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    Clinical Trial Results:
    LACunar Intervention (LACI-2) Trial-2: Assessment of safety and efficacy of cilostazol and isosorbide mononitrate to prevent recurrent lacunar stroke and progression of cerebral small vessel disease.

    Summary
    EudraCT number
    		 2016-002277-35
    Trial protocol
    		 GB  
    Global end of trial date
    12 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Sep 2023
    First version publication date
    16 Sep 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC16093
    Additional study identifiers
    ISRCTN number
    		 ISRCTN14911850
    US NCT number
    		 NCT03451591
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ACCORD
    Sponsor organisation address
    The Queen’s Medical Research Institute 47 Little France Crescent Edinburgh, , Edinburgh, United Kingdom, EH16 4TJ
    Public contact
    Fiach O'Mahony, University of Edinburgh, +44 01312429418, Fiach.omahony@ed.ac.uk
    Scientific contact
    Fiach O'Mahony, University of Edinburgh, +44 01312429418, Fiach.omahony@ed.ac.uk
    Sponsor organisation name
    ACCORD
    Sponsor organisation address
    The Queen’s Medical Research Institute 47 Little France Crescent , Edinburgh , United Kingdom, EH16 4TJ
    Public contact
    Heather Charles, NHS Lothian/University of Edinburgh, +44 01312423359, heathercharles@nhslothian.scot.nhs.uk
    Scientific contact
    Heather Charles, NHS Lothian/University of Edinburgh, +44 01312423359, heathercharles@nhslothian.scot.nhs.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Aug 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this trial is to find out whether a much larger scale study testing the effects of Cilostazol and ISMN on preventing brain damage from small vessel disease will be achievable in the future. We will assess how easy is it to identify suitable patients, how many of them are willing to take part in the study and how many stay on the study for the full 12 months. Feedback from participants on study procedures/burden will also inform any future studies. We will also collect information on how many patients have another stroke, experience difficulties in independent daily living or in thinking skills, and on drug safety such as bleeding.
    Protection of trial subjects
    The inclusion and exclusion criteria were put in place to ensure only suitable participants entered the study. Doses were escalated until participants are on their full dose by 1 month. If a patient encounters intolerable side effects at full dose, then they will be able to remain on the highest dose regime that they can tolerate and this dose will be recorded.
    Background therapy
    		 None
    Evidence for comparator
    		 There is no proven treatment for cerebral small vessel disease: conventional antiplatelet drugs may be ineffective or even hazardous, whilst antihypertensive treatment and statins may not have an effect. The disease mechanism is poorly understood but endothelial dysfunction, blood-brain barrier failure and vessel stiffness appear to contribute to the pathogenesis. Promising data available for licensed drugs with relevant modes of action, cilostazol (>6000 stroke patients in the Asia Pacific Region) and isosorbide mononitrate (ISMN, widely used in cardiac disease) support their testing in cerebral small vessel disease.
    Actual start date of recruitment
    08 Jan 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 363
    Worldwide total number of subjects
    363
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    186
    From 65 to 84 years
    173
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between 05/02/2018 and 31/05/2022, LACI-2 recruited 363/400 patients at 26 UK centres.

    Pre-assignment
    Screening details
    		 Following consent, the research doctor will confirm that the patient is eligible to participate in the trial as per the inclusion/exclusion criteria. This will be documented in the eCRF and in the patients medical notes.

    Period 1
    Period 1 title
    Baseline to Follow up (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    Structured symptom questionnaires, ascertainment of clinical outcomes and MRI analysis will be collected by individuals blinded to treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cilostazol
    Arm description
    		 Cilostazol, generic, as 50mg or 100mg tablets.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cilostazol
    Investigational medicinal product code
    B01A C
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cilostazol, generic, as 50mg or 100mg tablets.

    Investigational medicinal product name
    Isosorbide Mononitrate
    Investigational medicinal product code
    C01DA14
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Isosorbide mononitrate slow release, generic, for example as 25mg XL or 50mg XL tablets to the suggested target dose of 40-60mg daily. Isosorbide mononitrate, generic, as 20mg tablets to the suggested target dose of 40-60mg daily. Most isosorbide mononitrate preparations are slow release in the UK. However, where slow release preparations of isosorbide mononitrate are not available, then non-slow release preparations may be used, but the dose should be split half in the morning (e.g. 08.00 am) and half in the evening (e.g. 18.00hrs). Non-slow release preparations may only be available in 20mg tablets in which case the 20mg should be substituted for the 25mg dose. A target dose of ISMN is 40-60mg daily. Detailed prescribing and administration instructions will be provided in the treatment pack.

    Arm title
    		 Isosorbide Mononitrate
    Arm description
    		 Isosorbide mononitrate slow release, generic, for example as 25mg XL or 50mg XL tablets to the suggested target dose of 40-60mg daily. Isosorbide mononitrate, generic, as 20mg tablets to the suggested target dose of 40-60mg daily. Most isosorbide mononitrate preparations are slow release in the UK. However, where slow release preparations of isosorbide mononitrate are not available, then non-slow release preparations may be used, but the dose should be split half in the morning (e.g. 08.00 am) and half in the evening (e.g. 18.00hrs). Non-slow release preparations may only be available in 20mg tablets in which case the 20mg should be substituted for the 25mg dose. A target dose of ISMN is 40-60mg daily. Detailed prescribing and administration instructions will be provided in the treatment pack.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Isosorbide Mononitrate
    Investigational medicinal product code
    C01DA14
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Isosorbide mononitrate slow release, generic, for example as 25mg XL or 50mg XL tablets to the suggested target dose of 40-60mg daily. Isosorbide mononitrate, generic, as 20mg tablets to the suggested target dose of 40-60mg daily. Most isosorbide mononitrate preparations are slow release in the UK. However, where slow release preparations of isosorbide mononitrate are not available, then non-slow release preparations may be used, but the dose should be split half in the morning (e.g. 08.00 am) and half in the evening (e.g. 18.00hrs). Non-slow release preparations may only be available in 20mg tablets in which case the 20mg should be substituted for the 25mg dose. A target dose of ISMN is 40-60mg daily. Detailed prescribing and administration instructions will be provided in the treatment pack.

    Arm title
    		 Cilostazol + Isosorbide mononitrate
    Arm description
    		 Both Cilostazol and ISMN
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cilostazol
    Investigational medicinal product code
    B01A C
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cilostazol, generic, as 50mg or 100mg tablets.

    Investigational medicinal product name
    Isosorbide Mononitrate
    Investigational medicinal product code
    C01DA14
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Isosorbide mononitrate slow release, generic, for example as 25mg XL or 50mg XL tablets to the suggested target dose of 40-60mg daily. Isosorbide mononitrate, generic, as 20mg tablets to the suggested target dose of 40-60mg daily. Most isosorbide mononitrate preparations are slow release in the UK. However, where slow release preparations of isosorbide mononitrate are not available, then non-slow release preparations may be used, but the dose should be split half in the morning (e.g. 08.00 am) and half in the evening (e.g. 18.00hrs). Non-slow release preparations may only be available in 20mg tablets in which case the 20mg should be substituted for the 25mg dose. A target dose of ISMN is 40-60mg daily. Detailed prescribing and administration instructions will be provided in the treatment pack.

    Arm title
    		 No IMP
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Structured symptom questionnaires, ascertainment of clinical outcomes and MRI analysis will be collected by individuals blinded to treatment allocation so there is an element of blinding to the study.
    Number of subjects in period 1
    		Cilostazol Isosorbide Mononitrate Cilostazol + Isosorbide mononitrate No IMP
    Started
    91
    90
    91
    91
    Completed
    70
    70
    81
    87
    Not completed
    21
    20
    10
    4
         Consent withdrawn by subject
    7
    7
    3
    1
         Patient refused
    7
    -
    -
    -
         Lost to follow-up
    7
    8
    5
    3
         Refused
    -
    5
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cilostazol
    Reporting group description
    		 Cilostazol, generic, as 50mg or 100mg tablets.

    Reporting group title
    Isosorbide Mononitrate
    Reporting group description
    		 Isosorbide mononitrate slow release, generic, for example as 25mg XL or 50mg XL tablets to the suggested target dose of 40-60mg daily. Isosorbide mononitrate, generic, as 20mg tablets to the suggested target dose of 40-60mg daily. Most isosorbide mononitrate preparations are slow release in the UK. However, where slow release preparations of isosorbide mononitrate are not available, then non-slow release preparations may be used, but the dose should be split half in the morning (e.g. 08.00 am) and half in the evening (e.g. 18.00hrs). Non-slow release preparations may only be available in 20mg tablets in which case the 20mg should be substituted for the 25mg dose. A target dose of ISMN is 40-60mg daily. Detailed prescribing and administration instructions will be provided in the treatment pack.

    Reporting group title
    Cilostazol + Isosorbide mononitrate
    Reporting group description
    		 Both Cilostazol and ISMN

    Reporting group title
    No IMP
    Reporting group description
    		 -

    Reporting group values
    		 Cilostazol Isosorbide Mononitrate Cilostazol + Isosorbide mononitrate No IMP Total
    Number of subjects
    		 91 90 91 91 363
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (standard deviation)
    		 64 ± 73 65 ± 72 63 ± 72 64 ± 74 -
    Gender categorical
    Units: Subjects
        Female
    		 28 27 27 30 112
        Male
    		 63 63 64 61 251
    Stroke onset to randomisation ≤ v > 100 days
    Units: Subjects
        Stroke onset to randomisation ≤100 days
    		 53 54 46 53 206
        Stroke onset to randomisation > 100 days
    		 38 36 45 38 157
    Highest Education Level
    Units: Subjects
        Postgraduate
    		 6 5 10 6 27
        Undergraduate
    		 9 8 9 11 37
        A-Level or Equivalent
    		 14 8 14 18 54
        O-Level/GCSE or Equivalent
    		 30 34 27 23 114
        Secondary School
    		 32 34 31 32 129
        Primary School
    		 0 1 0 1 2
    Stroke onset to randomisation, days*
    Units: Days
        arithmetic mean (standard deviation)
    		 75 ± 238.0 74.5 ± 251.0 100 ± 252.0 77 ± 256.0 -
    Systolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 145.2 ± 20.6 145 ± 18.1 145.1 ± 19.3 142.7 ± 20.1 -

    End points

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    End points reporting groups
    Reporting group title
    Cilostazol
    Reporting group description
    		 Cilostazol, generic, as 50mg or 100mg tablets.

    Reporting group title
    Isosorbide Mononitrate
    Reporting group description
    		 Isosorbide mononitrate slow release, generic, for example as 25mg XL or 50mg XL tablets to the suggested target dose of 40-60mg daily. Isosorbide mononitrate, generic, as 20mg tablets to the suggested target dose of 40-60mg daily. Most isosorbide mononitrate preparations are slow release in the UK. However, where slow release preparations of isosorbide mononitrate are not available, then non-slow release preparations may be used, but the dose should be split half in the morning (e.g. 08.00 am) and half in the evening (e.g. 18.00hrs). Non-slow release preparations may only be available in 20mg tablets in which case the 20mg should be substituted for the 25mg dose. A target dose of ISMN is 40-60mg daily. Detailed prescribing and administration instructions will be provided in the treatment pack.

    Reporting group title
    Cilostazol + Isosorbide mononitrate
    Reporting group description
    		 Both Cilostazol and ISMN

    Reporting group title
    No IMP
    Reporting group description
    		 -

    Primary: Feasibility of Trial

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    End point title
    		 Feasibility of Trial [1]
    End point description
    Feasibility of Phase III trial, i.e. that eligible patients can be identified correctly, in sufficient numbers, enrolled and >95% retained in follow-up at one year, to achieve feasibility target sample size recruitment and randomisation of 400 patients in 24 months in the UK.
    End point type
    Primary
    End point timeframe
    12 month
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary endpoint is a count of participants recruited. No special analysis was completed for this endpoint and no p-values were presented.
    End point values
    		 Cilostazol Isosorbide Mononitrate Cilostazol + Isosorbide mononitrate No IMP
    Number of subjects analysed
    91
    90
    91
    91
    Units: 363
        Completed 12 month FU
    70
    70
    81
    87
        Withdrawn, Refused, Lost to FU
    21
    20
    10
    4
    No statistical analyses for this end point

    Secondary: Rate of Dose Specific Trial Medication Tolerability

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    End point title
    		 Rate of Dose Specific Trial Medication Tolerability
    End point description
    It is estimated that in this trial 75% of patients will be able to tolerate trial medication, in at least half dose, up to one year after randomisation (i.e. less than 25% will stop trial medication completely through inability to tolerate the drugs). Count of participants with adherence to medication at half dose or more at 12 months.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    Number of subjects analysed
    Units: 363
    No statistical analyses for this end point

    Secondary: Incidence of treatment emergent adverse effects [safety]

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    End point title
    		 Incidence of treatment emergent adverse effects [safety]
    End point description
    Safety - symptoms of systemic or intracranial bleeding, recurrent cerebral and systemic vascular events, and vascular and non-vascular causes of death will be collected. It is estimated that in this trial the absolute risk of death, including fatal haemorrhage, will not differ significantly (ie fall outside the upper 95% CI) from 2% per year on trial drugs versus no trial drugs, when given in addition to guideline drugs; and will not increase bleeding or ischaemic SVD lesions significantly (at the p<0.01 level) on MRI.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    Number of subjects analysed
    Units: 363
    No statistical analyses for this end point

    Secondary: Treatment efficacy - rate of individual participant events (stroke, TIA, myocardial ischaemia, cognitive impairment and dementia)

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    End point title
    		 Treatment efficacy - rate of individual participant events (stroke, TIA, myocardial ischaemia, cognitive impairment and dementia)
    End point description
    It is estimated that in this trial the combined rate of recurrent stroke, MI, death, cognitive impairment and dependency will be 40-50% at one year after enrolment in order to detect modest but clinically-important reductions in poor outcomes. Clinical, functional, QoL and global outcomes at 12 months- Stroke/TIA, MI, Cognitive impairment, Dependency, Death. Data are number (%), or mean (standard deviation).
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    Number of subjects analysed
    Units: 363
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From randomisation to 12 months
    Adverse event reporting additional description
    None
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Uni of Notts Stroke
    Dictionary version
    1.4.8
    Reporting groups
    Reporting group title
    Cilostazol
    Reporting group description
    		 Cilostazol, generic, as 50mg or 100mg tablets.

    Reporting group title
    Isosorbide Mononitrate
    Reporting group description
    		 Isosorbide mononitrate slow release, generic, for example as 25mg XL or 50mg XL tablets to the suggested target dose of 40-60mg daily. Isosorbide mononitrate, generic, as 20mg tablets to the suggested target dose of 40-60mg daily. Most isosorbide mononitrate preparations are slow release in the UK. However, where slow release preparations of isosorbide mononitrate are not available, then non-slow release preparations may be used, but the dose should be split half in the morning (e.g. 08.00 am) and half in the evening (e.g. 18.00hrs). Non-slow release preparations may only be available in 20mg tablets in which case the 20mg should be substituted for the 25mg dose. A target dose of ISMN is 40-60mg daily. Detailed prescribing and administration instructions will be provided in the treatment pack.

    Reporting group title
    Cilostazol + Isosorbide mononitrate
    Reporting group description
    		 Both Cilostazol and ISMN

    Reporting group title
    No IMP
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Only SAEs were collected for this study as per protocol
    Serious adverse events
    		 Cilostazol Isosorbide Mononitrate Cilostazol + Isosorbide mononitrate No IMP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 182 (15.93%)
    21 / 181 (11.60%)
    15 / 91 (16.48%)
    12 / 91 (13.19%)
         number of deaths (all causes)
    1
    1
    0
    1
         number of deaths resulting from adverse events
    1
    1
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour/Malignancy
         subjects affected / exposed
    4 / 182 (2.20%)
    1 / 181 (0.55%)
    1 / 91 (1.10%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiovascular
         subjects affected / exposed
    7 / 182 (3.85%)
    5 / 181 (2.76%)
    4 / 91 (4.40%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    2 / 7
    2 / 5
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous System
         subjects affected / exposed
    7 / 182 (3.85%)
    2 / 181 (1.10%)
    1 / 91 (1.10%)
    4 / 91 (4.40%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haematological
         subjects affected / exposed
    0 / 182 (0.00%)
    1 / 181 (0.55%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Other
         subjects affected / exposed
    6 / 182 (3.30%)
    5 / 181 (2.76%)
    3 / 91 (3.30%)
    4 / 91 (4.40%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal
         subjects affected / exposed
    8 / 182 (4.40%)
    7 / 181 (3.87%)
    5 / 91 (5.49%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory
         subjects affected / exposed
    2 / 182 (1.10%)
    1 / 181 (0.55%)
    1 / 91 (1.10%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Renal and urinary disorders
    Genitourinary
         subjects affected / exposed
    4 / 182 (2.20%)
    1 / 181 (0.55%)
    1 / 91 (1.10%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal
         subjects affected / exposed
    1 / 182 (0.55%)
    1 / 181 (0.55%)
    0 / 91 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infection/Sepsis
         subjects affected / exposed
    6 / 182 (3.30%)
    5 / 181 (2.76%)
    2 / 91 (2.20%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cilostazol Isosorbide Mononitrate Cilostazol + Isosorbide mononitrate No IMP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 182 (0.00%)
    0 / 181 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Dec 2017
    Substantial Amendment 1 Addition of 4 new sites (Glasgow, Northwick Park, Inverness, Doncaster)
    17 Jan 2018
    Substantial Amendment 2 Addition of 2 new sites (Aberdeen, Leicester)
    21 Mar 2018
    Substantial Amendment 3 Change of PI at 2 sites (Bradford, Aberdeen)
    30 Apr 2018
    Substantial Amendment 4 SPC updated, study cards added, study packs updated
    28 May 2018
    Substantial Amendment 5 Addition of 6 new sites (Winchester, Luton, Sandwell, Calderdale, Sheffield, Wolverhampton)
    12 Sep 2018
    Substantial Amendment 6 Addition of second Participant Invitation letter and Addition of 4 sites (Southampton, Musgrove Park, Devon, Homerton)
    13 Feb 2019
    Substantial Amendment 7 Updates to central follow-up documents and PI change (Northwick Park)
    22 Mar 2019
    Substantial Amendment 8 PI change St George's
    12 Jun 2019
    Substantial Amendment 9 PI change Wolverhampton
    16 Aug 2019
    Substantial Amendment 10 PI change Nottingham+ Inverness, minor updates to structured questionnaires
    13 Feb 2020
    Substantial Amendment 11 Clarification of exclusion criteria, Clarification of Adverse Event reporting requirements, Addition of central blinded review of Serious Adverse Events, Other minor changes to the protocol and the Structured Questionnaire

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Mar 2020
    In line with Sponsor guidance, recruitment was halted on 17Mar2020 due to the COVID-19 pandemic . LACI-2 received Sponsor approval to restart recruitment on 10Jun2020 and all sites were asked to complete the restart checklist when they had capacity to restart.
    10 Jun 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Open label design may facilitate bias, however, follow-up co-ordinators were blinded. Recruitment and follow-up at sites was affected by the COVID pandemic. As a factorial trial, comparison of the combination of drugs versus none was underpowered.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33072884
    http://www.ncbi.nlm.nih.gov/pubmed/37222252
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