Pilot Studies of Novel Therapies to Treat Resistant Focal Segmental Glomerulosclerosis (FSGS)
Condition: Focal Glomerulosclerosis
MeSH terms: Glomerulosclerosis, Focal Segmental
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      Description of study visits

      Screening Visit: Eligibility Studies

        1. History and physical examination

        2. Urine protein and creatinine excretion. Proteinuria (Up/c) will be expressed as the
           protein:creatinine ratio (mg:mg) in a single early morning specimen.

        3. Serum creatinine and calculated GFR. The GFR will be calculated using the Schwartz
           formula for patients below 18 years of age and Cockroft-Gault for those 18 years or
           older.

        4. Serum Na+, K+, HCO3-, Cl-, glucose, BUN, albumin, cholesterol, AST, ALT, alkaline
           phosphatase, CBC, ANA, CH50, pregnancy test

        5. HIV, Hepatitis B and C serology, if not done in the previous 12 months

        6. TB skin test, if not done in the previous 12 months

        7. Existing renal biopsy tissue will be assessed for all subjects who have not had the
           diagnosis of FSGS confirmed by an FSGS-CT core pathologist (only in screen failures).

      Baseline Visit: Week 0 Visit

        1. Serum glucose, albumin, and creatinine concentrations

        2. TNF-alpha level

        3. Baseline anti-adalimumab antibody (AAA) level in patients assigned to Humira® treatment

        4. A urine, plasma, serum and DNA sample will be collected for storage in the NIDDK FONT
           Biorepositories at Fisher Bioservice and the Rutgers Cell & DNA Repository for patients
           who consent to this procedure. A request will be made to store any residual renal tissue
           collected for clinical indications during the FONT trial in the NIDDK Biorepository.

        5. PK assessment (see below)

      Follow-up Assessment: Week 2, 4, 8, and 12 Visits

        1. Interval history, physical examination, assessment of adverse events

        2. Urine protein excretion

        3. Serum creatinine and calculated GFR, serum Na+, K+, HCO3, Cl-, glucose, BUN, ALT, AST at
           all visits

        4. Serum albumin, cholesterol, ANA, CH50 at 8-week visit, CBC at all visits except 2-week
           visit

        5. Trough serum adalimumab level in patients assigned to receive Humira® at all visits
           except 2-week visit

        6. Serum AAA level at 12-week visit in patients assigned to Humira® treatment

        7. Pregnancy test at 12-week visit

      Final Assessment: Week 16 Visit

        1. Interval history, physical examination, assessment of adverse events

        2. Urine protein excretion

        3. Serum creatinine and calculated GFR

        4. Serum Na+, K+, HCO3, Cl-, glucose, BUN, albumin, cholesterol, AST, ALT, alkaline
           phosphatase, CBC, ANA, CH50, and serum TNF-alpha levels

        5. Serum AAA level in patients assigned to Humira® treatment

        6. Serum, plasma, and urine samples to the NIDDK Biosample Repository at Fisher Bioservice

        7. Assessment of patient satisfaction with treatment using TSQM

        8. Steady state PK assessment (see below)

      The following Table summarizes the laboratory assessment during the R21 study.

      Study Medications:

      Study medication will be shipped in a single batch sufficient to complete the 4-month
      treatment period. A supply will be shipped to the participating site for each individual
      patient that is enrolled. Please complete the Site Registration Form and provide a complete
      and accurate shipping address for receipt of study medication during the week, Monday though
      Friday 9 AM - 5 PM. This information will be forwarded to the pharmaceutical companies to
      enable timely shipment of drug to each site.

      Formulation and administration of experimental novel therapies

      Adalimumab (Humira®): TNF-α antibody BB-IND #11714:

      This medication will be provided by Abbott Laboratories and will be available as a liquid. It
      will be administered as a subcutaneous injection every other week. The therapeutic dose of
      adalimumab will be 24 mg/m2 to a maximum of 40 mg/dose every other week for the entire
      treatment period.

      Patients should be instructed to rotate the site of injection. In order to reduce the pain
      associated with the biweekly adalimumab injections, patients can apply EMLA crème or steroid
      inhaler spray prior to administration of the medication. After the injection is completed,
      the patient can take Tylenol as needed or apply ice to the site for symptomatic pain relief.

      Patients receiving Humira® will be required to write down dates and times of drug
      administration and bring the administration log to each study visit. In addition, when a
      patient is assigned to the Humira® arm, a per protocol dose schedule listing the week and the
      optimal date of drug administration will be sent with the medication to the site. This sheet
      can be used to facilitate scheduling of visits and it can be shared with the patient.

      Rosiglitazone (Avandia®): PPARgamma agonist IND69,782:

      This medication will be provided by Glaxo Smith Kline and will be available as pills. It will
      be administered orally in two divided daily doses. The therapeutic dose of rosiglitazone will
      be 3 mg/m2/day administered in two divided doses to a maximum of 4 mg twice a day. The twice
      daily dosing schedule is based on studies indicating greater antiproteinuric effect of
      rosiglitazone in type 2 diabetes when administered in this manner.

      Pharmacokinetic (PK) Studies

      Sampling Scheme:

      The blood and urine collection scheme for the PK analysis will be conducted over 48 hours in
      a GCRC when the patient is scheduled to receive the first dose (single dose PK assessments)
      of adalimumab or rosiglitazone and after the 8th dose of adalimumab (~steady state of 105
      days) or during the 4th month of rosiglitazone therapy for multiple dose PK assessments.

      A blood sample, 2.5-4 ml/sample (1-2.5 ml plasma/serum), will be drawn at each time point.
      For adalimumab, a total of 6 serum samples (4 ml each, 24 ml of blood in total) will be
      obtained. For rosiglitazone a total of 11 plasma samples (2.5 ml each, 25 ml of blood in
      total) will be obtained during the 48-hour PK study. The total amount of blood drawn should
      be < 3 ml/kg over this period.

      Urine will be collected at the following intervals: 0-2, 2-12, 12-24, 24-36, and 36-48 hours.
      The total volume of urine for each time interval should be recorded in mL and an aliquot
      should be analyzed for protein:creatinine ratio in the local laboratory. The measurements of
      urinary protein excretion over the 48 hour period will be used to correlate PK parameters of
      the study medication with concurrent level of proteinuria.

      An aliquot of the urine sample collected during each time interval should be saved in the
      specimen kit for determination of urinary excretion of rosiglitazone. However, because
      adalimumab cannot be measured in the urine, urinary excretion of the monoclonal antibody will
      not be performed and an aliquot of urine will NOT be saved in the specimen kit for
      measurement of Humira®.

      If patients must go home after the first day of testing, then they will return to the GCRC on
      day 2 for repeat blood draws and to return urine collections.

      The exact sampling times (hours) for the 48-hour PK studies for each novel therapy, which
      coincide with the midpoint of the urine collections (see below), are outlined in the
      following Table:

      DRUG 0 0.5 1 2 4 6 8 12 18 30 42 Adalimumab X X X X X X Rosiglitazone* X X X X X X X X X X X

        -  Serum glucose concentration will be measured at each time point.

      Trough serum adalimumab levels should be drawn at 1 week after the first dose of the drug as
      part of the PK study but not as part of a formal patient visit. In addition to the PK
      studies, trough serum adalimumab levels will also be drawn prior to the dose at the 2-, 4-,
      8-, and 12-week visits.
    

Intervention name(s): Rosiglitazone (Avandia); Adalimumab (Humira)
Intervention type(s): Drug; Drug
Intervention description(s): oral drug administration; Injection of drug biweekly
Intervention MeSH terms: Rosiglitazone; Adalimumab
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: FSGS; Pharmacokinetics; Rosiglitazone; PPAR-gamma agonist; Adalimumab; TNF-alpha antagonist; Steroid and immunosuppressive drug resistance; Resistant primary FSGS