Acthar for Treatment of Proteinuria in Membranous Nephropathy Patients

A Randomized, Placebo-Controlled, Parallel-Group, Double-Blind Study of H.P. Acthar Gel (Acthar) in Treatment-Resistant Subjects With Persistent Proteinuria and Nephrotic Syndrome Due to Idiopathic Membranous Nephropathy (iMN)

The purpose of this study is to provide nephrologists with additional clinical evidence regarding the efficacy and safety of Acthar in subjects with treatment-resistant idiopathic membranous nephropathy. Approximately sixty (60) subjects will be randomized in this double-blind, parallel-group, placebo-controlled, multicenter study comparing Acthar and Placebo administered 2 times per week for a 24-week treatment period followed by a 24-week observation period. The primary objective of this study is to assess the proportion of treatment-resistant subjects (defined as subjects who either have had no response or have suffered a relapse after achieving a partial response to their most recent standard treatment regimen) who have a complete or partial remission of proteinuria in nephrotic syndrome due to idiopathic membranous nephropathy after 24 weeks of treatment.

For complete list of inclusion and exclusion criteria, please refer to contact below.

Inclusion Criteria:

• Male or female subjects ≥18 years of age, at screening Visit 1:

  a. If potential subjects are >75 years of age, discussion between the investigator and the Medical Monitor must take place;

• Body mass index ≤40 kg/m2, at screening Visit 1;

• A history of nephrotic syndrome due to iMN as confirmed by documented results from a renal biopsy performed within 4 years prior to screening Visit 1:

  a. If a biopsy has been performed between 4-8 years prior to screening, and if the subject has no signs or symptoms of diabetes or other clinical diagnoses that could suggest a change in renal histology in the opinion of the investigator and the Medical Monitor, the subject is eligible.

• Renal target disease requirements:

  1. Total urine protein of ≥3.0g (≥3000mg) from the 24-hour urine returned at Visit 1A, AND.
  2. An estimated glomerular filtration rate (eGFR) value >25mL/min/1.73m2 at Visit 1A (as calculated using the abbreviated Modification of Diet in Renal Disease [MDRD] equation.

• Any prior course of at least 1 month of treatment with ≥1 of an immunosuppressant therapy(ies) for iMN:

  1. Subjects must be followed for at least 3 months after treatment prior to screening with the exception of rituximab or a cytotoxic based therapy, where the follow-up period is 6 months after treatment. If after follow-up it was determined that the subject did not achieve a complete or partial remission or suffered a relapse after achieving a partial remission, the subject will be eligible for the study.
  2. If in the investigator's opinion, the subject should be enrolled prior to meeting the follow-up period criteria and the decrease in proteinuria is no longer occurring, discussion between the investigator and the Medical Monitor must take place for approval to enter screening.

• History of treatment-resistant iMN defined as either having had no remission or having suffered a relapse after achieving a partial remission to their most recent standard treatment regimen as defined in the Definition of Response Status Table despite treatment with at least 1 month of treatment with a prior therapy for iMN. Note the following:

  a. If the subject has been treated with prior standard therapy and can no longer be re-treated with any component of that therapy, regardless of whether a complete or partial remission was achieved, then the subject may be eligible, but approval from the Medical Monitor is required.

  i. For example, if early discontinuation of standard therapy occurred because of a serious adverse event (Grade 3 or 4) during the treatment, regardless of whether a partial or complete remission was achieved, then the subject may be eligible.

  b. If (a) does not apply, and the subject did not have either a partial or complete remission to the most recent treatment regimen, then the subject is eligible.

  c. If (a) does not apply, and the subject achieved a partial remission from the most recent treatment regimen, and later relapse occurred, then the subject is eligible.

• Antihypertensive treatment including use of ACE inhibitors and/or ARB:

  a. Unless there is a history of intolerance to ACE inhibitors or ARB therapy, the subject must be treated with at least one of these agents.

  b. Treatment with ACE inhibitor and/or ARB for ≥3 months prior to screening Visit 1A, with stable maintenance dose for ≥30 days prior to randomization.

  c. If treated with other antihypertensive therapies, treatment duration of ≥30 days and stable maintenance dose for ≥7 days prior to screening Visit 1A.

• Blood pressure determined by the average of ≥3 seated readings taken ≥5 minutes apart during the screening period at Visit 1A:

  1. Mean systolic blood pressure ≤140 mmHg and
  2. Mean diastolic blood pressure ≤80 mmHg.

Exclusion Criteria:

• Therapies and/or medications:

  1. History of previous use of Acthar for treatment of nephrotic syndrome;
  2. Prior sensitivity to Acthar or other porcine protein products; or
  3. Planned treatment with live or live attenuated vaccines once enrolled in the study.

• Contraindication to Acthar per Prescribing Information: 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 adrenocortical hyperfunction.

  a. For the purpose of this study: "history" of peptic ulcer is defined as ≤6 months prior to Visit 1A.

• Renal target disease exclusions:

  1. Subjects with known diabetic nephropathy or nephrotic syndrome due to a disease or process other than idiopathic membranous nephropathy, or
  2. Subjects requiring diagnostic or interventional procedure requiring a contrast agent must delay screening/randomization for at least 7 days.

• History of Systemic Lupus Erythematosus.

• Type 1 or Type 2 diabetes mellitus (prior diagnosis of gestational diabetes mellitus is not an exclusion).

• History of Deep Vein Thrombosis (DVT) ≤6 months prior to screening Visit 1A.

• Presence of renal vein thrombosis:

  1. Known current diagnosis by ultrasound, magnetic resonance imaging (MRI) or computed tomography scan;
  2. Signs or symptoms consistent with occurrence of acute renal vein thrombosis (hematuria in combination with flank pain and >30% unexplained acute rise in serum creatinine) with renal vein thrombosis confirmed by ultrasound, MRI or computed tomography scan.

• Cardiovascular exclusions:

  1. History of or active congestive heart failure (NYHA Functional Classification of CHF Class II through Class IV), or.
  2. History of known dilated cardiomyopathy with left ventricular ejection fraction ≤40%, or.
  3. Occurrence of any of the following within 3 months of screening Visit 1A:

  i. Unstable angina. ii. Myocardial infarction. iii. Coronary artery bypass graft or percutaneous transluminal coronary angioplasty.

iv. Transient ischemic attack or cerebrovascular disease. v. unstable arrhythmia.