Focal Glomerulosclerosis Clinical Trial
Official title:
Novel Therapies for Resistant 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.
;
Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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