Publications by authors named "Suzie Cro"

50 Publications

A review of the use of controlled multiple imputation in randomised controlled trials with missing outcome data.

BMC Med Res Methodol 2021 Apr 15;21(1):72. Epub 2021 Apr 15.

Imperial Clinical Trials Unit, Imperial College London, Stadium House, 68 Wood Lane, London, UK.

Background: Missing data are common in randomised controlled trials (RCTs) and can bias results if not handled appropriately. A statistically valid analysis under the primary missing-data assumptions should be conducted, followed by sensitivity analysis under alternative justified assumptions to assess the robustness of results. Controlled Multiple Imputation (MI) procedures, including delta-based and reference-based approaches, have been developed for analysis under missing-not-at-random assumptions. However, it is unclear how often these methods are used, how they are reported, and what their impact is on trial results. This review evaluates the current use and reporting of MI and controlled MI in RCTs.

Methods: A targeted review of phase II-IV RCTs (non-cluster randomised) published in two leading general medical journals (The Lancet and New England Journal of Medicine) between January 2014 and December 2019 using MI. Data was extracted on imputation methods, analysis status, and reporting of results. Results of primary and sensitivity analyses for trials using controlled MI analyses were compared.

Results: A total of 118 RCTs (9% of published RCTs) used some form of MI. MI under missing-at-random was used in 110 trials; this was for primary analysis in 43/118 (36%), and in sensitivity analysis for 70/118 (59%) (3 used in both). Sixteen studies performed controlled MI (1.3% of published RCTs), either with a delta-based (n = 9) or reference-based approach (n = 7). Controlled MI was mostly used in sensitivity analysis (n = 14/16). Two trials used controlled MI for primary analysis, including one reporting no sensitivity analysis whilst the other reported similar results without imputation. Of the 14 trials using controlled MI in sensitivity analysis, 12 yielded comparable results to the primary analysis whereas 2 demonstrated contradicting results. Only 5/110 (5%) trials using missing-at-random MI and 5/16 (31%) trials using controlled MI reported complete details on MI methods.

Conclusions: Controlled MI enabled the impact of accessible contextually relevant missing data assumptions to be examined on trial results. The use of controlled MI is increasing but is still infrequent and poorly reported where used. There is a need for improved reporting on the implementation of MI analyses and choice of controlled MI parameters.
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http://dx.doi.org/10.1186/s12874-021-01261-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048273PMC
April 2021

Skincare interventions in infants for preventing eczema and food allergy: A cochrane systematic review and individual participant data meta-analysis.

Clin Exp Allergy 2021 Mar 25;51(3):402-418. Epub 2021 Feb 25.

National Heart and Lung Institute, Imperial College London, London, UK.

Objective: Eczema and food allergy start in infancy and have shared genetic risk factors that affect skin barrier. We aimed to evaluate whether skincare interventions can prevent eczema or food allergy.

Design: A prospectively planned individual participant data meta-analysis was carried out within a Cochrane systematic review to determine whether skincare interventions in term infants prevent eczema or food allergy.

Data Sources: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to July 2020.

Eligibility Criteria For Selected Studies: Included studies were randomized controlled trials of infants <1 year with healthy skin comparing a skin intervention with a control, for prevention of eczema and food allergy outcomes between 1 and 3 years.

Results: Of the 33 identified trials, 17 trials (5823 participants) had relevant outcome data and 10 (5154 participants) contributed to IPD meta-analysis. Three of seven trials contributing to primary eczema analysis were at low risk of bias, and the single trial contributing to primary food allergy analysis was at high risk of bias. Interventions were mainly emollients, applied for the first 3-12 months. Skincare interventions probably do not change risk of eczema by age 1-3 years (RR 1.03, 95% CI 0.81, 1.31; I =41%; moderate certainty; 3075 participants, 7 trials). Sensitivity analysis found heterogeneity was explained by increased eczema in a trial of daily bathing as part of the intervention. It is unclear whether skincare interventions increase risk of food allergy by age 1-3 years (RR 2.53, 95% CI 0.99 to 6.47; very low certainty; 996 participants, 1 trial), but they probably increase risk of local skin infections (RR 1.34, 95% CI 1.02, 1.77; I =0%; moderate certainty; 2728 participants, 6 trials).

Conclusion: Regular emollients during infancy probably do not prevent eczema and probably increase local skin infections.
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http://dx.doi.org/10.1111/cea.13847DOI Listing
March 2021

Skin care interventions in infants for preventing eczema and food allergy.

Cochrane Database Syst Rev 2021 02 5;2:CD013534. Epub 2021 Feb 5.

National Heart & Lung Institute, Section of Inflammation and Repair, Imperial College London, London, UK.

Background: Eczema and food allergy are common health conditions that usually begin in early childhood and often occur together in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective in preventing eczema or food allergy.

Objectives: Primary objective To assess effects of skin care interventions, such as emollients, for primary prevention of eczema and food allergy in infants Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy.

Search Methods: We searched the following databases up to July 2020: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We searched two trials registers and checked reference lists of included studies and relevant systematic reviews for further references to relevant randomised controlled trials (RCTs). We contacted field experts to identify planned trials and to seek information about unpublished or incomplete trials.

Selection Criteria: RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (0 to 12 months) without pre-existing diagnosis of eczema, food allergy, or other skin condition were included. Comparison was standard care in the locality or no treatment. Types of skin care interventions included moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow-up was required.

Data Collection And Analysis: This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes were cumulative incidence of eczema and cumulative incidence of immunoglobulin (Ig)E-mediated food allergy by one to three years, both measured by the closest available time point to two years. Secondary outcomes included adverse events during the intervention period; eczema severity (clinician-assessed); parent report of eczema severity; time to onset of eczema; parent report of immediate food allergy; and allergic sensitisation to food or inhalant allergen.

Main Results: This review identified 33 RCTs, comprising 25,827 participants. A total of 17 studies, randomising 5823 participants, reported information on one or more outcomes specified in this review. Eleven studies randomising 5217 participants, with 10 of these studies providing IPD, were included in one or more meta-analysis (range 2 to 9 studies per individual meta-analysis). Most studies were conducted at children's hospitals. All interventions were compared against no skin care intervention or local standard care. Of the 17 studies that reported our outcomes, 13 assessed emollients. Twenty-five studies, including all those contributing data to meta-analyses, randomised newborns up to age three weeks to receive a skin care intervention or standard infant skin care. Eight of the 11 studies contributing to meta-analyses recruited infants at high risk of developing eczema or food allergy, although definition of high risk varied between studies. Durations of intervention and follow-up ranged from 24 hours to two years. We assessed most of this review's evidence as low certainty or had some concerns of risk of bias. A rating of some concerns was most often due to lack of blinding of outcome assessors or significant missing data, which could have impacted outcome measurement but was judged unlikely to have done so. Evidence for the primary food allergy outcome was rated as high risk of bias due to inclusion of only one trial where findings varied when different assumptions were made about missing data. Skin care interventions during infancy probably do not change risk of eczema by one to two years of age (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.81 to 1.31; moderate-certainty evidence; 3075 participants, 7 trials) nor time to onset of eczema (hazard ratio 0.86, 95% CI 0.65 to 1.14; moderate-certainty evidence; 3349 participants, 9 trials). It is unclear whether skin care interventions during infancy change risk of IgE-mediated food allergy by one to two years of age (RR 2.53, 95% CI 0.99 to 6.47; 996 participants, 1 trial) or allergic sensitisation to a food allergen at age one to two years (RR 0.86, 95% CI 0.28 to 2.69; 1055 participants, 2 trials) due to very low-certainty evidence for these outcomes. Skin care interventions during infancy may slightly increase risk of parent report of immediate reaction to a common food allergen at two years (RR 1.27, 95% CI 1.00 to 1.61; low-certainty evidence; 1171 participants, 1 trial). However, this was only seen for cow's milk, and may be unreliable due to significant over-reporting of cow's milk allergy in infants. Skin care interventions during infancy probably increase risk of skin infection over the intervention period (RR 1.34, 95% CI 1.02 to 1.77; moderate-certainty evidence; 2728 participants, 6 trials) and may increase risk of infant slippage over the intervention period (RR 1.42, 95% CI 0.67 to 2.99; low-certainty evidence; 2538 participants, 4 trials) or stinging/allergic reactions to moisturisers (RR 2.24, 95% 0.67 to 7.43; low-certainty evidence; 343 participants, 4 trials), although confidence intervals for slippages and stinging/allergic reactions are wide and include the possibility of no effect or reduced risk. Preplanned subgroup analyses show that effects of interventions were not influenced by age, duration of intervention, hereditary risk, FLG mutation,  or classification of intervention type for risk of developing eczema. We could not evaluate these effects on risk of food allergy. Evidence was insufficient to show whether adherence to interventions influenced the relationship between skin care interventions and risk of developing eczema or food allergy.

Authors' Conclusions: Skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema, and probably increase risk of skin infection. Effects of skin care interventions on risk of food allergy are uncertain. Further work is needed to understand whether different approaches to infant skin care might promote or prevent eczema and to evaluate effects on food allergy based on robust outcome assessments.
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http://dx.doi.org/10.1002/14651858.CD013534.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094581PMC
February 2021

Advantages of visualisations to evaluate and communicate adverse event information in randomised controlled trials.

Trials 2020 Dec 22;21(1):1028. Epub 2020 Dec 22.

Imperial Clinical Trials Unit, Imperial College London, 1st Floor Stadium House, 68 Wood Lane, London, W12 7RH, UK.

Background: Randomised controlled trials (RCTs) provide valuable information and inform the development of harm profiles of new treatments. Harms are typically assessed through the collection of adverse events (AEs). Despite AEs being routine outcomes collected in trials, analysis and reporting of AEs in journal articles are continually shown to be suboptimal. One key challenge is the large volume of AEs, which can make evaluation and communication problematic. Prominent practice is to report frequency tables of AEs by arm. Visual displays offer an effective solution to assess and communicate complex information; however, they are rarely used and there is a lack of practical guidance on what and how to visually display complex AE data.

Methods: In this article, we demonstrate the use of two plots identified to be beneficial for wide use in RCTs, since both can display multiple AEs and are suitable to display point estimates for binary, count, or time-to-event AE data: the volcano and dot plots. We compare and contrast the use of data visualisations against traditional frequency table reporting, using published AE information in two placebo-controlled trials, of remdesivir for COVID-19 and GDNF for Parkinson disease. We introduce statistical programmes for implementation in Stata.

Results/case Study: Visualisations of AEs in the COVID-19 trial communicated a risk profile for remdesivir which differed from the main message in the published authors' conclusion. In the Parkinson's disease trial of GDNF, the visualisation provided immediate communication of harm signals, which had otherwise been contained within lengthy descriptive text and tables. Asymmetry in the volcano plot helped flag extreme events that were less obvious from review of the frequency table and dot plot. The dot plot allowed a more comprehensive representation by means of a more detailed summary.

Conclusions: Visualisations can better support investigators to assimilate large volumes of data and enable improved informal between-arm comparisons compared to tables. We endorse increased uptake for use in trial publications. Care in construction of visual displays needs to be taken as there can be potential to overemphasise treatment effects in some circumstances.
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http://dx.doi.org/10.1186/s13063-020-04903-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754702PMC
December 2020

Association of Clinical and Demographic Factors With the Severity of Palmoplantar Pustulosis.

JAMA Dermatol 2020 11;156(11):1216-1222

St John's Institute of Dermatology, King's College London, London, United Kingdom.

Importance: Although palmoplantar pustulosis (PPP) can significantly impact quality of life, the factors underlying disease severity have not been studied.

Objective: To examine the factors associated with PPP severity.

Design, Setting, And Participants: An observational, cross-sectional study of 2 cohorts was conducted. A UK data set including 203 patients was obtained through the Anakinra in Pustular Psoriasis, Response in a Controlled Trial (2016-2019) and its sister research study Pustular Psoriasis, Elucidating Underlying Mechanisms (2016-2020). A Northern European cohort including 193 patients was independently ascertained by the European Rare and Severe Psoriasis Expert Network (2014-2017). Patients had been recruited in secondary or tertiary dermatology referral centers. All patients were of European descent. The PPP diagnosis was established by dermatologists, based on clinical examination and/or published consensus criteria. The present study was conducted from October 1, 2014, to March 15, 2020.

Main Outcomes And Measures: Demographic characteristics, comorbidities, smoking status, Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI), measuring severity from 0 (no sign of disease) to 72 (very severe disease), or Physician Global Assessment (PGA), measuring severity as 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe).

Results: Among the 203 UK patients (43 men [21%], 160 women [79%]; median age at onset, 48 [interquartile range (IQR), 38-59] years), the PPPASI was inversely correlated with age of onset (r = -0.18, P = .01). Similarly, in the 159 Northern European patients who were eligible for inclusion in this analysis (25 men [16%], 134 women [84%]; median age at onset, 45 [IQR, 34-53.3] years), the median age at onset was lower in individuals with a moderate to severe PGA score (41 years [IQR, 30.5-52 years]) compared with those with a clear to mild PGA score (46.5 years [IQR, 35-55 years]) (P = .04). In the UK sample, the median PPPASI score was higher in women (9.6 [IQR, 3.0-16.2]) vs men (4.0 [IQR, 1.0-11.7]) (P = .01). Likewise, moderate to severe PPP was more prevalent among Northern European women (57 of 134 [43%]) compared with men (5 of 25 [20%]) (P = .03). In the UK cohort, the median PPPASI score was increased in current smokers (10.7 [IQR, 4.2-17.5]) compared with former smokers (7 [IQR, 2.0-14.4]) and nonsmokers (2.2 [IQR, 1-6]) (P = .003). Comparable differences were observed in the Northern European data set, as the prevalence of moderate to severe PPP was higher in former and current smokers (51 of 130 [39%]) compared with nonsmokers (6 of 24 [25%]) (P = .14).

Conclusions And Relevance: The findings of this study suggest that PPP severity is associated with early-onset disease, female sex, and smoking status. Thus, smoking cessation intervention might be beneficial.
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http://dx.doi.org/10.1001/jamadermatol.2020.3275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495329PMC
November 2020

Treatment estimands in clinical trials of patients hospitalised for COVID-19: ensuring trials ask the right questions.

BMC Med 2020 09 9;18(1):286. Epub 2020 Sep 9.

MRC Clinical Trials Unit at UCL, London, UK.

When designing a clinical trial, explicitly defining the treatment estimands of interest (that which is to be estimated) can help to clarify trial objectives and ensure the questions being addressed by the trial are clinically meaningful. There are several challenges when defining estimands. Here, we discuss a number of these in the context of trials of treatments for patients hospitalised with COVID-19 and make suggestions for how estimands should be defined for key outcomes. We suggest that treatment effects should usually be measured as differences in proportions (or risk or odds ratios) for outcomes such as death and requirement for ventilation, and differences in means for outcomes such as the number of days ventilated. We further recommend that truncation due to death should be handled differently depending on whether a patient- or resource-focused perspective is taken; for the former, a composite approach should be used, while for the latter, a while-alive approach is preferred. Finally, we suggest that discontinuation of randomised treatment should be handled from a treatment policy perspective, where non-adherence is ignored in the analysis (i.e. intention to treat).
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http://dx.doi.org/10.1186/s12916-020-01737-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478913PMC
September 2020

How to design a pre-specified statistical analysis approach to limit p-hacking in clinical trials: the Pre-SPEC framework.

BMC Med 2020 09 7;18(1):253. Epub 2020 Sep 7.

Imperial Clinical Trials Unit, Imperial College London, Stadium House, 68 Wood Lane, London, W12 7RH, UK.

Results from clinical trials can be susceptible to bias if investigators choose their analysis approach after seeing trial data, as this can allow them to perform multiple analyses and then choose the method that provides the most favourable result (commonly referred to as 'p-hacking'). Pre-specification of the planned analysis approach is essential to help reduce such bias, as it ensures analytical methods are chosen in advance of seeing the trial data. For this reason, guidelines such as SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and ICH-E9 (International Conference for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) require the statistical methods for a trial's primary outcome be pre-specified in the trial protocol. However, pre-specification is only effective if done in a way that does not allow p-hacking. For example, investigators may pre-specify a certain statistical method such as multiple imputation, but give little detail on how it will be implemented. Because there are many different ways to perform multiple imputation, this approach to pre-specification is ineffective, as it still allows investigators to analyse the data in different ways before deciding on a final approach. In this article, we describe a five-point framework (the Pre-SPEC framework) for designing a pre-specified analysis approach that does not allow p-hacking. This framework was designed based on the principles in the SPIRIT and ICH-E9 guidelines and is intended to be used in conjunction with these guidelines to help investigators design the statistical analysis strategy for the trial's primary outcome in the trial protocol.
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http://dx.doi.org/10.1186/s12916-020-01706-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487509PMC
September 2020

A four-step strategy for handling missing outcome data in randomised trials affected by a pandemic.

BMC Med Res Methodol 2020 08 12;20(1):208. Epub 2020 Aug 12.

Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.

Background: The coronavirus pandemic (Covid-19) presents a variety of challenges for ongoing clinical trials, including an inevitably higher rate of missing outcome data, with new and non-standard reasons for missingness. International drug trial guidelines recommend trialists review plans for handling missing data in the conduct and statistical analysis, but clear recommendations are lacking.

Methods: We present a four-step strategy for handling missing outcome data in the analysis of randomised trials that are ongoing during a pandemic. We consider handling missing data arising due to (i) participant infection, (ii) treatment disruptions and (iii) loss to follow-up. We consider both settings where treatment effects for a 'pandemic-free world' and 'world including a pandemic' are of interest.

Results: In any trial, investigators should; (1) Clarify the treatment estimand of interest with respect to the occurrence of the pandemic; (2) Establish what data are missing for the chosen estimand; (3) Perform primary analysis under the most plausible missing data assumptions followed by; (4) Sensitivity analysis under alternative plausible assumptions. To obtain an estimate of the treatment effect in a 'pandemic-free world', participant data that are clinically affected by the pandemic (directly due to infection or indirectly via treatment disruptions) are not relevant and can be set to missing. For primary analysis, a missing-at-random assumption that conditions on all observed data that are expected to be associated with both the outcome and missingness may be most plausible. For the treatment effect in the 'world including a pandemic', all participant data is relevant and should be included in the analysis. For primary analysis, a missing-at-random assumption - potentially incorporating a pandemic time-period indicator and participant infection status - or a missing-not-at-random assumption with a poorer response may be most relevant, depending on the setting. In all scenarios, sensitivity analysis under credible missing-not-at-random assumptions should be used to evaluate the robustness of results. We highlight controlled multiple imputation as an accessible tool for conducting sensitivity analyses.

Conclusions: Missing data problems will be exacerbated for trials active during the Covid-19 pandemic. This four-step strategy will facilitate clear thinking about the appropriate analysis for relevant questions of interest.
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http://dx.doi.org/10.1186/s12874-020-01089-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422467PMC
August 2020

Public availability and adherence to prespecified statistical analysis approaches was low in published randomized trials.

J Clin Epidemiol 2020 12 28;128:29-34. Epub 2020 Jul 28.

Imperial Clinical Trials Unit, Imperial College London, London, UK.

Background And Objective: Prespecification of statistical methods in clinical trial protocols and statistical analysis plans can help to deter bias from p-hacking but is only effective if the prespecified approach is made available.

Study Design And Setting: For 100 randomized trials published in 2018 and indexed in PubMed, we evaluated how often a prespecified statistical analysis approach for the trial's primary outcome was publicly available. For each trial with an available prespecified analysis, we compared this with the trial publication to identify whether there were unexplained discrepancies.

Results: Only 12 of 100 trials (12%) had a publicly available prespecified analysis approach for their primary outcome; this document was dated before recruitment began for only two trials. Of the 12 trials with an available prespecified analysis approach, 11 (92%) had one or more unexplained discrepancies. Only 4 of 100 trials (4%) stated that the statistician was blinded until the SAP was signed off, and only 10 of 100 (10%) stated the statistician was blinded until the database was locked.

Conclusion: For most published trials, there is insufficient information available to determine whether the results may be subject to p-hacking. Where information was available, there were often unexplained discrepancies between the prespecified and final analysis methods.
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http://dx.doi.org/10.1016/j.jclinepi.2020.07.015DOI Listing
December 2020

Current approaches to handling rescue medication in asthma and eczema randomized controlled trials are inadequate: a systematic review.

J Clin Epidemiol 2020 09 3;125:148-157. Epub 2020 Jun 3.

Imperial College London, Imperial College Clinical Trials Unit, 1st Floor Stadium House, 68 Wood Lane, London W12 7RH, UK. Electronic address:

Objectives: The objective of this study was to examine how rescue medication is defined, reported, and accounted for in randomized controlled trials (RCTs) in eczema and asthma populations.

Study Design And Setting: This is a systematic review of phase II/III RCTs evaluating monoclonal antibodies for treating chronic eczema or asthma. A search of EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials was conducted to identify eligible RCTs.

Results: Sixty published RCTs were identified, of which 60 (100%) allowed use of rescue medication but only 28 (47%) reported its use. Twenty-seven (45%) articles summarized rescue use by arm, with an average of 25% (95% CI (17%, 36%)) greater use in the placebo arm. Nine (15%) trials undertook an analysis that adjusted the primary treatment effect estimate for rescue medication use, but 8 of these used a suboptimal approach using single imputation, including 4 which used "last observation carried forward" after setting postrescue data to missing.

Conclusion: Rescue medication use in eczema and asthma trials evaluating monoclonal antibodies is often permitted, but not routinely reported. There is evidence of imbalance in rescue use between arms, but few articles attempted to estimate a rescue-adjusted treatment effect. In trials that did, the methods used were suboptimal which could introduce bias.
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http://dx.doi.org/10.1016/j.jclinepi.2020.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482905PMC
September 2020

Total ankle replacement : comparison of the outcomes of STAR and Mobility.

Acta Orthop Belg 2020 Mar;86(1):109-114

Total Ankle Replacement is a recognised treatment for end-stage ankle arthritis and an alternative to arthrodesis. This study reviews a single centre series of prospectively collected outcome measures to determine whether the Mobility performs better than the Scandinavian ankle replacement. The primary outcome measure was the survivorship. Secondary outcome measures consisted of complications and international scoring systems. 147 Scandinavian and 162 Mobility ankle replacements were reviewed at a mean follow up of 12.4 and 7.7 years respectively. The revision rate, which included liner exchange, component exchange or removal of implant was at 7 years 12.3% (18) for Scandinavian and 5.2% (8) for Mobility. The complication rate was 16.5% (22) for Scandinavian compared to 9.9 % (15) for Mobility. The results of our unit compare favourably with previous published studies. In this study the Mobility has been shown to have more favourable results at 7 years compared to the Scandinavian.
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March 2020

Evidence of unexplained discrepancies between planned and conducted statistical analyses: a review of randomised trials.

BMC Med 2020 05 29;18(1):137. Epub 2020 May 29.

MRC Clinical Trials Unit at UCL, London, UK.

Background: Choosing or altering the planned statistical analysis approach after examination of trial data (often referred to as 'p-hacking') can bias the results of randomised trials. However, the extent of this issue in practice is currently unclear. We conducted a review of published randomised trials to evaluate how often a pre-specified analysis approach is publicly available, and how often the planned analysis is changed.

Methods: A review of randomised trials published between January and April 2018 in six leading general medical journals. For each trial, we established whether a pre-specified analysis approach was publicly available in a protocol or statistical analysis plan and compared this to the trial publication.

Results: Overall, 89 of 101 eligible trials (88%) had a publicly available pre-specified analysis approach. Only 22/89 trials (25%) had no unexplained discrepancies between the pre-specified and conducted analysis. Fifty-four trials (61%) had one or more unexplained discrepancies, and in 13 trials (15%), it was impossible to ascertain whether any unexplained discrepancies occurred due to incomplete reporting of the statistical methods. Unexplained discrepancies were most common for the analysis model (n = 31, 35%) and analysis population (n = 28, 31%), followed by the use of covariates (n = 23, 26%) and the approach for handling missing data (n = 16, 18%). Many protocols or statistical analysis plans were dated after the trial had begun, so earlier discrepancies may have been missed.

Conclusions: Unexplained discrepancies in the statistical methods of randomised trials are common. Increased transparency is required for proper evaluation of results.
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http://dx.doi.org/10.1186/s12916-020-01590-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257229PMC
May 2020

May Measurement Month 2019: The Global Blood Pressure Screening Campaign of the International Society of Hypertension.

Hypertension 2020 08 18;76(2):333-341. Epub 2020 May 18.

From the Imperial Clinical Trials Unit (T.B., S.C., N.R.P.).

Elevated blood pressure remains the single biggest risk factor contributing to the global burden of disease and mortality. May Measurement Month is an annual global screening campaign aiming to improve awareness of blood pressure at the individual and population level. Adults (≥18 years) recruited through opportunistic sampling were screened at sites in 92 countries during May 2019. Ideally, 3 blood pressure readings were measured for each participant, and data on lifestyle factors and comorbidities were collected. Hypertension was defined as a systolic blood pressure ≥140 mm Hg, or a diastolic blood pressure ≥90 mm Hg (mean of the second and third readings) or taking antihypertensive medication. When necessary, multiple imputation was used to estimate participants' mean blood pressure. Mixed-effects models were used to evaluate associations between blood pressure and participant characteristics. Of 1 508 130 screenees 482 273 (32.0%) had never had a blood pressure measurement before and 513 337 (34.0%) had hypertension, of whom 58.7% were aware, and 54.7% were on antihypertensive medication. Of those on medication, 57.8% were controlled to <140/90 mm Hg, and 28.9% to <130/80 mm Hg. Of all those with hypertension, 31.7% were controlled to <140/90 mm Hg, and 350 825 (23.3%) participants had untreated or inadequately treated hypertension. Of those taking antihypertensive medication, half were taking only a single drug, and 25% reported using aspirin inappropriately. This survey is the largest ever synchronized and standardized contemporary compilation of global blood pressure data. This campaign is needed as a temporary substitute for systematic blood pressure screening in many countries worldwide.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14874DOI Listing
August 2020

Sensitivity analysis for clinical trials with missing continuous outcome data using controlled multiple imputation: A practical guide.

Stat Med 2020 09 17;39(21):2815-2842. Epub 2020 May 17.

MRC Clinical Trials Unit at UCL, UCL, London, UK.

Missing data due to loss to follow-up or intercurrent events are unintended, but unfortunately inevitable in clinical trials. Since the true values of missing data are never known, it is necessary to assess the impact of untestable and unavoidable assumptions about any unobserved data in sensitivity analysis. This tutorial provides an overview of controlled multiple imputation (MI) techniques and a practical guide to their use for sensitivity analysis of trials with missing continuous outcome data. These include δ- and reference-based MI procedures. In δ-based imputation, an offset term, δ, is typically added to the expected value of the missing data to assess the impact of unobserved participants having a worse or better response than those observed. Reference-based imputation draws imputed values with some reference to observed data in other groups of the trial, typically in other treatment arms. We illustrate the accessibility of these methods using data from a pediatric eczema trial and a chronic headache trial and provide Stata code to facilitate adoption. We discuss issues surrounding the choice of δ in δ-based sensitivity analysis. We also review the debate on variance estimation within reference-based analysis and justify the use of Rubin's variance estimator in this setting, since as we further elaborate on within, it provides information anchored inference.
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http://dx.doi.org/10.1002/sim.8569DOI Listing
September 2020

An evaluation of inverse probability weighting using the propensity score for baseline covariate adjustment in smaller population randomised controlled trials with a continuous outcome.

BMC Med Res Methodol 2020 03 23;20(1):70. Epub 2020 Mar 23.

Imperial Clinical Trials Unit, Imperial College London, Stadium House, 68 Wood Lane, London, W12 7RH, UK.

Background: It is important to estimate the treatment effect of interest accurately and precisely within the analysis of randomised controlled trials. One way to increase precision in the estimate and thus improve the power for randomised trials with continuous outcomes is through adjustment for pre-specified prognostic baseline covariates. Typically covariate adjustment is conducted using regression analysis, however recently, Inverse Probability of Treatment Weighting (IPTW) using the propensity score has been proposed as an alternative method. For a continuous outcome it has been shown that the IPTW estimator has the same large sample statistical properties as that obtained via analysis of covariance. However the performance of IPTW has not been explored for smaller population trials (< 100 participants), where precise estimation of the treatment effect has potential for greater impact than in larger samples.

Methods: In this paper we explore the performance of the baseline adjusted treatment effect estimated using IPTW in smaller population trial settings. To do so we present a simulation study including a number of different trial scenarios with sample sizes ranging from 40 to 200 and adjustment for up to 6 covariates. We also re-analyse a paediatric eczema trial that includes 60 children.

Results: In the simulation study the performance of the IPTW variance estimator was sub-optimal with smaller sample sizes. The coverage of 95% CI's was marginally below 95% for sample sizes < 150 and ≥ 100. For sample sizes < 100 the coverage of 95% CI's was always significantly below 95% for all covariate settings. The minimum coverage obtained with IPTW was 89% with n = 40. In comparison, regression adjustment always resulted in 95% coverage. The analysis of the eczema trial confirmed discrepancies between the IPTW and regression estimators in a real life small population setting.

Conclusions: The IPTW variance estimator does not perform so well with small samples. Thus we caution against the use of IPTW in small sample settings when the sample size is less than 150 and particularly when sample size < 100.
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http://dx.doi.org/10.1186/s12874-020-00947-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092449PMC
March 2020

A randomised, multi-centre trial of total ankle replacement versus ankle arthrodesis in the treatment of patients with end stage ankle osteoarthritis (TARVA): statistical analysis plan.

Trials 2020 Feb 18;21(1):197. Epub 2020 Feb 18.

Comprehensive Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK.

Background: The total ankle replacement versus ankle arthrodesis (TARVA) trial aims to determine which surgical procedure confers the greatest improvement in pain-free function for patients with end-stage ankle osteoarthritis. Both procedures are effective but there has not yet been a direct comparison to establish which is superior. This article describes the statistical analysis plan for this trial as an update to the published protocol. It is written prior to the end of patient follow-up, while the outcome of the trial is still unknown.

Design And Methods: TARVA is a randomised, un-blinded, parallel group trial of total ankle replacement versus ankle arthrodesis. The primary outcome is the Manchester-Oxford Foot Questionnaire walking/standing domain score at 52 weeks post-surgery. Secondary outcomes include measures of pain, social interaction, physical function, quality of life, and range of motion. We describe in detail the statistical aspects of TARVA: the outcome measures, the sample size calculation, general analysis principles including treatment of missing data, the planned descriptive statistics and statistical models, and planned subgroup and sensitivity analyses.

Discussion: The TARVA statistical analysis will provide comprehensive and precise information on the relative effectiveness of the two treatments. The plan will be implemented in January 2020 when follow-up for the trial is completed.

Trial Registration: ISRCTN registry number 60672307, ClinicalTrials.gov registration number NCT02128555. Registered 1 May 2014. Recruitment started in January 2015 and ended in January 2019.
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http://dx.doi.org/10.1186/s13063-019-3973-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029552PMC
February 2020

A randomised placebo controlled trial of anakinra for treating pustular psoriasis: statistical analysis plan for stage two of the APRICOT trial.

Trials 2020 Feb 10;21(1):158. Epub 2020 Feb 10.

Imperial Clinical Trials Unit, Imperial College London, W12 7RH, London, UK.

Background: Current treatment options for Palmoplantar Pustulosis (PPP), a debilitating chronic skin disease which affects the hands and feet, are limited. The Anakinra for Pustular psoriasis: Response in a Controlled Trial (APRICOT) aims to determine the efficacy of anakinra in the treatment of PPP. This article describes the statistical analysis plan for the final analysis of this two-staged trial, which was determined prior to unblinding and database lock. This is an update to the published protocol and stage one analysis plan.

Methods: APRICOT is a randomised, double-blind, placebo-controlled trial of anakinra versus placebo, with two stages and an adaptive element. Stage one compared treatment arms to ensure proof-of-concept and determined the primary outcome for stage two of the trial. The primary outcome was selected to be the change in Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. Secondary outcomes include other investigator-assessed efficacy measures of disease severity, participant-reported measures of efficacy and safety measures. This manuscript describes in detail the outcomes, sample size, general analysis principles, the pre-specified statistical analysis plan for each of the outcomes, the handling of missing outcome data and the planned sensitivity and supplementary analyses for the second stage of the APRICOT trial.

Discussion: This statistical analysis plan was developed in compliance with international trial guidelines and is published to increase transparency of the trial analysis. The results of the trial analysis will indicate whether anakinra has a role in the treatment of PPP.

Trial Registration: ISCRTN, ISCRTN13127147. Registered on 1 August 2016. EudraCT Number 2015-003600-23. Registered on 1 April 2016.
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http://dx.doi.org/10.1186/s13063-020-4103-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011285PMC
February 2020

Reference-based multiple imputation for missing data sensitivity analyses in trial-based cost-effectiveness analysis.

Health Econ 2020 02 17;29(2):171-184. Epub 2019 Dec 17.

Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.

Missing data are a common issue in cost-effectiveness analysis (CEA) alongside randomised trials and are often addressed assuming the data are 'missing at random'. However, this assumption is often questionable, and sensitivity analyses are required to assess the implications of departures from missing at random. Reference-based multiple imputation provides an attractive approach for conducting such sensitivity analyses, because missing data assumptions are framed in an intuitive way by making reference to other trial arms. For example, a plausible not at random mechanism in a placebo-controlled trial would be to assume that participants in the experimental arm who dropped out stop taking their treatment and have similar outcomes to those in the placebo arm. Drawing on the increasing use of this approach in other areas, this paper aims to extend and illustrate the reference-based multiple imputation approach in CEA. It introduces the principles of reference-based imputation and proposes an extension to the CEA context. The method is illustrated in the CEA of the CoBalT trial evaluating cognitive behavioural therapy for treatment-resistant depression. Stata code is provided. We find that reference-based multiple imputation provides a relevant and accessible framework for assessing the robustness of CEA conclusions to different missing data assumptions.
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http://dx.doi.org/10.1002/hec.3963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004051PMC
February 2020

Treatment Effect of Omalizumab on Severe Pediatric Atopic Dermatitis: The ADAPT Randomized Clinical Trial.

JAMA Pediatr 2020 01;174(1):29-37

King's College London, School of Life Course Sciences & School of Immunology & Microbial Sciences, King's Health Partners, London, United Kingdom.

Importance: Systemic treatments for severe childhood atopic dermatitis have limited evidence and/or are unlicensed. Despite the efficacy of anti-IgE medication (omalizumab) in the treatment of atopy, no large randomized studies in childhood atopic dermatitis have been published.

Objective: To determine the effectiveness of omalizumab in treating severe atopic dermatitis in children.

Design, Setting, And Participants: The Atopic Dermatitis Anti-IgE Pediatric Trial (ADAPT) was a 24-week single-center, double-blind, placebo-controlled randomized clinical trial with a 24-week follow-up. Conducted from November 20, 2014, to August 31, 2017, at Guy's and St Thomas' Hospital NHS Foundation Trust and King's College London in the United Kingdom, this trial recruited participants after a screening visit. Eligible participants (n = 62) were aged 4 to 19 years and had severe eczema (with objective Scoring Atopic Dermatitis [SCORAD] index >40) that was unresponsive to optimum therapy. Statistical analysis was conducted using the intention-to-treat principle.

Interventions: Subcutaneous omalizumab or placebo for 24 weeks. The drug manufacturer's dosing tables were used to determine the dosage based on total IgE (30-1500 IU/mL) and body weight (in kilograms) at randomization.

Main Outcomes And Measures: Objective SCORAD index after 24 weeks of treatment.

Results: In total, 62 children (mean [SD] age, 10.3 [4.2] years; 32 (52%) were male) were randomized to either omalizumab (n = 30) or placebo (n = 32). Five participants withdrew from treatment (4 [13%] from the placebo group, and 1 [3%] from the omalizumab group). Follow-up attendance was 97% at week 24 and 98% at week 48. After adjustment for baseline objective SCORAD index, age, and IgE level, the mean difference in objective SCORAD index improvement between groups at week 24 was -6.9 (95% CI, -12.2 to -1.5; P = .01), significantly favoring omalizumab therapy and reflecting the results in other assessments of atopic dermatitis severity. Improved quality-of-life scores were seen in the omalizumab group, as measured by the Children's Dermatology Life Quality Index/Dermatology Life Quality Index (-3.5; 95% CI, -6.4 to -0.5) and Pediatric Allergic Disease Quality of Life Questionnaire score (-0.5; 95% CI, -0.9 to -0.0). Improvements in disease severity occurred despite lower potent topical corticosteroid use in the omalizumab group compared with the placebo group (median [interquartile range (IQR)] percentage of body surface area covered, 16% [10%-46%] vs 31% [14%-55%]; median [IQR] number of days of use, 109 [34-164] days vs 161 [82-171] days).

Conclusions And Relevance: This randomized clinical trial found that omalizumab significantly reduced atopic dermatitis severity and improved quality of life in a pediatric population with atopy and severe eczema despite highly elevated total IgE levels at baseline. The result was associated with a potent topical corticosteroid sparing effect and may suggest that omalizumab is a treatment option for difficult-to-manage severe eczema in children with atopy.

Trial Registration: ClinicalTrials.gov identifier: NCT02300701.
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http://dx.doi.org/10.1001/jamapediatrics.2019.4476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902112PMC
January 2020

May Measurement Month 2018: a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension.

Eur Heart J 2019 07;40(25):2006-2017

Imperial Clinical Trials Unit, Imperial College London, London, UK.

Aims: Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries.

Methods And Results: Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) hypertension.

Conclusion: May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk.
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http://dx.doi.org/10.1093/eurheartj/ehz300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600128PMC
July 2019

Information-anchored sensitivity analysis: theory and application.

J R Stat Soc Ser A Stat Soc 2019 Feb 16;182(2):623-645. Epub 2018 Nov 16.

Ashkirk UK.

Analysis of longitudinal randomized clinical trials is frequently complicated because patients deviate from the protocol. Where such deviations are relevant for the estimand, we are typically required to make an untestable assumption about post-deviation behaviour to perform our primary analysis and to estimate the treatment effect. In such settings, it is now widely recognized that we should follow this with sensitivity analyses to explore the robustness of our inferences to alternative assumptions about post-deviation behaviour. Although there has been much work on how to conduct such sensitivity analyses, little attention has been given to the appropriate loss of information due to missing data within sensitivity analysis. We argue that more attention needs to be given to this issue, showing that it is quite possible for sensitivity analysis to decrease and increase the information about the treatment effect. To address this critical issue, we introduce the concept of sensitivity analysis. By this we mean sensitivity analyses in which the proportion of information about the treatment estimate lost because of missing data is the same as the proportion of information about the treatment estimate lost because of missing data in the primary analysis. We argue that this forms a transparent, practical starting point for interpretation of sensitivity analysis. We then derive results showing that, for longitudinal continuous data, a broad class of controlled and reference-based sensitivity analyses performed by multiple imputation are information anchored. We illustrate the theory with simulations and an analysis of a peer review trial and then discuss our work in the context of other recent work in this area. Our results give a theoretical basis for the use of controlled multiple-imputation procedures for sensitivity analysis.
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http://dx.doi.org/10.1111/rssa.12423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378615PMC
February 2019

A randomised controlled feasibility trial to evaluate local heat preconditioning on wound healing after reconstructive breast surgery: the preHEAT trial.

Pilot Feasibility Stud 2019 11;5. Epub 2019 Jan 11.

1Department of Plastic Surgery, Guy's and St. Thomas' NHS Foundation Trust, Westminster Bridge Road, London, SE1 7EH UK.

Objective: preHEAT was a randomised controlled feasibility trial to determine how best to measure skin necrosis in breast reconstruction to inform the design of a larger multicentre trial.

Background: Mastectomy skin flap necrosis (MSFN) is a serious complication resulting in prolonged wound healing. Local heat preconditioning of the MSF before surgery has been shown to reduce skin necrosis in immediate breast reconstruction patients (IBR).

Method: preHEAT was a single-centre, randomised control two-arm single-blind parallel arm feasibility trial of local heat preconditioning in breast cancer patients undergoing SSM and NSM at Guy's and St Thomas' Hospital, London, UK. All patients undergoing IBR above the age of 18 were included. Intervention patients heated breast skin to 43 °C in three, 30-min cycles interrupted by spontaneous cooling using hot water bottles. The primary aim was to compare measurement of skin necrosis using binary 'yes/no' assessment, the SKIN score, and wound area.

Results: One hundred forty-one patients were randomised over a 2-year period (71 heated group, 70 controls). There was near perfect agreement between assessors using the "yes/no" measurement of necrosis. The proportion of patients experiencing necrosis in controls was 35% ( = 23/66) in the heated 26% ( = 18/68]). In the control group, 17% ( = 4/23) patients experiencing necrosis required surgical intervention for necrosis compared to 11% ( = 2/18) in the heated group.

Conclusion: The binary outcome of MSFN "yes/no" is a suitable and reliable primary outcome measure of necrosis and was superior to the SKIN Score or necrosis area. The trial study design is feasible for a larger definitive trial.

Trial Registration: ISRCTN15744669. Date of registration: 25/02/2018.
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http://dx.doi.org/10.1186/s40814-019-0392-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329155PMC
January 2019

Perioperative administration of buffered versus non-buffered crystalloid intravenous fluid to improve outcomes following adult surgical procedures: a Cochrane systematic review.

Perioper Med (Lond) 2018 13;7:27. Epub 2018 Dec 13.

11Department of Anaesthesia, UCL Centre for Anaesthesia, London, UK.

Background: Buffered intravenous fluid preparations contain substrates to maintain acid-base status. The objective of this systematic review was to compare the effects of buffered and non-buffered fluids administered during the perioperative period on clinical and biochemical outcomes.

Methods: We searched MEDLINE, EMBASE, CINAHL and the Cochrane Library until May 2017 and included all randomised controlled trials that evaluated buffered versus non-buffered fluids, whether crystalloid or colloid, administered to surgical patients. We assessed the selected studies for risk of bias and graded the level of evidence in accordance with Cochrane recommendations.

Results: We identified 19 publications of 18 randomised controlled trials, totalling 1096 participants. Mean difference (MD) in postoperative pH was 0.05 units lower immediately following surgery in the non-buffered group (12 studies of 720 participants; 95% confidence interval (CI) 0.04 to 0.07;  = 61%). This difference did not persist on postoperative day 1. Serum chloride concentration was higher in the non-buffered group at the end of surgery (10 trials of 530 participants; MD 6.77 mmol/L, 95% CI 3.38 to 10.17). This effect persisted until postoperative day 1 (5 trials of 258 participants; MD 8.48 mmol/L, 95% CI 1.08 to 15.88). Quality of this evidence was moderate. We identified variable protocols for fluid administration and total volumes of fluid administered to patients intraoperatively. Outcome data was variably reported at disparate time points and with heterogeneous patient groups. Consequently, the effect size and overall confidence interval was reduced, despite the relatively low inherent risk of bias. There was insufficient evidence on the effect of fluid composition on mortality and organ dysfunction. Confidence intervals of this outcome were wide and the quality of evidence was low (3 trials of 276 participants for mortality; odds ratio (OR) 1.85, 95% CI 0.37 to 9.33;  = 0%).

Conclusions: Small effect sizes for biochemical outcomes and lack of correlated clinical follow-up data mean that robust conclusions on major morbidity and mortality associated with buffered versus non-buffered perioperative fluid choices are still lacking. Buffered fluid may have biochemical benefits, including a significant reduction in postoperative hyperchloraemia and metabolic acidosis.
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http://dx.doi.org/10.1186/s13741-018-0108-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291967PMC
December 2018

Treatment of pustular psoriasis with anakinra: a statistical analysis plan for stage 1 of an adaptive two-staged randomised placebo-controlled trial.

Trials 2018 Oct 3;19(1):534. Epub 2018 Oct 3.

Imperial Clinical Trials Unit, School of Public Health, Imperial College London, Stadium House, 68 Wood Lane, London, W12 7RH, UK.

Background: Palmoplantar pustulosis (PPP) is a rare, chronic inflammatory skin disease. It is known to affect quality of life at a level comparable to that from major medical and psychiatric illness, yet current treatment options are remarkably limited. Recent evidence however suggests that interleukin-1 (IL-1) blockade with anakinra will deliver therapeutic benefit in PPP.

Methods: Anakinra for Pustular psoriasis: Response in a Controlled Trial (APRICOT) is a two-staged, adaptive, double-blind, randomised placebo-controlled trial which aims to test the hypothesis that IL-1 blockade with anakinra will deliver therapeutic benefit in PPP. During stage 1 a total of 24 patients will be randomised (1:1) to receive either placebo or anakinra. The two candidate primary outcomes are fresh pustule count (across palms and soles) and the Palmoplantar Pustulosis Area and Severity Index (PPPASI) score, recorded at baseline and at weeks 1, 4 and 8. Analysis at the end of stage 1 will compare treatment arms to ensure sufficient efficacy and safety in order to progress to stage 2. The primary outcome for stage 2 will also be identified following an assessment of the reliability and discriminative ability of fresh pustule count and PPPASI. The trial is powered to detect efficacy and will recruit an additional 40 patients in stage 2 (n = 64 in total). Analysis will follow the intention-to-treat principle and analyse patients as randomised.

Discussion: This manuscript describes the important features of the small population trial design for APRICOT and the pre-specified statistical analysis plan for stage 1. The statistical analysis plan has been developed prior to data extraction and in compliance with international guidelines. It will increase the transparency of the data analysis for the APRICOT trial. The findings of the trial will help to clarify the role of anakinra in the treatment of PPP.

Trial Registration: ISCRTN, ISCRTN13127147 . Registered on 1 August 2016. EudraCT Number 2015-003600-23 . Registered on 1 April 2016.
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http://dx.doi.org/10.1186/s13063-018-2914-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169096PMC
October 2018

A small population, randomised, placebo-controlled trial to determine the efficacy of anakinra in the treatment of pustular psoriasis: study protocol for the APRICOT trial.

Trials 2018 Aug 29;19(1):465. Epub 2018 Aug 29.

St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, 9th Floor Tower Wing, Guy's Hospital, London, UK.

Background: Palmoplantar pustulosis is a rare but painful and debilitating disease. It consistently ranks the highest of all psoriasis phenotypic variants in terms of symptoms and functional impairment. Management of plaque-type psoriasis has been revolutionised in the last 10 years with the advent of biologic therapies, but treatment options for pustular psoriasis remain profoundly limited. On the basis of mechanistic findings which suggest a key pathogenic role for interleukin (IL)-1 in pustular psoriasis, we hypothesise that anakinra (IL-1 blockade) will be an efficacious treatment for pustular psoriasis.

Methods/design: We will conduct a two-stage, adaptive, double-blind, randomised, placebo-controlled trial to test the hypothesis that anakinra, self-administered daily by subcutaneous injection over 8 weeks, will deliver therapeutic benefit in palmoplantar pustular psoriasis, a localised form of pustular psoriasis typically involving the palms and/or soles. Safety outcomes will be collected for 20 weeks. A total of 64 participants will be randomised to anakinra or placebo in a 1:1 ratio. At the end of stage 1, a decision to progress to stage 2 will be made. This decision will take place after 24 participants have been randomised and followed for 8 weeks and will be based on the ordering of the observed mean outcome values in both treatment arms. At the end of stage 1, the reliability of outcome measurements and method to collect the data will also be assessed, and the primary outcome will be confirmed for stage 2.

Discussion: We have undertaken an adaptive approach in which we will gain proof-of-concept data prior to completing a powered efficacy trial because pustular psoriasis is a rare disease, no validated outcome measures to detect change exist, and limited safety data for anakinra exist in this population. To our knowledge, this will be the first randomised controlled trial that will provide valuable evidence for the efficacy and safety of IL-1 blockade for treatment in pustular psoriasis.

Trial Registration: ISRCTN13127147 . Registered on 1st August 2016. EudraCT, 2015-003600-23 . Registered on 1st April 2016.
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http://dx.doi.org/10.1186/s13063-018-2841-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116430PMC
August 2018

Obesity surgery makes patients healthier and more functional: real world results from the United Kingdom National Bariatric Surgery Registry.

Surg Obes Relat Dis 2018 07 15;14(7):1033-1040. Epub 2018 Feb 15.

Department of Upper GI and Bariatric Surgery, Musgrove Park Hospital, Taunton, United Kingdom.

Background: The National Bariatric Surgery Registry (NBSR) is the largest bespoke database in the field in the United Kingdom.

Objectives: Our aim was to analyze the NBSR to determine whether the effects of obesity surgery on associated co-morbidities observed in small randomized controlled clinical trials could be replicated in a "real life" setting within U.K. healthcare.

Setting: United Kingdom.

Methods: All NBSR entries for operations between 2000 and 2015 with associated demographic and co-morbidity data were analyzed retrospectively.

Results: A total of 50,782 entries were analyzed. The patients were predominantly female (78%) and white European with a mean age of 45 ± 11 years and a mean body mass index of 48 ± 8 kg/m. Over 5 years of follow-up, statistically significant reductions in the prevalence of type 2 diabetes, hypertension, dyslipidemia, sleep apnea, asthma, functional impairment, arthritis, and gastroesophageal reflux disease were observed. The "remission" of these co-morbidities was evident 1 year postoperatively and reached a plateau 2 to 5 years after surgery. Obesity surgery was particularly effective on functional impairment and diabetes, almost doubling the proportion of patients able to climb 3 flights of stairs and halving the proportion of patients with diabetes related hyperglycemia compared with preoperatively. Surgery was safe with a morbidity of 3.1% and in-hospital mortality of .07% and a reduced median inpatient stay of 2 days, despite an increasingly sick patient population.

Conclusions: Obesity surgery in the U.K. results not only in weight loss, but also in substantial improvements in obesity-related co-morbidities. Appropriate support and funding will help improve the quality of the NBSR data set even further, thus enabling its use to inform healthcare policy.
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http://dx.doi.org/10.1016/j.soard.2018.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097875PMC
July 2018

Measuring skin necrosis in a randomised controlled feasibility trial of heat preconditioning on wound healing after reconstructive breast surgery: study protocol and statistical analysis plan for the PREHEAT trial.

Pilot Feasibility Stud 2018 17;4:34. Epub 2018 Jan 17.

1Imperial Clinical Trials Unit, School of Public Health, Imperial College London, London, UK.

Background: Essential strategies are needed to help reduce the number of post-operative complications and associated costs for breast cancer patients undergoing reconstructive breast surgery. Evidence suggests that local heat preconditioning could help improve the provision of this procedure by reducing skin necrosis. Before testing the effectiveness of heat preconditioning in a definitive randomised controlled trial (RCT), we must first establish the best way to measure skin necrosis and estimate the event rate using this definition.

Methods: PREHEAT is a single-blind randomised controlled feasibility trial comparing local heat preconditioning, using a hot water bottle, against standard care on skin necrosis among breast cancer patients undergoing reconstructive breast surgery. The primary objective of this study is to determine the best way to measure skin necrosis and to estimate the event rate using this definition in each trial arm. Secondary feasibility objectives include estimating recruitment and 30 day follow-up retention rates, levels of compliance with the heating protocol, length of stay in hospital and the rates of surgical versus conservative management of skin necrosis. The information from these objectives will inform the design of a larger definitive effectiveness and cost-effectiveness RCT.

Discussion: This article describes the PREHEAT trial protocol and detailed statistical analysis plan, which includes the pre-specified criteria and process for establishing the best way to measure necrosis. This study will provide the evidence needed to establish the best way to measure skin necrosis, to use as the primary outcome in a future RCT to definitively test the effectiveness of local heat preconditioning. The pre-specified statistical analysis plan, developed prior to unblinded data extraction, sets out the analysis strategy and a comparative framework to support a committee evaluation of skin necrosis measurements. It will increase the transparency of the data analysis for the PREHEAT trial.

Trial Registration: ISRCTN ISRCTN15744669. Registered 25 February 2015.
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http://dx.doi.org/10.1186/s40814-017-0223-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773051PMC
January 2018

Perioperative administration of buffered versus non-buffered crystalloid intravenous fluid to improve outcomes following adult surgical procedures.

Cochrane Database Syst Rev 2017 09 21;9:CD004089. Epub 2017 Sep 21.

Centre for Anaesthesia and Perioperative Medicine, University College London, London, UK, NW1 2BU.

Background: Perioperative fluid strategies influence clinical outcomes following major surgery. Many intravenous fluid preparations are based on simple solutions, such as normal saline, that feature an electrolyte composition that differs from that of physiological plasma. Buffered fluids have a theoretical advantage of containing a substrate that acts to maintain the body's acid-base status - typically a bicarbonate or a bicarbonate precursor such as maleate, gluconate, lactate, or acetate. Buffered fluids also provide additional electrolytes, including potassium, magnesium, and calcium, more closely matching the electrolyte balance of plasma. The putative benefits of buffered fluids have been compared with those of non-buffered fluids in the context of clinical studies conducted during the perioperative period. This review was published in 2012, and was updated in 2017.

Objectives: To review effects of perioperative intravenous administration of buffered versus non-buffered fluids for plasma volume expansion or maintenance, or both, on clinical outcomes in adults undergoing all types of surgery.

Search Methods: We electronically searched the Clinicaltrials.gov major trials registry, the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 6) in the Cochrane Library, MEDLINE (1966 to June 2016), Embase (1980 to June 2016), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to June 2016). We handsearched conference abstracts and, when possible, contacted leaders in the field. We reran the search in May 2017. We added one potential new study of interest to the list of 'Studies awaiting classification' and will incorporate this trial into formal review findings when we prepare the review update.

Selection Criteria: Only randomized controlled trials that compared buffered versus non-buffered intravenous fluids for surgical patients were eligible for inclusion. We excluded other forms of comparison such as crystalloids versus colloids and colloids versus different colloids.

Data Collection And Analysis: Two review authors screened references for eligibility, extracted data, and assessed risks of bias. We resolved disagreements by discussion and consensus, in collaboration with a third review author. We contacted trial authors to request additional information when appropriate. We presented pooled estimates for dichotomous outcomes as odds ratios (ORs) and for continuous outcomes as mean differences (MDs), with 95% confidence intervals (CIs). We analysed data via Review Manager 5.3 using fixed-effect models, and when heterogeneity was high (I² > 40%), we used random-effects models.

Main Results: This review includes, in total, 19 publications of 18 randomized controlled trials with a total of 1096 participants. We incorporated five of those 19 studies (330 participants) after the June 2016 update. Outcome measures in the included studies were thematically similar, covering perioperative electrolyte status, renal function, and acid-base status; however, we found significant clinical and statistical heterogeneity among the included studies. We identified variable protocols for fluid administration and total volumes of fluid administered to patients intraoperatively. Trial authors variably reported outcome data at disparate time points and with heterogeneous patient groups. Consequently, many outcome measures are reported in small group sizes, reducing overall confidence in effect size, despite relatively low inherent bias in the included studies. Several studies reported orphan outcome measures. We did not include in the results of this review one large, ongoing study of saline versus Ringer's solution.We found insufficient evidence on effects of fluid therapies on mortality and postoperative organ dysfunction (defined as renal insufficiency leading to renal replacement therapy); confidence intervals were wide and included both clinically relevant benefit and harm: mortality (Peto OR 1.85, 95% CI 0.37 to 9.33; I² = 0%; 3 trials, 6 deaths, 276 participants; low-quality evidence); renal insufficiency (OR 0.82, 95% CI 0.34 to 1.98; I² = 0%; 4 trials, 22 events, 276 participants; low-quality evidence).We noted several metabolic differences, including a difference in postoperative pH measured at end of surgery of 0.05 units - lower in the non-buffered fluid group (12 studies with a total of 720 participants; 95% CI 0.04 to 0.07; I² = 61%). However, this difference was not maintained on postoperative day one. We rated the quality of evidence for this outcome as moderate. We observed a higher postoperative serum chloride level immediately after operation, with use of non-buffered fluids reported in 10 studies with a total of 530 participants (MD 6.77 mmol/L, 95% CI 3.38 to 10.17), and this difference persisted until day one postoperatively (five studies with a total of 258 participants; MD 8.48 mmol/L, 95% CI 1.08 to 15.88). We rated the quality of evidence for this outcome as moderate.

Authors' Conclusions: Current evidence is insufficient to show effects of perioperative administration of buffered versus non-buffered crystalloid fluids on mortality and organ system function in adult patients following surgery. Benefits of buffered fluid were measurable in biochemical terms, particularly a significant reduction in postoperative hyperchloraemia and metabolic acidosis. Small effect sizes for biochemical outcomes and lack of correlated clinical follow-up data mean that robust conclusions on major morbidity and mortality associated with buffered versus non-buffered perioperative fluid choices are still lacking. Larger studies are needed to assess these relevant clinical outcomes.
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http://dx.doi.org/10.1002/14651858.CD004089.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483610PMC
September 2017

The role of anti-IgE (omalizumab/Xolair) in the management of severe recalcitrant paediatric atopic eczema (ADAPT): statistical analysis plan.

Trials 2017 05 23;18(1):231. Epub 2017 May 23.

Imperial Clinical Trials Unit, School of Public Health, Imperial College London, Stadium House, 68 Wood Lane, London, W12 7RH, UK.

Background: The Atopic Dermatitis Anti-IgE Paediatric Trial (ADAPT) is a trial to determine the clinical efficacy and safety of omalizumab for children with severe atopic eczema. This article describes the detailed statistical analysis plan for the ADAPT as an update to the published protocol and is submitted prior to knowing all outcomes.

Method And Design: The ADAPT is a randomised, double-blind, placebo-controlled trial with a primary objective to determine whether anti-IgE reduces eczema severity as assessed by the validated eczema score (objective SCORAD) after 24 weeks of treatment in children with severe eczema. This articles outline the overall analysis principles including considerations on sample definition in each analysis, missing data, and adjusted covariates. Comparability and representativeness of the randomised groups, primary and sensitivity analyses of the primary and secondary outcomes as well as subgroup analysis are described.

Results: This prespecified statistical analysis plan has been developed to comply with international guidelines which will increase the transparency of the data analysis for the ADAPT.

Trial Registration: ISRCTN, identifier: ISRCTN15090567 . Registered on 3 December 2014; EU Clinical Trials Register, EudraCT Number: 2010-020841-29 . Registered on 14 May 2010. The first participant was enrolled on 15 January 2015.
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http://dx.doi.org/10.1186/s13063-017-1976-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442690PMC
May 2017

Associations Between Clinical Evidence of Inflammation and Synovitis in Symptomatic Knee Osteoarthritis: A Cross-Sectional Substudy.

Arthritis Care Res (Hoboken) 2017 09 14;69(9):1340-1348. Epub 2017 Aug 14.

University of Oxford, Oxford, UK, and University of Southampton, Southampton, UK.

Objective: Painful knee osteoarthritis (KOA) has been associated with joint inflammation. There is, however, little literature correlating signs of localized inflammation with contrast-enhanced (CE) magnetic resonance imaging (MRI) of synovium. This study examined the relationship between clinical and functional markers of localized knee inflammation and CE MRI-based synovial scores.

Methods: Patients with symptomatic KOA were enrolled into the randomized, double-blind, Vitamin D Evaluation in Osteoarthritis (VIDEO) trial. In this cross-sectional substudy, associations between validated MRI-based semiquantitative synovial scores of the knee and the following markers of inflammation were investigated: self-reported pain and stiffness, effusion, warmth, joint line tenderness, erythrocyte sedimentation rate, radiographic severity, and functional ability tests.

Results: A total of 107 patients satisfied the inclusion criteria of complete data and were included in the analysis. Significant associations were found between the number of regions affected by synovitis and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, effusion, and joint line tenderness. Each additional region affected by synovitis was associated with an increase in WOMAC pain (1.82 [95% confidence interval (95% CI) 0.05, 3.58], P = 0.04), and the association with extent of medial synovitis was particularly strong (3.21 [95% CI 0.43, 5.99], P = 0.02). Extent of synovitis was positively associated with effusion (odds ratio 1.69 [95% CI 1.37, 2.08], P < 0.01) and negatively associated with joint line tenderness (relative risk 0.87 [95% CI 0.84, 0.90], P < 0.01).

Conclusion: There is a strong positive association between synovitis and self-reported patient pain and clinically detectable effusion. Nonoperative treatments directed at management of inflammation and future trials targeting the synovial tissue for treating KOA should consider these 2 factors as potential inclusion criteria.
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September 2017