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Low enrollment
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| Name | Class |
|---|---|
| Genentech, Inc. | INDUSTRY |
| Bristol-Myers Squibb | INDUSTRY |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Different TNF inhibitor | Active Comparator | 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. |
|
| Abatacept | Active Comparator | The participant will be prescribed abatacept in this arm. The treating rheumatologist selects the appropriate options for that therapy. |
|
| Tocilizumab | Active Comparator | The participant will be prescribed tocilizumab. The treating rheumatologist selects the appropriate options for that therapy. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TNF Antagonist (enbrel, humire, remicade, cimzia, symponi) | Drug | TNF Antagonist; treating rheumatologist selects specifics for the therapy chosen. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 0 to 3 months |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
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:
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
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| Name | Affiliation | Role |
|---|---|---|
| Larry W. Moreland, MD | University of Pittsburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pittsburgh | Pittsburgh | Pennsylvania | 15261 | United States |
Out of 10 enrolled subjects, 9 subjects were randomized to one of three arms. One subject withdrew consent prior to being screened/randomized.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 20, 2015 |
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| Abatacept | Drug | Abatacept; SQ; specifics to be determined by the treating rheumatologist. |
|
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| Tocilizumab | Drug | Tocilizumab; SQ; specifics determined by the treating rheumatologist. |
|
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| 0 to 3 months |
| Efficacy (DAS) | Efficacy as measured by DAS remission with a DAS28-CRP < 2.4 | 3 month and 6 month |
| ACR20, 50, and 70 Response | Efficacy as measured by ACR20, 50, and 70 response at 3 months and 6 months versus baseline | 3 month and 6 month |
| Efficacy (EULAR) | Efficacy as measured by European League against rheumatism (EULAR) response | 3 month and 6 month |
| Adherence | Adherence to drug regimen over course of clinical study | 3 month and 6 month |
| Steroid Use | Number of patients with steroid doses remaining below 10 mg/day | 3 month and 6 month |
| Corticosteroid Use | Average corticosteroid dose | 3 month and 6 month |
| DMARD Use | Number of patients without additional oral DMARDs or with a reduction in the number of oral DMARDs | 3 month and 6 month |
| Reason for Discontinuation of Treatment | Reason for discontinuation of treatment as provided by patient/provider (side effects, lack of efficacy, cost, patient compliance, etc.) | 3 month and 6 month |
| FG001 |
| 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. |
| FG002 | 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. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 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. |
| BG002 | 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. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Full Range | years |
| ||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| |||||||||||
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
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| CDAI | Clinical Disease Activity Index (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. | Mean | Full Range | units on a scale |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Mean | Full Range | Th17/TfH cell subset % change | 0 to 3 months |
|
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| |||||||||||||||||||||||||||||||
| 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. | CDAI change from 0 to 3 months was calculated for the 5 patients who had this data available. | Posted | Count of Participants | Participants | 0 to 3 months |
| ||||||||||||||||||||||||||||||||||
| Secondary | Efficacy (DAS) | Efficacy as measured by DAS remission with a DAS28-CRP < 2.4 | CRP assays were not run as the study was incomplete due to premature termination of study. | Posted | 3 month and 6 month |
| ||||||||||||||||||||||||||||||||||||
| Secondary | ACR20, 50, and 70 Response | Efficacy as measured by ACR20, 50, and 70 response at 3 months and 6 months versus baseline | ACR20, 50, 70 were not calculated since clinical parameter such as CRP were not collected due to premature termination of study. | Posted | 3 month and 6 month |
| ||||||||||||||||||||||||||||||||||||
| Secondary | Efficacy (EULAR) | Efficacy as measured by European League against rheumatism (EULAR) response | This parameter was not calculated as data was incomplete due to premature termination of study | Posted | 3 month and 6 month |
| ||||||||||||||||||||||||||||||||||||
| Secondary | Adherence | Adherence to drug regimen over course of clinical study | Number of patients who adhered to drug treatment through 6 months. | Posted | Count of Participants | Participants | 3 month and 6 month |
| ||||||||||||||||||||||||||||||||||
| Secondary | Steroid Use | Number of patients with steroid doses remaining below 10 mg/day | Steroid dose information was not collected at 3 and 6 months as the study was terminated early with insufficient patient enrollment. | Posted | 3 month and 6 month |
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| Secondary | Corticosteroid Use | Average corticosteroid dose | Data not collected due to early termination of study | Posted | 3 month and 6 month |
| ||||||||||||||||||||||||||||||||||||
| Secondary | DMARD Use | Number of patients without additional oral DMARDs or with a reduction in the number of oral DMARDs | Data was not collected for DMARDs due to premature termination of study due to insufficient patient enrollment. | Posted | 3 month and 6 month |
| ||||||||||||||||||||||||||||||||||||
| 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.) | 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. | Posted | 3 month and 6 month |
|
Adverse events were collected over the course of study participation which was 6 months.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. | 0 | 3 | 0 | 3 | 1 | 3 |
| EG001 | 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. | 0 | 3 | 0 | 3 | 2 | 3 |
| EG002 | 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. | 0 | 3 | 0 | 3 | 2 | 3 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
| ||
| Nausea | Gastrointestinal disorders | Systematic Assessment |
| ||
| Injection site reaction | Skin and subcutaneous tissue disorders | Systematic Assessment |
| ||
| Increase in cholesterol levels | Metabolism and nutrition disorders | Systematic Assessment |
| ||
| Headache | General disorders | Systematic Assessment |
| ||
| Fatigue | General disorders | Systematic Assessment |
| ||
| Eye floaters | Eye disorders | Systematic Assessment |
| ||
| Upper respiratory infection | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Pain in extremity | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
Due to the small number of patients enrolled in each group, it was not possible to perform statistical analyses of the primary endpoints. These are fairly broad measures that require large numbers to identify patterns in subset changes.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Larry Moreland, MD | University of Pittsburgh | 412-648-4098 | lwm5@pitt.edu |
| May 18, 2020 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D001172 | Arthritis, Rheumatoid |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D000079424 | Tumor Necrosis Factor Inhibitors |
| D000068800 | Etanercept |
| D000069285 | Infliximab |
| D000068582 | Certolizumab Pegol |
| D000068879 | Adalimumab |
| D000069594 | Abatacept |
| C502936 | tocilizumab |
| ID | Term |
|---|---|
| D000893 | Anti-Inflammatory Agents |
| D045506 | Therapeutic Uses |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D007141 | Immunoglobulin Fc Fragments |
| D007128 | Immunoglobulin Fragments |
| D010446 | Peptide Fragments |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D007127 | Immunoglobulin Constant Regions |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D018124 | Receptors, Tumor Necrosis Factor |
| D018121 | Receptors, Cytokine |
| D011971 | Receptors, Immunologic |
| D011956 | Receptors, Cell Surface |
| D008565 | Membrane Proteins |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D011092 | Polyethylene Glycols |
| D011108 | Polymers |
| D046911 | Macromolecular Substances |
| D007140 | Immunoglobulin Fab Fragments |
| D061067 | Antibodies, Monoclonal, Humanized |
| D018796 | Immunoconjugates |
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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.
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