Elicitation of expert prior opinion to design the BARJDM trial in juvenile dermatomyositis.

OBJECTIVES: To elicit and quantify expert opinion concerning the relative merits of two treatments for a rare inflammatory disease: Juvenile dermatomyositis (JDM). The formal expression of expert opinion reported in this paper will be used in a Bayesian analysis of a forthcoming randomised controlled trial known as BARJDM (baricitinib for juvenile dermatomyositis). METHODS: A Bayesian prior elicitation meeting was convened, following a previously described methodological template. Opinion was sought on the probability that a patient in the BARJDM trial would achieve clinically inactive disease, off glucocorticoids (GC) within a 12-month period with either methotrexate (standard of care); or baricitinib (a Janus kinase inhibitor, JAKi), with GC schedules identical in both arms of the trial. Experts' views were discussed and refined following presentation and further discussion of summated published data regarding efficacy of methotrexate or JAKi for JDM. RESULTS: Ten UK paediatric rheumatology consultants (including one adolescent paediatric rheumatologist) participated in the elicitation meeting. All had expertise in JDM, leading active National Health Service clinics for this disease. Consensus expert prior opinion was that the most likely probability of clinically inactive disease off GC within 12 months was 0.55 on baricitinib and 0.23 on methotrexate, with a greater degree of uncertainty for baricitinib. CONCLUSION: Experts currently think that baricitinib is superior to MTX for the treatment of JDM, although there is uncertainty around this. BARJDM will therefore integrate randomised trial data with this expert prior opinion to derive a posterior distribution for the relative efficacy of baricitinib compared with MTX.

The 3 + 3 design in dose-finding studies with small sample sizes: Pitfalls and possible remedies.

In the last few years, numerous novel designs have been proposed to improve the efficiency and accuracy of phase I trials to identify the maximum-tolerated dose (MTD) or the optimal biological dose (OBD) for noncytotoxic agents. However, the conventional 3+3 approach, known for its and poor performance, continues to be an attractive choice for many trials despite these alternative suggestions. The article seeks to underscore the importance of moving beyond the 3+3 design by highlighting a different key element in trial design: the estimation of sample size and its crucial role in predicting toxicity and determining the MTD. We use simulation studies to compare the performance of the most used phase I approaches: 3+3, Continual Reassessment Method (CRM), Keyboard and Bayesian Optimal Interval (BOIN) designs regarding three key operating characteristics: the percentage of correct selection of the true MTD, the average number of patients allocated per dose level, and the average total sample size. The simulation results consistently show that the 3+3 algorithm underperforms in comparison to model-based and model-assisted designs across all scenarios and metrics. The 3+3 method yields significantly lower (up to three times) probabilities in identifying the correct MTD, often selecting doses one or even two levels below the actual MTD. The 3+3 design allocates significantly fewer patients at the true MTD, assigns higher numbers to lower dose levels, and rarely explores doses above the target dose-limiting toxicity (DLT) rate. The overall performance of the 3+3 method is suboptimal, with a high level of unexplained uncertainty and significant implications for accurately determining the MTD. While the primary focus of the article is to demonstrate the limitations of the 3+3 algorithm, the question remains about the preferred alternative approach. The intention is not to definitively recommend one model-based or model-assisted method over others, as their performance can vary based on parameters and model specifications. However, the presented results indicate that the CRM, Keyboard, and BOIN designs consistently outperform the 3+3 and offer improved efficiency and precision in determining the MTD, which is crucial in early-phase clinical trials.

PROTEUS Study: A Prospective Randomized Controlled Trial Evaluating the Use of Artificial Intelligence in Stress Echocardiography.

BACKGROUND: Stress echocardiography (SE) is one of the most commonly used diagnostic imaging tests for coronary artery disease (CAD) but requires clinicians to visually assess scans to identify patients who may benefit from invasive investigation and treatment. EchoGo Pro provides an automated interpretation of SE based on artificial intelligence (AI) image analysis. In reader studies, use of EchoGo Pro when making clinical decisions improves diagnostic accuracy and confidence. Prospective evaluation in real world practice is now important to understand the impact of EchoGo Pro on the patient pathway and outcome. METHODS: PROTEUS is a randomized, multicenter, 2-armed, noninferiority study aiming to recruit 2,500 participants from National Health Service (NHS) hospitals in the UK referred to SE clinics for investigation of suspected CAD. All participants will undergo a stress echocardiogram protocol as per local hospital policy. Participants will be randomized 1:1 to a control group, representing current practice, or an intervention group, in which clinicians will receive an AI image analysis report (EchoGo Pro, Ultromics Ltd, Oxford, UK) to use during image interpretation, indicating the likelihood of severe CAD. The primary outcome will be appropriateness of clinician decision to refer for coronary angiography. Secondary outcomes will assess other health impacts including appropriate use of other clinical management approaches, impact on variability in decision making, patient and clinician qualitative experience and a health economic analysis. DISCUSSION: This will be the first study to assess the impact of introducing an AI medical diagnostic aid into the standard care pathway of patients with suspected CAD being investigated with SE. TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT05028179, registered on 31 August 2021; ISRCTN: ISRCTN15113915; IRAS ref: 293515; REC ref: 21/NW/0199.

Favipiravir, lopinavir-ritonavir, or combination therapy (FLARE): A randomised, double-blind, 2 × 2 factorial placebo-controlled trial of early antiviral therapy in COVID-19.

BACKGROUND: Early antiviral treatment is effective for Coronavirus Disease 2019 (COVID-19) but currently available agents are expensive. Favipiravir is routinely used in many countries, but efficacy is unproven. Antiviral combinations have not been systematically studied. We aimed to evaluate the effect of favipiravir, lopinavir-ritonavir or the combination of both agents on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral load trajectory when administered early. METHODS AND FINDINGS: We conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2 × 2 factorial, double-blind trial of ambulatory outpatients with early COVID-19 (within 7 days of symptom onset) at 2 sites in the United Kingdom. Participants were randomised using a centralised online process to receive: favipiravir (1,800 mg twice daily on Day 1 followed by 400 mg 4 times daily on Days 2 to 7) plus lopinavir-ritonavir (400 mg/100 mg twice daily on Day 1, followed by 200 mg/50 mg 4 times daily on Days 2 to 7), favipiravir plus lopinavir-ritonavir placebo, lopinavir-ritonavir plus favipiravir placebo, or both placebos. The primary outcome was SARS-CoV-2 viral load at Day 5, accounting for baseline viral load. Between 6 October 2020 and 4 November 2021, we recruited 240 participants. For the favipiravir+lopinavir-ritonavir, favipiravir+placebo, lopinavir-ritonavir+placebo, and placebo-only arms, we recruited 61, 59, 60, and 60 participants and analysed 55, 56, 55, and 58 participants, respectively, who provided viral load measures at Day 1 and Day 5. In the primary analysis, the mean viral load in the favipiravir+placebo arm had changed by -0.57 log10 (95% CI -1.21 to 0.07, p = 0.08) and in the lopinavir-ritonavir+placebo arm by -0.18 log10 (95% CI -0.82 to 0.46, p = 0.58) compared to the placebo arm at Day 5. There was no significant interaction between favipiravir and lopinavir-ritonavir (interaction coefficient term: 0.59 log10, 95% CI -0.32 to 1.50, p = 0.20). More participants had undetectable virus at Day 5 in the favipiravir+placebo arm compared to placebo only (46.3% versus 26.9%, odds ratio (OR): 2.47, 95% CI 1.08 to 5.65; p = 0.03). Adverse events were observed more frequently with lopinavir-ritonavir, mainly gastrointestinal disturbance. Favipiravir drug levels were lower in the combination arm than the favipiravir monotherapy arm, possibly due to poor absorption. The major limitation was that the study population was relatively young and healthy compared to those most affected by the COVID-19 pandemic. CONCLUSIONS: At the current doses, no treatment significantly reduced viral load in the primary analysis. Favipiravir requires further evaluation with consideration of dose escalation. Lopinavir-ritonavir administration was associated with lower plasma favipiravir concentrations. TRIAL REGISTRATION: Clinicaltrials.gov NCT04499677 EudraCT: 2020-002106-68.

Sample size calculation for randomized selection trials with a time-to-event endpoint and a margin of practical equivalence.

Selection trials are used to compare potentially active experimental treatments without a control arm. While sample size calculation methods exist for binary endpoints, no such methods are available for time-to-event endpoints, even though these are ubiquitous in clinical trials. Recent selection trials have begun using progression-free survival as their primary endpoint, but have dichotomized it at a specific time point for sample size calculation and analysis. This changes the clinical question and may reduce power to detect a difference between the arms. In this article, we develop the theory for sample size calculation in selection trials where the time-to-event endpoint is assumed to follow an exponential or Weilbull distribution. We provide a free web application for sample size calculation, as well as an R package, that researchers can use in the design of their studies.

Early phase dose-finding trials in virology.

Little has been published in terms of dose-finding methodology in virology. Aside from a few papers focusing on HIV, the considerable progress in dose-finding methodology of the last 25 years has focused almost entirely on oncology. While adverse reactions to cytotoxic drugs may be life threatening, for anti-viral agents we anticipate something different: side effects that provoke the cessation of treatment. This would correspond to treatment failure. On the other hand, success would not be yes/no but would correspond to a range of responses, from small, no more than say 20% reduction in viral load to the complete elimination of the virus. Less than total success matters since this may allow the patient to achieve immune-mediated clearance. The motivation for this article is an upcoming dose-finding trial in chronic norovirus infection. We propose a novel methodology whose goal is twofold: first, to identify the dose that provides the most favorable distribution of treatment outcomes, and, second, to do this in a way that maximizes the treatment benefit for the patients included in the study.

Stratified follow-up for endometrial cancer: a move to more personalized cancer care.

OBJECTIVE: Hospital based follow-up has been the standard of care for endometrial cancer. Patient initiated follow-up is a useful adjunct for lower risk cancers. The purpose of this study was to evaluate outcomes of endometrial cancer patients after stratification into risk groupings, with particular attention to salvageable relapses. METHODS: All patients treated surgically for International Federation of Gynecology and Obstetrics (FIGO) stage I-IVA endometrial cancer of all histological subtypes, from January 2009 until March 2019, were analyzed. Patient and tumor characteristics, treatment details, relapse, death, and last follow-up dates were collected. Site of relapse, presence of symptoms, and whether relapses were salvageable were also identified. The European Society of Medical Oncology-European Society of Gynecological Oncology 2020 risk stratification was assigned, and relapse free and overall survival were estimated. RESULTS: 900 patients met the eligibility criteria. Median age was 66 years (range 28-96) and follow-up duration was 35 months (interquartile range 19-57). In total, 16% (n=144) of patients relapsed, 1.3% (n=12) from the low risk group, 3.9% (n=35) from the intermediate risk group, 2.2% (n=20) from the high-intermediate risk group, and 8.7% (n=77) from the high risk group. Salvageable relapses were less frequent at 2% (n=18), of which 33% (n=6) were from the low risk group, 22% (n=4) from the intermediate risk group, 11% (n=2) from the high-intermediate risk group, and 33% (n=6) from the high risk group. There were only three asymptomatic relapses in the low risk patients, accounting for 0.33% of the entire cohort. CONCLUSIONS: Relapses were infrequent and most presented with symptoms; prognosis after relapse remains favorable. Overall salvageable relapses were infrequent and cannot justify intensive hospital based follow-up. Use of patient initiated follow-up is therefore appropriate, as per the British Gynaecological Cancer Society's guidelines, for all risk groupings.

Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI.

BACKGROUND: Coronary revascularization guided by fractional flow reserve (FFR) is associated with better patient outcomes after the procedure than revascularization guided by angiography alone. It is unknown whether the instantaneous wave-free ratio (iFR), an alternative measure that does not require the administration of adenosine, will offer benefits similar to those of FFR. METHODS: We randomly assigned 2492 patients with coronary artery disease, in a 1:1 ratio, to undergo either iFR-guided or FFR-guided coronary revascularization. The primary end point was the 1-year risk of major adverse cardiac events, which were a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization. The trial was designed to show the noninferiority of iFR to FFR, with a margin of 3.4 percentage points for the difference in risk. RESULTS: At 1 year, the primary end point had occurred in 78 of 1148 patients (6.8%) in the iFR group and in 83 of 1182 patients (7.0%) in the FFR group (difference in risk, -0.2 percentage points; 95% confidence interval [CI], -2.3 to 1.8; P<0.001 for noninferiority; hazard ratio, 0.95; 95% CI, 0.68 to 1.33; P=0.78). The risk of each component of the primary end point and of death from cardiovascular or noncardiovascular causes did not differ significantly between the groups. The number of patients who had adverse procedural symptoms and clinical signs was significantly lower in the iFR group than in the FFR group (39 patients [3.1%] vs. 385 patients [30.8%], P<0.001), and the median procedural time was significantly shorter (40.5 minutes vs. 45.0 minutes, P=0.001). CONCLUSIONS: Coronary revascularization guided by iFR was noninferior to revascularization guided by FFR with respect to the risk of major adverse cardiac events at 1 year. The rate of adverse procedural signs and symptoms was lower and the procedural time was shorter with iFR than with FFR. (Funded by Philips Volcano; DEFINE-FLAIR ClinicalTrials.gov number, NCT02053038 .).

Fractional Flow Reserve and Instantaneous Wave-Free Ratio as Predictors of the Placebo-Controlled Response to Percutaneous Coronary Intervention in Stable Single-Vessel Coronary Artery Disease.

BACKGROUND: There are no data on how fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are associated with the placebo-controlled efficacy of percutaneous coronary intervention (PCI) in stable single-vessel coronary artery disease. METHODS: We report the association between prerandomization invasive physiology within ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), a placebo-controlled trial of patients who have stable angina with angiographically severe single-vessel coronary disease clinically eligible for PCI. Patients underwent prerandomization research FFR and iFR assessment. The operator was blinded to these values. Assessment of response variables, treadmill exercise time, stress echocardiography score, symptom frequency, and angina severity were performed at prerandomization and blinded follow-up. Effects were calculated by analysis of covariance. The ability of FFR and iFR to predict placebo-controlled changes in response variables was tested by using regression modeling. RESULTS: Invasive physiology data were available in 196 patients (103 PCI and 93 placebo). At prerandomization, the majority had Canadian Cardiovascular Society class II or III symptoms (150/196, 76.5%). Mean FFR and iFR were 0.69±0.16 and 0.76±0.22, respectively; 97% had ≥1 positive ischemia tests. The estimated effect of PCI on between-arm prerandomization-adjusted total exercise time was 20.7 s (95% confidence interval [CI], -4.0 to 45.5; P=0.100) with no interaction of FFR ( Pinteraction=0.318) or iFR ( Pinteraction=0.523). PCI improved stress echocardiography score more than placebo (1.07 segment units; 95% CI, 0.70-1.44; P<0.00001). The placebo-controlled effect of PCI on stress echocardiography score increased progressively with decreasing FFR ( Pinteraction<0.00001) and decreasing iFR ( Pinteraction<0.00001). PCI did not improve angina frequency score significantly more than placebo (odds ratio, 1.64; 95% CI, 0.96-2.80; P=0.072) with no detectable evidence of interaction with FFR ( Pinteraction=0.849) or iFR ( Pinteraction=0.783). However, PCI resulted in more patient-reported freedom from angina than placebo (49.5% versus 31.5%; odds ratio, 2.47; 95% CI, 1.30-4.72; P=0.006) but neither FFR ( Pinteraction=0.693) nor iFR ( Pinteraction=0.761) modified this effect. CONCLUSIONS: In patients with stable angina and severe single-vessel disease, the blinded effect of PCI was more clearly seen by stress echocardiography score and freedom from angina than change in treadmill exercise time. Moreover, the lower the FFR or iFR, the greater the magnitude of stress echocardiographic improvement caused by PCI. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02062593.

Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial.

BACKGROUND: Symptomatic relief is the primary goal of percutaneous coronary intervention (PCI) in stable angina and is commonly observed clinically. However, there is no evidence from blinded, placebo-controlled randomised trials to show its efficacy. METHODS: ORBITA is a blinded, multicentre randomised trial of PCI versus a placebo procedure for angina relief that was done at five study sites in the UK. We enrolled patients with severe (≥70%) single-vessel stenoses. After enrolment, patients received 6 weeks of medication optimisation. Patients then had pre-randomisation assessments with cardiopulmonary exercise testing, symptom questionnaires, and dobutamine stress echocardiography. Patients were randomised 1:1 to undergo PCI or a placebo procedure by use of an automated online randomisation tool. After 6 weeks of follow-up, the assessments done before randomisation were repeated at the final assessment. The primary endpoint was difference in exercise time increment between groups. All analyses were based on the intention-to-treat principle and the study population contained all participants who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02062593. FINDINGS: ORBITA enrolled 230 patients with ischaemic symptoms. After the medication optimisation phase and between Jan 6, 2014, and Aug 11, 2017, 200 patients underwent randomisation, with 105 patients assigned PCI and 95 assigned the placebo procedure. Lesions had mean area stenosis of 84·4% (SD 10·2), fractional flow reserve of 0·69 (0·16), and instantaneous wave-free ratio of 0·76 (0·22). There was no significant difference in the primary endpoint of exercise time increment between groups (PCI minus placebo 16·6 s, 95% CI -8·9 to 42·0, p=0·200). There were no deaths. Serious adverse events included four pressure-wire related complications in the placebo group, which required PCI, and five major bleeding events, including two in the PCI group and three in the placebo group. INTERPRETATION: In patients with medically treated angina and severe coronary stenosis, PCI did not increase exercise time by more than the effect of a placebo procedure. The efficacy of invasive procedures can be assessed with a placebo control, as is standard for pharmacotherapy. FUNDING: NIHR Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, Philips Volcano, NIHR Barts Biomedical Research Centre.

Application of the DILEMMA score to improve lesion selection for invasive physiological assessment.

OBJECTIVES: We sought to assess the validity of the DILEMMA score against instantaneous wave-free ratio (iFR) and evaluate its utility in rationalizing the number of patients referred for invasive physiological assessment. BACKGROUND: The DILEMMA score is a validated angiographic scoring tool incorporating minimal lumen diameter, lesion length and subtended myocardial area that has been shown to predict the functional significance of lesions as assessed by fractional flow reserve (FFR). METHODS: Patients in the DEFINE-FLAIR study who had coronary stenosis of intermediate severity were randomized to either FFR or iFR. DILEMMA score was calculated retrospectively on a subset of this cohort by operators blinded to FFR or iFR values. RESULTS: Three hundred and forty-six lesions (181 assessed by FFR; 165 by iFR) from 259 patients (mean age 66.0 years, 79% male) were included. A DILEMMA score ≤ 2 had a negative predictive value of 96.3% and 95.7% for identifying lesions with FFR >0.80 and iFR >0.89, respectively. A DILEMMA score ≥ 9 had a positive predictive value of 88.9% and 100% for identifying lesions with FFR ≤0.80 and iFR ≤0.89, respectively. The receiver operating characteristic area under the curve values for DILEMMA score to predict FFR ≤0.80 and iFR ≤0.89 were 0.83 (95% CI 0.77-0.90) and 0.82 (0.75-0.89) respectively. A DILEMMA score ≤ 2 or ≥9 occurred in 172 of the 346 lesions (49.7%). CONCLUSIONS: Using DILEMMA score in patients with coronary stenosis of intermediate severity may reduce the need for pressure wire use, offering potential cost-savings and minimizing the risks associated with invasive physiological lesion assessment.

Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review.

BACKGROUND: Globally, most patients with hypertension are treated with monotherapy, and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on average. There is a pressing need for blood pressure-control strategies with improved efficacy and tolerability. We aimed to assess whether ultra-low-dose combination therapy could meet these needs. METHODS: We did a randomised, placebo-controlled, double-blind, crossover trial of a quadpill-a single capsule containing four blood pressure-lowering drugs each at quarter-dose (irbesartan 37·5 mg, amlodipine 1·25 mg, hydrochlorothiazide 6·25 mg, and atenolol 12·5 mg). Participants with untreated hypertension were enrolled from four centres in the community of western Sydney, NSW, Australia, mainly by general practitioners. Participants were randomly allocated by computer to either the quadpill or matching placebo for 4 weeks; this treatment was followed by a 2-week washout, then the other study treatment was administered for 4 weeks. Study staff and participants were unaware of treatment allocations, and masking was achieved by use of identical opaque capsules. The primary outcome was placebo-corrected 24-h systolic ambulatory blood pressure reduction after 4 weeks and analysis was by intention to treat. We also did a systematic review of trials evaluating the efficacy and safety of quarter-standard-dose blood pressure-lowering therapy against placebo. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614001057673. The trial ended after 1 year and this report presents the final analysis. FINDINGS: Between November, 2014, and December, 2015, 55 patients were screened for our randomised trial, of whom 21 underwent randomisation. Mean age of participants was 58 years (SD 11) and mean baseline office and 24-h systolic and diastolic blood pressure levels were 154 (14)/90 (11) mm Hg and 140 (9)/87 (8) mm Hg, respectively. One individual declined participation after randomisation and two patients dropped out for administrative reasons. The placebo-corrected reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14-23), and office blood pressure was reduced by 22/13 mm Hg (p<0·0001). During quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than 140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p=0·0013). There were no serious adverse events and all patients reported that the quadpill was easy to swallow. Our systematic review identified 36 trials (n=4721 participants) of one drug at quarter-dose and six trials (n=312) of two drugs at quarter-dose, against placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg and 7/5 mm Hg, respectively (both p<0·0001), and there were no side-effects from either regimen. INTERPRETATION: The findings of our small trial in the context of previous randomised evidence suggest that the benefits of quarter-dose therapy could be additive across classes and might confer a clinically important reduction in blood pressure. Further examination of the quadpill concept is needed to investigate effectiveness against usual treatment options and longer term tolerability. FUNDING: National Heart Foundation, Australia; University of Sydney; and National Health and Medical Research Council of Australia.

Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial.

BACKGROUND: For many years, first-line treatment for locally advanced or metastatic soft-tissue sarcoma has been doxorubicin. This study compared gemcitabine and docetaxel versus doxorubicin as first-line treatment for advanced or metastatic soft-tissue sarcoma. METHODS: The GeDDiS trial was a randomised controlled phase 3 trial done in 24 UK hospitals and one Swiss Group for Clinical Cancer Research (SAKK) hospital. Eligible patients had histologically confirmed locally advanced or metastatic soft-tissue sarcoma of Trojani grade 2 or 3, disease progression before enrolment, and no previous chemotherapy for sarcoma or previous doxorubicin for any cancer. Patients were randomly assigned 1:1 to receive six cycles of intravenous doxorubicin 75 mg/m2 on day 1 every 3 weeks, or intravenous gemcitabine 675 mg/m2 on days 1 and 8 and intravenous docetaxel 75 mg/m2 on day 8 every 3 weeks. Treatment was assigned using a minimisation algorithm incorporating a random element. Randomisation was stratified by age (≤18 years vs >18 years) and histological subtype. The primary endpoint was the proportion of patients alive and progression free at 24 weeks in the intention-to-treat population. Adherence to treatment and toxicity were analysed in the safety population, consisting of all patients who received at least one dose of their randomised treatment. The trial was registered with the European Clinical Trials (EudraCT) database (no 2009-014907-29) and with the International Standard Randomised Controlled Trial registry (ISRCTN07742377), and is now closed to patient entry. FINDINGS: Between Dec 3, 2010, and Jan 20, 2014, 257 patients were enrolled and randomly assigned to the two treatment groups (129 to doxorubicin and 128 to gemcitabine and docetaxel). Median follow-up was 22 months (IQR 15·7-29·3). The proportion of patients alive and progression free at 24 weeks did not differ between those who received doxorubicin versus those who received gemcitabine and docetaxel (46·3% [95% CI 37·5-54·6] vs 46·4% [37·5-54·8]); median progression-free survival (23·3 weeks [95% CI 19·6-30·4] vs 23·7 weeks [18·1-20·0]; hazard ratio [HR] for progression-free survival 1·28, 95% CI 0·99-1·65, p=0·06). The most common grade 3 and 4 adverse events were neutropenia (32 [25%] of 128 patients who received doxorubicin and 25 [20%] of 126 patients who received gemcitabine and docetaxel), febrile neutropenia (26 [20%] and 15 [12%]), fatigue (eight [6%] and 17 [14%]), oral mucositis (18 [14%] and two [2%]), and pain (ten [8%] and 13 [10%]). The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]). 154 (60%) of 257 patients died in the intention-to-treat population: 74 (57%) of 129 patients in the doxorubicin group and 80 (63%) of 128 in the gemcitabine and docetaxel group. No deaths were related to the treatment, but two deaths were due to a combination of disease progression and treatment. INTERPRETATION: Doxorubicin should remain the standard first-line treatment for most patients with advanced soft-tissue sarcoma. These results provide evidence for clinicians to consider with their patients when selecting first-line treatment for locally advanced or metastatic soft-tissue sarcoma. FUNDING: Cancer Research UK, Sarcoma UK, and Clinical Trial Unit Kantonsspital St Gallen.

Implementing and assessing Bayesian response-adaptive randomisation for backfilling in dose-finding trials.

Traditional approaches in dose-finding trials, such as the continual reassessment method, focus on identifying the maximum tolerated dose. In contemporary early-phase dose-finding trials, especially in oncology with targeted agents or immunotherapy, a more relevant aim is to identify the lowest dose level that maximises efficacy whilst remaining tolerable. Backfilling, defined as the practice of assigning patients to dose levels lower than the current highest tolerated dose, has been proposed to gather additional pharmacokinetic, pharmacodynamic and biomarker data to recommend the most appropriate dose to carry forward for subsequent studies. The first formal framework [5] for backfilling proposed randomising backfill patients with equal probability among those doses below the dose level where the study is currently at. Here, we propose to use Bayesian response-adaptive randomisation to backfill patients. This patient-oriented approach to backfilling aims to allocate more patients to dose levels in the backfill set with higher expected efficacy based on emerging data. The backfill set constitutes of the doses below the dose the dose-finding algorithm is at. At study completion, collective patient data inform the dose-response curve, suggesting an optimal dose level balancing toxicity and efficacy. Our simulation study across diverse clinical trial settings demonstrates that a backfilling strategy using Bayesian response-adaptive randomisation can result in a patient-oriented patient assignment procedure which simultaneously enhances the likelihood of correctly identifying the most appropriate dose level. This contribution offers a methodological framework and practical implementation for patient-oriented backfilling, encompassing design and analysis considerations in early-phase trials.

Recombinant fragment of human surfactant protein D to prevent neonatal chronic lung disease (RESPONSE): a protocol for a phase I safety trial in a tertiary neonatal unit.

INTRODUCTION: Chronic respiratory morbidity from bronchopulmonary dysplasia (BPD) remains the most common complication of preterm birth and has consequences for later respiratory, cardiovascular and neurodevelopmental outcomes. The early phases of respiratory illness are characterised by rapid consumption of endogenous surfactant and slow replenishment. Exogenous surfactant is routinely administered to infants born before 28 weeks of gestation as prophylaxis. Endogenous surfactant includes four proteins, known as surfactant proteins (SPs) A, B, C and D. Current bovine-derived and porcine-derived surfactant preparations only contain SPs B and C. SP-D has a key role in lung immune homeostasis as part of the innate immune system. Laboratory studies using recombinant SP-D have demonstrated reduced inflammation, which may be a pathway to reducing the associated morbidity from BPD. RESPONSE uses a recombinant fragment of human SP D (rfhSP-D), in a phase I safety and dose-escalation trial as the first stage in determining its effect in humans. METHODS AND ANALYSIS: This is a single-centre, dose-escalation, phase I safety study aiming to recruit 24 infants born before 30 weeks gestation with respiratory distress syndrome. In addition to routine surfactant replacement therapy, participants will receive three doses of rfhSP-D via endotracheal route at either 1 mg/kg, 2 mg/kg or 4 mg/kg. The study uses a Bayesian continual reassessment method to make dose escalation decisions. Dose-limiting events (DLE) in this trial will be graded according to the published Neonatal Adverse Event Severity Score. The primary outcome of this study is to evaluate the safety profile of rfhSP-D across each dose level based on the profile of DLE to establish the recommended phase 2 dose (RP2D) of rfhSP-D. ETHICS AND DISSEMINATION: The RESPONSE study has received ethical approval from London-Brent NHS Research Health Authority ethics committee. Results from the study will be published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBERS: ISRCTN17083028, NCT05898633. PROTOCOL VERSION: RESPONSE Protocol V.4.0 24th July 2024.

Feasibility of a new 'balanced binocular viewing' treatment for unilateral amblyopia in children aged 3-8 years (BALANCE): results of a phase 2a randomised controlled feasibility trial.

OBJECTIVES: This study aimed to evaluate the safety of dichoptic balanced binocular viewing (BBV) for amblyopia in children, plus feasibility, adherence, acceptability, trial methodology and clinical measures of visual function. DESIGN: We carried out an observer-masked parallel-group phase 2a feasibility randomised controlled trial. SETTING: Two study sites, a secondary/tertiary and a community site. PARTICIPANTS: We enrolled 32 children aged 3-8 years with unilateral amblyopia who had completed optical adaptation where indicated. 20 children attended the 16-week exit visit (retention 63%). INTERVENTIONS: Children were randomised to BBV (movies customised to interocular acuity difference at baseline) for 1 hour a day (active intervention) or standard management as per parental choice (part-time occlusion or atropine blurring, control). All interventions were used at home, daily for 16 weeks. PRIMARY OUTCOME MEASURE: 'VacMan suppression test' of interocular balance at 16 weeks from randomisation. SECONDARY OUTCOME MEASURES: feasibility outcomes (recruitment and retention ratios, adherence with the allocated intervention); safety outcomes at other time points (changes in prevalence of diplopia, manifest strabismus, suppression/interocular balance on a range of tests); efficacy outcomes (clinical measures of visual function, such as best-corrected visual acuity, BCVA). Outcome measures were identical to those planned in the protocol. RESULTS: Primary outcome: At baseline, values for the interocular balance point were higher (indicating greater suppression of the amblyopic eye) in the occlusion group than in the BBV group. These values shifted downwards on average for the occlusion group, significantly decreasing from baseline to week 16 (t8=4.49, p=0.002). Balance values did not change between baseline and week 16 for the BBV group (t9=-0.82, p=0.435). At 16 weeks, there was no statistical difference in interocular balance/suppression change over time between the two arms. The difference at follow-up between the arms, adjusted for baseline, was -0.02 (95% CI -0.28 to 0.23, p=0.87). FEASIBILITY: We prescreened 144 records of potentially eligible children. Between 28 October 2019 and 31 July 2021, including an interruption due to the COVID-19 pandemic, 32 children were screened and randomised (recruitment rate 22%), 16 to BBV and 16 to standard treatment. 20 children attended the 16-week exit visit (retention 63%). Mean adherence with BBV as proportion of viewing time prescribed was 56.1% (SD36) at 8 and 57.9% (SD 30.2) at 16 weeks. Mean adherence with prescribed occlusion time was 90.1% (SD 19.7) at 8 and 59.2% (SD 24.8) at 16 weeks. SECONDARY SAFETY/EFFICACY OUTCOMES: One child in the BBV arm reported transient double vision, which resolved; two reported headaches, which led to withdrawal. BCVA improved from mean 0.47 (SD0.18) logMAR at randomisation to 0.26 (0.14) with standard treatment, and from 0.55 (0.28) to 0.32 (0.26) with BBV. Outcomes at 16 weeks did not differ between treatments. PARTICIPANT EXPERIENCE: Families were generally positive about BBV, but families found both patching and BBV difficult to integrate into family routines. CONCLUSIONS: Recruitment rates indicate that a future phase 3 trial will require multiple sites or a longer enrolment period. Retention and adherence rates were lower than anticipated, which will influence future study designs. Dichoptic treatment may be equal to occlusion treatment in safety and efficacy; headaches may lead to discontinuation. Integration into family routines may constitute a barrier to implementation. TRIAL REGISTRATION NUMBER: NCT03754153.

Predicting radiotherapy response, Toxicities and quality-of-life related functional outcomes in soft tissue sarcoma of the extremities (PredicT) using dose-volume constraints development: a study protocol.

INTRODUCTION: Radiotherapy improves local tumour control in patients with soft tissue sarcoma of the extremities (STSE) but it also increases the probability of long-term toxicities such as tissue fibrosis, joint stiffness and lymphoedema. The use of radiation dose and volume thresholds, called dose constraints, may potentially reduce the development of toxicities in STSE. The aim of this study is to determine predictors of radiotherapy-related side effects for STSE. METHODS AND ANALYSIS: Predicting radiotherapy response, Toxicities and quality-of-life related functional outcomes in soft tissue sarcoma of the extremities (PredicT) is a multicentre observational study comprising two cohorts (PredicT A and B). PredicT A, a retrospective analysis of the UK VorteX (NCT00423618) and IMRiS clinical trials (NCT02520128), is aimed at deriving a statistical model for development of dose-volume constraints. This model will use receiving operator characteristics and multivariate analysis to predict radiotherapy side effects and patient-reported outcomes. PredicT B, a prospective cohort study of 150 patients with STSE, is aimed at testing the validity of those dose-volume constraints. PredicT B is open and planned to complete recruitment by September 2024. ETHICS AND DISSEMINATION: PredicT B has received ethical approval from North West - Liverpool Central Research Ethics Committee (20/NW/0267). Participants gave informed consent to participate in the study before taking part. We will disseminate our findings via publications, presentations, national and international conference meetings and engage with local charities. TRIAL REGISTRATION NUMBER: NCT05978024.

Safety and Efficacy of Metabolic Modulation With Ninerafaxstat in Patients With Nonobstructive Hypertrophic Cardiomyopathy.

BACKGROUND: In nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics. OBJECTIVES: This study sought to evaluate the safety and efficacy of ninerafaxstat in nHCM. METHODS: Patients with hypertrophic cardiomyopathy and left ventricular outflow tract gradient <30 mm Hg, ejection fraction ≥50%, and peak oxygen consumption <80% predicted were randomized to ninerafaxstat 200 mg twice daily or placebo (1:1) for 12 weeks. The primary endpoint was safety and tolerability, with efficacy outcomes also assessed as secondary endpoints. RESULTS: A total of 67 patients with nHCM were enrolled at 12 centers (57 ± 11.8 years of age; 55% women). Serious adverse events occurred in 11.8% (n = 4 of 34) in the ninerafaxstat group and 6.1% (n = 2 of 33) of patients in the placebo group. From baseline to 12 weeks, ninerafaxstat was associated with significantly better VE/Vco2 (ventilatory efficiency) slope compared with placebo with a least-squares (LS) mean difference between the groups of -2.1 (95% CI: -3.6 to -0.6; P = 0.006), with no significant difference in peak VO2 (P = 0.90). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was directionally, though not significantly, improved with ninerafaxstat vs placebo (LS mean 3.2; 95% CI: -2.9 to 9.2; P = 0.30); however, it was statistically significant when analyzed post hoc in the 35 patients with baseline Kansas City Cardiomyopathy Questionnaire Clinical Summary Score ≤80 (LS mean 9.4; 95% CI: 0.3-18.5; P = 0.04). CONCLUSIONS: In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a phase 3 study.

Controlled amplification in oncology dose-finding trials.

In oncology clinical trials the guiding principle of model-based dose-finding designs for cytotoxic agents is to progress as fast as possible towards, and identify, the dose level most likely to be the MTD. Recent developments with non-cytotoxic agents have broadened the scope of early phase trials to include multiple objectives. The ultimate goal of dose-finding designs in our modern era is to collect the relevant information in the study for final RP2D determination. While some information is collected on dose levels below and in the vicinity of the MTD during the escalation (using conventional tools such as the Continual Reassessment Method for example), designs that include expansion cohorts or backfill patients effectively amplify the information collected on the lower dose levels. This is achieved by allocating patients to dose levels slightly differently during the study in order to take into account the possibility that "less (dose) might be more". The objective of this paper is to study the concept of amplification. Under the heading of controlled amplification we can include dose expansion cohorts and backfill patients among others. We make some general observations by defining these concepts more precisely and study a specific design that exploits the concept of controlled amplification.