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Background Dupuytren’s contracture is caused by nodules and cords which pull the fingers towards the palm of the hand. Treatments include limited fasciectomy surgery, collagenase injection and needle fasciotomy. There is limited evidence comparing limited fasciectomy with collagenase injection. Objectives To compare whether collagenase injection is not inferior to limited fasciectomy when treating Dupuytren’s contracture. Design Pragmatic, two-arm, unblinded, randomised controlled non-inferiority trial with a cost-effectiveness evaluation and nested qualitative and photographic substudies. Setting Thirty-one National Health Service hospitals in England and Scotland. Participants Patients with Dupuytren’s contracture of ≥ 30 degrees who had not received previous treatment in the same digit. Interventions Collagenase injection with manipulation 1–7 days later was compared with limited fasciectomy. Main outcome measures The primary outcome was the Patient Evaluation Measure score, with 1 year after treatment serving as the primary end point. A difference of 6 points in the primary end point was used as the non-inferiority margin. Secondary outcomes included: Unité Rhumatologique des Affections de la Main scale; Michigan Hand Outcomes Questionnaire; recurrence; extension deficit and total active movement; further care/re-intervention; complications; quality-adjusted life-year; resource use; and time to function recovery. Randomisation and blinding Online central randomisation, stratified by the most affected joint, and with variable block sizes allocates participants 1 : 1 to collagenase or limited fasciectomy. Participants and clinicians were not blind to treatment allocation. Results Between 31 July 2017 and 28 September 2021, 672 participants were recruited (n = 336 per group), of which 599 participants contributed to the primary outcome analysis (n = 285 limited fasciectomy; n = 314 collagenase). At 1 year (primary end point) there was little evidence to support rejection of the hypothesis that collagenase is inferior to limited fasciectomy. The difference in Patient Evaluation Measure score at 1 year was 5.95 (95% confidence interval 3.12 to 8.77; p = 0.49), increasing to 7.18 (95% confidence interval 4.18 to 10.88) at 2 years. The collagenase group had more complications (n = 267, 0.82 per participant) than the limited fasciectomy group (n = 177, 0.60 per participant), but limited fasciectomy participants had a greater proportion of ‘moderate’/‘severe’ complications (5% vs. 2%). At least 54 participants (15.7%) had contracture recurrence and there was weak evidence suggesting that collagenase participants recurred more often than limited fasciectomy participants (odds ratio 1.39, 95% confidence interval 0.74 to 2.63). At 1 year, collagenase had an insignificantly worse quality-adjusted life-year gain (−0.003, 95% confidence interval −0.006 to 0.0004) and a significant cost saving (−£1090, 95% confidence interval −£1139 to −£1042) than limited fasciectomy with the probability of collagenase being cost-effective exceeding 99% at willingness to pay thresholds of £20,000–£30,000 per quality-adjusted life-year. At 2 years, collagenase was both significantly less effective (−0.048, 95% confidence interval −0.055 to −0.040) and less costly (−£1212, 95% confidence interval −£1276 to −£1147). The probability of collagenase being cost-effective was 72% at the £20,000 threshold but limited fasciectomy became the optimal treatment at thresholds over £25,488. The Markov model found the probability of collagenase being cost-effective at the lifetime horizon dropped below 22% at thresholds over £20,000. Semistructured qualitative interviews found that those treated with collagenase considered the outcome to be acceptable, though not perfect. The photography substudy found poor agreement between goniometry and both participant and clinician taken photographs, even after accounting for systematic differences from each method. Limitations Impacts of the COVID-19 pandemic resulted in longer waits for Dupuytren’s contracture treatment, meaning some participants could not be followed up for 2 years. This resulted in potential underestimation of Dupuytren’s contracture recurrence and/or re-intervention rates, which may particularly have impacted the clinical effectiveness and long-term Markov model findings. Conclusions Among adults with Dupuytren’s contracture, collagenase delivered in an outpatient setting is less effective but more cost-saving than limited fasciectomy. Further research is required to establish the longer-term implications of both treatments. Future work Recurrence and re-intervention usually occur after 1 year, and therefore follow-up to 5 years or more could resolve whether the differences observed in the Dupuytren’s interventions surgery versus collagenase trial to 2 years worsen. Study registration Current Controlled Trials ISRCTN18254597. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/102/04) and is published in full in Health Technology Assessment; Vol. 28, No. 78. See the NIHR Funding and Awards website for further award information. Plain language summary Dupuytren’s contracture happens when fibrous tissue builds up and over time bends the finger(s) into the palm, causing problems with hand function. To treat this, surgery is usually used to straighten the finger. A less intrusive alternative is an injection (collagenase), which softens the tissue after which the finger is moved to straighten it. The Dupuytren's interventions surgery versus collagenase trial recruited 672 patients who were equally and randomly assigned to have either surgery or collagenase injection. The study assessed whether the injection was as good and as safe as surgery at straightening the finger and how long the finger remained straightened. For up to 2 years after treatment, the participant’s hand function and general health were assessed. Some participants provided photographs to monitor changes to the finger, and some were asked about their experiences of Dupuytren’s contracture and treatments. We found: Hand health improved following both treatments. Initially, the injection treatment improved hand health more than surgery. However, by 1 year, surgery improved hand health more than the injection treatment. Recovery of hand function was quicker for participants who received the injection; however, they were more likely to need further treatment (i.e. further care and/or re-intervention). Participants said that the less positive longer-term outcome was acceptable for a better treatment experience. For both treatments, interviews found that participants were happy with the hand improvement they experienced at 3 months after treatment. More than half of participants had no complications, moderate or severe complications were rare, and participants who had surgery had more of these. The injection was cheaper but less effective than surgery at 1 year and was considered good value for money. However, by 2 years surgery became the better option due to its greater improvement in health benefits. Participant-taken photographs can help monitor Dupuytren’s contracture but do not give the same results as measurements taken in a clinic. Scientific summary Background Dupuytren’s disease affects over 2 million UK adults. Cords pull the fingers down towards the palm. This interferes with hand function and dexterity, impacting on quality of life. Current treatments to remove, dissolve or break the cords include surgical correction [limited fasciectomy (LF)], collagenase injection (an enzyme injected into the cord), and percutaneous needle fasciotomy (a needle is used to puncture, weaken and cut the cord). None of these treatments cure the tendency to develop Dupuytren’s contracture (DC) and so the cords and contracture can recur over time. Collagenase has some benefits over LF surgery including shorter recovery and no dependence on operating theatre availability for delivery of the intervention. There is, however, limited robust evidence comparing surgical correction and collagenase injection in terms of clinical effectiveness, cost-effectiveness, and in terms of patient’s experiences and preferences. Objectives The primary objective was to compare whether collagenase injection is not inferior to LF in the treatment of DC. Secondary objectives included investigation of recurrence at 1 and 2 years after treatment and cost-effectiveness. A qualitative substudy explored patients’ views of collagenase and LF, and a photography substudy investigated whether measurements of extension and flexion made on photographs taken by patients reflect goniometric measurements to assess recurrence. Methods Design The Dupytren's interventions surgery vs collagenase (DISC) trial was a multicentre, pragmatic, parallel two-arm randomised controlled non-inferiority trial with a cost-effectiveness evaluation, and nested qualitative and photography substudies. Participants were randomised on an equal basis to receive either of the two treatment options via a remote randomisation service. Randomisation was blocked, with randomly varying block sizes, and stratified by reference (worst-affected) joint [metacarpophalangeal (MCP) joint or proximal interphalangeal (PIP) joint]. Participants were followed up at 3 months, 6 months, 1 year and 2 years after treatment. Data collection included joint measurements and photography at baseline, and all follow-up time points. Setting Trial recruitment was undertaken in 31 NHS hand units across England and Scotland between June 2017 and September 2021. Participants Patients aged 18 years and over with a discrete, palpable Dupuytren’s cord causing contracture of ≥ 30 degrees and who were appropriate for both study treatments, were eligible for inclusion. Patients were excluded if they had severe contractures (> 135 degrees); had received treatment to the study digit; had other pre-existing disorders affecting hand function; had contraindications to collagenase; had a coagulation disorder; were female and pregnant or breastfeeding; had participated in a study involving another investigational medicinal product within 12 weeks or had another disease or disorder which would put them at risk if participating. Interventions The intervention was collagenase Clostridium histolyticum injection, supplied through routine NHS stocks. Collagenase was injected as three aliquots at set anatomical points in line with the current approved summary of product characteristics. After an interval of 1–7 days, participants returned to the clinic, where under local anaesthetic the cord was snapped to correct the contracture. The control group received LF surgery to remove the diseased nodules and cord to correct the contracture. Participants were followed up at routine wound check appointments following intervention. Outcomes The primary outcome was the Patient Evaluation Measure (PEM) score (0–100 with higher scores indicating worse outcome) at 1 year after treatment. The PEM was also completed at 3 months, 6 months and 2 years after treatment. Secondary outcomes included the Unité Rhumatologique des Affections de la Main (URAM) scale, Michigan Hand Outcomes Questionnaire (MHQ), recurrence, extension deficit and total active movement, complications, further treatments (including further care and/or re-intervention), health-related quality of life [EuroQol-5 Dimensions, five-level version (EQ-5D-5L)], resource use, time to recovery of function (using a single assessment numeric evaluation measure) and overall hand assessment. All outcomes were collected at 3 months, 6 months, 1 year and 2 years. The PEM was also recollected immediately prior to treatment delivery, and the time to recover function and quality of life were also collected at 2 and 6 weeks after treatment. Outcomes were collected primarily in hospital clinics, with some participants being followed up for postal, telephone, or video data collection during the COVID-19 pandemic. The qualitative substudy explored participants experiences of DC and treatments. The photography substudy explored the agreement between measurements obtained using a goniometer and photographs taken by participants at home, to determine whether the two methods of measurement might feasibly be used interchangeably. Results Clinical effectiveness In total 672 participants (64.6%) were recruited and randomised; 336 to receive collagenase injection and 336 to receive LF. Baseline characteristics were similar across groups. Of the 672 randomised participants, 621 (92.4%) received treatment as part of the trial. Cross-over was limited: one participant (0.3%) allocated to collagenase received LF; seven participants allocated to LF received collagenase (2.1%). On average participants received collagenase by 12.1 weeks [standard deviation (SD) 13.7] and LF in 17.7 weeks (SD 16.5) after randomisation. Most participants (n = 315, 95.2%) had just one digit treated. No participants required an unplanned inpatient admission following treatment and 62.0% (n = 201) collagenase participants and 78.3% (n = 224) LF participants had full correction following treatment. At 1 year (primary time-point) the difference in PEM scores showed that collagenase was inferior to LF; difference 5.95 [95% confidence interval (CI) 3.12 to 8.77; p = 0.49]. The benefit of LF over collagenase continued to increase to 2 years (7.18, 95% CI 4.18 to 10.88; p = 0.82). There were no material changes in these results for any of the sensitivity or additional analyses undertaken. The primary analysis therefore shows that there is little evidence to support rejection of the hypothesis that collagenase is inferior to LF at 1 and 2 years post treatment. Indeed, the observed data are highly compatible with LF being superior to collagenase with regard to the primary outcome measure at both these time points. Patient Evaluation Measure overall assessment scores corresponded with the primary outcome analyses and participants in both groups reported positive experiences of treatment. The estimated difference in URAM scores followed those of PEM, increasing in favour of LF over time from 3 months (0.82, 95% CI −0.21 to 1.84; p = 0.12) to 5.37 (95% CI 3.85 to 6.88; p ≤ 0.00005) at 2 years. At 1 year MHQ scores were higher (better) in the LF group (1 year: −4.69, 95% CI −7.27 to −2.12; p = 0.0004) and this continued at 2 years (2 years: −6.71, 95% CI −9.60 to −3.82; p ≤ 0.00005). Return to function was better in the short term for the collagenase group (week 2: 14.93, 95% CI 11.66 to 18.19; p ≤ 0.00005; 6 weeks: 5.00, 95% CI 2.29 to 7.70; p = 0.003) but by 1 year function was superior after LF (−4.93, 95% CI −7.63 to −2.22; p = 0.0004). At 1 year participants who received LF were more likely to respond as being ‘cured’ or ‘much better’ than participants who received collagenase [odds ratio (OR) 3.01, 95% 2.15 to 4.23; p ≤ 0.00005]. Passive extension deficit was similar between the groups at baseline (mean: 45.8°; SD 17.0). Following collagenase treatment, extension deficit seemed to be worse at all time points ranging from a difference of 5.73° (95% CI 2.88 to 8.59; p = 0.0001) at 3 months to 10.10° (95% CI 6.46 to 13.73; p ≤ 0.00005) at 1 year and increasing again up to 2 years. Results when imputed data were included were similar. Increases in reference joint passive range of movement (RoM) were similar between the two groups following treatment. However, from 6 months there was strong evidence that collagenase resulted in poorer passive RoM (−7.42°, 95% CI −11.54 to −3.29; p = 0.0004) and this difference increased further over time. Measurements of active extension deficit were similar between the two groups at baseline (mean: 51.9°, SD 16.1). Like passive extension deficit, active extension deficit was worse following collagenase treatment at all time points, ranging from a difference at 3 months of 5.57° (95% CI 3.02 to 8.12; p ≤ 0.00005) to 11.52° (95% CI 8.13 to 14.91; p

Abstract Background There is increasing interest in the capacity of adaptive designs to improve the efficiency of clinical trials. However, relatively little work has investigated how economic considerations – including the costs of the trial – might inform the design and conduct of adaptive clinical trials. Methods We apply a recently published Bayesian model of a value-based sequential clinical trial to data from the ‘Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis’ (HERO) trial. Using parameters estimated from the trial data, including the cost of running the trial, and using multiple imputation to estimate the accumulating cost-effectiveness signal in the presence of missing data, we assess when the trial would have stopped had the value-based model been used. We used re-sampling methods to compare the design’s operating characteristics with those of a conventional fixed length design. Results In contrast to the findings of the only other published retrospective application of this model, the equivocal nature of the cost-effectiveness signal from the HERO trial means that the design would have stopped the trial close to, or at, its maximum planned sample size, with limited additional value delivered via savings in research expenditure. Conclusion Evidence from the two retrospective applications of this design suggests that, when the cost-effectiveness signal in a clinical trial is unambiguous, the Bayesian value-adaptive design can stop the trial before it reaches its maximum sample size, potentially saving research costs when compared with the alternative fixed sample size design. However, when the cost-effectiveness signal is equivocal, the design is expected to run to, or close to, the maximum sample size and deliver limited savings in research costs.

Background In the UK, one in four patients are in work at the time of their hip or knee replacement surgery. These patients receive little support about their return to work (RTW). There is a need for an occupational support intervention that encourages safe and sustained RTW which can be integrated into National Health Service practice. We developed a two-arm intervention trial, based on a feasibility study, to assess whether an occupational support intervention (the OPAL (Occupational support for Patients undergoing Arthroplasty of the Lower limb) intervention) is effective in supporting a reduced time to full, sustained RTW compared with usual care in patients undergoing hip and knee replacement.Methods and analysis This is a multicentre, individually randomised controlled superiority trial comparing the OPAL intervention to usual care. 742 working adults listed for elective primary hip or knee replacement, who intend to RTW, will be randomised to the OPAL intervention or usual care. The intervention comprises: (1) multimedia information resources; and (2) support from a designated RTW coordinator. The primary outcome is time until ‘full’ sustained RTW without sick leave for a consecutive 4-week period. Secondary outcomes are: time to any RTW, measures of functional recovery, number of ‘sick days’ between surgery and ‘full’ sustained RTW and the use of workplace modifications to facilitate their return. A health economic evaluation and a mixed methods process evaluation will assess cost-effectiveness and the implementation, fidelity and acceptability of the intervention, respectively. Outcomes will be collected at baseline, 3, 6, 9 and 12-month follow-up time points, as well as a monthly RTW questionnaire.Ethics and dissemination Dissemination will focus on supporting the wider adoption and implementation of the intervention (if effective) and will target groups for whom the results will be relevant. This trial was approved by West Midlands—Edgbaston REC 23/WM/0013.Trial registration number ISRCTN13694911.

In a recent phase 2a clinical trial, the candidate leishmaniasis vaccine ChAd63-KH was shown to be safe and immunogenic in Sudanese patients with post kala-azar dermal leishmaniasis (PKDL). However, its value as a stand-alone therapeutic was unknown. To assess the therapeutic efficacy of ChAd63-KH, we conducted a randomized, double-blind, placebo-controlled phase 2b trial (ClinicalTrials.gov: NCT03969134). Primary outcomes were safety and efficacy (≥90% improvement in clinical disease). Secondary outcomes were change in severity grade and vaccine-induced immune response. 86 participants with uncomplicated PKDL of ≥6 month duration were randomized to receive ChAd63-KH (7.5 × 1010 viral particles, once by the intramuscular route) or placebo. 75 participants (87%) completed the trial as per protocol. No severe or serious adverse events were observed. At day 90 post-vaccination, 6/40 (15%) and 4/35 (11%) participants in the vaccine and placebo groups, respectively, showed ≥90% clinical improvement (risk ratio [RR] 1.31 [95% confidence interval (CI), 0.40–4.28], p = 0.742). There were also no significant differences in PKDL severity grade between study arms. Whole-blood transcriptomic analysis identified transcriptional modules associated with interferon responses and monocyte and dendritic cell activation. Thus, a single vaccination with ChAd63-KH showed no therapeutic efficacy in this subset of Sudanese patients with PKDL.

Abstract Background Proximal humerus fractures (PHF) are common and painful injuries, with the majority resulting from falls from a standing height. As with other fragility fractures, its age-specific incidence is increasing. Surgical treatment with hemiarthroplasty (HA) and reverse shoulder arthroplasty (RSA) have been increasingly used for displaced 3- and 4-part fractures despite a lack of good quality evidence as to whether one type of arthroplasty is superior to the other, and whether surgery is better than non-surgical management. The PROFHER-2 trial has been designed as a pragmatic, multicentre randomised trial to compare the clinical and cost-effectiveness of RSA vs HA vs Non-Surgical (NS) treatment in patients with 3- and 4-part PHF. Methods Adults over 65 years of age presenting with acute radiographically confirmed 3- or 4-part fractures, with or without associated glenohumeral joint dislocation, who consent for trial participation will be recruited from around 40 National Health Service (NHS) Hospitals in the UK. Patients with polytrauma, open fractures, presence of axillary nerve palsy, pathological (other than osteoporotic) fractures, and those who are unable to adhere to trial procedures will be excluded. We will aim to recruit 380 participants (152 RSA, 152 HA, 76 NS) using 2:2:1 (HA:RSA:NS) randomisation for 3- or 4-part fractures without joint dislocation, and 1:1 (HA:RSA) randomisation for 3- or 4-part fracture dislocations. The primary outcome is the Oxford Shoulder Score at 24 months. Secondary outcomes include quality of life (EQ-5D-5L), pain, range of shoulder motion, fracture healing and implant position on X-rays, further procedures, and complications. Independent Trial Steering Committee and Data Monitoring Committee will oversee the trial conduct, including the reporting of adverse events and harms. Discussion The PROFHER-2 trial is designed to provide a robust answer to guide the treatment of patients aged 65 years or over who sustain 3- and 4-part proximal humeral fractures. The pragmatic design and recruitment from around 40 UK NHS hospitals will ensure immediate applicability and generalisability of the trial findings. The full trial results will be made available in a relevant open-access peer-reviewed journal. Trial registration ISRCTN76296703. Prospectively registered on 5th April 2018

Aims: Early large treatment effects can arise in small studies, which lessen as more data accumulate. This study aimed to retrospectively examine whether early treatment effects occurred for two multicentre orthopaedic randomized controlled trials (RCTs) and explore biases related to this. Methods: Included RCTs were ProFHER (PROximal Fracture of the Humerus: Evaluation by Randomisation), a two-arm study of surgery versus non-surgical treatment for proximal humerus fractures, and UK FROST (United Kingdom Frozen Shoulder Trial), a three-arm study of two surgical and one non-surgical treatment for frozen shoulder. To determine whether early treatment effects were present, the primary outcome of Oxford Shoulder Score (OSS) was compared on forest plots for: the chief investigator’s (CI) site to the remaining sites, the first five sites opened to the other sites, and patients grouped in quintiles by randomization date. Potential for bias was assessed by comparing mean age and proportion of patients with indicators of poor outcome between included and excluded/non-consenting participants. Results: No bias in treatment effect was observed overall for the CI site, or the first five sites, compared with the remaining sites in either trial. An early treatment effect on the OSS was observed for the first quintile of participants recruited to ProFHER only (clinically relevant difference of seven points). Selection bias for age was observed in the ProFHER trial only, with slightly younger patients being recruited into the study. Both trials showed some selection bias for markers of poor prognosis, although these did not appear to change over time. Conclusion: No bias in treatment effects overall were found at the CI or early sites set-up. An early treatment effect was found in one of the two trials, which was likely a chance effect as this did not continue during the study. Selection bias was observed in both RCTs, however this was minimal and did not impact on outcome. Cite this article: Bone Jt Open 2023;4(2):96–103.

Abstract Background Adults with long-term health conditions (LTCs) are more likely to experience depressive symptoms which can worsen health outcomes and quality of life, and increase healthcare costs. Subthreshold depression may go undetected and/or untreated. The Community Pharmacies Mood Intervention Study (CHEMIST) explored whether community pharmacies represent a suitable setting to offer brief psychological support to people with LTCs and comorbid subthreshold depression. Methods A feasibility intervention study with a nested mixed methods evaluation was employed. Adults with subthreshold depression and a minimum of one LTC were recruited from community pharmacies/local general practices and offered a brief psychological support intervention (‘Enhanced Support Intervention’ (ESI)), based on behavioural activation within a Collaborative Care framework. The intervention included up to six sessions supported by pharmacy staff (‘ESI facilitators’) trained to deliver the ESI within the community pharmacy setting. Recruitment, retention rates and engagement with the ESI were assessed. Semi-structured, one-to-one interviews with pharmacy staff and study participants, and a focus group with pharmacy staff, explored experiences and acceptability of the study and the ESI. Themes were mapped onto constructs of the Theoretical Framework of Acceptability. Results Recruitment of ESI participants was challenging and slower than anticipated despite the varied methods of recruitment employed; although, this was useful in identifying barriers and enabling factors for participation. Engagament with the ESI was good with n=17 (71%) recruited participants commencing the ESI. The ESI was found to be acceptable to participants and ESI facilitators. Retention rate at 4 months was good n=20 (87.0%). The main barriers to identifying potential participants for pharmacy staff were lack of time, resources and limited experience in research. The ESI training and support manual were acceptable to ESI facilitators. The ESI and supporting patient workbook were acceptable to people with LTCs and subthreshold depression. Conclusions Community pharmacies were viewed as an acceptable setting in which to deliver preventative brief psychological support to people with LTCs at risk of depression. This feasibility study provided important data to inform the design of a pilot randomised controlled trial in this setting and highlighted important considerations for future pharmacy-based research. Trial registration ISRCTN11290592

Aims: This systematic review places a recently completed multicentre randomized controlled trial (RCT), UK FROST, in the context of existing randomized evidence for the management of primary frozen shoulder. UK FROST compared the effectiveness of pre-specified physiotherapy techniques with a steroid injection (PTSI), manipulation under anaesthesia (MUA) with a steroid injection, and arthroscopic capsular release (ACR). This review updates a 2012 review focusing on the effectiveness of MUA, ACR, hydrodilatation, and PTSI. Methods: MEDLINE, Embase, PEDro, Science Citation Index, Clinicaltrials.gov, CENTRAL, and the World Health Organization (WHO) International Clinical Trials Registry were searched up to December 2018. Reference lists of included studies were screened. No language restrictions applied. Eligible studies were RCTs comparing the effectiveness of MUA, ACR, PTSI, and hydrodilatation against each other, or supportive care or no treatment, for the management of primary frozen shoulder. Results: Nine RCTs were included. The primary outcome of patient-reported shoulder function at long-term follow-up (> 6 months and ≤ 12 months) was reported for five treatment comparisons across four studies. Standardized mean differences (SMD) were: ACR versus MUA: 0.21 (95% confidence interval (CI) 0.00 to 0.42), ACR versus supportive care: -0.13 (95% CI -1.10 to 0.83), and ACR versus PTSI: 0.33 (95% CI 0.07 to 0.59) and 0.25 (95% CI -0.34 to 0.85), all favouring ACR; MUA versus supportive care: 0 (95% CI -0.44 to 0.44) not favouring either; and MUA versus PTSI: 0.12 (95% CI -0.14 to 0.37) favouring MUA. None of these differences met the threshold of clinical significance agreed for the UK FROST and most confidence intervals included zero. Conclusion: The findings from a recent multicentre RCT provided the strongest evidence that, when compared with each other, neither PTSI, MUA, nor ACR are clinically superior. Evidence from smaller RCTs did not change this conclusion. The effectiveness of hydrodilatation based on four RCTs was inconclusive and there remains an evidence gap. Cite this article: Bone Jt Open 2021;2(9):773–784.

Abstract Background Dupuytren’s contracture is a fibro-proliferative disease of the hands affecting over 2 million UK adults, particularly the white, male population. Surgery is the traditional treatment; however, recent studies have indicated that an alternative to surgery—collagenase clostridium histolyticum (collagenase)—is better than a placebo in the treatment of Dupuytren’s contracture. There is however no robust randomised controlled trial that provides a definitive answer on the clinical effectiveness of collagenase compared with limited fasciectomy surgery. Dupuytren’s intervention surgery vs collagenase trial (DISC) trial was therefore designed to fill this evidence gap. Methods/design The DISC trial is a multi-centre pragmatic two-arm parallel-group, randomised controlled trial. Participants will be assigned 1:1 to receive either collagenase injection or surgery (limited fasciectomy). We aim to recruit 710 adult participants with Dupuytren’s contracture. Potential participants will be identified in primary and secondary care, screened by a delegated clinician and if eligible and consenting, baseline data will be collected and randomisation completed. The primary outcome will be the self-reported patient evaluation measure assessed 1 year after treatment. Secondary outcome measures include the Unité Rhumatologique des Affections de la Main Scale, the Michigan Hand Questionnaire, EQ-5D-5L, resource use, further procedures, complications, recurrence, total active movement and extension deficit, and time to return to function. Given the limited evidence comparing recurrence rates following collagenase injection and limited fasciectomy, and the importance of a return to function as soon as possible for patients, the associated measures for each will be prioritised to allow treatment effectiveness in the context of these key elements to be assessed. An economic evaluation will assess the cost-effectiveness of treatments, and a qualitative sub-study will assess participants’ experiences and preferences of the treatments. Discussion The DISC trial is the first randomised controlled trial, to our knowledge, to investigate the clinical and cost-effectiveness of collagenase compared to limited fasciectomy surgery for patients with Dupuytren’s contracture. Trial registration Clinical.Trials.gov ISRCTN18254597 . Registered on April 11, 2017.

Aims: A pragmatic multicentre randomized controlled trial, UK FROzen Shoulder Trial (UK FROST), was conducted in the UK NHS comparing the cost-effectiveness of commonly used treatments for adults with primary frozen shoulder in secondary care. Methods: A cost utility analysis from the NHS perspective was performed. Differences between manipulation under anaesthesia (MUA), arthroscopic capsular release (ACR), and early structured physiotherapy plus steroid injection (ESP) in costs (2018 GBP price base) and quality adjusted life years (QALYs) at one year were used to estimate the cost-effectiveness of the treatments using regression methods. Results: ACR was £1,734 more costly than ESP ((95% confidence intervals (CIs) £1,529 to £1,938)) and £1,457 more costly than MUA (95% CI £1,283 to £1,632). MUA was £276 (95% CI £66 to £487) more expensive than ESP. Overall, ACR had worse QALYs compared with MUA (-0.0293; 95% CI -0.0616 to 0.0030) and MUA had better QALYs compared with ESP (0.0396; 95% CI -0.0008 to 0.0800). At a £20,000 per QALY willingness-to-pay threshold, MUA had the highest probability of being cost-effective (0.8632) then ESP (0.1366) and ACR (0.0002). The results were robust to sensitivity analyses. Conclusion: While ESP was less costly, MUA was the most cost-effective option. ACR was not cost-effective. Cite this article: Bone Jt Open 2021;2(8):685–695.

Background: The leishmaniases are neglected tropical diseases caused by various Leishmania parasite species transmitted by sand flies. They comprise a number of systemic and cutaneous syndromes including kala-azar (visceral leishmaniasis, VL), cutaneous leishmaniasis (CL), and post-kala-azar dermal leishmaniasis (PKDL). The leishmaniases cause significant mortality (estimated 20 - 50,000 deaths annually), morbidity, psychological sequelae, and healthcare and societal costs. Treatment modalities remain difficult. E.g., East African PKDL requires 20 days of intravenous therapy, and frequently relapsing VL is seen in the setting of HIV and immunodeficiency. We developed a new therapeutic vaccine, ChAd63-KH for VL / CL / PKDL and showed it to be safe and immunogenic in a phase 1 trial in the UK, and in a phase 2a trial in PKDL patients in Sudan. Methods: This is a randomised double-blind placebo-controlled phase 2b trial to assess the therapeutic efficacy and safety of ChAd63-KH in patients with persistent PKDL in Sudan. 100 participants will be randomly assigned 1:1 to receive placebo or ChAd63-KH (7.5 x1010vp i.m.) at a single time point. Follow up is for 120 days after dosing and we will compare the clinical evolution of PKDL, as well as the humoral and cellular immune responses between the two arms. Discussion: Successful development of a therapeutic vaccine for leishmaniasis would have wide-ranging direct and indirect healthcare benefits that could be realized rapidly. For PKDL patients, an effective therapeutic vaccination used alone would have very significant clinical value, reducing the need for extensive hospitalization and chemotherapy. Combining vaccine with drug (immuno-chemotherapy) might significantly increase the effective life of new drugs, with lower dose / abbreviated regimens helping to limit the emergence of drug resistance. If therapeutic benefit of ChAd63-KH can be shown in PKDL further evaluation of the vaccine in other forms of leishmaniasis should be considered. Clinicaltrials.gov registration: NCT03969134.

Objectives To assess the cost-effectiveness of cytisine over and above brief behavioural support (BS) for smoking cessation among patients who are newly diagnosed with pulmonary tuberculosis (TB) in low-income and middle-income countries.Design An incremental cost-utility analysis was undertaken alongside a 12-month, double-blind, two-arm, individually randomised controlled trial from a public/voluntary healthcare sector perspective with the primary endpoint at 6 months post randomisation.Setting Seventeen subdistrict hospitals in Bangladesh and 15 secondary care hospitals in Pakistan.Participants Adults (aged ≥18 years in Bangladesh and ≥15 years in Pakistan) with pulmonary TB diagnosed within the last 4 weeks who smoked tobacco daily (n=2472).Interventions Two brief BS sessions with a trained TB health worker were offered to all participants. Participants in the intervention arm (n=1239) were given cytisine (25-day course) while those in the control arm (n=1233) were given placebo. No significant difference was found between arms in 6-month abstinence.Primary and secondary outcome measures Costs of cytisine and BS sessions were estimated based on research team records. TB treatment costs were estimated based on TB registry records. Additional smoking cessation and healthcare costs and EQ-5D-5L data were collected at baseline, 6-month and 12-month follow-ups. Costs were presented in purchasing power parity (PPP) adjusted US dollars (US$). Quality-adjusted life years (QALYs) were derived from the EQ-5D-5L. Incremental total costs and incremental QALYs were estimated using regressions adjusting for respective baseline values and other baseline covariates. Uncertainty was assessed using bootstrapping.Results Mean total costs were PPP US$57.74 (95% CI 49.40 to 83.36) higher in the cytisine arm than in the placebo arm while the mean QALYs were −0.001 (95% CI −0.004 to 0.002) lower over 6 months. The cytisine arm was dominated by the placebo arm.Conclusions Cytisine plus BS for smoking cessation among patients with TB was not cost-effective compared with placebo plus BS.Trial registration number ISRCTN43811467.

Aims: A pilon fracture is a severe ankle joint injury caused by high-energy trauma, typically affecting men of working age. Although relatively uncommon (5% to 7% of all tibial fractures), this injury causes among the worst functional and health outcomes of any skeletal injury, with a high risk of serious complications and long-term disability, and with devastating consequences on patients’ quality of life and financial prospects. Robust evidence to guide treatment is currently lacking. This study aims to evaluate the clinical and cost-effectiveness of two surgical interventions that are most commonly used to treat pilon fractures. Methods: A randomized controlled trial (RCT) of 334 adult patients diagnosed with a closed type C pilon fracture will be conducted. Internal locking plate fixation will be compared with external frame fixation. The primary outcome and endpoint will be the Disability Rating Index (a patient self-reported assessment of physical disability) at 12 months. This will also be measured at baseline, three, six, and 24 months after randomization. Secondary outcomes include the Olerud and Molander Ankle Score (OMAS), the five-level EuroQol five-dimenison score (EQ-5D-5L), complications (including bone healing), resource use, work impact, and patient treatment preference. The acceptability of the treatments and study design to patients and health care professionals will be explored through qualitative methods. Discussion: The two treatments being compared are the most commonly used for this injury, however there is uncertainty over which is most clinically and cost-effective. The Articular Pilon Fracture (ACTIVE) Trial is a sufficiently powered and rigorously designed study to inform clinical decisions for the treatment of adults with this injury. Cite this article: Bone Jt Open 2021;2(3):150–163.

Abstract Background Eighty per cent of UK women have at least one baby, making pregnancy an opportunity to help women stop smoking before their health is irreparably compromised. Smoking cessation during pregnancy helps protect infants from miscarriage, still birth, low birth weight, asthma, attention deficit disorder and adult cardiovascular disease. UK national guidelines highlight lack of evidence for effectiveness of financial incentives to help pregnant smokers quit. This includes a research recommendation: within a UK context, are incentives an acceptable, effective and cost-effective way to help pregnant women who smoke to quit? Methods The Cessation in Pregnancy Incentives Trial (CPIT) III is a pragmatic, 42-month, multi-centre, parallel-group, individually randomised controlled superiority trial of the effect on smoking status of adding to usual Stop Smoking Services (SSS) support, the offer of up to £400 of financial voucher incentives, compared with usual support alone, to quit smoking during pregnancy. Participants (n = 940) are pregnant smokers (age > 16 years,

Background: Depression is common in people with long-term health conditions, and this combination can lead to worsened health outcomes and increased health-care costs. Subthreshold depression, a risk factor for major depression, is prevalent in this population, but many people remain untreated due to the demand on services. The community pharmacy may be an alternative setting to offer mental health support; however, insufficient evidence exists to support implementation. Objectives: To conduct a feasibility study and pilot randomised controlled trial of a community pharmacy-delivered psychological intervention aimed at preventing depression in adults with long-term health conditions. Design: A feasibility study with nested qualitative evaluation and an external pilot, two-arm, 1 : 1 individually randomised controlled trial with nested process and economic evaluations. Setting: Community pharmacies in the north of England. Participants: Adults aged ≥ 18 years with subthreshold depression and at least one long-term health condition. Intervention: A bespoke enhanced support intervention (behavioural activation within a collaborative care framework) involving up to six sessions delivered by trained community pharmacy staff (intervention facilitators) compared with usual care. Main outcome measures: Recruitment and retention rates, completeness of outcome measures and intervention engagement. The intended primary outcome was depression severity at 4 months, assessed by the Patient Health Questionnaire-9. Results: In the feasibility study, 24 participants were recruited. Outcome measure completeness was 95–100%. Retention at 4 months was 83%. Seventeen participants (71%) commenced intervention sessions and all completed two or more sessions. Depression symptoms reduced slightly at 4 months. The process evaluation suggested that the intervention was acceptable to participants and intervention facilitators. In the pilot randomised controlled trial, 44 participants (target of 100 participants) were randomised (intervention, n = 24; usual care, n = 20). Outcome measure completeness was 100%. Retention at 4 months was 93%. Eighteen participants (75%) commenced intervention sessions and 16 completed two or more sessions. Depression symptoms reduced slightly at 4 months, with a slightly larger reduction in the usual-care arm, although the small sample size limits any conclusions. The process evaluation reported good acceptability of the intervention and identified barriers associated with study implementation and its impact on core pharmacy functions. The economic analysis revealed some indication of reduced resource use/costs associated with the intervention, but this is limited by the small sample size. Intervention costs were low. Limitations: The main limitation is the small sample size due to difficulties with recruitment and barriers to implementing the study within existing pharmacy practices. Conclusions: The community pharmacy represents a new setting to deliver a depression prevention intervention. Recruitment was a challenge and pharmacy staff encountered barriers to effective implementation of the study within busy pharmacy practice. Despite these challenges, good retention rates and intervention engagement were demonstrated, and process evaluation suggested that the intervention was acceptable in this setting. To the best of our knowledge, this is the first study to demonstrate that community pharmacy staff can be trained to deliver a depression prevention intervention. Future work: Further work is needed to address barriers to recruitment, intervention delivery and implementation of psychological interventions in the community pharmacy setting. Trial registration: This trial is registered as ISRCTN11290592. Funding: This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 10, No. 5. See the NIHR Journals Library website for further project information.

Background: An economic evaluation alongside the Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis (HERO) trial was undertaken to assess the cost-effectiveness of hydroxychloroquine compared with placebo for symptomatic treatment of hand osteoarthritis for patients with at least moderate hand pain and inadequate response to current therapies. Methods: A trial-based cost–utility analysis was undertaken from the perspective of the UK National Health Service and Personal Social Services over a 12-month time horizon, using evidence from 248 participants included in the HERO trial, conducted in England. Patient-level data were collected prospectively over a 12-month period, using participant-completed questionnaires and investigator forms, to collect healthcare utilisation, costs and quality-adjusted life years (QALYs) using the EQ-5D-5L. The base-case analysis was conducted on an intention-to-treat basis and used multiple imputation methods to deal with missing data. Results were presented in terms of incremental cost-effectiveness ratios (incremental cost per QALY) and net health benefit, with uncertainty surrounding the findings explored using cost-effectiveness acceptability curves. Results: The base-case analysis estimated slightly lower costs on average (−£11.80; 95% confidence interval (CI) −£15.60 to −£8.00) and marginally fewer QALYs (−0.0052; 95% CI −0.0057 to −0.0047) for participants in the hydroxychloroquine group versus placebo group at 12 months. The resulting incremental cost-effectiveness ratio of £2,267 per QALY lost indicated that although costs were saved, health-related quality of life was lost. Even assuming symmetrical preferences regarding losses and gains for health benefits, the findings do not fall within the cost-effective region. Similar findings arose for analyses conducted from the societal perspective and using complete cases only. Conclusions: This economic evaluation indicates that hydroxychloroquine is unlikely to provide a cost-effective pain relief option for improving health-related quality of life in adult patients with moderate-to-severe hand osteoarthritis.

Abstract Background Surgeon and patient treatment preferences are important threats to the internal and external validity of surgical trials such as PROFHER, which compared surgical versus non-surgical treatment for displaced fractures of the proximal humerus in adults. We explored the treatment preferences expressed by surgeons and patients in the trial and how these impacted on patient selection, trial conduct and patient outcome. Methods A series of exploratory secondary analyses of the PROFHER trial data were undertaken. We reviewed the extent of surgeon and patient treatment preferences (surgery or not surgery) at screening (n = 1250) as well as prior preference (including no preference) of randomised patients (n = 250), and assessed their impact on recruitment and adherence to follow-up and rehabilitation. Changes in treatment after 2 years’ follow-up were explored. Patient preference and characteristics associated with trial inclusion or treatment preference (t test, chi-squared test, Wilcoxon rank-sum test) were included as treatment interaction terms in the primary trial analysis of shoulder functioning (Oxford Shoulder Score, OSS). Results Surgeons excluded 17% of otherwise eligible patients based on lack of equipoise; these patients had less complex fractures (p

Abstract Feasibility study Objectives:(a)Refine a bespoke enhanced support intervention (ESI) (including self-help materials, intervention manual and training) for implementation by community pharmacy (CP) staff to people with sub-threshold depression and long-term conditions (LTCs) based upon evidence-supported interventions in primary care(b)Develop and refine study procedures (recruitment strategies and set up, screening, participant recruitment, assessment, suitability of outcome measures and data collection procedures) for testing in the pilot study phase Design: A case series/qualitative study Setting: UK community pharmacy Population: Adults with long-term health conditions who screen-positive for depression but who do not reach the threshold for DSM IV Moderate Depressive disorder Intervention: Enhanced support intervention (ESI) delivered by an appropriately trained community pharmacy team member involving four to six sessions over four months. ESI is a modified form of an intervention within the collaborative care framework for sub-threshold depression validated in previous studies in UK primary care which appears suitable for implementation in community settings. Sample size: 20–30 participants Outcomes: Study implementation (recruitment and attrition rates), quality of data collection at baseline and 4 months and ESI adherence (number of contacts, DNA and drop out) as per objectives 1a/b Qualitative evaluation: Semi-structured interviews with up to 10 participants and ESI facilitators and focus group(s) (range of pharmacy staff n = 8–10) will be conducted to explore the acceptability of the intervention and feasibility of the study, training and study procedures. External pilot study Objectives:(a)Quantify the flow of participants (eligibility, recruitment and follow-up rate)(b)Evaluate proposed recruitment, assessment and outcome measure collection methods(c)Examine the delivery of the enhanced support intervention in a community pharmacy setting (intervention uptake, retention and dose) to inform process evaluation(d)Process evaluation, using semi-structured interviews with participants across a range of socio-economic settings, and pharmacy staff to explore the acceptability of the ESI within community pharmacy, elements of the intervention that were considered useful (or not) and appropriateness of study procedures Design: Pilot randomised controlled trial, including a prospective economic and qualitative evaluation Setting: As above Population: As above Intervention: As above with adaptations post feasibility study Comparator: Usual care Sample size: 100 participants Outcomes: Data will be used to estimate recruitment, intervention delivery and study completion rates as per objectives 2a–d. Definitive estimates of the effectiveness of ESI will not be made. Primary outcome: Depression severity (Patient Health Questionnaire 9) at four months. Secondary outcomes: Patient acceptance, uptake and attrition. ICD10 depression status, anxiety (GAD 7), health-related quality of life (SF-12v2) and health-state utility (EQ5D 3L) will be measured at four months. Economic evaluation: The incremental cost per QALY will be calculated from both the NHS and societal perspective. Process evaluation: Using mixed methods, potential mediators/moderators of the intervention, the acceptability (to participants and pharmacy staff), barriers and facilitators to the use of ESI in community pharmacy, and impact on usual practice will be examined. Semi-structured interviews with approximately 30 study participants, 20 pharmacy staff and eight GPs near participating pharmacies will be conducted. Trial registration ISRCTN: ISRCTN11290592 Protocol version number: Version 4.1 (dated 16th January 2018) Study Sponsor Tees Esk and Wear Valleys NHS Foundation Trust

Background: Frozen shoulder causes pain and stiffness. It affects around 10% of people in their fifties and is slightly more common in women. Costly and invasive surgical interventions are used, without high-quality evidence that these are effective. Objectives: To compare the clinical effectiveness and cost-effectiveness of three treatments in secondary care for adults with frozen shoulder; to qualitatively explore the acceptability of these treatments to patients and health-care professionals; and to update a systematic review to explore the trial findings in the context of existing evidence for the three treatments. Design: This was a pragmatic, parallel-group, multicentre, open-label, three-arm, randomised superiority trial with unequal allocation (2 : 2 : 1). An economic evaluation and a nested qualitative study were also carried out. Setting: The orthopaedic departments of 35 hospitals across the UK were recruited from April 2015, with final follow-up in December 2018. Participants: Participants were adults (aged ≥ 18 years) with unilateral frozen shoulder, characterised by restriction of passive external rotation in the affected shoulder to

Background: Scaphoid fractures account for 90% of carpal fractures and occur predominantly in young men. Immediate surgical fixation of this fracture has increased. Objective: To compare the clinical effectiveness and cost-effectiveness of surgical fixation with cast treatment and early fixation in adults with scaphoid waist fractures that fail to unite. Design: Multicentre, pragmatic, open-label, parallel two-arm randomised controlled trial with an economic evaluation and a nested qualitative study. Setting: Orthopaedic departments of 31 hospitals in England and Wales recruited from July 2013, with final follow-up in September 2017. Participants: Adults (aged ≥ 16 years) presenting within 2 weeks of injury with a clear, bicortical fracture of the scaphoid waist on plain radiographs. Interventions: Early surgical fixation using Conformité Européenne-marked headless compression screws. Below-elbow cast immobilisation for 6–10 weeks and urgent fixation of confirmed non-union. Main outcome measures: The primary outcome and end point was the Patient-Rated Wrist Evaluation total score at 52 weeks, with a clinically relevant difference of 6 points. Secondary outcomes included Patient-Rated Wrist Evaluation pain and function subscales, Short Form questionnaire 12-items, bone union, range of movement, grip strength, complications and return to work. Results: The mean age of 439 participants was 33 years; 363 participants were male (83%) and 269 participants had an undisplaced fracture (61%). The primary analysis was on 408 participants with valid Patient-Rated Wrist Evaluation outcome data for at least one post-randomisation time point (surgery, n = 203 of 219; cast, n = 205 of 220). There was no clinically relevant difference in the Patient-Rated Wrist Evaluation total score at 52 weeks: the mean score in the cast group was 14.0 (95% confidence interval 11.3 to 16.6) and in the surgery group was 11.9 (95% confidence interval 9.2 to 14.5), with an adjusted mean difference of –2.1 in favour of surgery (95% confidence interval –5.8 to 1.6; p = 0.27). The non-union rate was low (surgery group, n = 1; cast group, n = 4). Eight participants in the surgery group had a total of 11 reoperations and one participant in the cast group required a reoperation for non-union. The base-case economic analysis at 52 weeks found that surgery cost £1295 per patient more (95% confidence interval £1084 to £1504) than cast treatment. The base-case analysis of a lifetime-extrapolated model confirmed that the cast treatment pathway was more cost-effective. The nested qualitative study identified patients’ desire to have a ‘sense of recovering’, which surgeons should address at the outset. Limitation: There were 17 participants who had initial cast treatment and surgery for confirmed non-union, which in 14 cases was within 6 months from randomisation and in three cases was after 6 months. Three of the four participants in the cast group who had a non-union at 52 weeks were not offered surgery. Conclusions: Adult patients with an undisplaced or minimally displaced scaphoid waist fracture should have cast immobilisation and suspected non-unions immediately confirmed and urgently fixed. Patients should be followed up at 5 years to investigate the effect of partial union, degenerative arthritis, malunion and screw problems on their quality of life. Trial registration: Current Controlled Trials ISRCTN67901257. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 52. See the NIHR Journals Library website for further project information.

Context: Vision rehabilitation (VR) services in England promote users’ health and wellbeing, and support all aspects of daily living through two dominant models: in-house and contracted-out VR services. The two models differ in terms of service delivery, but they share a common aim to enhance service users’ quality of life and reduce utilisation of social and health care services. Objective: This study investigated the cost-effectiveness of in-house versus contracted-out VR services. Methods: The analysis was performed from a social care perspective and a social and health care perspective. The analyses used data from a six-month follow-up observational study of VR users. Regression analysis was used to estimate differential outcomes and costs, taking user and local authority characteristics into account. Findings: At a cost-effectiveness threshold of £13,000 and £30,000 per QALY, in-house VR services have a high probability (greater than 90% vs. contracted-out VR services) of being cost-effective from a social care perspective. In-house VR services have a lower probability (lower than 25% vs. contracted-out VR services) of being cost-effective from a social and health care perspective. Limitations: Observational studies are prone to selection bias compared to randomised controlled trials due to confounding. We employed econometric techniques that control for several user and LA characteristics to reduce potential bias. Implications: Contracted-out VR services may be better value for money compared to in-house VR services in the context of integrated social and health care due to substantial healthcare resource savings.

Introduction Smoking has a negative impact on TB outcomes. We estimated the proportion of TB patients who smoke and are willing to quit in two high TB burden countries, Bangladesh and Pakistan. Methods A cross-sectional survey was conducted among TB patients to assess their eligibility and recruit them to a smoking cessation randomized controlled trial. Adults diagnosed with TB were recruited from 32 health facilities in Bangladesh and Pakistan. Data on smoking behaviour and willingness to quit were collected and analysed. Results In total, 13934 TB patients completed the survey between June 2017 and April 2018. The prevalence of smoking in these TB patients was estimated to be 22.5% (95% CI: 21.8, 23.2). Moreover, the prevalence of smoking in TB patient population was 8% (RR=1.49; 95% CI: 7.1–8.9; p

Background: Printed participant information about randomised controlled trials is often long, technical and difficult to navigate. Improving information materials is possible through optimisation and user-testing, and may impact on participant understanding and rates of recruitment. Methods: A study within a trial (SWAT) was undertaken within the CASPER trial. Potential CASPER participants were randomised to receive either the standard trial information or revised information that had been optimised through information design and user testing. Results: A total of 11,531 patients were randomised in the SWAT. Rates of recruitment to the CASPER trial were 2.0% in the optimised information group and 1.9% in the standard information group (odds ratio 1.027; 95% CI 0.79 to 1.33; p=0.202). Conclusions: Participant information that had been optimised through information design and user testing did not result in any change to rate of recruitment to the host trial. Registration: ISRCTN ID ISRCTN02202951; registered on 3 June 2009.

Abstract Background Frozen shoulder (also known as adhesive capsulitis) occurs when the capsule, or the soft tissue envelope around the ball and socket shoulder joint, becomes scarred and contracted, making the shoulder tight, painful and stiff. It affects around 1 in 12 men and 1 in 10 women of working age. Although this condition can settle with time (typically taking 1 to 3 years), for some people it causes severe symptoms and needs referral to hospital. Our aim is to evaluate the clinical and cost-effectiveness of two invasive and costly surgical interventions that are commonly used in secondary care in the National Health Service (NHS) compared with a non-surgical comparator of Early Structured Physiotherapy. Methods We will conduct a randomised controlled trial (RCT) of 500 adult patients with a clinical diagnosis of frozen shoulder, and who have radiographs that exclude other pathology. Early Structured Physiotherapy with an intra-articular steroid injection will be compared with manipulation under anaesthesia with a steroid injection or arthroscopic (keyhole) capsular release followed by manipulation. Both surgical interventions will be followed with a programme of post-procedural physiotherapy. These treatments will be undertaken in NHS hospitals across the United Kingdom. The primary outcome and endpoint will be the Oxford Shoulder Score (a patient self-reported assessment of shoulder function) at 12 months. This will also be measured at baseline, 3 and 6 months after randomisation; and on the day that treatment starts and 6 months later. Secondary outcomes include the Disabilities of Arm Shoulder and Hand (QuickDASH) score, the EQ-5D-5 L score, pain, extent of recovery and complications. We will explore the acceptability of the different treatments to patients and health care professionals using qualitative methods. Discussion The three treatments being compared are the most frequently used in secondary care in the NHS, but there is uncertainty about which one works best and at what cost. UK FROST is a rigorously designed and adequately powered study to inform clinical decisions for the treatment of this common condition in adults. Trial registration International Standard Randomised Controlled Trial Register, ID: ISRCTN48804508 . Registered on 25 July 2014.

Background: Perinatal depression is well recognised as a mental health condition but

Background: Opioid substitution therapy and needle exchanges have reduced blood-borne viruses (BBVs) among people who inject drugs (PWID). Some PWID continue to share injecting equipment. Objectives: To develop an evidence-based psychosocial intervention to reduce BBV risk behaviours and increase transmission knowledge among PWID, and conduct a feasibility trial among PWID comparing the intervention with a control. Design: A pragmatic, two-armed randomised controlled, open feasibility trial. Service users were Steering Group members and co-developed the intervention. Peer educators co-delivered the intervention in London. Setting: NHS or third-sector drug treatment or needle exchanges in Glasgow, London, Wrexham and York, recruiting January and February 2016. Participants: Current PWID, aged ≥ 18 years. Interventions: A remote, web-based computer randomisation system allocated participants to a three-session, manualised, psychosocial, gender-specific group intervention delivered by trained facilitators and BBV transmission information booklet plus treatment as usual (TAU) (intervention), or information booklet plus TAU (control). Main outcome measures: Recruitment, retention and follow-up rates measured feasibility. Feedback questionnaires, focus groups with participants who attended at least one intervention session and facilitators assessed the intervention’s acceptability. Results: A systematic review of what works to reduce BBV risk behaviours among PWID; in-depth interviews with PWID; and stakeholder and expert consultation informed the intervention. Sessions covered improving injecting technique and good vein care; planning for risky situations; and understanding BBV transmission. Fifty-six per cent (99/176) of eligible PWID were randomised: 52 to the intervention group and 47 to the control group. Only 24% (8/34) of male and 11% (2/18) of female participants attended all three intervention sessions. Overall, 50% (17/34) of men and 33% (6/18) of women randomised to the intervention group and 47% (14/30) of men and 53% (9/17) of women randomised to the control group were followed up 1 month post intervention. Variations were reported by location. The intervention was acceptable to both participants and facilitators. At 1 month post intervention, no increase in injecting in ‘risky’ sites (e.g. groin, neck) was reported by participants who attended at least one session. PWID who attended at least one session showed a trend towards greater reduction in injecting risk behaviours, a greater increase in withdrawal planning and were more confident about finding a vein. A mean cost of £58.17 per participant was calculated for those attending one session, £148.54 for those attending two sessions and £270.67 for those attending all three sessions, compared with £0.86 in the control group. Treatment costs across the centres vary as a result of the different levels of attendance, as total session costs are divided by attendees to obtain a cost per attendee. The economic analysis suggests that a cost-effectiveness study would be feasible given the response rates and completeness of data. However, we have identified aspects where the service use questionnaire could be abbreviated given the low numbers reported in several care domains. No adverse events were reported. Conclusions: As only 19% of participants attended all three intervention sessions and 47% were followed up 1 month post intervention, a future definitive randomised controlled trial of the intervention is not feasible. Exposure to information on improving injecting techniques did not encourage riskier injecting practices or injecting frequency, and benefits were reported among attendees. The intervention has the potential to positively influence BBV prevention. Harm reduction services should ensure that the intervention content is routinely delivered to PWID to improve vein care and prevent BBVs. Future work: The intervention did not meet the complex needs of some PWID, more tailoring may be needed to reach PWID who are more frequent injectors, who are homeless and female. Limitations: Intervention delivery proved more feasible in London than other locations. Non-attendance at the York trial site substantially influenced the results. Trial registration: Current Controlled Trials ISRCTN66453696 and PROSPERO 014:CRD42014012969. Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 72. See the NIHR Journals Library website for further project information.

Background: Depression in older adults is common and is associated with poor quality of life, increased morbidity and early mortality, and increased health and social care use. Collaborative care, a low-intensity intervention for depression that is shown to be effective in working-age adults, has not yet been evaluated in older people with depression who are managed in UK primary care. The CollAborative care for Screen-Positive EldeRs (CASPER) plus trial fills the evidence gap identified by the most recent guidelines on depression management. Objectives: To establish the clinical effectiveness and cost-effectiveness of collaborative care for older adults with major depressive disorder in primary care. Design: A pragmatic, multicentred, two-arm, parallel, individually randomised controlled trial with embedded qualitative study. Participants were automatically randomised by computer, by the York Trials Unit Randomisation Service, on a 1 : 1 basis using simple unstratified randomisation after informed consent and baseline measures were collected. Blinding was not possible. Setting: Sixty-nine general practices in the north of England. Participants: A total of 485 participants aged ≥ 65 years with major depressive disorder. Interventions: A low-intensity intervention of collaborative care, including behavioural activation, delivered by a case manager for an average of six sessions over 7–8 weeks, alongside usual general practitioner (GP) care. The control arm received only usual GP care. Main outcome measures: The primary outcome measure was Patient Health Questionnaire-9 items score at 4 months post randomisation. Secondary outcome measures included depression severity and caseness at 12 and 18 months, the EuroQol-5 Dimensions, Short Form questionnaire-12 items, Patient Health Questionnaire-15 items, Generalised Anxiety Disorder-7 items, Connor–Davidson Resilience Scale-2 items, a medication questionnaire, objective data and adverse events. Participants were followed up at 12 and 18 months. Results: In total, 485 participants were randomised (collaborative care, n = 249; usual care, n = 236), with 390 participants (80%: collaborative care, 75%; usual care, 86%) followed up at 4 months, 358 participants (74%: collaborative care, 70%; usual care, 78%) followed up at 12 months and 344 participants (71%: collaborative care, 67%; usual care, 75%) followed up at 18 months. A total of 415 participants were included in primary analysis (collaborative care, n = 198; usual care, n = 217), which revealed a statistically significant effect in favour of collaborative care at the primary end point at 4 months [8.98 vs. 10.90 score points, mean difference 1.92 score points, 95% confidence interval (CI) 0.85 to 2.99 score points; p

Visceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post kala azar dermal leishmaniasis (PKDL) is a stigmatizing skin condition that often occurs in patients after successful treatment for VL. Lack of effective or appropriately targeted cell mediated immunity, including CD8+ T cell responses, underlies the progression of VL and progression to PKDL, and can limit the therapeutic efficacy of anti-leishmanial drugs. Hence, in addition to the need for prophylactic vaccines against leishmaniasis, the development of therapeutic vaccines for use alone or in combined immuno-chemotherapy has been identified as an unmet clinical need. Here, we report the first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells.We conducted a first-in-human dose escalation Phase I trial in 20 healthy volunteers to assess the safety, tolerability and immunogenicity of a prime-only adenoviral vaccine for human VL and PKDL. ChAd63-KH is a replication defective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. Uniquely, the latter was engineered to reflect repeat domain polymorphisms and arrangements identified from clinical isolates. We monitored innate immune responses by whole blood RNA-Seq and antigen specific CD8+ T cell responses by IFNγ ELISPOT and intracellular flow cytometry.ChAd63-KH was safe at intramuscular doses of 1x1010 and 7.5x1010 vp. Whole blood transcriptomic profiling indicated that ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8+ T cell responses were induced by vaccination in 100% (20/20) of vaccinated subjects.The results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL.This clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359).

Background: Efforts to reduce the burden of illness and personal suffering associated with depression in older adults have focused on those with more severe depressive syndromes. Less attention has been paid to those with mild disorders/subthreshold depression, but these patients also suffer significant impairments in their quality of life and level of functioning. There is currently no clear evidence-based guidance regarding treatment for this patient group. Objectives: To establish the clinical effectiveness and cost-effectiveness of a low-intensity intervention of collaborative care for primary care older adults who screened positive for subthreshold depression. Design: A pragmatic, multicentred, two-arm, parallel, individually randomised controlled trial with a qualitative study embedded within the pilot. Randomisation occurred after informed consent and baseline measures were collected. Setting: Thirty-two general practitioner (GP) practices in the north of England. Participants: A total of 705 participants aged ≥ 75 years during the pilot phase and ≥ 65 years during the main trial with subthreshold depression. Interventions: Participants in the intervention group received a low-intensity intervention of collaborative care, which included behavioural activation delivered by a case manager for an average of six sessions over 7–8 weeks, alongside usual GP care. Control-arm participants received only usual GP care. Main outcome measures: The primary outcome measure was a self-reported measure of depression severity, the Patient Health Questionnaire-9 items PHQ-9 score at 4 months post randomisation. Secondary outcome measures included the European Quality of Life-5 Dimensions, Short Form questionnaire-12 items, Patient Health Questionnaire-15 items, Generalised Anxiety Disorder seven-item scale, Connor–Davidson Resilience Scale two-item version, a medication questionnaire and objective data. Participants were followed up for 12 months. Results: In total, 705 participants were randomised (collaborative care n = 344, usual care n = 361), with 586 participants (83%; collaborative care 76%, usual care 90%) followed up at 4 months and 519 participants (74%; collaborative care 68%, usual care 79%) followed up at 12 months. Attrition was markedly greater in the collaborative care arm. Model estimates at the primary end point of 4 months revealed a statistically significant effect in favour of collaborative care compared with usual care [mean difference 1.31 score points, 95% confidence interval (CI) 0.67 to 1.95 score points; p

ObjectivesTo assess the cost-effectiveness of acupuncture and usual care, and Alexander Technique lessons and usual care, compared with usual GP care alone for chronic neck pain patients.MethodsAn economic evaluation was undertaken alongside the ATLAS trial, taking both NHS and wider societal viewpoints. Participants were offered up to twelve acupuncture sessions or twenty Alexander lessons (equivalent overall contact time). Costs were in pounds sterling. Effectiveness was measured using the generic EQ-5D to calculate quality adjusted life years (QALYs), as well as using a specific neck pain measure-the Northwick Park Neck Pain Questionnaire (NPQ).ResultsIn the base case analysis, incremental QALY gains were 0.032 and 0.025 in the acupuncture and Alexander groups, respectively, in comparison to usual GP care, indicating moderate health benefits for both interventions. Incremental costs were £451 for acupuncture and £667 for Alexander, mainly driven by intervention costs. Acupuncture was likely to be cost-effective (ICER = £18,767/QALY bootstrapped 95% CI £4,426 to £74,562) and was robust to most sensitivity analyses. Alexander lessons were not cost-effective at the lower NICE threshold of £20,000/QALY (£25,101/QALY bootstrapped 95% CI -£150,208 to £248,697) but may be at £30,000/QALY, however, there was considerable statistical uncertainty in all tested scenarios.ConclusionsIn comparison with usual care, acupuncture is likely to be cost-effective for chronic neck pain, whereas, largely due to higher intervention costs, Alexander lessons are unlikely to be cost-effective. However, there were high levels of missing data and further research is needed to assess the long-term cost-effectiveness of these interventions.

Background: Proximal humeral fractures account for 5–6% of all fractures in adults. There is considerable variation in whether or not surgery is used in the management of displaced fractures involving the surgical neck. Objective: To evaluate the clinical effectiveness and cost-effectiveness of surgical compared with non-surgical treatment of the majority of displaced fractures of the proximal humerus involving the surgical neck in adults. Design: A pragmatic parallel-group multicentre randomised controlled trial with an economic evaluation. Follow-up was for 2 years. Setting: Recruitment was undertaken in the orthopaedic departments of 33 acute NHS hospitals in the UK. Patient care pathways included outpatient and community-based rehabilitation. Participants: Adults (aged ≥ 16 years) presenting within 3 weeks of their injury with a displaced fracture of the proximal humerus involving the surgical neck. Interventions: The choice of surgical intervention was left to the treating surgeons, who used techniques with which they were experienced. Non-surgical treatment was initial sling immobilisation followed by active rehabilitation. Provision of rehabilitation was comparable in both groups. Main outcome measures: The primary outcome was the Oxford Shoulder Score (OSS) assessed at 6, 12 and 24 months. Secondary outcomes were the 12-item Short Form health survey, surgical and other shoulder fracture-related complications, secondary surgery to the shoulder or increased/new shoulder-related therapy, medical complications during inpatient stay and mortality. European Quality of Life-5 Dimensions data and treatment costs were also collected. Results: The mean age of the 250 trial participants was 66 years and 192 (77%) were female. Independent assessment using the Neer classification identified 18 one-part fractures, 128 two-part fractures and 104 three- or four-part fractures. OSS data were available for 215 participants at 2 years. We found no statistically or clinically significant differences in OSS scores between the two treatment groups (scale 0–48, with a higher score indicating a better outcome) over the 2-year period [difference of 0.75 points in favour of the surgery group, 95% confidence interval (CI) –1.33 to 2.84; p = 0.479; data from 114 surgery and 117 non-surgery participants] or at individual time points. We found no statistically significant differences between surgical and non-surgical group participants in SF-12 physical or mental component summary scores; surgical or shoulder fracture-related complications (30 vs. 23 respectively); those undergoing further shoulder-related therapy, either surgery (11 vs. 11 respectively) or other therapy (seven vs. four respectively); or mortality (nine vs. five respectively). The base-case economic analysis showed that, at 2 years, the cost of surgical intervention was, on average, £1780.73 more per patient (95% CI £1152.71 to £2408.75) than the cost of non-surgical intervention. It was also slightly less beneficial in terms of utilities, although this difference was not statistically significant. The net monetary benefit associated with surgery is negative. There was only a 5% probability of surgery achieving the criterion of costing

New evidence on the clinical effectiveness of acupuncture plus usual care (acupuncture) and counselling plus usual care (counselling) for patients with depression suggests the need to investigate the health-related quality of life and costs of these treatments to understand whether they should be considered a good use of limited health resources.The cost-effectiveness analyses are based on the Acupuncture, Counselling or Usual care for Depression (ACUDep) trial results. Statistical analyses demonstrate a difference in mean quality adjusted life years (QALYs) and suggest differences in mean costs which are mainly due to the price of the interventions. Probabilistic sensitivity analysis is used to express decision uncertainty. Acupuncture and counselling are found to have higher mean QALYs and costs than usual care. In the base case analysis acupuncture has an incremental cost-effectiveness ratio (ICER) of £4,560 per additional QALY and is cost-effective with a probability of 0.62 at a cost-effectiveness threshold of £20,000 per QALY. Counselling compared with acupuncture is more effective and more costly with an ICER of £71,757 and a probability of being cost-effective of 0.36. A scenario analysis of counselling versus usual care, excluding acupuncture as a comparator, results in an ICER of £7,935 and a probability of 0.91.Acupuncture is cost-effective compared with counselling or usual care alone, although the ranking of counselling and acupuncture depends on the relative cost of delivering these interventions. For patients in whom acupuncture is unavailable or perhaps inappropriate, counselling has an ICER less than most cost-effectiveness thresholds. However, further research is needed to determine the most cost-effective treatment pathways for depressed patients when the full range of available interventions is considered.

Depression is a significant cause of morbidity. Many patients have communicated an interest in non-pharmacological therapies to their general practitioners. Systematic reviews of acupuncture and counselling for depression in primary care have identified limited evidence. The aim of this study was to evaluate acupuncture versus usual care and counselling versus usual care for patients who continue to experience depression in primary care.In a randomised controlled trial, 755 patients with depression (Beck Depression Inventory BDI-II score ≥ 20) were recruited from 27 primary care practices in the North of England. Patients were randomised to one of three arms using a ratio of 2.2.1 to acupuncture (302), counselling (302), and usual care alone (151). The primary outcome was the difference in mean Patient Health Questionnaire (PHQ-9) scores at 3 months with secondary analyses over 12 months follow-up. Analysis was by intention-to-treat. PHQ-9 data were available for 614 patients at 3 months and 572 patients at 12 months. Patients attended a mean of ten sessions for acupuncture and nine sessions for counselling. Compared to usual care, there was a statistically significant reduction in mean PHQ-9 depression scores at 3 months for acupuncture (-2.46, 95% CI -3.72 to -1.21) and counselling (-1.73, 95% CI -3.00 to -0.45), and over 12 months for acupuncture (-1.55, 95% CI -2.41 to -0.70) and counselling (-1.50, 95% CI -2.43 to -0.58). Differences between acupuncture and counselling were not significant. In terms of limitations, the trial was not designed to separate out specific from non-specific effects. No serious treatment-related adverse events were reported.In this randomised controlled trial of acupuncture and counselling for patients presenting with depression, after having consulted their general practitioner in primary care, both interventions were associated with significantly reduced depression at 3 months when compared to usual care alone.Controlled-Trials.com ISRCTN63787732 Please see later in the article for the Editors' Summary.

Background: This study compares the 5-level version of the EQ-5D (5L) with the 3-level version EQ-5D (3L) in older adults using individual patient data from the REFORM (REducing Falls with Orthoses and a Multifaceted podiatry intervention) trial. Methods: EQ-5D-5L and EQ-5D-3L were administered to men and women (n=151) over the age of 65 years alongside the REFORM trial. The two versions of the EQ-5D were assessed in terms of feasibility, level of consistency, ceiling effect and discriminatory power. We also undertook a comparison of the performance of different EQ-5D-3L and EQ-5D-5L value sets. Results: The proportion of participants that returned a complete questionnaire was higher for the 5L (96.7%) than for the 3L (92.7%). Missing values among dimensions were on average 1.59% (5L) and 1.45% (3L). The ceiling effect was reduced from 18.2% (3L) to 6% (5L). On average the proportion of inconsistent responses between both descriptive systems was 3.25%. Redistribution from 3L to 5L showed valid results for the majority of consistent level combinations, with slight inconsistency in the case of Anxiety/Depression. For the 5L, 67 unique health states were observed for the 5L compared to 27 for the 3L. The absolute informatively improved with the new classification system (5.48 for 5L versus 3.91 for 3L) and relative discriminatory power improved slightly on average (0.90 for 5L versus 0.84 for 3L). The mean difference between the EQ-5D-5L and EQ-5D-3L values was 0.091 (range -0.345 to 0.505); whilst the mean difference between the EQ-5D-5L and the crosswalk values was 0.082 (range -0.035 to 0.293). Conclusion: In the REFORM clinical trial involving an elderly population, our study supported the feasibility and convergent validity of both EQ-5D-3L and EQ-5D-5L. Results suggest that the 5L improves the ceiling effect and discriminatory power. The EQ-5D-5L scores were significantly higher than both EQ-5D-3L and crosswalk.

Background: An economic evaluation alongside the Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis (HERO) trial was undertaken to assess the cost-effectiveness of hydroxychloroquine compared with placebo for symptomatic treatment of hand osteoarthritis for patients with at least moderate hand pain and inadequate response to current therapies. Methods: A trial-based cost–utility analysis was undertaken from the perspective of the UK National Health Service and Personal Social Services over a 12-month time horizon, using evidence from 248 participants included in the HERO trial, conducted in England. Patient-level data were collected prospectively over a 12-month period, using participant-completed questionnaires and investigator forms, to collect healthcare utilisation, costs and quality-adjusted life years (QALYs) using the EQ-5D-5L. The base-case analysis was conducted on an intention-to-treat basis and used multiple imputation methods to deal with missing data. Results were presented in terms of incremental cost-effectiveness ratios (incremental cost per QALY) and net health benefit, with uncertainty surrounding the findings explored using cost-effectiveness acceptability curves. Results: The base-case analysis estimated slightly lower costs on average (−£11.80; 95% confidence interval (CI) −£15.60 to −£8.00) and marginally fewer QALYs (−0.0052; 95% CI −0.0057 to −0.0047) for participants in the hydroxychloroquine group versus placebo group at 12 months. The resulting incremental cost-effectiveness ratio of £2,267 per QALY lost indicated that although costs were saved, health-related quality of life was lost. Even assuming symmetrical preferences regarding losses and gains for health benefits, the findings do not fall within the cost-effective region. Similar findings arose for analyses conducted from the societal perspective and using complete cases only. Conclusions: This economic evaluation indicates that hydroxychloroquine is unlikely to provide a cost-effective pain relief option for improving health-related quality of life in adult patients with moderate-to-severe hand osteoarthritis.