Phase III Study Assessing the Efficacy and Safety of Pegcetacoplan in Patients With C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis

Study Overview
=================
Brief Summary
-----------------
This is a Phase 3 study to assess the efficacy and safety of twice-weekly subcutaneous (SC) doses of pegcetacoplan compared to placebo in patients with C3 glomerulopathy (C3G) or immune-complex membranoproliferative glomerulonephritis (IC-MPGN) on the basis of a reduction in proteinuria.

Official Title
-----------------
A Phase 3, Randomized, Placebo-Controlled, Double-Blinded, Multicenter Study to Evaluate the Efficacy and Safety of Pegcetacoplan in Patients With C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis

Conditions
-----------------
C3G, IC-MPGN, C3 Glomerulopathy, C3 Glomerulonephritis, Complement 3 Glomerulopathy, Complement 3 Glomerulopathy (C3G), Complement 3 Glomerulonephritis, Dense Deposit Disease, DDD, Membranoproliferative Glomerulonephritis, Membranoproliferative Glomerulonephritis (MPGN), Immune Complex Membranoproliferative Glomerulonephritis (IC-MPGN)

Intervention / Treatment
-----------------
* Drug: Pegcetacoplan
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Aged at least 18 years; where approved, adolescents (aged 12-17 years) weighing at least 30 kg may also be enrolled. A diagnosis of primary C3G or IC-MPGN (with or without previous renal transplant). Evidence of active renal disease, based on one or more of the following: In adults or adolescents with a baseline renal biopsy (either one collected during screening or a historic biopsy collected within 28 weeks prior to randomization), at least 2+ C3c staining on the baseline renal biopsy. In adolescents not providing a baseline renal biopsy, at least one of the following: Plasma sC5b-9 level above the upper limit of normal during screening Serum C3 below the LLN during screening Presence of an active urine sediment during screening, as evidenced by hematuria with at least 5 red blood cells (RBCs) per high-power field (HPF) and/or red blood cell casts on local or central microscopic analysis of urine. Presence of C3 nephritic factor within 6 months of screening, based on central laboratory results or medical history. No more than 50% global glomerulosclerosis or interstitial fibrosis on the baseline biopsy for adult participants or adolescent participants providing a baseline biopsy. At least 1 g/day of proteinuria on a screening 24-hour urine collection and a uPCR of at least 1000 mg/g in at least 2 first-morning spot urine samples collected during screening. eGFR ≥30 mL/min/1.73 m2 calculated by the Chronic Kidney Disease-Epidemiology Collaboration creatinine equation for adults or the Bedside Schwartz equation for adolescents. Stable regimen for C3G/IC-MPGN treatment, as described below: Angiotensin-converting enzyme inhibitor/, angiotensin receptor blocker, and/or sodium-glucose cotransporter-2 inhibitor therapy that is stable and optimized, in the opinion of the investigator, for at least 12 weeks prior to randomization Stable doses of other medications that can affect proteinuria (eg, steroids, mycophenolate mofetil, and/or other allowed immunosuppressants that the participant is receiving for treatment of C3G or IC-MPGN) for at least 812 weeks prior to the baseline renal biopsy and randomization. If a participant is on prednisone (or other systemic corticosteroid) for C3G or IC-MPGN treatment, the dosage is stable and no higher than 20 mg/day (or equivalent dosage of a corticosteroid other than prednisone) for at least 12 weeks prior to randomization. Have received vaccinations against S pneumoniae, N meningitidis (types A, C, W, Y, and B), and H influenzae (type B) within 5 years prior to randomization or agree to receive vaccinations during screening. Exclusion Criteria: Previous exposure to pegcetacoplan. C3G/IC-MPGN secondary to another condition (eg, infection, malignancy, monoclonal gammopathy, a systemic autoimmune disease such as systemic lupus erythematosus, chronic antibody-mediated rejection, or a medication), in the opinion of the investigator. Current or prior diagnosis of human immunodeficiency virus (HIV), hepatitis B (HBV), or hepatitis C (HCV) infection or positive serology during screening that is indicative of infection with any of these viruses. Body weight greater than 100 kg at screening. Hypersensitivity to pegcetacoplan or to any of the excipients. History of meningococcal disease. Malignancy, except for the following: Cured basal or squamous cell skin cancer Curatively treated in situ disease Malignancy-free and off treatment for ≥5 years Severe infection (eg, requiring IV antibiotic therapy) within 14 days prior to the first dose of pegcetacoplan. An absolute neutrophil count <1000 cells/mm3 at screening. Use of rituximab, belimumab, or any approved or investigational anticomplement therapy other than pegcetacoplan within 5 half-lives of that product prior to the screening period. Female participants who are pregnant or who are currently breastfeeding and are unwilling to discontinue for the duration of the study and for at least 90 days after the final dose of study drug. Presence or suspicion of severe infection during the screening period (including but not limited to recurrent or chronic infections) that, in the opinion of the investigator, may place the participant at unacceptable risk by study participation. Known or suspected hereditary fructose intolerance.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Pegcetacoplan administration<br>Subcutaneous infusion of 20mL (1080 mg), twice weekly (for adults or adolescents >50kg), and the three other weight-based doses either of 10mL (540mg), 12mL (648mg), or 15mL (810mg) | Drug: Pegcetacoplan<br>* Complement (C3) Inhibitor<br>|
| Placebo Comparator: Group 2: Placebo administration<br>Subcutaneous infusion of either 10mL, 12mL, 15mL, or 20mL, twice weekly | Other: Placebo<br>* Sterile solution of equal volume to active arm<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The log-transformed ratio of uPCR at week 26 compared to baseline |  | Baseline to week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of participants who meet the criteria for achieving a composite renal endpoint (a stable or improved eGFR compared to the baseline visit (≤15% reduction in eGFR), and a ≥50% reduction in uPCR compared to the baseline visit.) |  | Baseline to week 26 | 
| The proportion of participants with a reduction of at least 50% from baseline in uPCRF |  | Baseline to week 26 | 
| Change from baseline in eGFR |  | Baseline to week 26 | 
| For participants with evaluable renal biopsies, the change from baseline in the activity score of the C3G histologic index score |  | Baseline to week 26 | 
| The proportion of participants with evaluable renal biopsies showing decreases in C3c staining on renal biopsy from baseline |  | Baseline to week 26 |