Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN) (ACTH-NRDN)

This study has been completed.
Sponsor:
Collaborator:
Questcor Pharmaceuticals, Inc.
Information provided by (Responsible Party):
James A. Tumlin MD, Southeast Renal Research Institute
ClinicalTrials.gov Identifier:
NCT01028287
First received: December 8, 2009
Last updated: May 30, 2013
Last verified: May 2013
  Purpose

This is a prospective open labeled trial examining the efficacy of ACTHar Gel (porcine ACTH) on the level of proteinuria in patients with diabetic nephropathy and nephrotic range proteinuria.


Condition Intervention Phase
Diabetic Nephropathy
Nephrotic Syndrome
Drug: ACTH
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: "Safety and Efficacy of Acthar Gel on Albuminuria and Urinary Transforming Growth Factor Excretion in Type I or Type II Diabetics Requiring Medical Treatment of Hyperglycemia With Nephrotic Range Proteinuria: A Pilot Study"

Resource links provided by NLM:


Further study details as provided by Southeast Renal Research Institute:

Primary Outcome Measures:
  • Percentage of patients achieving less than 300 mg protein per 24 hours after 6 months of Acthar Gel. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Percentage of patients achieving greater than 50% reduction in urinary proteinuria after 6 months of Acthar Gel. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

Enrollment: 15
Study Start Date: May 2009
Study Completion Date: July 2011
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: ACTH-16 units
Patients with nephrotic range proteinuria randomized to this group will receive 16 units ACTHargel sub-cutaneously every day.
Drug: ACTH
Patients with nephrotic range proteinuria randomized to this group will receive 16 units ACTHargel sub-cutaneously every day.
Other Name: ACTHar Gel
Drug: ACTH
Patients with nephrotic range proteinuria randomized to this group will receive 32 units ACTHargel sub-cutaneously every day.
Other Name: ACTHar Gel
Active Comparator: ACTH-32 units
Patients with nephrotic range proteinuria randomized to this group will receive 32 units ACTHargel sub-cutaneously every day.
Drug: ACTH
Patients with nephrotic range proteinuria randomized to this group will receive 16 units ACTHargel sub-cutaneously every day.
Other Name: ACTHar Gel
Drug: ACTH
Patients with nephrotic range proteinuria randomized to this group will receive 32 units ACTHargel sub-cutaneously every day.
Other Name: ACTHar Gel

Detailed Description:

Diabetes Mellitus is a significant and growing health problem in the United States and other developed countries. Despite improving public awareness, end-organ complications including diabetic nephropathy and coronary atherosclerotic heart disease continues to grow by 5-10% per year. While improvements in the control of blood pressure and the wide-spread use of antagonists of the renin-angiotensin-aldosterone system have significantly improved renal outcomes, therapies designed to disrupt the more central pathogenic mechanisms of diabetic nephropathy are still needed. Recent observations have shown that effacement of podocyte foot-plate processes and accelerated apoptosis, are central to the pathogenesis of diabetic nephropathy. The resulting increase in glomerular permeability leads to nephrotic range proteinuria and interstitial fibrosis from local synthesis of transforming growth factor b (TGF-b) and direct toxicity to the renal epithelium. Recent studies have shown that synthetic forms of adrenocorticotropic hormone (ACTH) are able to achieve sustained reductions in proteinuria in non-diabetic glomerulopathies. Moreover, while the numbers of patients are quite limited, preliminary studies also suggest that pharmacologic administration of ACTH can reduce proteinuria in patients with diabetic nephropathy. The observation that ACTH can reduce proteinuria in a variety of glomerulopathies suggests that ACTH may be important for podocyte function and viability independent of the primary disease. Interestingly, recent studies confirm that melanocortin receptors are expressed in non-adrenal tissues including the circulating T and B cells and most recently the glomerular podocyte. Previous studies investigating the effect of diabetes and insulin therapy on ACTH levels have given mixed results. It is therefore unclear how podocytes in patients with diabetic nephropathy could become functionally deficient in ACTH. However, studies in adrenal cortical cells finds that TGF-b is able to down regulate the expression of ACTH receptors. Moreover, TGF-b is able block an ACTH-induced stimulation of melanocortin receptors. This intriguing link between TGF-b and ACTH signaling raises the question of whether impaired signaling of ACTH in the glomerulus leads to podocyte dysfunction, accelerated detachment and ultimately podocyte apoptosis. Moreover, we postulate that a complex interaction between TGF-b and ACTH expression exists within the glomerulus such that restoration of ACTH function will lead to a reduction in renal TGF-b expression. We therefore propose to study the effect of increasing doses of exogenous ACTH on rates of albuminuria and urinary TGF-b expression in diabetics with nephrotic range proteinuria. In addition to TGF-b we will examine whether a similar effect occurs on the 3 major isoforms of vascular endothelial growth factor, VEGF120, 164, and 180. We will also determine the duration of the effect and whether it is additive with ACE/ARB therapy inhibition.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age > 18 and < 80
  2. Type I or Type II Diabetes Mellitus
  3. Stable ACE or ARB therapy for 4 weeks prior to study enrollment
  4. Urinary protein > 3000 mg/24 hrs
  5. Patients with more than one protein lowering agent (e.g. ACE or ARB, or MR antagonist or Tekturna require two consecutive 24 hour urinary protein of 2000 mg/24 hrs.

Exclusion Criteria:

  1. Age <18 or >80
  2. HgbA1c > 9.0% or 11% if using the (DCCT / NGSP) method.
  3. eGFR < 20 mls/min by MDRD formula or eGFR by (Cockoff-Gault 20 mls/min)
  4. Dilated cardiomyopathy with known EF < 40%
  5. Pregnant or nursing mothers
  6. Patients with an admission for diabetic ketoacidosis, or non-ketotic hyperosmolar coma within 6 months of study enrollment.
  7. Patients with known mixed glomerulonephritis and diabetic glomerulopathy
  8. Patients within 3 mths of operative procedures or chronic non-healing wounds
  9. Patients with glucocorticoid-induced diabetes mellitus
  10. Patients with known sensitivity to porcine protein products
  11. Patients with bleeding gastric or duodenal ulcers requiring hospitalization six months prior to study enrollment
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01028287

Locations
United States, Tennessee
Southeast Renal Research Institute
Chattanooga, Tennessee, United States, 37404
Sponsors and Collaborators
Southeast Renal Research Institute
Questcor Pharmaceuticals, Inc.
Investigators
Principal Investigator: James A. Tumlin, MD Southeast Renal Research Institute
  More Information

No publications provided by Southeast Renal Research Institute

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: James A. Tumlin MD, Principal Investigator, Southeast Renal Research Institute
ClinicalTrials.gov Identifier: NCT01028287     History of Changes
Other Study ID Numbers: ACTH-NRDN
Study First Received: December 8, 2009
Last Updated: May 30, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Southeast Renal Research Institute:
Diabetic Nephropathy
Nephrotic syndrome

Additional relevant MeSH terms:
Diabetic Nephropathies
Kidney Diseases
Nephrotic Syndrome
Proteinuria
Urologic Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Nephrosis
Urination Disorders
Urological Manifestations
Signs and Symptoms
Adrenocorticotropic Hormone
Beta-Endorphin
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 23, 2014