Treatment of Rheumatoid Arthritis With DMARDs: Predictors of Response

Study Overview
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Brief Summary
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This is a 16-week, open-label study to identify factors that help predict clinical responses to DMARD therapies for RA (Rheumatoid Arthritis) patients. All patients will receive a starting dose of DMARD medication(s) which may be adjusted by the investigator as needed. If a subject becomes intolerant to a DMARD medication the subject will be withdrawn from the study at the discretion of the investigator. Visits (prior to week 16) where withdrawal is determined to be necessary will be considered end of study. End of study data (week 16) as well as study serum will be collected. (Serum only collected on those subjects who have consented to the addendum Serum and DNA of this study). A portion of the blood collected at baseline, week 8 and week 16 with the addendum portion of the study is for future research and will be utilized attempting to look to detect the generation of superoxide radicals. The radicals have been shown to be associated with inflammation and may correlate with the progression of RA. If this is true, then treatment with RA should decrease the levels of these radicals signaling response to treatment.

Detailed Description
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The purpose of the study is to gather, in a prospective manner, information on patients with rheumatoid arthritis and their response to DMARD therapy. Specific aims of this study are: A. To evaluate the efficacy of DMARD therapy as defined by attaining ACR 50 response after 16 weeks of therapy. B. To identify predictors of DMARD response in patients with RA. Does the presence of certain genetic factors such as the shared epitope predict DMARD response Does the presence of serological factors (e.g. ccp (cyclic citrullinated peptide) isotypes) predict DMARD response Does evidence of co-morbid conditions (e.g. periodontal disease) predict DMARD response A maximum of 400 RA patients will be consented for this protocol. Subject accrual for protocol v1.0 included UNMC (University of Nebraska Medical Center) and the RAIN (Rheumatoid Arthritis Investigational Network) sites. Subject accrual for protocol v2.0 will be derived exclusively from UNMC. Investigators have examined the discriminatory characteristics of several clinical and biologic parameters in predicting treatment response (at least 50% improvement based on ACR criteria) in initial analyses involving 54 participants with early RA treated with methotrexate monotherapy in past RAIN clinical trials. In the initial analyses, factors showing discriminatory characteristics have included rheumatoid factor (RF) isotypes (particularly IgA (Immunoglobulin A) and IgM (Immunoglobulin M), matrix metalloproteinase (MMP)-3, HLA-DRB1 (human leukocyte antigen-DR isotope) shared epitope (SE)-containing alleles, C-reactive protein, and interleukin (IL)-1. For instance, we have found that subjects with low serum concentrations of RF-IgM (< 27 IU/ml) are more likely to be non-responders than those with higher (> 27 IU/ml) serum concentrations (79% vs. 43%). Males and females will participate in this protocol. As RA is approximately three times more common in females, it is anticipated that a higher percentage of the study subjects will be female. Subjects will be > 19 years of age. This age range was chosen because the age of majority in Nebraska is 19. RA diagnosed before the age of 19 may not have the same disease characteristics as defined by the American College of Rheumatology (ACR) criterion for RA. Pediatric subjects will not be enrolled in this study. Rheumatoid arthritis occurs in all races. No enrollment restrictions have been based on race or ethnic origin.

Official Title
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Treatment of Rheumatoid Arthritis With DMARDs: Predictors of Response

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Methotrexate
* Drug: Abatacept
* Drug: Adalimumab
* Drug: Azathioprine
* Drug: Baricitinib
* Drug: Certolizumab
* Drug: Etanercept
* Drug: Golimumab
* Drug: Hydroxychloroquine
* Drug: Infliximab
* Drug: Leflunomide
* Drug: Minocycline
* Drug: Rituximab
* Drug: Sarilumab
* Drug: Sulfasalazine
* Drug: Tofacitinib


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Diag. with RA with 4 of 7 ACR criteria: 1) Morning stiffness for at least 1 hr. and at least 6 wks 2) Swelling of 3 or more joints for at least 6 wks. 3) Swelling of wrist, MCP, or proximal interphalangeal joints for 6 or more wks 4) Symmetric joint swelling. 5) Hand x-rays with erosions or bony decalcifications. 6) RA nodules 7) RF positive >19 yrs old at time of diagnosis of RA Current active disease with at least1 swollen joint Starting new DMARD medication(s) please circle: abatacept, adalimumab, azathioprine, barcitinib, certolizumab, etanercept, golimumab, hydroxychloroquine, infliximab, leflunomide, methotrexate, minocycline, rituximab, sarilumab, sulfasalazine, tofacitinib If on other DMARDS, must be on stable dose for ≥ 6 wks If on glucocorticoids must be on stable dose for 2 wks (< 10mg of Prednisone per day or equivalent) Able to adhere to study visit schedule: enrollment, 8 wks & 16 wks (+/- 2 wks) Hgb > 9g/dl WBC > 3.5 Neutrophils > 1.0 Platelets >100 Creatinine <1.6 AST or ALT not over 1.2 x upper limit Albumin: up to 1.0 g/dL less than lower limit of normal EXCLUSION CRITERIA: Pregnant or breastfeeding women Men and women of child bearing potential not willing to practice successful method of contraception

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Methotrexate Therapy<br>Subjects will receive methotrexate therapy for RA treatment. | Drug: Methotrexate<br>* Starting dose of Methotrexate of 15 mg once a week plus folic acid 1mg. daily.<br>* Other names: MTX;|
| Active Comparator: Abatacept Therapy<br>Subjects will receive abatacept therapy for RA treatment. | Drug: Abatacept<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Orencia;|
| Active Comparator: Adalimumab Therapy<br>Subjects will receive adalimumab therapy for RA treatment. | Drug: Adalimumab<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Humira;|
| Active Comparator: Azathioprine Therapy<br>Subjects will receive azathioprine therapy for RA treatment. | Drug: Azathioprine<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Imuran;|
| Active Comparator: Barcitinib Therapy<br>Subjects will receive barcitinib therapy for RA treatment. | Drug: Baricitinib<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Olimuant;|
| Active Comparator: Certolizumab Therapy<br>Subjects will receive certolizumab therapy for RA treatment. | Drug: Certolizumab<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Cimzia;|
| Active Comparator: Etanercept Therapy<br>Subjects will receive etanercept therapy for RA treatment. | Drug: Etanercept<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Enbrel;|
| Active Comparator: Golimumab Therapy<br>Subjects will receive golimumab therapy for RA treatment. | Drug: Golimumab<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Simponi;|
| Active Comparator: Hydroxycholoroquine Therapy<br>Subjects will receive hydroxychloroquine therapy for RA treatment. | Drug: Hydroxychloroquine<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Plaquenil;|
| Active Comparator: Infliximab Therapy<br>Subjects will receive infliximab therapy for RA treatment. | Drug: Infliximab<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Remicade;|
| Active Comparator: Leflunomide Therapy<br>Subjects will receive leflunomide therapy for RA treatment. | Drug: Leflunomide<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Arava;|
| Active Comparator: Minocycline Therapy<br>Subjects will receive minocycline therapy for RA treatment. | Drug: Minocycline<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Minocin;|
| Active Comparator: Rituximab Therapy<br>Subjects will receive rituximab therapy for RA treatment. | Drug: Rituximab<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Rituxin;|
| Active Comparator: Sarilumab Therapy<br>Subjects will receive sarilumab therapy for RA treatment. | Drug: Sarilumab<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Kevzara;|
| Active Comparator: Sulfasalazine Therapy<br>Subjects will receive sulfasalazine therapy for RA treatment. | Drug: Sulfasalazine<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Azulfidine;|
| Active Comparator: Tofacitinib Therapy<br>Subjects will receive tofacitinib therapy for RA treatment. | Drug: Tofacitinib<br>* Starting dose which may be adjusted as needed at the discretion of the investigator<br>* Other names: Xeljanz;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the efficacy of DMARD therapy for Rheumatoid Arthritis as defined by attaining ACR 50 response after 16 weeks of therapy. | The ACR50 is a composite measure defined as both improvement of 50% in the number of tender and number of swollen joints, and a 50% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). | 16 weeks | 
| To identify predictors of DMARD response in patients with RA | What are predictors of DMARD response in RA patients? | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Using ACR 50 composite measure, does the presence of certain genetic factors such as the shared epitope predict DMARD response | After 16 weeks of treatment, what is the number of participants with genetic factors such as the shared epitope demonstrating a 50% improvement in the number of tender and swollen joints, and a 50% improvement in three of five criteria: patient global assessment, physician global assessment, functional ability measure (most often Health Assessment Questionnaire/HAQ), visual analog pain scale and erythrocyte sedimentation rate or C-reactive protein (CRP). | 16 weeks | 
| Using ACR 50 composite measure, does the presence of serological factors (e.g. CCP isotypes) predict DMARD response | After 16 weeks of treatment, what is the number of participants with serological factors such as CCP isotypes demonstrating a 50% improvement in the number of tender and swollen joints, and a 50% improvement in three of five criteria: patient global assessment, physician global assessment, functional ability measure (most often Health Assessment Questionnaire/HAQ), visual analog pain scale and erythrocyte sedimentation rate or C-reactive protein (CRP). | 16 weeks | 
| Using ACR 50 composite measure, does evidence of co-morbid conditions (e.g. periodontal disease) predict DMARD response | After 16 weeks of treatment, what is the number of participants with co-morbid conditions such as periodontal disease, demonstrating a 50% improvement in the number of tender and swollen joints, and a 50% improvement in three of five criteria: patient global assessment, physician global assessment, functional ability measure (most often Health Assessment Questionnaire/HAQ), visual analog pain scale and erythrocyte sedimentation rate or C-reactive protein (CRP). | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Methotrexate, DMARD