Lupus Nephritis
Conditions
Keywords
Lupus Nephritis, Mycophenolate mofetil, VIB4920
Brief summary
This is a multi-center double-blind placebo controlled clinical trial evaluating the efficacy of VIB4920 combined with mycophenolate mofetil (MMF) and prednisone in achieving a renal response in participants with active lupus nephritis (LN).
Detailed description
Seventy-four eligible participants with active lupus nephritis (LN) will be randomized to receive VIB4920 1500 mg or placebo intravenously at Weeks 0, 2, 4, 8, 12, 16, 20, and 24. Participants will receive a total of 1000 mg of methylprednisolone according to either of the following schedules: * 1000 mg methylprednisolone IV at Day 0, or * 500 mg methylprednisolone IV at Day 0 and at Day 1. Participants who previously received 1000 mg of methylprednisolone IV within 42 days of Visit 0 will not receive additional methylprednisolone IV on Day 0. Participants who previously received less than 1000 mg of methylprednisolone IV within 42 days of Visit 0 will receive an additional dose of methylprednisolone IV at Day 0, according to the following formula, where X is the intravenous dose previously received and Y is the intravenous dose administered on Day 0: 1000 mg - X = Y. Participants will also receive MMF 2-3 g per day and will receive prednisone 25 mg/d beginning on Day 0, or on the day after completion of methylprednisolone. Prednisone will be tapered to 5 mg/d by Week 8.
Interventions
DRUGVIB4920
Participants will receive 1500 mg of VIB4920 at Weeks 0, 2, 4, 8, 12, 16, 20, and 24 while continuing on MMF and prednisone
Participants will receive placebo for VIB4920 at Weeks 0, 2, 4, 8, 12, 16, 20, and 24 while continuing on MMF and prednisone
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Individuals who meet all of the following criteria are eligible for enrollment as study participants: 1. Age 18 years or older. 2. Classification of Systemic Lupus Erythematosus (SLE) by any of the following criteria: the 1997 update of the 1982 American College of Rheumatology (ACR) criteria, the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria, or the 2019 European League Against Rheumatism (EULAR)/ACR criteria. 3. UPCR ≥ 1.0 based on a 24-hour urine collection at Visit -1 or within 14 days prior to Visit -1. 4. Renal biopsy within 24 weeks prior to Visit -1 of ISN/RPS LN with both of the following: 1. Class III, Class IV, or Class V in combination with Class III or IV, and 2. Modified NIH Activity Index ≥ 1.
Exclusion criteria
Individuals who meet any of these criteria are not eligible for enrollment as study participants: 1. Inability or unwillingness to give written informed consent or comply with study protocol. 2. Contraindication to treatment with MMF or mycophenolate sodium; or treatment with MMF or mycophenolate sodium is inappropriate in the opinion of the investigator. 3. Treatment with a biologic agent, except belimumab, or investigational agent within 90 days or 5 half-lives prior to Visit 0, whichever is longer. 4. Rituximab or other B cell depleting agent within 6 months prior to Visit 0. 5. Prior treatment with VIB4920. 6. Receipt of a live attenuated vaccine within 4 weeks prior to Visit 0. 7. Comorbidities requiring treatment with systemic corticosteroids, including those that have required 3 or more courses of systemic corticosteroids within 12 months prior to Visit 0. 8. Current malignancy or history of malignancy, except for adequately treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma in situ \> 12 months prior to Visit 0. 9. ESRD, defined as eGFR \< 20 ml/min/1.73m2. 10. History of transplantation. 11. The following risks for thromboembolic events: 1. Recent or recurrent deep venous thrombosis or arterial thromboembolism. 2. Immobilization or major surgery within 12 weeks prior to Visit 0. 3. History of congenital or inherited deficiency of antithrombin III, protein S, or protein C. 4. History of anti-phospholipid syndrome, according to the 2006 Sapporo classification criteria. 12. History of a severe allergy or hypersensitivity reaction to any component of the VIB4920 formulation. 13. Any one of the following laboratory abnormalities: 1. Peripheral B cell count \< 5/μl. 2. Neutropenia (absolute neutrophil count \< 1000/mm3). 3. Anemia (hemoglobin \< 8 g/dL). 4. Thrombocytopenia (platelets \< 50,000/mm3). 5. Aspartate aminiotransferase or alanine aminotransferase ≥ 2x upper limit of normal. 14. Evidence of current or prior tuberculosis infection, including any of the following: 1. Positive QuantiFERON-TB Gold or TB Gold Plus test. 2. Positive T-SPOT.TB test. 3. Positive purified protein derivation (PPD) tuberculin test, defined as \> 5mm induration. 15. Human immunodeficiency virus (HIV) infection. 16. Current or past hepatitis B (HBV) infection. 17. Current or past hepatitis C virus (HCV) infection, except adequately treated HCV with documented sustained virologic response. 18. Active bacterial, viral, fungal, or opportunistic infection. 19. History of significant, recurrent, or chronic infection that may pose additional risks from participating in the study, in the opinion of the investigator. 20. History of severe psychiatric condition that would interfere with the participant's ability to comply with the study protocol, in the opinion of the investigator. 21. Current substance abuse, or history of substance abuse within 12 months of Visit 0. 22. Lack of peripheral venous access. 23. Pregnancy. 24. Breastfeeding. 25. Unwillingness to use a medically acceptable form of contraception for the duration of the study if female of child-bearing potential or if male with a partner of childbearing potential. 26. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants achieving a complete renal response at week 36 | Week 36 | Complete renal response is defined as all of the following: 1. Urine protein-to-creatinine ratio (UPCR) \<= 0.5, based on a 24-hour urine collection 2. Estimated glomerular filtration rate (eGFR) \>= 120 ml/min/1.73 m\^2 or, if \< 120 ml/min/1.73 m\^2, then \>= 80 percent of the eGFR at baseline 3. Prednisone \<= 5 mg/day from Week 8, according to the prednisone dosing restrictions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants who achieve an overall renal response | Weeks 12, 24, 36, 48 and 60 | Overall renal response is defined as all of the following: 1. \>= 50 percent improvement in the urine protein-to-creatinine ratio (UPCR) compared to baseline, based on a 24-hour urine collection 2. Estimated glomerular filtration rate (eGFR) \>= 120 ml/min/1.73 m\^2, or if \< 120 ml/min/1.73 m\^2, then \> 80 percent of the eGFR at baseline, and 3. Prednisone \<= 5 mg/day from Week 8, according to the prednisone dosing restrictions |
| Proportion of participants who achieve a BLISS-LN primary efficacy renal response (PERR) | Weeks 12, 24, 36, 48, and 60 | BLISS-LN primary efficacy renal response (PERR) defined as all of the following: 1. UPCR ≤ 0.7, and 2. eGFR ≥ 60 ml/min/1.73m2, or if \< 60 ml/min/1.73m2, then ≥ 80% of the eGFR at baseline, and 3. no receipt of a prohibited immunosuppressive or immunomodulatory medication |
| Urine Protein-to-Creatinine Ratio (UPCR) | Weeks 12, 24, 36, 48, and 60 | Based on 24-hour urine collection |
| Anti-dsDNA antibodies | Weeks 12, 24, 36, 48, and 60 | The change in the proportion of participants who had a negative anti-dsDNA test will be summarized by arm, and will be analyzed using an exact conditional logistic regression model |
| Change in proportion of participants with lower C3 levels after treatment initiation | Weeks 12, 24, 36, 48, and 60 | The change in the proportion of participants who were hypocomplementemic for C3 and C4 after initiation of VIB4920 or placebo will be summarized by arm, and analyzed using an exact conditional logistic regression model |
| Change in proportion of participants with lower C4 levels after treatment initiation | Weeks 12, 24, 36, 48, and 60 | The change in the proportion of participants who were hypocomplementemic for C3 and C4 after initiation of VIB4920 or placebo will be summarized by arm, and analyzed using an exact conditional logistic regression model |
| Proportion of participants who achieve a complete renal response | Weeks 12, 24, 48, and 60 | Complete renal response is defined as all of the following: 1. Urine protein-to-creatinine ratio (UPCR) \<= 0.5, based on a 24-hour urine collection 2. Estimated glomerular filtration rate (eGFR) \>= 120 ml/min/1.73 m\^2 or, if \< 120 ml/min/1.73 m\^2, then \> 80 percent of the eGFR at Week 0 3. Prednisone tapered to \<= 5 mg/day by Week 8, and adherence to the prednisone dosing restrictions |
| Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for Systemic Lupus Erythematosus (SLICC/ACR-DI) | Weeks 24 and 60 | The change in SLICC/ACR-DI scores after initiation of VIB4920 or placebo will be summarized by arm, and analyzed using an ANCOVA model |
| Proportion of participants who experience treatment failures | Week 0 to Week 60 | Treatment failure is defined as any one of the following: 1. Receipt of SLE rescue therapy 2. End-stage renal disease (ESRD), defined as eGFR \< 20 ml/min/1.73m2 3. Worsening of proteinuria or eGFR from Week 24 onward, defined as either: 1. confirmed ≥ 50% increase in the UPCR to a value ≥ 3.0 compared to Visit -1, or 2. confirmed ≥ 30% increase in eGFR to a value of \< 60, compared to Visit -1 |
| Number of participants who experience at least one serious adverse event | Week 0 to Week 60 | The number of participants who experienced at least one SAE and the number of participants who experienced at least one AESI will be analyzed using a Fisher's exact test. |
| Number of participants who experience at least one adverse Events of Special Interest | Week 0 to Week 60 | Adverse Events of Special Interests include: 1. Anaphylaxis 2. Grade 3 or greater infusion reaction 3. Grade 3 or greater hypersensitivity reaction 4. Grade 3 or greater infection 5. Thromboembolic event |
| Change in Serum IgM over study participation | Weeks 12, 24, 36, 48, and 60 | Serum IgM levels will be analyzed using a longitudinal mixed effects model with the test results at the time points as the dependent variable |
| Change in Serum IgG over study participation | Weeks 12, 24, 36, 48, and 60 | Serum IgG levels will be analyzed using a longitudinal mixed effects model with the test results at the time points as the dependent variable |
| Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) | Weeks 12, 24, 36, 48, and 60 | The change in SLEDAI-2K scores after initiation of VIB4920 or placebo will be summarized by arm, and analyzed using an analysis of covariance (ANCOVA) model |
Countries
United States
Outcome results
None listed