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