ACTHAR Gel for Drug REsistant Nephrotic Syndrome in Children

We propose to study the use of purified porcine Acthar Gel (ACTHAR, Mallinckrodt Pharmaceuticals) for treatment of steroid resistance nephrotic syndrome (SRNS) in a prospective pilot study. We plan to enroll 25 children between the ages of 2 to 21 years. Children fulfilling strict inclusion criteria, whose parents agree to written informed consent after institutional IRB approval for the study, will be enrolled. Purified porcine Acthar Gel will be administered SQ to all children using a defined treatment protocol for a period of six months. Renal function, urine protein excretion, serum albumin levels, blood pressure and growth parameters will be monitored closely on all patients. Baseline urine protein excretion will be compared to end of treatment levels to determine successful response to therapy. There will be an 18 month enrollment period, 6 month treatment period and a 12 month follow-up period.

Treatment Protocol:

Patients who fulfill inclusion criteria and who agree to participate after signing informed consent and assent forms will be treated with the following protocol:

Acthar Gel will be dosed by body surface area (BSA) using the Dubois Method. The dose of Acthar Gel will be 80 units/1.73 m2 per dose administered subcutaneously (SQ) twice a week on Mondays and Thursdays.

Week 1 to 2:

During week 1, patients will receive 50% of initial calculated dose twice a week.

During week 2, patients will receive 75% of initial calculated dose twice a week.

Week 3 to 6 Months:

Patients will receive the full dose of Acthar Gel (80 units/1.73 m2 per dose) administered subcutaneously (SQ) twice a week on Mondays and Thursdays.

During this period, the treating physician will have the discretion of reducing the dose of Acthar Gel by 25-50% based on response with respect to reduction in proteinuria and tolerability of side-effects (uncontrolled hypertension, excessive weight gain, severe acne, hyperglycemia, etc.)

Patients will have the option of remaining on Acthar Gel after the 6 month study period based on clinical response at discretion of the co-PI. Study drug will be provided free of cost to patients in the first 6 months only.

Concomitant Treatments:

1. Amlodipine 0.1 mg/kg PO in one or two divided doses will be given to all patients who develop elevated blood pressure (\>95th percentile) starting after 14 days of initiation of Acthar Gel therapy and will continue till 6 months. Dose can be increased up to 0.5 mg/kg divided bid as needed to achieve goal BP \<95th percentile. If Amlodipine is not covered by the participants insurance, then an alternate calcium channel blocker will be started at the clinical discretion of the PI/co-PI that is covered by insurance. If the participant is not covered by any insurance the participant will have to pay out of pocket
2. If BP remains elevated despite maximum calcium channel therapy as described in the study protocol above, the choice and dose of additional anti-hypertensive agents will be at the discretion of the study investigator on an individualized and as needed basis.
3. Patients on prednisone on initiation of study will be tapered off over 2-4 weeks. Non-steroidal immunosuppression may be tapered off over four weeks after the start of Acthar Gel therapy at the discretion of the PI/Co-PI.
4. Additional standard of care therapy (statins, vitamin D, antacids, etc.) can be continued and modified based on the discretion and clinical judgment of the study PI/Co-PIs.

Quality of Life Assessment:

Quality of life will be measured using the patient and parent self-report versions of the Pediatric Quality of Life Inventory, ESRD, Acute Version. The PedsQL 3.0 ESRD Scales measure physical, emotional, social and role (i.e. school) dimensions. Scores are derived for physical functioning and psychological functioning, in addition to a total score, which enables comparison against healthy populations. Scales are rated on a 5-point Likert scale (0 = never, 1= almost never, 2 = sometimes, 3 = often, 4 = almost always), with scores linearly transformed to range from 0 - 100, with higher scores indicating fewer problems or symptoms.

Surveys will be administered by trained study personnel at enrollment (baseline), six months, 12 months, and 18 months.

Laboratory Testing:

Baseline and then once a month till the end of the treatment period (6 months): Serum electrolytes, BUN, creatinine, albumin, ACTH level, glucose, random cortisol, calcium, magnesium, phosphorus, ALT, AST, total and direct bilirubin, fasting cholesterol, triglycerides, HDL, LDL, urine protein to creatinine ratio. During the 12 month follow-up period laboratory evaluation will be performed every third month. (11 total blood draws). A urine pregnancy test shall be sent on all female patients of child-bearing potential at the beginning and end of treatment period.

All available biopsy slides will be reviewed by a blinded renal pathologist to insure accuracy and to confirm the initial histologic diagnosis.

Telephone Contact One, two and three weeks after initial dose. Phone contacts will screen for: adverse events, and review dosing of ACTHAR GEL.

Eligibility Criteria:
Inclusion Criteria:

1. Patients between the ages of 2-21 years who fail a minimum of 12 weeks of cumulative therapy with prednisone OR one other alternate immunosuppressive agent for treatment of nephrotic syndrome, will be eligible for inclusion. Nephrotic syndrome is defined as: Presence of edema, Edema, UP/C ≥2, ≥300mg/dl or 3+ protein on Albustix, and hypoalbuminemia ≤2.5 g/dL
2. Calculated GFR (eGFR) using modified Schwartz formula of \> 50 mls/min/m2. (Modified Schwartz formula = 0.413 x height (cms) ÷ serum creatinine mg/dL)
3. A clinical or biopsy diagnosis of nephrotic syndrome within the last 3 years prior to enrollment in the study.
4. Renal biopsy (if available) consistent with a diagnosis of Minimal Change Disease, IgM nephropathy, Mesangioproliferative Glomerulonephritis, Primary Focal Segmental Glomerulosclerosis or C1q Nephropathy

Exclusion Criteria:

1. Patients with an inherited or genetic disorder presenting with nephrotic syndrome (eg: NPHS 1 \& 2 defects, WT-1 mutations, α actinin 4 mutation, TRP-6 mutation).
2. Presence of diabetes or severe (stage 2) uncontrolled hypertension.
3. Any metabolic condition that specifically precludes the use of Acthar Gel for treatment.
4. Pregnancy or unwilling to agree to contraception which may include abstinence.
5. eGFR \<50 mls/min/m2