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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
University Health Network, Toronto
Genentech, Inc.
Rush University Medical Center
Information provided by (Responsible Party):
Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier:
NCT01573533
First received: April 5, 2012
Last updated: November 25, 2013
Last verified: November 2013
  Purpose

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 Intervention Phase
Primary Focal Segmental Glomerulosclerosis
Biological: Rituximab
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Sunnybrook Health Sciences Centre:

Primary Outcome Measures:
  • Changes in proteinuria (with stable renal function) [ Time Frame: 12 months ] [ Designated as safety issue: No ]

    The major outcomes will be categorized by changes in proteinuria (with stable renal function). The primary endpoint will be determined by patient status at 12 months of follow up defined as:

    In Adults:

    • Complete Remission - Proteinuria < 0.5 g/d daily
    • Partial Remission - Improvement in proteinuria by > 50% and to a level between 0.5-3.5g/d
    • Incomplete Remission - Improvement in proteinuria equal to or >50%, but residual proteinuria still >3.5g/d

    In Children:

    • Complete Remission - Urine protein/creatinine ratio < 0.2
    • Partial Remission - Improvement in proteinuria by > 50% and to a urine protein/creatinine value of 0.2-1.0
    • Incomplete Remission - Improvement in proteinuria equal to or > 50%, but residual urine protein/creatinine >1

    Or in both groups:

    • Worsening of renal function (serum creatinine > 30% above baseline) without significant improvement in proteinuria (<50% improvement) or no improvement in proteinuria(<50%).


Secondary Outcome Measures:
  • Change in suPAR levels [ Time Frame: 1, 3, 6 and 12 months ] [ Designated as safety issue: No ]
    Change from baseline suPAR level at 1, 3, 6 and 12 months following Rituximab treatment

  • Change in activation of podocyte β3 integrin [ Time Frame: 1, 3, 6, 12 months ] [ Designated as safety issue: No ]
    Change from baseline of activation of podocyte β3 integrin at 1, 3, 6 and 12 months following Rituximab treatment

  • Duration of complete or partial remission following treatment [ Time Frame: 1, 3, 6, 12 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
Study Start Date: October 2013
Estimated Study Completion Date: November 2015
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Rituxan®

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.

  Eligibility

Ages Eligible for Study:   6 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01573533

Locations
United States, Illinois
Rush University Medical Center
Chicago, Illinois, United States, 60612
United States, Minnesota
Mayo Clinic College of Medicine
Rochester, Minnesota, United States, 55905
United States, New York
Albert Einstein College of Medicine (The Children's Hospital at Monteflore)
Bronx, New York, United States, 10467
New York University Medical Center
New York, New York, United States, 10016
Canada, Ontario
Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada, M4N 3M5
University Health Network
Toronto, Ontario, Canada, M5G 2N2
Sponsors and Collaborators
Sunnybrook Health Sciences Centre
University Health Network, Toronto
Genentech, Inc.
Rush University Medical Center
Investigators
Principal Investigator: Michelle Hladunewich, MD, MSc, BSc University Health Network, Sunnybrook Health Sciences Centre
  More Information

No publications provided

Responsible Party: Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier: NCT01573533     History of Changes
Other Study ID Numbers: RDCRN# 6803, U54DK083912
Study First Received: April 5, 2012
Last Updated: November 25, 2013
Health Authority: Canada: Health Canada
United States: Food and Drug Administration

Keywords provided by Sunnybrook Health Sciences Centre:
Treatment Resistant Idiopathic FSGS
Glomerulosclerosis
Proteinuria
Rituximab

Additional relevant MeSH terms:
Glomerulosclerosis, Focal Segmental
Glomerulonephritis
Kidney Diseases
Nephritis
Urologic Diseases
Rituximab
Antineoplastic Agents
Antirheumatic Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014