The changes in levels of cortical amyloid load in the treatment group, compared with the placebo group, in the same subgroup as the tau PET substudy. Liraglutide, at doses up to 1. The doses used in the ELAD trial are those approved for diabetes, as at the time of the study design liraglutide was only approved for clinical use in diabetes. Liraglutide is thus suitable for once-daily subcutaneous injection given any time of the day, independent of meals [ 44 ]. Investigation of liraglutide metabolism in vitro and in healthy subjects has indicated that liraglutide is endogenously metabolised and that neither renal excretion nor hepatic extraction are major routes of clearance.
The pharmacokinetics of liraglutide has been investigated in human subjects with renal and hepatic impairment and has not raised any safety concerns. However, the therapeutic experience in subjects with hepatic or renal impairment is limited. The effects of age and gender on the pharmacokinetics of liraglutide have been investigated, and it was concluded that all participants, regardless of age or gender, should be dosed in accordance with the usual proposed dose regimen for liraglutide [ 45 ].
In the ELAD trial, participants will start with a dose of 0. The dose will be escalated in weekly steps of 0. Participants can stay on 1. The study medication will be provided as prefilled pens so that the active treatment and placebo cannot be identified, guaranteeing that the study remains double-blinded. At the beginning of the study, the study drug will be administered subcutaneously under supervision.
Participants and caregivers will be instructed in the administration and correct storage and handling of the pens. Landau et al.
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All participants will undergo the evaluations outlined in Fig. The week 16 W16 , week 28 W28 , week 36 W36 , and week 44 W44 visits will be a telephone call to check for any adverse events, with a follow-up visit at the study centre if needed. At the week 52 W52 visit, final efficacy and safety assessments will be carried out and unused study medication will be collected.
Four weeks after the end of the study, a final follow-up phone call will be made W The clinical assessments will be done by a trained research nurse and a trained research doctor, when indicated. The neuropsychological assessments will be done by a trained rater at the research sites. ELAD trial schedule of visits. Participants will be randomised to receive active drug or placebo with a allocation ratio using stratified block randomisation with a fixed block size.
The stratification factors are age and the Mini Mental State Examination. Randomisation will take place using an interactive voice response system. Mawdsleys [ 47 ] is the contractor responsible for randomising the ELAD participants and storing and distributing the drug. Participants who drop out of the ELAD study will be recorded as either defaulters or withdrawn. Defaulters are participants who withdraw their consent to participate in the trial, affecting both treatment and assessment.
No further assessments can be made of these participants. Withdrawn are participants who are withdrawn from treatment at the discretion of the chief investigator because of clinical factors, poor compliance, or a change in circumstances. Withdrawn participants will remain in the study and trial assessments will still be undertaken. The reason for dropping out will also be recorded.
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Investigators should be able to distinguish between drop-outs due to dementia-related factors e. Every effort will be made to collect outcome data on all participants who withdraw from treatment for whatever reason. If participants withdraw from treatment, all endpoint assessments should be carried out at the point of drop-out and at the month endpoint.
It may not be possible to complete some assessments with non-compliant participants. However, assessments will be carried out wherever possible and in all such cases at the month endpoint. Unblinding will take place when the study has been completed and the data files have been verified. Unblinding for any other reason will be considered a protocol violation. Clinical data will be entered into paper-based case report forms CRFs , and then transferred into computers via Inform version 4.
The data manager will arrange appropriate quality assurance checks. Participants eligible for study entry will be given a unique, sequential, centre-specific ELAD study identifier. After each assessment, data will be entered into CRFs and the study database at each site.
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Immediately after each assessment, the data will be backed up electronically and securely stored locally. These files will be backed-up onto a password-protected environment on a weekly basis. Hard copies will be stored locally, compliant with the Data Protection Act Every 2 weeks, data will be sent electronically to the data management centre at Imperial College London. Security will be maintained using email to and from password-protected, networked accounts and will comply with all regulatory requirements.
The data management centre will merge data across centres and assessment points. Safety and tolerability assessments will consist of monitoring and recording all adverse events and serious adverse events, and the regular monitoring of vital signs. Clinically significant abnormalities in vital signs, laboratory evaluations, ECG recordings, and physical examinations will be recorded as adverse events and followed up as appropriate.
As far as possible, each adverse event will be described by its duration, severity grade, and relationship to the study drug, the action s taken, and, if relevant, the outcome. Information about all serious adverse events will be collected on the ELAD trial. A Suspected Unexpected Serious Adverse Reaction SUSAR is any adverse reaction that is classed as serious and suspected to be caused by the investigational medicine product that is not consistent with the information about it in the summary of product characteristics i.
The trial protocol includes a list of known side effects for the drug in the study. If the event is not listed as expected or has occurred in a more serious form than anticipated, this will be considered a SUSAR. During each contact with trial site staff site visits and telephone contacts , participants will be asked about adverse events and technical complaints. All adverse events, either observed by the site investigator or reported by the participant, will be reported by the investigator and evaluated by the Principal Investigator at each site.
The primary analysis will be based on the modified intention-to-treat population. Participants will be analysed according to their allocated treatment group irrespective of what treatment they actually received. A full, detailed analysis plan will be prepared before the data are unblinded. Patient demographic characteristics and other baseline information will be summarised by treatment group.
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Numbers with percentages for binary and categorical variables and mean standard deviation or median interquartile or full range for continuous variables will be presented. The distribution of the change from baseline will be formally assessed for evidence of departure from normality.
If necessary, data will be transformed or analysed using a non-parametric equivalent. For outcomes measured on more than one occasion e. The data will be transformed or non-parametric methods used if the model assumptions are not met. If participants withdraw from treatment, the endpoint assessments should all be carried out at the point of drop-out and at the week endpoint.
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Although it may not be possible to complete some assessments of non-compliant participants, assessments should be carried out wherever possible and in all such cases at the week endpoint. The primary analysis will include all available data, including data from withdrawn participants irrespective of levels of treatment compliance. Assessing outcomes in participants with different levels of compliance will be performed as part of the per-protocol analysis with the per-protocol populations defined in the Statistical Analysis Plan.
The per-protocol population is all participants who received the allocated treatment with no major protocol deviations and who have provided results at the end of follow-up assessment. The chief investigator has overall responsibility for the conduct of the study. The trial management group has responsibility for the day-to-day management of the trial. The trial steering committee, comprising independent clinicians and an independent statistician, acts as the oversight body for the trial on behalf of the sponsor.