Lupus Nephritis, Immunoglobulin A Nephropathy
Conditions
Keywords
glomerulonephritis, IGA, lupus nephritis, complement C5
Brief summary
The objectives of this study are to evaluate the safety and efficacy of ravulizumab administered by intravenous (IV) infusion compared to placebo and demonstrate proof-of-concept of the efficacy of terminal complement inhibition in participants with LN (LN Cohort) or IgAN (IgAN Cohort).
Detailed description
This study consists of a 6-week Screening Period, 26-week Initial Evaluation Period, a 24-week Extension Period, and a 36-week post-treatment Follow-up Period.
Interventions
DRUGRavulizumab
Dosages (loading and maintenance) will be based on the participant's body weight.
DRUGPlacebo
Dosages (loading and maintenance) will be based on the participant's body weight.
OTHERBackground Therapy
Participants will receive background therapy consistent with the standard of care.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Participants, all investigative site personnel, and any Alexion employee, or designee, directly associated with the conduct of the study will be blinded to participant treatment assignments during the 26-week Initial Evaluation Period. Both the participants and the investigative site personnel will remain blinded for the remaining 24-week Extension Period.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Common to both disease cohorts: * Proteinuria ≥1 (gram \[g\]/day or g/g) * Vaccinated against meningococcal infection * Vaccinated for Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae according to national/local regulatory requirements For LN cohort: * Diagnosis of active focal or diffuse proliferative LN Class III or IV * Clinically active LN, requiring/receiving immunosuppression induction treatment For IgAN cohort: * Diagnosis of primary IgAN * Compliance with stable and optimal dose of renin-angiotensin system inhibitor treatment for ≥ 3 months
Exclusion criteria
Common to both disease cohorts: * eGFR \< 30 milliliters/minute/1.73 meters squared * Previously received a complement inhibitor (for example, eculizumab) * Concomitant significant renal disease other than LN or IgAN * History of other solid organ or bone marrow transplant * Uncontrolled hypertension For IgAN cohort: * Diagnosis of rapid progressive glomerulonephritis * Prednisone or prednisone equivalent \> 20 milligram (mg) per day for \> 14 consecutive days or any other immunosuppression within 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| IgAN Cohort: Percentage Change From Baseline in Proteinuria at Week 26 Measured by Absolute Protein (Based on 24-hour Urine Collections) | Baseline, Week 26 | Proteinuria, the presence of excess proteins in the urine, was measured by absolute protein in grams/day derived from 24-hour urine collections obtained at designated timepoints. A negative change from baseline indicated a reduction in symptoms. |
| LN Cohort: Percentage Change From Baseline in Proteinuria at Week 26 Measured by Urine Protein to Creatinine Ratio (UPCR) (Based on 24-hour Urine Collections) | Baseline, Week 26 | Proteinuria, the presence of excess proteins in the urine, was measured by UPCR in grams/gram derived from 24-hour urine collections obtained at designated timepoints. A negative change from baseline indicated a reduction in symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| IgAN Cohort: Percentage Change From Baseline in Proteinuria at Week 50 Measured by Absolute Protein (Based on 24-hour Urine Collections) | Baseline, Week 50 | Proteinuria, the presence of excess proteins in the urine, was measured by absolute protein in grams/day derived from 24-hour urine collections obtained at designated timepoints. A negative change from baseline indicated a reduction in symptoms. |
| LN Cohort: Percentage Change From Baseline in Proteinuria at Week 50 Measured by UPCR (Based on 24-hour Urine Collections) | Baseline, Week 50 | Proteinuria, the presence of excess proteins in the urine, was measured by UPCR in grams/gram derived from 24-hour urine collections obtained at designated timepoints. A negative change from baseline indicated a reduction in symptoms. |
| IgAN Cohort: Percentage of Participants With > 30% and > 50% Reduction in Proteinuria at Week 26 and Week 50 Compared to Baseline Assessed Using 24-hour Urine Collections | Baseline to Week 26 and Week 50 | Proteinuria, the presence of excess proteins in the urine, was measured by absolute protein in grams/day derived from 24-hour urine collections obtained at designated timepoints. |
| LN Cohort: Percentage of Participants With > 30% and > 50% Reduction in Proteinuria at Week 26 and Week 50 Compared to Baseline Assessed Using 24-hour Urine Collections | Baseline to Week 26 and Week 50 | Proteinuria, the presence of excess proteins in the urine, was measured by UPCR in grams/gram derived from 24-hour urine collections obtained at designated timepoints. |
| IgAN Cohort: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 26 and Week 50 | Baseline, Week 26 and Week 50 | Changes in kidney function were monitored using measurements of eGFR and calculated based on the Chronic Kidney Disease Epidemiology Collaboration formula. Results are reported in milliliters/minute/1.73 meters squared (mL/min/1.73 m\^2). Estimates of change from baseline are least-square means based on a mixed-effect model for repeated measures model that included change from baseline as the response variable, treatment as independent variable and adjusts for covariates of baseline and the stratification factor at randomization. An increase in eGFR in response to treatment indicated a reduction in symptoms. |
| LN Cohort: Change From Baseline in eGFR at Week 26 and Week 50 | Baseline, Week 26 and Week 50 | Changes in kidney function were monitored using measurements of eGFR and calculated based on the Chronic Kidney Disease Epidemiology Collaboration formula. Results are reported in mL/min/1.73 m\^2. Estimates of change from baseline are least-square means based on a mixed-effect model for repeated measures model that included change from baseline as the response variable, treatment as independent variable and adjusts for covariates of baseline and the stratification factor at randomization. An increase in eGFR in response to treatment indicated a reduction in symptoms. |
| IgAN Cohort: Change From Baseline in Serum Complement Component 3 (C3) and Complement Component 4 (C4) Concentrations at Week 26 and Week 50 | Baseline, Week 26 and Week 50 | — |
| LN Cohort: Change From Baseline in Serum C3 and C4 Concentrations at Week 26 and Week 50 | Baseline, Week 26 and Week 50 | — |
| LN Cohort: Percentage of Participants Meeting the Criteria for Complete Renal Response (CRR) | Week 26 and Week 50 | The CRR was defined as meeting all 3 of the following criteria: - UPCR ≤0.5 gram/gram (g/g); - eGFR \>60 mL/min/1.73 m\^2 or no eGFR reduction ≥20% from baseline; and - no treatment failure. Treatment failure was defined as the receipt of additional standard of care therapy at any time during the study for protocol-defined renal flare, severe extrarenal systemic lupus erythematosus (SLE) flare, or suboptimal response. |
| LN Cohort: Percentage of Participants Meeting the Criteria for Partial Renal Response (PRR) | Week 26 and Week 50 | The PRR was defined as meeting all 3 of the following criteria: - decrease of UPCR \>50% from baseline; - eGFR \>60 mL/min/1.73 m\^2 or no eGFR reduction ≥20% from baseline; and - no treatment failure. Treatment failure was defined as the receipt of additional standard of care therapy at any time during the study for protocol-defined renal flare, severe extrarenal SLE flare, or suboptimal response. |
| LN Cohort: Time to Urine Protein to Creatinine Ratio (UPCR) < 0.5 g/g, as Measured by Spot Urine Samples | Baseline through Week 50 | — |
| LN Cohort: Percentage of Participants Achieving Corticosteroid Taper to 7.5 Milligrams (mg)/Day | Week 14, Week 26, and Week 50 | A corticosteroid taper was carried out per protocol at the clinical discretion of the investigator. |
| LN Cohort: Percentage of Participants With Renal Flare | Baseline through Week 50 | Renal flare was determined in the opinion of the investigator and additional protocol-specified criteria. For participants who achieved a CRR, a renal flare was the reproducible recurrence of proteinuria ≥1g/g. For all other participants, a renal flare was either of the following: a reproducible increase of serum creatinine \>25% higher than baseline, above the upper limit of normal (plus additional protocol-specified criteria), or a reproducible doubling of the UPCR from a 24-hour urine collection compared with the lowest previous value obtained after the first dose of study intervention. |
| LN Cohort: Percentage of Participants With Extrarenal Systemic Lupus Erythematosus (SLE) Flare | Baseline through Week 50 | Extrarenal SLE flare was defined as an increase in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) Safety of Estrogens in Lupus Erythematosus National Assessment modification ≥4 points that was not accounted for by proteinuria, hematuria, urinary cellular casts, hypocomplementemia, or an increase in anti-double-stranded DNA antibody level. The SLEDAI-2K is an instrument that was used to assess the disease activity of extrarenal SLE flare across 18 disease descriptors. Each descriptor carried a weighted value ranging from 1-8, with the reported score calculated as the sum of these descriptors and ranging from 0 to 85. Higher scores represent increased degrees of disease activity. |
| LN Cohort: Percentage of Participants With Treatment Failure | Baseline through Week 50 | Treatment failure was defined as the receipt of additional standard of care therapy at any time during the study for protocol-defined renal flare, severe extrarenal SLE flare, or suboptimal response. |
| LN Cohort: Percentage of Participants With Suboptimal Response | Baseline through Week 50 | A suboptimal response was to be determined in the opinion of the investigator in addition to the following criterion: reproducible proteinuria ≤25% decreased compared to baseline based on UPCR on a 24-hour urine collection performed by a central laboratory. |
| LN Cohort: Change From Baseline in Serum Albumin at Week 26 and Week 50 | Baseline, Week 26, Week 50 | For the determination of serum albumin, blood samples were obtained at designated time points. |
| IgAN Cohort: Percentage of Participants Meeting the Criteria for Partial Remission | Week 26 and Week 50 | Partial remission was defined as mean proteinuria \<1 g/24 hours, based on two valid 24-hour urine collections obtained within 2 weeks prior to the study visit. |
Countries
Australia, Canada, France, Germany, Italy, Netherlands, Poland, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
For the lupus nephritis (LN) cohort, a total of 57 participants were enrolled in the study and randomized. For the immunoglobulin A nephropathy (IgAN) cohort, a total of 66 participants were enrolled in the study and randomized.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 121 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race/Ethnicity, Customized Race Asian | 35 Participants |
| Race/Ethnicity, Customized Race Asian, White | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race/Ethnicity, Customized Race Not Reported | 1 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants |
| Race/Ethnicity, Customized Race Unknown | 0 Participants |
| Race/Ethnicity, Customized Race White | 5 Participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 19 | 0 / 43 | 0 / 23 | 0 / 36 | 0 / 18 | 0 / 42 | 0 / 23 |
| other Total, other adverse events | 28 / 38 | 15 / 19 | 17 / 43 | 9 / 23 | 14 / 36 | 16 / 18 | 11 / 42 | 2 / 23 |
| serious Total, serious adverse events | 6 / 38 | 2 / 19 | 1 / 43 | 0 / 23 | 6 / 36 | 2 / 18 | 0 / 42 | 0 / 23 |
Outcome results
None listed