Pilot Studies of Novel Therapies to Treat Resistant Focal Segmental Glomerulosclerosis (FSGS)

This study has been completed.
Sponsor:
Collaborators:
University of North Carolina
The Cleveland Clinic
Information provided by:
North Shore Long Island Jewish Health System
ClinicalTrials.gov Identifier:
NCT00193648
First received: September 10, 2005
Last updated: October 19, 2007
Last verified: October 2007
  Purpose

The current management of primary FSGS is predicated on the assumption that the disease is caused by an immune-mediated disturbance in glomerular barrier function. Therefore, most treatment protocols have involved immunosuppressive drugs given singly or in combination. However, the efficacy of this type of therapy has been disappointing and the long-term prognosis for renal survival in patients with resistant FSGS is poor. An alternative approach that targets the fibrosis pathway may represent a novel approach to the treatment of resistant FSGS. In this R21, the investigators will test the hypothesis that two novel agents - a tumor necrosis factor-alpha (TNF-α) antagonist and a peroxisome proliferator activator receptor-gamma (PPARγ) agonist - can be administered safely to patients with resistant FSGS. In the R21 feasibility/pilot phase, pharmacokinetic studies will be conducted to assess the impact of proteinuria on the kinetics of the novel drugs in children and adults.

Specific Aim #1: To assess the safety and tolerability of two novel drugs - a TNF-α antagonist and a PPARγ agonist - in patients with resistant FSGS.

Specific Aim #2: To conduct a pharmacokinetic (PK) assessment of the selected agents to enable selection of medication regimens for investigation in a randomized Phase II study.


Condition Intervention Phase
Focal Glomerulosclerosis
Drug: Rosiglitazone (Avandia)
Drug: Adalimumab (Humira)
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Novel Therapies for Resistant FSGS

Resource links provided by NLM:


Further study details as provided by North Shore Long Island Jewish Health System:

Primary Outcome Measures:
  • Safety and tolerance of medications [ Time Frame: 16 week treatment period ]

Secondary Outcome Measures:
  • Reduction in proteinuria [ Time Frame: 16 week treatment period ]

Enrollment: 21
Study Start Date: July 2005
Study Completion Date: October 2007
Arms Assigned Interventions
Active Comparator: 1
Avandia (rosiglitazone)
Drug: Rosiglitazone (Avandia)
oral drug administration
Active Comparator: 2
Humira (adalimumab)
Drug: Adalimumab (Humira)
Injection of drug biweekly

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   2 Years to 40 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Aged 2-42 years at onset of proteinuria
  2. Aged ≤ 42 years at time of randomization (randomization date before 43rd birthday)
  3. Estimated glomerular filtration rate (GFR) ≥ 40 ml/min/1.73 m2 at most recent measurement prior to randomization

    1. For patients < age 18 years: Schwartz formula
    2. For patients ≥ age 18 years: Cockroft-Gault formula
  4. Up/c > 1.0 g/g creatinine on first morning void at time of randomization
  5. Biopsy confirmed as primary FSGS (including all subtypes) by study pathologist.
  6. Steroid resistance: During the last treatment course with high dose steroids prior to randomization, the patient must have demonstrated steroid resistance defined below and not have had a complete remission of proteinuria (Up/c < 0.2 or dipstick urine protein negative/trace) subsequently. The course of steroid treatment that defines resistance must be the same or equivalent to at least 4 weeks of every day dosing with a minimum cumulative dose of 56 mg/kg or 1680 mg of prednisone or its equivalent.
  7. May be taking angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocking agent (ARB), vitamin E, or lipid lowering therapy
  8. Willingness to comply with clinical trial protocol, medications, and follow-up visits, etc.
  9. Screen failure in FSGS-CT based on prior treatment with excluded medication
  10. Treatment failure in FSGS-CT based on failure to achieve remission after 26 weeks or 52 weeks of test therapy, i.e., cyclosporine or mycophenolate mofetil (MMF) + oral dexamethasone pulses

Exclusion Criteria

  1. Secondary FSGS
  2. Treated with cyclophosphamide, chlorambucil, levamisole, methotrexate, nitrogen mustard, or other immunosuppressive medications in the 30 days prior to randomization
  3. Lactation, pregnancy, or refusal of birth control in women of child bearing potential
  4. Participation in another therapeutic trial concurrently or for 30 days prior to randomization
  5. Active/serious infection (including, but not limited to hepatitis B or C, HIV)
  6. Malignancy
  7. Systemic lupus erythematosus (SLE) or multiple sclerosis
  8. Hepatic disease defined as serum AST/ALT > 2.5X the upper limit of normal
  9. Patients with blood pressure > 140/95 or > 95th percentile for age/height while receiving maximal doses of 3 or more antihypertensive agents.
  10. Diabetes mellitus (DM) type I or II.
  11. Hematocrit < 30%
  12. Organ transplantation
  13. Obesity (based on estimated dry weight at disease onset prior to steroid therapy) defined as:

    1. Body mass index (BMI) > 97th percentile for age if aged 2-20 years
    2. BMI > 40 kg/m2 if aged ≥ 21 years
  14. Allergy to study medications
  15. Inability to consent/assent
  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: NCT00193648

Locations
United States, New York
Howard Trachtman
New Hyde Park, New York, United States, 11040
United States, North Carolina
Debbie Gipson
Chapel Hill, North Carolina, United States, 27599-7155
Sponsors and Collaborators
North Shore Long Island Jewish Health System
University of North Carolina
The Cleveland Clinic
Investigators
Principal Investigator: Howard Trachtman, MD Schneider Children's Hospital of North Shore-LIJ Health System
Principal Investigator: Debbie Gipson, MD University of North Carolina
Principal Investigator: Tom Greene, PhD The Cleveland Clinic
  More Information

Additional Information:
No publications provided

ClinicalTrials.gov Identifier: NCT00193648     History of Changes
Other Study ID Numbers: DK70341
Study First Received: September 10, 2005
Last Updated: October 19, 2007
Health Authority: United States: Food and Drug Administration

Keywords provided by North Shore Long Island Jewish Health System:
FSGS
Pharmacokinetics
Rosiglitazone
PPAR-gamma agonist
Adalimumab
TNF-alpha antagonist
Steroid and immunosuppressive drug resistance
Resistant primary FSGS

Additional relevant MeSH terms:
Glomerulosclerosis, Focal Segmental
Glomerulonephritis
Kidney Diseases
Nephritis
Urologic Diseases
Adalimumab
Rosiglitazone
Anti-Inflammatory Agents
Antirheumatic Agents
Hypoglycemic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014