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    Clinical Trial Results:
    Naltrexone Enhanced Addiction Treatment (NEAT): A randomised controlled trial of the clinical and cost-effectiveness of extended-release naltrexone and oral naltrexone.

    Summary
    EudraCT number
    		 2013-002584-25
    Trial protocol
    		 GB  
    Global end of trial date
    09 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Mar 2019
    First version publication date
    23 Mar 2019
    Other versions
    Summary report(s)
    		 FINAL STUDY REPORT

    Trial information

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    Trial identification
    Sponsor protocol code
    10/46/01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    King's College London
    Sponsor organisation address
    The Strand, London, United Kingdom, WC2R 2LS
    Public contact
    Professor Sir John Strang, Institute of Psychiatry, Psychology & Neuroscience (IoPPN) , 44 0207 848 5109, john.strang@kcl.ac.uk
    Scientific contact
    Professor Sir John Strang, Institute of Psychiatry, Psychology & Neuroscience (IoPPN) , 44 0207 848 5109, john.strang@kcl.ac.uk
    Sponsor organisation name
    South London & Maudsley NHS Foundation Trust
    Sponsor organisation address
    Bethlem Royal Hospital, Monks Orchard Road, Beckenham, United Kingdom, BR3 3BX
    Public contact
    Professor Sir John Strang, South Londn & Maudsley NHS Foundation Trust, 44 207848 5109, john.strang@kcl.ac.uk
    Scientific contact
    Professor Sir John Strang, South Londn & Maudsley NHS Foundation Trust, 44 207848 5109, john.strang@kcl.ac.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
    09 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    A. Is XR-NTX treatment more effective than placebo at reducing heroin use? B. Is XR-NTX more effective than O-NTX at reducing heroin use? C. Is XR-NTX more cost- effective than placebo in terms of quality-adjusted life years? D. Is XR-NTX more cost-effective than O-NTX in terms of quality-adjusted life year?
    Protection of trial subjects
    Oral medication will be administered under direct supervision in the outpatients clinics on Mondays (100mg), Wednesdays (100mg) and Fridays (150mg, a higher dose to last till Monday) for the first 4 weeks. Oral medication during weeks 1-4 will be directly observed. Small doses may be given as take away medication if clinic attendance is impossible (e.g. due to court appearances, urgent hospital appointments etc). Contingent on good adherence during the first month, patients will be able to self-administer oral medication (weeks 5-12 dispensed on a week by week basis and contingent on attendance at the clinic three times a week to complete research measures and return packaging and report dosing. If there are any adherence problems, the patient will be supervised for 2 weeks and will return to self-administration if adherence picks up.
    Background therapy
    		 Participants are voluntarily seeking opioid antagonist treatment for opioid use disorder.
    Evidence for comparator
    		 not applicable
    Actual start date of recruitment
    01 Mar 2015
    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: 6
    Worldwide total number of subjects
    6
    EEA total number of subjects
    6
    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)
    6
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from a well-established specialist NHS outpatient addiction clinic in London between 2015 and 2018

    Pre-assignment
    Screening details
    		 1. Is 18 years of age or older. 2. Can demonstrate a verbal understanding of the study patient information material, and confirm willingness to comply with the protocol. 3. Has a diagnosis of opioid use disorder based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5: past 12 months),) conducted at

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    • O-NTX - Active and placebo oral medications packaged identically in blister strips . • XR- NTX Active and placebo implant devices packaged identically.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A - Active XR-NTX and placebo O-NTX
    Arm description
    		 • 1 iGen/Atral-Cipan (XR-NTX) implant (765mg) or matching placebo at Day 0 of Study Week 1. • 3 x O-NTX tablets (2 x 50mg, Monday and Wednesday; 3 x 50mg, Friday) or matching placebo at Day 0 of Study Week 1 (for 12 weeks), directly observed for first 4 weeks and then patient reporting self-consumption for next 8 weeks when attending clinic to complete research measures. (NB: The higher dose given on Fridays is to cover the weekend period). The oral placebo tablet has the same excipients as the active medication. The tablet core contains: lactose Anhydrous, lactose monohydrate, microcrystalline cellulose, and magnesium stearate. Each tablet is film-coated with: Opadry II Yellow and purified water pheur. .
    Arm type
    		 Experimental

    Investigational medicinal product name
    NALTREXONE IMPLANT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Naltrexolle Tablet 765mg for Implantation is supplied as a slow release copolymer based fannulation of naltrexone for Implantation. to be administered surgically inserted into the subcutaneous tissues of the inguinal area.

    Investigational medicinal product name
    PLACEBO TABLET FOR ORAL USE
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matched placebo tablet administered orally

    Arm title
    		 Group B - Placebo XR-NTX and active O-NTX
    Arm description
    		 • 1 iGen/Atral-Cipan (XR-NTX) implant (765mg) or matching placebo at Day 0 of Study Week 1. • 3 x O-NTX tablets (2 x 50mg, Monday and Wednesday; 3 x 50mg, Friday) or matching placebo at Day 0 of Study Week 1 (for 12 weeks), directly observed for first 4 weeks and then patient reporting self-consumption for next 8 weeks when attending clinic to complete research measures. (NB: The higher dose given on Fridays is to cover the weekend period). The oral placebo tablet has the same excipients as the active medication. The tablet core contains: lactose Anhydrous, lactose monohydrate, microcrystalline cellulose, and magnesium stearate. Each tablet is film-coated with: Opadry II Yellow and purified water pheur. .
    Arm type
    		 Active comparator

    Investigational medicinal product name
    PLACEBO TABLET IMPLANT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo tablet for Implantation to be administered surgically inserted into the subcutaneous tissues of the inguinal area.

    Investigational medicinal product name
    Naltrexone Hydrochloride 50 mg film-coated tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Naltrexone Hydrochloride 50 mg film-coated tabletsO administered under direct supervision in the outpatients clinics on Mondays (100mg), Wednesdays (100mg) and Fridays (150mg, a higher dose to last till Monday) for the first 4 weeks. Oral medication during weeks 1-4 will be directly observed. Small doses may be given as take away medication if clinic attendance is impossible (e.g. due to court appearances, urgent hospital appointments etc). Contingent on good adherence during the first month, patients will be able to self-administer oral medication (weeks 5-12 dispensed on a week by week basis and contingent on attendance at the clinic three times a week to complete research measures and return packaging and report dosing. If there are any adherence problems, the patient will be supervised for 2 weeks and will return to self-administration if adherence picks up.

    Arm title
    		 Group C - Placebo XR-NTX and placebo O-NTX
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    PLACEBO IMPLANT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo tablet surgically inserted into the subcutaneoustissues of the inguinal area.

    Investigational medicinal product name
    PLACEBO TABLET FOR ORAL USE
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matched placebo tablet administered orally

    Number of subjects in period 1
    		Group A - Active XR-NTX and placebo O-NTX Group B - Placebo XR-NTX and active O-NTX Group C - Placebo XR-NTX and placebo O-NTX
    Started
    2
    1
    3
    Completed
    2
    1
    3

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Group A - Active XR-NTX and placebo O-NTX
    Reporting group description
    		 • 1 iGen/Atral-Cipan (XR-NTX) implant (765mg) or matching placebo at Day 0 of Study Week 1. • 3 x O-NTX tablets (2 x 50mg, Monday and Wednesday; 3 x 50mg, Friday) or matching placebo at Day 0 of Study Week 1 (for 12 weeks), directly observed for first 4 weeks and then patient reporting self-consumption for next 8 weeks when attending clinic to complete research measures. (NB: The higher dose given on Fridays is to cover the weekend period). The oral placebo tablet has the same excipients as the active medication. The tablet core contains: lactose Anhydrous, lactose monohydrate, microcrystalline cellulose, and magnesium stearate. Each tablet is film-coated with: Opadry II Yellow and purified water pheur. .

    Reporting group title
    Group B - Placebo XR-NTX and active O-NTX
    Reporting group description
    		 • 1 iGen/Atral-Cipan (XR-NTX) implant (765mg) or matching placebo at Day 0 of Study Week 1. • 3 x O-NTX tablets (2 x 50mg, Monday and Wednesday; 3 x 50mg, Friday) or matching placebo at Day 0 of Study Week 1 (for 12 weeks), directly observed for first 4 weeks and then patient reporting self-consumption for next 8 weeks when attending clinic to complete research measures. (NB: The higher dose given on Fridays is to cover the weekend period). The oral placebo tablet has the same excipients as the active medication. The tablet core contains: lactose Anhydrous, lactose monohydrate, microcrystalline cellulose, and magnesium stearate. Each tablet is film-coated with: Opadry II Yellow and purified water pheur. .

    Reporting group title
    Group C - Placebo XR-NTX and placebo O-NTX
    Reporting group description
    		 Placebo

    Primary: Primary Endpoints

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    End point title
    		 Primary Endpoints [1]
    End point description
    The aim of the NEAT study was to determine the clinical effectiveness and cost-effectiveness of enhanced naltrexone in the treatment of OUD, with the primary objective of answering the following questions: 1. Is extended-release naltrexone treatment more effective than placebo extended-release naltrexone at reducing heroin use? 2. Is extended-release naltrexone is more effective than oral naltrexone at reducing heroin use? 3. What is the relative cost-effectiveness of extended-release naltrexone and oral naltrexone treatment in terms of quality-adjusted life-years? 4. Is extended-release naltrexone more cost-effective than oral naltrexone in terms of quality-adjusted life-years gained?
    End point type
    Primary
    End point timeframe
    Duration of trial.
    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: Please see attachment for full results.
    End point values
    		 Group A - Active XR-NTX and placebo O-NTX Group B - Placebo XR-NTX and active O-NTX Group C - Placebo XR-NTX and placebo O-NTX
    Number of subjects analysed
    2
    1
    3
    Units: whole
    2
    1
    3
    Attachments
    		 FINAL RESULTS
    No statistical analyses for this end point

    Secondary: Secondary Endpoints

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    End point title
    		 Secondary Endpoints
    End point description
    1. compare treatment retention and medication and psychological intervention adherence rates among the extended-release naltrexone, oral naltrexone and placebo conditions 2. contrast the extended-release naltrexone, oral naltrexone and placebo conditions on quality-of-life indices 3. contrast extended-release naltrexone, oral naltrexone and placebo conditions on: l heroin and cocaine craving l self-reported opioid, cocaine, amphetamine and benzodiazepine use (with past 48-hour abstinence verified via UDS) l alcohol use l injection health risk behaviours l psychological health (depression and anxiety symptoms)
    End point type
    Secondary
    End point timeframe
    Duration of Trial
    End point values
    		 Group A - Active XR-NTX and placebo O-NTX Group B - Placebo XR-NTX and active O-NTX Group C - Placebo XR-NTX and placebo O-NTX
    Number of subjects analysed
    2
    1
    3
    Units: whole
    2
    1
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    36 weeks trial duration.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Whole Trial
    Reporting group description
    		 -

    Serious adverse events
    		 Whole Trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Heroin Overdose
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Whole Trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    General disorders and administration site conditions
    Pain at site of inplant
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Sep 2015
    Addition of new secondary objective and deletion of a secondary objective. Changes to IMP labelling
    15 Jan 2016
    Plasma naltrexone’ added to the secondary endpoint summary as it is mentioned in the text of the’ plasma monitoring’ section later in the protocol but not in the summary. The ‘naloxone challenge’ was moved from week 1 to randomisation as it was entered in week 1 in error Text was added to the ‘Dispensing and distribution’ section to allow for emergency issuing of drug. Reference to ‘antipsychotics, anticonvulsants, antidepressants and anxiolytics’ was removed in the ‘Concomitant Medication’ section as there is no evidence to support those types of drugs being prohibited medication. The 48 hour minimum time period was removed from Inclusion Criteria 2 The text in Inclusion Criteria 5 ‘a Morphone 2000 [opioid]’ was removed as that type of UDS cup is no longer being used in the study. Exclusion criteria 18 has been amended due to concern of potentially vulnerable patients not having naltrexone to carry them through screening period. Some potential patients will need naltrexone during the screening period as they would have just been released from prison and the normal clinical practice is to give these patients naltrexone so they won’t overdose. Exclusion criteria 20 was changed from ‘Current (past 30 day) suicidal ideation/plan, or recent (past six months) suicidal ideation or suicide attempt’ to ‘Current (past 30 day) suicidal planning, or recent (past six months) suicide attempt.’ as this is more in line with clinical practice. In the ‘Primary Effectiveness Parameters’ the analysis model has been changed from an analysis of covariance model to a regression model.
    09 May 2016
    Change in the language of the exclusion criteria to allow a holding does of naltrexone if there is a length of time between randomisation and the start of treatment. Addition of more detailed statistics section

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    It is not possible to reach firm conclusions from the observations on the small number of study participants who entered the study. This is a major limitation within this report.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30702059
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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