Accounting for deaths in neonatal trials: is there a correct approach?

Parekh, Shalin; Field, David; Johnson, Samantha; Juszczak, Edmund

doi:10.1136/archdischild-2014-306730

Cited by 9 publications

(7 citation statements)

References 27 publications

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“…Accounting for deaths in a trial that focuses on neurodevelopmental outcomes is a hotly debated topic. 40 The team felt that various methods should be included as sensitivity analyses to ensure that results were consistent. Death was included in four different ways.…”

Section: Sensitivity Analysismentioning

confidence: 99%

Ten-year follow-up of a randomised trial of drainage, irrigation and fibrinolytic therapy (DRIFT) in infants with post-haemorrhagic ventricular dilatation

Luyt

Jary

Lea

et al. 2019

Health Technol Assess

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Background The drainage, irrigation and fibrinolytic therapy (DRIFT) trial, conducted in 2003–6, showed a reduced rate of death or severe disability at 2 years in the DRIFT compared with the standard treatment group, among preterm infants with intraventricular haemorrhage (IVH) and post-haemorrhagic ventricular dilatation. Objectives To compare cognitive function, visual and sensorimotor ability, emotional well-being, use of specialist health/rehabilitative and educational services, neuroimaging, and economic costs and benefits at school age. Design Ten-year follow-up of a randomised controlled trial. Setting Neonatal intensive care units (Bristol, Katowice, Glasgow and Bergen). Participants Fifty-two of the original 77 infants randomised. Interventions DRIFT or standard therapy (cerebrospinal fluid tapping). Main outcome measures Primary – cognitive disability. Secondary – vision; sensorimotor disability; emotional/behavioural function; education; neurosurgical sequelae on magnetic resonance imaging; preference-based measures of health-related quality of life; costs of neonatal treatment and of subsequent health care in childhood; health and social care costs and impact on family at age 10 years; and a decision analysis model to estimate the cost-effectiveness of DRIFT compared with standard treatment up to the age of 18 years. Results By 10 years of age, 12 children had died and 13 were either lost to follow-up or had declined to participate. A total of 52 children were assessed at 10 years of age (DRIFT, n = 28; standard treatment, n = 24). Imbalances in gender and birthweight favoured the standard treatment group. The unadjusted mean cognitive quotient (CQ) score was 69.3 points [standard deviation (SD) 30.1 points] in the DRIFT group compared with 53.7 points (SD 35.7 points) in the standard treatment group, a difference of 15.7 points, 95% confidence interval (CI) –2.9 to 34.2 points; p = 0.096. After adjusting for the prespecified covariates (gender, birthweight and grade of IVH), this evidence strengthened: children who received DRIFT had a CQ advantage of 23.5 points (p = 0.009). The binary outcome, alive without severe cognitive disability, gave strong evidence that DRIFT improved cognition [unadjusted odds ratio (OR) 3.6 (95% CI 1.2 to 11.0; p = 0.026) and adjusted OR 10.0 (95% CI 2.1 to 46.7; p = 0.004)]; the number needed to treat was three. No significant differences were found in any secondary outcomes. There was weak evidence that DRIFT reduced special school attendance (adjusted OR 0.27, 95% CI 0.07 to 1.05; p = 0.059). The neonatal stay (unadjusted mean difference £6556, 95% CI –£11,161 to £24,273) and subsequent hospital care (£3413, 95% CI –£12,408 to £19,234) costs were higher in the DRIFT arm, but the wide CIs included zero. The decision analysis model indicated that DRIFT has the potential to be cost-effective at 18 years of age. The incremental cost-effectiveness ratio (£15,621 per quality-adjusted life-year) was below the National Institute for Health and Care Excellence threshold. The cost-effectiveness results were sensitive to adjustment for birthweight and gender. Limitations The main limitations are the sample size of the trial and that important characteristics were unbalanced at baseline and at the 10-year follow-up. Although the analyses conducted here were prespecified in the analysis plan, they had not been prespecified in the original trial registration. Conclusions DRIFT improves cognitive function when taking into account birthweight, grade of IVH and gender. DRIFT is probably effective and, given the reduction in the need for special education, has the potential to be cost-effective as well. A future UK multicentre trial is required to assess efficacy and safety of DRIFT when delivered across multiple sites. Trial registration Current Controlled Trials ISRCTN80286058. Funding This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 4. See the NIHR Journals Library website for further project information. The DRIFT trial and 2-year follow-up was funded by Cerebra and the James and Grace Anderson Trust.

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Section: Sensitivity Analysismentioning

confidence: 99%

Ten-year follow-up of a randomised trial of drainage, irrigation and fibrinolytic therapy (DRIFT) in infants with post-haemorrhagic ventricular dilatation

Luyt

Jary

Lea

et al. 2019

Health Technol Assess

View full text Add to dashboard Cite

show abstract

“…As the aim of the current study was to investigate survival and developmental outcomes, we chose to evaluate our long‐term results by including deceased children in the analysis. A composite outcome ‘survival without disability’ was used to account for bias due to different survival rates. The second reason for loss to follow‐up was unavailable or inaccurate contact data to approach parents for participation.…”

Section: Discussionmentioning

confidence: 99%

Pessary for prevention of preterm birth in twin pregnancy with short cervix: 3‐year follow‐up study

Hooft

Lee

Opmeer

et al. 2018

Ultrasound in Obstet & Gyne

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“…It was suggested by some interviewees that this temporal shift may feature less in the future as neonatal intensive care trials focus on interventions which are less likely to affect mortality. Parekh and colleagues [ 13 ] argue that major advances in care have increased survival such that it is the condition in which survivors survive that is now the priority. As a consequence, trials may be driven by a focus on the impact of an intervention on morbidity and long term neurodevelopment with mortality as a lesser focus.…”

Section: Discussionmentioning

confidence: 99%

“…We might expect trials in the neonatal intensive care setting to involve similar issues to trials in other settings with technological and clinical similarities such as paediatric and adult intensive care, or paediatric oncology where trials also involve sick children and their families. Parekh and colleagues [ 13 ] have, however, argued that complex considerations for neonatal intensive care trials set them apart even from trials in apparently similar settings. Rather than assuming commonality, it is important to consider the potential for unique issues and challenges which might flow from the context in which trials are set.…”

Section: Introductionmentioning

confidence: 99%

"You have to keep your nerve on a DMC." Challenges for Data Monitoring Committees in neonatal intensive care trials: Qualitative accounts from the BRACELET Study

et al. 2018

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BackgroundData Monitoring Committees (DMCs) are essential to the good conduct of many trials. Typically they comprise a small expert group which monitors safety, efficacy, progress and early outcome data as trials recruit. DMCs can recommend protocol revisions and early stopping of a trial. As DMC meetings usually consider unblinded interim data confidentially, their deliberations are seldom exposed to research scrutiny. Although there have been some case studies from trials from mixed specialties which offer insights into some of the common issues faced by DMCs, we have, however, little empirical information about the challenges faced within specific clinical settings.MethodsIn-depth interviews with participants in the BRACELET Study on death and bereavement in neonatal intensive care trials produced qualitative accounts of experiences and views of a subgroup of 18 DMC members. These interviews explored views of DMC members in relation to the clinical context of neonatal intensive care and the conduct of neonatal intensive care trials.ResultsInterviewees felt that an understanding of both the neonatal intensive care setting and population was crucial in a DMC. They considered the neonatal intensive care research population especially vulnerable, and that outcomes that included both death and severe disability raised particular challenges rarely faced in other settings. In exploring these key outcomes they were mindful of the need to meet high scientific standards and the needs of babies in the trials and their families. DMC members discussed particular difficulties around the composite outcome of death and severe disability, especially when mortality data were available long before data on longer term disability. While statistical stopping guidance is helpful, DMC members described decisions about stopping, revising or continuing a trial being informed by a wider set of considerations and discussions than a pre-set p value. These included potentially competing needs of current trial participants and future patients, and reflections on the nature of benefit and harm. Given their cognisance of the potential impact and consequences of the decisions made by DMCs in this setting of life, death, and disability, interviewees commonly used the imagery of bravery, and described DMCs either holding or losing their nerve.ConclusionsDMCs for trials in other fields may also face difficult ethical trade-offs in monitoring composite outcomes. The experience from this sample of DMC members suggest that for neonatal intensive care trials there are some very specific challenges seldom faced elsewhere. The vulnerability of the population, and the different timescales for essential data becoming available to inform decisions, presented particular challenges. We suggest that it is important to consider the challenges raised in other settings to better understand the complex work of these committees and to prepare future generations of DMC members.

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Accounting for deaths in neonatal trials: is there a correct approach?

Cited by 9 publications

References 27 publications

Ten-year follow-up of a randomised trial of drainage, irrigation and fibrinolytic therapy (DRIFT) in infants with post-haemorrhagic ventricular dilatation

Ten-year follow-up of a randomised trial of drainage, irrigation and fibrinolytic therapy (DRIFT) in infants with post-haemorrhagic ventricular dilatation

Pessary for prevention of preterm birth in twin pregnancy with short cervix: 3‐year follow‐up study

"You have to keep your nerve on a DMC." Challenges for Data Monitoring Committees in neonatal intensive care trials: Qualitative accounts from the BRACELET Study

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