Cost effectiveness analysis of larval therapy for leg ulcers

Objective: To assess the cost effectiveness of larval therapy compared with hydrogel in the management of leg ulcers. Design: Cost effectiveness and cost utility analyses carried out alongside a pragmatic multicentre, randomised, open trial with equal randomisation. Population: Intention to treat population comprising 267 patients with a venous or mixed venous and arterial ulcers with at least 25% coverage of slough or necrotic tissue. Interventions: Patients were randomly allocated to debridement with bagged larvae, loose larvae, or hydrogel. Main outcome measure: The time horizon was 12 months and costs were estimated from the UK National Health Service perspective. Cost effectiveness outcomes are expressed in terms of incremental costs per ulcer-free day (cost effectiveness analysis) and incremental costs per quality adjusted life years (cost utility analysis). Results: The larvae arms were pooled for the main analysis. Treatment with larval therapy cost, on average, 96.70 pound ((sic)109.61; $140.57) more per participant per year (95% confidence interval -491.9 pound to 685.8) pound than treatment with hydrogel. Participants treated with larval therapy healed, on average, 2.42 days before those in the hydrogel arm (95% confidence interval -0.95 to 31. 91 days) and had a slightly better health related quality of life, as the annual difference in QALYs was 0.011 (95% confidence interval -0.067 to 0.071). However, none of these differences was statistically significant. The incremental cost effectiveness ratio for the base case analysis was estimated at 8826 pound per QALY gained and 40 pound per ulcer-free day. Considerable uncertainty surrounds the outcome estimates. Conclusions: Debridement of sloughy or necrotic leg ulcers with larval therapy is likely to produce similar health benefits and have similar costs to treatment with hydrogel. Trial registration: Current Controlled Trials ISRCTN55114812 and National Research Register N0484123692

A dose-effect network meta-analysis model with application in antidepressants using restricted cubic splines.

Network meta-analysis has been used to answer a range of clinical questions about the preferred intervention for a given condition. Although the effectiveness and safety of pharmacological agents depend on the dose administered, network meta-analysis applications typically ignore the role that drugs dosage plays in the results. This leads to more heterogeneity in the network. In this paper, we present a suite of network meta-analysis models that incorporate the dose-effect relationship using restricted cubic splines. We extend existing models into a dose-effect network meta-regression to account for study-level covariates and for groups of agents in a class-effect dose-effect network meta-analysis model. We apply our models to a network of aggregate data about the efficacy of 21 antidepressants and placebo for depression. We find that all antidepressants are more efficacious than placebo after a certain dose. Also, we identify the dose level at which each antidepressant's effect exceeds that of placebo and estimate the dose beyond which the effect of antidepressants no longer increases. When covariates were introduced to the model, we find that studies with small sample size tend to exaggerate antidepressants efficacy for several of the drugs. Our dose-effect network meta-analysis model with restricted cubic splines provides a flexible approach to modelling the dose-effect relationship in multiple interventions. Decision-makers can use our model to inform treatment choice

Using discrete choice experiments to elicit preferences for digital wearable health technology for self-management of chronic kidney disease

Objectives: Wearable digital health technologies (DHTs) have the potential to improve chronic kidney disease (CKD) management through patient engagement. This study aimed to investi gate and elicit preferences of individuals with CKD toward wearable DHTs designed to support self-management of their condition. Methods: Using the results of our review of the published literature and after conducting qualitative patient interviews, five-choice attributes were identified and included in a discrete choice experiment. The design consisted of 10-choice tasks, each comprising two hypothetical technologies and one opt-out scenario. We collected data from 113 adult patients with CKD stages 3–5 not on dialysis and analyzed their responses via a latent class model to explore preference heterogeneity. Results: Two patient segments were identified. In all preference segments, the most important attributes were the device appearance, format, and type of information provided. Patients within the largest preference class (70 percent) favored information provided in any format except the audio, while individuals in the other class preferred information in text format. In terms of the style of engagement with the device, both classes wanted a device that provides options rather than telling them what to do. Conclusions: Our analysis indicates that user preferences differ between patient subgroups, supporting the case for offering a different design of the device for different patients’ strata, thus moving away from a one-size-fits-all service provision. Furthermore, we showed how to leverage the information from user preferences early in the R&D process to inform and support the provision of nuanced person-centered wearable DHT

Process evaluation protocol for the I-WOTCH study: an opioid tapering support programme for people with chronic non-malignant pain

58.<Nichols VP, Abraham C, Eldabe S, Sandhu HK, Underwood M, Seers K onbehalf of the I-WOTCH Team (Iglesias CP is member of the I-WOTCH team).. BMJ Open 2019; 9(10):e028998. Published online 2019 Oct 10. DOI: 10.1136/bmjopen-2019-028998PMID: 3160158

Reducing Opioid Use for Chronic Pain With a Group-Based Intervention: A Randomized Clinical Trial

IMPORTANCE: Opioid use for chronic nonmalignant pain can be harmful. OBJECTIVE: To test whether a multicomponent, group-based, self-management intervention reduced opioid use and improved pain-related disability compared with usual care. DESIGN, SETTING, AND PARTICIPANTS: Multicentered, randomized clinical trial of 608 adults taking strong opioids (buprenorphine, dipipanone, morphine, diamorphine, fentanyl, hydromorphone, methadone, oxycodone, papaveretum, pentazocine, pethidine, tapentadol, and tramadol) to treat chronic nonmalignant pain. The study was conducted in 191 primary care centers in England between May 17, 2017, and January 30, 2019. Final follow-up occurred March 18, 2020. INTERVENTION: Participants were randomized 1:1 to either usual care or 3-day-long group sessions that emphasized skill-based learning and education, supplemented by 1-on-1 support delivered by a nurse and lay person for 12 months. MAIN OUTCOMES AND MEASURES: The 2 primary outcomes were Patient-Reported Outcomes Measurement Information System Pain Interference Short Form 8a (PROMIS-PI-SF-8a) score (T-score range, 40.7-77; 77 indicates worst pain interference; minimal clinically important difference, 3.5) and the proportion of participants who discontinued opioids at 12 months, measured by self-report. RESULTS: Of 608 participants randomized (mean age, 61 years; 362 female [60%]; median daily morphine equivalent dose, 46 mg [IQR, 25 to 79]), 440 (72%) completed 12-month follow-up. There was no statistically significant difference in PROMIS-PI-SF-8a scores between the 2 groups at 12-month follow-up (-4.1 in the intervention and -3.17 in the usual care groups; between-group difference: mean difference, -0.52 [95% CI, -1.94 to 0.89]; P = .15). At 12 months, opioid discontinuation occurred in 65 of 225 participants (29%) in the intervention group and 15 of 208 participants (7%) in the usual care group (odds ratio, 5.55 [95% CI, 2.80 to 10.99]; absolute difference, 21.7% [95% CI, 14.8% to 28.6%]; P < .001). Serious adverse events occurred in 8% (25/305) of the participants in the intervention group and 5% (16/303) of the participants in the usual care group. The most common serious adverse events were gastrointestinal (2% in the intervention group and 0% in the usual care group) and locomotor/musculoskeletal (2% in the intervention group and 1% in the usual care group). Four people (1%) in the intervention group received additional medical care for possible or probable symptoms of opioid withdrawal (shortness of breath, hot flushes, fever and pain, small intestinal bleed, and an overdose suicide attempt). CONCLUSIONS AND RELEVANCE: In people with chronic pain due to nonmalignant causes, compared with usual care, a group-based educational intervention that included group and individual support and skill-based learning significantly reduced patient-reported use of opioids, but had no effect on perceived pain interference with daily life activities. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN49470934

Protocol for an economic analysis of the randomised controlled trial of improving the wellbeing 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 Wellbeing 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 to 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 programme 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 programme. Ethics and dissemination: Full ethics approval was granted by Yorkshire & The Humber – South Yorkshire Research Ethics Committee on September 13th, 2016 (16/YH/0325). Current protocol: version 1.7, date 31 July 2019. Findings will be disseminated in peer reviewed journals, scientific conferences, newsletters, and websites. Registration details: International Standard Randomised Controlled Trial Number: 49470934 (6 Feb 2017)

Developing a model Fracture Liaison Service consultation with patients, carers and clinicians: a Delphi survey to inform content of the iFraP complex consultation intervention

Summary Fracture Liaison Services are recommended to deliver best practice in secondary fracture prevention. This modified Delphi survey, as part of the iFraP (Improving uptake of Fracture Prevention drug Treatments) study, provides consensus regarding tasks for clinicians in a model Fracture Liaison Service consultation. Purpose The clinical consultation is of pivotal importance in addressing barriers to treatment adherence. The aim of this study was to agree to the content of the ‘model Fracture Liaison Service (FLS) consultation’ within the iFraP (Improving uptake of Fracture Prevention drug Treatments) study. Methods A Delphi survey was co-designed with patients and clinical stakeholders using an evidence synthesis of current guidelines and content from frameworks and theories of shared decision-making, communication and medicine adherence. Patients with osteoporosis and/or fragility fractures, their carers, FLS clinicians and osteoporosis specialists were sent three rounds of the Delphi survey. Participants were presented with potential consultation content and asked to rate their perception of the importance of each statement on a 5-point Likert scale and to suggest new statements (Round 1). Lowest rated statements were removed or amended after Rounds 1 and 2. In Round 3, participants were asked whether each statement was ‘essential’ and percentage agreement calculated; the study team subsequently determined the threshold for essential content. Results Seventy-two, 49 and 52 patients, carers and clinicians responded to Rounds 1, 2 and 3 respectively. One hundred twenty-two statements were considered. By Round 3, consensus was reached, with 81 statements deemed essential within FLS consultations, relating to greeting/introductions; gathering information; considering therapeutic options; eliciting patient perceptions; establishing shared decision-making preferences; sharing information about osteoporosis and treatments; checking understanding/summarising; and signposting next steps. Conclusions This Delphi consensus exercise has summarised for the first time patient/carer and clinician consensus regarding clearly defined tasks for clinicians in a model FLS consultation

Testing a support programme for opioid reduction for people with chronic non-malignant pain: The I-WOTCH randomised controlled trial protocol

Introduction: Chronic non-malignant pain has a major impact on the wellbeing, mood and productivity of those affected. Opioids are increasingly being prescribed to manage this type of pain, but the increasing risk of other disabling symptoms, and their effectiveness for this type of pain has been questioned. This trial is designed to implement and evaluate a patient-centred intervention targeting withdrawal of strong opioids in patients with chronic pain. . Methods and analysis: A pragmatic, multi–centre, randomised controlled trial will assess the clinical and cost-effectiveness of a group-based multicomponent intervention combined with individualised clinical facilitator led support for the management of chronic non-malignant pain against the control intervention (self-help booklet and relaxation CD). An embedded process evaluation will examine fidelity of delivery and investigate experiences of the intervention. The twoprimary outcomes are activities of daily living (measured by PROMIS Pain Interference Short Form (8A)) and opioid use. The secondary outcomes are pain severity, quality of life, sleep quality, self-efficacy, adverse events, and NHS health care resource use. Participants are followed up at four, eight, and 12 months, with a primary endpoint of 12 months. Between-group differences will indicate effectiveness; we are looking for a difference of 3.5 points on our pain interference outcome (scale 40-77). We will undertake an NHS perspective cost-effectiveness analysis using Quality Adjusted Life Years. Ethics: Full approval was given by Yorkshire & The Humber - South Yorkshire Research Ethics Committee on September 13th, 2016 (16/YH/0325). Appropriate local approvals were sought for each area in which recruitment was undertaken. The current protocol version is 1.6. date 19th December 2018. Dissemination: Publication of results in peer reviewed journals, including the development and theoretical framework of the intervention, will inform the scientific and clinical community. We will disseminate results to patient participants and study facilitators in a study newsletter as well as a lay summary of results on the study website. Trial registration: This trial is registered with an International Standard Randomised Controlled Trial Number (ISRCTN) Register. ISRCTN number: 49470934 (06 Feb 2017

Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study

Background Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn’s disease (CD) patients in real-world clinical practice. Methods A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. Results A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). Conclusions Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice