Rheumatoid Arthritis Memory B Cells and Abatacept

NCT03652961 | Completed Phase 4 Results FDA Drug

• 1 other identifier: s18-01164
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

Single-Open Label Study to Assess Changes in the Immune Profile in Response to Treatment with Intravenous Abatacept Adults with Rheumatoid Arthritis who are Naive to Biologic Disease-Modifying Antirheumatic Drugs

Conditions

Rheumatoid Arthritis

Outcome Measures

Primary Outcomes (4)

• CDAI Score

  Clinical Disease Activity Index (CDAI) is a composite index used to assess rheumatoid arthritis (RA) disease activity. The CDAI score is the sum of the Swollen 28-Joint Count (SJC28) + Tender 28-Joint Count (TJC) + Patient Global disease Activity (PGA, patient's assessment of overall RA disease activity on a scale 1-10 where 10 is maximal activity) + Evaluator's Global disease Activity (EGA, evaluator's assessment of overall RA disease activity on a scale 1-10 where 10 is maximal activity). The total score range is 2-76; higher scores (CDAI \> 22) indicate HIgh Disease Activity.

  Day 1

• CDAI Score

  Clinical Disease Activity Index (CDAI) is a composite index used to assess rheumatoid arthritis (RA) disease activity. The CDAI score is the sum of the Swollen 28-Joint Count (SJC28) + Tender 28-Joint Count (TJC) + Patient Global disease Activity (PGA, patient's assessment of overall RA disease activity on a scale 1-10 where 10 is maximal activity) + Evaluator's Global disease Activity (EGA, evaluator's assessment of overall RA disease activity on a scale 1-10 where 10 is maximal activity). The total score range is 2-76; higher scores (CDAI \> 22) indicate HIgh Disease Activity.

  Month 6

• DAS-28 CRP Score

  Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP) is a composite index used to assess rheumatoid arthritis (RA) disease activity. The DAS-28 CRP score is calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (scored on 11-point Likert scale from 0 \[no disease activity\] to 10 \[maximum disease activity\]), and high-sensitivity C-reactive protein levels (in mg/L). DAS28-CRP Scores range from 0 to 10; higher scores indicate more active disease.

  Month 3

• DAS-28 CRP Score

  Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP) is a composite index used to assess rheumatoid arthritis (RA) disease activity. The DAS-28 CRP score is calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (scored on 11-point Likert scale from 0 \[no disease activity\] to 10 \[maximum disease activity\]), and high-sensitivity C-reactive protein levels (in mg/L). DAS28-CRP Scores range from 0 to 10; higher scores indicate more active disease.

  Month 6

Secondary Outcomes (2)

• DAS-28 CRP Score After Abatacept Hold

  Month 9

• CDAI Score After Abatacept Hold

  Month 9

Study Arms (1)

Abatacept plus DMARD

EXPERIMENTAL

Abatacept will be used concomitantly with standard of care disease-modifying anti-rheumatic drugs (DMARDs), other than tumor necrosis factor (TNF) antagonists or Janus kinase (JAK) inhibitors. Intravenous (IV) Abatacept will be administered as a 30-minute IV infusion utilizing weight range-based dosing: 1. Less than 60 kg: 500 mg 2. 60 to 100 kg: 750 mg 3. More than 100 kg: 1000 mg Following the initial IV Abatacept administration, an IV infusion will be given at Weeks 2 and 4 after the first infusion and every 4 weeks thereafter for a total of 7 Abatacept doses. Abatacept will be discontinued after 6 months in all patients. Patients who have flared or failed to achieve low disease activity at 6 months will exit the trial except for one post-study visit for lab work at 9 months. In patients who have achieved low disease activity, Abatacept will be held for 6 months or until a flare results while DMARD use is continued.

Drug: Abatacept; Drug: DMARDs

Interventions

Abatacept DRUG

Abatacept for reconstitution and dilution prior to intravenous (IV) administration. Each single-use vial of Abatacept for injection provides 250-mg Abatacept, maltose (500 mg), monobasic sodium phosphate (17.2 mg), and sodium chloride (14.6 mg) for administration.

Abatacept plus DMARD

DMARDs DRUG

Patients will receive methotrexate or remain on pre-existing conventional synthetic disease-modifying anti-rheumatic drug (DMARD) if already prescribed.

Abatacept plus DMARD

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed Written Informed Consent
• \. Subject is willing to participate in the study and has signed the informed consent.
• Target Population
• Men or women (not nursing or pregnant) over 18 years old who have active Rheumatoid Arthritis, defined as symptoms of Rheumatoid Arthritis prior to screening and have satisfied the American College of Rheumatology/ European League Against Rheumatism 2010 criteria for the classification of Rheumatoid Arthritis prior to signing t the informed consent.
• Subjects must have a Disease Activity Score 28-joint count C reactive protein (CRP) or Clinical Disease Activity Index (CDAI) assessment at screening and have at least 3 tender and at least 3 swollen joints (excluding distal interphalangeal joints) at screening and at Day 1. Patients must have at least moderate disease activity {CDAI\>16); Disease Activity Score and C-reactive protein test (DAS28CRP (\>4.0 )\].
• Subjects must be naive to biologic Disease-modifying antirheumatic drugs (DMARDs)
• Subjects must be naive to targeted synthetic DMARDs such as tofacitinib, baricitinib, and investigational therapies for RA.
• Subjects receiving oral corticosteroids must be on a stable dose and at the equivalent of 10 mg prednisone daily for at least 4 weeks. Subjects may not receive an intravenous (IV), intramuscular (IM) or intra-arterial (IA) administration of a corticosteroid within 4 weeks prior to screening visit or initiation of therapy
• Subjects must have a DAS28CRP and Clinical Disease Activity Index (CDAI) at screening and have at least 3 tender and at least 3 swollen joints (excluding distal interphalangeal joints) at screening and at Day 1.
• Age and Reproductive Status
• Men and women, age's 18 years (or age of majority)
• Women of childbearing potential (WOCBP) must have a negative serum or urine
• pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
• hours prior to the start of study drug.
• Women must not be breastfeeding and must agree not to breastfeed during the study and for 100 days thereafter

You may not qualify if:

• Target Disease Exceptions
• Subjects with autoimmune disease other than RA \[e.g., psoriasis, systemic lupus erythematosus (SLE), vasculitis, seronegative spondyloarthritis, Inflammatory Bowel Disease, Sjogren's syndrome\] or currently active fibromyalgia.
• Prior history of or current inflammatory joint disease other than RA (such as psoriatic arthritis, gout, reactive arthritis, Lyme disease).
• Medical History and Concurrent Diseases 1.Subjects at risk for tuberculosis (TB) defined as follows:
• Current clinical, radiographic or laboratory evidence of active TB. Chest x-rays (posterior anterior and lateral) obtained within the 3 months prior to obtaining written informed consent will be permitted but the images must be available and reviewed by the investigator. TB testing (IFN-gamma release assay or PPD) performed in the past month prior to Screening will be accepted; however, a copy of the report must be placed in the subject binder.
• A history of active TB
• Subjects with a positive TB screening test indicative of latent TB will not be eligible for the study unless they:
• Have no evidence of current TB based on chest x-ray performed And they are actively being treated for TB or the site has documentation of successful prior treatment of latent TB. Treatment regimens should be dictated by local guidelines as long as the treatment dose and duration meet or exceed local health authority guidelines. 2.Subjects with recent acute infection defined as:
• <!-- -->
• Any acute infection within 60 days prior to randomization that required hospitalization or treatment with parenteral antibiotics.
• Any acute infection within 30 days prior to randomization that required oral antimicrobial or antiviral therapy. 3. Subjects with history of chronic or recurrent bacterial infection (such as chronic pyelonephritis, osteomyelitis, and bronchiectasis etc.). 4. Subjects with any history of infection of a joint prosthesis or artificial joint.
• \. Subjects who have a history of systemic fungal infections (such as histoplasmosis, blastomycosis, or coccidiomycosis). 6. Subjects with history of recurrent herpes zoster (more than 1 episode) or disseminated (more than 1 dermatome) herpes zoster or disseminated herpes simplex, or ophthalmic zoster will be excluded. Symptoms of herpes zoster or herpes simplex must have resolved more than 60 days prior to screening. 7. Subjects with history of Human Immunodeficiency Virus (HIV) infection or who tested positive for HIV 8. Subjects with history of primary immunodeficiency
• <!-- -->
• Subjects who have a present malignancy or previous malignancy within the last 5 years prior to screening (except documented history of cured non-metastatic squamous or basal cell skin carcinoma or cervical carcinoma in situ). Subjects who had a screening procedure that is suspicious for malignancy, and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory or other diagnostic evaluations. 10. Current clinical findings or a history of a demyelinating disorder 11. New York Heart Association (NYHA) Class III or IV heart failure 12. Any previous or current medical conditions that are warnings against the use of TNF inhibitor agents. 13. Current clinical findings of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, psychiatric, cardiac, endocrine, neurological, or cerebral disease including severe and uncontrolled infections, such as sepsis and opportunistic infections. Concomitant medical conditions that, in the opinion of the investigator, might place the subject at unacceptable risk for participation in this study. 14. Subjects who have received any live vaccines within 3 months of the study drug administration or are scheduled to receive live vaccines during the study. Study subjects should not be administered a live virus vaccine for a minimum of 3 months f following the last dose of study medication. Subjects who are in close contact with others who have received a live vaccine may be enrolled at the investigator's discretion. 15. Subjects who have undergone a major surgical procedure within the 60 days prior to randomization. 16. Subjects for whom 5 or more joints cannot be assessed for tenderness or swelling (i.e. due to surgery, fusion, amputation, etc.). 17.Subjects who are prisoners, or compulsory detained.

Sponsors & Collaborators

• NYU Langone Health: lead
• Dartmouth-Hitchcock Medical Center: collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

Related Publications (15)

• Wolfe F. The epidemiology of drug treatment failure in rheumatoid arthritis. Baillieres Clin Rheumatol. 1995 Nov;9(4):619-32. doi: 10.1016/s0950-3579(05)80305-x.

  PMID: 8591645 BACKGROUND

• Hochberg MC, Spector TD. Epidemiology of rheumatoid arthritis: update. Epidemiol Rev. 1990;12:247-52. doi: 10.1093/oxfordjournals.epirev.a036058.

  PMID: 2286222 BACKGROUND

• Markenson JA. Worldwide trends in the socioeconomic impact and long-term prognosis of rheumatoid arthritis. Semin Arthritis Rheum. 1991 Oct;21(2 Suppl 1):4-12. doi: 10.1016/0049-0172(91)90046-3.

  PMID: 1836280 BACKGROUND

• Spector TD. Rheumatoid arthritis. Rheum Dis Clin North Am. 1990 Aug;16(3):513-37.

  PMID: 2217956 BACKGROUND

• Zvaifler NJ. Etiology and pathogenesis of rheumatoid arthritis. In: Arthritis and Allied Conditions. Philadelphia, PA: Lea & Febiger;1993:723-736.

  BACKGROUND

• Lindqvist E, Jonsson K, Saxne T, Eberhardt K. Course of radiographic damage over 10 years in a cohort with early rheumatoid arthritis. Ann Rheum Dis. 2003 Jul;62(7):611-6. doi: 10.1136/ard.62.7.611.

  PMID: 12810421 BACKGROUND

• Boissier MC, Semerano L, Challal S, Saidenberg-Kermanac'h N, Falgarone G. Rheumatoid arthritis: from autoimmunity to synovitis and joint destruction. J Autoimmun. 2012 Sep;39(3):222-8. doi: 10.1016/j.jaut.2012.05.021. Epub 2012 Jun 16.

  PMID: 22704962 BACKGROUND

• Bristol-Myers Squibb Abatacept Investigator Brochure, version 18, version date 13-Nov-2014

  BACKGROUND

• Schiff M. Co-stimulation Therapy in Rheumatoid Arthritis: Today and Tomorrow. Curr Treatm Opt Rheumatol. 2015;1(4):334-349. doi: 10.1007/s40674-015-0029-0. Epub 2015 Sep 29.

  PMID: 28936386 BACKGROUND

• Emery P, Burmester GR, Bykerk VP, Combe BG, Furst DE, Barre E, Karyekar CS, Wong DA, Huizinga TW. Evaluating drug-free remission with abatacept in early rheumatoid arthritis: results from the phase 3b, multicentre, randomised, active-controlled AVERT study of 24 months, with a 12-month, double-blind treatment period. Ann Rheum Dis. 2015 Jan;74(1):19-26. doi: 10.1136/annrheumdis-2014-206106. Epub 2014 Nov 3.

  PMID: 25367713 BACKGROUND

• Pelzek AJ, Gronwall C, Rosenthal P, Greenberg JD, McGeachy M, Moreland L, Rigby WFC, Silverman GJ. Persistence of Disease-Associated Anti-Citrullinated Protein Antibody-Expressing Memory B Cells in Rheumatoid Arthritis in Clinical Remission. Arthritis Rheumatol. 2017 Jun;69(6):1176-1186. doi: 10.1002/art.40053. Epub 2017 May 3.

  PMID: 28118534 BACKGROUND

• Kanbe K, Chiba J, Nakamura A. Immunohistological analysis of synovium treated with abatacept in rheumatoid arthritis. Rheumatol Int. 2013 Jul;33(7):1883-7. doi: 10.1007/s00296-011-2326-8. Epub 2012 Jan 3.

  PMID: 22212411 BACKGROUND

• Gazeau P, Alegria GC, Devauchelle-Pensec V, Jamin C, Lemerle J, Bendaoud B, Brooks WH, Saraux A, Cornec D, Renaudineau Y. Memory B Cells and Response to Abatacept in Rheumatoid Arthritis. Clin Rev Allergy Immunol. 2017 Oct;53(2):166-176. doi: 10.1007/s12016-017-8603-x.

  PMID: 28477078 BACKGROUND

• Marasco E, Aquilani A, Cascioli S, Moneta GM, Caiello I, Farroni C, Giorda E, D'Oria V, Marafon DP, Magni-Manzoni S, Carsetti R, De Benedetti F. Switched Memory B Cells Are Increased in Oligoarticular and Polyarticular Juvenile Idiopathic Arthritis and Their Change Over Time Is Related to Response to Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol. 2018 Apr;70(4):606-615. doi: 10.1002/art.40410. Epub 2018 Mar 25.

  PMID: 29316374 BACKGROUND

• Westhovens R, Robles M, Ximenes AC, Nayiager S, Wollenhaupt J, Durez P, Gomez-Reino J, Grassi W, Haraoui B, Shergy W, Park SH, Genant H, Peterfy C, Becker JC, Covucci A, Helfrick R, Bathon J. Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors. Ann Rheum Dis. 2009 Dec;68(12):1870-7. doi: 10.1136/ard.2008.101121. Epub 2009 Jan 5.

  PMID: 19124524 BACKGROUND

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Abatacept; Antirheumatic Agents

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Globulins; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Results Point of Contact

• Title: Gregg J. Silverman, MD MACR
• Organization: NYU Langone Health

Gregg.Silverman@nyulangone.org

212 263 9440

Study Officials

• Gregg Silverman, MD

  NYU Langone Health

  PRINCIPAL INVESTIGATOR

• William Rigby, MD

  Dartmouth-Hitchcock Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 23, 2018
• First Posted: August 31, 2018
• Study Start: June 2, 2019
• Primary Completion: September 27, 2021
• Study Completion: September 27, 2021
• Last Updated: July 3, 2024
• Results First Posted: February 6, 2023

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)