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Mechanistic Studies of B- and T-Cell Function in RA Patients Treated With TNF Antagonists, Tocilizumab, or Abatacept (MAZERATI)

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ClinicalTrials.gov Identifier: NCT02353780
Recruitment Status : Unknown
Verified August 2017 by Dr. Larry W. Moreland, University of Pittsburgh.
Recruitment status was:  Active, not recruiting
First Posted : February 3, 2015
Last Update Posted : June 3, 2019
Sponsor:
Collaborators:
Genentech, Inc.
Bristol-Myers Squibb
Information provided by (Responsible Party):
Dr. Larry W. Moreland, University of Pittsburgh

Brief Summary:
An Agency for Healthcare Research and Quality executive summary indicated that better comparative effectiveness trial designs are needed to determine the relative merits of existing versus new and expensive biologic drug therapies for rheumatoid arthritis (RA). There are now 9 biologic therapies approved for treating RA. Four classes of biologics (TNF antagonists, B-cell inhibitors, T-cell co-stimulator blocker, and Interleukin-6 receptor blocker) are approved for use in RA patients with moderate or severe disease activity. Several critical questions have arisen, such as 1) what therapy should be prescribed after failure of methotrexate and/or other oral disease modifying antirheumatic drugs (DMARDs) to adequately control disease activity; 2) what is the level of efficacy of the various biologic therapies when compared in head-to-head trials; and 3) what are the mechanisms associated with failure of methotrexate and/or other oral DMARD therapy and responsiveness to biologic therapies. The MAZERATI study will provide the foundation for answering these questions and determining the mechanisms associated with these biologic therapies.

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis (RA) Drug: TNF Antagonist (enbrel, humire, remicade, cimzia, symponi) Drug: Abatacept Drug: Tocilizumab Phase 4

Detailed Description:

Single center, randomized, assessor-blinded, observational longitudinal assessment. Subjects will be randomized to treatment with an anti-TNF therapy, tocilizumab or abatacept and evaluated at baseline, and after 1, 3 and 6 months of therapy. All biologics will be administered subcutaneously (SQ). A blinded assessor will perform clinical disease activity assessments and blood samples will be obtained for mechanistic studies.

After randomization, patients must take at least one dose of the assigned medication and must maintain their baseline prednisone and oral disease modifying anti-rheumatic drug (DMARD) medications until they have received their first dose of assigned medication to be considered per protocol participants. During the first 3 months of therapy, patients and their physicians will be permitted to taper but not increase corticosteroids. Adjustments of study medication or oral DMARDs will not be permitted during the first 3 months of the study except as outlined in the protocol. Adjustments or additions of analgesics will be permitted throughout the study period.

Following randomization and treatment initiation, study participants will be seen in the clinic at 1 month (3-5 weeks), 3 months (10-14 weeks), and 6 months (22-30 weeks) after the initiation of therapy; at each time point, a blinded clinical disease activity assessment will occur and blood samples will be obtained for mechanistic studies. The occurrence and severity of unanticipated problems will be recorded continuously throughout the study.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Mechanistic Studies of B- and T-Cell Function in Rheumatoid Arthritis Patients Treated With TNF Antagonists, Tocilizumab, or Abatacept
Study Start Date : March 2015
Estimated Primary Completion Date : July 2019
Estimated Study Completion Date : July 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Different TNF inhibitor
The participant will be prescribed any TNF antagonist in this arm. The treating rheumatologist selects the TNF antagonist and the appropriate options for that therapy.
Drug: TNF Antagonist (enbrel, humire, remicade, cimzia, symponi)
TNF Antagonist; treating rheumatologist selects specifics for the therapy chosen.
Other Names:
  • Enbrel
  • Humira
  • Remicade
  • Cimzia
  • Symponi

Active Comparator: Abatacept
The participant will be prescribed abatacept in this arm. The treating rheumatologist selects the appropriate options for that therapy.
Drug: Abatacept
Abatacept; SQ; specifics to be determined by the treating rheumatologist.
Other Name: Orencia

Active Comparator: Tocilizumab
The participant will be prescribed tocilizumab. The treating rheumatologist selects the appropriate options for that therapy.
Drug: Tocilizumab
Tocilizumab; SQ; specifics determined by the treating rheumatologist.
Other Name: Actemra




Primary Outcome Measures :
  1. Mechanistic Comparisons (changes in frequencies of peripheral blood immune cell subsets following institution of a subcutaneously administered TNF antagonist, tocilizumab or abatacept.) [ Time Frame: 6 months ]
    There will be no primary efficacy endpoints for the study. The primary endpoint of the study will be changes in frequencies of peripheral blood immune cell subsets following institution of a subcutaneously administered TNF antagonist, tocilizumab or abatacept.


Secondary Outcome Measures :
  1. Efficacy as measured by CDAI remission < 2.8 [ Time Frame: 3 month and 6 month ]
    Efficacy as measured by CDAI remission < 2.8

  2. Efficacy as measured by DAS remission with a DAS28-CRP < 2.4 [ Time Frame: 3 month and 6 month ]
    Efficacy as measured by DAS remission with a DAS28-CRP < 2.4

  3. Efficacy as measured by ACR20, 50, and 70 response [ Time Frame: 3 month and 6 month ]
    Efficacy as measured by ACR20, 50, and 70 response

  4. Efficacy as measured by EULAR response [ Time Frame: 3 month and 6 month ]
    Efficacy as measured by EULAR response

  5. Adherence to drug regimen [ Time Frame: 3 month and 6 month ]
    Adherence to drug regimen

  6. Number of patients with steroid doses remaining below 10 mg/day [ Time Frame: 3 month and 6 month ]
    Number of patients with steroid doses remaining below 10 mg/day

  7. Average corticosteroid dose [ Time Frame: 3 month and 6 month ]
    Average corticosteroid dose

  8. Number of patients without additional oral DMARDs or with a reduction in the number of oral DMARDs [ Time Frame: 3 month and 6 month ]
    Number of patients without additional oral DMARDs or with a reduction in the number of oral DMARDs

  9. Reason for discontinuation of treatment (side effects, lack of efficacy, cost, patient compliance, etc.) [ Time Frame: 3 month and 6 month ]
    Reason for discontinuation of treatment (side effects, lack of efficacy, cost, patient compliance, etc.)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of RA by a physician as defined by the 1987 and/or 2010 ACR criteria.
  • 18 years of age or less than or equal to 64 at the time of diagnosis of RA.
  • RA Disease Activity CDAI > 10
  • If using oral corticosteroids, must have been on stable dose (≤ 10 mg/day) for at least 2 weeks prior to study drug initiation.
  • PPD negative or if PPD positive documentation of therapy with INH for at least 1 month prior to study initiation and negative chest x-ray.
  • Must have been treated within the past year with either methotrexate (MTX), leflunomide (LEF), hydrochloroquine (HCQ) and/or sulfasalazine (SSZ) for ≥ 3 months.
  • Prior or concurrent use of other oral DMARD therapy, including MTX, leflunomide, SSZ, and HCQ, is permitted. Patients taking oral DMARDs must be on stable doses of DMARDs for at least 4 weeks prior to study drug initiation. Subjects are not required to be taking an oral DMARD.

Exclusion Criteria:

  • Use of cyclophosphamide, penicillamine, cyclosporine A, tacrolimus or gold therapy is not permitted in the 6 months prior to enrollment.
  • Patients who are using or have used other biologic agents or tofacitinib concomitantly or prior to this study
  • History of active and/or chronic infection such as hepatitis, pneumonia, pyelonephritis,herpetic infections or chronic skin infections and any active opportunistic infection, including but not limited to evidence of active cytomegalovirus, active Pneumocystis carinii, aspergillosis, histoplasmosis or atypical mycobacterium infection.
  • Active TB or evidence of latent TB (positive PPD skin test or a history of old or latent TB on chest x-ray) without adequate therapy for TB.
  • Pregnant or lactating women.
  • Patients with current signs or symptoms of uncontrolled renal, gastrointestinal, endocrine, pulmonary, cardiac, neurologic or cerebral disease.
  • Diagnosis of liver disease or elevated hepatic enzymes, as defined by ALT, AST or both >1.5 x the upper limit of normal (ULN) or total bilirubin > ULN.
  • Any of the following hematologic abnormalities, confirmed by repeat tests:

    1. White blood count < 3,000/µL or > 14,000/µL
    2. Lymphocyte count <500/µL
    3. Platelet count < 100,000/µL
    4. Hemoglobin < 8.0 g/dL
    5. Neutrophil count < 2,000 cells/µL
  • Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
  • Immunization with a live/attenuated vaccine within 2 months prior to baseline or 3 months of last study visit.
  • History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
  • History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer
  • Patients with reproductive potential not willing to use an effective method of contraception
  • History of alcohol, drug or chemical abuse with 1 year prior to screening

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02353780


Locations
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United States, Pennsylvania
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15261
Sponsors and Collaborators
Dr. Larry W. Moreland
Genentech, Inc.
Bristol-Myers Squibb
Investigators
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Principal Investigator: Larry W. Moreland, MD University of Pittsburgh

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Responsible Party: Dr. Larry W. Moreland, Chief, Division of Rheumatology and Clinical Immunology, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT02353780     History of Changes
Other Study ID Numbers: PRO10100422
First Posted: February 3, 2015    Key Record Dates
Last Update Posted: June 3, 2019
Last Verified: August 2017
Keywords provided by Dr. Larry W. Moreland, University of Pittsburgh:
Rheumatoid arthritis
TNF inhibitors
Additional relevant MeSH terms:
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Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Etanercept
Abatacept
Infliximab
Certolizumab Pegol
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Gastrointestinal Agents
Dermatologic Agents