CD40L Antagonism in Rheumatoid Arthritis (RA)

• Status: Not yet recruiting
• Trial end date: 2025-03-01
• Target enrollment: 0
• Participant gender: All

Summary

Patients with moderately-to-highly active Rheumatoid arthritis receive a 12-week VIB4920 treatment with Tumor necrosis factor alpha inhibitor (TNFi) compared to background disease-modifying (RA) therapy with TNFi and without the addition of VIB4920. The primary objective is to determine if the addition of a 12-week course of treatment with VIB4920 to a TNFi in patients with RA who have had an inadequate response to a TNFi results in improved clinical disease control.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborator: Immune Tolerance Network (ITN)

Criteria

Inclusion Criteria:

1. Participant or legally authorized representative must be able to understand and provide informed consent

2. Adult 18-70 years of age

3. Diagnosed with RA by fulfilling the ACR/EULAR 2010 Classification Criteria for Rheumatoid Arthritis (RA) >= 6 months prior to screening

4. Documented positive test for rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibody (ACPA)

5. Simplified Disease Activity Index (SDAI) >= 17

6. At least 4 tender and 4 swollen joints by a 44 joint count

7. Tumor necrosis factor alpha inhibitor (TNFi) therapy:

1. Current treatment with etanercept 50 mg SC weekly or adalimumab 40 mg SC every other week for at least 12 weeks

2. Willing to continue or discontinue treatment with their current TNFi at the same dose depending upon study arm assignment

8. If treated with leflunomide, sulfasalazine, or hydroxychloroquine, must be taking a stable dose for at least 12 weeks

9. If treated with methotrexate, must be taking a stable dose for at least 12 weeks. The following exceptions are permitted within the 12 weeks prior to screening:

1. Holding methotrexate for 1 week after each dose of a 2 dose SARS-CoV-2 vaccine

2. Holding methotrexate for 2 weeks after a single dose SARS-CoV-2 vaccine

3. Holding methotrexate for 1 or 2 weeks after influenza vaccination

10. Received at least 3 doses of any combination of the Moderna or Pfizer COVID-19 vaccine, or 1 dose of the Janssen COVID-19 vaccine followed by a dose of either the Pfizer or Moderna COVID-19 vaccine, unless the participant had a significant adverse reaction to COVID-19 vaccination. Participants who have had a significant adverse reaction to COVID-19 vaccination must have received at a minimum 2 doses of any combination of the Moderna or Pfizer COVID-19 vaccine, or 1 dose of the Janssen COVID-19 vaccine followed by a dose of either the Pfizer or Moderna COVID-19 vaccine. The last COVID-19 vaccine dose must have been administered at least 14 days prior to the initiation of study drug (Visit 0).

11. All participants who engage in sexual activity that could lead to pregnancy must agree to use abstinence or an US Food and Drug Administration (FDA) approved contraception for the duration of the study to prevent pregnancy

Exclusion Criteria:

1. Inability or unwillingness to give written informed consent or comply with the study protocol

2. Prior or ongoing systemic inflammatory or autoimmune disease (other than Rheumatoid Arthritis (RA) and secondary Sjögren's syndrome) requiring or potentially requiring other systemic immunomodulatory therapy during the 40-week study period

3. Use of glucocorticoid and/or disease-modifying therapies as specified below:

1. Prior treatment with any B cell depleting therapy (e.g., rituximab)

2. History of treatment with more than two Tumor necrosis factor alpha inhibitors (TNFi), including ongoing treatment with etanercept or adalimumab

3. Treatment with other biologic therapy (i.e., not targeting TNF-alfa), including abatacept, tocilizumab, or sarilumab within the previous 12 weeks

4. Treatment with a Janus kinase (JAK) inhibitor within the previous 12 weeks

5. Concurrent use of methotrexate and leflunomide

6. Prednisone > 10 mg a day or equivalent glucocorticoid use within the previous 4 weeks

7. Intramuscular, intra-articular, or intravenous glucocorticoids within the previous 4 weeks

8. Other immunomodulatory medications within the previous 12 weeks except for methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine

4. Lack of any subjective or objective clinical response (i.e., complete non-responder) to current TNFi use, in the opinion of the study investigator based on information provided by the patient and referring rheumatologist

5. Use of an investigational agent including VIB4920 in the past 30 days or 5 half-lives, whichever is longer

6. History of a severe allergy, hypersensitivity reaction, or infusion reaction to any component of the VIB4920 formulation

7. History of Felty's syndrome

8. History of interstitial lung disease with FVC < 70% predicted, DLCO < 70% predicted, or requiring supplemental oxygen

9. Hypercoagulable state as specified below:

1. Previous deep venous or arterial thrombosis or thromboembolism, or pulmonary embolism

2. Known hypercoagulable state (e.g., inherited thrombin III deficiency, protein S deficiency, protein C deficiency, antiphospholipid antibody syndrome, MTHFR mutation)

3. Risk factors for deep venous or arterial thromboembolism (e.g., immobilization or major surgery within 12 weeks prior to enrollment)

4. Anti-phospholipid antibodies:

i. Positive anti-cardiolipin IgG, IgM, or IgA antibodies at a moderate titer or higher (>= 40 U) ii. Positive anti-beta-2-glycoprotein I IgG, IgM, or antibodies at a moderate titer or higher (>= 40 U) iii. Positive lupus anticoagulant test

10. Infection:

1. Evidence of current or prior infection with hepatitis B, as indicated by a positive test for the hepatitis B surface antigen (HBsAg) or a positive test for the hepatitis B core antibody (HBcAb)

2. Positive Hepatitis C Virus (HCV) serology unless treated with an anti-viral regimen resulting in a sustained virologic response (undetectable viral load 24 weeks after cessation of therapy)

3. Evidence of Human Immunodeficiency Virus (HIV) infection

4. Evidence of active tuberculosis, untreated or incompletely treated latent tuberculosis, or recent close contact with a person who has active tuberculosis

5. Positive QuantiFERON-TB Gold or QuantiFERON-TB Gold Plus test without history of previous treatment for latent TB

6. Indeterminate QuantiFERON-TB Gold or QuantiFERON-TB Gold Plus test which remains indeterminate on repeat testing, and any of the following:

i. History of tuberculosis exposure ii. History of travel to an area where tuberculosis is endemic iii. Findings on chest radiograph obtained in the past 3 months suggestive of prior exposure to tuberculosis (e.g., granulomas or apical scarring) iv. Positive purified protein derivative (PPD) skin test for tuberculosis obtained in the past 3 months v. Prior history of a positive QuantiFERON-TB Gold, QuantiFERON-TB Gold Plus, T-SPOT.TB, or purified protein derivative (PPD) test without history of previous treatment for latent tuberculosis (TB)

g. Positive test for acute COVID-19 infection (e.g., PCR test for SARS-CoV-2 or alternative viral test according to CDC guidance)

h. Symptoms of presumed or documented COVID-19 infection in the past 30 days

i. More than one episode of herpes zoster in the past 12 months

j. An opportunistic infection in the past 12 months

k. Acute or chronic infection, including current use of suppressive systemic anti-microbial therapy for chronic or recurrent bacterial or fungal infection, hospitalization for treatment of infection in the past 60 days, or parenteral anti-microbial (including anti-bacterial, anti-viral, or anti-fungal agents) use in the past 60 days for infection

l. History of bronchiectasis with recurrent pulmonary infections

11. History of a primary immunodeficiency disorder

12. Vaccination with a live vaccine within the past 30 days

13. Women who are pregnant or breast-feeding

14. White Blood Cell (WBC) count < 3.0 x 10^3/mcl

15. Absolute neutrophil count < 1.5 x 10^3/mcl

16. Hemoglobin < 9 g/dL

17. Platelet count < 100 x 10^3/mcl

18. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥=2x the upper limit of normal (ULN)

19. History of malignant neoplasm within the last 5 years, except for basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the uterine cervix treated locally

20. Current, diagnosed, mental illness or current, diagnosed or self-reported drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements

21. Any new or uncontrolled condition occurring within the past 12 weeks which, in the judgment of the investigator, could interfere with participation in the trial (e.g., diabetes mellitus with HbA1c = 9.0%, myocardial infarction, or stroke)

22. 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

23. Inability to comply with study and follow-up procedures