Lynn Murphy

Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial: study protocol for a randomized controlled trial

BackgroundAcute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI.Methods/DesignPatients fulfilling the American-European Consensus Conference Definition of ALI will be randomized in a 1:1 ratio to receive enteral simvastatin 80 mg or placebo once daily for a maximum of 28 days. Allocation to randomized groups will be stratified with respect to hospital of recruitment and vasopressor requirement. Data will be recorded by participating ICUs until hospital discharge, and surviving patients will be followed up by post at 3, 6 and 12 months post randomization. The primary outcome is number of ventilator-free days to day 28. Secondary outcomes are: change in oxygenation index and sequential organ failure assessment score up to day 28, number of non pulmonary organ failure free days to day 28, critical care unit mortality; hospital mortality; 28 day post randomization mortality and 12 month post randomization mortality; health related quality of life at discharge, 3, 6 and 12 months post randomization; length of critical care unit and hospital stay; health service use up to 12 months post-randomization; and safety. A total of 540 patients will be recruited from approximately 35 ICUs in the UK and Ireland. An economic evaluation will be conducted alongside the trial. Plasma and urine samples will be taken up to day 28 to investigate potential mechanisms by which simvastatin might act to improve clinical outcomes.Trial registrationCurrent Controlled Trials ISRCTN88244364.

Evaluating early administration of the hydroxymethylglutaryl-CoA reductase inhibitor simvastatin in the prevention and treatment of delirium in critically ill ventilated patients (MoDUS trial): study protocol for a randomized controlled trial

BackgroundThe incidence of delirium in ventilated patients is estimated at up to 82%, and it is associated with longer intensive care and hospital stays, and long-term cognitive impairment and mortality. The pathophysiology of delirium has been linked with inflammation and neuronal apoptosis. Simvastatin has pleiotropic properties; it penetrates the brain and, as well as reducing cholesterol, reduces inflammation when used at clinically relevant doses over the short term. This is a single centre randomised, controlled trial which aims to test the hypothesis that treatment with simvastatin will modify delirium incidence and outcomes.Methods/DesignThe ongoing study will include 142 adults admitted to the Watford General Hospital Intensive Care Unit who require mechanical ventilation in the first 72 hours of admission. The primary outcome is the number of delirium- and coma-free days in the first 14 days. Secondary outcomes include incidence of delirium, delirium- and coma-free days in the first 28 days, days in delirium and in coma at 14 and 28 days, number of ventilator-free days at 28 days, length of critical care and hospital stay, mortality, cognitive decline and healthcare resource use. Informed consent will be taken from patient’s consultee before randomisation to receive either simvastatin (80 mg) or placebo once daily. Daily data will be recorded until day 28 after randomisation or until discharge from the ICU if sooner. Surviving patients will be followed up on at six months from discharge. Plasma and urine samples will be taken to investigate the biological effect of simvastatin on systemic markers of inflammation, as related to the number of delirium- and coma-free days, and the potential of cholinesterase activity and beta-amyloid as predictors of the risk of delirium and long-term cognitive impairment.DiscussionThis trial will test the efficacy of simvastatin on reducing delirium in the critically ill. If patients receiving the statin show a reduced number of days in delirium compared with the placebo group, the inflammatory theory implicated in the pathogenesis of delirium will be strengthened.Trial registrationThe trial was registered with the International Standard Randomised Controlled Trial Registry (ISRCTN89079989) on 26 March 2013.

Evaluation of early administration of simvastatin in the prevention and treatment of delirium in critically ill patients undergoing mechanical ventilation (MoDUS): a randomised, double-blind, placebo-controlled trial

BACKGROUND Delirium in critically ill patients is associated with poor clinical outcomes. Neuroinflammation might be an important mechanism in the pathogenesis of delirium, and since simvastatin has anti-inflammatory properties it might reduce delirium. We aimed to establish whether early treatment with simvastatin would decrease the time that survivors of critical illness spent in delirium or coma. METHODS We undertook this randomised, double-blind, placebo-controlled trial in a general adult intensive care unit (ICU) in Watford General Hospital (Watford, UK). We enrolled critically ill patients (≥18 years) needing mechanical ventilation within 72 h of admission. We randomly assigned patients (1:1 ratio) to receive either simvastatin 80 mg or placebo daily for up to a maximum of 28 days, irrespective of coma or delirium status. We assessed delirium using the Confusion Assessment Method for the ICU (CAM-ICU). The primary outcome was number of days alive and was assessed as delirium-free and coma-free in the first 14 days after being randomly allocated to receive treatment or placebo. ICU clinical and research staff and patients were masked to treatment. We did intention-to-treat analyses with no extrapolation. This trial is registered with the International Standard Randomised Controlled Trial Registry, number ISRCTN89079989. FINDINGS Between Feb 1, 2013, and July 29, 2016, 142 patients were randomly assigned to receive simvastatin (n=71) or placebo (n=71), and were included in the final analysis. The mean number of days alive without delirium and without coma at day 14 did not differ significantly between the two groups (5·7 days [SD 5·1] with simvastatin and 6·1 days [5·2] with placebo; mean difference 0·4 days, 95% CI -1·3 to 2·1; p=0·66). The most common adverse event was an elevated creatine kinase concentration to more than ten times the upper limit of normal (eight [11%] in the simvastatin group vs three [4%] in the placebo group p=0·208). No patient had a serious adverse event related to the study drug. INTERPRETATION These results do not support the hypothesis that simvastatin modifies duration of delirium and coma in critically ill patients. FUNDING National Institute for Health Research.

A randomised controlled trial to measure the effects and costs of a dental caries prevention regime for young children attending primary care dental services: the Northern Ireland Caries Prevention In Practice (NIC-PIP) trial.

BACKGROUND Dental caries is the most common disease of childhood. The NHS guidelines promote preventative care in dental practices, particularly for young children. However, the cost-effectiveness of this policy has not been established. OBJECTIVE To measure the effects and costs of a composite fluoride intervention designed to prevent caries in young children attending dental services. DESIGN The study was a two-arm, parallel-group, randomised controlled trial, with an allocation ratio of 1 : 1. Randomisation was by clinical trials unit, using randomised permuted blocks. Children/families were not blinded; however, outcome assessment was blinded to group assessment. SETTING The study took place in 22 NHS dental practices in Northern Ireland, UK. PARTICIPANTS The study participants were children aged 2-3 years, who were caries free at baseline. INTERVENTIONS The intervention was composite in nature, comprising a varnish containing 22,600 parts per million (p.p.m.) fluoride, a toothbrush and a 50-ml tube of toothpaste containing 1450 p.p.m. fluoride; plus standardised, evidence-based prevention advice provided at 6-monthly intervals over 3 years. The control group received the prevention advice alone. MAIN OUTCOME MEASURES The primary outcome measure was conversion from caries-free to caries-active states. Secondary outcome measures were the number of decayed, missing or filled tooth surfaces in primary dentition (dmfs) in caries-active children, the number of episodes of pain, the number of extracted teeth and the costs of care. Adverse reactions (ARs) were recorded. RESULTS A total of 1248 children (624 randomised to each group) were recruited and 1096 (549 in the intervention group and 547 in the control group) were included in the final analyses. A total of 87% of the intervention children and 85% of control children attended every 6-month visit (p = 0.77). In total, 187 (34%) children in the intervention group converted to caries active, compared with 213 (39%) in the control group [odds ratio (OR) 0.81, 95% confidence interval (CI) 0.64 to 1.04; p = 0.11]. The mean number of tooth surfaces affected by caries was 7.2 in the intervention group, compared with 9.6 in the control group (p = 0.007). There was no significant difference in the number of episodes of pain between groups (p = 0.81). However, 164 out of the total of 400 (41%) children who converted to caries active reported toothache, compared with 62 out of 696 (9%) caries-free children (OR 7.1 95% CI 5.1 to 9.9; p < 0.001). There was no statistically significant difference in the number of teeth extracted in caries-active children (p = 0.95). Ten children in the intervention group had ARs of a minor nature. The average direct dental care cost was £155.74 for the intervention group and £48.21 for the control group over 3 years (p < 0.05). The mean cost per carious surface avoided over the 3 years was estimated at £251.00. LIMITATIONS The usual limitations of a trial such as generalisability and understanding the underlying reasons for the outcomes apply. There is no mean willingness-to-pay threshold available to enable assessment of value for money. CONCLUSIONS A statistically significant effect could not be demonstrated for the primary outcome. Once caries develop, pain is likely. There was a statistically significant difference in dmfs in caries-active children in favour of the intervention. Although adequately powered, the effect size of the intervention was small and of questionable clinical and economic benefit. FUTURE WORK Future work should assess the caries prevention effects of interventions to reduce sugar consumption at the population and individual levels. Interventions designed to arrest the disease once it is established need to be developed and tested in practice. TRIAL REGISTRATION Current Controlled Trials ISRCTN36180119 and EudraCT 2009-010725-39. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 71. See the NIHR Journals Library website for further project information.

A Randomized Controlled Trial of Caries Prevention in Dental Practice

We conducted a parallel group randomized controlled trial of children initially aged 2 to 3 y who were caries free, to prevent the children becoming caries active over the subsequent 36 mo. The setting was 22 dental practices in Northern Ireland, and children were randomly assigned by a clinical trials unit (CTU) (using computer-generated random numbers, with allocation concealed from the dental practice until each child was recruited) to the intervention (22,600-ppm fluoride varnish, toothbrush, 50-mL tube of 1,450 ppm fluoride toothpaste, and standardized, evidence-based prevention advice) or advice-only control at 6-monthly intervals. The primary outcome measure was conversion from caries-free to caries-active states. Secondary outcome measures were number of decayed, missing, or filled teeth (dmfs) in caries-active children, number of episodes of pain, and number of extracted teeth. Adverse reactions were recorded. Calibrated external examiners, blinded to the child’s study group, assessed the status of the children at baseline and after 3 y. In total, 1,248 children (624 randomized to each group) were recruited, and 1,096 (549 intervention, 547 control) were included in the final analyses. Eighty-seven percent of intervention and 86% of control children attended every 6-mo visit (P = 0.77). A total of 187 (34%) in the intervention group converted to caries active compared to 213 (39%) in the control group (odds ratio, 0.81; 95% confidence interval, 0.64–1.04; P = 0.11). Mean dmfs of those with caries in the intervention group was 7.2 compared to 9.6 in the control group (P = 0.007). There was no significant difference in the number of episodes of pain between groups (P = 0.81) or in the number of teeth extracted in caries-active children (P = 0.95). Ten children in the intervention group had adverse reactions of a minor nature. This well-conducted trial failed to demonstrate that the intervention kept children caries free, but there was evidence that once children get caries, it slowed down its progression (EudraCT No: 2009-010725-39; ISRCTN: ISRCTN36180119).

Cost-Effectiveness of Caries Prevention in Practice: A Randomized Controlled Trial

A 2-arm parallel-group randomized controlled trial measured the cost-effectiveness of caries prevention in caries-free children aged 2 to 3 y attending general practice. The setting was 22 dental practices in Northern Ireland. Participants were centrally randomized into intervention (22,600 ppm fluoride varnish, toothbrush, a 50-mL tube of 1,450 ppm fluoride toothpaste, and standardized prevention advice) and control (advice only), both provided at 6-monthly intervals during a 3-y follow-up. The primary outcome measure was conversion from caries-free to caries-active states assessed by calibrated and blinded examiners; secondary outcome measures included decayed, missing, or filled teeth surfaces (dmfs); pain; and extraction. Cumulative costs were related to each of the trial’s outcomes in a series of incremental cost effectiveness ratios (ICERs). Sensitivity analyses examined the impact of using dentist’s time as measured by observation rather than that reported by the dentist. The costs of applying topical fluoride were also estimated assuming the work was undertaken by dental nurses or hygienists rather than dentists. A total of 1,248 children (624 randomized to each group) were recruited, and 1,096 (549 in the intervention group and 547 in the control group) were included in the final analyses. The mean difference in direct health care costs between groups was £107.53 (£155.74 intervention, £48.21 control, P < 0.05) per child. When all health care costs were compared, the intervention group’s mean cost was £212.56 more than the control group (£987.53 intervention, £774.97 control, P < 0.05). Statistically significant differences in outcomes were only detected with respect to carious surfaces. The mean cost per carious surface avoided was estimated at £251 (95% confidence interval, £454.39–£79.52). Sensitivity analyses did not materially affect the study’s findings. This trial raises concerns about the cost-effectiveness of a fluoride-based intervention delivered at the practice level in the context of a state-funded dental service (EudraCT No: 2009-010725-39; ISRCTN: ISRCTN36180119).

Steps Towards Alcohol Misuse Prevention Programme (STAMPP): a school-based and community-based cluster randomised controlled trial

Objectives To assess the effectiveness of a combined classroom curriculum and parental intervention (the Steps Towards Alcohol Misuse Prevention Programme (STAMPP)), compared with alcohol education as normal (EAN), in reducing self-reported heavy episodic drinking (HED) and alcohol-related harms (ARHs) in adolescents. Setting 105 high schools in Northern Ireland (NI) and in Scotland. Participants Schools were stratified by free school meal provision. Schools in NI were also stratified by school type (male/female/coeducational). Eligible students were in school year 8/S1 (aged 11–12 years) at baseline (June 2012). Intervention A classroom-based alcohol education intervention, coupled with a brief alcohol intervention for parents/carers. Primary outcomes (1) The prevalence of self-reported HED in the previous 30 days and (2) the number of self-reported ARHs in the previous 6 months. Outcomes were assessed using two-level random intercepts models (logistic regression for HED and negative binomial for number of ARHs). Results At 33 months, data were available for 5160 intervention and 5073 control students (HED outcome), and 5234 and 5146 students (ARH outcome), respectively. Of those who completed a questionnaire at either baseline or 12 months (n=12 738), 10 405 also completed the questionnaire at 33 months (81.7%). Fewer students in the intervention group reported HED compared with EAN (17%vs26%; OR=0.60, 95% CI 0.49 to 0.73), with no significant difference in the number of self-reported ARHs (incident rate ratio=0.92, 95% CI 0.78 to 1.05). Although the classroom component was largely delivered as intended, there was low uptake of the parental component. There were no reported adverse effects. Conclusions Results suggest that STAMPP could be an effective programme to reduce HED prevalence. While there was no significant reduction in ARH, it is plausible that effects on harms would manifest later. Trial registration number ISRCTN47028486; Post-results.