Abstract. Objective: A randomised double- blind placebo controlled withdrawal clinical trial of prednisone versus placebo in patients with rheumatoid arthritis (RA), treated in usual clinical care with 1–4 mg/day prednisone, withdrawn to the same dose of 1 mg prednisone or identical placebo tablets. Methods: All patients were from one academic setting and all trial visits were conducted in usual clinical care. Patients were taking stable doses of 1–4 mg prednisone with stable clinical status, documented quantitatively by patient questionnaire scores. The protocol included three phases: (1) equivalence: 1–4 study prednisone 1 mg tablets taken for 1. Adverse Event (AE) A negative experience encountered by an individual during the course of a clinical trial, that is associated with the drug. An AE can include. The primary outcome was withdrawal due to patient- reported lack of efficacy versus continuation in the trial for 2. Results: Thirty- one patients were randomised, 1. In “intent- to- treat” analyses, 3/1. Among participants eligible for the primary outcome, 3/1. No meaningful adverse events were reported, as anticipated. Conclusion: Efficacy of 1–4 mg prednisone was documented.
Evidence of statistically significant differences with only 3. The use of glucocorticoids in the treatment of rheumatoid arthritis (RA) has evoked controversy for more than half a century. Disease modification was documented during the 1. Therefore, from the 1. RA only as “bridging therapy” while awaiting anticipated benefits of disease- modifying antirheumatic drugs (DMARDs), or for acute severe disease flares or life- threatening vasculitis. A reassessment began during the 1. RA8. 9 and clinical experience indicating relatively limited toxicity associated with low doses of glucocorticoids. ![]() An open study,1. 0 a 2. Reports indicating disease modification even with low doses of prednisone or prednisolone of 5–7. Prednisone or prednisolone for RA generally is initiated with a dose of 1. The medical literature includes varying criteria for “low- dose” prednisone, generally 5 mg or 1. A few clinicians, including the senior author, have treated most patients over the last decade with an initial dose of 3 mg/day. The efficacy of prednisone in doses of < 5 mg/day has not been established in patients with RA, and rheumatologists continue to disagree on the use of glucocorticoids. A double- blind clinical trial to analyse the efficacy of < 5 mg/day prednisone would therefore appear desirable. A large multicentre prospective randomised double- blind clinical trial in patients with no previous glucocorticoid therapy, to be taken with their usual RA treatment, might appear ideal. However, resources for such a multicentre clinical trial have not been available. Therefore, with partial support from the United States Arthritis Foundation, we performed a single- centre withdrawal trial of prednisone < 5 mg/day in the course of usual care. Methods. Patients. All patients were recruited from one academic clinical care setting at Vanderbilt University and all clinical trial visits were conducted during usual clinical care. Most patients with RA in this clinical setting have been treated with long- term prednisone 1–5 mg/day, with a usual initial dose of 3 mg/day since the mid- 1. Clinical efficacy without severe toxicity has been observed,2. Withdrawal clinical trial protocol. Patients with stable clinical status who were taking stable doses of prednisone 1–4 mg/day in 1 mg tablets or one 5 mg tablet per day (although no patients taking 5 mg were actually enrolled in the trial) over the previous 1. All participants gave informed consent to participate. The trial was approved by the Institutional Review Board of Vanderbilt University, and supported in part by the United States Arthritis Foundation. The trial was designed to be broadly inclusive with few exclusion criteria. Inclusion criteria were: age at least 1. American Rheumatism Association (ARA) criteria for RA; 2. Stable clinical status was documented by an absolute change of less than 3 units from 1. RAPID3), an index of the three patient- reported outcomes, on a multidimensional health assessment questionnaire (MDHAQ)2. Exclusion criteria were relatively few: no prednisone therapy; prednisone dose > 5 mg/day; improving or worsening clinical status; anticipation of joint replacement or other elective surgery; uncontrolled hypertension, diabetes or other comorbidities; severe fibromyalgia; inability to complete English language questionnaires; and pregnancy or nursing. The protocol included three phases: Equivalence: all participants were given a 1. These tablets were taken in lieu of the patients’ usual prednisone obtained at their own pharmacies to ascertain similar efficacy of the study prednisone to the usual prednisone. Transfer: participants who reported “equivalence” over the 1. The gradual transfer was performed to avoid abrupt reduction of prednisone usage in subjects randomised for transfer to placebo. Plan to “transfer” patients from low- dose prednisone tablets to study prednisone or placebo tablets. Comparison: participants were maintained over 2. Each visit included assessment and recording of weight and blood pressure; completion of an MDHAQ by the patient and scoring of RAPID3 by the rheumatologist; and laboratory tests of erythrocyte sedimentation rate (ESR), C- reactive protein (CRP), liver function and haematological status to monitor possible adverse events of prednisone or concomitant methotrexate or other medications. Prednisone and placebo tablets. Prednisone 1 mg tablets and identical placebo tablets were purchased from Apotex Inc, Toronto, Canada. Tablets were packaged in bottles containing 1. The bottles were relabelled at the trial site with two types of labels: “Bottle A”, known to be prednisone, and “Bottle B” which contained “unknown” tablets (either prednisone or placebo). The appropriate number of Bottle A study prednisone tablets in bottles of 1. Packets were prepared for visits 2, 3 and 4 based on the participant’s daily baseline dose (1–5 mg/day), according to a randomisation scheme in groups of 4 (2 prednisone and 2 placebo) for each dose. Packets for the entire study were prepared for 6. Study packets included the appropriate number of “Bottle A” bottles of 1. Bottle B” bottles of 1 mg prednisone or identical placebo tablets (table 1). Study visits. Visit 1 included an explanation of the trial and completion of informed consent. Participants were given a 1. Bottle A” 1 mg study prednisone tablets to take instead of their usual daily prednisone dosage for 1. This phase was designed to establish whether or not “equivalence” of the same dose of study prednisone to the patient’s usual prednisone tablets could be seen. Visit 2 occurred 1. Participants who reported “equivalence” of study prednisone to their usual prednisone dose over the 1. Each participant received a specific written schedule with specific dates every 4 weeks to reduce by one the number of tablets to be taken from “Bottle A” (of 1 mg prednisone tablets) and to increase by one the number of “Bottle B” (of unknown study tablets, either 1 mg prednisone or identical placebo tablets) over a 1. Substitution of one “Bottle B” tablet for one “Bottle A” tablet occurred at 0, 4, 8, 1. Therefore, at the end of the 1. Bottle B” study medication. The gradual tapering was designed to avoid an abrupt discontinuation of prednisone which might favour prednisone. Visit 3 occurred 4–1. All participants whose baseline daily dose was 2–4 mg prednisone then started taking only unknown Bottle B prednisone or placebo and began the “comparison” phase. Visit 4 occurred 1. Participants completed the usual MDHAQ and the trial status was reviewed with the investigator. Visit 5 occurred 1. The participants completed the final usual MDHAQ and prednisone was reinstated at the pretrial dose. Clinical trial outcomes. The predetermined primary outcome was withdrawal (“drop- out”) after visit 2 due to perceived lack of efficacy of study tablets (prednisone or placebo), ie, during the “transfer” or “comparison” phases of the trial, versus remaining in the trial until completion of the 2. Secondary outcomes included a change in any of the three RA Core Data Set variables. MDHAQ (as well as the HAQ) for physical function, pain and global estimate, all scored 0–1. RAPID3 0–3. 0 composite scores. Weight, systolic and diastolic blood pressure and laboratory tests of ESR, CRP, haematology and liver profiles were recorded at each visit and analysed as indicators of possible adverse events. Data management and statistical analyses.
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November 2017
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