Phase 3 Multicenter Randomized Double-Blind Placebo-Controlled Study of Anifrolumab in Adults with Active Proliferative Lupus Nephritis
- Trial ID
- 2023-506359-68-00
- Protocol
- IRIS, D3466C00001
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of anifrolumab compared with placebo, when added to standard of care (SOC), in patients with active proliferative **Lupus Nephritis** (LN). The focus is on the proportion of participants achieving a complete renal response (CRR). This is clinically relevant as achieving CRR is indicative of improved renal function and disease control in patients with LN, potentially reducing the risk of long-term renal damage and associated complications.
Secondary objectives include:
- Evaluating the effect of anifrolumab compared with placebo on sustained oral corticosteroid (OCS) reduction.
- Assessing the onset of sustained CRR.
- Investigating the impact on proteinuria.
- Determining the early onset of CRR.
- Evaluating the onset of renal-related events or death through Week 52 and Week 76.
These secondary objectives aim to provide a comprehensive understanding of anifrolumab's potential benefits in managing LN, including its effects on steroid use, renal function markers, and overall patient outcomes.
Participants
The clinical trial involves a total of **267 participants** diagnosed with **Active Proliferative Lupus Nephritis**. The study population includes both male and female subjects, aged between 18 and 70 years, who meet specific health criteria. Participants were selected based on their fulfillment of updated 2019 SLE criteria and other health parameters, such as a body weight of at least 40 kg and an eGFR of 35 mL/min/1.73 m² or higher. The trial includes individuals with a urine protein to creatinine ratio greater than 1 mg/mg, indicating significant proteinuria. Participants are required to have adequate peripheral venous access and no evidence of active infections or malignancies as confirmed by chest radiographs or CT scans. The trial population is characterized by a need for high-dose corticosteroids and immunosuppressive therapy, as determined by a renal biopsy within six months prior to the study. Lifestyle considerations such as contraceptive use are aligned with local regulations, and participants must have a negative PCR or antigen test for COVID-19 at screening. The study does not exclude vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographic groups.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** Phase 3 study to evaluate the efficacy and safety of **anifrolumab** in adult patients with active proliferative **lupus nephritis**. The trial aims to assess the efficacy of anifrolumab compared to placebo, in addition to standard of care, by measuring the proportion of participants achieving a complete renal response (CRR) at Week 52. The study is expected to run from February 2022 to March 2028, with a maximum treatment period of 128 weeks for each participant.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, body weight, and specific medical conditions. The screening process will include tests for **autoantibodies** and a renal biopsy if not conducted within the last six months. Following successful screening, participants will be randomized to receive either anifrolumab or placebo via **intravenous infusion**. The trial will include regular follow-up visits to monitor safety, efficacy, and any adverse events. These visits will assess primary and secondary endpoints, including sustained oral corticosteroid reduction and time to renal-related events.
The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants may be withdrawn from the study if they experience significant adverse effects, fail to adhere to the protocol, or if the investigator deems it necessary for their safety. The expected length of participant involvement is up to 128 weeks, contingent upon adherence to the study protocol and absence of conditions necessitating early withdrawal.
Treatment
The clinical trial involves the administration of **Saphnelo**, a 300 mg **concentrate for solution for infusion** containing the active substance **anifrolumab**. This investigational medication is provided in a pharmaceutical form suitable for **intravenous use**. The administration of Saphnelo is conducted as part of a randomized, double-blind, placebo-controlled study to assess its efficacy and safety in adult patients with active proliferative **lupus nephritis**. The maximum treatment period for Saphnelo is 128 days. The dosing schedule and frequency of administration are determined by the study protocol, ensuring adherence to the specified regimen. Participant compliance is monitored throughout the trial to ensure accurate assessment of the treatment's efficacy and safety.
In addition to the experimental treatment, a **placebo** is utilized as a comparator in this study. The placebo is designed to match the investigational product in appearance and administration route, ensuring the integrity of the double-blind study design. The placebo does not contain any active substance and is used to evaluate the efficacy of anifrolumab by comparison. The administration of the placebo follows the same schedule and frequency as the investigational product, with compliance monitoring in place to maintain the study's validity.
Efficacy
The efficacy of anifrolumab in the treatment of active proliferative **Lupus Nephritis** will be assessed in a multicenter, randomized, double-blind, placebo-controlled Phase 3 clinical trial. The primary endpoint for evaluating efficacy is the proportion of participants achieving Complete Renal Response (CRR) at Week 52. CRR is defined by meeting all of the following criteria: urine protein to creatinine ratio (UPCR) ≤ 0.5 mg/mg and estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m² or no decrease from baseline of ≥ 20%.
Secondary endpoints include sustained oral corticosteroid (OCS) reduction, time to sustained CRR, cumulative UPCR as determined by the standardized area under the curve (AUC) from baseline up to and including Week 52, CRR at Week 24, time to renal event, and time to renal-related event or death through Week 76. The sustained OCS reduction is defined as an OCS dose of ≤ 7.5 mg/day prednisone or equivalent by Week 24 and maintained from Week 24 through Week 52. Time to sustained CRR is measured from the first study intervention dose to achieving CRR that is sustained through Week 52. Renal events include end-stage kidney disease (ESKD), doubling of serum creatinine, renal worsening, renal disease treatment failure, or death.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age 18 through 70 years at the time of Screening.
- Fulfills updated 2019 SLE criteria.
- Positive ANA, anti-dsDNA, or anti-Sm test result in sample obtained during Screening or historical.
- Urine protein to creatinine ratio > 1 mg/mg (113.17 mg/mmol) (mean of 2 spot UPCR [FMV] samples obtained during Screening).
- Active proliferative LN Class III or IV either with or without the presence of Class V (excluding pure Class III[C], IV-S[C], or IV-G[C]) according to the 2003 ISN/RPS classification based on a renal biopsy obtained within 6 months prior to signing the ICF or during Screening Period, and in the opinion of the investigator, participant needs high dose corticosteroids and immunosuppressive therapy.
- eGFR ≥ 35 mL/min/1.73 m2 (as calculated by the Chronic Kidney Disease Epidemiology Collaboration formula).
- Adequate peripheral venous access.
- Chest radiograph (obtained during Screening or within 12 weeks prior to signing of the informed consent) or a CT scan of the chest (within 12 weeks of signing the informed consent) that meets all of the following criteria: No evidence of current active infection (eg, pneumonia, TB) or previous TB; No evidence of malignancy; No evidence of pulmonary nodules suspicious for lung cancer that have not been appropriately followed-up prior to enrolment, No clinically significant abnormalities (unless due to SLE).
- Meets all of the following TB criteria: No signs or symptoms of active TB prior to or during any Screening visit; No medical history or past physical examinations suggestive of active TB; A chest radiograph during the Screening Period or within 12 weeks prior to signing the ICF with no evidence of active or signs of prior TB infection; No recent contact with a person with active TB OR if there has been such contact, referral to a physician specializing in TB to undergo additional evaluation prior to Week 0 (Day 1) (documented comprehensively in source) and, if warranted, receipt of appropriate treatment for latent TB at or before the first administration of study intervention; No history of latent TB prior to signing the ICF, with the exception of latent TB with documented completion of appropriate treatment. The participant must undergo an IGRA (eg, QFT-G test) test for TB obtained from the study central laboratory at Screening with results in line with protocol specified rules.
- Any negative PCR or antigen test result (central or local laboratory, as appropriate) as per local policies at Screening in addition to no known or suspected COVID 19 exposure within 2 weeks prior to Screening.
- Body weight ≥ 40.0 kg.
- Females who have been or are sexually-active with an intact cervix must have documentation of a cervical cancer screening (Pap smear or HPV tests as per local guidelines) with a normal test result within 2 years prior to randomization. Females aged < 25 years, who have never been sexually active or have well documented HPV vaccination records may not, at the Investigator’s discretion, require a cervical cancer screening test.
- Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies (as described in protocol).
Exclusion Criteria
- A diagnosis of pure Class V LN based on renal biopsy obtained within 6 months prior to signing the ICF or during Screening
- History of dialysis within 12 months prior to the ICF or expected need for renal replacement therapy (dialysis or renal transplant) within a 6-month period
- History of, or current renal diseases (other than LN) that could interfere with the LN assessment and confound the disease activity assessment (eg, diabetic nephropathy)
- "History of recurrent infection requiring hospitalization and/or IV antibiotics (eg, 2 or more of the same type of infection over the previous 52 weeks)"
- Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the participant to infection, or a positive result for HIV confirmed by the central lab at Screening
- Confirmed positive test for hepatitis B serology (HBsAB or HBcAB+HBV DNA above the LLOQ) To remain eligible for the study, the participant’s HBV DNA levels must remain below the LLOQ as per the central lab
- Active hepatitis C infection (defined as positive hepatitis C virus antibody and detectable HCV ribonucleotide (RNA) as confirmed by central lab
- Any severe case of HZ infection at any time prior to Week 0 (Day 1)
- Any clinical CMV or EBV infection that has not completely resolved within 12 weeks prior to the ICF
- Opportunistic infection requiring hospitalization or IV antimicrobial treatment within 3 years prior to the ICF
- Clinically significant chronic infection within 8 weeks prior to signing the ICF (chronic nail infections are allowed) or any infection requiring hospitalization or treatment with IV anti-infectives not completed at least 4 weeks prior to the ICF
- Any infection requiring oral anti-infectives (including antivirals) within 2 weeks prior to Week 0 (Day 1)
- History of cancer, apart from: Squamous or basal cell carcinoma of the skin treated with documented success of curative therapy ≥3 months prior to Week 0 (Day 1); Cervical cancer in situ treated with apparent success with curative therapy ≥1 year prior to Week 0 (Day 1)
- Any history of severe COVID-19 infection or any prior COVID-19 infection with documented long COVID and/or clinically significant unresolved sequelae. Any mild/asymptomatic COVID-19 infection within the last 6 weeks prior to first dosing
- Failure to comply with all required Screening procedures due to circumstances related to pandemic or public health emergency
- Prior receipt of anifrolumab
- Previous receipt of >2 investigational treatments for LN since time of diagnosis of LN and through signing the ICF
- Known intolerance to ≤1.0 g/day of MMF
- Receipt of any commercially available biologic agent within 5 half-lives prior to signing of the ICF
- Receipt of any of the following prior to signing the ICF: Receipt of B cell-depleting therapy ≤26 weeks prior to signing the ICF or if therapy was administered >26 weeks ago, if absolute B cell count is <50 cells/microliter
- A known history of allergy or reaction to any component of the study intervention formulation or history of anaphylaxis to any human gamma globulin therapy, human proteins, or monoclonal antibodies
- "Receipt of any of the following: -Any live or attenuated vaccine within 8 weeks prior to signing the ICF (killed vaccines are acceptable) -Any prohibited medication listed in Appendix O not discontinued according to the prescribed timeframe prior to signing of ICF -Blood transfusion or receipt of blood products, except human albumin, within 4 weeks prior to signing the ICF -Any of the following for current LN flare (ie, since the qualifying renal biopsy): IV cyclophosphamide >2 pulses of high-dose (≥0.5 g/m2) or >4 doses of low dose (500 mg every 2 weeks) or Average MMF >2.5 g/day (or >1800 mg/day of enteric coated mycophenolate sodium) for > 8 weeks or Tacrolimus >4 mg/day for more than 8 weeks or 4 weeks prior to signing the ICF; Cyclosporine for more than 8 weeks or during last 8 weeks prior to signing the ICF; Voclosporin for more than 8 weeks or during last 8 weeks prior to signing the ICF; Belimumab for more than 12 weeks or during last 12 weeks prior to signing the ICF"
- Receipt of any commercially available Janus kinase (JAK) inhibitor ≤12 weeks or Bruton’s tyrosine kinase (BTK) inhibitor ≤24 weeks prior to the ICF
- Any new medicinal cannabinoid should not be started during the course of the study.
- Participation in another clinical study with another intervention (besides anifrolumab) administered within 4 weeks prior to ICF signing or within 5 half-lives of the study intervention used in that study, whichever is longer
- "Within 4 weeks of Week 0 (Day 1),any of the following: -AST >2.5 × ULN -ALT >2.5 × ULN -TBL >ULN (unless due to Gilbert’s syndrome) -Glycosylated hemoglobin > 8% (or >0.08) at Screening (diabetic participants only) -Neutrophil count <1 × 10^3/μL (or <1.0 × 109/L) -Platelet count <25 × 10^3/μL (or <25 × 109/L) -Hemoglobin <8 g/dL (or <80 g/L)"
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 15 Feb 2022 | 6 |
 Bulgaria | Not Recruiting | 15 Feb 2022 | 4 |
 France | Not Recruiting | 15 Feb 2022 | 12 |
 Germany | Not Recruiting | 15 Feb 2022 | 12 |
 Hungary | Not Recruiting | 15 Feb 2022 | 16 |
 Italy | Not Recruiting | 15 Feb 2022 | 8 |
 The Netherlands | Not Recruiting | 15 Feb 2022 | — |
 Poland | Not Recruiting | 15 Feb 2022 | 8 |
| Netherlands | — | — | 3 |
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 |
|---|---|---|---|---|---|---|
Anifrolumab Placebo | Placebo | N/A | — | — | — | N/A |
Saphnelo 300 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 0 | 128 | PRD9504474 |