Friedman 2004.

Trial name or title	Focal segmental glomerulosclerosis clinical trial (FSGS‐CT)
Methods	Treatment, randomized, open label, active control, parallel assignment, efficacy study
Participants	Age: 2 to 40 years Gender: Both 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 may be re‐evaluated at a later time to determine if the conditions have changed so that all entry criteria are met. In particular, if blood pressure > 140/95 or > 95th percentile for age/height while the participant is on less than three antihypertensive agents, the participant may be re‐evaluated for eligibility after adding other antihypertensive agents so long as the total number of agents does not exceed three
Interventions	Control: Cyclosporin Participants assigned to this group will initiate treatment with CSA, 5‐6 mg/kg/d with a 250 mg/d maximum starting dose, divided into two daily doses. The CSA dose will be adjusted based on drug levels determined at specified study visits in order to achieve a 12‐hour trough concentration in the therapeutic range of 100‐250 ng/mL. Treatment: MMF and Dexamethasone MMF: 25‐36 mg/kg/d with a maximum dose of 2 g/d divided into two daily doses. The dose range reflects the use of fixed size (250 mg) capsules and application of defined daily doses to specific weight ranges. In younger children or those participants who are unable to swallow capsules, a liquid formulation will be used to provide 36 mg/kg/d to a maximum of 2 g/d. The starting MMF dose will be 0.5‐0.67 of the full dose for 2 weeks before advancing to the full dose for the duration of the 12‐month treatment period. Dexamethasone: 0.9 mg/kg/dose, with a maximum dose of 40 mg
Outcomes	Primary outcomes The primary outcome is a 6‐level ordinal variable defined based on the achievement of remission from proteinuria during the first 52 weeks after randomization [time frame: first 52 weeks after randomization]. Secondary outcomes The main secondary outcome is a 5‐level ordinal variable defined based on the persistence of remissions after immunosuppressive agents are withdrawn [time frame: based on the participant's level of proteinuria during the period from week 52 through week 78 following withdrawal of CSA or MMF/Pulse steroids].
Starting date	November 2004
Contact information	Aaron Friedman, MD Tel: +1 401 4445648 Email: AFriedman@Lifespan.org Jennifer Gassman, PhD Tel: +1 216 4449938 Email: fsgs_dcc@bio.ri.ccf.org
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