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Appleton RE, Rainford NEA, Gamble C, et al. Levetiracetam as an alternative to phenytoin for second-line emergency treatment of children with convulsive status epilepticus: the EcLiPSE RCT. Southampton (UK): NIHR Journals Library; 2020 Nov. (Health Technology Assessment, No. 24.58.)

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

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

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Appendix 4Changes to the protocol

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

Protocol sectionSummary of changes
Protocol summary
  • Study participation increased from 24 hours to 14 days. Follow-up at 14 days for safety only
  • Schematic of study design: updated to align with new follow-up and change to inclusion criteria number 3
Primary end point
  • Defined as time to cessation of all visible signs of convulsive seizure activity, will be calculated from the time of randomisation. A secondary analysis will use time from the start of the infusion
Internal pilot
  • Clarified that the internal pilot will involve five centres, but other centres may also open during this period
Inclusion criteria
  • Inclusion criterion 2: definitions of presenting seizures have been clarified
  • Inclusion criterion 3: amended to ‘First-line treatment administered according to APLS guidelines or the child’s personalised rescue care plan to try and terminate the presenting seizure’
  • Eligibility notes: amended to align with the changes to the inclusion criteria and clarify the definitions of first-line treatment
Exclusion criteria
  • Exclusion criterion 3: amended to align with updated inclusion criterion 3
  • Exclusion criterion 6: amended to ‘Known to have previously been treated as part of EcLiPSE’
Screening
  • Process for assessing eligibility clarified
  • Screening will now commence once a child has arrived in the ED and has started first-line treatment. Reference to two doses of benzodiazepines removed
Randomisation
  • Change to randomisation envelopes used. Randomisation packs will instead include CRFs that are prepopulated with the randomisation number and treatment allocation
  • Process for patients who are randomised but not treated with second-line treatment while in the ED defined
Patients randomised but not treated with a second-line treatment in the ED
  • Process for obtaining consent for patients randomised but not administered a second-line treatment defined
Trial treatments introduction
  • Guidance on ‘actual’ weight removed
Preparation, dosage and administration of levetiracetam
  • Following sentence removed to ensure clarity on the dilution of levetiracetam: ‘Levetiracetam should be diluted in accordance with the manufacturers SmPC’
Accountability procedures for study treatments
  • Updated to align with new randomisation packs (see section 6.3)
Assessment of compliance with study treatments
  • Updated to align with new randomisation packs (see section 6.3)
Co-enrolment guidelines
  • Updated to include ‘should co-enrolment issues arise, patients are permitted to enter EcLiPSE while participating in another trial. This is providing that the other trial will not impact the EcLiPSE primary end point. Any queries regarding co-enrolment should be discussed with the CTU who will contact the chief investigator’
Schedule for follow-up
  • New follow-up period defined to include:
    • follow-up for patients not administered a second-line treatment
    • 14-day safety follow-up
Trial assessments
  • Follow-up time points clarified
  • Height assessment removed
  • Heart rate, oxygen saturation, respiratory rate and blood pressure assessment removed
  • 14-day safety follow-up added
Seizure activity
  • Seizure follow-up clarified as ‘24 hours after the second-line infusion was started’
Procedures for assessing safety
  • Clarified AEs to be recorded from randomisation to 24 hours after second-line infusion started
  • Process for 14-day safety follow-up added:
    • 14-day follow-up questionnaire
    • 14-day hospital follow-up
Blood samples
  • Blood sample to be taken updated to ‘between 1.5 mls and 2 mls’
Consent study
  • Table inserted to clarify when each section of the consent study is applicable
Part A: audio-recordings
  • Transcriptions to be completed by ‘VoiceScript’ website
Sample size estimate
  • Updated to include ‘Due to deferred consent process this will require 308 randomised patients for whom consent has been sought and randomised treatment received’
Notes on AE recording timelines
  • Updated to align with changes to follow-up as per section 8.3
Flow chart for reporting requirements of AEs
  • Updated to align with changes to follow-up as per section 8.3
Reporting of overdose
  • Overdose classified as > 20% of the recommended dose
CRFs
  • Updated as per new randomisation process
  • Reference to two-part, no carbon copy removed
N/A
  • Other minor typographical errors corrections and clarifications to ensure consistency made throughout

CTU, Clinical Trials Unit; N/A, not applicable; SmPC, Summary of Product Characteristics.

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

Protocol sectionSummary of changes
Trial treatments introduction
  • Concentration of levetiracetam updated to a maximum of 50 mg/ml with sodium chloride 0.9%
  • Concentration of phenytoin updated to a maximum of 10 mg/ml with sodium chloride 0.9%
Preparation, dosage and administration of levetiracetam
  • Concentration of levetiracetam updated to a maximum of 50 mg/ml with sodium chloride 0.9%
Preparation, dosage and administration of phenytoin
  • Concentration of phenytoin updated to a maximum of 10 mg/ml with sodium chloride 0.9%

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

Protocol sectionSummary of changes
N/A
  • Additional reference numbers inserted
Protocol summary: schematic study design
  • Maximum dose and infusion times for phenytoin updated
Trial treatments introduction
  • Maximum dose of phenytoin increased to 2000 mg
  • Infusion times for phenytoin updated:
    • Infusion time for dose ≤ 1000 mg: over 20 minutes
    • Infusion time for dose > 1000 mg and ≤ 1500 mg: between 20 and 30 minutes
    • Infusion time for dose > 1500 mg and ≤ 2000 mg: between 30 and 40 minutes
Preparation, dosage and administration of levetiracetam
  • Reference to the New Zealand guidelines updated
Preparation, dosage and administration of phenytoin
  • Updated to confirm that the ‘total maximum dose of phenytoin administered should be 2000 mg. However, sites should confirm prior to study start if their local procedure states that the maximum phenytoin dose is less than 2000 mg. If this is the case then maximum dose for phenytoin should be as per local procedure and should be adhered to’
  • Infusion times for phenytoin updated
Part B: parent/legal representative questionnaires
  • Updated to confirm online version of the questionnaire can be completed
  • Clarified that if more than one parent/legal representative is involved in the consent discussion, both can complete a questionnaire
  • Updated to confirm that the consent study team may follow-up for missing questionnaires when completing consent follow-up, if consent has been obtained for this
Part C: interviews
  • Updated to allow face-to-face interviews for parents/legal representatives who live in (or close to) the Merseyside area if this preferred
N/A
  • Other minor typographical errors corrections and clarifications to ensure consistency made throughout

N/A, not applicable.

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

Protocol sectionSummary of changes
Contact details
  • Contact details updated for CTRC, Richard Appleton and Anand Iyer
Protocol summary
  • Contractual title with the HTA programme added
Randomisation
  • Updated to confirm that ‘Once randomised, the patient should be administered the randomly allocated treatment when required clinically to terminate seizure activity. If seizure activity has ceased or the patient has been given a RSI prior to administration of any second-line treatment then the decision to administer a second-line treatment is outside the EcLiPSE trial the patient should be treated as per standard care. Follow-up will be as detailed in section 8.1 and consent should be sought as per section 6.4.11’
Consent/assent form completion
  • Clarification on where original consent forms should be filed if the trust has moved to electronic medical records
Definitions of legal representatives
  • Definitions updated to include Northern Ireland and Scottish minors
Death prior to deferred consent being sought
  • Allowable window added for sending information via post to bereaved families
Discharge/transfer prior to deferred consent being sought
  • Time window added for when information should be sent to the families once the telephone call has been completed
  • 14-day follow-up questionnaire added as a document to be sent to families when following the consent from home process
Patients randomised but not treated with second-line treatment in the ED or second-line treatment administered after RSI/seizure stop time
  • Confirmation that patients administered RSI or seizure stopped prior to second-line treatment should follow the not-treated pathway
  • Questionnaire for not-treated participants added
  • Confirmation that those participants consented as not treated are not included in the recruitment figures for the study, as they were not administered second-line treatment as per the APLS protocol
Deferred consent declined
  • Consent tracking form will confirm that the patient has declined consent and which (if any) second-line treatment was administered
Participant transfers
  • Confirmation that if a patient is transferred to another EcLiPSE trial recruiting site then the transferred site can assist with the consent of the patient
Trial treatments: introduction
  • Clarification on the route of administration. The following text inserted: ‘At the time of randomisation if it is clear that the trial treatment needs to be administered via the intraosseous route then the patient should not be randomised. If this becomes the case after the patient has been randomised then this should be documented appropriately on the CRFs and all follow-up data collected’
Arm A: levetiracetam – formulation
  • Confirmation of the SmPC used for levetiracetam reference safety information
  • Clarification that sites will no longer be provided with example SmPCs and instead should use the current SmPC available from the eMC website or equivalent
Arm B: phenytoin – formulation
  • Confirmation of the SmPC used for phenytoin reference safety information
  • Clarification that sites will no longer be provided with example SmPCs and instead should use the current SmPC available from the eMC website or equivalent
Schedule for follow-up
  • Table updated to include patients who are administered second-line treatment after RSI/seizure stop time
  • Column included to confirm consent process for each patient
14-day follow-up questionnaire
  • 14-day follow-up questionnaire to be provided to both participants who have consented on site and at home
  • Follow-up for participants who have not completed their 14-day follow-up questionnaire. Research nurse to complete the follow-up via telephone
Blood samples
  • Location of blood sample: ‘Capillary/cannula samples are acceptable’
Consent study
  • Consent study interviews to occur until data saturation is achieved (maximum of 25 interviews removed)
  • Not-treated participants now included in the consent study
Urgent safety measures
  • Process for urgent safety measures added
Protocol deviation and serious breaches
  • Process for protocol deviations and serious breaches reporting added
Records retention
  • Maximum archiving period updated to 25 years
  • Clarification when study information is sent via encrypted e-mails
  • Removal of records management service by the University of Liverpool. Regulations to be followed when archiving quoted
N/A
  • Other minor typographical errors, corrections and clarifications to ensure consistency made throughout

CTRC, Clinical Trials Research Centre; eMC, electronic medicines compendium; HTA, Health Technology Assessment; N/A, not applicable; SmPC, Summary of Product Characteristics.

Copyright © 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.
Bookshelf ID: NBK564083
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