Evaluation of Ravulizumab Efficacy and Safety in Adult Patients with Immunoglobulin A Nephropathy: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2023-507851-31-00
- Protocol
- ALXN1210-IgAN-320
- Sponsor
- Alexion Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the **efficacy** of ravulizumab compared with placebo in reducing proteinuria and assessing changes in estimated glomerular filtration rate (eGFR) in adult participants with Immunoglobulin A Nephropathy (IgAN). This is clinically relevant as proteinuria and eGFR are critical markers of kidney function, and their improvement can indicate a potential therapeutic benefit in managing IgAN.
Secondary objectives include:
- Evaluating the efficacy of ravulizumab compared with placebo on measures of kidney function in adult participants with IgAN.
- Assessing quality of life based on participant-reported outcomes in adult participants with IgAN based on treatment with ravulizumab compared with placebo.
- Characterizing the safety and tolerability of ravulizumab in adult participants with IgAN.
- Assessing immunogenicity to ravulizumab in adult participants with IgAN.
- Characterizing the pharmacokinetics/pharmacodynamics (PK/PD) of ravulizumab in adult participants with IgAN.
Participants
The clinical trial involves a total of **350 participants** diagnosed with **Immunoglobulin A Nephropathy (IgAN)**. The study population includes both male and female adults, aged 18 years and older, who are in general good health with controlled blood pressure and a body weight of at least 30 kg. Participants were selected based on their ability to adhere to stable doses of RASI, SGLT2I, DEARA, MRA, or ERA medications for at least three months prior to screening, with no planned changes during the study period. All participants must have been vaccinated against meningococcal infection within three years prior to the study intervention. The trial does not include any vulnerable populations. Participants are required to have a documented diagnosis of IgAN established through kidney biopsy, with specific criteria for estimated glomerular filtration rate (eGFR) and urine protein-to-creatinine ratio (UPCR) at screening. The selection process ensures that participants are capable of providing informed consent and complying with the study's requirements and restrictions.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of **ravulizumab** in adult participants with **Immunoglobulin A Nephropathy (IgAN)**. The trial aims to assess the reduction in proteinuria and changes in estimated glomerular filtration rate (eGFR) as primary endpoints. The study is expected to commence recruitment on June 28, 2024, and conclude by March 30, 2029, with a total duration of approximately 5 years. Participants will be randomly assigned to receive either ravulizumab or a placebo, administered via intravenous infusion.
The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age, blood pressure control, and prior vaccination against meningococcal infection. Participants must have a documented diagnosis of IgAN established through kidney biopsy. Following the screening, participants will undergo regular follow-up visits to monitor changes in proteinuria and eGFR, with interim analyses conducted at Week 34 and final analyses at Week 106. The end-of-study visit will assess the long-term effects of the treatment.
Participant involvement is expected to last up to 106 weeks, with conditions for early termination including non-compliance with study protocols, adverse events, or withdrawal of consent. The study will ensure adherence to stable doses of renin-angiotensin system inhibitors and other specified medications throughout the trial period. The trial will also monitor secondary endpoints such as changes in albuminuria, fatigue, and the incidence of adverse events. The study is not categorized as low intervention and is designed to demonstrate the safety and efficacy of ravulizumab in a new indication for patients with IgAN.
Treatment
The clinical trial involves the administration of **ravulizumab**, marketed under the name Ultomiris, which is a **concentrate for solution for infusion**. This experimental medication is administered via **intravenous infusion**. The pharmaceutical form is a solution for infusion, with a concentration of 1,100 mg/11 mL. The maximum daily dose is 3,600 mg, and the total dose over the treatment period can reach up to 93,900 mg. The treatment period extends up to 204 days. Ravulizumab is a protein-based therapeutic agent, specifically classified under the ATC code L04AA43. The product is manufactured by Alexion Europe SAS and is authorized for use in the European Union under the marketing authorization number EU/1/19/1371/003.
The study also includes a **placebo** control, referred to as Anti C5 Complement mAb Placebo. 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 experimental drug, via intravenous infusion, to ensure consistency in the administration process. The placebo does not contain any active pharmaceutical ingredients and serves as a comparator to evaluate the efficacy and safety of ravulizumab in reducing proteinuria and changing eGFR in adult participants with **Immunoglobulin A Nephropathy (IgAN)**.
Efficacy
The efficacy of ravulizumab in the treatment of **Immunoglobulin A Nephropathy (IgAN)** will be assessed through a series of primary and secondary endpoints. The primary endpoint for the interim analysis is the change from baseline in proteinuria, measured by the 24-hour urine protein-to-creatinine ratio (UPCR) at Week 34. For the final analysis, the primary endpoint is the change from baseline in estimated glomerular filtration rate (eGFR) at Week 106.
Secondary endpoints include changes from baseline in proteinuria at various timepoints (Weeks 10, 26, 34, 50, and 106), changes in eGFR at Weeks 34 and 50, and reduction in 24-hour UPCR by at least 50% from baseline over time. Additional secondary endpoints involve partial remission, changes in albuminuria, annualized eGFR slope, and time to sustained eGFR decline. The study will also evaluate the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (TESAEs), and adverse events of special interest (AESI), as well as the incidence of anti-drug antibodies (ADA) and neutralizing antibodies (NAb).
Measurements will be collected at specified intervals throughout the study, with key timepoints including Weeks 10, 26, 34, 50, and 106. The efficacy assessments will utilize validated laboratory tests and patient-reported outcomes, such as the FACIT-Fatigue scale, to ensure comprehensive evaluation of the treatment's impact on IgAN. Serum concentrations of ravulizumab, total C5, and free C5 will also be monitored over time to support the analysis of efficacy and safety.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be ≥ 18 years of age at the time of signing the informed consent
- Adherence to and compliance with stable and maximum allowed or tolerated RAASI (ACEI and/or ARB) dose for ≥ 3 months prior to Screening with no planned change during Screening through Week 106. Participants with intolerance to RAASI medications may be included (Section 6.9).
- Participants who are receiving SGLT2I, DEARA (eg, sparsentan), MRA, or ERA must be on a stable and maximum allowed or tolerated dose for ≥ 3 months prior to Screening with no planned change in dose through Week 106
- Controlled blood pressure of < 140/90 mmHg at Screening
- To reduce the risk of meningococcal infection (N meningitidis), all participants must be vaccinated against meningococcal infection from serogroups A, C, W, Y (and B where available) within 3 years prior to study intervention on Day 1. If vaccination occurs < 2 weeks from Day 1, the participant will receive prophylactic antibiotics for at least 2 weeks after initial meningococcal vaccination
- Documentation of IgAN diagnosis established on kidney biopsy obtained any time prior to or during the Screening Period for participants with eGFR ≥ 30 mL/min/1.73 m2 a. For participants in the AdKD cohorts: eGFR 20 to 29 mL/min/1.73 m2, a kidney biopsy is required within 6 months prior to Screening or during the Screening Period. Kidney biopsy report must demonstrate < 75% each of interstitial fibrosis, tubular atrophy, and glomerular sclerosis.
- UPCR ≥ 0.75 g/g or UP ≥1 g/day calculated from the mean of two 24-hour urine samples collected during the Screening Period
- Estimated GFR ≥ 30 mL/min/1.73 m2 at Screening as calculated by the CKD-EPI formula (Section 8.2.3). a. Participants in the AdKD cohorts require eGFR 20 to 29 mL/min/1.73 m2 at Screening.
- Body weight ≥ 30 kg at Screening
- Male or female
- Agree to follow protocol-specified contraception guidance
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
Exclusion Criteria
- Diagnosis of rapid progressive glomerulonephritis as measured by eGFR loss ≥ 50% over a period of 3 months prior to Screening
- History of Neisseria meningitidis infection
- Known history of human immunodeficiency virus (HIV) infection as documented by HIV-1/HIV-2 testing or positive HIV-1/HIV-2 antibody titer at Screening.
- Evidence of active hepatitis B infection −Positive HBsAg or −Positive core antibody (anti-HBc): participants with positive anti-HBc but negative HBsAg may be enrolled if the hepatitis B virus DNA test result is negative during the Screening Period (local or central lab)
- Active systemic bacterial, viral, or fungal infection within 14 days prior to randomization.
- Drug or alcohol abuse or dependence within 1 year prior to Screening that interferes with ability to participate in the clinical study.
- History of malignancy within 5 years of Screening, except for nonmelanoma skin cancer or carcinoma in situ of the cervix that has been treated with no evidence of recurrence.
- Hypersensitivity to any ingredient contained in the study intervention, including to murine proteins.
- Systemic corticosteroid therapy or any other systemic immunosuppression (except biologics) within 3 months of Screening (except short course steroids [approximately 14 days] for non-IgAN treatment) (Section 6.9).
- Ongoing budesonide therapy or budesonide therapy within 6 months prior to Screening
- Biologic(s) for the treatment of IgAN ≤ 6 months prior to Screening
- Secondary IgAN (eg, due to SLE, cirrhosis, or celiac disease; IgAV-N may be eligible, see Exclusion Criterion 5).
- Traditional Chinese medicines and Chinese proprietary medicines with systemic immunosuppressive properties including but not limited to Tripterygium Wilfordii or Tripterygium Wilfordii-containing medicines for the treatment of IgAN within 6 months prior to Screening
- Currently receiving or previously received a complement inhibitor within 30 days or 5 half-lives, whichever is longer, prior to Screening
- Participation in another investigational drug or investigational device study within 30 days before Day 1 or within 5 half-lives of that investigational product, whichever is greater.
- Pregnant, breastfeeding, or intending to conceive during the study.
- Inability to travel to the clinic for specified visits during the study or fulfill the logistical requirements of study intervention administration
- Participant is imprisoned or lawfully retained at an institution via administrative or judicial order.
- Participant is involved in the planning and/or conduct of the study (applies to both sponsor personnel and/or staff at the study site).
- Concomitant clinically significant renal disease other than IgAN.
- Uncontrolled diabetes mellitus with glycosylated hemoglobin (HbA1c) > 8.5%
- Henoch-Schonlein purpura (IgAV) requiring systemic immunosuppressive therapy within 12 months of Screening
- History of kidney transplant or planned kidney transplant during the Treatment Period. a. Participants listed for kidney transplant may be eligible for the AdKD cohorts
- History of other solid organ (heart, lung, small bowel, pancreas, or liver) or bone marrow transplant; or planned transplant during the Treatment Period or open-label Exploratory Cohort, except for corneal transplant.
- Body mass index ≥ 38 kg/m2.
- Splenectomy or functional asplenia
- Evidence of active hepatitis C infection −Positive HCV antibody: Participants with positive HCV antibody and negative HCV RNA test during the Screening Period (local or central laboratory) and absence of cirrhosis may be enrolled.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 28 Jun 2024 | 3 |
 Belgium | Not Recruiting | 28 Jun 2024 | 3 |
 Czechia | Not Recruiting | 28 Jun 2024 | 10 |
 France | Not Recruiting | 28 Jun 2024 | 24 |
 Germany | Not Recruiting | 28 Jun 2024 | 14 |
 Greece | Not Recruiting | 28 Jun 2024 | 8 |
 Hungary | Not Recruiting | 28 Jun 2024 | 4 |
 Italy | Not Recruiting | 28 Jun 2024 | 26 |
 The Netherlands | Not Recruiting | 28 Jun 2024 | — |
 Poland | Not Recruiting | 28 Jun 2024 | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Anti C5 Complement mAb Placebo | Placebo | N/A | — | — | — | N/A |
Ultomiris 1,100 mg/11 mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 3600 | 112 | PRD8534297 |