IgA Nephropathy
Conditions
Keywords
IgA nephropathy, IgAN, Proteinuria, Chronic kidney disease, IgAN autoantibodies, eGFR, EGFR slope, UPE, Narsoplimab
Brief summary
The primary objective of this study is to evaluate the effect of OMS721 on 24-hour urine protein excretion (UPE) in IgA nephropathy (IgAN) patients with high baseline proteinuria (high-risk proteinuria group; 24-hour UPE ≥ 2 g/day) assessed at 36 weeks from baseline.
Detailed description
This is a Phase 3, double-blind, randomized, placebo-controlled, study in patients aged 18 years and above with a biopsy-confirmed diagnosis of IgAN and with 24-hour UPE that is \> 1 g/day. The purpose of this study is to evaluate the efficacy and safety of narsoplimab (OMS721) compared to placebo on proteinuria and whether narsoplimab has the ability to slow disease progression in primary IgAN patients. The primary objective of the study is to evaluate proteinuria reduction as assessed by 24-hour UPE at 36 weeks from baseline. The trial will continue beyond 36 weeks in a blinded fashion to provide confirmatory evidence of long-term efficacy based on the annualized slope of eGFR over 24 months. The trial will enroll approximately 450 patients with 225 patients per arm, all having biopsy-proven IgAN with eGFR≥30 mL/min/1.73m\^2 and 24 hour UPE \>1g/day. The study duration for each patient is expected to last approximately 112 weeks.
Interventions
BIOLOGICALOMS721
Biological: OMS721
OTHERVehicle (D5W or saline)
5% Dextrose in water or normal saline solution
Sponsors
Omeros Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Eligible patients will be randomized 1:1 to receive OMS721 or placebo
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 years or older at the onset of Screening * Biopsy confirmed diagnosis of IgAN within 8 years prior to Screening or Run-in Visit 1 * Documented history of proteinuria of \> 1 g/day within 6 months prior to Screening or uPCR \> 0.75 by spot urine at Screening * Mean of two proteinuria measurements \> 1 g/day at baseline * Estimated glomerular filtration rate of ≥ 30 mL/min/1.73 m² at Screening and baseline
Exclusion criteria
* Treatment with immunosuppressants (e.g., azathioprine or cyclophosphamide), Chinese traditional medicine with immunosuppressive function, cytotoxic drugs, or eculizumab within 8 weeks prior to Screening, unless such treatment is given for indications other than IgA. * Treatment with systemic corticosteroids within 8 weeks prior to Screening * Uncontrolled BP, a systolic BP of \> 150 mmHg and a diastolic BP of \> 100 mmHg at rest despite the combination of two or more anti-hypertensives including ACE inhibitors, ARBs, or direct renin inhibitors * Female patients who are pregnant, breast feeding, or planning to become pregnant up through 12 weeks after the last dose of study drug, including possible retreatments. Males who are planning to father children up through 12 weeks after the last dose of study drug, including possible retreatments * Clinical or biological evidence of Type 1 diabetes mellitus (DM), or poorly controlled DM with hemoglobin A1c \> 7.5 or with evidence of diabetic nephropathy on biopsy, systemic lupus erythematosus, IgA vasculitis (Henoch-Schonlein purpura), secondary IgAN, or other renal disease during Screening and Run-In * Presence of significant morbidity or other major illness or disease that may confound the interpretation of the clinical trial results or may result in death within 2 years of Screening * History of renal transplantation * Have a known hypersensitivity to any constituent of the investigational product * Rapidly progressive glomerulonephritis, defined as a fall in eGFR of \> 30 mL/min/1.73 m\^2 within 24 weeks or \> 15 mL/min/1.73 m\^2 within 12 weeks prior to Screening * Significant abnormalities in clinical laboratory values * History of human immunodeficiency virus (HIV), evidence of immune suppression, active hepatitis C virus (HCV) infection (patients with positive anti-HCV antibody but a non-detected HCV RNA PCR can enroll), hepatitis B virus (HBV) infection (patients with positive HBsAg are excluded; for patients with isolated positive anti-HBc antibody, HBV DNA test by PCR must be non-detectable to enroll). * Diagnosis of a malignancy except for adequately treated and cured basal or squamous cell skin cancer, curatively treated in situ disease, or other cancer from which the patient has been disease-free for ≥ 5 years * Have received any other investigational drug or device or experimental procedures within 30 days of the Screening Visit (SV) or within 5 times the plasma half-life of the administered experimental drug, whichever is longer * Initiation or change in dosing of sodium glucose co-transporter 2 inhibitors (SGLT2i) during Screening and Run-In Periods. However, a stable dose regimen established at least 8 weeks prior to screening is acceptable * Treatment with Tarpeyo™ (budesonide) or other approved treatments for IgAN within 6 months prior to screening. Treatment with Tarpeyo is not allowed during Screening and Run-In Periods * Treatment with Kerendia® (finerenone) within 6 months prior to screening. Treatment with Kerendia is not allowed during Screening and Run-In Periods * Initiation of treatment with Filspari™ (sparsentan), a dual Endothelin Angiotensin Receptor Antagonist (dEARA) or similar medication within three months prior to screening. A stable dose initiated at minimum 3 months before screening is acceptable and will take the place of ACEi/ARB as background therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in 24-hour UPE in g/Day Compared to Baseline | 36 Weeks | The Primary Endpoint of this Study is the Percent Change from Baseline in Log-transformed 24-hour UPE in g/Day at 36 Weeks in Patients with High Baseline Proteinuria (High-risk Proteinuria Group; 24-hour UPE ≥ 2 g/day. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Annualized eGFR Compared to Baseline. | 96 Weeks | The Rate of Change in eGFR up to 96 Weeks from Baseline in Patients with High Baseline Proteinuria (High-risk Proteinuria Group; 24-hour UPE ≥ 2 g/Day) |
| Change in Annualized eGFR Compared to Baseline in All Patients. | 96 Weeks | The Rate of Change in eGFR up to 96 Weeks from Baseline in the All-patients Population (24-hour UPE \> 1 g/Day) |
| Change in 24-hour UPE in g/Day Compared to Baseline in All Patients | 36 Weeks | Change From Baseline in Log-transformed 24-hour UPE at Week 36 in the All-patients Population. (24-hour UPE \> 1 g/Day) |
| Change in 24-hour UPE in g/Day Between 36 Weeks and 72 Weeks in All Patients | 36 weeks and 72 weeks | Time-averaged Change from Baseline in the Log-transformed 24-hour UPE between 36 Weeks and 72 Weeks in the All-patients Population |
| Change in 24-hour UPE in g/Day Between 36 Weeks and 72 Weeks in Patients With >= 2 g/Day UPE at Baseline (High-risk Proteinuria Group). | 36 weeks and 72 weeks | Time-averaged Change from Baseline in the Log-transformed 24-hour UPE Between 36 Weeks and 72 Weeks in Patients with ≥ 2 g/Day UPE at Baseline (High-risk Proteinuria Group) |
| Change in 24-hour UPE in g/Day Between 36 Weeks and 48 Weeks in All Patients | 36 weeks and 48 weeks | Time-averaged Change from Baseline in the Log-transformed 24-hour UPE Between 36 Weeks and 48 Weeks in the All-patients Population |
| Safety and Tolerability of Narsoplimab for the Treatment of IgAN as Assessed by AEs, Vital Signs, Clinical Laboratory Tests, and ECGs | Week 112 | As assessed by the incidence of adverse events through study completion (Week 112) in the patient group in the all-patients population. Clinically meaningful abnormalities in vital signs, clinical laboratory tests, and ECGs were collected as AEs. |
| Change in 24-hour UPE in g/Day Between 36 Weeks and 48 Weeks. | 36 weeks and 48 weeks | Change From Baseline in the Log-transformed 24-hour UPE Between 36 Weeks and 48 Weeks in Patients With ≥ 2 g/Day UPE at Baseline (High-risk Proteinuria Group) |
Countries
Argentina, Australia, Belgium, Bulgaria, Canada, Czechia, Germany, Greece, Hungary, India, Italy, Lithuania, Poland, Singapore, Slovakia, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Pre-assignment details
Patients with 24-hour UPE \> 2 g/day at baseline will be allowed to receive 12-weeks of open-label active drug (OMS721) on Week 72 (18 months post randomization), provided they meet certain criteria: * Less than 30% reduction in UPE at the OL assessment visit from baseline UPE * Proteinuria is ≥ 3.0 g/day at 72 weeks from randomization, confirmed by 2 measurements at least 2 weeks apart, but \< 3 weeks * Worsening renal function, defined as a decline in eGFR of \> 5 mL/min/m\^2 from baseline
Participants by arm
| Arm | Count |
|---|---|
| OMS721 Administration of OMS721
OMS721: Biological: OMS721 | 181 |
| Placebo Administration of Vehicle (D5W or Saline Solution)
Vehicle (D5W or saline): 5% Dextrose in water or normal saline solution | 179 |
| Total | 360 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Open-Label Period: OMS721 | Adverse Event | 1 | 0 |
| Open-Label Period: OMS721 | Lack of Efficacy | 1 | 0 |
| Open-Label Period: OMS721 | Lost to Follow-up | 1 | 0 |
| Open-Label Period: OMS721 | Study Terminated By Sponsor | 11 | 0 |
| Open-Label Period: OMS721 | Withdrawal by Subject | 5 | 0 |
| Treatment Period | Adverse Event | 1 | 5 |
| Treatment Period | Death | 0 | 1 |
| Treatment Period | Lack of Efficacy | 4 | 3 |
| Treatment Period | Lost to Follow-up | 2 | 6 |
| Treatment Period | Physician Decision | 6 | 10 |
| Treatment Period | Pregnancy | 1 | 0 |
| Treatment Period | Protocol Violation | 1 | 2 |
| Treatment Period | Site Terminated by Sponsor | 1 | 0 |
| Treatment Period | Study terminated by sponsor | 82 | 68 |
| Treatment Period | Withdrawal by Subject | 46 | 45 |
Baseline characteristics
| Characteristic | OMS721 | Total | Placebo |
|---|---|---|---|
| Age, Continuous Mean (SD) | 40.7 years STANDARD_DEVIATION 12.01 | 41.2 years STANDARD_DEVIATION 12.38 | 41.6 years STANDARD_DEVIATION 12.76 |
| Baseline BMI (kg/m^2) | 28.3 kg/m^2 STANDARD_DEVIATION 6.51 | 28.1 kg/m^2 STANDARD_DEVIATION 6.69 | 27.8 kg/m^2 STANDARD_DEVIATION 6.87 |
| Baseline Diastolic Blood Pressure (mmHG) | 78.3 mmHg STANDARD_DEVIATION 8.3 | 78.1 mmHg STANDARD_DEVIATION 8.72 | 77.8 mmHg STANDARD_DEVIATION 9.15 |
| Baseline Estimated Glomerular Filtration Rate (mL/min/SSA), n(%) Greater than 45 | 116 participants | 233 participants | 117 participants |
| Baseline Estimated Glomerular Filtration Rate (mL/min/SSA), n(%) Greater than or equal to 30 and Less than or equal to 45 | 63 participants | 125 participants | 62 participants |
| Baseline Height (cm) | 170.8 cm STANDARD_DEVIATION 9.39 | 171.4 cm STANDARD_DEVIATION 9.75 | 171.9 cm STANDARD_DEVIATION 10.1 |
| Baseline Systolic Blood Pressure (mmHG) | 125.7 mmHg STANDARD_DEVIATION 10.13 | 125.3 mmHg STANDARD_DEVIATION 11.11 | 124.8 mmHg STANDARD_DEVIATION 12.03 |
| Baseline Urine Protein Creatinine Ratio | 2.0 (g/g) STANDARD_DEVIATION 1.21 | 2.1 (g/g) STANDARD_DEVIATION 1.2 | 2.1 (g/g) STANDARD_DEVIATION 1.19 |
| Baseline Urine Protein Excretion Rate (mg/24hrs) | 2780.5 mg/24hrs STANDARD_DEVIATION 1633.49 | 2824.9 mg/24hrs STANDARD_DEVIATION 1717.98 | 2869.3 mg/24hrs STANDARD_DEVIATION 1802 |
| Baseline Weight (kg) | 82.7 kg STANDARD_DEVIATION 19.95 | 82.6 kg STANDARD_DEVIATION 21.17 | 82.5 kg STANDARD_DEVIATION 22.39 |
| Child Bearing Potential, n (%) No | 18 participants | 34 participants | 16 participants |
| Child Bearing Potential, n (%) Not Applicable (Male Subjects) | 114 participants | 232 participants | 118 participants |
| Child Bearing Potential, n (%) Yes | 49 participants | 94 participants | 45 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 22 Participants | 33 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 157 Participants | 323 Participants | 166 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 52 Participants | 114 Participants | 62 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) White | 120 Participants | 232 Participants | 112 Participants |
| Sex: Female, Male Female | 67 Participants | 128 Participants | 61 Participants |
| Sex: Female, Male Male | 114 Participants | 232 Participants | 118 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 181 | 1 / 179 | 0 / 34 |
| other Total, other adverse events | 137 / 181 | 121 / 179 | 25 / 34 |
| serious Total, serious adverse events | 22 / 181 | 20 / 179 | 7 / 34 |
Outcome results
Primary
Percent Change in 24-hour UPE in g/Day Compared to Baseline
The Primary Endpoint of this Study is the Percent Change from Baseline in Log-transformed 24-hour UPE in g/Day at 36 Weeks in Patients with High Baseline Proteinuria (High-risk Proteinuria Group; 24-hour UPE ≥ 2 g/day.
Time frame: 36 Weeks
Population: The prespecified Primary Interim Analysis was in patients who had a 24-hour UPE ≥ 2 g/day at baseline. The study was terminated after the Primary Analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OMS721 | Percent Change in 24-hour UPE in g/Day Compared to Baseline | -21.3 Percent Change | Standard Error 0.0672 |
| Placebo | Percent Change in 24-hour UPE in g/Day Compared to Baseline | -16.6 Percent Change | Standard Error 0.068 |
Secondary
Change in 24-hour UPE in g/Day Between 36 Weeks and 48 Weeks.
Change From Baseline in the Log-transformed 24-hour UPE Between 36 Weeks and 48 Weeks in Patients With ≥ 2 g/Day UPE at Baseline (High-risk Proteinuria Group)
Time frame: 36 weeks and 48 weeks
Population: Outcome measure data for this secondary outcome measure are available for a subset of 131 of the 180 participants (66 OMS721 and 65 placebo). These data are presented. Because the data collected up to the time of study termination for this outcome measure are incomplete, reliance on the data could provide inaccurate and/or misleading information.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OMS721 | Change in 24-hour UPE in g/Day Between 36 Weeks and 48 Weeks. | 4.1 g/24hr | Standard Deviation 0.5 |
| Placebo | Change in 24-hour UPE in g/Day Between 36 Weeks and 48 Weeks. | 4.4 g/24hr | Standard Deviation 0.6 |
Secondary
Change in 24-hour UPE in g/Day Between 36 Weeks and 48 Weeks in All Patients
Time-averaged Change from Baseline in the Log-transformed 24-hour UPE Between 36 Weeks and 48 Weeks in the All-patients Population
Time frame: 36 weeks and 48 weeks
Population: Outcome measure data for this secondary outcome measure are available for a subset of 229 of the 360 participants (118 OMS721 and 111 placebo). These data are presented. Because the data collected up to the time of study termination for this outcome measure are incomplete, reliance on the data could provide inaccurate and/or misleading information.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OMS721 | Change in 24-hour UPE in g/Day Between 36 Weeks and 48 Weeks in All Patients | 6.2 g/24hr | Standard Deviation 0.5 |
| Placebo | Change in 24-hour UPE in g/Day Between 36 Weeks and 48 Weeks in All Patients | 3.5 g/24hr | Standard Deviation 0.6 |
Secondary
Change in 24-hour UPE in g/Day Between 36 Weeks and 72 Weeks in All Patients
Time-averaged Change from Baseline in the Log-transformed 24-hour UPE between 36 Weeks and 72 Weeks in the All-patients Population
Time frame: 36 weeks and 72 weeks
Population: Outcome measure data for this secondary outcome measure are available for a subset of 203 of the 360 participants (103 OMS721 and 100 placebo). These data are presented. Because the data collected up to the time of study termination for this outcome measure are incomplete, reliance on the data could provide inaccurate and/or misleading information.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OMS721 | Change in 24-hour UPE in g/Day Between 36 Weeks and 72 Weeks in All Patients | 10.9 g/24hr | Standard Deviation 0.7 |
| Placebo | Change in 24-hour UPE in g/Day Between 36 Weeks and 72 Weeks in All Patients | 14.2 g/24hr | Standard Deviation 0.8 |
Secondary
Change in 24-hour UPE in g/Day Between 36 Weeks and 72 Weeks in Patients With >= 2 g/Day UPE at Baseline (High-risk Proteinuria Group).
Time-averaged Change from Baseline in the Log-transformed 24-hour UPE Between 36 Weeks and 72 Weeks in Patients with ≥ 2 g/Day UPE at Baseline (High-risk Proteinuria Group)
Time frame: 36 weeks and 72 weeks
Population: Outcome measure data for this secondary outcome measure are available for a subset of 121 of the 180 participants (60 OMS721 and 61 placebo). These data are presented. Because the data collected up to the time of study termination for this outcome measure are incomplete, reliance on the data could provide inaccurate and/or misleading information.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OMS721 | Change in 24-hour UPE in g/Day Between 36 Weeks and 72 Weeks in Patients With >= 2 g/Day UPE at Baseline (High-risk Proteinuria Group). | 11.6 g/24hr | Standard Deviation 0.7 |
| Placebo | Change in 24-hour UPE in g/Day Between 36 Weeks and 72 Weeks in Patients With >= 2 g/Day UPE at Baseline (High-risk Proteinuria Group). | 7.5 g/24hr | Standard Deviation 0.8 |
Secondary
Change in 24-hour UPE in g/Day Compared to Baseline in All Patients
Change From Baseline in Log-transformed 24-hour UPE at Week 36 in the All-patients Population. (24-hour UPE \> 1 g/Day)
Time frame: 36 Weeks
Population: Outcome data for this secondary outcome measure are available for a subset of 260 of the 360 participants (132 OMS721 and 128 placebo). These data are presented. Because the data collected up to the time of study termination for this outcome measure are incomplete, reliance on these measures could provide inaccurate and/or misleading information.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OMS721 | Change in 24-hour UPE in g/Day Compared to Baseline in All Patients | -14.2 g/ 24hrs | Standard Deviation 0.7 |
| Placebo | Change in 24-hour UPE in g/Day Compared to Baseline in All Patients | -10.3 g/ 24hrs | Standard Deviation 0.6 |
Secondary
Change in Annualized eGFR Compared to Baseline.
The Rate of Change in eGFR up to 96 Weeks from Baseline in Patients with High Baseline Proteinuria (High-risk Proteinuria Group; 24-hour UPE ≥ 2 g/Day)
Time frame: 96 Weeks
Population: The prespecified secondary outcome analysis was in patients who had a 24-hour UPE ≥ 2 g/day at baseline. Since the study was terminated early, not all patients reached week 96, therefore the last observation was carried forward for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OMS721 | Change in Annualized eGFR Compared to Baseline. | -8.3 mL/min/1.73 m²/year | Standard Deviation 0.9 |
| Placebo | Change in Annualized eGFR Compared to Baseline. | -7.9 mL/min/1.73 m²/year | Standard Deviation 0.9 |
Secondary
Change in Annualized eGFR Compared to Baseline in All Patients.
The Rate of Change in eGFR up to 96 Weeks from Baseline in the All-patients Population (24-hour UPE \> 1 g/Day)
Time frame: 96 Weeks
Population: The prespecified secondary outcome analysis was in patients who had a 24-hour UPE \> 1 g/day at baseline. Since the study was terminated early, not all patients reached week 96, therefore the last observation was carried forward for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OMS721 | Change in Annualized eGFR Compared to Baseline in All Patients. | -6.4 mL/min/1.73 m²/year | Standard Deviation 0.7 |
| Placebo | Change in Annualized eGFR Compared to Baseline in All Patients. | -7.6 mL/min/1.73 m²/year | Standard Deviation 0.7 |
Secondary
Safety and Tolerability of Narsoplimab for the Treatment of IgAN as Assessed by AEs, Vital Signs, Clinical Laboratory Tests, and ECGs
As assessed by the incidence of adverse events through study completion (Week 112) in the patient group in the all-patients population. Clinically meaningful abnormalities in vital signs, clinical laboratory tests, and ECGs were collected as AEs.
Time frame: Week 112
Population: Any patient who received study drug (N=360)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OMS721 | Safety and Tolerability of Narsoplimab for the Treatment of IgAN as Assessed by AEs, Vital Signs, Clinical Laboratory Tests, and ECGs | 181 Participants |
| Placebo | Safety and Tolerability of Narsoplimab for the Treatment of IgAN as Assessed by AEs, Vital Signs, Clinical Laboratory Tests, and ECGs | 179 Participants |