Novel Therapies to Treat Resistant Focal Segmental Glomerulosclerosis: Phase II Clinical Trial (FSGS/FONT)

General Description

Therapeutic interventions for the treatment of Focal Segmental Glomerulosclerosis Clinical (FSGS) have been widely reported. However, evidence-based treatment guidelines have not been developed because of the lack of controlled studies and the small number of participants included in most reports. The FSGS Clinical Trial (FSGS-CT) was a multi-center, prospective, controlled, open label randomized trial designed to determine if treatment with mycophenolate mofetil (MMF) in conjunction with pulse steroids is superior to treatment with Cyclosporine-A (CSA) in inducing remission from proteinuria over 12 months. The rationale and background related to each of the drugs chosen to be a part of the FSGS-CT therapeutic interventions are outlined in the study protocol.

Objectives

The primary objective was to conduct a multi-center, prospective, randomized trial to compare the effectiveness of a treatment regimen including CSA to a regimen including MMF and oral pulse steroids in inducing remission of proteinuria in participants with steroid resistant FSGS. Both of the regimens also included an ACE inhibitor and alternate-day low dose prednisone. On a therapeutic background of alternate day steroids and inhibition of the renin/angiotensin system, the main research hypotheses were that participants with steroid resistant FSGS who are treated with MMF/oral pulse dexamethasone would have a significantly greater proportion with:

• remission of proteinuria after 52 weeks on therapy and/or
• remission of proteinuria 26 weeks after withdrawal of therapy when compared to similar participants receiving CSA.

Additional research hypotheses were that one or more of the following would differ between the two therapeutic groups:

• Improved quality of life
• Decreased numbers of adverse events and extra renal complications
• Preservation of renal function.

Outcome Measure

The primary outcome was a 6-level ordinal variable classification based on the achievement of remission during the first 52 weeks after randomization. The least favorable outcome, designated as level 6, was assigned if no partial or complete remission was achieved between weeks 2 through 26, inclusive. Level 5 was assigned if the participant achieved at least one partial or complete remission between weeks 2 and 20, but did not achieve either a partial or complete remission at week 26. By this definition, the primary outcome is not affected by the urine protein/creatinine ratio (UP/C) after 26 weeks if a partial or complete remission is not achieved at 26 weeks, allowing those participants to switch to alternative therapies without affecting the primary analysis.

For participants with a partial or complete remission at week 26, a score between 1 and 4 was assigned depending on the remission status between week 26 and week 52. Level 4 was assigned if the participant failed to achieve either a partial or complete remission at week 52 or had a sustained relapse between weeks 26 and 52. Level 3 was assigned if the participant achieved a partial remission at week 52. Level 2 was assigned if the participant achieved a complete remission at week 52 but had at least one UP/C > 0.2 after week 26 but before week 52. Level 1 was assigned if the participant achieved a complete remission at week 52 and had had UP/C < 0.2 since the week 26 visit.
The main secondary outcome was a 5-level ordinal variable classification which evaluated the extent to which remissions from proteinuria persisted during the period from week 52 to week 78 after immunosuppressive therapy was withdrawn but while remaining on ACEI or ARB treatment.

Other outcomes included the change in quality of life, the numbers of adverse events and extra-renal complications, and the preservation of renal function.

Criteria

Inclusion Criteria:

• Age 2-40 years at onset of signs or symptoms of FSGS
• Age ≤ 40 years at time of randomization (randomization date before 41st birthday)
• Estimated GFR ≥ 40 ml/min/1.73 m2 at most recent measure prior to randomization
  • For participants < age 18 years: Schwartz formula
  • For participants ≥ age 18 years: Cockroft-Gault formula
• UP/C > 1.0 g protein/g creatinine on first am void at time of randomization
• Biopsy confirmed as primary FSGS (including all subtypes) by study pathologist. A minimum of 1 glomerulus demonstrating segmental sclerosis on light microscopy will be required to confirm the diagnosis.
• Steroid resistance: The participant must have demonstrated steroid resistance (defined as a failure to achieve a sustained UP/C ≤ 1.0) based on at least one treatment course with high dose steroids prior to randomization which satisfies both of the following conditions:
• minimal treatment duration of 4 weeks
• minimum cumulative dose of 56 mg/kg or 1680 mg of prednisone or its equivalent. In addition, the participant must not have had a complete remission of proteinuria (UP/C < 0.2 or dipstick urine protein 0/trace) subsequent to the latest qualifying 4-week course demonstrating steroid resistance.
• Willingness to follow the clinical trial protocol, including medications, and baseline and follow-up visits and procedures.
• Participants may be taking ACEI, ARB, Vitamin E, or lipid lowering therapy.

Exclusion Criteria:

• Secondary FSGS
• Prior therapy with sirolimus, CSA, tacrolimus, MMF, or azathioprin (Imuran)
• Treated with cytoxan, chlorambucil, levamisole, methotrexate, or nitrogen mustard in the last 30 days
• Lactation, pregnancy, or refusal of birth control in women of child bearing potential
• Participation in another therapeutic trial concurrently or 30 days prior to randomization
• Active/serious infection (including, but not limited to Hepatitis B, C, or HIV)
• Malignancy
• Blood pressure > 140/95 or > 95th percentile for age/height.
• Participant is receiving 4 or more antihypertensive agents for the primary purpose of controlling blood pressure.
• Participants with previously diagnosed diabetes mellitus type I or II: the diagnosis of DM I or II will be based on local criteria for participants with an established diagnosis. If hyperglycemia is detected during the screening period, the WHO criteria for the diagnosis of DM I and II will be used.
• Clinical evidence of cirrhosis or chronic active liver disease
• Abnormal laboratory values at the time of study entry:
  • Absolute neutrophil count (ANC) < 2000/mm3, or
  • Hematocrit (HCT) < 28%
• History of significant gastrointestinal disorder, e.g, severe chronic diarrhea (> 5 watery stools per day) or active peptic ulcer disease.
• Organ transplantation
• Obesity (based on estimated dry weight at onset of disease prior to steroid therapy) defined as
  • BMI > 97th percentile for age if aged 2-20 years
  • BMI > 40 kg/m2 for age ≥21 years
• Allergy to study medications
• Inability to consent/assent

Note: Participants with conditions meeting exclusion criteria at a particular evaluation for eligibility could be re-evaluated at a later time to determine if the conditions had changed so that all entry criteria are met. In particular, if blood pressure > 140/95 or > 95th percentile for age/height while the participant was on less than three antihypertensive agents, the participant could be re-evaluated for eligibility after adding other antihypertensive agents so long as the total number of agents does not exceed three.

Outcome

FSGS-CT compared the efficacy of a 12-month course of CSA to a combination of oral pulse dexamethasone and MMF in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to CSA (72) or to MMF/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with MMF/dexamethasone compared to CSA was not significant. Partial or complete remission was achieved in 22 MMF/dexamethasone- and 33 CSA-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with CSA and 7 with MMF/dexamethasone died or developed kidney failure. Thus, this study did not find a difference in rates of proteinuria remission following 12 months of CSA compared to MMF/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect.