Novel Therapies for Resistant FSGS (FONTII): Phase II Clinical Trial
Condition: Focal Segmental Glomerulosclerosis
MeSH terms: Glomerulosclerosis, Focal Segmental
Study type: Interventional
Phase: Phase 2

Summary: 
      This project will test whether adalimumab,and/or galactose can safely reduce proteinuria
      (abnormal amounts of protein in the urine) and protect kidney function better than standard
      treatment for patients with focal segmental glomerulosclerosis (FSGS).
    

Detailed description: 
      SPECIFIC AIMS A significant percentage of patients with primary FSGS are resistant to
      corticosteroids and other immunosuppressive medications. In view of the rising incidence of
      this disease and the grim prognosis for patients with resistant disease, it is imperative
      that new therapeutic approaches be evaluated in an efficient and systematic manner. This will
      enable accurate assessment of the risk-benefit ratio of novel therapies and guide the design
      of future Phase III randomized clinical trials.

      Specific Aim #1: To evaluate two novel therapies for resistant FSGS -- anti-TNF-α antibody
      and galactose -- against standard therapy

      Specific Aim #2: To identify one or more novel agents as candidates for future study in a
      Phase III randomized clinical trial

      OVERALL STUDY DESIGN Screening/Run-In: There is no formal run-in period in the phase II trial
      because patients with resistant FSGS who will be eligible for this study often have unstable
      kidney function and are prone to sudden decline in glomerular filtration rate (GFR). An
      effort will be made to achieve randomization within 2 weeks of the screening visit.

      In order to achieve a comparable baseline assessment prior to initiation of one of the novel
      therapies, the patients must be off all immunosuppressive medications for 30 days. In
      addition, patients will be placed on the maximal tolerated doses of an angiotensin-converting
      enzyme inhibitor (ACEI), an angiotensin receptor blocker (ARB), and a lipid-lowering drug
      defined above based upon measurements of blood pressure, serum K+, creatinine, and
      cholesterol concentrations. Patients will have to be on stable doses of the ACEI/ARB
      treatment for a minimum of 2 weeks prior to randomization into the FONT Phase II study to
      insure that the initiation of novel therapy does not coincide with a hemodynamically induced
      change in proteinuria. In order to implement this part of conservative medical therapy, a
      2-12 week Screening/Run-In period will precede randomization. Rescreening will be necessary
      if patients are not randomized to one of the three treatment arms within 12 weeks of the
      initial screening assessment.

      Duration of novel therapy: Novel therapies will be administered for 6 months before assessing
      efficacy, i.e., >50% reduction in proteinuria. Although the novel therapies target renal
      fibrosis, it is anticipated that this period of treatment will be sufficient to document a
      beneficial effect on proteinuria.

      Screening/Run-In: There is no formal run-in period in the phase II trial because patients
      with resistant FSGS who will be eligible for this study often have unstable kidney function
      and are prone to sudden decline in GFR. An effort will be made to achieve randomization
      within 2 weeks of the screening visit.

      Frequency of visits: Patients will be evaluated after 0, 2, 8, 16, and 26 weeks of treatment
      with the novel therapy or conservative medical therapy alone. Thus, there will be a total of
      6 visits during the treatment period. A follow-up evaluation will be performed at 1 month, 3
      months, and 6 months after discontinuation of the novel therapy, and then every 6 months
      until the end of the funding period.

      Baseline studies

        1. Interval History and physical examination

        2. Urine protein and creatinine excretion Proteinuria (Up/c) will be expressed as the
           protein: creatinine ratio (mg: mg) in an early morning specimen.

        3. Serum creatinine and calculated GFR, glucose, albumin, pregnancy test

        4. A urine, plasma, serum and DNA sample will be collected for storage in the NIDDK FSGS-CT
           Biorepository. A request will be made to store any residual renal tissue collected for
           clinical indications during the FONT trial in the NIDDK Biorepository.

      Follow-up assessment: Week 2, 8, and 16 Visits

        1. Interval history, physical examination, assessment of adverse events

        2. First morning urine protein excretion

        3. Laboratory analysis as charted below. Urine pregnancy test at 8 and 16 week visit

      Final Outcome Visit (Week 26)

        1. History and physical examination

        2. Morning urine protein and creatinine excretion x 2 (The value will represent the average
           of two samples collected during the week before the visit.)

        3. Serum creatinine and calculated GFR, Serum Na+, K+, HCO3, Cl-, glucose, CPK

        4. Blood urea nitrogen (BUN), albumin, cholesterol, aspartate transaminase (AST), alanine
           transaminase (ALT), alkaline phosphatase, complete blood count (CBC), antinuclear
           antibodies (ANA), C3 levels, pregnancy test

        5. Urine, serum and plasma for biorepository

        6. TSQM patient questionnaire

      Preliminary safety, patient tolerance, and pharmacokinetic (PK) data for the two novel
      therapies, rosiglitazone and adalimumab, that will be used in the Phase II trial were
      generated through the successful performance of a Phase I study.

      In the phase I study, a total of 21 patients were enrolled. 11 were assigned to receive
      rosiglitazone, and 10 were assigned to receive adalimumab. The patients were evenly divided
      by gender and pubertal stage. All patients had a GFR >50 mL/min/1.73 m2.

      There were no serious adverse events necessitating the withdrawal of study drug.

      Rosiglitazone was stopped in one child due to a questionable allergy. The patients tolerated
      the experimental medications adequately based on the results of the Treatment Satisfaction
      Questionnaire for Medication (TSQM) which was administered at week 16.

      The PK analyses indicated that the rosiglitazone dose needs to be increased to account for
      increased clearance and reduced area under the curve in patients with resistant FSGS and
      nephrotic range proteinuria. For adalumimab, clearance was also enhanced especially after
      receiving multiple doses. However, these results of the adalimumab PK analyses indicate that
      no dose adjustment was required.

      The PK data for each drug were presented in abstract form at the annual meeting of the
      American Society of Nephrology and a manuscript summarizing the complete findings in patients
      treated with rosiglitazone has been submitted for publication.

      This Phase II will again rely on the considerable investment of time and resources on the
      part of the study investigators and the NIH/NIDDK gained through the FSGS-CT (UO1-DK-63455)
      and the Phase I portion of the FONT study (DK70341). Schneider Children's Hospital (SCH) and
      University of North Carolina-Chapel Hill (UNC) resources including the GCRCs that were
      utilized in the R21phase of them study will be available for the R33 portion of the FONT
      project.
    

Intervention name(s): Adalimumab; Lisinopril, losartan, and atorvastatin; galactose
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Adalimumab 24 mg/m^2 (maximum dose 40 mg) sc q 14 days; Lisinopril PO 10-20 mg per day Losartan PO 25-50 mg per day Atorvastatin PO 10-20 mg per day; galactose 0.2 g/kg/dose (maximum dose 15 g)po BID
Intervention MeSH terms: Adalimumab; Losartan; Lisinopril; Atorvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Primary FSGS; Steroid Resistant; Rosiglitazone; Adalimumab; Resistant primary FSGS; GALACTOSE