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Novel Therapies for Resistant FSGS

Phase 1
2 Years
40 Years
Not Enrolling
Focal Glomerulosclerosis

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Trial Information

Novel Therapies for Resistant FSGS

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

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

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

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

- 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

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

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

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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety and tolerance of medications

Outcome Time Frame:

16 week treatment period

Principal Investigator

Howard Trachtman, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Schneider Children's Hospital of North Shore-LIJ Health System


United States: Food and Drug Administration

Study ID:




Start Date:

July 2005

Completion Date:

October 2007

Related Keywords:

  • Focal Glomerulosclerosis
  • FSGS
  • Pharmacokinetics
  • Rosiglitazone
  • PPAR-gamma agonist
  • Adalimumab
  • TNF-alpha antagonist
  • Steroid and immunosuppressive drug resistance
  • Resistant primary FSGS
  • Glomerulosclerosis, Focal Segmental



Howard TrachtmanNew Hyde Park, New York  11040
Debbie GipsonChapel Hill, North Carolina  27599-7155