Protocol for a multicentre randomised controlled trial of STeroid Administration Routes For Idiopathic Sudden sensorineural Hearing loss: The STARFISH trial.

Idiopathic sudden sensorineural hearing loss (ISSNHL) is the rapid onset of reduced hearing due to loss of function of the inner ear or hearing nerve of unknown aetiology. Evidence supports improved hearing recovery with early steroid treatment, via oral, intravenous, intratympanic or a combination of routes. The STARFISH trial aims to identify the most clinically and cost-effective route of administration of steroids as first-line treatment for ISSNHL. STARFISH is a pragmatic, multicentre, assessor-blinded, three-arm intervention, superiority randomised controlled trial (1:1:1) with an internal pilot (ISRCTN10535105, IRAS 1004878). 525 participants with ISSNHL will be recruited from approximately 75 UK Ear, Nose and Throat units. STARFISH will recruit adults with sensorineural hearing loss averaging 30dBHL or greater across three contiguous frequencies (confirmed via pure tone audiogram), with onset over a ≤3-day period, within four weeks of randomisation. Participants will be randomised to 1) oral prednisolone 1mg/Kg/day up to 60mg/day for 7 days; 2) intratympanic dexamethasone: three intratympanic injections 3.3mg/ml or 3.8mg/ml spaced 7±2 days apart; or 3) combined oral and intratympanic steroids. The primary outcome will be absolute improvement in pure tone audiogram average at 12-weeks following randomisation (0.5, 1.0, 2.0 and 4.0kHz). Secondary outcomes at 6 and 12 weeks will include: Speech, Spatial and Qualities of hearing scale, high frequency pure tone average thresholds (4.0, 6.0 and 8.0kHz), Arthur Boothroyd speech test, Vestibular Rehabilitation Benefit Questionnaire, Tinnitus Functional Index, adverse events and optional weekly online speech and pure tone hearing tests. A health economic assessment will be performed, and presented in terms of incremental cost effectiveness ratios, and cost per quality-adjusted life-year. Primary analyses will be by intention-to-treat. Oral prednisolone will be the reference. For the primary outcome, the difference between group means and 97.5% confidence intervals at each time-point will be estimated via a repeated measures mixed-effects linear regression model.

Study protocol for a randomised controlled trial to investigate the effectiveness of thoracic epidural and paravertebral blockade in reducing chronic post-thoracotomy pain: 2 (TOPIC 2).

BACKGROUND: Thoracotomy is considered one of the most painful surgical procedures and can cause debilitating chronic post-surgical pain lasting months or years postoperatively. Aggressive management of acute pain resulting from thoracotomy may reduce the likelihood of developing chronic pain. This trial compares the two most commonly used modes of acute analgesia provision at the time of thoracotomy (thoracic epidural blockade (TEB) and paravertebral blockade (PVB)) in terms of their clinical and cost-effectiveness in preventing chronic post-thoracotomy pain. METHODS: TOPIC 2 is a multi-centre, open-label, parallel group, superiority, randomised controlled trial, with an internal pilot investigating the use of TEB and PVB in 1026 adult (≥ 18 years old) patients undergoing thoracotomy in up to 20 thoracic centres throughout the UK. Patients (N = 1026) will be randomised in a 1:1 ratio to receive either TEB or PVB. During the first year, the trial will include an integrated QuinteT (Qualitative Research Integrated into Trials) Recruitment Intervention (QRI) with the aim of optimising recruitment and informed consent. The primary outcome is the incidence of chronic post-surgical pain at 6 months post-randomisation defined as 'worst chest pain over the last week' equating to a visual analogue score greater than or equal to 40 mm indicating at least a moderate level of pain. Secondary outcomes include acute pain, complications of regional analgesia and surgery, health-related quality of life, mortality and a health economic analysis. DISCUSSION: Both TEB and PVB have been demonstrated to be effective in the prevention of acute pain following thoracotomy and nationally practice is divided. Identification of which mode of analgesia is both clinically and cost-effective in preventing chronic post-thoracotomy pain could ameliorate the debilitating effects of chronic pain, improving health-related quality of life, facilitating return to work and caring responsibilities and resulting in a cost saving to the NHS. TRIAL REGISTRATION: NCT03677856 [ClinicalTrials.gov] registered September 19, 2018. https://clinicaltrials.gov/ct2/show/NCT03677856 . First patient recruited 8 January 2019.

A vein bypass first versus a best endovascular treatment first revascularisation strategy for patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal revascularisation procedure to restore limb perfusion (BASIL-2): an open-label, randomised, multicentre, phase 3 trial.

BACKGROUND: Chronic limb-threatening ischaemia is the severest manifestation of peripheral arterial disease and presents with ischaemic pain at rest or tissue loss (ulceration, gangrene, or both), or both. We compared the effectiveness of a vein bypass first with a best endovascular treatment first revascularisation strategy in terms of preventing major amputation and death in patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion. METHODS: Bypass versus Angioplasty for Severe Ischaemia of the Leg (BASIL)-2 was an open-label, pragmatic, multicentre, phase 3, randomised trial done at 41 vascular surgery units in the UK (n=39), Sweden (n=1), and Denmark (n=1). Eligible patients were those who presented to hospital-based vascular surgery units with chronic limb-threatening ischaemia due to atherosclerotic disease and who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion. Participants were randomly assigned (1:1) to receive either vein bypass (vein bypass group) or best endovascular treatment (best endovascular treatment group) as their first revascularisation procedure through a secure online randomisation system. Participants were excluded if they had ischaemic pain or tissue loss considered not to be primarily due to atherosclerotic peripheral artery disease. Most vein bypasses used the great saphenous vein and originated from the common or superficial femoral arteries. Most endovascular interventions comprised plain balloon angioplasty with selective use of plain or drug eluting stents. Participants were followed up for a minimum of 2 years. Data were collected locally at participating centres. In England, Wales, and Sweden, centralised databases were used to collect information on amputations and deaths. Data were analysed centrally at the Birmingham Clinical Trials Unit. The primary outcome was amputation-free survival defined as time to first major (above the ankle) amputation or death from any cause measured in the intention-to-treat population. Safety was assessed by monitoring serious adverse events up to 30-days after first revascularisation. The trial is registered with the ISRCTN registry, ISRCTN27728689. FINDINGS: Between July 22, 2014, and Nov 30, 2020, 345 participants (65 [19%] women and 280 [81%] men; median age 72·5 years [62·7-79·3]) with chronic limb-threatening ischaemia were enrolled in the trial and randomly assigned: 172 (50%) to the vein bypass group and 173 (50%) to the best endovascular treatment group. Major amputation or death occurred in 108 (63%) of 172 patients in the vein bypass group and 92 (53%) of 173 patients in the best endovascular treatment group (adjusted hazard ratio [HR] 1·35 [95% CI 1·02-1·80]; p=0·037). 91 (53%) of 172 patients in the vein bypass group and 77 (45%) of 173 patients in the best endovascular treatment group died (adjusted HR 1·37 [95% CI 1·00-1·87]). In both groups the most common causes of morbidity and death, including that occurring within 30 days of their first revascularisation, were cardiovascular (61 deaths in the vein bypass group and 49 in the best endovascular treatment group) and respiratory events (25 deaths in the vein bypass group and 23 in the best endovascular treatment group; number of cardiovascular and respiratory deaths were not mutually exclusive). INTERPRETATION: In the BASIL-2 trial, a best endovascular treatment first revascularisation strategy was associated with a better amputation-free survival, which was largely driven by fewer deaths in the best endovascular treatment group. These data suggest that more patients with chronic limb-threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion should be considered for a best endovascular treatment first revascularisation strategy. FUNDING: UK National Institute of Health Research Health Technology Programme.

Phase III, two arm, multi-centre, open label, parallel-group randomised designed clinical investigation of the use of a personalised early warning decision support system to predict and prevent acute exacerbations of chronic obstructive pulmonary disease: 'Predict & Prevent AECOPD' - study protocol.

INTRODUCTION: With 65 million cases globally, chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death and imposes a heavy burden on patients' lives and healthcare resources worldwide. Around half of all patients with COPD have frequent (≥2 per year) acute exacerbations of COPD (AECOPD). Rapid readmissions are also common. Exacerbations impact significantly on COPD outcomes, causing significant lung function decline. Prompt exacerbation management optimises recovery and delays the time to the next acute episode. METHODS/ANALYSIS: The Predict & Prevent AECOPD trial is a phase III, two arm, multi-centre, open label, parallel-group individually randomised clinical trial investigating the use of a personalised early warning decision support system (COPDPredict) to predict and prevent AECOPD. We aim to recruit 384 participants and randomise each individual in a 1:1 ratio to either standard self-management plans with rescue medication (RM) (control arm) or COPDPredict with RM (intervention arm).The trial will inform the future standard of care regarding management of exacerbations in COPD patients. The main outcome measure is to provide further validation, as compared with usual care, for the clinical effectiveness of COPDPredict to help guide and support COPD patients and their respective clinical teams in identifying exacerbations early, with an aim to reduce the total number of AECOPD-induced hospital admissions in the 12 months following each patient's randomisation. ETHICS AND DISSEMINATION: This study protocol is reported in accordance with the guidance set out in the Standard Protocol Items: Recommendations for Interventional Trials statement. Predict & Prevent AECOPD has obtained ethical approval in England (19/LO/1939). On completion of the trial and publication of results a lay findings summary will be disseminated to trial participants. TRIAL REGISTRATION NUMBER: NCT04136418.

Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT.

BACKGROUND: Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes. OBJECTIVES: We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease. DESIGN: This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab. SETTING: Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated. PARTICIPANTS: Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m2 or diffuse alveolar haemorrhage attributable to active anti-neutrophil cytoplasm antibody-associated vasculitis. INTERVENTIONS: Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician. PRIMARY OUTCOME: The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial. RESULTS: The study recruited 704 patients from June 2010 to September 2016. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86, 95% confidence interval 0.65 to 1.13; p = 0.3). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023, 95% confidence interval 0.034 to 0.08; p = 0.5), thus meeting our non-inferiority hypothesis. Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% confidence interval 0.52 to 0.93; p = 0.016). CONCLUSIONS: Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections. FUTURE WORK: A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis. LIMITATIONS: This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study. TRIAL REGISTRATION: This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 38. See the NIHR Journals Library website for further project information.

Anti-neutrophil cytoplasm antibody vasculitis is a rare and severe disease in which the patient makes antibodies that damage their blood vessels. It can cause lung damage, kidney failure and early death. Treatment aims to suppress the harmful effects of the antibodies and associated inflammation. In particular: Plasma exchange aims to remove the antibodies from the bloodstream.Steroids aim to reduce the harmful activity of the antibodies. Unfortunately, plasma exchange is expensive and time-consuming, and we do not know if it really works long term to reduce kidney damage or the risk of death. We know steroids work, but they have many severe side effects that are related to higher doses. Again, we do not know if lower doses are equally effective. We conducted a randomised trial, PEXIVAS (Plasma Exchange In VASculitis), to measure the clinical effectiveness of plasma exchange and of reduced steroid doses. Anti-neutrophil cytoplasm antibody vasculitis patients with severe kidney or lung disease were allocated randomly to either plasma exchange or no plasma exchange. The same patients were then randomly allocated to a 'reduced' or 'standard' steroid dose. All patients received an immunosuppressive drug: cyclophosphamide or rituximab. The primary end point for both trials was the occurrence of either kidney failure or death. A total of 704 patients were recruited between 2010 and 2016, and they were followed up until the end of the trial in July 2017. Ninety-nine patients died and 138 developed kidney failure. Plasma exchange did not reduce the chances of death or kidney failure. There was also no difference between the two steroid dose groups in the number of deaths or patients developing kidney failure. However, there were fewer serious infections in the reduced steroid dose group. These results do not support the routine use of plasma exchange for all patients with severe vasculitis. They do show that the reduced-dose steroid regimen is just as effective as, and safer than, a 'standard'-dose steroid regimen. These results have the potential to save money and make the treatment of vasculitis patients safer in the future.

Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: Results from a British Thoracic Oncology Group randomised phase III trial.

BACKGROUND: Platinum-based combination chemotherapy is standard treatment for the majority of patients with advanced non-small-cell lung cancer (NSCLC). The trial investigates the importance of the choice of platinum agent and dose of cisplatin in relation to patient outcomes. METHODS: The three-arm randomised phase III trial assigned patients with chemo-naïve stage IIIB/IV NSCLC in a 1:1:1 ratio to receive gemcitabine 1250 mg/m2 on days 1 and 8 of a 3-week cycle with cisplatin 80 mg/m2 (GC80) or cisplatin 50 mg/m2 (GC50) or carboplatin AUC6 (GCb6) for a maximum of four cycles. Primary outcome measure was survival time, aiming to test for a difference between treatment arms and also assess non-inferiority with pre-defined margin selected as hazard ratio (HR) of 1.2. Secondary outcome measures included response rate, adverse events and quality of life (QoL). FINDINGS: The trial recruited 1363 patients. Survival time differed significantly across the three treatment arms (p = 0.046) with GC50 worst with median 8.2 months compared to 9.5 for GC80 and 10.0 for GCb6. HRs (adjusted) for GC50 compared to GC80 was 1.13 (95% confidence interval [CI] 0.99-1.29) and for GC50 compared to GCb6 was 1.23 (95% CI: 1.08-1.41). GCb6 was significantly non-inferior to GC80 (HR = 0.93, upper limit of one-sided 95% CI 1.04). Adjusting for QoL did not change the findings. Best objective response rates were 29% (GC80), 20% (GC50) and 27% (GCb6), p < 0.007. There were more dose reductions and treatment delays in the GCb6 arm and more adverse events (60% with at least one grade 3-4 compared to 43% GC80 and 30% GC50). INTERPRETATION: In combination with gemcitabine, carboplatin at AUC6 is not inferior to cisplatin at 80 mg/m2 in terms of survival. Carboplatin was associated with more adverse events and not with better quality of life. Cisplatin at the lower dose of 50 mg/m2 has worse survival which is not compensated by better quality of life. CLINICALTRIALS. GOV IDENTIFIER: NCT00112710. EUDRACT NUMBER: 2004-003868-30. CANCER RESEARCH UK TRIAL IDENTIFIER: CRUK/04/009.

BAlloon versus Stenting in severe Ischaemia of the Leg-3 (BASIL-3): study protocol for a randomised controlled trial.

BACKGROUND: Severe limb ischaemia (SLI) is defined as the presence of rest pain and/or tissue loss secondary to lower extremity atherosclerotic peripheral arterial disease. The superficial femoral and popliteal arteries are the most commonly diseased vessels in such patients and are being increasingly treated using endovascular revascularisation techniques. However, it is currently unknown whether drug-eluting stents and drug-coated balloons confer additional clinical benefits over more established techniques using plain balloons and bare metal stents, or whether they represent a cost-effective use of NHS resources. METHODS: The BASIL-3 trial is a UK National Institute for Health Research, Health Technology Assessment Programme-funded, multicentre, randomised controlled trial (RCT) comparing the clinical and cost-effectiveness of plain balloon angioplasty with or without bail-out bare metal stenting, drug-coated balloon angioplasty with or without bail-out bare metal stenting, and primary stenting with drug-eluting stents for SLI secondary to femoro-popliteal disease. Patients with 'multilevel' disease may receive aorto-iliac and/or infrapopliteal treatments concurrently with their randomised femoro-popliteal intervention. The primary clinical outcome is amputation-free survival defined as the time to major (above the ankle) amputation of the index limb or death from any cause. The primary outcome for the economic analysis is cost per quality-adjusted life year. Secondary outcome measures include overall survival, major adverse limb events, major adverse cardiac events, relief of ischaemic pain, healing of tissue loss, and quality of life. The required sample size has been calculated at 861 participants (287 on each arm). These patients will be recruited over 3 years and followed-up for between 2 and 5 years. DISCUSSION: BASIL-3 is a pragmatic RCT designed to reflect current UK clinical practice. The results will inform decision-making regarding the appropriateness of funding the use of drug-coated balloons and drug-eluting stents, by the NHS, for the management of SLI due to femoro-popliteal disease. TRIAL REGISTRATION: ISRCTN Registry, identifier: ISRCTN14469736 . Registered on 22 October 2015.

Bypass versus angio plasty in severe ischaemia of the leg - 2 (BASIL-2) trial: study protocol for a randomised controlled trial.

BACKGROUND: Severe limb ischaemia is defined by ischaemic rest/night pain, tissue loss, or both, secondary to arterial insufficiency and is increasingly caused by infra-popliteal (below the knee) disease, mainly as a result of the increasing worldwide prevalence of diabetes. Currently, it is unknown whether vein bypass surgery or the best endovascular treatment (angioplasty or stenting) represents the optimal revascularisation strategy in terms of amputation-free survival, overall survival, relief of symptoms, quality of life and cost-effective use of health care resources. METHODS/DESIGN: The Bypass vs. Angioplasty in Severe Ischaemia of the Leg - 2 Trial is a UK National Institute of Health Research, Health Technology Assessment funded, multi-centre randomised controlled trial that compares, at the point of clinical equipoise, the clinical and cost-effectiveness of a 'vein bypass first' and a 'best endovascular treatment first' revascularisation strategy for severe limb ischaemia due to infra-popliteal disease. The primary clinical outcome is amputation-free survival defined as the time to major (above the ankle) amputation of the trial limb or death from any cause. The primary outcome for the cost-effectiveness analysis is cost per quality-adjusted life year. Secondary outcomes include overall survival, quality of life, in-hospital mortality and morbidity, repeat and crossover interventions, healing of tissue loss and haemodynamic changes following revascularisation. Sample size is estimated at 600 patients. An economic evaluation will be conducted from the perspective of the National Health Service and comprise a 'within-study' analysis, based on prospectively collected trial data and a 'model-based' analysis, which will extrapolate and compare costs and effects beyond the study follow-up period. DISCUSSION: The BASIL-2 trial is designed to be pragmatic and represent current practice within the United Kingdom. Patients with severe limb ischaemia can only be randomised into the trial where clinical equipose exists. The advent of hybrid operating procedures should not be a barrier to randomisation, should a patient require inflow correction prior to tibial revascularisation. ISRCTN: 27728689 Date of registration: 12 May 2014.