Levetiracetam as an alternative to phenytoin for second-line emergency treatment of children with convulsive status epilepticus: the EcLiPSE RCT

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 12/127/134. The contractual start date was in June 2014. The draft report began editorial review in November 2019 and was accepted for publication in July 2020. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Disclaimer

This report contains transcripts of interviews conducted in the course of the research and contains language that may offend some readers.

Copyright statement

© Queen’s Printer and Controller of HMSO 2020. This work was produced by Appleton et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2020 Queen’s Printer and Controller of HMSO

Scientific background

Convulsive status epilepticus (CSE) is the most common life-threatening neurological emergency in children, with an incidence of 20 per 100,000 children per year. 4,5 It is the second most common reason for unplanned admission to paediatric intensive care units (PICUs) in the UK, accounting for 5.6% of all PICU admissions. 6 Mortality is low, but morbidity, including neurodisability, learning difficulties and de novo and drug-resistant epilepsy, may be as high as 22%. 7–10 Predictably, these may result in major long-term demands on acute and chronic health and social care resources. 4 The longer the duration of CSE, the more difficult it is to terminate and the greater the morbidity risk. 4,9,10

The current UK emergency care pathway for the management of childhood CSE is the stepwise algorithm that is advocated in advanced paediatric life support (APLS) guidance. 11 First-line treatment is two doses of a benzodiazepine given 10 minutes apart. A second-line anticonvulsant is administered if the child continues to fit 10 minutes after the second dose of benzodiazepine. APLS guidance recommends phenytoin (Epanutin, Pfizer Inc., New York, NY, USA) as the first-choice second-line anticonvulsant. Phenobarbital (AAH Pharmaceuticals, Coventry, UK) is recommended if the child is allergic to phenytoin, has previously not responded to it or has experienced a serious adverse event (SAE). Failure to stop CSE necessitates rapid sequence induction (RSI), intubation and admission to PICU, with consequent potential for iatrogenic consequences, including pneumonia, hospital-acquired infections and prolonged admission.

There is reasonable randomised controlled trial (RCT) evidence to support the use of benzodiazepines as first-line anticonvulsants,12 but there is a dearth of evidence for second-line drug treatment and no high-quality RCT evidence to support any second-line treatment. 13 There is an absence of randomised evidence to support the use of phenytoin as the second-line anticonvulsant, despite its use as a standard intravenous (i.v.) anticonvulsant for the treatment of CSE since the 1940s. A retrospective case note review, in which 87% (331/381) of children administered a second-line anticonvulsant received phenytoin, reported seizure cessation in 190 cases (50%). 14 There is considerably more literature on phenytoin’s potential adverse effects, including potentially fatal cardiac arrhythmias and Stevens–Johnson syndrome (Tables 1 and 2). 15–18 The risk of a cardiac arrhythmia is related to the rate of infusion and, therefore, phenytoin must be infused over a period of at least 20 minutes. 18

Levetiracetam (Keppra, UCB Pharma, Brussels, Belgium) is a broad-spectrum anticonvulsant that effectively treats focal and generalised tonic–clonic and myoclonic seizures. A growing body of evidence, predominantly, but not exclusively, anecdotal, suggests that i.v. levetiracetam is safe and effective in the treatment of acute repetitive seizures and both CSE and non-CSE, with reported seizure cessation rates between 76% and 100%. 19–27 There is limited evidence that i.v. levetiracetam may also be as effective as i.v. lorazepam (Ativan, Pfizer Inc.), which is the current first-choice first-line anticonvulsant in the treatment of CSE. Levetiracetam and lorazepam administered intravenously to 79 patients (the majority of whom were adults) were equally effective in terminating CSE {levetiracetam terminated CSE in 76.3% of patients and lorazepam in 75.6% of patients [relative risk 0.97, 95% confidence interval (CI) 0.44 to 2.13]}. 28 A systematic review of levetiracetam published in 201229 indicated that efficacy ranged from 44% to 94%, with reported higher rates in retrospective studies. Two RCTs, published in 2015, involving predominantly adults, directly compared i.v. levetiracetam with either i.v. phenytoin30 or i.v. phenytoin plus i.v. sodium valproate (Epilim, Sanofi, Paris, France)31 and showed no difference between the comparators. Chakravarthi et al. 30 reported on 44 patients who presented with ‘consecutive status’ and were randomised to treatment with phenytoin (20 mg/kg) or levetiracetam (20 mg/kg). Both drugs showed a similar efficacy in status termination within 30 minutes of commencement of drug infusion. Phenytoin achieved control in 15 out of 22 (68.2%) patients and levetiracetam in 13 out of 22 (59.1%) patients (p = 0.53). 30 In the study reported by Mundlamuri et al. ,31 the presenting seizure was controlled with lorazepam plus phenytoin infusion in 34 out of 50 (68%) patients, lorazepam plus valproate infusion in 34 out of 50 (68%) patients and with lorazepam plus levetiracetam infusion in 39 out of 50 (78%) patients. There was no statistically significant difference between the subgroups (p = 0.44). 31 Reported i.v. levetiracetam doses range from 20 to 60 mg/kg. Chakravarthi et al. 30 and Mundlamuri et al. 31 used doses of 20 mg/kg and 25 mg/kg, respectively. Adverse reactions (ARs) with levetiracetam seem to be infrequent and mild, even at high doses. These include dizziness, somnolence, headache and transient agitation, but there have been no reports of cardiac arrhythmias, hypotension, tissue extravasation reactions, Stevens–Johnson syndrome or hepatotoxicity. 32–34 Levetiracetam can be infused over 5–10 minutes, which suggests that, theoretically, CSE may be terminated more rapidly than with phenytoin. Consequently, a reasonable hypothesis is that levetiracetam may be more effective and safer than i.v. phenytoin in terminating CSE. 13,35,36

Convulsive status epilepticus management was identified as a key priority area for research by a number of sources, including the Paediatric Emergency Research in the UK and Ireland (PERUKI)37,38 in its inaugural prioritisation exercise,38 and the National Institute for Health and Care Excellence in its update of national epilepsy guidelines published in January 2012. 39 A high-quality RCT is, therefore, essential to determine whether phenytoin or levetiracetam is the better drug in managing CSE, as highlighted in a recent systematic review. 13 A meta-analysis published in 2014 concluded with the following statement:

The evidence does not support the first-line use of phenytoin. There is not enough evidence to support the routine use of lacosamide. Randomized controlled trials are urgently needed. 36

One RCT has recently been completed that evaluated the efficacy and safety of i.v. levetiracetam and phenytoin in the management of CSE in children aged 3 months to 16 years. 40,41 A second RCT recently evaluated i.v. fosphenytoin, levetiracetam and sodium valproate in the management of CSE in children (aged > 2 years) and adults. 42

The Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in children (EcLiPSE) trial was a Phase IV, multicentre, parallel-group, randomised controlled open-label superiority trial comparing i.v. levetiracetam with i.v. phenytoin.

Rationale for research

Convulsive status epilepticus is the most common life-threatening neurological emergency in childhood. It can result in significant morbidity, with acute and chronic impacts on the family and health and social care systems. The current recommended first-choice second-line treatment in children aged ≥ 6 months is i.v. phenytoin (fosphenytoin, which is a pro-drug of phenytoin in the USA). However, this is not based on any robust RCT evidence and the drug is associated with significant and potentially serious adverse reactions (SARs). Emerging evidence suggests that i.v. levetiracetam may be effective as a second-line agent for CSE, and fewer ARs have been described. This trial was designed to determine whether i.v. phenytoin or i.v. levetiracetam is the more effective and safer drug in the treatment of childhood CSE.

Intervention

The EcLiPSE trial was an open-label trial using investigational medicinal products (IMPs) with marketing authorisation in the UK. These became IMPs only when the packaging was opened in the setting of this study. IMP provision was the responsibility of each site in accordance with standard clinical practice. Both IMPs were stored in line with local requirements for general medicine supplies.

A single dose of the randomly allocated treatment was administered by i.v. infusion. The levetiracetam dose was 40 mg/kg (with a maximum dose of 2500 mg) over 5 minutes, diluted to a maximum of 50 mg/ml with 0.9% sodium chloride. The dose of 40 mg/kg was based on the available published data at the time of the full study application to the Health Technology Assessment programme in 2013. The phenytoin dose was 20 mg/kg (with a maximum dose of 2000 mg) at a rate not exceeding 1 mg/kg/minute (or > 20 minutes for doses of > 1 g), diluted with 0.9% sodium chloride to a maximum concentration of 10 mg/ml. This dose was based on national guidelines available in 2013. 11

The allocated treatment was prepared and administered in accordance with standard clinical care, with independent checking performed by two trained personnel. Trial-specific labelling was not required, rather an approved ‘i.v. additive label’ was used. If the randomised treatment was discontinued prior to administration of the full dose this was recorded. If CSE persisted at the end of the IMP infusion, further medical management was decided by the local clinical team independent of the trial protocol (Figure 1).

FIGURE 1.

Study design. a, Administration of the first-line treatment may have occurred prior to arrival in the ED. b, If a patient was randomised but not treated with a second-line anticonvulsant, follow-up would end at this point. ED, emergency department.

Objectives

The study objectives were to determine:

1. whether i.v. phenytoin or i.v. levetiracetam is the more efficacious second-line anticonvulsant for the emergency management of CSE in children

2. whether or not i.v. levetiracetam is associated with fewer ARs or adverse events (AEs) than i.v. phenytoin

3. the potential barriers and solutions to recruitment and consent in the EcLiPSE trial to inform future trials with regard to recruiter training and trial conduct in this clinical setting (i.e. a nested consent study).

Trial registration and ethics

The trial was approved by the National Research Ethics Service Committee North West – Liverpool Central on 3 March 2016 (reference 15/NW/0090). The trial is registered as ISRCTN22567894 (registered 27 August 2015) and EudraCT identifier 2014-002188-13 (registered on 21 May 2014).

Participant inclusion and exclusion criteria

The full study protocol was published in 2017. 2

Recruitment

Thirty EDs (‘sites’) throughout Great Britain and Northern Ireland participated in the study. The sites were selected from the membership of PERUKI [a collaborative paediatric emergency medicine (PEM) research network]. 37 Participating sites included tertiary or district general hospitals with EDs that treat children only, or children and adults. A full list of participating centres is included in Appendix 3. Centres were selected based on factors such as membership of PERUKI, site research infrastructure, projected number of recruits based on the local population and proposed training strategy.

Screening commenced once a child arrived in the ED and received their first-line treatment for CSE. A unique participant screening form was used and included an eligibility assessment and reasons for non-randomisation where appropriate. If eligible, the participant was randomised to the trial.

Informed consent

The trial used research without prior consent (RWPC), also known as ‘deferred consent’, because of the time-critical management of CSE, in accordance with regulatory requirements, RWPC guidance and pre-trial research. 43,44 Parents/legal representatives/patients (hereafter termed ‘participants’) were approached once the child’s clinical condition was stable. This was ideally within 24 hours of randomisation and prior to discharge from hospital, at which point written informed consent was sought to continue data collection and use data already collected.

If consent was not sought prior to discharge the participant would be contacted within 5 working days of randomisation by a delegated member of the research team and informed of the participant’s involvement and details of the trial. Written information and a consent form were posted to the family. The covering letter asked participants to return the enclosed form, indicating their consent for use of the data already collected and continued participation in trial follow-up, within 4 weeks of the date of the letter. If no response was received within 4 weeks, the covering letter verified that the participant was included within the trial.

If the participant died before consent was sought, the site research team obtained information from colleagues and bereavement counsellors to establish the most appropriate time and the most appropriate practitioner to notify the parents/legal representative of their child’s involvement in the research study.

When it was considered inappropriate to seek consent prior to the parent/legal representative’s departure from hospital, the parent/legal representative was notified by a personalised letter and written information about the trial from the most appropriate practitioner 4 weeks after randomisation. Wherever possible, this practitioner would already be known to the family. The letter explained the EcLiPSE trial, reasons for deferred consent, how to opt in or out of the trial and provided contact details if parents wished to discuss the trial with a member of the research team (either in person or by telephone).

A second letter was sent to the bereaved family if there had been no response within 4 weeks of the initial letter. The second letter included information about the EcLiPSE trial, reasons for deferred consent and how to opt in or out of the trial. It also provided contact details if parents wished to discuss the EcLiPSE trial with a member of the research team, either in person or by telephone. Finally, it informed the family that the participant’s data would be included in the trial if no consent form was returned within 4 weeks of the letter being sent, unless the family first notified the site team.

Finally, there was also a qualitative mixed-method study involving participants to explore approaches to recruitment and deferred consent. This is outlined in Chapter 4.

Randomisation

Participants were randomised to levetiracetam or phenytoin in a ratio of 1 : 1 using random variable block sizes of two and four. A computer-generated randomisation schedule was produced by an independent statistician who had no further involvement in the trial. Randomisation was stratified by centre for logistical purposes. Centres were provided with sequentially numbered and EcLiPSE trial-labelled randomisation packs. These were stored in an appropriate secure location within the ED for ready access on presentation of eligible patients.

Randomisation packs were opaque brown cardboard tamper-proof A4 envelopes. The construction was resistant to accidental damage or tampering and contents could not be viewed without fully opening the envelope. Each pack was sequentially numbered and during randomisation the clinician/nurse used the next sequentially numbered pack.

The case report form (CRF) that was completed at the patient’s bedside while the patient was in the ED was included in the randomisation pack. The CRF was prepopulated with the centre code, participant randomisation number and the randomly allocated treatment.

The randomisation pack should have been opened only once eligibility was confirmed on the screening form. However, because of the time required to prepare the randomised treatment for infusion, this was undertaken prior to when the infusion was required to avoid trial participation creating a delay in treatment. This meant that some randomised participants would experience seizure cessation while the infusion was being prepared.

Once randomised, the patient was administered the randomly allocated treatment, as required clinically, to terminate seizure activity.

If the participant was randomised but the seizure terminated prior to infusion of the randomly allocated treatment, the patient could subsequently be treated with the randomised treatment allocation if the patient’s seizure restarted while still in the ED. However, if the patient’s seizure restarted after leaving the ED, the randomised treatment could not be given.

If the randomised treatment was not administered while the patient was in the ED and instead the comparator second-line was administered in error, the participant was still considered as recruited and the randomisation number applied. The treatment administered was recorded, along with reasons why it had not been possible to treat as per allocation.

If the patient had been given a RSI prior to administration of any second-line treatment the decision to administer a second-line treatment was outside the EcLiPSE trial and the patient was treated as per the site’s routine care.

Blinding

It was not possible to blind the trial interventions in the EcLiPSE trial because of the different times required for their infusion. Although a double-dummy approach was considered, this would have increased complexity during a paediatric emergency situation. Therefore, this was an open-label study.

Outcome measures

Data collection

Sample size

The sample size was calculated on the basis of published seizure cessation rates for phenytoin (50–60%)14 and levetiracetam (76–100%). 19–27 A sample size of 140 randomised and consented participants per group, with a total of 183 events of CSE cessation, was required for a 0.05-level two-sided log-rank test for equality of survival curves to detect an increase in seizure cessation rates from 60% to 75% [a constant hazard ratio (HR) of 0.661] at 80% power. The sample size was increased to 308 participants to allow for 10% loss to follow-up, which proved unnecessary. The final sample size was 286 participants and the Independent Data and Safety and Monitoring Committee (IDSMC) and Trial Steering Committee (TSC) were consulted before the decision to stop recruitment because of low attrition and completeness of data. The difference to detect was influenced by the size of difference deemed to be clinically important and convincing to change clinical practice. Although smaller differences could also have been considered important, they needed to be balanced against the costs of the medicinal products and the experience of delivering them within emergency care setting.

Trial management and oversight

Internal pilot

The EcLiPSE trial included an 18-month internal pilot and involved five centres.

The 18-month period was chosen to allow five centres to be opened, be fully up to speed with trial procedures and be achieving the optimal recruitment rate (assumed to be achieved 3 months after opening). This time frame also allowed each site a minimum of 6 months of active recruitment at the optimal level to demonstrate their recruitment rates and support prediction of trial activity into the main phase of the trial.

Success criteria of the pilot were based on the below.

Statistical methods

A detailed statistical analysis plan is available online [see NIHR Journals Library project web page URL: www.journalslibrary.nihr.ac.uk/programmes/hta/12127134/# (accessed 25 September 2020)]. All analyses were undertaken with SAS^® software, version 9.4 (SAS Institute Inc., Cary, NC, USA).

The primary analysis was based on a modified intention-to-treat principle. All randomised and consented participants who received a second-line treatment were included in the analysis according to their allocated treatment. Children who were randomised but whose CSE stopped without requiring second-line treatment (and did not restart in the ED) were excluded. The safety analysis included the same participants, grouped according to the actual treatment received. To avoid double counting, SAEs were reported separately from AEs.

Statistical tests were two-sided at a 5% significance level and results are presented with 95% CIs. The primary outcome was analysed using the log-rank test and is presented as a Kaplan–Meier curve. All participants were followed up to cessation of CSE, with censoring used in the event of RSI or death. If RSI was administered, time was censored at RSI plus 12 hours (i.e. 720 minutes). In patients who died before cessation of CSE, time was censored at the time of death plus 48 hours (i.e. 2880 minutes). RSI and death represent informative censoring and, therefore, the censoring times were inflated to signify the negative outcome for the child with further sensitivity analyses. The sensitivity analyses considered the robustness of the results to the primary analysis approach and included Gray’s test, treating RSI as a competing risk, calculating time to cessation of CSE from start of infusion instead of randomisation and censoring participants at the time of an additional second-line treatment after no response to the allocated treatment. Additional analysis using a Cox proportional hazards model adjusted for baseline characteristics of weight (i.e. < 12 kg, 12–36 kg or > 36 kg), sex and whether or not this was the child’s first seizure. Two covariates (i.e. site of infusion and additional anticonvulsants given in parallel) specified in the analysis plan were not included because they were measured after randomisation. Additionally, centre (i.e. the site) could not be included as a factor in the Cox model because of the lack of convergence. Schoenfeld residual plots were used to check the assumption of proportionality. The binary secondary outcomes of need for further anticonvulsants, RSI and admission to critical care were analysed using the chi-square test and presented with relative risks. Logistic regression models were fitted as additional analyses to the primary chi-square tests, with adjustments as per the Cox proportional hazards model. No adjustment was made for multiplicity for the secondary outcomes. Baseline categorical data and AE data are summarised using numbers and percentages, and continuous data are summarised as medians and interquartile ranges (IQRs). A post hoc analysis was undertaken for the reasons underlying the further management of the presenting episode of CSE, the assessment of which was carried out without knowledge of the allocated intervention.

Role of the funding source

The trial funder monitored trial progress and approved oversight committee membership, but had no role in trial design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all data in the trial.

Changes to the protocol

The EcLiPSE trial opened to recruitment on version 3.0 of the protocol and closed on version 5.0. Changes to the protocol are summarised in Appendix 4. In summary, the key changes from version 1.0 to version 2.0 included increasing the follow-up period to 14 days to collect longer-term safety data, adding information that the primary outcome would be calculated from the time of randomisation and providing additional clarifications on eligibility criteria. Amendments between subsequent versions included clarification on dose, safety reporting, questionnaire administration and consent process.

Recruitment

Participants were recruited from a total of 30 sites, all EDs. Although 30 sites were formally opened, two subsequently closed with neither site having recruited any participants. The first participant was recruited from Alder Hey Children’s Hospital, Liverpool, on 22 July 2015 under version 3.0 of the protocol and the last participant was recruited from Southampton General Hospital, Southampton, on 7 April 2018 under version 5.0 of the protocol.

The five top-recruiting sites recruited 124 out of the 286 (43.4%) participants.

The observed site opening and participant recruitment rates closely followed those predicted (Figure 2).

FIGURE 2.

Recruitment graph.

Study commencement was delayed by approximately 6 weeks because of contractual issues between the two co-sponsors of the study and, therefore, recruitment closed 6 weeks later than planned, on 10 April 2018.

Participant screening and throughput are summarised in Figure 3.

FIGURE 3.

Consolidated Standards of Reporting Trials (CONSORT) flow diagram. ITT, intention to treat.

Of the 1432 children screened for eligibility, 404 were randomised (i.e. the randomisation pack was opened). A total of 1028 children were excluded before randomisation, including 972 children who did not meet the eligibility criteria (see Tables 1 and 2). Reasons for not randomising 53 children who were considered eligible included no trial-trained doctor available, loss of, or failure to, achieve i.v. access, clinical judgement (e.g. child too sick) and treatment given before random allocation.

Inclusion criterion 2 (see Table 1) combined seizure type with the need for second-line treatment. Table 2 looks at this inclusion criteria in greater detail to distinguish eligibility owing to seizure type and ongoing need for second-line treatment.

Of the 404 children randomised, 93 did not require a second-line treatment. Of those children randomised who did require a second-line treatment, 25 were excluded from the analysis as consent was either incompletely documented (n = 6) or declined (n = 19). Table 3 provides the reasons why consent was declined.

Compliance with the intervention

Data on compliance (adherence) with treatment are shown in Tables 4 and 5.

Baseline characteristics

The baseline characteristics of the study participants were comparable (Table 6). However, the levetiracetam-treated group comprised more participants in whom the presenting episode of CSE [n = 69 (45%) vs. n = 49 (37%)] represented their first convulsive seizure ever, with a lower proportion of participants with a chronic epilepsy, as evidenced by participants taking oral maintenance antiepileptic drugs [n = 51 (34%) vs. n = 55 (41%)].

Primary outcome

Seizure cessation was achieved in 106 out of the 152 (70%) levetiracetam-treated participants and in 86 out of the 134 (64%) phenytoin-treated participants.

Table 8 provides the median time to seizure cessation from randomisation and Figure 4 shows the Kaplan–Meier curve and log-rank test. As the event of interest (i.e. seizure cessation) is positive, the lower curve indicates a shorter time to seizure cessation; however, there is no statistically significant difference between the treatment arms (log-rank p-value > 0.05).

FIGURE 4.

Kaplan–Meier plot time from randomisation to seizure cessation. Product-limit survival estimates with number of subjects at risk. This figure been reused from Lyttle et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) license, which permits others to copy and redistribute the material in any medium or format, provided the original work is properly cited. See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

This figure been reused from Lyttle et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) license, which permits others to copy and redistribute the material in any medium or format, provided the original work is properly cited. See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

The unadjusted HR was 1.2 (95% CI 0.91 to 1.6; p = 0.2) in favour of levetiracetam. The Schoenfeld residuals for the unadjusted model (p = 0.72) indicated the independency of time and the validity of the proportionality assumption. The Schoenfeld residuals for the adjusted model indicated that the assumption of proportionality for weight was not met (p = 0.05, p-value ranged from 0.27 to 0.71 for other variables). The data were subgrouped according to weight category as per the baseline table (i.e. < 12 kg, 12–36 kg and > 36 kg) and estimates from the adjusted model calculated (see Appendix 6, Tables 15–29). The proportionality assumption within each subgroup of data was supported by the Schoenfeld residuals. Direction of treatment effect was consistent across subgroups, CIs were wide and results were not statistically significant. The treatment effect was increased for children in the > 36 kg subgroup, but remained non-significant and numbers within this group are small.

A range of sensitivity analyses were considered to assess seizure cessation from the start of the infusion, rather than from randomisation (see Appendix 7, Table 32) and the impact censoring regarding RSI and death. The results demonstrated robustness of conclusions and are presented in Appendices 6 and 7.

Secondary outcomes

The study comprised four secondary outcomes. These assessed the efficacy and safety of the two trial interventions (Table 9).

One participant who was allocated and received phenytoin experienced a SAR. This was profound hypotension, which was considered to be immediately life-threatening and responded to emergency treatment. This participant also experienced a severe unexpected serious adverse reaction (SUSAR), which manifested as a large increase in seizure frequency and marked sedation within 24 hours of receiving phenytoin. The SUSAR was considered medically significant and the participant required admission to the intensive care unit. The SUSAR resolved without complication.

Safety, tolerability and compliance

Two patients died in the study, but neither death was considered related to the randomised treatment. One participant presented to the ED in a generalised tonic–clonic seizure and unconscious. Resuscitation was immediate. The participant received levetiracetam (the randomised treatment) and then phenytoin, followed by RSI with thiopentone (Archimedes, Reading, UK) because of abnormal posturing. The participant died 36 hours following admission and a post-mortem examination revealed severe brain oedema secondary to encephalitis. Consent for recruitment into the study was subsequently obtained from the participant’s carers. The death was considered to be unrelated to the randomised treatment by the principal investigator and chief investigator.

The second participant received phenytoin. The participant died and the results of the post-mortem examination were not available prior to closure to recruitment to the study. The principal investigator and chief investigator considered the death to be unrelated to the randomised treatment. Consent was sought from the participant’s carers but had not been obtained by the time recruitment to the study closed on 10 April 2018 and, therefore, this participant’s data are not included in the analysis.

Laboratory parameters (haematological, biochemical analysis and urinalysis)

Laboratory analyses in the trial protocol were limited to measurements of blood levels of levetiracetam and phenytoin in the randomised, treated and consented participants. Blood samples were obtained between 1 and 2 hours after completion of infusion of the two treatments. Biochemistry laboratories in each site processed the samples in accordance with their standard operating procedures. The reference ranges for blood levels of levetiracetam were provided by a single central laboratory that analysed all of the samples of levetiracetam-treated participants. The reference ranges for blood levels of phenytoin were provided by the biochemistry department of each participating site that analysed samples of its phenytoin-treated participants.

A total of 192 participants underwent measurement of a blood level [96 participants in the levetiracetam-treated group (63.2%) and 96 participants in the phenytoin-treated group (77.7%)] and the results are shown in Figures 5 and 6.

FIGURE 5.

Levetiracetam blood levels.

FIGURE 6.

Phenytoin blood levels.

Background

Convulsive status epilepticus is a medical emergency that has insufficient time to obtain informed consent within the therapeutic window. The use of RWPC (also known as deferred consent) in the EcLiPSE trial was supported by parents who took part in trial feasibility work. 43

A nested study was designed to identify potential barriers and solutions to recruitment and consent in the EcLiPSE trial, and to inform recruiter training on recruitment, consent, trial conduct and future trials in this setting.

Objectives

Consent study objectives were to explore:

• how information about the trial and RWPC was exchanged during recruitment discussions

• parents’ and practitioners’ views and experiences of RWPC and consent decision-making

• the impact of an unblinded trial design.

We included a strand of work that aimed to develop trial recruiter training on RWPC using recommendations made by parents in the feasibility study and related guidance. 43,46–49 Our objective was to evaluate the effectiveness of the EcLiPSE trial site initiation visit (SIV) training on practitioners’ confidence in recruitment, consent and trial conduct.

Methods

Data analysis

Results

Participants: parents

Two hundred and eighteen parents of the 289 (75%) children randomised and treated in the EcLiPSE trial consented to participate in some aspect of the consent study. A total of 212 out of 218 (97%) parents consented to complete a questionnaire and in 13 instances two parents completed a questionnaire for one child. A total of 143 out of 212 (67%) paper-version questionnaires were received (Figure 7). No parents chose to complete the questionnaire using the online version.

FIGURE 7.

Parent characteristics by method.

Recorded trial discussions and interview elements closed in August 2017 (with 193 patients treated and randomised at that stage of the trial) as we reached the data saturation point. 55 Just under half (95/193, 49%) of eligible parents gave consent for the recorded trial discussion. Of these recorded discussions, 76 out of 95 (80%) were received and analysed. Of 114 (59%) of the 193 eligible parents who agreed to be approached for interview, 59 (51%) were invited to participate in an interview by telephone or e-mail. Of these, eight (13%) had incorrect contact details, 10 (16%) did not respond and 11 (18%) declined to interview on telephone contact. Interview and recorded trial discussions data were obtained from 17 out of 25 (68%) sites. Of these, 36 out of 76 (47%) recorded trial discussions were led by doctors and 19 out of 76 (25%) conversations were led by nurses or research nurses. Most (45/76, 60%) practitioners recorded one trial discussion, 24 out of 76 (31%) recorded two parts of a trial discussion and 7 out of 76 (9%) recorded three or more parts. In 37 (49%) cases, it was clear that only the second part of the conversation had been recorded. We obtained a full data set (i.e. the questionnaire, recorded trial discussions and parental interview) for 19 families.

Discussion

Our findings show how interactive site training, developed using pre-trial research and RWPC guidance, can significantly alleviate practitioner concerns about recruitment and consent in a challenging PEM trial. For many participating hospitals, the EcLiPSE trial was the first time that teams worked together to ensure that critically ill children were randomised to a trial during resuscitation without prior informed consent. Prior to site training, many practitioners expressed concerns about conducting the trial and lacked confidence in how to communicate to parents some of its elements, including RWPC. Practitioners rated highly the clarity and content of SIV training. Significant improvements were observed in practitioners’ confidence in explaining the study, randomisation and RWPC to families, as well as how to respond to parents who might object to their child being randomised during an emergency resuscitation. Site training provided an opportunity to discuss and learn about the potential challenges and solutions to trial recruitment and conduct. 62,63 Our findings suggest that the use of training videos significantly aided this process and helped practitioners to visualise potentially difficult trial processes, including screening in a resuscitation situation. Practitioners particularly valued the RWPC video, which had been informed by data on parents’ views and priorities from pre-trial research43 and CONNECT study guidance on RWPC. 48,49 The video provided practitioners with examples of how to communicate RWPC to parents,48,49 as well as preparing them for a range of questions parents might ask about the trial. 43

Recorded trial discussions and interviews conducted with parents and practitioners throughout the EcLiPSE trial provided insights into how information about the trial and RWPC had been exchanged and understood. Overall, trial practitioners provided parents with a brief but balanced description of the two interventions to parents. Parental understanding of the trial was enhanced when practitioners clearly described trial aims, the reason for RWPC, uncertainty about which intervention was better, a balanced description of both interventions and the randomisation process, and welcomed questions. We provide a bespoke seven-step framework to optimise PEM trial RWPC discussions. Further testing of this framework in future PEM trials is required, as are parent and practitioners views and experiences of RWPC.

Multiple factors, including trial design, logistics and leadership, were found to both challenge and contribute to trial recruitment and conduct. Importantly, both parents and practitioners wanted to know the answer to the research question, which appeared to underpin many of the decisions and behaviours identified in our study. Our findings also suggest that practitioners were engaged and invested in the EcLiPSE trial because of its pragmatic design, which aimed to answer an important clinical question that they believed would quickly inform their daily practice. This engagement was apparent across the majority of EcLiPSE trial sites, despite initial concerns about whether or not the trial was possible, which was often confounded by inexperience of conducting an ED-led trial. Our findings highlight the important role of researchers and funding panels when the clinical relevance of the research questions and how challenging trials are more likely to succeed, if these are relevant and important to all key stakeholders, including patients, family members and clinicians. 64,65

As has been shown in recent pilot studies56,66 exploring treatments for paediatric suspected infection, parents and practitioners found RWPC to be acceptable. They understood its principle of avoiding unethical delays in the delivery of potentially life-saving treatments. Practitioner concerns that parents would notice the randomisation envelope being opened in the ED and would object to the trial or RWPC, or both, were mostly unfounded. Parents of children who had a prior diagnosis of epilepsy seemed to be more likely to notice something different was occurring, such as the opening of the randomisation envelope. These parents valued how practitioners provided them with brief description of the study, including what drug had been allocated. As shown in other studies57,67,68 that have explored trial recruitment and decision-making, patients and family members often prioritise verbal over written information provision, while the highly stressful and time-critical ED context is likely to impact on parental capacity and, indeed, desire to read even short written study information. 47 Future trials would benefit from considering how their study and RWPC could be briefly communicated to parents of children who are regular ED attenders, if deemed appropriate.

Added value of this study

This is an adequately powered RCT that pragmatically and directly compares two anticonvulsants in the second-line treatment of paediatric CSE in an emergency setting. It is also, to the best of our knowledge, the first scientifically-robust clinical trial to compare the efficacy and safety of levetiracetam with phenytoin in this common paediatric neurological emergency. We found no significant differences between the two anticonvulsants in any primary or secondary outcomes, including time to seizure cessation, need for additional anticonvulsants and progression to RSI. The safety profile was similar between both treatments (note that this is in contrast to existing observational evidence that phenytoin appears to have a worse safety profile, including causing a potentially fatal cardiac arrhythmia).

The study comprised a number of challenges, but also opportunities, that might have adversely affected recruitment, including research within a paediatric emergency situation that involved RWPC, which was a new concept to many participating centres. Early input from parents was obtained through pre-trial feasibility43 and CONNECT guidance,46–48 which informed site training to maximise recruitment into the EcLiPSE trial. The nested consent study provides valuable insight from parents and practitioners to inform the design and conduct of future trials in this setting, including a bespoke seven-step framework to optimise PEM trial recruitment discussions. Multiple factors, including trial design, organisation and leadership, were found to both challenge and contribute to trial recruitment and conduct. Early engagement with PERUKI optimised success of the trial through collaboration with clinicians and researchers in the development and delivery of the study, together with the selection of the most appropriate sites in which to recruit patients.

Implications of all the available evidence

The results of the EcLiPSE trial indicate that levetiracetam could be considered as an alternative treatment to phenytoin for the second-line management of paediatric CSE. Recently published RCT data from the ConSEPT trial41 and ESTT70,71 seem to confirm our results and our conclusion.

Additional treatment-related factors may be important to consider and are likely to be relevant to the wider interpretation of our findings. First, levetiracetam is widely used as oral maintenance therapy for many childhood epilepsies because of its broad-spectrum activity and safety profile; this was clearly reflected in the EcLiPSE trial, with levetiracetam being the most commonly used oral antiepileptic drug in all participants on presentation to the ED. By contrast, phenytoin is a rarely used maintenance antiepileptic drug because of its complex pharmacokinetics and potential toxicity. However, despite its rare use, anecdotally, many ED clinicians are reluctant to give a loading dose of phenytoin in CSE to children on oral maintenance phenytoin because of the risk of potential overdosing and the risk of potential cardiovascular toxicity, including a fatal arrhythmia. There seemed to be no similar concerns for levetiracetam, and there was no observed increase in AEs following the i.v. administration of a dose of 40 mg/kg to children already receiving maintenance levetiracetam. In addition, in the levetiracetam-treated participants, blood levels of the drug showed no obvious difference between those who were and were not receiving it as a maintenance oral antiepileptic drug on presentation. Second, a significant minority of children who present in CSE for the first time will be commenced on maintenance therapy prior to discharge. This is more likely to be with levetiracetam than phenytoin because of the latter’s adverse safety profile and unreliable pharmacokinetics. One observational study in adults showed that 8% of patients treated with i.v. fosphenytoin for CSE were subsequently commenced on oral phenytoin, compared with 78% of patients treated with i.v. levetiracetam who were subsequently commenced on oral levetiracetam. 72 Third, ease of drug preparation and administration is also important in the management of CSE.

Throughout the EcLiPSE trial, levetiracetam was reported by all clinical teams to be easier to prepare and administer than phenytoin because of the latter’s calculations performed in reconstituting the drug, the number of vials required and procedures needed for its administration (these observations are supported by the literature20,74).

The majority of participants in the EcLiPSE trial were managed in accordance with the national APLS algorithm, unless the clinical team considered otherwise. For children in whom the second-line anticonvulsant fails to terminate CSE, RSI with thiopentone or another agent is the next step in the algorithm. However, treatment strategies in the management of CSE are evolving. This includes the emerging use of two, rarely three, second-line anticonvulsants in preference to the traditional practice of immediate progression to RSI after failure of the first second-line drug. Clinicians might consider the risks of RSI, and its potential iatrogenic consequences, to be greater than the administration and assessment of a second second-line treatment. In total, 24 out of the 286 participants (8.4%) in the EcLiPSE trial received both treatments sequentially (17 of these were randomised to, and received, levetiracetam first). This could reflect the acceptance of a second second-line treatment being conditional on the amount of time elapsed since CSE-onset.

In the ConSEPT trial,41 if CSE continued following administration of the randomised drug then the alternative drug was given, with further assessment of seizure activity performed 5 minutes after the infusion of the second trial drug was completed. Persisting CSE after the administration of both drugs was subsequently managed by local protocols, all of which advised RSI and intubation. Consequently, 42 participants received phenytoin followed by levetiracetam and 48 participants received levetiracetam followed by phenytoin. Clinical cessation of seizure activity at 2 hours following the administration of the randomised drug only was seen in 62 (54%) participants in the phenytoin-treated group and 61 (51%) participants in the levetiracetam-treated group. However, seizure cessation at 2 hours having received one or both study drugs increased this to 89 (78%) participants in the phenytoin-treated group and 86 (72%) participants in the levetiracetam-treated group. The authors41 concluded that although both drugs failed to terminate CSE in a significant number of patients when given alone, treatment with one drug and followed by the other reduced the failure rate by > 50% at the expense of only an additional 10 minutes (compared with giving phenytoin alone). The authors41 argued that clinicians should, therefore, consider the sequential use of either medication first, before progressing to RSI and intubation. It is understandable that clinicians might consider the risks of RSI and intubation to be greater than the risks of administration and assessment of an additional second-line treatment. However, the administration of two second-line treatments might substantially delay the use of RSI. The ConSEPT trial team suggest that any delay would be < 10 minutes. 41 However, in practice, the preparation and administration of levetiracetam is likely to take > 10 minutes and closer to 15 minutes and phenytoin is likely to take closer to 20 or 25 minutes because of its more complicated preparation. Such a delay would significantly add to the overall period of CSE since its onset and would increase the potential risk of neurological and cognitive impairment.

Contributions of authors

Richard E Appleton (https://orcid.org/0000-0002-0742-2113) (Consultant Paediatric Neurologist) conceived the study, designed the study and protocol, analysed the data, and prepared and reviewed the manuscript.

Naomi EA Rainford (https://orcid.org/0000-0002-5876-3946) (Trial Statistician, Clinical Trials Research Centre) designed the study and protocol, analysed the data, and prepared and reviewed the manuscript.

Carrol Gamble (https://orcid.org/0000-0002-3021-1955) (Lead Statistician and Head of Biostatistics, Clinical Trials Research Centre) designed the study and protocol, analysed the data, and prepared and reviewed the manuscript.

Shrouk Messahel (https://orcid.org/0000-0003-0645-3070) (Consultant in PEM) designed the study and protocol, and prepared and reviewed the manuscript.

Amy Humphreys (https://orcid.org/0000-0002-5996-2613) (Trial Manager, Clinical Trials Centre) designed the study and protocol, was responsible for trial management, and prepared and reviewed the manuscript.

Helen Hickey (https://orcid.org/0000-0003-0467-0362) (Head of Trials Management, Clinical Trials Research Centre) designed the study and protocol, was responsible for trial management, and prepared and reviewed the manuscript.

Kerry Woolfall (https://orcid.org/0000-0002-5726-5304) (Senior Lecturer, Department of Health Services Research) designed the study and protocol, analysed the data for the nested consent study, and prepared and reviewed the manuscript.

Louise Roper (https://orcid.org/0000-0002-2918-7628) (Chartered Health Psychologist) was responsible for data analysis of the nested consent study, and prepared and reviewed the manuscript.

Joanne Noblet (https://orcid.org/0000-0001-5232-8495) (Senior Sister in Paediatric Emergency Care) designed the study and protocol, and reviewed the manuscript.

Elizabeth Lee (https://orcid.org/0000-0002-2846-2448) (Research Nurse in Paediatric Emergency Care) designed the study and protocol, and reviewed the manuscript.

Sarah Potter (https://orcid.org/0000-0003-1463-279X) (Senior Sister in Paediatric Emergency Care) designed the study and protocol, and reviewed the manuscript.

Paul Tate (https://orcid.org/0000-0002-4246-1409) (Data Manager) was responsible for data collation and data management.

Nadia Al Najjar (https://orcid.org/0000-0002-2851-0913) (Trial Manager) was responsible for trial management.

Anand Iyer (https://orcid.org/0000-0002-3932-4729) (Consultant Paediatric Neurologist) designed the study and protocol, and prepared and reviewed the manuscript.

Vicki Evans (Parent and PPI representative) designed the study and protocol, and reviewed the manuscript.

Mark D Lyttle (https://orcid.org/0000-0002-8634-7210) (Consultant in PEM) designed the study and protocol, and prepared and reviewed the manuscript.

Publications

EcLiPSE Study. Convulsive status epilepticus: an update. Epilepsy Professional 2017;47:14–19.

Lyttle MD, Gamble C, Shrouk M, Hickey H, Iyer A, Woolfall K, et al. Emergency treatment with levetiracetam or phenytoin in status epilepticus in children-the EcLiPSE study: study protocol for a randomised controlled trial. Trials 2017;18:283.

Cook R, Davidson P, Martin R, NIHR Dissemination Centre. Levetiracetam is a useful alternative to phenytoin for epileptic seizures in children. BMJ 2019;367:l5464.

Lyttle MD, Rainford NEA, Gamble C, Messahel S, Humphreys A, Hickey H, et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial. Lancet 2019;393:2125–34.

Woolfall K, Roper L, Humphreys A, Lyttle MD, Messahel S, Lee E, et al. Enhancing practitioners’ confidence in recruitment and consent in the EcLiPSE trial: a mixed-method evaluation of site training – a Paediatric Emergency Research in the United Kingdom and Ireland (PERUKI) study. Trials 2019;20:181.

Roper L, Lyttle MD, Gamble C, Humphreys A, Messahel S, Lee ED, et al. Planning for success: overcoming challenges to recruitment and conduct of an open-label emergency department–led paediatric trial. Emerg Med J 2020;0:1–7.

Data-sharing statement

All data requests should be submitted to the corresponding author for consideration. Access to anonymised data may be granted following review.

Disclaimers

This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care.

Trial Steering Committee

The independent members of the TSC were as follows: Professor Imti Choonara (chairperson), Professor Caroline Doré, Dr Michael Barrett, Dr Ronan O’Sullivan, Gail Miller, Jane Morgan and Denise Bustansy.

The non-independent member of the TSC was Professor (Honours) Richard Appleton.

Independent Data and Safety Monitoring Committee

Professor Steff Lewis (chairperson), Dr Julie Ellison and Professor Tony Marson.

Trial Management Group

Dr Richard Appleton, Dr Mark Lyttle, Professor Carrol Gamble, Helen Hickey, Amy Humphreys, Nadia Al-Najjar, Naomi Rainford (née: Bacon), Dr Kerry Woolfall, Louise Roper, Victoria Evans, Dr Shrouk Messahel, Dr Anand Iyer, Joanna Noblet, Elizabeth Lee, Rachel Greenwood-Bibby, Tracey Bingham, Alice Smith, Sarah Potter, Phoebe Moulsdale, Holly Lavigne-Smith, Lucy Cooper, Emma Johnston and Dr Mary Ryan.

Statistical lead

Professor Carrol Gamble.

Senior trial manager

Helen Hickey.

Senior data managers

Clare Jackson and Sue Howlin.

Trial co-ordinators

Amy Humphreys and Nadia Al-Najjar.

Statisticians, data managers and database developers

Database development and Information Systems quality control

Janet Harrison and Linda Kane.

Data manager

Paul Tate.

Summary of amendments from protocol v1.0 (13 January 2015) to protocol v2.0 (23 April 2015)

Summary of amendments from protocol v2.0 (23 April 2015) to protocol v3.0 (17 June 2015)

Summary of amendments from protocol v3.0 (17 June 2015) to protocol v4.0 (27 august 2015)

Summary of amendments from protocol v4.0 (27 August 2015) to protocol v5.0 (5 April 2017)

Aims

The key aims of her involvement were to comment on the clinical relevance of the subject of the trial and to provide input on those methodologies that related to patient-recruitment and RWPC, including the patient and participation information leaflets and the process for obtaining consent post discharge.

Methodology

The methodology focused on the following.

• Providing input on the terminology and practice of ‘deferred consent’ (i.e. RWPC). This included advice on the content and structure of site training for the simulated interview of taking informed deferred consent from families.

• A review of the parent/patient information leaflets and covering letters.

• Attendance at the TMG meetings, which were predominantly undertaken by telephone conference.

Study results

The lead PPI attended TMG meetings at which the results of the EcLiPSE trial and the nested consent study were discussed.

Reflections

The PPI agreed that the trial was important and felt that the primary and secondary outcomes were appropriate and relevant. She felt that she had a specific value in guiding other members of the TMG in the potential consequences of seeking deferred consent in an emergency and emotionally sensitive situation. This included invaluable comments in how to best communicate with the parents of a child who had died and had been recruited into the EcLiPSE trial. She was concerned about two issues over her involvement. First, that she was unable to participate in many of the regular TMG meetings, primarily because of their dates and times, which clashed with her work responsibilities and childcare. Second, because of the specialised pharmacological aspects of the trial, which at times she felt were somewhat ‘over her head’, despite explanations provided by the chief investigator and clinical members of the TMG.

Report writing, academic paper preparation and dissemination

The PPI was not actively involved in the writing of the protocol (published in the online journal Trials2), but did comment on the final draft prior to its publication. Her input was similar in the definitive results paper (published online in The Lancet1). She also contributed to the final report to the Health Technology Assessment programme, with her focus being on the Plain English summary and preparation of the end-of-study results information sheet for all participating sites and their teams. She will continue to be involved in dissemination activities and preparation of academic papers.

All children

Children with a weight of < 12 kg

FIGURE 8.

Kaplan–Meier for children with a weight of < 12 kg. Product-limit survival estimates with number of subjects at risk.

Children with a weight between 12 and 36 kg

FIGURE 9.

Kaplan–Meier for children with a weight between 12 and 36 kg. Product-limit survival estimates with number of subjects at risk.

FIGURE 10.

Kaplan–Meier for children with a weight of > 36 kg. Product-limit survival estimates with number of subjects at risk.

Time to seizure cessation using Gray’s test for competing risks

FIGURE 11.

Cumulative incidence plot.

Time to seizure cessation from infusion

Time to seizure cessation censoring at time of second second-line treatment

Characteristics: parents

All parents who took part in the consent study had consented to the use of their child’s information in the EcLiPSE trial. Despite attempts to involve decliners, none of the 19 parents who declined the use of their child’s data in the EcLiPSE trial consented to participate in the consent study. None of the parents included in the nested consent study lost a child, although fortunately very few children involved in the EcLiPSE trial died. No individuals identified themselves as legal representatives and therefore this term is not used in the remainder of this appendix.

Of the 143 parents who returned a questionnaire, 93 (65%) were mothers and 39 (27%) were fathers. Ten (7%) had missing parent information.

One parent was present in approximately half (41/76, 54%) of the recorded trial discussions, whereas two parents (or family members) were present in 35 (46%) discussions. Details of who (e.g. mother, father or relative) took part in recorded trial discussions could not be fully established, as not all individuals recorded completed the consent form. Of the 76 recorded trial discussions, 37 (49%) children had received phenytoin and 35 (46%) children had received levetiracetam. In four discussions it was unclear which study drug the child had received. Recorded trial discussion data suggested that 31 out of 76 (40%) children in this subsample had experienced previous seizures, whereas 17 (22%) had not. In 28 (36%) children it was not clear whether or not the child had experienced a previous seizure. In total, 21 out of the 76 (21%) parents indicated that their child had previously taken, or was currently taking, levetiracetam as a preventative treatment.

LR interviewed 30 parents (i.e. 25 mothers and five fathers) over the telephone at a mean of 6 weeks (range 1–8 weeks) after their child had been discharged from hospital. Interviews ranged from 18 to 63 minutes (mean 34 minutes). Eighteen parents reported that their child had experienced previous seizures prior to their child’s involvement in the EcLiPSE trial. For 12 parents, this was their child’s first seizure. Children of parents involved in the consent study were aged between 9 months and 8.5 years at the time of recruitment to the EcLiPSE trial (with a median of 2.8 years) compared with a range of 6 months to 17 years 11 months (with a median of 2.8 years) for the EcLiPSE trial sample (379 children).

Thirteen parents reported their child being randomised to levetiracetam and 10 parents said that their child was randomised to phenytoin. In six cases, the parent reported that they could not remember what trial drug was given and one knew both had been given, but was unsure of the order in which they were given.

Characteristics: practitioners

As shown in Figure 12, SIV questionnaire respondents comprised 45 (36%) nurses and 57 (46%) doctors. Those who defined themselves as ‘other’ had specific roles (e.g. ‘nurse specialist hospice’). Six nurses and four doctors took part in a telephone interview. All had a lead role (e.g. principal investigator, lead research nurse) in the EcLiPSE trial recruitment. Telephone interviews lasted, on average, 37 (range 21–47) minutes. Of the 36 practitioners who took part in one of the six focus groups, 20 (56%) were nurses and 16 (44%) were doctors. On average, focus groups lasted 61 (range 37–88) minutes. Of the 199 practitioners who took part in the online questionnaire, 39% (n = 78) were nurses, 59% (n = 117) were doctors and 5% (n = 3) were classified as ‘other’ (e.g. clinical research lead). It is likely that some of the practitioners who took part in a telephone interview, focus group or SIV questionnaire also completed the online questionnaire.

FIGURE 12.

Practitioner characteristics by method.