Acthar for Treatment of Proteinuria in Diabetic Nephropathy Patients

Study Overview
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Brief Summary
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This Phase 2A study is an adaptive design pilot study investigating the efficacy and safety of daily Acthar administration in diabetic patients with nephropathy and proteinuria. Patients with type 1 diabetes mellitus (T1DM) or T2DM who currently take insulin will be enrolled and randomized into 6 study groups and will be treated with either Acthar or Placebo for 36 weeks, followed by a 4 week dose taper, and a 12 week observation period. The study will compare three dose regimens of Acthar (8 U [0.1 mL], 16 U [0.2 mL], and 32 U [0.4 mL]) to equivalent volumes of Placebo to ensure the double-blind nature of the study. Insulin-requiring patients are being enrolled to aid compliance with the daily SC administration of study medication and to allow for ease of blood glucose control by adjustment of current insulin therapy in the event of glycemic excursions. Routine safety measures, including glycemic control, will be monitored throughout the study. The adaptive design component of the study allows for the re-assignment of the high dose group to the mid dose group if unacceptable toxicity is noted as per study protocol in the high dose group. Efficacy will be assessed by monitoring serum creatinine, calculated eGFR, and proteinuria (via urinary protein to creatinine ratio [PCR]). Serum cortisol concentration and additional biomarkers in blood and urine will also be monitored.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Adaptive Design Pilot Safety and Efficacy Study of H.P. Acthar Gel (Acthar) in Patients With Diabetic Nephropathy and Proteinuria.

Conditions
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Diabetic Nephropathy

Intervention / Treatment
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* Drug: Repository Corticotropin Injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (numbers 2, 3, 4, 5, 6, and 7 per protocol): Body mass index ≤ 45 kg/m2 at screening. Diagnosis of T1DM or T2DM, with HbA1c ≤ 9.0% at Visit 1A. Diagnosis of T2DM should have been made at > 30 years of age (if diabetes developed at a younger age, C-peptide level may be obtained to confirmed the diagnosis). Currently insulin-requiring Patients on oral hypoglycemic therapy plus insulin are eligible provided that oral hypoglycemic agent(s) administered and the dosing regimen(s) of oral hypoglycemic therapy have been stable for ≥ 12 weeks prior to screening. No changes in oral hypoglycemic therapy should be planned or anticipated during the treatment period. Renal Target Disease Requirements: The average of two eGFR values collected during screening (Visits 1 and 1A) must be between 20-60 mL/min/1.73m2 (calculated using the abbreviated Modification of Diet in Renal Disease [MDRD] equation AND Protein to creatinine ratio (PCR) ≥ 3.0 g/g OR total urine protein ≥ 3.0 g from the 24-hour urine collection returned at Visit 1A. Antihypertensive Therapy: Treatment with an ACEI and/or an ARB for at least 6 weeks prior to screening Visit 1A, with stable maintenance dose for ≥ 14 days prior to screening Visit 1A. No change in ACEI or ARB therapy should be planned or anticipated for the period of the study. If treated with additional antihypertensive therapy(ies), duration of therapy ≥ 30 days prior to screening Visit 1A, with stable maintenance dose for ≥ 14 days prior to screening Visit 1A. If the patient has documented intolerance to ACEI and/or ARB therapy (e.g. angioedema, hyperkalemia), they may be eligible for study entry, but the Medical Monitor must be consulted in these cases prior to randomization. Mean systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≤ 90 mmHg on ≥ 3 seated readings taken at least 5 minutes apart during the screening period at Visit 1A. Exclusion Criteria (numbers 2, 3, 4, 5, 7, and 11 per protocol): Therapies and/or Medications: History of prior sensitivity to Acthar or other porcine protein products. Chronic systemic corticosteroid use, defined as ≥ 20 mg of prednisone or equivalent systemic corticosteroid taken for more than 4 consecutive weeks within 6 months prior to randomization. Topical, inhaled, or intra-articular corticosteroids are allowed. Planned treatment with live or live attenuated vaccines once enrolled in the study. Previous treatment on a drug being investigated for the treatment of diabetic nephropathy within 6 months prior to randomization. Contraindication to Acthar per Prescribing Information Section 4: scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of peptic ulcer, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, or adrenal cortical hyperfunction. For the purpose of this study, history of peptic ulcer is defined as ≤ 6 months prior to Visit 1A. Diabetes Target Disease Exceptions: Severely uncontrolled diabetes mellitus as judged by the Principal Investigator HbA1c > 9% at screening Visit 1A. Fasting serum glucose > 230 mg/dL at BOTH screening Visits 1 and 1A. History of diabetic ketoacidosis or non-ketotic hyperosmolar coma within 6 months of screening. History of ocular laser photocoagulation therapy within 6 months of screening OR diabetic retinopathy, diabetic macular edema, or cataracts associated with impairment of visual acuity that will affect adherence with the dosing or administration of SC injections. Patients unwilling to titrate insulin for blood glucose control if adjustment of hypoglycemic therapy is required during the study. Renal Target Disease Exceptions: History of clinical or renal biopsy evidence of non-diabetic renal disease Patients requiring diagnostic or interventional procedure requiring an intravenous contrast agent must delay screening/randomization for at least 14 days Tuberculosis: Any patient with a positive Interferon-gamma release assay, OR signs and symptoms concerning for active tuberculosis. Cardiovascular: History of congestive heart failure (NYHA Functional Class III-IV). History of dilated cardiomyopathy with ejection fraction < 40%. 1. Exceptions require approval by the Medical Monitor. Patient has had any of the following within 3 months of screening: Unstable angina Myocardial infarction Coronary artery bypass graft or percutaneous transluminal coronary angioplasty Transient ischemic attack or cerebrovascular accident Unstable arrhythmia

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: The 32U group was discontinued after 2 patients met pre-specified criteria related to tolerability and patients assigned to the 32U were re-assigned to the 16U group.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acthar 8 U (0.1 mL) daily<br>Repository Corticotropin Injection | Drug: Repository Corticotropin Injection<br>* H.P. Acthar Gel (repository corticotropin injection) is administered via daily SC injection for 36 weeks in the three dose groups [8 U (0.1 mL), 16 U (0.2 mL), or 32 U (0.4 mL)].<br>* Other names: ACTH;|
| Placebo Comparator: Placebo (0.1 mL) daily<br>Placebo | Drug: Placebo<br>* Placebo contains the same inactive ingredients as H.P. Acthar Gel without the active pharmaceutical ingredient (API). Placebo is administered via daily SC injection for 36 weeks in equal volumes as the Acthar comparator volumes.<br>|
| Experimental: Acthar 16 U (0.2 mL) daily<br>Repository Corticotropin Injection | Drug: Repository Corticotropin Injection<br>* H.P. Acthar Gel (repository corticotropin injection) is administered via daily SC injection for 36 weeks in the three dose groups [8 U (0.1 mL), 16 U (0.2 mL), or 32 U (0.4 mL)].<br>* Other names: ACTH;|
| Placebo Comparator: Placebo (0.2 mL) daily<br>Placebo | Drug: Placebo<br>* Placebo contains the same inactive ingredients as H.P. Acthar Gel without the active pharmaceutical ingredient (API). Placebo is administered via daily SC injection for 36 weeks in equal volumes as the Acthar comparator volumes.<br>|
| Experimental: Acthar 32 U (0.4 mL) daily<br>Repository Corticotropin Injection | Drug: Repository Corticotropin Injection<br>* H.P. Acthar Gel (repository corticotropin injection) is administered via daily SC injection for 36 weeks in the three dose groups [8 U (0.1 mL), 16 U (0.2 mL), or 32 U (0.4 mL)].<br>* Other names: ACTH;|
| Placebo Comparator: Placebo (0.4 mL) daily<br>Placebo | Drug: Placebo<br>* Placebo contains the same inactive ingredients as H.P. Acthar Gel without the active pharmaceutical ingredient (API). Placebo is administered via daily SC injection for 36 weeks in equal volumes as the Acthar comparator volumes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Estimated Glomerular Filtration Rate (eGFR) at Visit 12 | Percent change in eGFR at Visit 12 (Week 36) compared to average baseline eGFR obtained during screening | Visit 12 (Week 36) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in eGFR at Visit 17 | Percent change in eGFR at Visit 17 (Week 52) compared to baseline eGFR obtained during screening | Visit 17 (Week 52) | 
| Frequency of Patients With a Doubling of Serum Creatinine, Progression to End-stage Renal Disease (ESRD), or Death |  | Visit 12 (Week 36) and Visit 17 (Week 52) | 
| Complete or Partial Remission of Proteinuria | Proportion of patients with complete remission (PCR 0.5 g/g) or partial remission (reduction in PCR of >50% from baseline, plus PCR≤2.5 g/g but >0.5 g/g) of proteinuria at Visit 12 (Week 36) and/or at Visit 17 (Week 52) | Visit 12 (Week 36) and Visit 17 (Week 52) | 
| Percent Change in eGFR Calculated Using Cystatin C | Percent change in eGFR calculated using cystatin C compared to baseline obtained at Visit 2. | Visit 12 (Week 36) and Visit 17 (Week 52) | 
| Percent Change From Baseline in eGFR by Visit | Percent change from baseline in eGFR by visit | Visit 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and 17 | 
| Percent Change From Baseline in Protein to Creatinine Ratio (PCR) | Percent change from baseline in PCR | Visits 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and 17 | 
| Proportion of Subjects Whose Best Response Was Complete or Partial Remission of Proteinuria | Proportion of subjects whose best response was complete remission (PCR 0.5 g/g) or partial remission (reduction in PCR of >50% from baseline, plus PCR≤2.5 g/g but >0.5 g/g) of proteinuria | Visit 12 (Week 36) and Visit 17 (Week 52) | 
| Percent Change From Baseline of Serum Total Cholesterol, Triglycerides, LDL, HDL, Lp(a), Albumin, and Cortisol | Percent change from baseline of serum total cholesterol, triglycerides, LDL, HDL, Lp(a), albumin, and cortisol | Visit 6, 9, 12, and 17 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acthar, H.P. Acthar Gel, diabetic nephropathy, proteinuria, nephrotic syndrome