IgA Nephropathy (IgAN), Berger Disease, Glomerulonephritis, IgA
Conditions
Brief summary
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.
Interventions
DRUGPlacebo
Normal saline (0.9% NaCl) matching volume of cemdisiran doses were administered SC.
DRUGCemdisiran
Cemdisiran was administered by SC injection.
Sponsors
Alnylam Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in UPCR as Measured in 24-hour Urine at Week 32 | Baseline to 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Partial Clinical Remission at Week 32 | Week 32 | Partial clinical remission was defined as having UP \<1.0 g/24-hours. |
| Percentage of Participants With >50% Reduction in 24-hour Proteinuria at Week 32 | Week 32 | — |
| Percent Change From Baseline in 24-hour Proteinuria at Week 32 | Baseline to 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. |
| Number of Participants With Change From Baseline in Hematuria at Week 32 | Baseline to 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. |
| Number of Participants With Adverse Events (AEs) | Up to 126 weeks | An 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. |
| Change From Baseline in UPCR as Measured in a Spot Urine at Week 32 | Baseline to 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. |
Countries
Canada, France, Malaysia, Philippines, Singapore, Spain, Sweden, Taiwan, United Kingdom
Participant flow
Recruitment details
Participants were enrolled in the study at 19 investigative centers in Canada, France, Malaysia, Philippines, Singapore, Spain, Sweden, Taiwan, and the United Kingdom from 30 Sept 2019 to 27 June 2023.
Pre-assignment details
A total of 31 participants were enrolled in this study to receive cemdisiran or placebo. This study has two parts: Double Blind Treatment (DBT) Period and Open-Label Extension (OLE) Period.
Participants by arm
| Arm | Count |
|---|---|
| DBT Period: Placebo 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. | 9 |
| DBT Period: Cemdisiran Participants received cemdisiran, 600 mg, SC injection, Q4W in combination with standard of care treatment up to a maximum of 38 weeks in the DBT period. | 22 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-blind Treatment (DBT) Period | Death | 1 | 1 | 0 | 0 |
| Open-Label Extension (OLE) Period | Adverse Event | 0 | 0 | 1 | 2 |
| Open-Label Extension (OLE) Period | Death | 0 | 0 | 0 | 1 |
| Open-Label Extension (OLE) Period | Other Reason Not Specified | 0 | 0 | 2 | 5 |
| Open-Label Extension (OLE) Period | Physician Decision | 0 | 0 | 1 | 3 |
| Open-Label Extension (OLE) Period | Study termination by Sponsor | 0 | 0 | 4 | 9 |
Baseline characteristics
| Characteristic | DBT Period: Placebo | DBT Period: Cemdisiran | Total |
|---|---|---|---|
| Age, Continuous | 37.6 years STANDARD_DEVIATION 10.4 | 40.5 years STANDARD_DEVIATION 10.1 | 39.7 years STANDARD_DEVIATION 10.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 18 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 12 Participants | 16 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 8 Participants | 12 Participants |
| Sex: Female, Male Female | 6 Participants | 9 Participants | 15 Participants |
| Sex: Female, Male Male | 3 Participants | 13 Participants | 16 Participants |
| Urine Protein to Creatinine Ratio | 1.972 g/g STANDARD_DEVIATION 0.815 | 1.554 g/g STANDARD_DEVIATION 1.032 | 1.676 g/g STANDARD_DEVIATION 0.979 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 9 | 1 / 22 | 0 / 8 | 1 / 22 | 2 / 30 |
| other Total, other adverse events | 8 / 9 | 19 / 22 | 8 / 8 | 22 / 22 | 30 / 30 |
| serious Total, serious adverse events | 0 / 9 | 1 / 22 | 3 / 8 | 2 / 22 | 5 / 30 |
Outcome results
Primary
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.
Time frame: Baseline to Week 32
Population: mITT Analysis Set included all participants who received any amount of study drug and had at least one post baseline 24-hour UPCR assessment. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DBT Period: Placebo | Percent Change From Baseline in UPCR as Measured in 24-hour Urine at Week 32 | 1.095 percent change | Standard Error 0.258 |
| DBT Period: Cemdisiran | Percent Change From Baseline in UPCR as Measured in 24-hour Urine at Week 32 | 0.686 percent change | Standard Error 0.098 |
p-value: 0.103290% CI: [-60.951, 0.46]MMRM
Secondary
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.
Time frame: Baseline to Week 32
Population: mITT Analysis Set included all participants who received any amount of study drug and had at least one post baseline 24-hour UPCR assessment. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DBT Period: Placebo | Change From Baseline in UPCR as Measured in a Spot Urine at Week 32 | 1.344 gram per gram (g/g) | Standard Error 0.139 |
| DBT Period: Cemdisiran | Change From Baseline in UPCR as Measured in a Spot Urine at Week 32 | 0.729 gram per gram (g/g) | Standard Error 0.109 |
p-value: 0.002190% CI: [-60.093, -26.309]MMRM
Secondary
Number of Participants With Adverse Events (AEs)
An 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.
Time frame: Up to 126 weeks
Population: DBT Period: Safety Analysis Set: All participants who received any amount of study drug.~DBT + OLE and All Cemdisiran: All Cemdisiran Treated Set: All participants who received at least one dose of cemdisiran, including participants who received cemdisiran during the DB Period and participants who first take placebo during the DB Period and switch to cemdisiran during the OLE Period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DBT Period: Placebo | Number of Participants With Adverse Events (AEs) | 8 Participants |
| DBT Period: Cemdisiran | Number of Participants With Adverse Events (AEs) | 19 Participants |
| DBT Period: Placebo + OLE Period: Cemdisiran | Number of Participants With Adverse Events (AEs) | 8 Participants |
| DBT Period: Cemdisiran + OLE Period: Cemdisiran | Number of Participants With Adverse Events (AEs) | 22 Participants |
| All Cemdisiran | Number of Participants With Adverse Events (AEs) | 30 Participants |
Secondary
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.
Time frame: Baseline to Week 32
Population: mITT Analysis Set included all participants who received any amount of study drug and had at least one post-baseline 24-hour UPCR assessment. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DBT Period: Placebo | Number of Participants With Change From Baseline in Hematuria at Week 32 | Post-Baseline Category: Negative | 0 Participants |
| DBT Period: Placebo | Number of Participants With Change From Baseline in Hematuria at Week 32 | Post-Baseline Category: Small | 2 Participants |
| DBT Period: Placebo | Number of Participants With Change From Baseline in Hematuria at Week 32 | Post-Baseline Category: Moderate | 2 Participants |
| DBT Period: Placebo | Number of Participants With Change From Baseline in Hematuria at Week 32 | Post-Baseline Category: Large | 4 Participants |
| DBT Period: Cemdisiran | Number of Participants With Change From Baseline in Hematuria at Week 32 | Post-Baseline Category: Large | 1 Participants |
| DBT Period: Cemdisiran | Number of Participants With Change From Baseline in Hematuria at Week 32 | Post-Baseline Category: Negative | 4 Participants |
| DBT Period: Cemdisiran | Number of Participants With Change From Baseline in Hematuria at Week 32 | Post-Baseline Category: Moderate | 4 Participants |
| DBT Period: Cemdisiran | Number of Participants With Change From Baseline in Hematuria at Week 32 | Post-Baseline Category: Small | 11 Participants |
Secondary
Percentage of Participants With >50% Reduction in 24-hour Proteinuria at Week 32
Time frame: Week 32
Population: mITT Analysis Set included all participants who received any amount of study drug and had at least one post baseline 24-hour UPCR assessment. Percentages are rounded off to the nearest decimal point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DBT Period: Placebo | Percentage of Participants With >50% Reduction in 24-hour Proteinuria at Week 32 | 0 percentage of participants |
| DBT Period: Cemdisiran | Percentage of Participants With >50% Reduction in 24-hour Proteinuria at Week 32 | 22.7 percentage of participants |
p-value: 0.153390% CI: [0.45, 20.34]Cochran-Mantel-Haenszel
90% CI: [-0.13, 0.42]
Secondary
Percentage of Participants With Partial Clinical Remission at Week 32
Partial clinical remission was defined as having UP \<1.0 g/24-hours.
Time frame: Week 32
Population: mITT Analysis Set included all participants who received any amount of study drug and had at least one post baseline 24-hour UPCR assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DBT Period: Placebo | Percentage of Participants With Partial Clinical Remission at Week 32 | 0 percentage of participants |
| DBT Period: Cemdisiran | Percentage of Participants With Partial Clinical Remission at Week 32 | 22.7 percentage of participants |
p-value: 0.117790% CI: [0.43, 21.27]Cochran-Mantel-Haenszel
90% CI: [-0.13, 0.42]
Secondary
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.
Time frame: Baseline to Week 32
Population: mITT Analysis Set included all participants who received any amount of study drug and had at least one post baseline 24-hour UPCR assessment. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DBT Period: Placebo | Percent Change From Baseline in 24-hour Proteinuria at Week 32 | 1.051 percent change | Standard Error 0.266 |
| DBT Period: Cemdisiran | Percent Change From Baseline in 24-hour Proteinuria at Week 32 | 0.671 percent change | Standard Error 0.104 |
p-value: 0.143290% CI: [-61.552, 5.978]MMRM