ACTHar in the Treatment of Lupus Nephritis

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

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

Conditions
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Lupus Nephritis

Intervention / Treatment
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* Drug: CellCept
* Drug: ACTHar gel
* Drug: ACTHar gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Systemic Lupus Erythematosus (SLE) by American College of Rheumatology (ACR)/SLICC criteria Age ≥ 16 years 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 Ability to provide informed consent Exclusion Criteria: Moderately severe anemia (Hgb < 8 mg/dL) Neutropenia (< 1,000/mm3) Thrombocytopenia (platelets < 50,000/mm3) Positive purified protein derivative (PPD) test confirmed by positive Quantiferon TB gold. Pulmonary fibrotic changes on chest radiograph consistent with prior healed tuberculosis Active infections that in the opinion of the investigator increase the risks to the subject. Known human immunodeficiency virus (HIV) and hepatitis B or C End-stage renal disease (estimated GFR clearance < 20 mL/min/1.73 m2) History of cancer, except carcinoma in situ and treated basal and squamous cell carcinomas Pregnancy Lactation 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) Previous failure to respond to MMF Use of rituximab within the past year Use of experimental therapeutic agents within the past 60 days 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) 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 Current substance abuse

Ages Eligible for Study
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Minimum Age: 16 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: CellCept daily & ACTHar gel biw<br>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<br>* For both arms: CellCept 3 grams daily, oral, from Week 0-24 CellCept 2 grams daily, oral, from Week 25-144<br>* Other names: Mycophenolate Mofetil;Drug: ACTHar gel<br>* Arm 1: 80 U biw, subcutaneous, for 3 months. Optionally additional 3 months of 80 U biw if a patient has partial response.<br>* Other names: Repository corticotropin;|
| Active Comparator: CellCept daily & ACTHar gel qod<br>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<br>* For both arms: CellCept 3 grams daily, oral, from Week 0-24 CellCept 2 grams daily, oral, from Week 25-144<br>* Other names: Mycophenolate Mofetil;Drug: ACTHar gel<br>* 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.<br>* Other names: Repository corticotropin;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lupus, Lupus Nephritis, ACTHar, Columbia, Rheumatology, CUMC, Autoimmune, SLE, Proliferative Lupus Nephritis