Efficacy and Safety Evaluation of Ravulizumab in Adults with Proliferative Lupus Nephritis or Immunoglobulin A Nephropathy: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of ravulizumab compared with placebo in adult participants diagnosed with Proliferative **Lupus Nephritis** (LN) and **Immunoglobulin A Nephropathy** (IgAN). This is clinically relevant as both LN and IgAN are serious kidney conditions that can lead to significant morbidity, and effective treatment options are limited. Understanding the efficacy of ravulizumab could potentially offer a new therapeutic avenue for these patients.

Secondary objectives include assessing the **safety** and **tolerability** of ravulizumab, as well as additional efficacy measures. These objectives are crucial for determining the overall benefit-risk profile of ravulizumab in the treatment of LN and IgAN, ensuring that any therapeutic benefits are not outweighed by adverse effects.

The clinical trial involves a total of **58 participants** diagnosed with **Lupus Nephritis (LN)** and **Immunoglobulin A Nephropathy (IgAN)**. The study population comprises adults aged between 18 and 75 years, including both male and female subjects. Participants were selected based on specific inclusion criteria, such as having proteinuria ≥ 1 g/d or g/g and being vaccinated against meningococcal infection, Haemophilus influenzae type b (Hib), and Streptococcus pneumoniae. For the LN cohort, individuals must have a diagnosis of active focal or diffuse proliferative LN Class III or IV and require or receive immunosuppression induction treatment. For the IgAN cohort, participants must have a diagnosis of primary IgAN and comply with a stable and optimal dose of RAS inhibitor treatment for at least 3 months. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **Phase II**, double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of **ravulizumab** in adult participants with **Lupus Nephritis (LN)** or **Immunoglobulin A Nephropathy (IgAN)**. The trial aims to compare the efficacy of ravulizumab with a placebo in reducing proteinuria among participants. The study is expected to run from May 10, 2021, to May 26, 2026, with a maximum treatment period of 50 weeks for each participant. Participants will be randomly assigned to receive either ravulizumab or a placebo, administered intravenously as a concentrate for solution for infusion.

The trial will include several study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (18-75 years), proteinuria levels, and vaccination status against specific infections. Participants with active focal or diffuse proliferative LN or primary IgAN will be considered for inclusion. Following the screening, participants will undergo regular follow-up visits to monitor treatment efficacy and safety, including assessments of proteinuria and estimated glomerular filtration rate (eGFR). The primary endpoint is the percentage change in proteinuria, while secondary endpoints include changes in eGFR and various renal response criteria specific to each disease cohort.

The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted to evaluate the overall outcomes of the trial. Participant involvement is expected to last up to 50 weeks, with conditions for early termination including adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial is structured to ensure rigorous evaluation of the investigational product's efficacy and safety, adhering to the highest standards of clinical research methodology.

The clinical trial involves the administration of **ravulizumab**, marketed under the name Ultomiris, which is a **concentrate for solution for infusion**. This investigational medicinal product is provided in a concentration of 300 mg/30 mL and is administered via the **intravenous** route. The maximum daily dose is 5400 mg, with a total maximum dose of 36300 mg over a treatment period of up to 50 days. The product is identical to the commercially available ravulizumab, except for the cap color, which is blue for the marketed product and yellow for the clinical trial product. The active substance, ravulizumab, is a protein of other origin, specifically designed for the treatment of conditions such as Proliferative Lupus Nephritis (LN) and Immunoglobulin A Nephropathy (IgAN). Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The study also includes a **placebo** control, which is a **concentrate for solution for infusion**. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in the same manner as the active treatment, via the intravenous route, to provide a valid comparison of efficacy and safety between the active treatment and the placebo group. The placebo does not contain any active pharmaceutical ingredients and is used solely for the purpose of comparison in the study.

The efficacy of **ravulizumab** in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percentage change in proteinuria, which will be measured to evaluate the drug's impact on kidney function in participants with Proliferative Lupus Nephritis (LN) or Immunoglobulin A Nephropathy (IgAN). Secondary endpoints include additional parameters common to both disease cohorts, such as the percentage change in proteinuria and change from baseline in estimated Glomerular Filtration Rate (eGFR).

For the LN cohort, specific secondary endpoints include the percentage of participants meeting the criteria for Complete Renal Response and Partial Renal Response, time to achieve a Urine Protein to Creatinine Ratio (UPCR) of less than 0.5 g/g, percentage of participants achieving corticosteroid taper to 7.5 mg/day, and the percentage of participants experiencing Renal Flare or Extrarenal Systemic Lupus Erythematosus (SLE) Flare. For the IgAN cohort, the secondary endpoint is the percentage of participants meeting the criteria for Partial Remission.