Rheumatoid Arthritis (RA)
Conditions
Keywords
Rheumatoid arthritis, TNF inhibitors
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.
Interventions
DRUGTNF Antagonist (enbrel, humire, remicade, cimzia, symponi)
TNF Antagonist; treating rheumatologist selects specifics for the therapy chosen.
DRUGAbatacept
Abatacept; SQ; specifics to be determined by the treating rheumatologist.
DRUGTocilizumab
Tocilizumab; SQ; specifics determined by the treating rheumatologist.
Sponsors
Genentech, Inc.
Bristol-Myers Squibb
Dr. Larry W. Moreland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mechanistic Comparisons (Changes in Frequencies of Peripheral Blood Immune Cell Subsets Following Institution of a Subcutaneously Administered TNF Antagonist, Tocilizumab or Abatacept.) | 0 to 3 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. Flow ctyometry was performed on peripheral blood T cells to determine frequency of Th17/TfH cells based on cell surface markers. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy (DAS) | 3 month and 6 month | Efficacy as measured by DAS remission with a DAS28-CRP \< 2.4 |
| ACR20, 50, and 70 Response | 3 month and 6 month | Efficacy as measured by ACR20, 50, and 70 response at 3 months and 6 months versus baseline |
| Efficacy (EULAR) | 3 month and 6 month | Efficacy as measured by European League against rheumatism (EULAR) response |
| Adherence | 3 month and 6 month | Adherence to drug regimen over course of clinical study |
| Efficacy (CDAI) | 0 to 3 months | Efficacy of therapy, as measured by number of participants with Clinical Disease Activity Index (CDAI) of less than 2.8 (remission). CDAI is a composite score of RA disease activity based on patient survey (up to 10 points), physician survey (up to 10 points), + number of swollen joints + number of tender joints. 0 = no disease, max score is 60, higher score = more severe disease. Number of patients achieving remission is reported. |
| Corticosteroid Use | 3 month and 6 month | Average corticosteroid dose |
| DMARD Use | 3 month and 6 month | Number of patients without additional oral DMARDs or with a reduction in the number of oral DMARDs |
| Reason for Discontinuation of Treatment | 3 month and 6 month | Reason for discontinuation of treatment as provided by patient/provider (side effects, lack of efficacy, cost, patient compliance, etc.) |
| Steroid Use | 3 month and 6 month | Number of patients with steroid doses remaining below 10 mg/day |
Countries
United States
Participant flow
Pre-assignment details
Out of 10 enrolled subjects, 9 subjects were randomized to one of three arms. One subject withdrew consent prior to being screened/randomized.
Participants by arm
| Arm | Count |
|---|---|
| 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.
TNF Antagonist (enbrel, humire, remicade, cimzia, symponi): TNF Antagonist; treating rheumatologist selects specifics for the therapy chosen. | 3 |
| Abatacept The participant will be prescribed abatacept in this arm. The treating rheumatologist selects the appropriate options for that therapy.
Abatacept: Abatacept; SQ; specifics to be determined by the treating rheumatologist. | 3 |
| Tocilizumab The participant will be prescribed tocilizumab. The treating rheumatologist selects the appropriate options for that therapy.
Tocilizumab: Tocilizumab; SQ; specifics determined by the treating rheumatologist. | 3 |
| Total | 9 |
Baseline characteristics
| Characteristic | Different TNF Inhibitor | Abatacept | Tocilizumab | Total |
|---|---|---|---|---|
| Age, Continuous | 44 years | 51 years | 52 years | 49 years |
| CDAI | 23 units on a scale | 17.3 units on a scale | 17.3 units on a scale | 19.2 units on a scale |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 1 / 3 | 2 / 3 | 2 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Mechanistic Comparisons (Changes in Frequencies of Peripheral Blood Immune Cell Subsets Following Institution of a Subcutaneously Administered TNF Antagonist, Tocilizumab or Abatacept.)
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. Flow ctyometry was performed on peripheral blood T cells to determine frequency of Th17/TfH cells based on cell surface markers.
Time frame: 0 to 3 months
Population: Patients (total of 5) who provided blood samples at 0 and 3 months and flow cytometry was performed before study discontinuation are included in the analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Different TNF Inhibitor | Mechanistic Comparisons (Changes in Frequencies of Peripheral Blood Immune Cell Subsets Following Institution of a Subcutaneously Administered TNF Antagonist, Tocilizumab or Abatacept.) | 0.9 Th17/TfH cell subset % change |
| Abatacept | Mechanistic Comparisons (Changes in Frequencies of Peripheral Blood Immune Cell Subsets Following Institution of a Subcutaneously Administered TNF Antagonist, Tocilizumab or Abatacept.) | 2.9 Th17/TfH cell subset % change |
| Tocilizumab | Mechanistic Comparisons (Changes in Frequencies of Peripheral Blood Immune Cell Subsets Following Institution of a Subcutaneously Administered TNF Antagonist, Tocilizumab or Abatacept.) | 0.9 Th17/TfH cell subset % change |
Secondary
ACR20, 50, and 70 Response
Efficacy as measured by ACR20, 50, and 70 response at 3 months and 6 months versus baseline
Time frame: 3 month and 6 month
Population: ACR20, 50, 70 were not calculated since clinical parameter such as CRP were not collected due to premature termination of study.
Secondary
Adherence
Adherence to drug regimen over course of clinical study
Time frame: 3 month and 6 month
Population: Number of patients who adhered to drug treatment through 6 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Different TNF Inhibitor | Adherence | 3 Participants |
| Abatacept | Adherence | 3 Participants |
| Tocilizumab | Adherence | 3 Participants |
Secondary
Corticosteroid Use
Average corticosteroid dose
Time frame: 3 month and 6 month
Population: Data not collected due to early termination of study
Secondary
DMARD Use
Number of patients without additional oral DMARDs or with a reduction in the number of oral DMARDs
Time frame: 3 month and 6 month
Population: Data was not collected for DMARDs due to premature termination of study due to insufficient patient enrollment.
Secondary
Efficacy (CDAI)
Efficacy of therapy, as measured by number of participants with Clinical Disease Activity Index (CDAI) of less than 2.8 (remission). CDAI is a composite score of RA disease activity based on patient survey (up to 10 points), physician survey (up to 10 points), + number of swollen joints + number of tender joints. 0 = no disease, max score is 60, higher score = more severe disease. Number of patients achieving remission is reported.
Time frame: 0 to 3 months
Population: CDAI change from 0 to 3 months was calculated for the 5 patients who had this data available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Different TNF Inhibitor | Efficacy (CDAI) | 0 Participants |
| Abatacept | Efficacy (CDAI) | 0 Participants |
| Tocilizumab | Efficacy (CDAI) | 0 Participants |
Secondary
Efficacy (DAS)
Efficacy as measured by DAS remission with a DAS28-CRP \< 2.4
Time frame: 3 month and 6 month
Population: CRP assays were not run as the study was incomplete due to premature termination of study.
Secondary
Efficacy (EULAR)
Efficacy as measured by European League against rheumatism (EULAR) response
Time frame: 3 month and 6 month
Population: This parameter was not calculated as data was incomplete due to premature termination of study
Secondary
Reason for Discontinuation of Treatment
Reason for discontinuation of treatment as provided by patient/provider (side effects, lack of efficacy, cost, patient compliance, etc.)
Time frame: 3 month and 6 month
Population: all 9 patients enrolled and assigned to a study group were analyzed for completion of therapy. All patients completed therapy and none discontinued so no additional data to report.
Secondary
Steroid Use
Number of patients with steroid doses remaining below 10 mg/day
Time frame: 3 month and 6 month
Population: Steroid dose information was not collected at 3 and 6 months as the study was terminated early with insufficient patient enrollment.