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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.
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Teorema de Bayes , Análisis Costo-Beneficio , Osteoartritis , Proyectos de Investigación , Humanos , Análisis Costo-Beneficio/métodos , Análisis Costo-Beneficio/estadística & datos numéricos , Osteoartritis/economía , Osteoartritis/tratamiento farmacológico , Osteoartritis/terapia , Hidroxicloroquina/uso terapéutico , Hidroxicloroquina/economía , Ensayos Clínicos como Asunto/métodos , Ensayos Clínicos como Asunto/economía , Ensayos Clínicos como Asunto/estadística & datos numéricos , Tamaño de la MuestraRESUMEN
BACKGROUND: Treatments for osteoarthritis (OA) are limited. Previous small studies suggest that the antirheumatic drug methotrexate may be a potential treatment for OA pain. OBJECTIVE: To assess symptomatic benefits of methotrexate in knee OA (KOA). DESIGN: A multicenter, randomized, double-blind, placebo-controlled trial done between 13 June 2014 and 13 October 2017. (ISRCTN77854383; EudraCT: 2013-001689-41). SETTING: 15 secondary care musculoskeletal clinics in the United Kingdom. PARTICIPANTS: A total of 207 participants with symptomatic, radiographic KOA and knee pain (severity ≥4 out of 10) on most days in the past 3 months with inadequate response to current medication were approached for inclusion. INTERVENTION: Participants were randomly assigned 1:1 to oral methotrexate once weekly (6-week escalation 10 to 25 mg) or matched placebo over 12 months and continued usual analgesia. MEASUREMENTS: The primary end point was average knee pain (numerical rating scale [NRS] 0 to 10) at 6 months, with 12-month follow-up to assess longer-term response. Secondary end points included knee stiffness and function outcomes and adverse events (AEs). RESULTS: A total of 155 participants (64% women; mean age, 60.9 years; 50% Kellgren-Lawrence grade 3 to 4) were randomly assigned to methotrexate (n = 77) or placebo (n = 78). Follow-up was 86% (n = 134; methotrexate: 66, placebo: 68) at 6 months. Mean knee pain decreased from 6.4 (SD, 1.80) at baseline to 5.1 (SD, 2.32) at 6 months in the methotrexate group and from 6.8 (SD, 1.62) to 6.2 (SD, 2.30) in the placebo group. The primary intention-to-treat analysis showed a statistically significant pain reduction of 0.79 NRS points in favor of methotrexate (95% CI, 0.08 to 1.51; P = 0.030). There were also statistically significant treatment group differences in favor of methotrexate at 6 months for Western Ontario and McMaster Universities Osteoarthritis Index stiffness (0.60 points [CI, 0.01 to 1.18]; P = 0.045) and function (5.01 points [CI, 1.29 to 8.74]; P = 0.008). Treatment adherence analysis supported a dose-response effect. Four unrelated serious AEs were reported (methotrexate: 2, placebo: 2). LIMITATION: Not permitting oral methotrexate to be changed to subcutaneous delivery for intolerance. CONCLUSION: Oral methotrexate added to usual medications demonstrated statistically significant reduction in KOA pain, stiffness, and function at 6 months. PRIMARY FUNDING SOURCE: Versus Arthritis.
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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. 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. 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. 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.
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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.
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Artroplastía de Reemplazo de Hombro , Hemiartroplastia , Articulación del Hombro , Humanos , Anciano , Hombro/cirugía , Artroplastía de Reemplazo de Hombro/efectos adversos , Artroplastía de Reemplazo de Hombro/métodos , Hemiartroplastia/efectos adversos , Calidad de Vida , Medicina Estatal , Articulación del Hombro/cirugía , Húmero/cirugía , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
During the coronavirus 2019 (COVID-19) pandemic, the implementation of non-contact infrared thermometry (NCIT) became an increasingly popular method of screening body temperature. However, data on the accuracy of these devices and the standardisation of their use are limited. In the current study, the body temperature of non-febrile volunteers was measured using infrared (IR) thermography, IR tympanic thermometry and IR gun thermometry at different facial feature locations and distances and compared with SpotOn core-body temperature. Poor agreement was found between all IR devices and SpotOn measurements (intra-class correlation coefficient <0.8). Bland-Alman analysis showed the narrowest limits of agreement with the IR gun at 3 cm from the forehead (bias = 0.19°C, limits of agreement (LOA): -0.58°C to 0.97°C) and widest with the IR gun at the nose (bias = 1.40°C, LOA: -1.15°C to 3.94°C). Thus, our findings challenge the established use of IR thermometry devices within hospital settings without adequate standard operating procedures to reduce operator error.
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COVID-19 , Termometría , Humanos , Temperatura Corporal , Temperatura , Termometría/métodos , COVID-19/diagnóstico , VoluntariosRESUMEN
OBJECTIVE: To explore the predictors of emergency department attendance and admission for mothers and their infants. METHODS: Self-reported emergency department (ED) attendance and admission, sociodemographic, mental health, and other measures were recorded at baseline and at 12 months at 4 sites in England between May 2017 and March 2020. RESULTS: Infants' gestational age (OR 0.73, 95% CI 0.61 to 0.88, p = 0.001), mothers' mental health (OR 2.40, 95% CI 1.30 to 4.41, p = 0.005) and mothers' attendance at ED (OR 2.34, 95% CI 1.13 to 4.84, p = 0.022) predicted infant ED attendance. Frequency of attendance was predicted by ED site (IRR 0.46, 95% CI 0.29 to 0.73, p = 0.001) and mothers' age (IRR 0.96, 95% CI 0.92 to 1.00, p = 0.028). Infant hospital admissions were predominantly for respiratory (40%) and other infectious diseases (21%) and were predicted by previous health problems (OR 3.25, 95% CI 1.76 to 6.01, p < 0.001). Mothers' ED attendance was predicted by mixed or multiple ethnic origin (OR 9.62, 95% CI 2.19 to 42.27, p = 0.003), having a male infant (OR 2.08, 95% CI 1.03 to 4.20, p = 0.042), and previous hospitalisation (OR 4.15, 95% CI 1.81 to 9.56, p = 0.001). Hospital admission was largely for reproductive health issues (61%) with frequency predicted by having attended the ED at least once (IRR 3.39, 95% CI 1.66 to 6.93, p = 0.001), and being anxious or depressed (IRR 3.10, 95% CI 1.14 to 8.45, p = 0.027). CONCLUSIONS FOR PRACTICE: Improving the reproductive and mental health of mothers may help to avoid poor maternal and infant health outcomes and reduce emergency service utilisation and hospitalisation.
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Hospitalización , Madres , Femenino , Humanos , Lactante , Masculino , Estudios Prospectivos , Edad Materna , Servicio de Urgencia en HospitalRESUMEN
OBJECTIVE: To examine effectiveness, cost effectiveness, generalisability, and acceptability of financial incentives for smoking cessation during pregnancy in addition to variously organised UK stop smoking services. DESIGN: Pragmatic, multicentre, single blinded, phase 3, randomised controlled trial (Cessation in Pregnancy Incentives Trial phase 3 (CPIT III)). SETTING: Seven UK stop smoking services provided in primary and secondary care facilities in Scotland, Northern Ireland, and England. PARTICIPANTS: 944 pregnant women (age ≥16 years) who self-reported as being smokers (at least one cigarette in the past week) when asked at first maternity visit, less than 24 weeks' gestation, and notified to the trial team by routine stop smoking services. INTERVENTIONS: Participants in the control group were offered the standard stop smoking services, which includes the offer of counselling by specially trained workers using withdrawal orientated therapy and the offer of free nicotine replacement therapy. The intervention was the offer of usual support from the stop smoking services and the addition of up to £400 ($440; 455) of LoveToShop financial voucher incentives for engaging with current stop smoking services or to stop smoking, or both, during pregnancy. MAIN OUTCOME MEASURES: Self-reported smoking cessation in late pregnancy (between 34 and 38 weeks' gestation) corroborated by saliva cotinine (and anabasine if using nicotine replacement products). Results were adjusted for age, smoking years, index of multiple deprivation, Fagerström score, before or after covid, and recruitment site. Secondary outcomes included point and continuous abstinence six months after expected date of delivery, engagement with stop smoking services, biochemically validated abstinence from smoking at four weeks after stop smoking date, birth weight of baby, cost effectiveness, generalisability documenting formats of stop smoking services, and acceptability to pregnant women and their carers. RESULTS: From 9 January 2018 to 4 April 2020, of 4032 women screened by stop smoking services, 944 people were randomly assigned to the intervention group (n=471) or the control group (n=470). Three people asked for their data to be removed. 126 (27%) of 471 participants stopped smoking from the intervention group and 58 (12%) of 470 from the control group (adjusted odds ratio 2.78 (1.94 to 3.97) P<0.001). Serious adverse events were miscarriages and other expected pregnancy events requiring hospital admission; all serious adverse events were unrelated to the intervention. Most people who stopped smoking from both groups relapsed after their baby was born. CONCLUSIONS: The offer of up to £400 of financial voucher incentives to stop smoking during pregnancy as an addition to current UK stop smoking services is highly effective. This bolt-on intervention supports new guidance from the UK National Institute for Health and Care Excellence, which includes the addition of financial incentives to support pregnant women to stop smoking. Continuing incentives to 12 months after birth is being examined to prevent relapse. TRIAL REGISTRATION: ISRCTN Registry ISRCTN15236311.
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COVID-19 , Cese del Hábito de Fumar , Femenino , Humanos , Embarazo , Adolescente , Cese del Hábito de Fumar/métodos , Motivación , Mujeres Embarazadas , Dispositivos para Dejar de Fumar Tabaco , Cotinina , Anabasina , Fumar/efectos adversos , EscociaRESUMEN
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.
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Alcaloides , Cese del Hábito de Fumar , Tuberculosis Pulmonar , Adolescente , Adulto , Azocinas , Análisis Costo-Beneficio , Humanos , QuinolizinasRESUMEN
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.
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BACKGROUND: Treatment of established depression is the dominant approach to care of older adults, but prevention holds much promise. Self-help interventions are a feasible preventive approach, since they are scalable and low cost. There are few trials in this area. Behavioral Activation (BA) is a credible candidate psychological approach, which has been shown to work in therapist led care but not been trialled in a self-help form. AIM: To test the effectiveness of an unguided self-help intervention based on BA for older adults. METHODS: We compared a self-help intervention based on BA for older people (n = 172) to usual care (n = 160) in a pragmatic randomized controlled trial. Outcomes were depression status and severity (PHQ9) and health related quality of life (SF12). The primary timepoint of the primary outcome was depression at 4 months, with longer term follow up at 12 months to test sustained impact of the primary outcome. RESULTS: At 4 months adjusted PHQ-9 scores for BA self-help were 0.79 lower (95% CI: -1.70 to 0.13; p = 0.09) and the proportion of participants with case-level depression was significantly reduced (BA 31/137 (22.6%) versus usual care 41/141 (29.1%); Odds Ratio 0.48; 95% CI: 0.26-0.92; p = 0.03). There was no PHQ-9 difference at 12 months or for health related quality of life at any point (4 or 12 months). DISCUSSION: Self-help using BA for older people at risk of depression is a feasible and scalable intervention with potential short-term benefits in preventing depression.
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Depresión , Calidad de Vida , Anciano , Análisis Costo-Beneficio , Depresión/prevención & control , Humanos , Reino UnidoRESUMEN
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 x10 10vp 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.
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BACKGROUND: Despite treatment, patients with tuberculosis (TB) who smoke have poorer outcomes compared with non-smokers. It is unknown, however, if quitting smoking during the 6 months of TB treatment improves TB outcomes. METHODS: The TB & Tobacco Trial was a double-blind, placebo-controlled randomised trial of cytisine for smoking cessation in 2472 patients with pulmonary TB in Bangladesh and Pakistan. In a secondary analysis, we investigated the hypothesis that smoking cessation improves health outcomes in patients during the TB treatment course. The outcomes included an eight-point TB clinical score, sputum conversion rates, chest X-ray grades, quality of life (EQ-5D-5L), TB cure plus treatment completion rates and relapse rates. These were compared between those who stopped smoking and those who did not, using regression analysis. RESULTS: We analysed the data of 2273 (92%) trial participants. Overall, 25% (577/2273) of participants stopped smoking. Compared with non-quitters, those who quit had better TB cure plus treatment completion rates (91% vs 80%, p<0.001) and lower TB relapse rates (6% vs 14%, p<0.001). Among quitters, a higher sputum conversion rate at week 9 (91% vs 87%, p=0.036), lower mean TB clinical scores (-0.20 points, 95% CI -0.31 to -0.08, p=0.001) and slightly better quality of life (mean EQ-5D-5L 0.86 vs 0.85, p=0.015) at 6 months were also observed. These differences, except quality of life, remained statistically significant after adjusting for baseline values, trial arm and TB treatment adherence rates. CONCLUSION: Patients with TB who stop smoking may have better outcomes than those who don't. Health professionals should support patients in stopping smoking.
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Cese del Hábito de Fumar , Tuberculosis , Humanos , Recurrencia Local de Neoplasia , Evaluación de Resultado en la Atención de Salud , Calidad de Vida , Fumar , NicotianaRESUMEN
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.
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Hidroxicloroquina , Osteoartritis , Adulto , Análisis Costo-Beneficio , Humanos , Hidroxicloroquina/uso terapéutico , Osteoartritis/tratamiento farmacológico , Calidad de Vida , Medicina EstatalRESUMEN
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.
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Contractura de Dupuytren , Recurrencia Local de Neoplasia , Adulto , Colagenasas/efectos adversos , Contractura de Dupuytren/diagnóstico , Contractura de Dupuytren/tratamiento farmacológico , Contractura de Dupuytren/cirugía , Fasciotomía , Humanos , Masculino , Colagenasa Microbiana/efectos adversos , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
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.
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BACKGROUND/AIMS: There is growing interest in the use of adaptive designs to improve the efficiency of clinical trials. We apply a Bayesian decision-theoretic model of a sequential experiment using cost and outcome data from the ProFHER pragmatic trial. We assess the model's potential for delivering value-based research. METHODS: Using parameter values estimated from the ProFHER pragmatic trial, including the costs of carrying out the trial, we establish when the trial could have stopped, had the model's value-based stopping rule been used. We use a bootstrap analysis and simulation study to assess a range of operating characteristics, which we compare with a fixed sample size design which does not allow for early stopping. RESULTS: We estimate that application of the model could have stopped the ProFHER trial early, reducing the sample size by about 14%, saving about 5% of the research budget and resulting in a technology recommendation which was the same as that of the trial. The bootstrap analysis suggests that the expected sample size would have been 38% lower, saving around 13% of the research budget, with a probability of 0.92 of making the same technology recommendation decision. It also shows a large degree of variability in the trial's sample size. CONCLUSIONS: Benefits to trial cost stewardship may be achieved by monitoring trial data as they accumulate and using a stopping rule which balances the benefit of obtaining more information through continued recruitment with the cost of obtaining that information. We present recommendations for further research investigating the application of value-based sequential designs.
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Proyectos de Investigación , Teorema de Bayes , Simulación por Computador , Análisis Costo-Beneficio , Humanos , Tamaño de la MuestraRESUMEN
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.
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BACKGROUND: The faecal immunochemical test (FIT) is now available to support clinicians in the assessment of patients at low risk of colorectal cancer (CRC) and within the bowel cancer screening programme. AIM: To determine the diagnostic accuracy of FIT for CRC and clinically significant disease in patients referred as they were judged by their GP to fulfil National Institute for Health and Care Excellence guideline 12 (NG12) criteria for suspected CRC. DESIGN AND SETTING: Patients referred from primary care with suspected CRC, meeting NG12 criteria, to 12 secondary care providers in Yorkshire and Humber were asked to complete a FIT before investigation. METHOD: The diagnostic accuracy of FIT based on final diagnosis was evaluated using receiver operating characteristics analysis. This permitted a statistically optimal cut-off value for FIT to be determined based on the maximisation of sensitivity and specificity. Clinicians and patients were blinded to the FIT results. RESULTS: In total, 5040 patients were fully evaluated and CRC was detected in 151 (3.0%). An optimal cut-off value of 19 µg Hb/g faeces for CRC was determined, giving a sensitivity of 85.4% (95% confidence interval [CI] = 78.8% to 90.6%) and specificity of 85.2% (95% CI = 84.1% to 86.2%). The negative predictive value at this cut-off value was 99.5% (95% CI = 99.2% to 99.7%) and the positive predictive value 15.1% (95% CI = 12.8% to 17.7%). Sensitivity and specificity of FIT for CRC and significant premalignant polyps at this cut-off value were 62.9% (95% CI = 57.5% to 68.0%) and 86.4% (95% CI = 85.4% to 87.4%), respectively; and when including all organic enteric disease were 35.7% (95% CI = 32.9% to 38.5%) and 88.6% (95% CI = 87.5% to 89.6%), respectively. CONCLUSION: FIT used in patients fulfilling NG12 criteria should allow for a more personalised CRC risk assessment. FIT should permit effective, patient-centred decision-making to inform the need for, type, and timing of further investigation.
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Neoplasias Colorrectales , Colonoscopía , Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer , Heces/química , Hemoglobinas , Humanos , Sangre Oculta , Sensibilidad y EspecificidadRESUMEN
Post-kala-azar dermal leishmaniasis (PKDL) is a chronic, stigmatizing skin condition occurring frequently after apparent clinical cure from visceral leishmaniasis. Given an urgent need for new treatments, we conducted a phase IIa safety and immunogenicity trial of ChAd63-KH vaccine in Sudanese patients with persistent PKDL. LEISH2a (ClinicalTrials.gov: NCT02894008) was an open-label three-phase clinical trial involving sixteen adult and eight adolescent patients with persistent PKDL (median duration, 30 months; range, 6-180 months). Patients received a single intramuscular vaccination of 1 × 1010 viral particles (v.p.; adults only) or 7.5 × 1010 v.p. (adults and adolescents), with primary (safety) and secondary (clinical response and immunogenicity) endpoints evaluated over 42-120 days follow-up. AmBisome was provided to patients with significant remaining disease at their last visit. ChAd63-KH vaccine showed minimal adverse reactions in PKDL patients and induced potent innate and cell-mediated immune responses measured by whole-blood transcriptomics and ELISpot. 7/23 patients (30.4%) monitored to study completion showed >90% clinical improvement, and 5/23 (21.7%) showed partial improvement. A logistic regression model applied to blood transcriptomic data identified immune modules predictive of patients with >90% clinical improvement. A randomized controlled trial to determine whether these clinical responses were vaccine-related and whether ChAd63-KH vaccine has clinical utility is underway.
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Antígenos de Protozoos/inmunología , Linfocitos T CD8-positivos/inmunología , Leishmania/inmunología , Vacunas contra la Leishmaniasis/administración & dosificación , Leishmaniasis Cutánea/prevención & control , Vacunas Sintéticas/administración & dosificación , Adenovirus de los Simios/genética , Adolescente , Adulto , Niño , Femenino , Humanos , Inyecciones Intramusculares , Leishmania/aislamiento & purificación , Vacunas contra la Leishmaniasis/inmunología , Leishmaniasis Cutánea/inmunología , Leishmaniasis Cutánea/parasitología , Masculino , Pronóstico , Vacunas Sintéticas/inmunología , Adulto JovenRESUMEN
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.