Date||August 31, 2023 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
An individual who meets any of the following criteria will be excluded from participation in this study:
1. Known genetic cause of FSGS 2. Patients with FSGS secondary to another condition (obesity, viral infection, medications, etc.) 3. 4. Received rituximab within 1 year prior to transplant 5. Known hypersensitivity to rituximab, to any of its excipients, or to murine proteins 6. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies 7. Known active bacterial, viral (e.g. HIV, hepatitis B, hepatitis C), fungal, mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with iv antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening visit.
8. Participation in another therapeutic trial within 30 days of enrollment or 5 half-lives of the investigational drug (whichever is longer) 9. ANC < 1.5 x 103 10. Hemoglobin: < 8.0 gm/dL 11. Platelets: < 100,000/mm 12. AST or ALT >2.5 x Upper Limit of Normal at the local institution's laboratory 13. History of drug, alcohol, or chemical abuse within 6 months prior to screening visit.
14. Pregnant, lactating, or refusal of birth control in an adolescent of child-bearing potential 15. Concomitant malignancies or previous malignancies 16. History of psychiatric disorder that would interfere with normal participation in this protocol 17. History of significant cardiac (including arrhythmias) or pulmonary disease (including obstructive pulmonary disease) 18. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications 19. Inability to comply with study and follow-up procedures
|Ages ICMJE||1 Year to 65 Years (Child, Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT03763643|
|Other Study ID Numbers ICMJE||PEDS-2018-25868|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Current Responsible Party||University of Minnesota|
|Original Responsible Party||Same as current|
|Current Study Sponsor ICMJE||University of Minnesota|
|Original Study Sponsor ICMJE||Same as current|
|Collaborators ICMJE||United States Department of Defense|
|PRS Account||University of Minnesota|
|Verification Date||February 2023|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP