Novel Therapies for Resistant FSGS (FONTII): Phase II Clinical Trial (FONTII)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00814255
Recruitment Status : Completed
First Posted : December 24, 2008
Results First Posted : July 11, 2016
Last Update Posted : July 11, 2016
University of Michigan
The Cleveland Clinic
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
New York University School of Medicine

Brief 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).

Condition or disease Intervention/treatment Phase
Focal Segmental Glomerulosclerosis Drug: Adalimumab Drug: Lisinopril, losartan, and atorvastatin Drug: galactose Phase 2

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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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Novel Therapies for Resistant Focal Segmental Glomerulosclerosis
Study Start Date : December 2008
Actual Primary Completion Date : June 2013
Actual Study Completion Date : February 2014

Arm Intervention/treatment
Experimental: 2
Conservative medical therapy plus adalimumab
Drug: Adalimumab
Adalimumab 24 mg/m^2 (maximum dose 40 mg) sc q 14 days
Active Comparator: 1
Conservative medical therapy (lisinopril, losartan, atorvastatin)
Drug: Lisinopril, losartan, and atorvastatin
Lisinopril PO 10-20 mg per day Losartan PO 25-50 mg per day Atorvastatin PO 10-20 mg per day
Experimental: conservative medical therapy plus galactose
drug: galactose 0.2 g /kg/dose (maximum dose 15g) po BID
Drug: galactose
galactose 0.2 g/kg/dose (maximum dose 15 g)po BID

Primary Outcome Measures :
  1. Number of Participants With a Reduction in Proteinuria at 6 Months by > 50% of the Value at Screening AND Stable GFR Defined as Greater Than 75 ml/Min/1.73m2 in Those With an Initial Value Above 90 OR Within 25% of Baseline for Remaining Patients [ Time Frame: baseline and 6 months ]
    Number of participants with a reduction in proteinuria at 6 months by > 50% of the value at screening AND stable GFR defined as greater than 75 ml/min/1.73m2 in those with an initial value above 90 OR within 25% of baseline for remaining patients.

Secondary Outcome Measures :
  1. Patient Satisfaction Score Using the Treatment Satisfaction Questionnaire for Medication (TSQM Questionnaire) [ Time Frame: Baseline and 6 months ]
    Patient Satisfaction Score Using the Treatment Satisfaction Questionnaire for Medication (TSQM Questionnaire)

  2. Number of Participants With Adverse Events [ Time Frame: Up to 7 months ]
  3. Percent Change in Proteinuria [ Time Frame: Baseline and 6 months ]
  4. Percent Change in or Time to Doubling of Serum Creatinine [ Time Frame: Baseline and 6 months ]

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Ages Eligible for Study:   1 Year to 65 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Primary FSGS confirmed by renal biopsy OR documentation of a genetic mutation in a podocyte protein associated with the disease
  • Failure to respond to prior therapy at least one of the following immunosuppressive medications -- cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus - or other agents prescribed to lower proteinuria
  • Age 1-65 years at onset of proteinuria
  • Age 1-65 years at time of randomization
  • Estimated GFR ≥40 mL/min/1.73 m2 using Schwartz (age <18 yr) or Cockroft-Gault (age <18 yr) formula at screening and ≥30 mL/min/1.73 m2 at the end of the Run-In Period and at the time of randomization
  • Up/c > 1.0 g/g creatinine on first morning void
  • Steroid resistance defined as failure to achieve sustained Up/c < 1.0 following a standard course of prednisone/prednisolone/methylprednisolone prescribed for FSGS therapy, OR contraindication/anticipated intolerance to steroid therapy defined as severe obesity, documented decreased bone density, family history of diabetes, or a psychiatric disorder.
  • Willingness to follow the protocol, including medications, baseline and follow-up visits, and procedures.

Exclusion Criteria:

  • Lactation, pregnancy, or refusal of birth control in women of child bearing potential
  • Participation in another therapeutic trial involving protocol mandated administration of a immunosuppressive medication concurrently or 30 days prior to randomization
  • Active/serious infection (including, but not limited to Hepatitis B or C, HIV)
  • History of malignancy
  • Abnormality in age appropriate cancer screening in accord with ACS 2003 guidelines (appendix 17.6)
  • Patients with uncontrolled blood pressure > 140/90 or > 95th percentile for age/height at the end of the run in period
  • Diabetes mellitus Type I or II
  • Organ transplantation
  • Congestive heart failure
  • History of prior myocardial infarction
  • SLE or multiple sclerosis
  • Hepatic disease, defined as serum ALT/AST levels more than 2.5x the upper limit of normal
  • Hematocrit <27%
  • Immunosuppressive therapy with cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, or rapamycin in the 30 days prior or Rituximab in the 90 days prior to randomization
  • Prior treatment with the study medications, rosiglitazone or adalimumab
  • Allergy to one of the study medications, i.e., rosiglitazone, adalimumab, lisinopril, losartan or atorvastatin

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00814255

United States, Florida
University of Miami
Miami, Florida, United States, 33136
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, Kansas
University of Kansas
Kansas City, Kansas, United States, 66160
United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55901
United States, Missouri
Children's Mercy Hospital
Kansas City, Missouri, United States, 64108
Cardinal Glennon Children's Medical Center
Saint Louis, Missouri, United States, 63104
United States, New York
Steven and Alexandra Cohen Children's Medical Center of New York
New Hyde Park, New York, United States, 11040
NYU Langone Medical Center
New York, New York, United States, 10016
Columbia University Medical Center
New York, New York, United States, 10032
United States, North Carolina
Carolinas Medical Center
Charlotte, North Carolina, United States, 28207
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Ohio State University
Columbus, Ohio, United States, 43205
United States, Oregon
Doernbecher Children's Hospital
Portland, Oregon, United States, 97239
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Texas
Texas Tech University
El Paso, Texas, United States, 79905
Canada, Alberta
University of Alberta
Edmonton, Alberta, Canada, T6G 2R7
Sponsors and Collaborators
New York University School of Medicine
University of Michigan
The Cleveland Clinic
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Principal Investigator: Howard Trachtman, MD NYU Langone Medical Center
Principal Investigator: Debbie Gipson, MD University of Michigan
Principal Investigator: Jennifer Gassman, PhD The Cleveland Clinic

Publications of Results:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: New York University School of Medicine Identifier: NCT00814255     History of Changes
Other Study ID Numbers: DK70341FII
R33DK070341 ( U.S. NIH Grant/Contract )
First Posted: December 24, 2008    Key Record Dates
Results First Posted: July 11, 2016
Last Update Posted: July 11, 2016
Last Verified: July 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: will comply with NIDDK guidelines

Keywords provided by New York University School of Medicine:
Primary FSGS
Steroid Resistant
Resistant primary FSGS

Additional relevant MeSH terms:
Glomerulosclerosis, Focal Segmental
Kidney Diseases
Urologic Diseases
Atorvastatin Calcium
Anticholesteremic Agents
Hypolipidemic Agents
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Anti-Inflammatory Agents
Antirheumatic Agents
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Cardiotonic Agents
Protective Agents
Physiological Effects of Drugs