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

Primary Purpose

Glomerulonephritis

Status

Completed

Phase

Phase 1

Locations

Canada

Study Type

Interventional

Intervention

Adrenocorticotrophic hormone ACTH

About this trial

This is an interventional treatment trial for Glomerulonephritis focused on measuring Kidney disease, Glomerulonephritis

Eligibility Criteria

18 Years - 72 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

University Health Network- Toronto General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

ACTH (HP Acthar gel) 40 units

ACTH (HP Acthar gel) 80 units

Arm Description

Outcomes

Primary Outcome Measures

change in proteinuria from baseline to value at 3 months .

Secondary Outcome Measures

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%

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

Full Information

NCT ID

NCT01093157

First Posted

March 24, 2010

Last Updated

May 2, 2017

Sponsor

University Health Network, Toronto

Collaborators

Mallinckrodt

1. Study Identification

Unique Protocol Identification Number

NCT01093157

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2013

Overall Recruitment Status

Completed

Study Start Date

February 2010 (undefined)

Primary Completion Date

January 2013 (Actual)

Study Completion Date

February 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Health Network, Toronto

Collaborators

Mallinckrodt

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Glomerulonephritis

Keywords

Kidney disease, Glomerulonephritis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

ACTH (HP Acthar gel) 40 units

Arm Type

Active Comparator

Arm Title

ACTH (HP Acthar gel) 80 units

Arm Type

Active Comparator

Intervention Type

Drug

Intervention Name(s)

Adrenocorticotrophic hormone ACTH

Other Intervention Name(s)

HP Acthar gel

Intervention Description

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.

Primary Outcome Measure Information:

Title

change in proteinuria from baseline to value at 3 months .

Time Frame

3 months

Secondary Outcome Measure Information:

Title

Complete Remission(CR) or Partial Remission (PR) at 3 months

Description

Time Frame

3 months

Title

Adverse effects

Description

Time Frame

Throughout three months of this study and for nine months follow-up

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

72 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Daniel Cattran, M.D

Organizational Affiliation

University Health Network, Toronto

Official's Role

Principal Investigator

Facility Information:

Facility Name

University Health Network- Toronto General Hospital

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G2C4

Country

Canada

12. IPD Sharing Statement

Citations:

PubMed Identifier

34778952

Citation

von Groote TC, Williams G, Au EH, Chen Y, Mathew AT, Hodson EM, Tunnicliffe DJ. Immunosuppressive treatment for primary membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2021 Nov 15;11(11):CD004293. doi: 10.1002/14651858.CD004293.pub4.

Results Reference

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

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