Novel Therapies for Resistant FSGS (FONTII): Phase II Clinical Trial (FONTII)
|Focal Segmental Glomerulosclerosis||Drug: Adalimumab Drug: Lisinopril, losartan, and atorvastatin Drug: galactose||Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Novel Therapies for Resistant Focal Segmental Glomerulosclerosis|
- 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.
- 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)
- Number of Participants With Adverse Events [ Time Frame: Up to 7 months ]
- Percent Change in Proteinuria [ Time Frame: Baseline and 6 months ]
- Percent Change in or Time to Doubling of Serum Creatinine [ Time Frame: Baseline and 6 months ]
|Study Start Date:||December 2008|
|Study Completion Date:||February 2014|
|Primary Completion Date:||June 2013 (Final data collection date for primary outcome measure)|
Conservative medical therapy plus 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
galactose 0.2 g/kg/dose (maximum dose 15 g)po BID
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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.
- Interval History and physical examination
- Urine protein and creatinine excretion Proteinuria (Up/c) will be expressed as the protein: creatinine ratio (mg: mg) in an early morning specimen.
- Serum creatinine and calculated GFR, glucose, albumin, pregnancy test
- 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
- Interval history, physical examination, assessment of adverse events
- First morning urine protein excretion
- Laboratory analysis as charted below. Urine pregnancy test at 8 and 16 week visit
Final Outcome Visit (Week 26)
- History and physical examination
- Morning urine protein and creatinine excretion x 2 (The value will represent the average of two samples collected during the week before the visit.)
- Serum creatinine and calculated GFR, Serum Na+, K+, HCO3, Cl-, glucose, CPK
- 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
- Urine, serum and plasma for biorepository
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00814255
|United States, Florida|
|University of Miami|
|Miami, Florida, United States, 33136|
|United States, Georgia|
|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|
|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|
|University of Alberta|
|Edmonton, Alberta, Canada, T6G 2R7|
|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|