A Pilot Study to Assess the Efficacy of Rituximab Therapy in Treatment Resistant FSGS

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01573533
• Collaborator: University Health Network, Toronto (Other), National Institutes of Health (NIH) (NIH), Genentech, Inc. (Industry), Rush University Medical Center (Other), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 9
• Locations: 4
• Arm: 1
• Actual Duration (Months): 61.5
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether Rituximab therapy is safe and effective in treating patients with the kidney condition, focal segmental glomerulosclerosis (FSGS), that is no longer responsive to traditional therapies.

Condition or Disease	Intervention/Treatment	Phase
Primary Focal Segmental Glomerulosclerosis	Biological: Rituximab	Phase 2

Detailed Description

This is a pilot trial to assess the safety, feasibility and efficacy of Rituximab therapy in 20 adult and pediatric patients with either steroid and/or calcineurin inhibitor resistant FSGS or with a significant intolerance or contraindication to the use of these agents. In addition to clinical criteria, elevated levels of suPAR will define inclusion. Changes in the baseline levels of the potential biomarkers (suPAR, as well as activation of beta-3 integrin) in response to treatment will be compared to clinical measures of efficacy.

Participants will have a screening/baseline visit to confirm eligibility within 6 weeks prior to the first of two Rituximab infusions (at Day 1 and Day 15). Participants will then attend follow up visits at 1, 3, 6 and 12 months after Rituximab treatment to assess adverse events and collect safety blood and urine samples.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study to Assess the Efficacy of Rituximab Therapy in Patients With Treatment Resistant Idiopathic Focal Segmental Glomerulosclerosis (FSGS): Integrating an Assessment of the Relevance of suPAR and Activation of Podocyte β3 Integrin
• Actual Study Start Date: Oct 1, 2013
• Actual Primary Completion Date: Nov 15, 2018
• Actual Study Completion Date: Nov 15, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rituximab	Biological: Rituximab; Rituximab will be infused intravenously on Day 1 and Day 15 at a dose of 375 mg/m2 up to a maximum of 1000mg per dose in children and at a dose of 1000 mg on Day 1 and Day 15 in adults.; Other Names: Rituxan®

Outcome Measures

Primary Outcome Measures

1. Changes in Proteinuria (With Stable Renal Function) [Baseline, 12 months]

   The amount of protein in excreted urine measured by grams per day (g/day). Remission status defined by the following criteria at 12 months: Complete Remission - Proteinuria < 0.5 g/day Partial Remission - Improvement in proteinuria by > 50% and to a level between 0.5-3.5g/day Incomplete Remission - Improvement in proteinuria equal to or >50%, but residual proteinuria still >3.5g/day

Secondary Outcome Measures

1. Change in suPAR Levels [Baseline, 1, 3, 6 and 12 months]

   SuPAR concentrations will be determined by quantitative ELISA immunoassay reported in picograms per milliliters (pg/ml)

2. Change in Activation of Podocyte β3 Integrin [Baseline, 1, 3, 6, 12 months]

   To quantitatively examine the effect of FSGS patient sera on podocyte β3 integrin activity, a human podocyte cell line is cultured at 37 degrees Celsius for 14 days for complete differentiation. The cells are then incubated in 5-10% of FSGS patient serum for 24 hours with recombinant suPAR protein as a positive control. Cells are fixed with 4% paraformaldehyde (PFA) and proceeded for immunofluorescence staining for AP5 and paxillin. After immunostaining, confocal images are taken to quantify the AP5 and paxillin intensity for each sample treatment. Paxillin signal is used to correct AP5 signal. The relative AP5 signal (AP5/paxillin ratio) from each patient serum is then normalized against that of normal blood donor included in each assay for final report.

3. Number of Subjects With Complete or Partial Remission Following Treatment [12 months]

   Total number of subjects with complete or partial remission following treatment using the following criteria: Complete Remission - Proteinuria < 0.5 g/day Partial Remission - Improvement in proteinuria by > 50% and to a level between 0.5-3.5g/day Incomplete Remission - Improvement in proteinuria equal to or >50%, but residual proteinuria still >3.5g/day

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• FSGS involving native kidneys with a diagnostic biopsy performed within the last 3 years

• Patients >6 years of age and < 80 years of age

• suPAR > 3500 pg ml-1

• Treatment with an ACEI and/or ARB as tolerated for at least 3 months prior to enrollment to with a target a systolic blood pressure ≤ 140 mmHg and a diastolic pressure ≤ 90 mmHg in adults and blood pressure readings less than the 95th percentile for age, gender and height in children in at least 75% of readings

• Proteinuria ≥ 3.0 grams as measured by 24-hour urine collection in adults and urine protein:creatinine ratio ≥ 1.0 in the first morning urine in children, despite ACE inhibitor / ARB treatment as tolerated and a minimum of 8 weeks of prednisone therapy at ≥ 1 mg/kg/day, a trial of calcineurin inhibitor for=> 3 months or a contraindication/intolerance to such therapy (diabetes, osteoporosis/osteonecrosis, age >60, BMI ≥35)

• Negative serum pregnancy test (for women of child bearing age)

• Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months (1 year) after completion of the trial

• Able and willing to give written informed consent and comply with study requirements

Exclusion Criteria:

• Estimated GFR < 40 ml/min per1.73m2. The rationale is that patients with advanced renal failure may progress rapidly towards ESRD.

• Collapsing variant of FSGS, as it is rare and has been associated with an aggressive course

• Concurrent use of immunosuppressive therapy with the exceptions of prednisone 10 mg/day. Patients who are taking other immunosuppressive therapy, must be off immunosuppressive medications for equal to or > 3 months prior to enrollment into the study with the exception of patients demonstrating significant worsening of proteinuria (of >30% above baseline) during the washout period. These resistant patients can be treated after 1 month of washout due to the high likelihood of progression and/or lack of delayed (previous) immunosuppression effect.

• Patients with medical conditions that may cause FSGS (e.g. HIV, lymphoma, heroin use) or have a secondary form of FSGS due to hyperfiltration injury (massive obesity, vesicoureteral reflux, or renal mass reduction)

• Type 1 or type 2 diabetes mellitus as diabetic glomerulosclerosis may be contributing to proteinuria in these patients

• History of serious recurrent or chronic infection

• Presence or suspicion of active infection including TB, HIV, Hepatitis B and HCV with positive tests for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HBcAb), Hepatitis B virus (HBV), Hepatitis C serology, HIV serology or a positive TB skin test, which require further investigation to rule out active disease (ie. chest x-ray)

• Known active infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks or oral antibiotics within 2 weeks of the study initiation

• Low immunoglobulins (level to be based on age)

• Absolute neutrophil count < 1.5 x103/mL

• Patients in receipt of a live vaccine within 4 weeks of the study initiation

• Concomitant malignancies or previous malignancies within the last five years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix

• Previous Treatment with a B-cell depleting antibody

• History of severe allergic reactions to humanized or murine monoclonal antibodies

• Treatment with any investigational agent within 4 weeks of the study initiation

• History of major psychiatric disorder, drug or alcohol abuse within the previous 6 months

• Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory that provides a 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rush University Medical Center	Chicago	Illinois	United States	60612
2	Mayo Clinic College of Medicine	Rochester	Minnesota	United States	55905
3	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
4	University Health Network	Toronto	Ontario	Canada	M5G 2N2

Sponsors and Collaborators

• Mayo Clinic
• University Health Network, Toronto
• National Institutes of Health (NIH)
• Genentech, Inc.
• Rush University Medical Center
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Michelle Hladunewich, MD, MSc, BSc, University Health Network, Sunnybrook Health Sciences Centre
• Principal Investigator: Fernando C Fervenza, MD, PhD, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 30, 2017

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Fernando Fervenza, PI, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01573533
• Other Study ID Numbers: 12-005640; U54DK083912
• First Posted: Apr 9, 2012
• Last Update Posted: Feb 10, 2020
• Last Verified: Jan 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Fernando Fervenza, PI, Mayo Clinic: Treatment Resistant Idiopathic FSGS; Glomerulosclerosis; Proteinuria; Rituximab
• Additional relevant MeSH terms: Glomerulosclerosis, Focal Segmental; Rituximab

Study Results

Participant Flow

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab: Rituximab will be infused intravenously on Day 1 and Day 15 at a dose of 375 mg/m2 up to a maximum of 1000mg per dose in children and at a dose of 1000 mg on Day 1 and Day 15 in adults.
Period Title: Overall Study
STARTED	9
COMPLETED	9
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab: Rituximab will be infused intravenously on Day 1 and Day 15 at a dose of 375 mg/m2 up to a maximum of 1000mg per dose in children and at a dose of 1000 mg on Day 1 and Day 15 in adults.
Overall Participants	9
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.4 (16.2)
Sex: Female, Male (Count of Participants)
Female	4 44.4%
Male	5 55.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	9 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 22.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 11.1%
White	6 66.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	1 11.1%
Canada	8 88.9%

Outcome Measures

1. Primary Outcome

Title	Changes in Proteinuria (With Stable Renal Function)
Description	The amount of protein in excreted urine measured by grams per day (g/day). Remission status defined by the following criteria at 12 months: Complete Remission - Proteinuria < 0.5 g/day Partial Remission - Improvement in proteinuria by > 50% and to a level between 0.5-3.5g/day Incomplete Remission - Improvement in proteinuria equal to or >50%, but residual proteinuria still >3.5g/day
Time Frame	Baseline, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab: Rituximab will be infused intravenously on Day 1 and Day 15 at a dose of 375 mg/m2 up to a maximum of 1000mg per dose in children and at a dose of 1000 mg on Day 1 and Day 15 in adults.
Measure Participants	9
Baseline	7.6 (4.67)
12 months	7.27 (7.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab
	Comments	Baseline vs 12 months
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.49
	Comments
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Change in suPAR Levels
Description	SuPAR concentrations will be determined by quantitative ELISA immunoassay reported in picograms per milliliters (pg/ml)
Time Frame	Baseline, 1, 3, 6 and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab: Rituximab will be infused intravenously on Day 1 and Day 15 at a dose of 375 mg/m2 up to a maximum of 1000mg per dose in children and at a dose of 1000 mg on Day 1 and Day 15 in adults.
Measure Participants	9
Baseline	4120 (1169)
1 month	3730 (1229)
3 month	4231 (1871)
6 month	4491 (2217)
12 month	3788 (1836)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab
	Comments	Baseline vs 12 months
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.41
	Comments
	Method	ANOVA
	Comments

3. Secondary Outcome

Title	Change in Activation of Podocyte β3 Integrin
Description	To quantitatively examine the effect of FSGS patient sera on podocyte β3 integrin activity, a human podocyte cell line is cultured at 37 degrees Celsius for 14 days for complete differentiation. The cells are then incubated in 5-10% of FSGS patient serum for 24 hours with recombinant suPAR protein as a positive control. Cells are fixed with 4% paraformaldehyde (PFA) and proceeded for immunofluorescence staining for AP5 and paxillin. After immunostaining, confocal images are taken to quantify the AP5 and paxillin intensity for each sample treatment. Paxillin signal is used to correct AP5 signal. The relative AP5 signal (AP5/paxillin ratio) from each patient serum is then normalized against that of normal blood donor included in each assay for final report.
Time Frame	Baseline, 1, 3, 6, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab: Rituximab will be infused intravenously on Day 1 and Day 15 at a dose of 375 mg/m2 up to a maximum of 1000mg per dose in children and at a dose of 1000 mg on Day 1 and Day 15 in adults.
Measure Participants	9
Baseline	1.56 (0.59)
1 month	1.17 (0.17)
3 month	1.13 (0.34)
6 month	1.15 (0.30)
12 month	1.24 (0.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab
	Comments	Baseline vs 12 months
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Number of Subjects With Complete or Partial Remission Following Treatment
Description	Total number of subjects with complete or partial remission following treatment using the following criteria: Complete Remission - Proteinuria < 0.5 g/day Partial Remission - Improvement in proteinuria by > 50% and to a level between 0.5-3.5g/day Incomplete Remission - Improvement in proteinuria equal to or >50%, but residual proteinuria still >3.5g/day
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab: Rituximab will be infused intravenously on Day 1 and Day 15 at a dose of 375 mg/m2 up to a maximum of 1000mg per dose in children and at a dose of 1000 mg on Day 1 and Day 15 in adults.
Measure Participants	9
Count of Participants [Participants]	0 0%

Adverse Events

Time Frame	The study period during which all AEs and SAEs must be reported begins after informed consent is obtained and ends 30 days after study discontinuation/termination for each participant.
Arm/Group Title	Rituximab
Arm/Group Description	Rituximab: Rituximab will be infused intravenously on Day 1 and Day 15 at a dose of 375 mg/m2 up to a maximum of 1000mg per dose in children and at a dose of 1000 mg on Day 1 and Day 15 in adults.
All Cause Mortality
	Rituximab
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Serious Adverse Events
	Rituximab
	Affected / at Risk (%)	# Events
Total	3/9 (33.3%)
Infections and infestations
Lung Infection	1/9 (11.1%)	1
Upper respiratory tract infection	1/9 (11.1%)	1
Renal and urinary disorders
Acute Kidney Infection	1/9 (11.1%)	1
Other (Not Including Serious) Adverse Events
	Rituximab
	Affected / at Risk (%)	# Events
Total	9/9 (100%)
Blood and lymphatic system disorders
Neutropenia	1/9 (11.1%)	1
Gastrointestinal disorders
Nausea	1/9 (11.1%)	1
Vomiting	1/9 (11.1%)	1
General disorders
Infusion related reaction	1/9 (11.1%)	1
Sore Throat	1/9 (11.1%)	1
Cramps	1/9 (11.1%)	1
Dizziness	1/9 (11.1%)	1
Weakness	1/9 (11.1%)	1
Rash	1/9 (11.1%)	1
Headache	1/9 (11.1%)	1
Infections and infestations
Nail Infection	1/9 (11.1%)	1
Renal and urinary disorders
Relapse of Nephrotic Syndrome	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/9 (11.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.