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    Clinical Trial Results:
    Effectiveness and cost of integrating a protocol with use of liraglutide 3.0mg into an obesity service (STRIVE Study)

    Summary
    EudraCT number
    		 2017-002998-20
    Trial protocol
    		 GB  
    Global end of trial date
    25 Feb 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Mar 2023
    First version publication date
    11 Mar 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    UNOLE0626
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03036800
    WHO universal trial number (UTN)
    		 U1111-1189-5726
    Other trial identifiers
    		 REC: 17/NW/0517
    Sponsors
    Sponsor organisation name
    University of Leicester Research Governance Office - Sponsor
    Sponsor organisation address
    Leicester General Hospital, Gwendolen Road, Leicester, United Kingdom, LE5 4PW
    Public contact
    Professor Melanie Davies, University of Leicester, +44 0116 258 6481, melanie.davies@uhl-tr.nhs.uk
    Scientific contact
    Professor Melanie Davies, University of Leicester, +44 0116 258 6481, melanie.davies@uhl-tr.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
    04 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Feb 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective will be to compare the proportion of participants with severe and complicated obesity (defined as BMI ≥35 kg/m2 with at least one major obesity-related comorbidity) achieving weight loss ≥15% at 1 year (52 weeks) with a targeted prescribing pathway (i.e. use of LIRA 3mg according to a pre-specified protocol in combination with standard care provided in Tier 3 services) versus standard care provided in Tier 3 services alone.
    Protection of trial subjects
    Severe and complicated obesity’ is a substantial health problem that is defined as a body mass index (BMI) ≥35kg/m2 with at least one major obesity-related comorbidity. In England, the proportion of adults with severe and complicated obesity has risen alarmingly over the last two decades. Approximately 10% of the adult population in England now has a BMI ≥35kg/m2. In this group, 8-16% have type 2 diabetes mellitus (T2DM), imposing colossal direct and indirect healthcare costs. In the United Kingdom, standard care for patients with severe and complicated obesity is currently variable, but generally includes referral to a ‘Tier 3’ or specialist weight management service, which comprises a multi-disciplinary team of experts, including psychological support. Depending on the centre, this team uses a combination strategy of optimal diet and lifestyle advice, meal replacements, and pharmacological therapies to facilitate weight loss. According to current guidelines, individuals with severe and complicated obesity qualify for bariatric surgery, which is one of the treatment options also available in a Tier 3 specialist weight management service. However, the majority of patients prefer not to have surgical interventions for their obesity, but are unable to achieve adequate long term weight loss with currently available non-surgical options. All participants will be reviewed regularly by the study clinician via face to face and telephone consultations. Those on the liraglutide arm will have additional visit to those on the control arm. All adverse events will be monitored at each study visit and all serious adverse events will be reported to the sponsor within the agreed timelines. All AE's and SAE's will be followed up at each study visit. The safety of the participants will be monitored very closely.
    Background therapy
    		 Liraglutide 3.0 mg (LIRA 3mg) has been recently approved for the treatment of obesity by the European Medicines Agency (EMA) and Food and Drug Administration (FDA), as evidence from large randomised controlled trials (RCTs) has demonstrated that it is a safe and effective treatment option for obesity in diverse patient groups. The majority of the trials involving LIRA 3mg have been placebo controlled, have included patients with BMI as low as 27 kg/m2, and have all continued LIRA 3mg treatment from the start of treatment for up to 3 years, irrespective of individual effectiveness, even for patients who fail to lose any weight. Best clinical practice would suggest that patients who fail to lose weight should not be continued on treatment because they are exposed to increased risk of adverse effects without significant benefit in terms of weight loss. Moreover, being randomised, with the uncertainty as to whether an active agent is being given, is a disincentive to compliance with diet and exercise advice for some patients. Effect sizes may be affected by the strict protocols of an RCT and these data may not be optimal for health economic analyses as real-world applicability and generalisability of RCTs are limited. Nonetheless, within the populations studied, LIRA 3mg resulted in ≥15% weight loss in 14% of patients, compared with 3.5% of patients with placebo, a reduction which is likely to generate major health benefits and long-term cost-savings, especially if weight loss can be maintained. Among obese patients with T2DM, weight loss is less, but the potential cost-savings are greater.
    Evidence for comparator
    		 Post-hoc analysis of the SCALE Obesity trial comparing “early responders” (lost ≥5% of their starting weight after 16 weeks of LIRA 3mg treatment) with “early non-responders” (lost <5% of their starting weight after 16 weeks of LIRA 3mg treatment) found that 24.2% of early responders had lost ≥15% of their bodyweight at 56 weeks compared with 1.8% of early non-responders. A different model for the use of LIRA 3mg has been suggested by the SCALE Maintenance study which required a substantial weight loss (≥5% of the baseline weight) with lifestyle changes (including meal replacement strategies) during a period of 12 weeks prior to commencing the drug. The study resulted in 26% of patients achieving ≥15% weight loss one year after treatment with LIRA 3mg compared with 6% of patients on placebo. Overall, these results suggest that the patients who are more likely to achieve clinically significant long-term weight loss with LIRA 3mg are those who achieve ≥5% weight loss during the first 12-16 weeks either with lifestyle changes or with LIRA 3mg treatment. It would be unethical to prescribe LIRA 3mg to all patients with severe and complicated obesity because the risk of adverse events would be increased without any likely benefit to the patient. Moreover, the cost of LIRA 3mg is likely to preclude routine use for the full range of patients included in clinical trials, or for all patients who currently present for treatment in ’Tier 3’ obesity services in the UK. Conversely, there is strong evidence that LIRA 3mg can lead to substantial weight reduction in some patients with severe and complicated obesity, thus it is imperative that this treatment is available to those who would benefit from it. We therefore propose testing a targeted prescribing pathway that would provide a pragmatic means by which to optimise the use of LIRA 3mg in a specialist obesity service.
    Actual start date of recruitment
    28 Nov 2017
    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
    Ireland: 124
    Country: Number of subjects enrolled
    United Kingdom: 268
    Worldwide total number of subjects
    392
    EEA total number of subjects
    124
    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)
    341
    From 65 to 84 years
    51
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were recruited from five sites across the UK & Ireland. Sites: University Hospitals Leicester, Guys & St Thomas Hospital London, Aintree University Hospital Liverpool, Glasgow Royal Infirmary and St Vincent's Dublin. Recruitment open: 22/11/2017 First recruit: 28/11/2017 Last recruit: 28/02/2020 Recruitment closed: 29/02/2020

    Pre-assignment
    Screening details
    		 Participants were screened for eligibility by their age, ability to understand English and give consent, their BMI, a stable body weight, whether they had been referred to their local tier 3 service and having one of the following: pre-diabetes, diabetes, hypertension and/or obstructive sleep apnoea. We screened a total of 434 participants.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard care (control group)
    Arm description
    		 Participants in the control group will follow the best medical care provided by the Tier 3 service at their site. This typically involves dietary advice to reduce energy intake, accompanied by a physical activity programme, both supported by behavioural change techniques with regular professional contacts. The nature of the standard care will vary between the different Tier 3 services at each site, as this is a pragmatic ‘real-world’ study. Clinician input will include the medical assessment of participants for severe and complicated obesity and the prescription of anti-obesity drugs as per local Tier 3 service policy. Those patients taking antihypertensive or antidepressant medication will be assessed and it will be at the clinician’s discretion as to whether these medications are changed. Participants will remain routinely in the Tier 3 service and may also be offered treatment options within the duration of the study, including bariatric surgery, in line with NICE guidance.
    Arm type
    		 Control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Liraglutide 3mg (intervention)
    Arm description
    		 Participants in the intervention group received the same standard care as those in the control group plus liraglutide 3mg was prescribed. Dose escalation of liraglutide occurred according to a pre-specified titration protocol, from 0.6mg to a maximum of 3.0mg daily. The liraglutide dose was initiated at 0.6mg and then increased to 1.2mg in Week 2, 1.8mg in Week 3, 2.4mg in Week 4, and 3.0mg in Week 5. Participants in the LIRA arm were made aware that continued use of LIRA 3mg was based upon their response to the treatment in terms of them achieving pre-defined weight loss targets at 16, 32 and 52 weeks. Stopping rule one: only those who had lost ≥5% of their baseline weight were offered further treatment with LIRA 3mg for another 16 weeks. Stopping rule two: only those who had lost ≥10% of their baseline weight were offered another 20 weeks. Stopping rule three: only those who had lost ≥15% of their baseline weight were offered another 52 weeks on LIRA 3mg.
    Arm type
    		 Intervention

    Investigational medicinal product name
    Liraglutide 3mg
    Investigational medicinal product code
    Other name
    Saxenda
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Saxenda 6mg/ml solution for injection in pre-filled pen in which 1ml of solution contains 6mg of liraglutide (human glucagon like peptide1 (GLP1) analogue produced by recombinant DNA technology in Saccharomyces Cerevisiae). One prefilled pen contains 18mg liraglutide in 3ml and can deliver doses of 0.6mg, 1.2mg, 1.8mg, 24.mg or 3mg via subcutaneous injection only. The IMP was formulated and supplied by Novo Nordisk for this trial.

    Number of subjects in period 1
    		Standard care (control group) Liraglutide 3mg (intervention)
    Started
    132
    260
    Completed
    132
    260
    Period 2
    Period 2 title
    Week 16
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard care (control group)
    Arm description
    		 Participants in the control group will follow the best medical care provided by the Tier 3 service at their site. This typically involves dietary advice to reduce energy intake, accompanied by a physical activity programme, both supported by behavioural change techniques with regular professional contacts. The nature of the standard care will vary between the different Tier 3 services at each site, as this is a pragmatic ‘real-world’ study. Clinician input will include the medical assessment of participants for severe and complicated obesity and the prescription of anti-obesity drugs as per local Tier 3 service policy. Those patients taking antihypertensive or antidepressant medication will be assessed and it will be at the clinician’s discretion as to whether these medications are changed. Participants will remain routinely in the Tier 3 service and may also be offered treatment options within the duration of the study, including bariatric surgery, in line with NICE guidance.
    Arm type
    		 Control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Liraglutide 3mg (intervention)
    Arm description
    		 Participants in the intervention group received the same standard care as those in the control group plus liraglutide 3mg was prescribed. Dose escalation of liraglutide occurred according to a pre-specified titration protocol, from 0.6mg to a maximum of 3.0mg daily. The liraglutide dose was initiated at 0.6mg and then increased to 1.2mg in Week 2, 1.8mg in Week 3, 2.4mg in Week 4, and 3.0mg in Week 5. Participants in the LIRA arm were made aware that continued use of LIRA 3mg was based upon their response to the treatment in terms of them achieving pre-defined weight loss targets at 16, 32 and 52 weeks. Stopping rule one: only those who had lost ≥5% of their baseline weight were offered further treatment with LIRA 3mg for another 16 weeks. Stopping rule two: only those who had lost ≥10% of their baseline weight were offered another 20 weeks. Stopping rule three: only those who had lost ≥15% of their baseline weight were offered another 52 weeks on LIRA 3mg.
    Arm type
    		 Intervention

    Investigational medicinal product name
    Liraglutide 3mg
    Investigational medicinal product code
    Other name
    Saxenda
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Saxenda 6mg/ml solution for injection in pre-filled pen in which 1ml of solution contains 6mg of liraglutide (human glucagon like peptide1 (GLP1) analogue produced by recombinant DNA technology in Saccharomyces Cerevisiae). One prefilled pen contains 18mg liraglutide in 3ml and can deliver doses of 0.6mg, 1.2mg, 1.8mg, 24.mg or 3mg via subcutaneous injection only. The IMP was formulated and supplied by Novo Nordisk for this trial.

    Number of subjects in period 2
    		Standard care (control group) Liraglutide 3mg (intervention)
    Started
    132
    260
    Completed
    117
    252
    Not completed
    15
    8
         Tolerance
    -
    1
         Reason not stated
    15
    6
         Protocol deviation
    -
    1
    Period 3
    Period 3 title
    Week 32
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard care (control group)
    Arm description
    		 Participants in the control group will follow the best medical care provided by the Tier 3 service at their site. This typically involves dietary advice to reduce energy intake, accompanied by a physical activity programme, both supported by behavioural change techniques with regular professional contacts. The nature of the standard care will vary between the different Tier 3 services at each site, as this is a pragmatic ‘real-world’ study. Clinician input will include the medical assessment of participants for severe and complicated obesity and the prescription of anti-obesity drugs as per local Tier 3 service policy. Those patients taking antihypertensive or antidepressant medication will be assessed and it will be at the clinician’s discretion as to whether these medications are changed. Participants will remain routinely in the Tier 3 service and may also be offered treatment options within the duration of the study, including bariatric surgery, in line with NICE guidance.
    Arm type
    		 Control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Liraglutide 3mg (intervention)
    Arm description
    		 Participants in the intervention group received the same standard care as those in the control group plus liraglutide 3mg was prescribed. Dose escalation of liraglutide occurred according to a pre-specified titration protocol, from 0.6mg to a maximum of 3.0mg daily. The liraglutide dose was initiated at 0.6mg and then increased to 1.2mg in Week 2, 1.8mg in Week 3, 2.4mg in Week 4, and 3.0mg in Week 5. Participants in the LIRA arm were made aware that continued use of LIRA 3mg was based upon their response to the treatment in terms of them achieving pre-defined weight loss targets at 16, 32 and 52 weeks. Stopping rule one: only those who had lost ≥5% of their baseline weight were offered further treatment with LIRA 3mg for another 16 weeks. Stopping rule two: only those who had lost ≥10% of their baseline weight were offered another 20 weeks. Stopping rule three: only those who had lost ≥15% of their baseline weight were offered another 52 weeks on LIRA 3mg.
    Arm type
    		 Intervention

    Investigational medicinal product name
    Liraglutide 3mg
    Investigational medicinal product code
    Other name
    Saxenda
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Saxenda 6mg/ml solution for injection in pre-filled pen in which 1ml of solution contains 6mg of liraglutide (human glucagon like peptide1 (GLP1) analogue produced by recombinant DNA technology in Saccharomyces Cerevisiae). One prefilled pen contains 18mg liraglutide in 3ml and can deliver doses of 0.6mg, 1.2mg, 1.8mg, 24.mg or 3mg via subcutaneous injection only. The IMP was formulated and supplied by Novo Nordisk for this trial.

    Number of subjects in period 3
    		Standard care (control group) Liraglutide 3mg (intervention)
    Started
    117
    252
    Completed
    113
    243
    Not completed
    4
    9
         Tolerance
    -
    1
         Reason not stated
    4
    8
    Period 4
    Period 4 title
    Week 52
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard care (control group)
    Arm description
    		 Participants in the control group will follow the best medical care provided by the Tier 3 service at their site. This typically involves dietary advice to reduce energy intake, accompanied by a physical activity programme, both supported by behavioural change techniques with regular professional contacts. The nature of the standard care will vary between the different Tier 3 services at each site, as this is a pragmatic ‘real-world’ study. Clinician input will include the medical assessment of participants for severe and complicated obesity and the prescription of anti-obesity drugs as per local Tier 3 service policy. Those patients taking antihypertensive or antidepressant medication will be assessed and it will be at the clinician’s discretion as to whether these medications are changed. Participants will remain routinely in the Tier 3 service and may also be offered treatment options within the duration of the study, including bariatric surgery, in line with NICE guidance.
    Arm type
    		 Control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Liraglutide 3mg (intervention)
    Arm description
    		 Participants in the intervention group received the same standard care as those in the control group plus liraglutide 3mg was prescribed. Dose escalation of liraglutide occurred according to a pre-specified titration protocol, from 0.6mg to a maximum of 3.0mg daily. The liraglutide dose was initiated at 0.6mg and then increased to 1.2mg in Week 2, 1.8mg in Week 3, 2.4mg in Week 4, and 3.0mg in Week 5. Participants in the LIRA arm were made aware that continued use of LIRA 3mg was based upon their response to the treatment in terms of them achieving pre-defined weight loss targets at 16, 32 and 52 weeks. Stopping rule one: only those who had lost ≥5% of their baseline weight were offered further treatment with LIRA 3mg for another 16 weeks. Stopping rule two: only those who had lost ≥10% of their baseline weight were offered another 20 weeks. Stopping rule three: only those who had lost ≥15% of their baseline weight were offered another 52 weeks on LIRA 3mg.
    Arm type
    		 Intervention

    Investigational medicinal product name
    Liraglutide 3mg
    Investigational medicinal product code
    Other name
    Saxenda
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Saxenda 6mg/ml solution for injection in pre-filled pen in which 1ml of solution contains 6mg of liraglutide (human glucagon like peptide1 (GLP1) analogue produced by recombinant DNA technology in Saccharomyces Cerevisiae). One prefilled pen contains 18mg liraglutide in 3ml and can deliver doses of 0.6mg, 1.2mg, 1.8mg, 24.mg or 3mg via subcutaneous injection only. The IMP was formulated and supplied by Novo Nordisk for this trial.

    Number of subjects in period 4
    		Standard care (control group) Liraglutide 3mg (intervention)
    Started
    113
    243
    Completed
    110
    237
    Not completed
    3
    6
         Non compliance
    -
    1
         Reason not stated
    3
    5
    Period 5
    Period 5 title
    Week 104
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard care (control group)
    Arm description
    		 Participants in the control group will follow the best medical care provided by the Tier 3 service at their site. This typically involves dietary advice to reduce energy intake, accompanied by a physical activity programme, both supported by behavioural change techniques with regular professional contacts. The nature of the standard care will vary between the different Tier 3 services at each site, as this is a pragmatic ‘real-world’ study. Clinician input will include the medical assessment of participants for severe and complicated obesity and the prescription of anti-obesity drugs as per local Tier 3 service policy. Those patients taking antihypertensive or antidepressant medication will be assessed and it will be at the clinician’s discretion as to whether these medications are changed. Participants will remain routinely in the Tier 3 service and may also be offered treatment options within the duration of the study, including bariatric surgery, in line with NICE guidance.
    Arm type
    		 Control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Liraglutide 3mg (intervention)
    Arm description
    		 Participants in the intervention group received the same standard care as those in the control group plus liraglutide 3mg was prescribed. Dose escalation of liraglutide occurred according to a pre-specified titration protocol, from 0.6mg to a maximum of 3.0mg daily. The liraglutide dose was initiated at 0.6mg and then increased to 1.2mg in Week 2, 1.8mg in Week 3, 2.4mg in Week 4, and 3.0mg in Week 5. Participants in the LIRA arm were made aware that continued use of LIRA 3mg was based upon their response to the treatment in terms of them achieving pre-defined weight loss targets at 16, 32 and 52 weeks. Stopping rule one: only those who had lost ≥5% of their baseline weight were offered further treatment with LIRA 3mg for another 16 weeks. Stopping rule two: only those who had lost ≥10% of their baseline weight were offered another 20 weeks. Stopping rule three: only those who had lost ≥15% of their baseline weight were offered another 52 weeks on LIRA 3mg.
    Arm type
    		 Intervention

    Investigational medicinal product name
    Liraglutide 3mg
    Investigational medicinal product code
    Other name
    Saxenda
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Saxenda 6mg/ml solution for injection in pre-filled pen in which 1ml of solution contains 6mg of liraglutide (human glucagon like peptide1 (GLP1) analogue produced by recombinant DNA technology in Saccharomyces Cerevisiae). One prefilled pen contains 18mg liraglutide in 3ml and can deliver doses of 0.6mg, 1.2mg, 1.8mg, 24.mg or 3mg via subcutaneous injection only. The IMP was formulated and supplied by Novo Nordisk for this trial.

    Number of subjects in period 5
    		Standard care (control group) Liraglutide 3mg (intervention)
    Started
    110
    237
    Completed
    104
    215
    Not completed
    6
    22
         Adverse event, serious fatal
    -
    1
         Tolerance
    -
    3
         Reason not stated
    6
    17
         Lost to follow-up
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Standard care (control group)
    Reporting group description
    		 Participants in the control group will follow the best medical care provided by the Tier 3 service at their site. This typically involves dietary advice to reduce energy intake, accompanied by a physical activity programme, both supported by behavioural change techniques with regular professional contacts. The nature of the standard care will vary between the different Tier 3 services at each site, as this is a pragmatic ‘real-world’ study. Clinician input will include the medical assessment of participants for severe and complicated obesity and the prescription of anti-obesity drugs as per local Tier 3 service policy. Those patients taking antihypertensive or antidepressant medication will be assessed and it will be at the clinician’s discretion as to whether these medications are changed. Participants will remain routinely in the Tier 3 service and may also be offered treatment options within the duration of the study, including bariatric surgery, in line with NICE guidance.

    Reporting group title
    Liraglutide 3mg (intervention)
    Reporting group description
    		 Participants in the intervention group received the same standard care as those in the control group plus liraglutide 3mg was prescribed. Dose escalation of liraglutide occurred according to a pre-specified titration protocol, from 0.6mg to a maximum of 3.0mg daily. The liraglutide dose was initiated at 0.6mg and then increased to 1.2mg in Week 2, 1.8mg in Week 3, 2.4mg in Week 4, and 3.0mg in Week 5. Participants in the LIRA arm were made aware that continued use of LIRA 3mg was based upon their response to the treatment in terms of them achieving pre-defined weight loss targets at 16, 32 and 52 weeks. Stopping rule one: only those who had lost ≥5% of their baseline weight were offered further treatment with LIRA 3mg for another 16 weeks. Stopping rule two: only those who had lost ≥10% of their baseline weight were offered another 20 weeks. Stopping rule three: only those who had lost ≥15% of their baseline weight were offered another 52 weeks on LIRA 3mg.

    Reporting group values
    		 Standard care (control group) Liraglutide 3mg (intervention) Total
    Number of subjects
    		 132 260 392
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 113 228 341
        From 65-84 years
    		 19 32 51
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.81 ± 10.77 51.10 ± 10.81 -
    Gender categorical
    Units: Subjects
        Female
    		 79 173 252
        Male
    		 53 87 140
    Ethnic Group
    Units: Subjects
        White
    		 114 225 339
        Black
    		 11 13 24
        South Asian
    		 3 11 14
        Mixed/Other
    		 4 11 15
    Body Mass Index
    Units: Subjects
        <40 kg/m2
    		 25 53 78
        ≥40 kg/m2
    		 106 207 313
        Missing
    		 1 0 1
    Smoking Status
    Units: Subjects
        Never smoker
    		 71 144 215
        Ex-smoker
    		 48 90 138
        Current smoker
    		 13 25 38
        Missing
    		 0 1 1
    Glycaemic Status
    Units: Subjects
        Normogylcaemia
    		 66 110 176
        Prediabetes
    		 20 42 62
        Diabetes remission
    		 3 9 12
        Diabetes
    		 41 98 139
        Missing
    		 2 1 3
    Hypertension Status
    Units: Subjects
        No
    		 44 96 140
        Yes
    		 88 162 250
        Missing
    		 0 2 2
    Sleep apnoea status
    Units: Subjects
        No
    		 54 113 167
        Yes
    		 68 124 192
        Missing
    		 10 23 33
    Type of diabetes medication
    Units: Subjects
        SGLT-2
    		 4 6 10
        Metformin
    		 28 59 87
        Sulphonylureas
    		 1 5 6
        Glitazones
    		 1 1 2
        Missing
    		 0 1 1
        N/A
    		 98 188 286
    Statin use
    Units: Subjects
        No
    		 101 190 291
        Yes
    		 31 70 101
    Number of all medications
    Units: Subjects
        None
    		 30 55 85
        One
    		 11 24 35
        Two
    		 17 17 34
        Three
    		 9 32 41
        Four
    		 7 24 31
        Five and over
    		 58 108 166
    Number of diabetes medications
    Units: Subjects
        Does not have diabetes
    		 91 162 253
        None
    		 12 35 47
        One
    		 22 52 74
        Two
    		 6 9 15
        3 and over
    		 1 2 3
    Number of antihypertensive medications
    Units: Subjects
        Does not have hypertension
    		 44 98 142
        None
    		 24 44 68
        One
    		 25 55 80
        Two
    		 22 33 55
        3 and over
    		 17 30 47
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 127.09 ± 21.42 129.02 ± 25.33 -
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 45.52 ± 7.25 46.22 ± 7.75 -
    Heart rate
    Units: beats/minute
        arithmetic mean (standard deviation)
    		 78.37 ± 12.24 78.27 ± 11.21 -
    Waist circumference
    Units: centimetre
        arithmetic mean (standard deviation)
    		 131.81 ± 12.95 132.44 ± 15.56 -
    HbA1c
    Units: millimole/mole
        arithmetic mean (standard deviation)
    		 44.71 ± 10.79 46.10 ± 13.72 -
    HbA1c
    Units: percent
        arithmetic mean (standard deviation)
    		 6.24 ± 0.99 6.36 ± 1.27 -
    Systolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 138.12 ± 17.79 135.77 ± 18.26 -
    Diastolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 81.99 ± 12.04 81.35 ± 10.94 -
    LDL cholesterol
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    		 2.70 ± 0.83 2.71 ± 0.84 -
    HDL cholesterol
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    		 1.25 ± 0.55 1.24 ± 0.30 -
    Total cholesterol
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    		 4.74 ± 0.95 4.76 ± 1.00 -
    Triglycerides
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    		 1.86 ± 0.94 1.85 ± 0.94 -
    Average total MET
    Units: minutes/week
        arithmetic mean (standard deviation)
    		 5463.48 ± 7958.59 5246.83 ± 7145.63 -

    End points

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    End points reporting groups
    Reporting group title
    Standard care (control group)
    Reporting group description
    		 Participants in the control group will follow the best medical care provided by the Tier 3 service at their site. This typically involves dietary advice to reduce energy intake, accompanied by a physical activity programme, both supported by behavioural change techniques with regular professional contacts. The nature of the standard care will vary between the different Tier 3 services at each site, as this is a pragmatic ‘real-world’ study. Clinician input will include the medical assessment of participants for severe and complicated obesity and the prescription of anti-obesity drugs as per local Tier 3 service policy. Those patients taking antihypertensive or antidepressant medication will be assessed and it will be at the clinician’s discretion as to whether these medications are changed. Participants will remain routinely in the Tier 3 service and may also be offered treatment options within the duration of the study, including bariatric surgery, in line with NICE guidance.

    Reporting group title
    Liraglutide 3mg (intervention)
    Reporting group description
    		 Participants in the intervention group received the same standard care as those in the control group plus liraglutide 3mg was prescribed. Dose escalation of liraglutide occurred according to a pre-specified titration protocol, from 0.6mg to a maximum of 3.0mg daily. The liraglutide dose was initiated at 0.6mg and then increased to 1.2mg in Week 2, 1.8mg in Week 3, 2.4mg in Week 4, and 3.0mg in Week 5. Participants in the LIRA arm were made aware that continued use of LIRA 3mg was based upon their response to the treatment in terms of them achieving pre-defined weight loss targets at 16, 32 and 52 weeks. Stopping rule one: only those who had lost ≥5% of their baseline weight were offered further treatment with LIRA 3mg for another 16 weeks. Stopping rule two: only those who had lost ≥10% of their baseline weight were offered another 20 weeks. Stopping rule three: only those who had lost ≥15% of their baseline weight were offered another 52 weeks on LIRA 3mg.
    Reporting group title
    Standard care (control group)
    Reporting group description
    		 Participants in the control group will follow the best medical care provided by the Tier 3 service at their site. This typically involves dietary advice to reduce energy intake, accompanied by a physical activity programme, both supported by behavioural change techniques with regular professional contacts. The nature of the standard care will vary between the different Tier 3 services at each site, as this is a pragmatic ‘real-world’ study. Clinician input will include the medical assessment of participants for severe and complicated obesity and the prescription of anti-obesity drugs as per local Tier 3 service policy. Those patients taking antihypertensive or antidepressant medication will be assessed and it will be at the clinician’s discretion as to whether these medications are changed. Participants will remain routinely in the Tier 3 service and may also be offered treatment options within the duration of the study, including bariatric surgery, in line with NICE guidance.

    Reporting group title
    Liraglutide 3mg (intervention)
    Reporting group description
    		 Participants in the intervention group received the same standard care as those in the control group plus liraglutide 3mg was prescribed. Dose escalation of liraglutide occurred according to a pre-specified titration protocol, from 0.6mg to a maximum of 3.0mg daily. The liraglutide dose was initiated at 0.6mg and then increased to 1.2mg in Week 2, 1.8mg in Week 3, 2.4mg in Week 4, and 3.0mg in Week 5. Participants in the LIRA arm were made aware that continued use of LIRA 3mg was based upon their response to the treatment in terms of them achieving pre-defined weight loss targets at 16, 32 and 52 weeks. Stopping rule one: only those who had lost ≥5% of their baseline weight were offered further treatment with LIRA 3mg for another 16 weeks. Stopping rule two: only those who had lost ≥10% of their baseline weight were offered another 20 weeks. Stopping rule three: only those who had lost ≥15% of their baseline weight were offered another 52 weeks on LIRA 3mg.
    Reporting group title
    Standard care (control group)
    Reporting group description
    		 Participants in the control group will follow the best medical care provided by the Tier 3 service at their site. This typically involves dietary advice to reduce energy intake, accompanied by a physical activity programme, both supported by behavioural change techniques with regular professional contacts. The nature of the standard care will vary between the different Tier 3 services at each site, as this is a pragmatic ‘real-world’ study. Clinician input will include the medical assessment of participants for severe and complicated obesity and the prescription of anti-obesity drugs as per local Tier 3 service policy. Those patients taking antihypertensive or antidepressant medication will be assessed and it will be at the clinician’s discretion as to whether these medications are changed. Participants will remain routinely in the Tier 3 service and may also be offered treatment options within the duration of the study, including bariatric surgery, in line with NICE guidance.

    Reporting group title
    Liraglutide 3mg (intervention)
    Reporting group description
    		 Participants in the intervention group received the same standard care as those in the control group plus liraglutide 3mg was prescribed. Dose escalation of liraglutide occurred according to a pre-specified titration protocol, from 0.6mg to a maximum of 3.0mg daily. The liraglutide dose was initiated at 0.6mg and then increased to 1.2mg in Week 2, 1.8mg in Week 3, 2.4mg in Week 4, and 3.0mg in Week 5. Participants in the LIRA arm were made aware that continued use of LIRA 3mg was based upon their response to the treatment in terms of them achieving pre-defined weight loss targets at 16, 32 and 52 weeks. Stopping rule one: only those who had lost ≥5% of their baseline weight were offered further treatment with LIRA 3mg for another 16 weeks. Stopping rule two: only those who had lost ≥10% of their baseline weight were offered another 20 weeks. Stopping rule three: only those who had lost ≥15% of their baseline weight were offered another 52 weeks on LIRA 3mg.
    Reporting group title
    Standard care (control group)
    Reporting group description
    		 Participants in the control group will follow the best medical care provided by the Tier 3 service at their site. This typically involves dietary advice to reduce energy intake, accompanied by a physical activity programme, both supported by behavioural change techniques with regular professional contacts. The nature of the standard care will vary between the different Tier 3 services at each site, as this is a pragmatic ‘real-world’ study. Clinician input will include the medical assessment of participants for severe and complicated obesity and the prescription of anti-obesity drugs as per local Tier 3 service policy. Those patients taking antihypertensive or antidepressant medication will be assessed and it will be at the clinician’s discretion as to whether these medications are changed. Participants will remain routinely in the Tier 3 service and may also be offered treatment options within the duration of the study, including bariatric surgery, in line with NICE guidance.

    Reporting group title
    Liraglutide 3mg (intervention)
    Reporting group description
    		 Participants in the intervention group received the same standard care as those in the control group plus liraglutide 3mg was prescribed. Dose escalation of liraglutide occurred according to a pre-specified titration protocol, from 0.6mg to a maximum of 3.0mg daily. The liraglutide dose was initiated at 0.6mg and then increased to 1.2mg in Week 2, 1.8mg in Week 3, 2.4mg in Week 4, and 3.0mg in Week 5. Participants in the LIRA arm were made aware that continued use of LIRA 3mg was based upon their response to the treatment in terms of them achieving pre-defined weight loss targets at 16, 32 and 52 weeks. Stopping rule one: only those who had lost ≥5% of their baseline weight were offered further treatment with LIRA 3mg for another 16 weeks. Stopping rule two: only those who had lost ≥10% of their baseline weight were offered another 20 weeks. Stopping rule three: only those who had lost ≥15% of their baseline weight were offered another 52 weeks on LIRA 3mg.
    Reporting group title
    Standard care (control group)
    Reporting group description
    		 Participants in the control group will follow the best medical care provided by the Tier 3 service at their site. This typically involves dietary advice to reduce energy intake, accompanied by a physical activity programme, both supported by behavioural change techniques with regular professional contacts. The nature of the standard care will vary between the different Tier 3 services at each site, as this is a pragmatic ‘real-world’ study. Clinician input will include the medical assessment of participants for severe and complicated obesity and the prescription of anti-obesity drugs as per local Tier 3 service policy. Those patients taking antihypertensive or antidepressant medication will be assessed and it will be at the clinician’s discretion as to whether these medications are changed. Participants will remain routinely in the Tier 3 service and may also be offered treatment options within the duration of the study, including bariatric surgery, in line with NICE guidance.

    Reporting group title
    Liraglutide 3mg (intervention)
    Reporting group description
    		 Participants in the intervention group received the same standard care as those in the control group plus liraglutide 3mg was prescribed. Dose escalation of liraglutide occurred according to a pre-specified titration protocol, from 0.6mg to a maximum of 3.0mg daily. The liraglutide dose was initiated at 0.6mg and then increased to 1.2mg in Week 2, 1.8mg in Week 3, 2.4mg in Week 4, and 3.0mg in Week 5. Participants in the LIRA arm were made aware that continued use of LIRA 3mg was based upon their response to the treatment in terms of them achieving pre-defined weight loss targets at 16, 32 and 52 weeks. Stopping rule one: only those who had lost ≥5% of their baseline weight were offered further treatment with LIRA 3mg for another 16 weeks. Stopping rule two: only those who had lost ≥10% of their baseline weight were offered another 20 weeks. Stopping rule three: only those who had lost ≥15% of their baseline weight were offered another 52 weeks on LIRA 3mg.

    Subject analysis set title
    Complete cases at 52 weeks
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Complete cases at 52 weeks - Standard care and Liraglutide

    Subject analysis set title
    Intention-to-treat at 52 weeks
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention-to-treat at 52 weeks - Standard care and Liraglutide arm

    Subject analysis set title
    Per protocol at 52 weeks
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol at 52 weeks - Standard care and Liraglutide arm

    Subject analysis set title
    Responder at 52 weeks
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Responder at 52 weeks - Standard care and Liraglutide arm

    Subject analysis set title
    Complete cases primary outcome - Control arm
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Complete cases at 52 weeks - Standard care

    Subject analysis set title
    Complete cases primary outcome - Liraglutide arm
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Complete cases at 52 weeks - Liraglutide

    Subject analysis set title
    Per protocol primary outcome - Control arm
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol at 52 weeks - Standard care

    Subject analysis set title
    Per protocol primary outcome - Liraglutide arm
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol at 52 weeks - Liraglutide arm

    Subject analysis set title
    Intention-to-treat - Control
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention-to-treat - 52 weeks - Standard care

    Subject analysis set title
    Intention-to-treat - Liraglutide
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention-to-treat - 52 weeks - Liraglutide

    Primary: Binary outcome indicating whether weight loss of ≥15% was achieved at 52 weeks

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    End point title
    		 Binary outcome indicating whether weight loss of ≥15% was achieved at 52 weeks
    End point description
    N.B. For participants who did not attend the week 52 visit, routine data was used to obtain the weight measurement. N.B. Four participants that achieved the primary outcome in the intention-to-treat population had bariatric surgery before week 52 and so were not eligible for the complete cases population. Numbers given for reporting group subjects analysed are based on the primary analysis population, complete case population.
    End point type
    Primary
    End point timeframe
    Compare the proportion of participants with severe & complicated obesity achieving weight loss ≥15% at 1 year (52 weeks) with a targeted prescribing pathway (i.e. use of LIRA 3mg in combination with standard care (tier 3)) vs standard care alone (tier 3).
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention) Complete cases primary outcome - Control arm Complete cases primary outcome - Liraglutide arm Per protocol primary outcome - Control arm Per protocol primary outcome - Liraglutide arm Intention-to-treat - Control Intention-to-treat - Liraglutide
    Number of subjects analysed
    93
    201
    93
    201
    51
    108
    132
    260
    Units: Number
    6
    51
    6
    51
    5
    40
    6
    55
    Statistical analysis title
    		 Primary analysis of primary outcome
    Statistical analysis description
    A logistic regression model will be used with a binary indicator showing whether or not ≥15% weight loss was achieved at 52 weeks as the outcome, randomisation group (intervention or control) as the main covariate, & the stratification factors of site(non-ordinal categorical variable) & baseline BMI (>45kg/m2; <45kg/m2) as additional covariates. The adjusted odds ratio with 95% CI & p-value will be presented. This analysis uses the complete cases population, therefore missing data isn't imputed
    Comparison groups
    Complete cases primary outcome - Control arm v Complete cases primary outcome - Liraglutide arm
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.09
         upper limit
    		 12.88
    Statistical analysis title
    		 ITT of primary outcome
    Statistical analysis description
    The analysis of the primary outcome in the ITT population, uses the same model as the primary analysis. Missing primary outcome data are imputed for the ITT analysis; this will be done by assuming that these participants did not achieve ≥15% weight loss at 52 weeks, which is a conservative approach.
    Comparison groups
    Liraglutide 3mg (intervention) v Standard care (control group)
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.45
         upper limit
    		 14.4
    Statistical analysis title
    		 Per Protocol analysis of primary outcome
    Statistical analysis description
    The same model as specified for the primary outcome was fitted using the per-protocol population
    Comparison groups
    Per protocol primary outcome - Control arm v Per protocol primary outcome - Liraglutide arm
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.81
         upper limit
    		 14.01

    Secondary: Referral rates to other obesity interventions (intention-to-treat) - Tier 4

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    End point title
    		 Referral rates to other obesity interventions (intention-to-treat) - Tier 4
    End point description
    Number of participants referred to Tier 4 for bariatric surgery over the 104 weeks study period.
    End point type
    Secondary
    End point timeframe
    104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    69
    150
    Units: Number
        No
    64
    125
        Yes
    5
    25
    No statistical analyses for this end point

    Secondary: Long-term maintenance (defined as the proportion of patients maintaining ≥15% weight loss at 104 weeks among those who achieved ≥15% weight loss at 52 weeks)

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    End point title
    		 Long-term maintenance (defined as the proportion of patients maintaining ≥15% weight loss at 104 weeks among those who achieved ≥15% weight loss at 52 weeks)
    End point description
    Proportion of participants maintaining weight loss of ≥15% among those who lost ≥15% at 52 weeks
    End point type
    Secondary
    End point timeframe
    104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    5
    41
    Units: Number
    2
    12
    Statistical analysis title
    		 ≥15% weight loss at 2yrs in those ≥15% at 1yr
    Statistical analysis description
    A Logistic regression model was fitted with the binary variable of ≥15% weight loss at 2yrs as the outcome, the main covariate being randomised arm and adjusting for for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2) as well. This was fitted for individuals with weight loss of ≥15% at 1yr.
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.601
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.08
         upper limit
    		 4.24

    Secondary: Absolute BMI (kg/m2) at 52 weeks

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    End point title
    		 Absolute BMI (kg/m2) at 52 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    80
    180
    Units: kg/m2
    arithmetic mean (standard deviation)
        Baseline
    44.41 ± 5.71
    45.20 ± 7.19
        Follow-up
    43.25 ± 6.42
    41.37 ± 7.63
        Change from baseline
    -1.17 ± 2.84
    -3.84 ± 3.29
    Statistical analysis title
    		 Complete case analysis of change in BMI from BL
    Statistical analysis description
    Linear regression with change in BMI from baseline as the outcome, randomised group as the main covariate, adjusting also for covariates of site and BMI strata.
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 -1.91

    Secondary: Absolute waist circumference (cm) at 52 weeks

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    End point title
    		 Absolute waist circumference (cm) at 52 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    58
    137
    Units: centimetre
    arithmetic mean (standard deviation)
        Baseline
    131.57 ± 13.73
    130.62 ± 13.87
        Follow-up
    125.99 ± 13.81
    121.74 ± 14.19
        Change from baseline
    -5.58 ± 8.48
    -8.88 ± 7.89
    Statistical analysis title
    		 Analysis of change in waist circumference
    Statistical analysis description
    Carried out in the complete case population. Linear regression with change in waist circumference from BL as the outcome, randomised arm as the main covariate, adjusting also for site and BMI strata.
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.77
         upper limit
    		 -0.8

    Secondary: Improving obesity-related co-morbidities (obstructive sleep apnoea, prediabetes, diabetes, hypertension, dyslipidaemia, depression) 52 weeks

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    End point title
    		 Improving obesity-related co-morbidities (obstructive sleep apnoea, prediabetes, diabetes, hypertension, dyslipidaemia, depression) 52 weeks
    End point description
    This will be assessed by the Kings College Obesity Staging (KCOS) score. The score is 0-3.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    63
    145
    Units: number
        Normal health at baseline
    0
    0
        Normal health at follow-up
    0
    1
        At risk of disease at baseline
    5
    6
        At risk of disease at follow-up
    12
    23
        Established disease at baseline
    41
    97
        Established disease at follow up
    43
    108
        Advanced disease at baseline
    17
    42
        Advanced disease at follow up
    8
    13
    No statistical analyses for this end point

    Secondary: Improving obesity-related co-morbidities (obstructive sleep apnoea, prediabetes, diabetes, hypertension, dyslipidaemia, depression) 104 weeks

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    End point title
    		 Improving obesity-related co-morbidities (obstructive sleep apnoea, prediabetes, diabetes, hypertension, dyslipidaemia, depression) 104 weeks
    End point description
    This will be assessed by the Kings College Obesity Staging (KCOS) score. The score is 0-3.
    End point type
    Secondary
    End point timeframe
    104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    51
    115
    Units: number
        Normal health at baseline
    0
    0
        Normal health at follow-up
    0
    2
        At risk of disease at baseline
    4
    5
        At risk of disease at follow-up
    10
    16
        Established disease at baseline
    37
    84
        Established disease at follow up
    35
    86
        Advanced disease at baseline
    10
    26
        Advanced disease at follow up
    6
    11
    No statistical analyses for this end point

    Secondary: Referral rates to other obesity interventions (intention-to-treat) Per site bariatric referrals

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    End point title
    		 Referral rates to other obesity interventions (intention-to-treat) Per site bariatric referrals
    End point description
    Referrals for bariatric surgery by 104 weeks by site.
    End point type
    Secondary
    End point timeframe
    104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    5
    25
    Units: number
        Dublin
    3
    3
        Glasgow
    0
    0
        Leicester
    0
    10
        Liverpool
    1
    2
        London
    1
    10
    No statistical analyses for this end point

    Secondary: Referral rates to other obesity interventions (intention-to-treat) - Had bariatric surgery by week 104

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    End point title
    		 Referral rates to other obesity interventions (intention-to-treat) - Had bariatric surgery by week 104
    End point description
    Had bariatric surgery by 104 weeks
    End point type
    Secondary
    End point timeframe
    104 weeks.
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    68
    148
    Units: number
        No
    64
    142
        Yes
    4
    6
    No statistical analyses for this end point

    Secondary: Attended at least 70% of scheduled Tier 3 appointments by 52 weeks

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    End point title
    		 Attended at least 70% of scheduled Tier 3 appointments by 52 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    89
    200
    Units: number
        No
    1
    0
        Yes
    51
    115
        Attended week 52 visit but variable missing
    37
    85
    No statistical analyses for this end point

    Secondary: Attended at least 70% of scheduled Tier 3 appointments by 104 weeks

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    End point title
    		 Attended at least 70% of scheduled Tier 3 appointments by 104 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    66
    143
    Units: number
        No
    0
    0
        Yes
    46
    92
        Attended week 104 visit but variable missing
    20
    51
    No statistical analyses for this end point

    Secondary: Stopped treatment with liraglutide 3mg due to adverse effects by 52 weeks

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    End point title
    		 Stopped treatment with liraglutide 3mg due to adverse effects by 52 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Liraglutide 3mg (intervention)
    Number of subjects analysed
    114
    Units: number
        No
    111
        Yes
    3
        Missing
    0
    No statistical analyses for this end point

    Secondary: Stopped treatment with liraglutide 3mg due to adverse effects by 104 weeks

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    End point title
    		 Stopped treatment with liraglutide 3mg due to adverse effects by 104 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    104 weeks
    End point values
    		 Liraglutide 3mg (intervention)
    Number of subjects analysed
    55
    Units: number
        No
    53
        Yes
    2
        Missing
    0
    No statistical analyses for this end point

    Secondary: Compliant with liraglutide 3mg treatment up to 52 weeks

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    End point title
    		 Compliant with liraglutide 3mg treatment up to 52 weeks [1]
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome is for up to 52 weeks and therefore we've had to select baseline rather than 52 weeks since it includes individuals that withdrew from the trial before 52 weeks. This was defined using the questionnaire answers as detailed in Appendix 7 of the SAP, and so includes all participants (i.e., not only those who attended the visit) up to the point when they stopped treatment or withdrew from the study.
    End point values
    		 Liraglutide 3mg (intervention)
    Number of subjects analysed
    260
    Units: number
        No
    23
        Yes
    233
        Missing
    4
    No statistical analyses for this end point

    Secondary: Compliant with liraglutide 3mg treatment up to 104 weeks

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    End point title
    		 Compliant with liraglutide 3mg treatment up to 104 weeks [2]
    End point description
    End point type
    Secondary
    End point timeframe
    104 weeks
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome is for up to 104 weeks and therefore we've had to select baseline rather than 104 weeks since it includes individuals that withdrew from the trial before 104 weeks. This was defined using the questionnaire answers as detailed in Appendix 7 of the SAP, and so includes all participants (i.e., not only those who attended the visit) up to the point when they stopped treatment or withdrew from the study.
    End point values
    		 Liraglutide 3mg (intervention)
    Number of subjects analysed
    260
    Units: number
        No
    27
        Yes
    229
        Missing
    4
    No statistical analyses for this end point

    Secondary: Stopped liraglutide 3mg treatment at 16 weeks

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    End point title
    		 Stopped liraglutide 3mg treatment at 16 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 Liraglutide 3mg (intervention)
    Number of subjects analysed
    260
    Units: number
        No
    181
        Yes
    79
        Missing
    0
    No statistical analyses for this end point

    Secondary: Stopped liraglutide 3mg treatment at 32 weeks

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    End point title
    		 Stopped liraglutide 3mg treatment at 32 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    32 weeks
    End point values
    		 Liraglutide 3mg (intervention)
    Number of subjects analysed
    181
    Units: number
        No
    110
        Yes
    71
        Missing
    0
    No statistical analyses for this end point

    Secondary: Stopped liraglutide 3mg treatment at 52 weeks

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    End point title
    		 Stopped liraglutide 3mg treatment at 52 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Liraglutide 3mg (intervention)
    Number of subjects analysed
    110
    Units: number
        No
    53
        Yes
    57
        Missing
    0
    No statistical analyses for this end point

    Secondary: Completed 52 weeks of the Tier 3 programme despite stopping liraglutide 3mg by 16 weeks

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    End point title
    		 Completed 52 weeks of the Tier 3 programme despite stopping liraglutide 3mg by 16 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Liraglutide 3mg (intervention)
    Number of subjects analysed
    260
    Units: number
        No
    60
        Yes
    19
        N/A (still using liraglutide 3mg at 16 weeks)
    181
        Missing
    0
    No statistical analyses for this end point

    Secondary: Completed 52 weeks of the Tier 3 programme despite stopping liraglutide 3mg by 32 weeks

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    End point title
    		 Completed 52 weeks of the Tier 3 programme despite stopping liraglutide 3mg by 32 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Liraglutide 3mg (intervention)
    Number of subjects analysed
    181
    Units: number
        No
    49
        Yes
    22
        N/A (still using liraglutide at 32 weeks)
    110
        Missing
    0
    No statistical analyses for this end point

    Secondary: Started on anti-obesity drugs at 52 weeks

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    End point title
    		 Started on anti-obesity drugs at 52 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    93
    206
    Units: number
        No
    92
    3
        Yes
    1
    203
    No statistical analyses for this end point

    Secondary: Started on anti-obesity drugs at 104 weeks

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    End point title
    		 Started on anti-obesity drugs at 104 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    66
    147
    Units: number
        No
    64
    144
        Yes
    2
    3
    No statistical analyses for this end point

    Secondary: Weight loss of ≥5% from baseline

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    End point title
    		 Weight loss of ≥5% from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    16, 32, 52 and 104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    86
    237
    79
    208
    93
    201
    61
    132
    Units: number
    34
    186
    34
    158
    29
    127
    17
    62
    Statistical analysis title
    		 16 week weight loss of ≥5% from baseline
    Statistical analysis description
    This was carried out using the complete case population. A logistic regression with a binary outcome of Weight loss of ≥5% from baseline was fitted. The main covariate was randomised arm, with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    10.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.26
         upper limit
    		 19.48
    Statistical analysis title
    		 32 week weight loss of ≥5% from baseline
    Statistical analysis description
    This was carried out using the complete case population. A logistic regression with a binary outcome of Weight loss at 32 weeks of ≥5% from baseline was fitted. The main covariate was randomised arm, with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    287
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.86
         upper limit
    		 9.36
    Statistical analysis title
    		 52 week weight loss of ≥5% from baseline
    Statistical analysis description
    This was carried out using the complete case population. A logistic regression with a binary outcome of Weight loss at 52 weeks of ≥5% from baseline was fitted. The main covariate was randomised arm, with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.39
         upper limit
    		 7.22
    Statistical analysis title
    		 104 week weight loss of ≥5% from baseline
    Statistical analysis description
    This was carried out using the complete case population. A logistic regression with a binary outcome of Weight loss at 104 weeks of ≥5% from baseline was fitted. The main covariate was randomised arm, with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.23
         upper limit
    		 4.84

    Secondary: Weight loss of ≥10% from baseline

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    End point title
    		 Weight loss of ≥10% from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    16, 32, 52 and 104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    86
    237
    79
    208
    93
    90
    61
    132
    Units: number
    9
    60
    14
    110
    9
    90
    8
    32
    Statistical analysis title
    		 16 week weight loss of ≥10% from baseline
    Statistical analysis description
    This was carried out using the complete case population. A logistic regression with a binary outcome of Weight loss at 16 weeks of ≥10% from baseline was fitted. The main covariate was randomised arm, with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.14
         upper limit
    		 12.39
    Statistical analysis title
    		 32 week weight loss of ≥10% from baseline
    Statistical analysis description
    This was carried out using the complete case population. A logistic regression with a binary outcome of Weight loss at 32 week of ≥10% from baseline was fitted. The main covariate was randomised arm, with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    287
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.32
         upper limit
    		 12.86
    Statistical analysis title
    		 52 week weight loss of ≥10% from baseline
    Statistical analysis description
    This was carried out using the complete case population. A logistic regression with a binary outcome of Weight loss at 52 weeks of ≥10% from baseline was fitted. The main covariate was randomised arm, with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    8.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.8
         upper limit
    		 17.16
    Statistical analysis title
    		 104 week weight loss of ≥10% from baseline
    Statistical analysis description
    This was carried out using the complete case population. A logistic regression with a binary outcome of Weight loss at 104 weeks of ≥10% from baseline was fitted. The main covariate was randomised arm, with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.065
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 5.47

    Secondary: Weight loss of ≥15% from baseline

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    End point title
    		 Weight loss of ≥15% from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    16, 32, 52 and 104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    86
    237
    79
    208
    93
    201
    61
    132
    Units: number
    2
    10
    5
    32
    6
    51
    2
    15
    Statistical analysis title
    		 16 week weight loss of ≥15% from baseline
    Statistical analysis description
    This was carried out using the complete case population. A logistic regression with a binary outcome of Weight loss at 16 weeks of ≥15% from baseline was fitted. The main covariate was randomised arm, with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.206
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 14.34
    Statistical analysis title
    		 32 week weight loss of ≥15% from baseline
    Statistical analysis description
    This was carried out using the complete case population. A logistic regression with a binary outcome of Weight loss at 32 week of ≥15% from baseline was fitted. The main covariate was randomised arm, with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    287
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.023
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.17
         upper limit
    		 8.9
    Statistical analysis title
    		 52 week Weight loss of ≥15% from baseline
    Statistical analysis description
    N.B. This is the primary analysis of the primary outcome and is included again here for completeness of looking at this outcome over the different time points. This analysis was carried out in the complete case population. A logistic regression model was fitted for the binary outcome of Weight loss at 52 weeks of ≥15% from baseline. The main covariate was randomised arm and the model was also adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Liraglutide 3mg (intervention) v Standard care (control group)
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.09
         upper limit
    		 12.88
    Statistical analysis title
    		 104 week Weight loss of ≥15% from baseline
    Statistical analysis description
    This analysis was carried out in the complete case population. A logistic regression model was fitted for the binary outcome of Weight loss at 104 weeks of ≥15% from baseline. The main covariate was randomised arm and the model was also adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 18.93

    Secondary: Absolute weight (kg) at 16 weeks

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    End point title
    		 Absolute weight (kg) at 16 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    86
    237
    Units: kg
    arithmetic mean (standard deviation)
        Baseline
    125.31 ± 20.95
    127.49 ± 23.62
        Follow-up
    119.77 ± 20.61
    117.88 ± 23.20
        Change from baseline
    -5.54 ± 5.87
    -9.61 ± 5.38
    Statistical analysis title
    		 16 week absolute weight change from baseline
    Statistical analysis description
    This analysis was carried out in the complete case population. A linear regression model was fitted for the outcome of absolute weight change from BL at 16 weeks (kg). The main covariate was randomised arm and the model was also adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -4.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.85
         upper limit
    		 -3.4

    Secondary: Absolute weight (kg) at 32 weeks

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    End point title
    		 Absolute weight (kg) at 32 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    32 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    79
    208
    Units: kg
    arithmetic mean (standard deviation)
        Baseline
    125.76 ± 20.61
    125.92 ± 23.21
        Follow-up
    120.06 ± 21.43
    114.64 ± 22.81
        Change from baseline
    -5.70 ± 7.16
    -11.27 ± 7.70
    Statistical analysis title
    		 32 week absolute weight change from baseline
    Statistical analysis description
    This analysis was carried out in the complete case population. A linear regression model was fitted for the outcome of absolute weight change from BL at 32 weeks (kg). The main covariate was randomised arm and the model was also adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    287
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    -5.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.76
         upper limit
    		 -4.02

    Secondary: Absolute weight (kg) at 52 weeks

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    End point title
    		 Absolute weight (kg) at 52 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    93
    201
    Units: kg
    arithmetic mean (standard deviation)
        Baseline
    128.28 ± 20.66
    126.40 ± 23.57
        Follow-up
    125.07 ± 23.25
    116.25 ± 24.41
        Change from baseline
    -3.21 ± 8.66
    -10.15 ± 9.45
    Statistical analysis title
    		 52 week absolute weight change from baseline
    Statistical analysis description
    This analysis was carried out in the complete case population. A linear regression model was fitted for the outcome of absolute weight change from BL at 52 weeks (kg). The main covariate was randomised arm and the model was also adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    -6.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.03
         upper limit
    		 -4.71

    Secondary: Absolute weight (kg) at 104 weeks

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    End point title
    		 Absolute weight (kg) at 104 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    61
    132
    Units: kg
    arithmetic mean (standard deviation)
        Baseline
    126.15 ± 19.95
    124.86 ± 23.80
        Follow-up
    124.89 ± 23.66
    118.35 ± 24.09
        Change from baseline
    -1.27 ± 10.30
    -6.51 ± 9.28
    Statistical analysis title
    		 104 week absolute weight change from baseline
    Statistical analysis description
    This analysis was carried out in the complete case population. A linear regression model was fitted for the outcome of absolute weight change from BL at 104 weeks (kg). The main covariate was randomised arm and the model was also adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    -5.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.34
         upper limit
    		 -2.53

    Secondary: Absolute BMI (kg/m2) at 104 weeks

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    End point title
    		 Absolute BMI (kg/m2) at 104 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    61
    132
    Units: kg/m2
    arithmetic mean (standard deviation)
        Baseline
    43.73 ± 5.23
    44.90 ± 7.42
        Follow-up
    43.24 ± 6.78
    42.59 ± 7.99
        Change from baseline
    -0.49 ± 3.57
    -2.30 ± 3.29
    Statistical analysis title
    		 104 week absolute BMI change from baseline
    Statistical analysis description
    This analysis was carried out in the complete case population. A linear regression model was fitted for the outcome of absolute BMI change from BL at 104 weeks. The main covariate was randomised arm and the model was also adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    -1.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.91
         upper limit
    		 -0.86

    Secondary: Absolute change in waist circumference (cm) at 104 weeks

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    End point title
    		 Absolute change in waist circumference (cm) at 104 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    48
    101
    Units: centimetre
    arithmetic mean (standard deviation)
        Baseline
    130.81 ± 11.72
    129.76 ± 14.16
        Follow-up
    129.89 ± 16.45
    132.34 ± 15.49
        Change from baseline
    -0.93 ± 12.54
    -6.42 ± 8.44
    Statistical analysis title
    		 104 week waist circumference change from baseline
    Statistical analysis description
    This analysis was carried out in the complete case population. A linear regression model was fitted for the outcome of change in waist circumference from BL at 104 weeks (cm). The main covariate was randomised arm and the model was also adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Regression, Linear
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    -5.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.09
         upper limit
    		 -1.94

    Secondary: Weight loss of ≥5% from baseline (responder population)

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    End point title
    		 Weight loss of ≥5% from baseline (responder population)
    End point description
    Responder population.
    End point type
    Secondary
    End point timeframe
    16, 32, 52 and 104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    86 [3]
    54 [4]
    79 [5]
    53 [6]
    93 [7]
    51 [8]
    61 [9]
    42 [10]
    Units: number
    34
    54
    34
    53
    29
    51
    17
    33
    Notes
    [3] - Responder population
    [4] - Responder population
    [5] - Responder population
    [6] - Responder population
    [7] - Responder population
    [8] - Responder population
    [9] - Responder population
    [10] - Responder population
    Statistical analysis title
    		 Responder popn week 104 weight loss of ≥5% from BL
    Statistical analysis description
    This analysis was carried out in the responder population. A logistic regression model for the binary outcome of week 104 weight loss of ≥5% from BL was fitted. The covariate was randomised arm , with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    10.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.83
         upper limit
    		 28.97

    Secondary: Weight loss of ≥10% from baseline (responder population)

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    End point title
    		 Weight loss of ≥10% from baseline (responder population)
    End point description
    Responder population.
    End point type
    Secondary
    End point timeframe
    16, 32, 52 and 104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    86 [11]
    54 [12]
    79 [13]
    53 [14]
    93 [15]
    51 [16]
    61 [17]
    42 [18]
    Units: number
    9
    34
    14
    53
    9
    51
    8
    23
    Notes
    [11] - Responder population
    [12] - Responder population
    [13] - Responder population
    [14] - Responder population
    [15] - Responder population
    [16] - Responder population
    [17] - Responder population
    [18] - Responder population
    Statistical analysis title
    		 Responder popn week 16 weight loss of ≥10% from BL
    Statistical analysis description
    This analysis was carried out in the responder population. A logistic regression model for the binary outcome of week 16 weight loss of ≥10% from BL was fitted. The covariate was randomised arm , with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    23.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.55
         upper limit
    		 70.67
    Statistical analysis title
    		 Responder popn week104 weight loss of ≥10% from BL
    Statistical analysis description
    This analysis was carried out in the responder population. A logistic regression model for the binary outcome of week 104 weight loss of ≥10% from BL was fitted. The covariate was randomised arm , with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    7.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.75
         upper limit
    		 21.6

    Secondary: Weight loss of ≥15% from baseline (responder population)

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    End point title
    		 Weight loss of ≥15% from baseline (responder population)
    End point description
    Responder population.
    End point type
    Secondary
    End point timeframe
    16, 32, 52 and 104 weeks
    End point values
    		 Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention) Standard care (control group) Liraglutide 3mg (intervention)
    Number of subjects analysed
    86 [19]
    54 [20]
    79 [21]
    53 [22]
    93 [23]
    51 [24]
    61 [25]
    42 [26]
    Units: number
    2
    8
    5
    24
    6
    51
    2
    12
    Notes
    [19] - Responder population
    [20] - Responder population
    [21] - Responder population
    [22] - Responder population
    [23] - Responder population
    [24] - Responder population
    [25] - Responder population
    [26] - Responder population
    Statistical analysis title
    		 Responder popn week 16 weight loss of ≥15% from BL
    Statistical analysis description
    This analysis was carried out in the responder population. A logistic regression model for the binary outcome of week 104 weight loss of ≥15% from BL was fitted. The covariate was randomised arm , with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.032
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.16
         upper limit
    		 32.32
    Statistical analysis title
    		 Responder popn week 32 weight loss of ≥15% from BL
    Statistical analysis description
    This analysis was carried out in the responder population. A logistic regression model for the binary outcome of week 32 weight loss of ≥15% from BL was fitted. The covariate was randomised arm , with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    11.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.8
         upper limit
    		 34.67
    Statistical analysis title
    		 Responder popn week104 weight loss of ≥15% from BL
    Statistical analysis description
    This analysis was carried out in the responder population. A logistic regression model for the binary outcome of week 104 weight loss of ≥15% from BL was fitted. The covariate was randomised arm , with the model also being adjusted for the stratification variables: site and baseline body mass index (>45kg/m2; <45kg/m2).
    Comparison groups
    Standard care (control group) v Liraglutide 3mg (intervention)
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    13.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.47
         upper limit
    		 75.09

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded throughout the study (BL-Wk104) whether serious or not. Members of research team asked participants about AEs at each study visit and recorded these on AE/SAE logs and reported SAEs as per sponsor and regulatory requirements.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    2.0
    Reporting groups
    Reporting group title
    Standard care (control group)
    Reporting group description
    		 Participants in the control group will follow the best medical care provided by the Tier 3 service at their site. This typically involves dietary advice to reduce energy intake, accompanied by a physical activity programme, both supported by behavioural change techniques with regular professional contacts. The nature of the standard care will vary between the different Tier 3 services at each site, as this is a pragmatic ‘real-world’ study. Clinician input will include the medical assessment of participants for severe and complicated obesity and the prescription of anti-obesity drugs as per local Tier 3 service policy. Those patients taking antihypertensive or antidepressant medication will be assessed and it will be at the clinician’s discretion as to whether these medications are changed. Participants will remain routinely in the Tier 3 service and may also be offered treatment options within the duration of the study, including bariatric surgery, in line with NICE guidance.

    Reporting group title
    Liraglutide 3mg (intervention)
    Reporting group description
    		 Participants in the intervention group received the same standard care as those in the control group plus liraglutide 3mg was prescribed. Dose escalation of liraglutide occurred according to a pre-specified titration protocol, from 0.6mg to a maximum of 3.0mg daily. The liraglutide dose was initiated at 0.6mg and then increased to 1.2mg in Week 2, 1.8mg in Week 3, 2.4mg in Week 4, and 3.0mg in Week 5. Participants in the LIRA arm were made aware that continued use of LIRA 3mg was based upon their response to the treatment in terms of them achieving pre-defined weight loss targets at 16, 32 and 52 weeks. Stopping rule one: only those who had lost ≥5% of their baseline weight were offered further treatment with LIRA 3mg for another 16 weeks. Stopping rule two: only those who had lost ≥10% of their baseline weight were offered another 20 weeks. Stopping rule three: only those who had lost ≥15% of their baseline weight were offered another 52 weeks on LIRA 3mg.

    Serious adverse events
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 132 (8.33%)
    47 / 260 (18.08%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm malignant
    Additional description: Site unspecified.
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hernia repair
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nail operation
    Additional description: therapeutic procedures
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Therapeutic procedure
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Febrile infection
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
    Additional description: and discomfort
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
    Additional description: and anaphylactoid responses
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vulvovaginal disorder
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
    Additional description: and obstruction.
         subjects affected / exposed
    2 / 132 (1.52%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural infection
    Additional description: and inflammation
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary thrombosis
    Additional description: thrombotic and embolic conditions
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Auscultation
    Additional description: Cardiac auscultatory investigations
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Limb fracture
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle injury
    Additional description: Tendon and ligament injuries.
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
    Additional description: Non-site specific
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Conduction disorder
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
    Additional description: Noninfectious
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient cerebrovascular event
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
    Additional description: Acute and chronic.
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal vascular occlusion and infarction
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Bile duct infections and inflammations
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
    Additional description: and cholelithiasis
         subjects affected / exposed
    0 / 132 (0.00%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal lithiasis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Posterior pituitary disorder
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
    Additional description: Musculoskeletal and connective tissue pain and discomfort
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue disorder
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    3 / 132 (2.27%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Female reproductive tract disorder
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 132 (0.76%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
    Additional description: and muscle infections.
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 132 (1.52%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 132 (0.00%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Standard care (control group) Liraglutide 3mg (intervention)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    89 / 132 (67.42%)
    238 / 260 (91.54%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 132 (1.52%)
    38 / 260 (14.62%)
         occurrences all number
    2
    49
    Neurological symptom
         subjects affected / exposed
    6 / 132 (4.55%)
    27 / 260 (10.38%)
         occurrences all number
    6
    31
    General disorders and administration site conditions
    Asthenic conditions
         subjects affected / exposed
    3 / 132 (2.27%)
    30 / 260 (11.54%)
         occurrences all number
    3
    32
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 132 (6.06%)
    72 / 260 (27.69%)
         occurrences all number
    8
    92
    Dyspepsia
         subjects affected / exposed
    0 / 132 (0.00%)
    38 / 260 (14.62%)
         occurrences all number
    0
    44
    Flatulence
         subjects affected / exposed
    0 / 132 (0.00%)
    33 / 260 (12.69%)
         occurrences all number
    0
    39
    Gastrointestinal pain
         subjects affected / exposed
    5 / 132 (3.79%)
    37 / 260 (14.23%)
         occurrences all number
    6
    48
    Gastrointestinal hypomotility
         subjects affected / exposed
    12 / 132 (9.09%)
    93 / 260 (35.77%)
         occurrences all number
    12
    117
    Nausea
         subjects affected / exposed
    5 / 132 (3.79%)
    109 / 260 (41.92%)
         occurrences all number
    5
    183
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    15 / 132 (11.36%)
    34 / 260 (13.08%)
         occurrences all number
    16
    43
    Infections and infestations
    Ear infection
         subjects affected / exposed
    10 / 132 (7.58%)
    5 / 260 (1.92%)
         occurrences all number
    12
    6
    Influenza
         subjects affected / exposed
    5 / 132 (3.79%)
    14 / 260 (5.38%)
         occurrences all number
    5
    15
    Lower respiratory tract infection
         subjects affected / exposed
    17 / 132 (12.88%)
    41 / 260 (15.77%)
         occurrences all number
    22
    63
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 132 (6.06%)
    18 / 260 (6.92%)
         occurrences all number
    8
    19
    Urinary tract infection
         subjects affected / exposed
    5 / 132 (3.79%)
    21 / 260 (8.08%)
         occurrences all number
    8
    26
    Viral infection
         subjects affected / exposed
    7 / 132 (5.30%)
    36 / 260 (13.85%)
         occurrences all number
    8
    41

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Mar 2018
    Changes made to management of sleep apnoea patients and tests. Removal of lipase blood test and exclusion criteria. Addition of lipase for confirming a suspected case of acute pancreatitis where amylase levels are normal, change to GLP-1 exclusion. Transfer responsibility for Trial Management and associated activities from the LCTU to the LDC. To add the use of Participant Identification Centre’s (PIC) where applicable for recruitment purposes. Recruitment period error corrected to ‘up to 24months’ and ‘4-6 patients/month’ to reflect the study contract with funder and the current REC approved LPLV timeframes which have not altered. Clarification to table visit windows (weeks vs no’s) and visualisation of the titration profile for Appendix 3. Additional information given in the key. Administrative changes for clarity and to correct errors that do not alter the study procedures.
    08 Jun 2018
    (REC approved SA1-UK v3; HPRA non-acceptance (not approved) is addresses in this SA2-UK v4) Same as above clarifying concerns raised by HPRA in non-acceptance of SA1-UK.
    07 Jan 2019
    Change to the visit schedule to allow for some visits to be classified as optional. For participants in both arms of the study visits held at 2/52 (visit 3), 4/52 (visit 4), 12/52 (visit 6), 20/52 (visit 8), 40/52 (visit 10) and 78/52 (visit 12/13) will be defined as ‘optional’ to reduce study burden and maximise participant retention, as per the visit schedule (see Protocol, Appendix 3); Remove wording included in error following previous amendment sleep study capture in schedule, and Secondary Outcomes (see Protocol, Appendix 3; and Section 7.3; Clarification of reference ranges for TSH in terms of eligibility in the protocol to be amended to reflect the different normal ranges labs at each site used. This was highlighted at a recent monitoring visit where the ‘normal’ range stated in the protocol was different to that used in routine clinical assessment at site due the variable of local pathology laboratory reference ranges (see Protocol, Section 7.3); Update the exclusion criteria clarifying the time scale since weight loss procedures/surgery and the scope to allow for removal of gastric bands and gastric balloon whilst still be eligible for the study (see Protocol, Section 7.3). The consent form has been modified to include an extra question (question 3) surrounding lost to follow up and non attendance. This has been added as optional with yes or no boxes. Questions 8 and 10 have also been changed to optional yes or no boxes. Update to the current SmPC. Version 12/2016 will be replaced by version 06/2018.
    20 Feb 2019
    Change to add a legal representative in Ireland due to Brexit coming into force on 29th March 2019. Clinical trials legislation required that the sponsor or legal representative of the sponsor is established in the EU/EEA. Change of the legal representative for the Strive study from University of Leicester to the University College Dublin. Sponsor responsibilities will continue to reside with University of Leicester but the University College Dublin will act as the legal representative for the study in the EU/EEA.
    26 Mar 2020
    This was to update the recruitment target, which was increased from 384 to 392 and to update the recruitment end date which was amended from 31/12/2019 to 29/02/2020.
    19 May 2020
    As a result of the COVID19 global pandemic a risk assessment was conducted and an urgent safety measure was sent to the MHRA. The study team made several changes to the management and running of the trial due to the risks associated with face to face visits during the pandemic, in summary these include: provision of scales for participants to weigh themselves at home, adapted study drug deliveries/returns procedures, and virtual consultations via phone or video call. During this period the BP/HR measurements for those participants who do not have a home monitor and blood sampling for V11 and V13 visits will not be conducted. Addition of monetary incentive for all participants to aid retention, as suggested by the data monitoring safety committee (DMSC) and the trial steering committee (TSC). Extended the visit window for V11 primary end-point to support data collection; from+/- 14 days to +/- 3 months. QoL questionnaires to be issued to participants at an interim time point during the COVID19 pandemic. The study end date and recruitment target was amended in March 2020 as an NSA for all UK sites. Dublin site (IRE) requested that this be submitted as a substantial amendment so this has been added for IRE as part of this amendment (detailed in the IRE protocol).
    29 Jan 2021
    Update to the current SmPC. Version 5.0 will be replaced by version 10.0. The study end date has been updated from 30/04/2022 to 30/06/2022. Update to the details around COVID-19 in section 8.10.

    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.
    Although the trial was not interrupted during COVID-19 we did issue an USM to the REC & MHRA during the pandemic to explain that certain aspects of the trial would not be possible, however measures were put in place to ensure participant safety.
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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