A Study of Cemdisiran in Adults With Immunoglobulin A Nephropathy (IgAN)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of cemdisiran on proteinuria in adults with immunoglobulin A nephropathy (IgAN), who excrete >1 gram (gm) of protein per day despite standard of care, which includes treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB). These participants are at high risk for progression of kidney disease, which can result in end-stage renal failure.

Official Title
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A Phase 2, Randomized, Double-blind, Placebo-controlled Study of Cemdisiran in Adult Patients With IgA Nephropathy

Conditions
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IgA Nephropathy (IgAN), Berger Disease, Glomerulonephritis, IgA

Intervention / Treatment
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* Drug: Placebo
* Drug: Cemdisiran


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with primary IgAN Currently being treated for IgAN with stable, optimal therapy, including an ACE inhibitor or ARB. Has urine protein greater than or equal to 1 gram/24-hour Has hematuria (blood cells present in urine) Exclusion Criteria: Has renal disease other than IgAN Has a diagnosis of rapidly progressive glomerulonephritis Has a diagnosis of Henoch-Schonlein Purpura (IgA Vasculitis) Has poor kidney function with estimated glomerular filtration rate (eGFR) <30 milliliters per minute per 1.73 meters square (mL/min/1.73 m^2) Has known human immunodeficiency virus (HIV) infection, hepatitis C virus (HCV) infection or hepatitis B virus (HBV) infection Has on-going high blood pressure Treated with systemic corticosteroids for more than 7 days, or other immunosuppressant agents in the past 6 months Received an organ transplant

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Double-Blind Treatment (DBT) Period: Cemdisiran<br>Participants received cemdisiran, 600 milligrams (mg), subcutaneous (SC) injection, once every 4 weeks (Q4W) in combination with standard of care treatment up to a maximum of 38 weeks in the DBT period. | Drug: Cemdisiran<br>* Cemdisiran was administered by SC injection.<br>* Other names: ALN-CC5;|
| Placebo Comparator: DBT Period: Placebo<br>Participants received cemdisiran matching placebo, SC injection, Q4W in combination with standard of care treatment up to a maximum of 38 weeks in the DBT period. | Drug: Placebo<br>* Normal saline (0.9% NaCl) matching volume of cemdisiran doses were administered SC.<br>|
| Experimental: DBT Period: Cemdisiran to Open-Label Extension (OLE) Period: Cemdisiran<br>Participants who were randomized to receive cemdisiran in the DBT period continued receiving cemdisiran, 600 mg, SC injection, Q4W in combination with standard of care treatment up to a maximum of 88 weeks in the OLE treatment period. | Drug: Cemdisiran<br>* Cemdisiran was administered by SC injection.<br>* Other names: ALN-CC5;|
| Placebo Comparator: DBT Period: Placebo to OLE Period: Cemdisiran<br>Participants who were randomized to receive cemdisiran matching placebo in the DBT period started receiving cemdisiran, 600 mg, SC injection, Q4W in combination with standard of care treatment up to a maximum of 88 weeks in the OLE treatment period. | Drug: Cemdisiran<br>* Cemdisiran was administered by SC injection.<br>* Other names: ALN-CC5;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in UPCR as Measured in 24-hour Urine at Week 32 | UPCR is a way of assessing the amount of protein in the urine. The primary analysis for UPCR was performed using Mixed-Effect Model Repeated Measures (MMRM) approach. Geometric mean (GM)ratios were obtained by exponentially back-transforming the arithmetic mean of change in log-transformed 24h UPCR. Standard error of the mean (SEM) was calculated as exponential (mean of change in log-transformed data) * (standard error of change in log-transformed data). Adjusted GM ratio to baseline and 90% confidence interval (CIs) were calculated by exponentially back-transforming the model-based least square (LS) mean and the corresponding 90% CI. | Baseline to Week 32 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in 24-hour Proteinuria at Week 32 | Proteinuria is high levels of protein in the urine. 24-hour proteinuria assessment included 24-hour urine collections to assess total protein excretion per 24 hours. Analysis was performed using the MMRM model. GM ratios were obtained by exponentially back-transforming the arithmetic mean of change in log-transformed 24h urine protein (UP). SEM was calculated as exp (mean of change in log-transformed data) *(standard error of change in log-transformed data). Adjusted GM ratio to baseline and 90% CIs are calculated by exponentially back-transforming the model-based LS Means and the corresponding 90% CI. | Baseline to Week 32 | 
| Percentage of Participants With Partial Clinical Remission at Week 32 | Partial clinical remission was defined as having UP <1.0 g/24-hours. | Week 32 | 
| Percentage of Participants With >50% Reduction in 24-hour Proteinuria at Week 32 |  | Week 32 | 
| Change From Baseline in UPCR as Measured in a Spot Urine at Week 32 | UPCR was calculated by dividing the level of protein in a spot urine test by the creatinine level. Analysis was performed using MMRM model. GM ratios were obtained by exponentially back-transforming the arithmetic mean of change in log-transformed spot UPCR. SEM was calculated as exp (mean of change in log-transformed data) *(standard error of change in log-transformed data). Adjusted GM ratio to baseline and 90% CIs are calculated by exponentially back-transforming the model-based LS Means and the corresponding 90% CI. | Baseline to Week 32 | 
| Number of Participants With Change From Baseline in Hematuria at Week 32 | Hematuria is the presence of blood in the urine. Hematuria from spot urine collections was evaluated to assess the effect of cemdisiran on disease course in participants. The degree of hematuria was assessed by microscopic examination of the spun urine sediment (red blood cell (RBC)/ high power field [hpf]) and by urine dipstick. | Baseline to Week 32 | 
| Number of Participants With Adverse Events (AEs) | AE is any untoward medical occurrence in a participant or clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. | Baseline up to 240 weeks |