NCT05097989 - Study of ALXN2050 in Proliferative Lupus Nephritis (LN) or Immunoglobulin A Nephropathy (IgAN) | Crick

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: Both Cohorts * Participants on sodium-glucose cotransporter-2 (SGLT 2) inhibitors (eg, empagliflozin) must be on a stable dose for ≥ 3 months with no planned change in dose during the Blinded Treatment Periods (through Week 50). LN Cohort * Clinical diagnosis of SLE by 2019 American College of Rheumatology and European League Against Rheumatism criteria. * Diagnosis of 2018 Revised International Society of Nephrology/Renal Pathology Society classification (active focal or diffuse proliferative LN Class III or IV) confirmed by biopsy obtained ≤ 6 months prior to Screening or during Screening Period. Participants may co-exhibit Class V disease. Participants with de novo or relapsing disease may be eligible. * Clinically active LN at Screening requiring/receiving immunosuppression induction treatment in the opinion of the Investigator. * Proteinuria with UPCR ≥ 1 g/g based on one 24 hour urine collection during the Screening Period. IgAN Cohort * Established diagnosis of primary IgAN based on kidney biopsy obtained any time prior to or during the Screening Period. * Mean proteinuria ≥ 1 g/day on 2 complete and valid 24 hour urine collections during the Screening Period. * For participants with a kidney biopsy performed \> 1 year prior to Screening that was used for eligibility: Presence of hematuria as defined by a positive result for blood on urine dipstick or ≥ 10 red blood cells (RBCs)/high power field (hpf) microscopy on urine sediment (documented by the local laboratory) during Screening Period. Presence of hematuria documented by the central laboratory may also be acceptable. * Compliance with stable and optimal dose of RAS inhibitor treatment including maximum allowed or tolerated ACE inhibitor and/or ARB dose for ≥ 3 months prior to Screening with no expected change in dose during the Blinded Treatment Periods (through Week 50) (participants with established intolerance to RAS inhibitors may be included). * Controlled and stable blood pressure (defined as \< 140/90 millimeters of mercury \[mmHg\]) over the past 3 months prior to randomization. Key Exclusion Criteria: Both Cohorts * eGFR ≤ 30 milliliters/minute/1.73 squared meters during Screening calculated by Chronic Kidney Disease Epidemiology Collaboration. * For participants with eGFR \< 45 mL/min/1.73 m2 at Screening, presence of any of the following in glomeruli on most recent kidney biopsy prior to or during the Screening Period: 1. ≥ 50% interstitial fibrosis and tubular atrophy 2. ≥ 50% glomerular sclerosis 3. ≥ 50% active crescent formation * Concomitant significant renal disease other than LN or IgAN on the most recent biopsy prior to or during the Screening Period. * History of solid organ or bone marrow transplant, or planned transplant during the Blinded Extended Treatment Period (50 weeks). * Splenectomy or functional asplenia. * Known or suspected complement deficiency, unless attributable to underlying disease (that is, LN and IgAN). * Bone marrow insufficiency with absolute neutrophil count \< 1.3 × 10\^3/microliter; thrombocytopenia (platelet count \< 50,000/cubic millimeter). LN Cohort * Participants who have initiated any of the following treatments for the current active LN flare: 1. Cyclophosphamide ≤ 6 months prior to Screening 2. CNIs ≤ 1 months prior to Screening 3. A cumulative dose of intravenous (IV) methylprednisolone \> 3 g 4. Mycophenolate mofetil \> 2 g/day (or equivalent) for ≥ 8 consecutive weeks prior to Screening 5. Prednisone or prednisone equivalent ≥ 0.5 mg/kg/day for ≥ 8 consecutive weeks prior to Screening * Uncontrolled hypertension (systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 110 mmHg) on 2 or more measurements during the Screening Period. * Prior history or clinically active SLE-related cerebritis, seizures, stroke, or stroke syndrome requiring treatment or clinically active pericarditis * Inability to take or tolerate the standard of care background therapies IgAN Cohort * Diagnosis of rapid progressive glomerulonephritis as measured by eGFR loss ≥ 30% over a period of 3 months prior to or during the Screening Period. * Secondary etiologies of IgAN. * Prednisone or prednisone equivalent \> 20 mg/day for \> 14 consecutive days or any other systemic immunosuppression for the treatment of IgAN ≤ 6 months prior to Screening * Blood pressure of ≥ 140/90 mmHg during the Screening Period confirmed on 2 measures \> 30 minutes apart.

Outcomes

Primary Outcomes

Both Cohorts: Percentage Change in Proteinuria From Baseline at Week 26

Proteinuria, the presence of excess proteins in the urine, was assessed using 24-hour urine collections obtained at designated timepoints. A negative change from baseline indicated an improvement in symptoms.

Time frame: Baseline, Week 26

Secondary Outcomes

Both Cohorts: Percentage Change in Proteinuria From Baseline at Week 50

Time frame: Baseline, Week 50

Both Cohorts: Percentage of Participants Achieving >30% and >50% Reduction in Proteinuria at Week 26 and Week 50 Compared to Baseline

Proteinuria, the presence of excess proteins in the urine, was assessed using 24-hour urine collections obtained at designated timepoints. A reduction from baseline indicated an improvement in symptoms.

Time frame: Week 26 and Week 50

Both Cohorts: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at 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 an improvement in symptoms.

Time frame: Baseline, Week 26 and Week 50

LN Cohort: Percentage of Participants Meeting the Criteria for Complete Renal Response at Week 26 and Week 50

Complete renal response was defined as a decrease in urine protein to creatinine ratio (UPCR) to ≤0.5 gram/gram (g/g), an eGFR rate \>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.

Time frame: Week 26 and Week 50

LN Cohort: Percentage of Participants Meeting the Criteria for Partial Renal Response at Week 26 and Week 50

Partial renal response was defined as a decrease in UPCR ≥50% compared to baseline, an eGFR rate \>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.

Time frame: Week 26 and Week 50

LN Cohort: Time to the First Occurrence of UPCR ≤0.5 g/g as Measured by a Spot Urine Sample

UPCR was assessed using 24-hour urine collections obtained at designated time points. The time to the first occurrence of UPCR ≤0.5 g/g was summarized by spot urine sample analysis.

Time frame: Up to Week 50

LN Cohort: Percentage of Participants Achieving Corticosteroid Taper to 7.5 mg/Day at Weeks 12, 26, and 50

A corticosteroid taper was carried out per protocol at the clinical discretion of the investigator.

Time frame: Week 12, Week 26, And Week 50

LN Cohort: Percentage of Participants Experiencing a Renal Flare Through Week 50

Renal flare was determined in the opinion of the investigator and additional protocol-specified criteria. For participants who achieved a complete renal response, 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 or 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.

Time frame: Baseline Through Week 50

LN Cohort: Percentage of Participants Experiencing an Extrarenal SLE Flare 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 assesses 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.

Time frame: Baseline Through Week 50

LN Cohort: Percentage of Participants Meeting the Criteria for Treatment Failure 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.

Time frame: Baseline through Week 50

LN Cohort: Change From Baseline in Serum Albumin at Week 26 and Week 50

For the determination of serum albumin, blood samples were obtained at designated time points. Results reported as grams/liter (g/L).

Time frame: Baseline, Week 26 and Week 50

LN Cohort: Percentage of Participants Meeting the Criteria for Suboptimal Response 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.

Time frame: Baseline Through Week 50

IgAN Cohort: Percentage of Participants Meeting the Criteria for Partial Remission at 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.

Time frame: Week 26 and Week 50

Study of ALXN2050 in Proliferative Lupus Nephritis (LN) or Immunoglobulin A Nephropathy (IgAN)

Overview

Conditions

Interventions

Eligibility

Locations (71)

Outcomes

Primary Outcomes

Secondary Outcomes