Protocol for an economic analysis of the randomised controlled trial of Improving the Well-being of people with Opioid Treated CHronic pain: I-WOTCH Study

Introduction Over the last two decades, the use of opioids for the treatment of chronic pain in England has steadily increased despite lack of evidence of both long-term effectiveness in pain relief and significant, well-documented physical and mental adverse events. Guidelines recommend tapering when harms outweigh benefits, but the addictive nature of opioids hinders simple dose-reduction strategies. Improving the Well-being of people with Opioid Treated CHronic pain (I-WOTCH) trial tests a multicomponent self-management intervention aimed to help patients with chronic non-malignant pain taper opioid doses. This paper outlines the methods to be used for the economic analysis of the I-WOTCH intervention compared with the best usual care. Methods and analysis Economic evaluation alongside the I-WOTCH study, prospectively designed to identify, measure and value key healthcare resource use and outcomes arising from the treatment strategies being compared. A within-trial cost-consequences analysis and a model-based long-term cost-effectiveness analysis will be conducted from the National Health Service and Personal Social Service perspective in England. The former will quantify key parameters to populate a Markov model designed to estimate the long-term cost and quality-adjusted life years of the I-WOTCH intervention against best usual care. Regression equations will be used to estimate parameters such as transition probabilities, utilities, and costs associated with the model’s states and events. Probabilistic sensitivity analysis will be used to assess the impact of parameter uncertainty onto the predicted costs and health outcomes, and the resulting value for money assessment of the I-WOTCH intervention. Ethics and dissemination Full ethics approval was granted by Yorkshire & The Humber—South Yorkshire Research Ethics Committee on 13 September 2016 (16/YH/0325). Current protocol: V.1.7, date 31 July 2019. Findings will be disseminated in peer-reviewed journals, scientific conferences, newsletters and websites. Trial registration number International Standard Randomised Controlled Trial Number (49 470 934); Pre-result.

I found the paper to be clearly written and well organized. Key elements of the data and the analytical approach are described succinctly. These descriptions are valuable to other researchers who may be considering economic analyses of cost and outcomes data from clinical trials.
My only suggestion for improvement is a thorough re-read of the paper to correct minor errors in writing/typing, and to ensure that the terminology used by the paper is either widely-understood or clearly defined. The first paragraph had a couple of instances where clarification may be useful. For example, I assume that "~34%" is meant to be read as "approximately 34%". I was also a little puzzled by the term "absolute rate" where the authors probably meant "combined rate" or "total rate".
Again, these suggestions are very minor in the context of an excellent paper.

REVIEWER
Ceri Phillips Professor of Health Economics and Head of College of Human and Health Sciences, Swansea University REVIEW RETURNED 18-May-2020

GENERAL COMMENTS
Thank you for the opportunity to review this paper. It is very well written and conforms to recognised conventions for economic evaluations of 'complex' interventions. The authors highlight the potential limitations in their proposed approach and therefore the only other query I have relates to the paper in preparation, which describes a detailed description of the conceptualization of the model, health states definition, clinical events and associated transitions.I appreciate that it is the topic for another paper, but some more detail of the model etc. would be of value to this paper as well.

VERSION 1 -AUTHOR RESPONSE
Reviewer: 1 4. This paper provides an excellent description of the economic analyses planned in conjunction with the I-WOTCH trial.
Response : Thanks 5. I found the paper to be clearly written and well organized.
Response : Thanks 6. Key elements of the data and the analytical approach are described succinctly. These descriptions are valuable to other researchers who may be considering economic analyses of cost and outcomes data from clinical trials.

Response :
We agree and very much hope our efforts in this sense can help others design their health economics studies.
7. My only suggestion for improvement is a thorough re-read of the paper to correct minor errors in writing/typing, and to ensure that the terminology used by the paper is either widely-understood or clearly defined.

Response :
Thank you for this suggestion. We have asked all co-authors to proof-read the manuscript to i) identify any additional typos and ii) make sure that the terminology used is either widely-understood or clearly defined.
8. The first paragraph had a couple of instances where clarification may be useful. For example, I assume that "~34%" is meant to be read as "approximately 34%". I was also a little puzzled by the term "absolute rate" where the authors probably meant "combined rate" or "total rate".

Response :
Many thanks for these comments. We have corrected the text to read "approximately 34%." Also, we went back to the relevant source reference to verify the statement on the "absolute rate" of opioidrelated adverse events. We confirmed that the source reference refers to an "absolute rate of adverse events in trials using a placebo as a comparator." Thus, for clarity, we modified our statement to read "at an estimated absolute rate of 78% in trials using a placebo as a comparator." Please see paragraph 1 on page 4. 9. Again, these suggestions are very minor in the context of an excellent paper.
Response : Thank you again for such a positive review.
Reviewer: 2 10. Thank you for the opportunity to review this paper. It is very well written and conforms to recognised conventions for economic evaluations of 'complex' interventions.
Response : We appreciate the positive feedback 11. The authors highlight the potential limitations in their proposed approach and therefore the only other query I have relates to the paper in preparation, which describes a detailed description of the conceptualization of the model, health states definition, clinical events and associated transitions. I appreciate that it is the topic for another paper, but some more detail of the model etc. would be of value to this paper as well.

Response :
We appreciate it may be difficult to assess a protocol paper without the fine details of the subsequent model. Here we have done our best to provide as much detail as possible within the constraints of the word limits imposed by the journal. We are planning on submitting the model conceptualisation paper very soon and would be happy to share a copy, strictly in confidence, with the referee if that helps.