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Common Protocol Template Rheumatoid Arthritis (RA) Library v002Section in Common Protocol Template (CPT)Library Content3. Objectives and [Estimands/Endpoints] Objectives and corresponding [estimands/endpoints] for the rheumatoid arthritis (RA) study5. Study PopulationInclusion criteria related to Type of ParticipantExclusion criteria related to Medical Conditions and Prior/Concomitant Therapy8. Study Assessments and ProceduresRecommended text for various study assessments11. ReferencesInstructional references3. Objectives and [Estimands/Endpoints] For randomized placebo controlled studies the primary estimand/endpoint should be measured at Week 12 per Health Authorities.Primary ObjectivesPrimary [Estimands/Endpoints]ACR 20To evaluate the efficacy of [study intervention X] at [Week 12, Week/month X] as measured by the American College of Rheumatology 20% improvement criteria (ACR 20) in adult subjects with [moderate to severe, active] RAACR [20,50] at Week [12, 16, 24, 52]DAS28To evaluate the efficacy of [study intervention X] at Week [X] as measured by the Disease Activity Score – 28 joints (DAS28) [CRP, ESR] in adult subjects with [moderate to severe, active] RADAS28-[CRP/ESR] at Week [12, 16, 24, 52]Secondary ObjectivesSecondary [Estimands/Endpoints]Disease Activity Week 12To evaluate the effect of [study interventionX] on other measures of disease activity at Week?12 ACR 50/70 Week 12ACR [50/70] at Week 12DAS28-ESR Week 12Disease Activity Score - 28 joints calculated using the erythrocyte sedimentation rate formula (DAS28-ESR) score and change from baseline at Week 12DAS28-CRP Week 12Disease Activity Score (28 joints) calculated using the C-reactive protein formula (DAS28-CRP) score and change from baseline at Week 12Radiographic ProgressionTo evaluate the effect of [study intervention X] on radiographic progressionChange from baseline in [Sharp score, van der Heijde score, Genant score] at Week [24, 52] (The VAS will be recorded directly [onto a paper worksheet, which will serve as the source documentation OR onto the electronic tablet, which will serve as the source documentation and will not be transcribed to a CRF].Tertiary/Exploratory Objectives Tertiary/Exploratory [Estimands/Endpoints]Disease Activity OtherTo explore the effect of [study intervention X] on other measures of disease activity at various timepointsACR [20/50/70] at all other timepoints collectedDAS28-ESR [and/or] DAS28-CRP score and change from baseline at all timepoints collectedDAS28-ESR remission defined as DAS28-ESR <2.6 at all timepoints collectedDAS28-CRP remission defined as DAS28-CRP <2.6 at all timepoints collectedDAS28-ESR low disease activity defined as DAS28-ESR ≤3.2 at all timepoints collected DAS28-CRP low disease activity defined as DAS28-CRP ≤3.2 at all timepoints collectedSimplified Disease Activity Index (SDAI) change from baseline at all measured timepointsSimplified Disease Activity Index (SDAI) remission defined as SDAI ≤3.3 at all timepoints collected Physician Global Assessment of Disease Activity (PGA) score at Week [X]PROTo describe the effect of [study intervention X] on patient reported outcomes.Health Assessment Questionnaire Disability Index (HAQ-DI) score and change from baseline at Week 12Medical Outcomes Short Form-36 Questionnaire Version 2 (PRO SF36v2) score and change from baseline at Week 12 Patient Global Assessment of Disease Activity (PRO patient global DA) score and change from baseline at Week 12 Patient Global Assessment of Joint Pain (PRO patient pain) score and change from baseline at Week 12 Work Productivity and Activity Impairment Questionnaire (WPAI) score and change from baseline at Week 12 5. Study Population5.1 Inclusion CriteriaType of ParticipantA diagnosis of RA consistent with the 1987 or 2010 American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria.Active RA defined as: ≥[4, 6, 8] swollen joints (based on [28, 66] joint count) and ≥[4, 6, 8] tender joints (based on [28, 68] joint count) at screening and baseline. [The distal interphalangeal joint should be evaluated but not included in the total count to determine eligibility.][C-reactive protein (CRP), ESR] greater than [upper limit of normal (ULN), absolute value X.X ] per the [central, local] laboratory at screening.DAS28 [ESR/CRP] [ >2.6, x.x] at screeningDemonstrated an inadequate response to, loss of response to, or intolerance to [at least one or more than one] [immunomodulatory, anti-tumor-necrosis factor (TNF)] treatment as defined below:Signs and symptoms of persistently active disease despite a history of at least one 12-week regimen of [oral azathioprine, methotrexate, hydroxychloroquine, sulfasalazine, anti-TNF agent, biologic disease-modifying antirheumatic drugs (DMARD)] ORHistory of intolerance to at least one [immunomodulator (including, but not limited to nausea/vomiting, abdominal pain, pancreatitis, liver function test abnormalities, lymphopenia, infection)] or [anti-TNF agent (including, but not limited to infusion/injection related reaction, demyelination, congestive heart failure, infection)]Receiving treatment with methotrexate for ≥12 weeks and on a stable dose ≥15mg weekly for ≥8 weeks prior to Day 1. A lower methotrexate dose is acceptable (but no lower than [7.5 mg weekly, 10 mg weekly]) if it is the highest tolerated dose and gastrointestinal or hematologic toxicity at doses ≥15 mg weekly is documented by the investigator.Receiving treatment with folic or folinic acid per investigator judgment or according to local standard of care.Receiving a stable dose of prednisone ≤10?mg daily or other equivalent corticosteroid dose and the dose must be stable for ≥2?weeks prior to Day 1.Immunizations (tetanus, diphtheria, pertussis, seasonal influenza [during flu season], and pneumococcal [polysaccharide] vaccinations) up to date per local standards as determined by the investigator.5.2. Exclusion CriteriaMedical ConditionsClass IV RA according to ACR revised response criteriaPresence of one or more significant concurrent medical conditions per investigator judgment, including but not limited to the following: poorly controlled diabetes or hypertension; chronic kidney disease stage IIIb, IV, or V; [symptomatic heart failure (New York Heart Association class II, III, or IV); myocardial infarction or unstable angina pectoris within the past 12 months prior to randomization]; severe chronic pulmonary disease (e.g., requiring oxygen therapy); major chronic inflammatory disease or connective tissue disease other than RA (e.g., systemic lupus erythematosus with the exception of secondary Sj?gren’s syndrome)Prior/concomitant therapyCurrently receiving or had treatment with cyclophosphamide, chlorambucil, nitrogen mustard, or any other alkylating agent ≤ 6 months prior to Day 1.Currently receiving or had treatment with any of the following ≤ 12 weeks prior to Day 1: azathioprine; cyclosporine; gold; mycophenolate mofetil; Prosorba column; Tacrolimus.Currently receiving or had treatment with leflunomide ≤ 12 weeks prior to Day 1 unless an active washout with cholestyramine has been performed.Currently receiving or had treatment with oral janus kinase inhibitor (e.g., tofacitinib, baricitinib) ≤ 4 weeks prior to Day 1.Currently receiving or had treatment with intra-articular, intramuscular or intravenous corticosteroids, including adrenocorticotropic hormone ≤ 4 weeks prior to Day 1.Currently receiving or had treatment with intra-articular hyaluronic acid injections ≤ 4 weeks prior to Day 1.8. Study Assessments and Procedures8.1 Efficacy AssessmentsTender and Swollen Joint Count (Joint Counts)All joint assessments will be performed by an experienced independent and blinded joint evaluator who has been certified as trained by [Sponsor/CRO] and must be identified on the delegation of authority for this responsibility. Each participant should have their assessments done by the same assessor throughout the study and the initials of the joint assessor are recorded in the CRF. The score for each joint will be recorded directly [onto a paper worksheet, which will serve as the source documentation OR onto the electronic tablet, which will serve as the source documentation and will not be transcribed to a CRF]. [Joints that have been replaced or injected with intra-articular steroids during the study are considered unevaluable]. [For the [screening and baseline] joint assessments, distal interphalangeal joints should be evaluated, but should not be included in the total count to determine eligibility.]Swollen Joint Count Assessments – A total [66, 28] joints will be scored for presence or absence of swelling.Tender Joint Count Assessments – A total [68, 28] joints will be scored for presence or absence of tenderness.Simplified Disease Activity Index (SDAI)The SDAI is the numerical sum of five outcome parameters: tender and swollen joint count (based on a 28-joint assessment), patient and physician global assessment of disease activity [visual analogue scale (VAS) 0-10 cm] and level of C-reactive protein (mg/dl, normal <1 mg/dl).Physician Global Assessment of Disease Activity (PGA)This assessment will be completed by a health care provider (HCP) other than the joint assessor when possible. The global assessment of the participant’s arthritis will be assessed by the HCP by completion of a visual analog scale (VAS). The VAS is 100 mm in length with “0” and [”No Activity at All”, No Arthritis Activity”] on the left end of the line and “100” and [“Worst Activity Imaginable”, “Extremely Active Arthritis”] at the right end of the line. The HCP will be asked to draw a vertical line through a horizontal line to indicate the participant’s disease activity. The HCP assessing the participant’s global disease will have access to the joint assessments. [Each participant should have their global assessment of disease activity done by the same HCP throughout the study and the initials of the HCP are recorded in the CRF.] The participant and HCP must complete the global assessments independently from each other. The study coordinator or designee will measure the line from the left end of the line to the HCP’s mark and will record this length in mm (0 to 100) on the form. The VAS will be recorded directly [onto a paper worksheet, which will serve as the source documentation OR onto the electronic tablet, which will serve as the source documentation and will not be transcribed to a CRF].Patient Reported OutcomesPatient Global Assessment of Joint Pain (PRO patient pain)The severity of the participant’s joint pain will be assessed by completion of a VAS. The VAS is 100 mm in length with “0” and [“no pain at all”, “no pain”] on the left end of the line and “100” and [“worst pain imaginable”, “the worst possible pain”] on the right end of the line. The participant will be asked to draw a vertical line through a horizontal line to indicate how much pain they are experiencing “today”. The study coordinator or designee will measure the line from the left end of the line to the participant’s mark and will record this length in mm (0 to 100) on the form. The VAS will be recorded directly [onto a paper worksheet, which will serve as the source documentation OR onto the electronic tablet, which will serve as the source documentation and will not be transcribed to a CRF].This questionnaire should take approximately 1 minute to complete.Patient Global Assessment of Disease Activity (PRO patient global DA)The subject’s global assessment of their arthritis disease activity will be assessed by completion of a VAS. The VAS is 100 mm in length with “0” and [“No Activity At All”, “Very Well”] on the left end of the line and “100” and [ “Worst Activity Imaginable”, “Very Poor”] on the right end of the line. The participant will be asked to draw a vertical line through a horizontal line to indicate their disease activity. The participant and HCP must complete the global assessments independently from each other. The study coordinator or designee will measure the line from the left end of the line to the participant’s mark and will record this length in mm (0 to 100) on the form. This questionnaire should take approximately 1 minute to complete.Health Assessment Questionnaire Disability Index (PRO HAQ-DI)HAQ-DI will be utilized to assess the subject’s physical function or disability according to the subject. The HAQ-DI asks about the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities [errands and chores]). Responses in each functional area are scored from 0 indicating no difficulty to 3 indicating inability to perform a task in that area. The study staff should not clarify any of the questions for the participant. This questionnaire should take approximately 5 minutes to complete.Medical Outcomes Short Form-36 Questionnaire Version 2 (PRO SF36v2)SF36v2 Health Survey contains 36 items and is a revised version of the SF36 Health Survey. The SF36v2 is a generic measure of health-related quality of life. This survey yields assessments of 8 domains of health-related quality of life: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. The scores from the 8 domains can further be aggregated into 2 summary component norm-based measures of physical and mental health. The SF36v2 has either a 7 day recall (acute) or 4 week recall (standard), and the 7 day recall will be used in this study.This survey takes approximately 5 to 10 minutes to complete.Work Productivity and Activity Impairment Questionnaire (WPAI)This self-administered questionnaire is designed to address impairment to the work productivity and activity of subjects due to rheumatoid arthritis. This questionnaire should take approximately 5 minutes to complete.11. ReferencesAletaha D, Neogi T, Silman A, et al. Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69(9):1580-8. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315-24. Cutolo M, Kitas GD, van Riel PL. Burden of disease in treated rheumatoid arthritis patients: going beyond the joint. Sem Arthritis Rheum. 2014;43(4):479-88. del Rincon ID, Williams K, Stern MP, et al. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001;44:2737-45. Gabriel, SE. Cardiovascular morbidity and mortality in rheumatoid arthritis. Am J Med. 2008;121(10A):S09-14. Genant HK. Methods of assessing radiologic change in rheumatoid arthritis. Am J Med. 1983;75(6a):35-47. Hochberg MC, Chang RW, Dwosh I, et al. The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum. 1992;35(5):498-502. Kallberg H, Ding B, Padyukov L, et al. EIRA Study Group. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann Rheum Dis. 70(3):508-11. Listing J, Gerhold K, Zink A. The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment. Rheumatology. 2013;52(1):53-61. Listing J, Strangfeld A, Kary S, et al. Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum. 2005;52:3403-12. Novosad SA, Winthrop KL. Beyond tumor necrosis factor inhibition: the expanding pipeline of biologic therapies for inflammatory diseases and their associated infectious sequelae. Clin Infect Dis. 2014;58(11):1587-98. ?stergaard M, Peterfy C, Conaghan P, et al. OMERACT Rheumatoid Arthritis Magnetic Resonance Imaging Studies: core set of MRI acquisitions, joint pathology definitions, and the OMERACT RA-MRI scoring system [erratum appears in J Rheumatol 2004;31:198]. J Rheumatol 2003;30:1385-6. Sharp JT, Young DY, Bluhm GB, et al. How many joints in the hands and wrists should be included in a score of radiologic abnormalities used to assess rheumatoid arthritis? Arthritis Rheum. 1985;28:1326-35. Smitten AL, Simon TA, Hochberg MC, et al. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res Ther. 2008;10:R45. Smolen JS, van de Heijde D, Machold KP, e al. Proposal for a new nomenclature of disease-modifying antirheumatic drugs. Ann Rheum Dis. 2014;73:3-5. Smolen JS, Breedveld FC, Schiff MH et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology 2003, 42 (2):244-257van der Heijde DM, van Riel PL, Nuver-Zwart IH, et al. Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis. Lancet. 1989;1(8646):1036-38. Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum. 2004;50:1740-51 ................
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