Clinical trial NCT02353780: Mechanistic Studies of B- and T-Cell Function in RA Patients Treated With TNF Antagonists, Tocilizumab, or Abatacept
Official title: Mechanistic Studies of B- and T-Cell Function in Rheumatoid Arthritis Patients Treated With TNF Antagonists, Tocilizumab, or Abatacept
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Rheumatoid Arthritis (RA)
Keywords: Rheumatoid arthritis
TNF inhibitors
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
name: Bristol-Myers Squibb
First posted: 2015-02-03
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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

Primary outcomes:
measure: Mechanistic Comparisons (Changes in Frequencies of Peripheral Blood Immune Cell Subsets Following Institution of a Subcutaneously Administered TNF Antagonist, Tocilizumab or Abatacept.)
timeFrame: 0 to 3 months
Secondary outcomes:
measure: Efficacy (CDAI)
timeFrame: 0 to 3 months
measure: Efficacy (DAS)
timeFrame: 3 month and 6 month
measure: ACR20, 50, and 70 Response
timeFrame: 3 month and 6 month
measure: Efficacy (EULAR)
timeFrame: 3 month and 6 month
measure: Adherence
timeFrame: 3 month and 6 month
measure: Steroid Use
timeFrame: 3 month and 6 month
measure: Corticosteroid Use
timeFrame: 3 month and 6 month
measure: DMARD Use
timeFrame: 3 month and 6 month
measure: Reason for Discontinuation of Treatment
timeFrame: 3 month and 6 month
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Larry W. Moreland, MD
role: PRINCIPAL_INVESTIGATOR
References: