ACTHar in the Treatment of Lupus Nephritis (ACTHar)

Open-label Prospective Randomized Study to Determine the Efficacy and Safety of Two Dosing Regimens of ACTHar in the Treatment of Proliferative Lupus Nephritis.

Systemic Lupus Erythematosus (SLE) is a disease in which the immune system attacks the healthy cells and tissues, causing inflammation that can damage organs in the body. About 50% of SLE patients experience inflammation in the kidneys. The purpose of this study is to determine the effectiveness and safety of two dosing arms of ACTHar gel in treating proliferative Lupus Nephritis (LN). This study hypothesizes that both dosing arms of ACTHar are safe and effective in treating proliferative LN (Class III and IV).

Study Overview

• Status: Recruiting
• Conditions: Lupus Nephritis
• Intervention / Treatment: Drug: CellCept; Drug: ACTHar gel; Drug: ACTHar gel

Detailed Description

Systemic Lupus Erythematosus (SLE) is an autoimmune disease of unknown etiology that mainly affects females of childbearing age. The disease is characterized by immune activation and the development of autoantibodies.

About 50% of SLE patients experience inflammation of the kidneys. Lupus Nephritis (LN) is a major cause of morbidity and mortality in patients with SLE. Mycophenolate Mofetil (MMF), accompanied by Prednisone, is considered the current standard of care for LN. However, long-term use of Prednisone has many serious side effects.

ACTHar Gel is an FDA approved drug comprised of an active substance called adrenocorticotropic hormone (ACTH). ACTH belongs to an anti-inflammatory group called melanocortins and carries out its effects by binding to five different melanocortin receptors (MCRs). Specifically, ACTH binding to melanocortin 2 receptor subtype (MC2R) on the adrenal cortex stimulates the production of cortisol that reduces inflammation in the kidney. In addition to binding to melanocortin 1-5 receptor subtype (MC1-5R) and acting directly on kidney tissues, ACTH may bind to MCRs on various cell types, such as immune cells, and activate processes to protect the kidney.

This study will evaluate the most effective dose of ACTHar gel in proliferative LN (Class III and IV) when given with MMF, the standard of care LN therapy. The intent of this study is to determine the effectiveness and safety of ACTHar gel in an attempt to change the clinical care requirements regarding steroid use in treating LN.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Anca D Askanase, MD, MPH; Phone Number: 212-305-0856; Email: ada20@cumc.columbia.edu
• Study Contact Backup: Name: Rachel A Drolet, RN, MSN, AGNP-BC; Phone Number: 212-342-1622; Email: rad2145@cumc.columbia.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University - Herbert Irving Pavilion
      • Contact: Pooja Mahadeshwar; Phone Number: 212-342-9051; Email: pm2844@cumc.columbia.edu
      • Contact: Samantha C Nguyen; Phone Number: 212-342-1587; Email: scn2119@cumc.columbia.edu
      • Sub-Investigator: Rachel A Drolet, RN, MSN, AGNP-BC
      • Principal Investigator: Anca D Askanase, MD, MPH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of Systemic Lupus Erythematosus (SLE) by American College of Rheumatology (ACR)/SLICC criteria
2. Age ≥ 16 years

3. Active lupus nephritis defined by:

   a. Kidney biopsy documentation of International Society of Nephrology/Renal Pathology Society (ISN/RPS) Class III or Class IV proliferative nephritis (including Class V occurring in combination with Class III or IV) within 12 months and a urine protein/creatinine ratio >1 at time of entry to study

4. Ability to provide informed consent

Exclusion Criteria:

1. Moderately severe anemia (Hgb < 8 mg/dL)
2. Neutropenia (< 1,000/mm3)
3. Thrombocytopenia (platelets < 50,000/mm3)
4. Positive purified protein derivative (PPD) test confirmed by positive Quantiferon TB gold.
5. Pulmonary fibrotic changes on chest radiograph consistent with prior healed tuberculosis
6. Active infections that in the opinion of the investigator increase the risks to the subject.
7. Known human immunodeficiency virus (HIV) and hepatitis B or C
8. End-stage renal disease (estimated GFR clearance < 20 mL/min/1.73 m2)
9. History of cancer, except carcinoma in situ and treated basal and squamous cell carcinomas
10. Pregnancy
11. Lactation
12. Unwillingness to use a medically acceptable form of birth control (including but not limited to a diaphragm, an intrauterine device, progesterone implants or injections, oral contraceptives, the double-barrier method, or a condom)
13. Previous failure to respond to MMF
14. Use of rituximab within the past year
15. Use of experimental therapeutic agents within the past 60 days
16. Greater than or equal to 5 times the upper limit of normal of liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], or alkaline phosphatase)
17. Severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, or neurological disease (or, in the investigator's opinion, any other concomitant medical condition that places the participant at risk by participating in this study) with the exception of diseases or conditions related to active SLE
18. Current substance abuse

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CellCept daily & ACTHar gel biw; Patients will be treated with CellCept 3 grams daily and ACTHar gel 80 U biw for 3 months. After 3 months, patients with complete response will stop ACTHar gel but continue CellCept 3 grams daily for another 3 months whereas patients with partial response will continue CellCept 3 grams daily and be offered the option to continue ACTHar 80 U biw for another 3 months. After 6 months, all patients will continue CellCept at a dose of 2 grams daily for another 18 months.	Drug: CellCept; For both arms: CellCept 3 grams daily, oral, from Week 0-24 CellCept 2 grams daily, oral, from Week 25-144; Other Names: Mycophenolate Mofetil; Drug: ACTHar gel; Arm 1: 80 U biw, subcutaneous, for 3 months. Optionally additional 3 months of 80 U biw if a patient has partial response.; Other Names: Repository corticotropin; ACTHar; H.P. ACTHar Gel; Drug: ACTHar gel; Arm 2: 80 U qod, subcutaneous, for 1 month, then 80 U biw, subcutaneous, for 2 months. Optionally additional 3 months of 80 U biw if a patient has partial response.; Other Names: Repository corticotropin; ACTHar; H.P. ACTHar Gel
Active Comparator: CellCept daily & ACTHar gel qod; Patients will be treated with CellCept 3 grams daily for 3 months, and ACTHar gel 80 U qod for the first month and ACTHar gel 80 U biw for the following 2 months. After 3 months, patients with complete response will stop ACTHar gel but continue CellCept 3 grams daily for another 3 months whereas patients with partial response will continue CellCept 3 grams daily and be offered the option to continue ACTHar 80 U biw for another 3 months. After 6 months, all patients will continue CellCept at a dose of 2 grams daily for another 18 months.	Drug: CellCept; For both arms: CellCept 3 grams daily, oral, from Week 0-24 CellCept 2 grams daily, oral, from Week 25-144; Other Names: Mycophenolate Mofetil; Drug: ACTHar gel; Arm 1: 80 U biw, subcutaneous, for 3 months. Optionally additional 3 months of 80 U biw if a patient has partial response.; Other Names: Repository corticotropin; ACTHar; H.P. ACTHar Gel; Drug: ACTHar gel; Arm 2: 80 U qod, subcutaneous, for 1 month, then 80 U biw, subcutaneous, for 2 months. Optionally additional 3 months of 80 U biw if a patient has partial response.; Other Names: Repository corticotropin; ACTHar; H.P. ACTHar Gel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of patients with a complete response (CR)	Complete response (CR) is defined as all of the following criteria having been achieved: Stabilization of estimated glomerular filtration rate (eGFR) (i.e., a 6-month eGFR level ± 10% of baseline) or improvement if the screening value is changed from patient's baseline; Inactive urinary sediment (red blood cells per high-power field [RBCs/HPF] < 5-10, not due to gyn bleeding); Urine protein/creatinine ratio < 0.5	6 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent responders	Frequency of responders = CR + Partial Responders (PR). PR = improvement from baseline of at least ≥ 50% in all abnormal renal parameters (proteinuria and serum creatinine) without deterioration of any measurements at 6 months	6 Months
Percent of patients with extra-renal flares	Frequency of extra-renal flares as defined by the SELENA-SLEDAI Flare Index. Extra-renal disease activity measured by SELENA-SLEDAI and BILAG	6 Months
Mean cortisol levels	Cortisol levels 8 hours after ACTHar dose in 2-3 patients per dosing arm	6 Months
Percent of patients with steroid -like side effects	Steroid -like side effects: increase in blood pressure (BP) by 20 mmHg for both systolic blood pressure (SBP) and diastolic blood pressure (DBP), increased blood sugar with a fasting plasma glucose level ≥ 126 mg/dl, weight gain ≥ 10% of the initial weight, infections	6 Months
Mean urinary lymphocytes	Urinary markers of active inflammatory nephritis	6 Months
Percent of patients with side effects	Side effects from taking ACTHar	6 Months

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: Anca D Askanase, MD, MPH, Columbia University

Publications and helpful links

General Publications

• Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002 Feb;29(2):288-91.
• 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.
• Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy D, Eitner F, Appel GB, Contreras G, Lisk L, Solomons N; ALMS Group. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. 2011 Nov 17;365(20):1886-95. doi: 10.1056/NEJMoa1014460.
• Lam GK, Petri M. Assessment of systemic lupus erythematosus. Clin Exp Rheumatol. 2005 Sep-Oct;23(5 Suppl 39):S120-32.
• Austin HA 3rd, Muenz LR, Joyce KM, Antonovych TT, Balow JE. Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome. Kidney Int. 1984 Apr;25(4):689-95. doi: 10.1038/ki.1984.75.
• Weening JJ, D'Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, Ferrario F, Fogo AB, Ginzler EM, Hebert L, Hill G, Hill P, Jennette JC, Kong NC, Lesavre P, Lockshin M, Looi LM, Makino H, Moura LA, Nagata M; International Society of Nephrology Working Group on the Classification of Lupus Nephritis; Renal Pathology Society Working Group on the Classification of Lupus Nephritis. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004 Feb;65(2):521-30. doi: 10.1111/j.1523-1755.2004.00443.x. Erratum In: Kidney Int. 2004 Mar;65(3):1132.
• Schweitzer EJ, Yoon S, Fink J, Wiland A, Anderson L, Kuo PC, Lim JW, Johnson LB, Farney AC, Weir MR, Bartlett ST. Mycophenolate mofetil reduces the risk of acute rejection less in African-American than in Caucasian kidney recipients. Transplantation. 1998 Jan 27;65(2):242-8. doi: 10.1097/00007890-199801270-00017.
• Belmont HM, Levartovsky D, Goel A, Amin A, Giorno R, Rediske J, Skovron ML, Abramson SB. Increased nitric oxide production accompanied by the up-regulation of inducible nitric oxide synthase in vascular endothelium from patients with systemic lupus erythematosus. Arthritis Rheum. 1997 Oct;40(10):1810-6. doi: 10.1002/art.1780401013.

Helpful Links

• CUMC Rheumatology Research Website

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Anticipated): January 1, 2024
• Study Completion (Anticipated): July 1, 2024

Study Registration Dates

• First Submitted: August 25, 2014
• First Submitted That Met QC Criteria: August 25, 2014
• First Posted (Estimate): August 27, 2014

Study Record Updates

• Last Update Posted (Estimate): March 18, 2016
• Last Update Submitted That Met QC Criteria: March 17, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Lupus; SLE; Rheumatology; Lupus Nephritis; Autoimmune; Columbia; ACTHar; CUMC; Proliferative Lupus Nephritis
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Kidney Diseases; Urologic Diseases; Connective Tissue Diseases; Glomerulonephritis; Lupus Erythematosus, Systemic; Nephritis; Lupus Nephritis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Mycophenolic Acid; Adrenocorticotropic Hormone
• Other Study ID Numbers: AAAN4752