Pharmacological conditioning in the treatment of recent-onset rheumatoid arthritis: a randomized controlled trial study protocol

Abstract

BackgroundIn pharmacological conditioning associations are formed between the effects of medication and contextual factors related to the medication. Pharmacological conditioning with placebo medication can result in comparable treatment effects and reduced side effects compared to regular treatment in various clinical populations, and may be applied to achieve enhanced drug effects. In the current study protocol, pharmacological conditioning is applied to achieve enhanced treatment effects in patients with recent-onset rheumatoid arthritis (RA). The results from this study broaden the knowledge on the potential of pharmacological conditioning and provide a potential innovative treatment option to optimize long-term pharmacological treatment effectiveness for patients with inflammatory conditions, such as recent-onset RA.MethodsA multicenter, randomized controlled clinical trial is conducted in patients with recent-onset RA. Participants start on standardized pharmacological treatment for 16 weeks, which consists of methotrexate (MTX) 15 mg/week and a tapered schedule of prednisone 60 mg or 30 mg. After 4 months, participants in clinical remission (based on the rheumatologist’s opinion and a targeted score below 1.6 on a 44-joint disease activity score (DAS44)) are randomized to 1 of 2 groups: (1) the control group (C), which continues with a standardized treatment schedule of MTX 15 mg/week or (2) the pharmacological conditioning group (PC), which receives an MTX treatment schedule in alternating high and low dosages. In the case of persistent clinical remission after 8 months, treatment is tapered and discontinued linearly in the C group and variably in the PC group. Both groups receive the same cumulative amount of MTX during each period. Logistic regression analysis is used to compare the proportion of participants with drug-free clinical remission after 12 months between the C group and the PC group. Secondary outcome measures include clinical functioning, laboratory assessments, and self-reported measures after each 4-month period up to 18 months after study start.DiscussionThe results from this study broaden the knowledge on the potential of pharmacological conditioning and provide a potential innovative treatment option to optimize long-term pharmacological treatment effectiveness in patients with inflammatory conditions, such as recent-onset RA.Trial registrationNetherlands Trial Register, NL5652. Registered on 3 March 2016.

Can Pharmacological Conditioning as an Add-On Treatment Optimize Standard Pharmacological Treatment in Patients with Recent-Onset Rheumatoid Arthritis? A Proof-of-Principle Randomized Clinical Trial

“…Patients with recent-onset rheumatoid arthritis (according to the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 classification criteria [ 1 ]) were recruited from the Department of Rheumatology at the Leiden University Medical Center (LUMC) and other hospitals in the Medical Delta vicinity in the Netherlands. Eligibility was assessed by the patient’s treating clinician according to specific inclusion and exclusion criteria [ 17 ]. An eligible patient was asked to sign informed consent after obtaining written information about the study.…”

“…This study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization (ICH) Guidelines on Good Clinical Practice (GCP). This study was preregistered at the Netherlands Trial Register (https://www.onderzoekmetmensen.nl/en/ trial/20702; registered 03-03-2016), which was transferred to the International Clinical Trials Registry Platform (https://trialsearch.who.int/?trialid=NTR5770), and the analysis plan was published in a protocol paper [17].…”

“…Patients who do not respond well to standard combination therapy often receive intensified and expensive pharmacological treatments, including a combination of small-molecule drugs and biologics [ 4 , 5 , 6 , 7 , 10 ]. Pharmacological conditioning [ 11 , 12 , 13 , 14 , 15 , 16 ] could be applied as an add-on treatment to optimize standard pharmacological treatment effects while minimizing possible side effects and health care costs and may result in more patients attaining a (drug-free) clinical remission [ 17 ].…”

“…It was expected that add-on pharmacological conditioning to standard treatment would result in a higher percentage of patients attaining a drug-free clinical remission (primary outcome) than standard treatment alone. Secondary outcomes include clinical functioning, self-reported outcomes, and laboratory outcomes [ 17 ].…”

Pharmacological conditioning for juvenile idiopathic arthritis: a potential solution to reduce methotrexate intolerance

“…However, in contrast to the JIA population, side effects in the adult population are less common and therefore this population may be suboptimal to test this design first (37). Nonetheless, a currently ongoing pharmacological conditioning study with MTX and RA patients did indicate the potential for conditioning with MTX (38). Finally, an important consideration is whether conditioning of therapeutic effects may also lead to conditioning of the unwanted side effects.…”