Primary Focal Segmental Glomerulosclerosis
Conditions
Keywords
Treatment Resistant Idiopathic FSGS, Glomerulosclerosis, Proteinuria, Rituximab
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.
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.
Interventions
BIOLOGICALRituximab
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.
Sponsors
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)
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 80 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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. |
| 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 |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rituximab 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. | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | Rituximab |
|---|---|
| Age, Continuous | 37.4 years STANDARD_DEVIATION 16.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment Canada | 8 participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 9 |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 3 / 9 |
Outcome results
Primary
Changes in Proteinuria (With Stable Renal Function)
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rituximab | Changes in Proteinuria (With Stable Renal Function) | Baseline | 7.6 g/day | Standard Deviation 4.67 |
| Rituximab | Changes in Proteinuria (With Stable Renal Function) | 12 months | 7.27 g/day | Standard Deviation 7.3 |
Comparison: Baseline vs 12 monthsp-value: 0.49ANOVA
Secondary
Change in Activation of Podocyte β3 Integrin
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rituximab | Change in Activation of Podocyte β3 Integrin | Baseline | 1.56 AP5/paxillin ratio | Standard Deviation 0.59 |
| Rituximab | Change in Activation of Podocyte β3 Integrin | 1 month | 1.17 AP5/paxillin ratio | Standard Deviation 0.17 |
| Rituximab | Change in Activation of Podocyte β3 Integrin | 3 month | 1.13 AP5/paxillin ratio | Standard Deviation 0.34 |
| Rituximab | Change in Activation of Podocyte β3 Integrin | 6 month | 1.15 AP5/paxillin ratio | Standard Deviation 0.3 |
| Rituximab | Change in Activation of Podocyte β3 Integrin | 12 month | 1.24 AP5/paxillin ratio | Standard Deviation 0.27 |
Comparison: Baseline vs 12 monthsp-value: 0.06ANOVA
Secondary
Change in suPAR Levels
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rituximab | Change in suPAR Levels | Baseline | 4120 pg/ml | Standard Deviation 1169 |
| Rituximab | Change in suPAR Levels | 1 month | 3730 pg/ml | Standard Deviation 1229 |
| Rituximab | Change in suPAR Levels | 3 month | 4231 pg/ml | Standard Deviation 1871 |
| Rituximab | Change in suPAR Levels | 6 month | 4491 pg/ml | Standard Deviation 2217 |
| Rituximab | Change in suPAR Levels | 12 month | 3788 pg/ml | Standard Deviation 1836 |
Comparison: Baseline vs 12 monthsp-value: 0.41ANOVA
Secondary
Number of Subjects With Complete or Partial Remission Following Treatment
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Number of Subjects With Complete or Partial Remission Following Treatment | 0 Participants |