ACTHAR Gel for Drug REsistant Nephrotic Syndrome in Children (ADRENL)

ADRENL - ACTHAR Gel for Drug REsistant Nephrotic Syndrome in Children, Pilot Study

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.

Study Overview

• Status: Withdrawn
• Conditions: Steroid-Resistant Nephrotic Syndrome
• Intervention / Treatment: Drug: Acthar Gel 80 UNT/ML Injectable Solution

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Acthar Gel treatment group; Participants will be treated with 'Acthar Gel 80 UNT/ML Injectable Solution'. Initial dose for week 1 will be 50% of 80 units, injected twice per week. Week 2 is 75% of 80 units, week 3 and throughout treatment period (6 months in total) will be 80 units/ml twice per week.	Drug: Acthar Gel 80 UNT/ML Injectable Solution; Participant will self inject 'Acthar Gel 80 UNT/ML Injectable Solution' 2 x per week for six months.; Other Names: H.P. Acthar gel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Remission of proteinuria	Partial remission: Greater than or equal to 50% reduction in proteinuria when compared to baseline. Complete remission: Greater than or equal to 90% reduction in proteinuria when compared to baseline or Urine Protein Creatinine ratio less than 0.5.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood pressure	Blood pressure during study visit as measured in mm/Hg	18 months
Serum Creatinine	Serum value in mg/dL	18 months
BMI	Weight (kgs) and height (cms) will be combined to report BMI in kg/m^2	18 months
Serum Glucose	Serum value in mg/dL	18 months
Serum Lipids	Serum Value in mg/dL	18 months
Quality of life measures obtained via survey	PedsQL 3.0 will be used as the standardized survey tool	18 months

Collaborators and Investigators

• Sponsor: Rhode Island Hospital
• Collaborators: University of Minnesota; Mallinckrodt; Medalytics
• Investigators: Principal Investigator: Mohammed K Faizan, MD, Rhode Island Hospital

Publications and helpful links

General Publications

• Coppo R. Non-steroidal and non-cytotoxic therapies for nephrotic syndrome. Nephrol Dial Transplant. 2008 Jun;23(6):1793-6. doi: 10.1093/ndt/gfn211. Epub 2008 Apr 25. No abstract available.
• Mackay MT, Weiss SK, Adams-Webber T, Ashwal S, Stephens D, Ballaban-Gill K, Baram TZ, Duchowny M, Hirtz D, Pellock JM, Shields WD, Shinnar S, Wyllie E, Snead OC 3rd; American Academy of Neurology; Child Neurology Society. Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society. Neurology. 2004 May 25;62(10):1668-81. doi: 10.1212/01.wnl.0000127773.72699.c8.
• Rauen T, Michaelis A, Floege J, Mertens PR. Case series of idiopathic membranous nephropathy with long-term beneficial effects of ACTH peptide 1-24. Clin Nephrol. 2009 Jun;71(6):637-42. doi: 10.5414/cnp71637.
• Ponticelli C, Passerini P, Salvadori M, Manno C, Viola BF, Pasquali S, Mandolfo S, Messa P. A randomized pilot trial comparing methylprednisolone plus a cytotoxic agent versus synthetic adrenocorticotropic hormone in idiopathic membranous nephropathy. Am J Kidney Dis. 2006 Feb;47(2):233-40. doi: 10.1053/j.ajkd.2005.10.016.
• Berg AL, Arnadottir M. ACTH-induced improvement in the nephrotic syndrome in patients with a variety of diagnoses. Nephrol Dial Transplant. 2004 May;19(5):1305-7. doi: 10.1093/ndt/gfh110. No abstract available.
• Bomback AS, Tumlin JA, Baranski J, Bourdeau JE, Besarab A, Appel AS, Radhakrishnan J, Appel GB. Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel. Drug Des Devel Ther. 2011 Mar 14;5:147-53. doi: 10.2147/DDDT.S17521.
• Bomback AS, Canetta PA, Beck LH Jr, Ayalon R, Radhakrishnan J, Appel GB. Treatment of resistant glomerular diseases with adrenocorticotropic hormone gel: a prospective trial. Am J Nephrol. 2012;36(1):58-67. doi: 10.1159/000339287. Epub 2012 Jun 19.
• LAUSON HD, FORMAN CW, McNAMARA H, MATTAR G, BARNETT HL. The effect of corticotropin (ACTH) on glomerular permeability to albumin in children with the nephrotic syndrome. J Clin Invest. 1954 Apr;33(4):657-64. doi: 10.1172/JCI102936. No abstract available.

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2018
• Primary Completion (Anticipated): January 1, 2021
• Study Completion (Anticipated): July 1, 2021

Study Registration Dates

• First Submitted: January 8, 2018
• First Submitted That Met QC Criteria: January 22, 2018
• First Posted (Actual): January 24, 2018

Study Record Updates

• Last Update Posted (Actual): April 23, 2019
• Last Update Submitted That Met QC Criteria: April 19, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Syndrome; Nephrotic Syndrome; Nephrosis; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Adrenocorticotropic Hormone
• Other Study ID Numbers: 1050945-5

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes