The CORRONA Treat to Target Trial

The CORRONA Data Collection Program is a voluntary registry which collects physician and patient level data on care and outcomes of enrolled RA patients The Treat to Target Trial is a sub-study of the CORRONA Data Collection Program. New and existing CORRONA sites and patients may be recruited to participate as subjects in this 12 month trial examining outcomes and feasibility of implementing a Treat to Target approach, when compared with a control group of subjects treated with usual care.

The Treat to Target Trial is a sub-study of the CORRONA Data Collection Program. New and existing CORRONA sites and patients may be recruited to participate as subjects in this 12 month trial examining outcomes and feasibility of implementing a Treat to Target approach, requiring routine monthly monitoring and regular escalations of treatment for subjects not achieving low disease activity (LDA) when compared with a control group of subjects treated with usual care.

Several studies have demonstrated that RA can have a significant impact on the lives of patients who have this disease. Many RA patients have difficulty carrying out common household tasks and are unable to work. Other illnesses and adverse events appear to occur more frequently in patients with RA. Some of these problems may be related to the therapies used to treat RA, and others may be due to the disease itself. Similarly, prevalent conditions such as Psoriatic Arthritis (PsA) affect a large segment of our population and impose significant morbidity, care costs, and changes in lifestyle. Current estimates of patient outcomes, morbidity, mortality, quality of life measures, and drug cost, effectiveness and toxicity are often based on limited data sets, retrospective reviews and physician or patient surveys.

Purpose The primary purpose of the Treat to Target study is to determine whether practices implementing a multi-dimensional T2T process can more effectively control active Rheumatoid Arthritis (RA) in patients eligible-for-acceleration compared to those practices which continue usual care. The trial will also determine if the process of treating to target for the selected subjects is different between the two groups.

A wide variety of therapies is used in clinical practice to treat patients with RA, PsA, and other rheumatoid diseases. The Consortium of Rheumatology Researchers of North America, Inc. (CORRONA) Data Collection Program is designed to systematically collect and document utilization patterns, effectiveness, and safety of DMARDs (Disease Modifying Anti-Rheumatic Drugs), biologic agents, and many other treatments currently used in the management of RA, PsA, and other rheumatoid diseases. It is anticipated that the study data may help improve the quality of information upon which clinical decisions are based. This is not a specific drug treatment study, but rather an observational, disease-based registry study of all therapeutic interventions.

Objectives Co-primary Objectives 1. To measure rates of low disease activity (by CDAI score) between treatment arms (T2T vs usual care) at 12 months.

1a. .To assess implementation of a T2T Protocol in the U.S by comparing rates of acceleration, frequency of visits, time to next visit conditional on disease activity, and probability of acceleration conditional on disease activity between subjects treated in a T2T intervention group, compared with a control group treated with usual care (UC) at 12 months.

Secondary Objectives

1. To determine mediators of differences in LDA rates between the two randomized groups.
2. To determine the association between the process of treating to target and LDA (regardless of randomization).
3. To determine the proportion of subjects with active RA and moderate to high disease activity by CDAI eligible for acceleration at Baseline that will have achieved low disease activity (LDA) by CDAI at 6 months in subjects treated in a T2T intervention group compared with a control group treated with usual care (UC), and to baseline disease activity.

4. To compare performance of derived outcome metrics between the T2T intervention and usual care at 6 and 12 months, including:

   1. DAS28 ESR
   2. Patient Reported Outcomes- RAPID 3
5. To determine the frequency of ineligibility for treatment acceleration due to risks, comorbidities, concomitant medication or clinician judgment in potential T2T study enrollees.
6. To compare rates of drug toxicities between the T2T and UC groups over12 months.
7. To compare rates of Targeted Adverse Events (TAEs) between the T2T intervention and UC arms.

Exploratory Objectives To determine the rates and reasons for non-acceleration of subjects with qualifying CDAIs, enrolled in the T2T and UC arms The CORRONA Data Collection Program represents a novel advance by collecting, analyzing, and reporting real-time data trends on these issues. Information gathered through the CORRONA Data Collection Program is maintained in a comprehensive database (the CORRONA Database). The CORRONA Organization provides participating sites with access to technology that enables them to interact with and manipulate data maintained in the CORRONA Database on their own patient populations. The CORRONA Organization uses the CORRONA Database for purposes related to clinical, marketing, and outcomes research. Significantly, the CORRONA Organization intends to conduct its own novel clinical trials in rheumatology. In addition, the CORRONA Organization provides reports regarding information contained in the CORRONA Database for a fee to select industry subscribers who are not allowed direct access to the CORRONA Database. Rather, they are permitted to submit research queries to the CORRONA Organization which are executed by the CORRONA biostatisticians who generate appropriate responses to queries.

Data Collection Program Main Study Design Subjects with moderate to severe Rheumatoid Arthritis disease activity (defined as CDAI score >10) will be enrolled in the trial at participating sites. Sites will be randomized to either the Treat to Target or Usual Care arms. Visits will include a Screening, Baseline, Month 3, 6,9, and 12 visit for all subjects. In addition, subjects enrolled at sites participating in the Treat to Target Arm that have not achieved low disease activity (CDAI ≤10) will be expected to return for Monthly Assessment visits. Treatment acceleration will be expected to occur as frequently as monthly and at least every 3 months in these subjects, unless contraindicated.

Treatment acceleration for the purposes of this trial include the following options: Change in prescribed treatment or dosage of "traditional" or "biologic" Disease Modifying Anti Rheumatic Drugs (DMARDs) or a change in the route of Methotrexate administration (from oral to subcutaneous) Physicians and subjects complete CORRONA Data Collection Program Questionnaires (see Appendix B) approximately every four months (RA) or six months (PsA and UA). During the course of a regularly-scheduled office visit, the physician performs assessments as mandated on the CORRONA Data Collection Program Physician Questionnaires with recording of pertinent data. Results from certain laboratory tests are included, but not mandated, on these Questionnaires. Subjects are asked to complete Data Collection Program Questionnaires designed to capture information ranging from their general demographics and experience with prescription drug use to an overall global assessment of their disease. During their regularly-scheduled physician office visits, it is anticipated that they will spend approximately five to ten minutes completing the Questionnaires. Neither the Questionnaires completed by physicians nor the Questionnaires completed by subjects contain subject's names, addresses, telephone numbers, email addresses, or social security numbers.

Study Visits Visits will include a Screening, Baseline, Month 3, 6,9, and 12 visit for all subjects. In addition, subjects enrolled at sites participating in the Treat to Target Arm that have not achieved low disease activity (CDAI ≤10) will be expected to return for Monthly Assessment visits.

Patients are enrolled in the CORRONA Data Collection Program during regularly-scheduled office visits. Upon enrollment, physicians complete a set of Enrollment Questionnaires, including a 28 joint count (see Appendix C) and the New Biologic Start (NBS) Questionnaire when appropriate. Subjects also complete a CORRONA Data Collection Program Enrollment Questionnaire along with Health

Assessment and EQ5D Questionnaires. After the enrollment visit, RA patients then complete CORRONA Data Collection Program Follow-up Questionnaires during regularly scheduled clinical encounters approximately every four months, and PsA and UA patients approximately every six months.

In the event of a biologic new start or biologic switch in a RA patient, the physician will complete the NBS Questionnaire, Appendix A. Appendix B is to be completed by the physician and subject cooperatively at the very next CORRONA visit. If the Appendix B of this Questionnaire is completed at a visit other than the next subsequent visit, the set of Appendices will be null and void. In the event a subject initiates A NEW BIOLOGIC and discontinues a biologic at the same visit, then both Appendices A (FOR THE NEW BIOLOGIC) and B (FOR THE BIOLOGIC BEING DISCONTINUED) will be completed at the same visit.

Data are collected on subjects for as long as they consent to remain in the study.

Targeted Adverse Event Reporting Qualifying adverse events which occur during participation in the Data Collection program are reported on the Targeted Adverse Event (TAE) Questionnaires. TAE Questionnaires are completed and submitted when a flagged event on a CORRONA Data Collection Program Physician Follow-up Questionnaire has been selected. Submission of de-identified source documents (i.e. hospital records, laboratory results, etc.) in support of the reported TAE is required in order to be valid, unless otherwise determined by the CORRONA Organization. The TAE should be simultaneously reported on both the TAE Questionnaire and on the CORRONA Data Collection Program Physician Follow-up Questionnaire visit date that most closely follows the event (unless the TAE occurs on the date of the Follow-up Visit).

In addition, sites will be encouraged to forward CORRONA, Inc.de-identified reports on qualifying Serious Adverse Events within 24 hrs of learning of them using the CORRONA SAE report form.

Data Collection, Storage, and Confidentiality SAs described above, subjects and their physicians complete a set of CORRONA Data Collection Program Questionnaires at each study visit. In addition, a set of trial specific-CRFs will be used by sites to collect data pertinent to the trial outcomes under study. during the course of a regularly-scheduled office visit. Data contained in these Questionnaires are incorporated into the CORRONA Database, which is maintained by Court Square Group, Inc. (a Springfield, MA company) for CORRONA, and will be stored in the CORRONA Database indefinitely. The data are also stored in the Biostatistical Unit of The University of Massachusetts in Worcester, MA, directed by Dr. George Reed.

Data submitted for inclusion in the CORRONA Database does not include the names, addresses, telephone numbers, email addresses, or social security numbers of subjects. Data from Questionnaires are tracked in the CORRONA Database by a unique CORRONA identifier that will be assigned at the physician's office. A link is maintained at the physician's office between patient-identifying information (e.g., name, address, telephone number) and the unique CORRONA identifier. The physician's office does not share information with CORRONA that is needed to match subject names with these unique CORRONA identifiers.

Each subject's physician will be responsible for maintaining the subject's medical record in a manner that is consistent with applicable laws and regulations concerning confidentiality of patient records. Each subject's research record will be kept in a secure file within the physician's office or institution for an indefinite period of time. Medical records and data generated by the study may be reviewed by:

• The Department of Health and Human Services (DHHS)- Office of Human Research and Protection (OHRP)
• Food and Drug Administration (FDA)
• Other federal, state, and local agencies, as determined by applicable laws
• The applicable institutional review board (IRB) for the participating site. Therefore, absolute confidentiality cannot be guaranteed. While combined information for all subjects may be presented at meetings or in publications, no information that can reasonably be expected to identify any individual subjects can be released or published.

Since CORRONA does not have access to names, addresses, telephone numbers, email addresses, or social security numbers of subjects, those outside the participating physician's practice who obtain information from the CORRONA Database do not have access to this information either. Researchers, clinicians, biostatisticians, and others within the CORRONA Organization do access the CORRONA Database directly for purposes related to clinical, marketing, and outcomes research. The CORRONA Organization also permits select pharmaceutical companies, biotechnology companies, contract research organizations, other clinical trial sponsors, academic researchers, and clinicians to obtain information derived from the CORRONA Database for purposes related to clinical, market, and outcomes research. The CORRONA Organization does not permit these outside individuals and entities to access the CORRONA Database directly. Instead, they submit requests for statistical analyses, reports, and related services to the CORRONA Organization. These requests are screened by the CORRONA Organization, and, if accepted, a CORRONA biostatistician will access the CORRONA Database to generate a report that provides the answers needed. Since the CORRONA Organization does not have subjects' names, addresses, phone numbers, email addresses, or social security numbers, this information is not included in any such reports.

For example, a pharmaceutical company may request that a CORRONA biostatistician complete a statistical analysis comparing the efficacy of one therapy compared with another. Or, a company may ask for a report on the percentage of subjects in the CORRONA Database who are eligible to participate in a clinical trial of a new treatment. If it is determined that a subject would qualify for such a research study, the subject's physician would be contacted, and would determine in his or her sole discretion whether to contact the patient to discuss potential enrollment.

Further, since reports and analyses produced by CORRONA biostatisticians for outside individuals and entities will not include subjects' names, addresses, phone numbers, email addresses, or social security numbers, subjects will not receive direct mailings from pharmaceutical companies urging them to try new prescription drugs or be contacted by outside physicians seeking to enroll subjects in clinical trials as a result of their participation in the CORRONA Data Collection Program.

Site Enrollment Selected rheumatologists are invited to participate as investigators in the CORRONA Data Collection Program and Treat to Target sub-study.one or both of the Pharmacogenetic and CORRONA CERTAIN Sub-studies. Not all rheumatologists who are involved in the CORRONA Data Collection Program will be involved in these Sub-studies. Physicians are selected carefully in an effort to identify sites that have the appropriate qualifications and infrastructure to support the needs of the trial and comply with applicable regulations and Good Clinical Practices to protect the rights of human subjects.in an effort to ensure enrollment of subjects that represent a reasonable representation of a cross-section of the population throughout the country with rheumatic diseases. All potential sites are screened for clinical research experience and adherence to GCP (Good Clinical Practice) guidelines.

IRB/Ethics Committee Review Board Investigators must obtain Institutional Review Board (IRB) approval. Private physician offices and those not affiliated with an academic institution may submit to New England IRB (NEIRB). Sites at academic centers are typically required to submit to the local institutional IRB following designated templates and guidelines for submission, or to the NEIRB if this is approved by their institutional IRB.

Subject Informed Consent Informed consent will be obtained by the investigator and/or his or her associate(s) as designated by the principal investigator. Informed consent is obtained in the office setting, and secured in accordance with FDA regulations and guidelines prior to commencement of any study-specific related activities. Patient participation is voluntary, and participants may withdraw their consent at any time, or refuse to answer any questions without penalty. A copy of the signed informed consent form will be given to the participant and retained on site. Participants in the Treat to Target study are required to have signed consent for both the CORRONA Data Collection Program and the Treat to Target-specific consent form.For participation in one or more of the Sub-studies, the patient must signed a separate informed consent form.

Data Quality Assurance To ensure the quality and integrity of the CORRONA Database, including all Sub-studies, data collected on Questionnaires from physicians and subjects is submitted via on-line digital data entry at either the site level or by CORRONA personnel. Quality control edit checks are built into the on-screen data entry form in an attempt to reduce queries back to the site for omissions and out of range errors. The CORRONA Organization management conducts random checks of bulk data received from individual sites for consistency and completeness. The CORRONA Organization reserves the right to perform random or systematic audits of source documentation at sites in order to determine if the data collected represents events as documented in the medical records. All sites participating in the Treat to Target trial are expected to have at least one on-site monitoring visit during the course of the trial. This frequency may be adjusted, as needed, to address data quality issues.

• Experimental: Treat to Target Intervention Strategy
  Intervention: Other: Treatment Acceleration
• No Intervention: Control Group Treated with Usual Care

Inclusion Criteria:

• Patients eligible for the study will be both male and female adult (at least 18 years of age) patients who have a documented diagnosis of RA, are enrolled or willing to be enrolled in the CORRONA registry for the duration of the trial, have signed appropriate informed consent documents, are willing to participate in the trial, are medically appropriate for participation in the opinion of the investigator, and have moderate to severe RA disease activity as defined by CDAI >10.

Exclusion Criteria:

1. Patients under the age of 18
2. Women who are pregnant, breastfeeding or planning to become pregnant during the study period.
3. Patients with chronic or acute pain condition(s) other than active RA which, in the opinion of the investigator, is likely to confound or interfere with assessments of RA disease activity.
4. Functional class IV as defined by the ACR classification of functional status
5. Patients receiving a daily dose of prednisone of >10 mg within the 4 weeks prior to enrollment.
6. History of positive tuberculin skin test or equivalents that have not received documented treatment for latent tuberculosis (TB).
7. Patients with a significant, uncontrolled concomitant illness such as, but not limited to cardiovascular, renal, neurological, endocrinological, gastrointestinal, hepatic, metabolic, pulmonary or lymphatic disease.