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PRI-VENT FSGS: Preemptive Rituximab to Prevent Recurrent Focal Segmental Glomerulosclerosis Post-Transplant

Primary Purpose

Focal Segmental Glomerulosclerosis

Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Rituximab
Plasmapheresis
Sponsored by
University of Minnesota
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Focal Segmental Glomerulosclerosis

Eligibility Criteria

1 Year - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

  1. Age 1-65 years at the time of kidney transplant
  2. Biopsy proven diagnosis of primary FSGS or minimal change disease
  3. History of nephrotic syndrome (proteinuria, edema, hypoalbuminemia)
  4. First kidney transplant or second or third transplant with a history of recurrent FSGS in the first or second kidney transplant.
  5. The patient (if ≥18 years old) or the child's parent or guardian must be able and willing to give written informed consent and comply with the requirements of the study protocol. Patient assent if <18 years old will be required per local IRB requirements.
  6. Negative urine pregnancy test prior to randomization (for females who are post-menarche).
  7. Males and females of reproductive potential (sexually active in boys or post-menarche in girls) must agree to use an acceptable method of birth control during treatment and for twelve months (1 year) after completion of treatment with rituximab.

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

Sites / Locations

  • University of AlabamaRecruiting
  • University of California at DavisRecruiting
  • Lurie Children's HospitalRecruiting
  • University of IowaRecruiting
  • Children's Hospital of ColoradoRecruiting
  • Hennepin HealthRecruiting
  • University of MinnesotaRecruiting
  • Mayo ClinicRecruiting
  • Duke UniversityRecruiting
  • University of CincinnatiRecruiting
  • Cincinnati Children's HospitalRecruiting
  • Children's Hospital of PhiladelphiaRecruiting
  • Seattle Children's HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Rituximab + plasmapharesis

Placebo + plasmapharesis

Arm Description

This is a phase III, multicenter, randomized, open-label clinical trial. Participants with FSGS will be randomized 1:1 to receive rituximab or placebo on day -1, 0 and +1 prior to or after kidney transplantation in addition to standard plasmapheresis.

This is a phase III, multicenter, randomized, open-label clinical trial. Participants with FSGS will be randomized 1:1 to receive rituximab or placebo on day -1, 0 and +1 prior to or after kidney transplantation in addition to standard plasmapheresis.

Outcomes

Primary Outcome Measures

Feasibility assessment
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.

Secondary Outcome Measures

Patient and graft survival at 1 year post-transplant
Outcome is reported as the number of participants who survive with a functional graft one year post-transplant.
Graft function at 1 year post-transplant
Graft function will be assessed using the glomerular filtration rate (GFR) and Schwartz equation (for age ≤17 years) or the CKD-EPI (for age ≥18 years).
Proportion with acute rejection at 1 year post-transplant
Outcome is reported as the percentage of participants who experience an acute graft rejection at one ear post-transplant.
Proportion with CD19+ <1%
Outcome is reported as the percentage with participants with a reconstitution of CD19+ B cells at one year post-transplant.
Recurrent FSGS free survival
To determine the difference in rate of recurrent FSGS after 1 year post-transplant in patients receiving plasmapheresis and rituximab prior to or at the time of kidney transplantation compared to those receiving plasmapheresis alone.

Full Information

First Posted
August 7, 2018
Last Updated
October 3, 2023
Sponsor
University of Minnesota
Collaborators
United States Department of Defense
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1. Study Identification

Unique Protocol Identification Number
NCT03763643
Brief Title
PRI-VENT FSGS: Preemptive Rituximab to Prevent Recurrent Focal Segmental Glomerulosclerosis Post-Transplant
Official Title
PRI-VENT FSGS: Preemptive Rituximab to Prevent Recurrent Focal Segmental Glomerulosclerosis Post-Transplant
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 1, 2019 (Actual)
Primary Completion Date
August 31, 2025 (Anticipated)
Study Completion Date
December 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Minnesota
Collaborators
United States Department of Defense

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Focal Segmental Glomerulosclerosis

7. Study Design

Primary Purpose
Prevention
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Model Description
Control group and treatment/intervention group
Masking
None (Open Label)
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Rituximab + plasmapharesis
Arm Type
Experimental
Arm Description
This is a phase III, multicenter, randomized, open-label clinical trial. Participants with FSGS will be randomized 1:1 to receive rituximab or placebo on day -1, 0 and +1 prior to or after kidney transplantation in addition to standard plasmapheresis.
Arm Title
Placebo + plasmapharesis
Arm Type
Placebo Comparator
Arm Description
This is a phase III, multicenter, randomized, open-label clinical trial. Participants with FSGS will be randomized 1:1 to receive rituximab or placebo on day -1, 0 and +1 prior to or after kidney transplantation in addition to standard plasmapheresis.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Intervention Description
Rituximab 375mg/m2 intravenous on day 0 or -1 prior to kidney transplant
Intervention Type
Procedure
Intervention Name(s)
Plasmapheresis
Intervention Description
1.5 volume exchange plasmapheresis with fresh frozen plasma replacement
Primary Outcome Measure Information:
Title
Feasibility assessment
Description
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.
Time Frame
through study completion, an average of 1 year
Secondary Outcome Measure Information:
Title
Patient and graft survival at 1 year post-transplant
Description
Outcome is reported as the number of participants who survive with a functional graft one year post-transplant.
Time Frame
through study completion, an average of 1 year
Title
Graft function at 1 year post-transplant
Description
Graft function will be assessed using the glomerular filtration rate (GFR) and Schwartz equation (for age ≤17 years) or the CKD-EPI (for age ≥18 years).
Time Frame
through study completion, an average of 1 year
Title
Proportion with acute rejection at 1 year post-transplant
Description
Outcome is reported as the percentage of participants who experience an acute graft rejection at one ear post-transplant.
Time Frame
through study completion, an average of 1 year
Title
Proportion with CD19+ <1%
Description
Outcome is reported as the percentage with participants with a reconstitution of CD19+ B cells at one year post-transplant.
Time Frame
1 month, 6 months, and 12 months
Title
Recurrent FSGS free survival
Description
To determine the difference in rate of recurrent FSGS after 1 year post-transplant in patients receiving plasmapheresis and rituximab prior to or at the time of kidney transplantation compared to those receiving plasmapheresis alone.
Time Frame
after 1 year post-transplant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
In order to be eligible to participate in this study, an individual must meet all of the following criteria: Age 1-65 years at the time of kidney transplant Biopsy proven diagnosis of primary FSGS or minimal change disease History of nephrotic syndrome (proteinuria, edema, hypoalbuminemia) First kidney transplant or second or third transplant with a history of recurrent FSGS in the first or second kidney transplant. The patient (if ≥18 years old) or the child's parent or guardian must be able and willing to give written informed consent and comply with the requirements of the study protocol. Patient assent if <18 years old will be required per local IRB requirements. Negative urine pregnancy test prior to randomization (for females who are post-menarche). Males and females of reproductive potential (sexually active in boys or post-menarche in girls) must agree to use an acceptable method of birth control during treatment and for twelve months (1 year) after completion of treatment with rituximab. 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Amy Hanson
Phone
612-626-4424
Email
amhanson@umn.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Kayla Arndt
Email
arndt374@umn.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michelle Rheault, MD
Organizational Affiliation
University of Minnesota
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama
City
Tuscaloosa
State/Province
Alabama
ZIP/Postal Code
35487
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael Siefert, MD
Email
mseifert@uabmc.edu
First Name & Middle Initial & Last Name & Degree
Michael Siefert, MD
Facility Name
University of California at Davis
City
Davis
State/Province
California
ZIP/Postal Code
95616
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Junichuro Sageshima, MD
Email
jsageshima@ucdavis.edu
First Name & Middle Initial & Last Name & Degree
Junichuro Sageshima, MD
Facility Name
Lurie Children's Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Priya Verghese, MD, MPH
Email
pverghese@luriechildren.org
First Name & Middle Initial & Last Name & Degree
Priya Verghese, MD, MPH
Facility Name
University of Iowa
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christie Thomas, MD
Email
Christie-thomas@uiowa.edu
First Name & Middle Initial & Last Name & Degree
Christie Thomas, MD
First Name & Middle Initial & Last Name & Degree
Lyndsay Harshman, MD, MS
Facility Name
Children's Hospital of Colorado
City
Aurora
State/Province
Minnesota
ZIP/Postal Code
80045
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Margret Bock, MD, MS
Email
Margret.bock@childrenscolorado.org
First Name & Middle Initial & Last Name & Degree
Margret Bock, MD, MS
Facility Name
Hennepin Health
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55415
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ajay Israni, MD, MS
Email
Isran001@umn.edu
First Name & Middle Initial & Last Name & Degree
Ajay Israni, MD, MS
Facility Name
University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michelle Rheault, MD
Phone
612-626-2922
Email
rheau002@umn.edu
First Name & Middle Initial & Last Name & Degree
Michelle Rheault, MD
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Amer Hatem, MD
Email
Amer.hatem@mayo.edu
First Name & Middle Initial & Last Name & Degree
Amer Hatem, MD
First Name & Middle Initial & Last Name & Degree
Mireille El Ters, MD
First Name & Middle Initial & Last Name & Degree
Carl Cramer, MD
Facility Name
Duke University
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27708
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rasheed Gbadegesin, MD, MBBS
Email
Rasheed.gbadegesin@duke.edu
First Name & Middle Initial & Last Name & Degree
Rasheed Rasheed.gbadegesin@duke.edu, MD, MBBS
First Name & Middle Initial & Last Name & Degree
Eileen Tsai Chambers, MD
Facility Name
University of Cincinnati
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45221
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Amit Govil, MD
Email
govilat@ucmail.uc.edu
First Name & Middle Initial & Last Name & Degree
Amit Govil, MD
Facility Name
Cincinnati Children's Hospital
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
David Hooper, MD, MS
Email
David.Hooper@cchmc.org
First Name & Middle Initial & Last Name & Degree
David Hooper, MD, MD
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sandra Amaral, MD, MHS
Email
AmaralS@email.chop.edu
First Name & Middle Initial & Last Name & Degree
Sandra Amaral, MD, MHS
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jodi Smith, MD, MPH
Email
Jodi.smith@seattlechildrens.org
First Name & Middle Initial & Last Name & Degree
Jodi Smith, MD, MPH

12. IPD Sharing Statement

Plan to Share IPD
No

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PRI-VENT FSGS: Preemptive Rituximab to Prevent Recurrent Focal Segmental Glomerulosclerosis Post-Transplant

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