Treatment of Rheumatoid Arthritis With DMARDs: Predictors of Response

• ClinicalTrials.gov Identifier: NCT03414502
• Recruitment Status: Recruiting
• First Posted: January 30, 2018
• Last Update Posted: September 13, 2023
• Sponsor: University of Nebraska
• Information provided by (Responsible Party): University of Nebraska

Study Description

Brief Summary:

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 If a subject becomes intolerant to a DMARD medication the subject will be withdrawn from the study at the discretion of the investigator.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.

Condition or disease	Intervention/treatment	Phase
Rheumatoid Arthritis	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	Phase 3

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 400 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Treatment of Rheumatoid Arthritis With DMARDs: Predictors of Response
• Actual Study Start Date: December 10, 2007
• Estimated Primary Completion Date: March 2025
• Estimated Study Completion Date: March 2027

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. To evaluate the efficacy of DMARD therapy for Rheumatoid Arthritis as defined by attaining ACR 50 response after 16 weeks of therapy. [ Time Frame: 16 weeks ]
   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).
2. To identify predictors of DMARD response in patients with RA [ Time Frame: 16 weeks ]
   What are predictors of DMARD response in RA patients?

Secondary Outcome Measures :

1. Using ACR 50 composite measure, does the presence of certain genetic factors such as the shared epitope predict DMARD response [ Time Frame: 16 weeks ]
   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).
2. Using ACR 50 composite measure, does the presence of serological factors (e.g. CCP isotypes) predict DMARD response [ Time Frame: 16 weeks ]
   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).
3. Using ACR 50 composite measure, does evidence of co-morbid conditions (e.g. periodontal disease) predict DMARD response [ Time Frame: 16 weeks ]
   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).

Eligibility Criteria

• Ages Eligible for Study: 19 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Aimee B Schreiner, MS; 402-559-4873; aischreiner@unmc.edu

Locations

United States, Nebraska

University of Nebraska Medical Center; Recruiting

Omaha, Nebraska, United States, 68198

Contact: Aimee Schreiner, MS 402-559-7288 aischreiner@unmc.edu

Contact: Bridget Kramer, RN 402-559-7288 bridget.kramer@unmc.edu

Principal Investigator: James R O'Dell, MD

Sponsors and Collaborators

University of Nebraska

Investigators

• Principal Investigator: James R O'Dell, MD; University of Nebraska

More Information

• Responsible Party: University of Nebraska
• ClinicalTrials.gov Identifier: NCT03414502
• Other Study ID Numbers: 0439-23-FB
• First Posted: January 30, 2018
• Last Update Posted: September 13, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Data remains stored at UNMC for approved investigators at this site only at this time

Keywords provided by University of Nebraska:

Methotrexate; DMARD

Additional relevant MeSH terms:

Hydroxychloroquine; Arthritis; Arthritis, Rheumatoid; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Minocycline; Sulfasalazine; Adalimumab; Infliximab; Golimumab; Certolizumab Pegol; Etanercept; Rituximab; Abatacept; Methotrexate; Azathioprine; Leflunomide; Tofacitinib; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents