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20/21 Subcutaneous vs Oral Methotrexate for Rheumatoid Arthritis
We understand that many people will be prioritising NHS work and supporting COVID 19 research during the current pandemic. It is NIHR policy that these should always be the priority as reinforced by our April Programme Director’s message. It is also NIHR policy https://www.nihr.ac.uk/documents/qanda-on-the-impact-of-covid-19-on-research-funded-or-supported-by-nihr/24467 to keep the future research pipeline healthy and to support the research community. The HTA programme is therefore advertising the following topics for stage 1 applications with a 16 week preparation period and deadline of 29 July 2020 unless otherwise stated. Please also note that these first stage applications do not need to contain a large amount of detail and that we only ask for estimates of costs at this stage.
The aim of the HTA Programme is to ensure that high quality research information on the effectiveness, costs and broader impact of health technology is produced in the most efficient way for those who use, manage, provide care in or develop policy for the NHS. Topics for research are identified and prioritised to meet the needs of the NHS. Health technology assessment forms a substantial portfolio of work within the National Institute for Health Research and each year about fifty new studies are commissioned to help answer questions of direct importance to the NHS. The studies include both primary research and evidence synthesis.
What is the clinical and cost-effectiveness of subcutaneous methotrexate compared with oral methotrexate for adults with rheumatoid arthritis?
Intervention: Subcutaneous methotrexate - to be defined by applicants.
Patient group: Adults with active rheumatoid arthritis who are being offered the disease-modifying anti-rheumatic drug (DMARD) methotrexate for the first time.
Applications are encouraged which include recruitment from geographic populations with high disease burden which have been historically underserved by research activity in this field and who may have barriers to self-administration.
Comparator: Oral methotrexate, as per current guidelines.
Study design: A randomised controlled trial with an internal pilot phase to test the ability to recruit and randomise. Clear stop/go criteria should be provided to inform progression from pilot to full trial.
Important outcomes: Disease activity; pain and function; quality of life; cost-effectiveness with consideration of appropriate maintenance treatment.
Other outcomes: Patient acceptability; drug survival; side-effects; fatigue; cumulative dose of glucocorticoids; progression to biologic therapy; occupational outcomes.
Where established Core Outcomes exist, they should be included amongst the list of outcomes unless there is good reason to do otherwise.
Minimum duration of follow-up: At least 12 months.
Longer-term follow up: Researchers should consider obtaining consent from participants to allow potential future follow up through efficient means (such as routine data) as part of a separately funded study.
Rheumatoid arthritis (RA) is an inflammatory disease which most commonly affects the small joints of the hands and feet, causing considerable pain and functional impairment. It is a systemic disease and so can affect the whole body, including the heart, lungs and eyes, causing a wide range of complications for people with the disease, their carers, the NHS and society in general. While RA predominantly affects people in their seventies, it can occur at any age. Approximately one-third of people stop work because of the disease within 2 years of onset, and this increases thereafter.
Pharmacological management is the mainstay of treatment. Early initiation and rapid dose escalation of disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate aim to alleviate pain and stiffness, control inflammation and prevent progression, with the ultimate goal of achieving remission.
Current UK guidance recommends initiating methotrexate orally. However, gastrointestinal side-effects (nausea, vomiting, mouth ulceration) are common and gastrointestinal absorption of oral methotrexate is variable, especially at higher doses, affecting bioavailability and subsequent clinical response. Should patients fail to respond to methotrexate or find themselves unable to tolerate it, their treatment will need to be escalated to newer, more powerful and considerably more expensive biologic drugs.
Alternatively, methotrexate can be given by injection under the skin, self-administered by the patient. Some clinicians currently prescribe subcutaneous methotrexate as a first-line treatment as it may be better tolerated and its effects may be superior to the oral form. However, whilst it is important maximise the benefit of treatment, subcutaneous preparations of methotrexate are considerably more expensive than oral therapy and evidence of its clinical and cost-effectiveness is currently lacking such that NICE was unable to recommend this route of administration in its latest guideline. It is possible that the increased costs of the drug and associated prescription processes are balanced by the improved management of the condition and hence a reduction in resource use, but its use within the NHS needs to be evidence based. In addition, other important factors such as patient acceptability of self-injecting and, indeed, patients’ ability to self-inject also need to be determined. For these reasons, NICE have highlighted this as a topic of high importance and the outcomes of this research should be suitable to inform future updates of the rheumatoid arthritis guideline.