A Dose Escalation Study of Long-acting ACTH Gel in Membranous Nephropathy

Study Overview
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Brief Summary
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Membranous Nephropathy (MN) is an immune-mediated kidney disease that affects the glomerulus or the filter that removes toxins from the blood. Damage to the membrane that separates blood from urine results in loss of protein into the urine (proteinuria) and in some cases loss of kidney function.There is no standard specific treatment for MN. ACTH has a pronounced lipid-lowering effect in healthy individuals, in steroid-treated patients with renal disease and in hemodialysis patients Some studies suggest that prolonged synthetic ACTH therapy may represent an effective therapy in patients with idiopathic MN, more extensive randomized studies with longer follow-up are needed before therapeutic recommendations can be made. We propose to do a pilot study to test the hypothesis that biologic ACTH, a slow-release formulation of corticotropin extracted from porcine pituitary glands (H.P. Acthar gel) will be effective in reducing proteinuria and improving lipid profile in patients with idiopathic MN.

Official Title
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A Dose-finding Pilot Study of ACTH (Adrenocorticotropic Hormone) on the Proteinuria and Serum Lipoprotein Profile in Patients With Idiopathic Membranous Nephropathy (MN)

Conditions
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Glomerulonephritis

Intervention / Treatment
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* Drug: Adrenocorticotrophic hormone ACTH


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria:• Idiopathic MN with diagnostic biopsy performed less than 36 months from the time of dose randomization. Patients need to be treated with an ACEI and/or ARB, for at least 3 months prior to ACTH treatment and have adequately controlled blood pressure (BP <130/75 mm Hg in >75% of the readings). Patients with documented evidence of >3 months treatment with maximal Ang II blockade, target BP (BP <130/75 mm Hg in >75% of the readings) and who remain with proteinuria >4.0g/24h may enter the ACTH phase of the study without the need to have the run-in/conservative phase of the study. Proteinuria as measured by Uprot/Ucr > 4.0 on a spot sample aliquot from a 24-hour urine collection. The choice of Uprot/UCr is in accord with recent NKF-CKD guidelines.[9] Estimated GFR ≥ 40 ml/min/1.73m2 while taking ACEI/ARB therapy. The GFR will be estimated using the 4 variable MDRD equation as published in the NKF-CKD guidelines.[9] The same NKF-CKD guidelines also promote the use of estimated GFR (GFRest) values rather than serum creatinine levels or CrCl measurements as the preferred non-invasive method of determining glomerular filtration rates.[9] Exclusion Criteria:• Age <18 years. Estimated GFR < 40 ml/min/1.73m2, or serum creatinine >2.0 mg/dl. Renal biopsy showing more than 30% glomerulosclerosis and/or tubular atrophy. Patient must be off glucocorticoid, calcineurin inhibitors (cyclosporin A, tacrolimus) or mycophenolic mofetil for > 1 month, and alkylating agents or rituximab for >6 months. Resistance to the following immunosuppressive routines e.g. steroids alone, calcineurin inhibitors plus or minus steroids, cytotoxic agents plus or minus steroids. Patients with active infections or secondary causes of MN (e.g. hepatitis B, SLE, medications, malignancies). Testing for HIV, Hepatitis B and C should have occurred < 2 years prior to enrollment into the study. Type 1 or 2 diabetes mellitus: to exclude proteinuria secondary to diabetic nephropathy. Patients who have recent history of steroid induced diabetes but no evidence on renal biopsy performed within 6 months of entry into the study are eligible for enrollment. Pregnancy or nursing - for safety reasons. Acute renal vein thrombosis documented prior to entry by renal US or CT scan and requiring anticoagulation therapy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 72 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ACTH (HP Acthar gel) 40 units<br> | Drug: Adrenocorticotrophic hormone ACTH<br>* There will be two arms to the study: one arm receive 40 units and the second arm 80 units of the ACTH gel subcutaneously both given in a dose escalating frequency beginning at once every two weeks escalating to a maximum of twice per week over a total of three months exposed.An ammendment(approved by Health Canada and the UHN IRB allows an additional 1 month of the perscribed therapy of ACTH )if there is an improvement in proteinuria at the end of the 3 month exposure.<br>* Other names: HP Acthar gel;|
| Active Comparator: ACTH (HP Acthar gel) 80 units<br> | Drug: Adrenocorticotrophic hormone ACTH<br>* There will be two arms to the study: one arm receive 40 units and the second arm 80 units of the ACTH gel subcutaneously both given in a dose escalating frequency beginning at once every two weeks escalating to a maximum of twice per week over a total of three months exposed.An ammendment(approved by Health Canada and the UHN IRB allows an additional 1 month of the perscribed therapy of ACTH )if there is an improvement in proteinuria at the end of the 3 month exposure.<br>* Other names: HP Acthar gel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in proteinuria from baseline to value at 3 months . |  | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Remission(CR) or Partial Remission (PR) at 3 months | Definition of proteinuric status. UP = urinary protein (g/24h) Complete remission (CR) UP ≤ 0.3 g Partial remission (PR) Reduction in UP of > 50% plus final UP ≤ 3.5 g but >0.3g Non-response (NR) Reduction in UP of < 50%. (includes increase in UP <50%) Progression Proteinuria increases by > 50% | 3 months | 
| Adverse effects | Patients will be directly questioned every two weeks during the drug exposure and then at monthly intervals during follow-up. In addition a contact number will be provided to the subjects to call if they experience any adverse affect or if they suspect adverse effect at any time between specific visits | Throughout three months of this study and for nine months follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney disease, Glomerulonephritis