Clinical trial NCT03036800
Conditions: Obesity Weight Loss Diabetes Mellitus
Sponsor: University of Leicester
Start date: 2017-11-28; Completion date: 2022-02-25
Enrollment: 392 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A two year, parallel, two group, open-label, real-world randomised controlled trial (RCT) design for subjects with severe and complex obesity who are referred to a Tier 3 or equivalent specialist weight management/obesity service. Participants will be randomised to receive 1) standard care (obesity-specialist care), or 2) targeted prescribing pathway (obesity-specialist care plus targeted use of Liraglutide 3.0mg \[LIRA 3mg\] with pre-specified stopping rules for the medication). The aim of the study is to compare the effectiveness, budget impact, and cost-effectiveness between the two groups in a real-world setting among otherwise largely unselected patients.

Detailed description:
Summary of Trial Design A two year, parallel, two group, open-label, real-world, RCT design for patients with severe and complex obesity who are referred to a Tier 3 obesity service (including patients who are referred to a Tier 3 service as part of the bariatric surgery pathway). The total duration of participation will be 104 weeks (+/-2 weeks).

The first 52 weeks of the study (after randomisation) will determine whether using the targeted prescribing pathway in a Tier 3 setting will result in more participants attaining ≥15% weight loss compared with standard care. The second 52 weeks of the study will assess whether patients who lose ≥15% of their baseline weight by the first 52 weeks are more likely to maintain ≥15% weight loss for another 52 weeks in the targeted prescribing pathway compared with standard care. Further, budget impact, cost-effectiveness, improvement in obesity-related co-morbidities, complementary aspects of safety, effectiveness, adherence, and treatment satisfaction of both treatment groups will be assessed and compared.

Participants will be randomised in a 2:1 fashion to either the intervention (targeted prescribing pathway + standard care) or control (standard care) group (2 intervention: 1 control). The control group will receive standard care in a specialist obesity service (Tier 3 or equivalent), according to the best practice in each site and can include total or partial meal replacement strategies. The intervention group will receive the same standard care as the control group (i.e. according to the best practice in each site) plus all participants will initially receive LIRA with pre-specified stopping rules. The targeted prescribing pathway: participants who do not meet the definition of a 'early and good responder' (defined as achieving ≥5% weight loss at 16 weeks, ≥10% weight loss at 32 weeks and ≥15% weight loss at 52 weeks) will have their LIRA 3mg treatment stopped. It is important to note that all participants will be analysed in the group to which they are randomised; in particular, participants in the intervention group who stop receiving LIRA 3mg will remain in the intervention group and will continue to receive standard care for the remainder of the study as per the targeted prescribing pathway (albeit, the part of the pathway where LIRA 3mg is not prescribed; see Figure 1).

The study is intentionally designed to reflect a pragmatic "real-world" scenario and each Tier 3 provider may require a different number of visits for their programme. However, study appointments for data collection, titration reviews, application of the stopping rules of LIRA 3mg, and dispensing will be standardised for all of the five sites.

Intervention (Targeted Prescribing Pathway)

The NHS Weight Management pathway is divided into four distinct tiers:

Tier 1: health promotion Tier 2: lifestyle interventions Tier 3: specialist multidisciplinary weight management services Tier 4: bariatric surgery

Across the UK, each region has a specialist Tier 3 obesity and/or weight management service or equivalent, usually referred to as Tier 3. This includes a clinician led multidisciplinary team approach, potentially including a specialist physician, nurse, dietician, psychologist, physiotherapist, etc. From this point forwards, Tier 3 specialist weight management and/or equivalent services will be referred to as 'Tier 3' throughout the remainder of this protocol.

Participants in the intervention group will receive the same standard care as those in the control group, i.e. the best medical practice delivered by the Tier 3 service at each site. Additionally, at baseline, LIRA 3mg will be prescribed to all of the participants in the intervention group at a starting dose of 0.6mg daily. Dose escalation of Liraglutide will occur according to a pre-specified titration protocol, from 0.6mg to a maximum of 3.0mg daily. Liraglutide dose will be 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 intervention group will be aware that the LIRA 3mg treatment may be stopped at various time points throughout the duration of the study and that continued use of LIRA 3mg is based upon their response to the treatment in terms of them achieving pre-defined weight loss targets at 16, 32 and 52 weeks.. Specifically, participants in the intervention group will continue to be prescribed LIRA 3mg for the 104 week duration of the study, unless one of the following stopping rules applies:

1. st stopping rule: After 16 weeks (± 14 days) on the medication, only those participants who have lost ≥5% of their baseline weight will be offered further treatment with LIRA 3mg for another 16 weeks. Participants who have not met this weight loss target will have their LIRA 3mg treatment stopped but will still continue in the targeted prescribing pathway but will receive standard care only during the remainder of the study.
2. nd stopping rule: After 32 weeks (± 14 days) on the medication, only those participants who have lost ≥10% of their baseline weight and are still on treatment with LIRA 3mg will be offered another 20 weeks on LIRA 3mg. Participants who have not met this weight loss target will have their LIRA 3mg treatment stopped but will still continue in the targeted prescribing pathway but will receive standard care only during the remainder of the study.
3. rd stopping rule: After the first year of treatment (week 52; ± 14 days), only those participants who have lost ≥15% of their baseline weight and are still on treatment with LIRA 3mg will be offered another 52 weeks on LIRA 3mg. Participants who have not met this weight loss target will have their LIRA 3mg treatment stopped but will still continue in the targeted prescribing pathway but will receive standard care only during the remainder of the study.

Participants who fail to reach the pre-defined weight-loss targets to continue LIRA 3mg treatment, or who choose to stop receiving LIRA 3mg, will continue to be offered the standard care provided by the Tier 3 service. These participants will still attend the Clinical Review Visits but not the additional visits for participants who are still on LIRA 3mg (e.g. Weeks 65 \& 91) because these visits will not be relevant to them; visits at Weeks 65 and 91 are intended to provide a new prescription of LIRA 3mg and to discuss adherence and any side effects;; see Appendices 2 \& 3).

Participants will remain routinely in the Tier 3 service in-line with NICE guidance throughout the duration of the research study. Participants may be offered treatment options within the duration of the study, including bariatric surgery, as per NICE guidance and according to the decision of the local Tier 3 Multidisciplinary Team. Participants who have undergone bariatric surgery after randomisation will only be included in the intention to treat (ITT) analysis. This decision was made because the proportion of participants undergoing bariatric surgery is likely to be unbalanced between the treatment groups (i.e. more participants in the control group are expected to have bariatric surgery than in the targeted prescribing pathway treatment group), and thus weight loss in these individuals could unduly influence the study results. Participants who have been prescribed and start anti-obesity medication (such as Orlistat) will be ineligible for LIRA 3mg treatment.

Control (Standard Care) Participants in the control group will follow the best medical care provided by the Tier 3 service at the relevant site. This typically involves dietary advice to reduce energy intake (and may include a period of partial or total meal replacement), accompanied - if available - 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 (such as Orlistat) as per local Tier 3 service policy. As with the LIRA 3mg group 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 in-line with NICE guidance throughout the duration of the research study. Participants may be offered treatment options within the duration of the study, including bariatric surgery, as per NICE guidance and according to the decision of the local Tier 3 Multidisciplinary Team.

Arms: arm 1: Standard care plus targeted use of the intervention Liraglutide (LIRA) 3mg when pre-specified stopping rules for the medication apply arm 2: standard Tier 3 obesity specialist service care
Interventions: intervention 1: Saxenda intervention 2: Specialist Obesity Management Services
Intervention descriptions: intervention 1: standard care plus targeted use of Liraglutide (LIRA) 3mg when pre-specified stopping rules for the medication apply. Liraglutide (Saxenda) 6 mg/mL solution for injection in pre-filled pen, administered by subcutaneous injection. Dose escalation to 3.0 mg daily (or maximum tolerated dose) intervention 2: Specialist Obesity Management Services standard of care

Protocol documents:
Prot_000.pdf: 
 
 
STRIVE Protocol                                        Version 7.0; 29/01/2021 - IRAS ID: 232120  
Page 1 of 65 
 
 
 
 
Effectiveness and cost of integrating a protocol with use of 
Liraglutide 3.0mg into an obesity service  
  
STRIVE STUDY 
Sponsor Reference No:  
 
UNOLE 0626  
Ethics Ref:  
 
 
 
17 NW 0517 
EudraCT Number:  
 
 
2017-002998-20 
Universal Trial Number (UTN):   
U1111-1189-5726 
Date and Version No:  
 
Version 7.0; 29/01/2021              
 
Chief Investigator:  
 
 
Professor Melanie Davies 
 
Chief Investigator Address:  
 
Diabetes Research Centre 
Broadleaf, Leicester Diabetes Centre (LDC) 
Leicester General Hospital 
Gwendolen Road 
Leicester, LE5 4PW 
 
Chief Investigator Contact Details:  
0116 258 6481 / melanie.davies@uhl-tr.nhs.uk 
 
Sponsor Name:  
 
 
University of Leicester 
Sponsor Address:  
Research Governance Office, Academic Departments, 
Leicester General Hospital, Gwendolen Road,  
Leicester, LE5 4PW 
 
Main Study Address:   
 
Leicester Diabetes Centre 
Leicester General Hospital 
Gwendolen Rd 
Leicester LE5 4PW 
 
Main Study Contact Details:   
 
0116 258 4322 STRIVE@uhl-tr.nhs.uk 


 
 
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Co – Principal Investigators:  
Professor Carel le Roux (Professor of Experimental Pathology,                
                                                      
University College Dublin) 
                                                      
Tel: 0171 66 831 
Email: carel.leroux@ucd.ie  
 
                                               
Professor John Wilding (Professor of Medicine, University of   
                                               
Liverpool) 
                                                      
Tel: 0151 529 5899 
Email:  J.P.H.Wilding@liverpool.ac.uk    
 
Professor Donal O’Shea (Professor of Endocrinology, University         
College Dublin) 
Tel: 0171 62 425             Email: info@dosheaendo.ie 
 
                                                      
Professor Mike Lean (Professor of Human Nutrition, University of  
                                               
Glasgow) 
                                                Tel: 0141 201 8604 
Email: mike.lean@glasgow.ac.uk  
 
                                               
Dr Barbara McGowan (Consultant in Diabetes and Endocrinology,    
                                                Guy’s and St Thomas’ NHS Foundation Trust) 
                                                Tel: 020 7188 1912 
E-mail: barbara.mcGowan@gstt.nhs.uk  
                                                
Dr David Webb (Senior Lecturer in Diabetes & Honourable 
Consultant, Leicester General Hospital) 
                                                      
Tel: 0116 258 8554 
E-mail: david.webb@uhl-tr.nhs.uk 
 
 Co-Investigators:                       Professor Kamlesh Khunti (Primary Care Diabetes & Vascular Med,       
                                                      
University of Leicester) 
                                                      
Tel: 0116 258 4994         E-mail: kk22@le.ac.uk 
 
 
                                                      
Dr Dimitris Papamargaritis (Clinician, University of Leicester) 
                                                      
Tel:  0116 258 8602      E-mail: dimitris.papamargaritis@uhl-tr.nhs.uk  
 
 
 
             
         
Dr Shaun Barber (Medical Statistician, University of Leicester, 
Clinical Trials Unit) 
Tel: +44 (0)116 229 7129 E-mail: sb766@leicester.ac.uk 
 
Dr Cassandra Brookes (Principal Statistician, University of Leicester, 
Clinical Trials Unit) 
Tel: 0116 258 8632 
E-mail: cassey.brookes@leicester.ac.uk 
 
Dr Emer Brady (Senior Research Associate, University Hospitals of 
Leicester NHS Trust) 
 
 
 
 
Tel: 0116 258 8959 
E-mail: emer.brady@uhl-tr.nhs.uk  
 
Funder:  
 
 
Novo Nordisk 
 
Safety Monitor:                          University of Leicester 
 
Confidentiality Statement 
All information contained within this protocol is regarded as, and must be kept confidential.  No part 
of it may be disclosed to anyone other than the Sponsor, the Investigator Team, host NHS Trust, 
regulatory authorities and members of the Research Ethics Committee, by any Receiving Party to 


 
 
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Page 3 of 65 
 
 
 
 
any Third Party, at any time, or in any form without the express written permission from the Chief 
Investigator and/or Sponsor. 
 
SIGNATURES 
 
PROTOCOL: Effectiveness and cost of integrating a protocol with use of Liraglutide 3.0mg into an 
obesity service (STRIVE Study) 
VERSION:  Version 7.0;29/01/2021 
 
By my signature below, I confirm that I have read this protocol and its attachments, I understand it, 
and I will work according to this protocol. I will also work consistently with the ethical principles that 
have their origin in the Declaration of Helsinki and that are consistent with ICH Guidelines on good 
clinical practices and the applicable local laws and regulations. I will accept a monitor for the 
Sponsor overseeing the study. I will abide by the publication plan set forth in my agreement with 
Novo Nordisk, including all statements regarding confidentiality.  
 
Chief Investigator:____________________________________________ 
 [Title/Name] 
 
Name of Facility: ___________________________________________________________ 
 [Study Site] 
 
Signed: _______________________________________  
Date: _____________________ 
 
 
Principal Investigator: ____________________________________________ 
 [Title/Name] 
 
Name of Facility: ___________________________________________________________ 
 [Study Site] 
 
Signed: _______________________________________  
Date: _____________________ 
 
 
Sponsor Representative: ____________________________________________ 
 [Title/Name] 
 
Name of Organisation: ___________________________________________________________ 
 
Signed: _______________________________________  
Date: _____________________ 


 
 
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TABLE OF CONTENTS 
1. AMENDMENT HISTORY 
 
 
 
 
 
 
 
 
 7 
2. PROTOCOL SYNOPSIS  
 
 
 
 
 
 
 
 
 10 
3. ABBREVIATIONS  
 
 
 
 
 
 
 
 
 
 12 
4. BACKGROUND AND RATIONALE  
 
 
 
 
 
 
 
 13 
5. OBJECTIVES  
 
 
 
 
 
 
 
 
 
 15 
5.1 Primary Objectives  
 
 
 
 
 
 
 
 
 15 
5.2 Secondary Objectives   
 
 
 
 
 
 
 
 15 
6. STUDY DESIGN  
 
 
 
 
 
 
 
 
 
 16 
6.1 Summary of Trial Design  
 
 
 
 
 
 
 
 16 
6.2 Intervention (Targeted Prescribing Pathway) 
 
 
 
 
 
 18 
6.3 Control (Standard Care)   
 
 
 
 
 
 
 
 19 
6.4 Primary and Secondary Outcomes  
 
 
 
 
 
 
 19 
 
6.4.1 Primary Outcome   
 
 
 
 
 
 
 
 19 
 
6.4.2 Secondary Outcomes  
 
 
 
 
 
 
 
 20 
7. TRIAL PARTICIPANTS  
 
 
 
 
 
 
 
 
 25 
7.1 Participant Identification and Recruitment  
 
 
 
 
 
 25 
7.2 Inclusion Criteria  
 
 
 
 
 
 
 
 
 25 
7.3. Exclusion Criteria  
 
 
 
 
 
 
 
 
 25 
8. STUDY PROCEDURES  
 
 
 
 
 
 
 
 
 27 
8.1 Invitation of Eligible Participants  
 
 
 
 
 
 
 27 
8.2 Screening and Consent Visit (Day -42 to -1)  
 
 
 
 
 
 27 
8.3 Data Collection Visits (Baseline, Weeks 52 and 104 
 
 
 
 
 28 
 
8.3.1 Baseline Visit (Day 0) – All Participants) 
 
 
8.3.1.1 Randomisation   
 
 
 
 
 
 
 29 
 
 
8.3.1.2 Titration Protocol  
 
 
 
 
 
 
 29 
8.3.2 Weeks 52 and 104 – All Participants 
 
 
 
 
 
 30 
8.4 Clinical Review (safety and retention) Visits (Weeks 2, 4, 8, 12, 16, 20, 32, 40 and 78)  
- All Participants  
 
 
 
 
 
 
 
 
 
 32 
 
8.4.1 Clinical Review (safety and retention) Visits for LIRA 3mg group (Weeks 65 and 91)  33 
8.5 Co-morbidity related investigations  
 
 
 
 
 
 
 33 
8.6 Source Data  
 
 
 
 
 
 
 
 
 
 34 
8.7 Definition of End of Trial   
 
 
 
 
 
 
 
 34 
8.8 Withdrawal of participants from the study and discontinuation of treatment    
 
 34 
8.8.1 Withdrawal from the study 
 
 
 
 
 
 
 34 
8.8.2 Treatment discontinuations (outside of the pre-specified stopping rules) 
 
 35 
8.8.3 Permanent treatment discontinuation (outside of the pre-specified stopping rules)  35 
8.8.4 Handling of participants after permanent treatment discontinuation 
 
 36 
8.8.5 Handling of participants after temporary treatment discontinuation 
 
 36 
8.9 Continued provision of the intervention for participants (if appropriate)    
 
 37 
8.10 Response to the COVID19 global pandemic (USM) 
 
 
 
 
 37 
9. TREATMENT OF TRIAL PARTICIPANTS  
 
 
 
 
 
 
 38 
9.1 Description of Study Treatment & Pharmacy Process  
 
 
 
 
 38 
9.2 Dosage Information  
 
 
 
 
 
 
 
 
 38 
9.3 Storage of Study Treatment   
 
 
 
 
 
 
 
 39 
9.4 Compliance with Study Treatment   
 
 
 
 
 
 
 39 
9.5 Accountability of the Study Treatment    
 
 
 
 
 
 40 
9.6 Concomitant Medication   
 
 
 
 
 
 
 
 40 
10. SAFETY REPORTING  
 
 
 
 
 
 
 
 
 41 
10.1 Definitions  
 
 
 
 
 
 
 
 
 
 41 


 
 
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10.1.1 Adverse Event (AE)   
 
 
 
 
 
 
 
 41 
 
10.1.2 Adverse Reaction (AR)  
 
 
 
 
 
 
 
 41 
 
10.1.3 Severe Adverse Event (SAE)  
 
 
 
 
 
 
 41 
 
10.1.4 Serious Adverse Event (SAE) of Serious Adverse Reaction (SAR)  
 
 
 41 
10.1.5 Suspected Unexpected Serious Adverse Reactions (SUSAR)  
 
 
 42 
10.2 Assessment Periods    
 
 
 
 
 
 
 
 43 
10.3 Expected Serious Adverse Events/Reactions   
 
 
 
 
 
 43  
10.4 Definitions of hypoglycaemia ______  
 
 
                                            43 
 
10.4.1 Classification of hypoglycaemia for participants with type 2 diabetes  
 
 43 
 
10.4.2 Novo Nordisk definition   
 
 
 
 
 
 
 44 
 
10.4.3 ADA hypoglycaemia definition  
 
 
 
 
 
 
 44 
10.4.4 Classification of hypoglycaemia for participants without diabetes   
 
 44 
10.5 Reporting Procedures for All Adverse Events  
 
 
 
 
 
 45 
10.6 Pregnancy  
 
______  
 
 
 
                                            45 
10.7 Follow up of Adverse Events  
 
 
 
 
 
 
 
 45 
10.8 Reporting Procedures for Serious Adverse Events  
 
 
 
 
 46 
10.9 Reporting Serious Unexpected Suspected Adverse Reactions (SUSARs)   
 
 46 
10.10 Reporting of Adverse Events to Novo Nordisk   
 
 
 
 
 48 
11. STATISTICS   
 
 
 
 
 
 
 
 
 
 49 
11.1 Statistical Methods and Analysis  
 
 
 
 
 
 
 49 
11.2 Sample Size    
 
 
 
 
 
 
 
 
 50 
11.3 Missing/unused/spurious data procedure  
 
 
 
 
 
 50 
11.4 Disposition of Patients   
 
 
 
 
 
 
 
 50 
11.5 Analysis Populations    
 
 
 
 
 
 
 
 50 
11.6 Health Economic Input   
 
 
 
 
 
 
 
 51 
12. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS   
 
 
 
 
 
 53 
13. QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES   
 
 
 
 53 
13.1 Responsibilities of Principal Investigator(s)  
 
 
 
 
 
 53 
13.2 Responsibilities of the Sponsor  
 
 
 
 
 
 
 53 
13.3 Deviation Procedures    
 
 
 
 
 
 
 
 54 
13.4 Misconduct or Serious Breaches of GCP/Protocol   
 
 
 
 
 55 
14. CODES OF PRACTICE AND REGULATIONS   
 
 
 
 
 
 
 55 
14.1 Clinical Trials Authorisation (CTA)  
 
 
 
 
 
 
 55 
14.2 Ethics   
 
 
 
 
 
 
 
 
 
 55 
14.3 HRA   
 
 
 
 
 
 
 
 
 
 56 
14.4 Sponsorship and Indemnity   
 
 
 
 
 
 
 
 56 
14.5 Host Organisation (R&I) Approvals   
 
 
 
 
 
 
 56 
14.6 Sponsor Standard Operating Procedures   
 
 
 
 
 
 56 
14.7 Declaration of Helsinki   
 
 
 
 
 
 
 
 56 
14.8 ICH Guidelines for Good Clinical Practice  
 
 
 
 
 
 56 
14.9 Laws and Regulations    
 
 
 
 
 
 
 
 56 
14.10 Other Ethical Considerations   
 
 
 
 
 
 
 57 
 
14.10.1 Known and Potential Risks   
 
 
 
 
 
 
 57 
 
14.10.2 Known and Potential Benefits   
 
 
 
 
 
 57 
15. DATA MANAGEMENT  
 
 
 
 
 
 
 
 
 58 
15.1 CRF/DATA Collection Sheet Management   
 
 
 
 
 
 58 
15.2 Documentation Storage, Access and Security    
 
 
 
 
 58 
15.3 Database Management   
 
 
 
 
 
 
 
 59 
15.4 Data Confidentiality    
 
 
 
 
 
 
 
 59 
16. STUDY GOVERNANCE   
 
 
 
 
 
 
 
 
 59 
16.1 Trial Steering Committee (TSC)   
 
 
 
 
 
 
 59 


 
 
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16.2 Trial Management Group (TMG)   
 
 
 
 
 
 
 60 
16.3 Data Safety and Monitoring Committee (DSMC)   
 
 
 
 
 60 
16.4 Premature Discontinuation of the Study   
 
 
 
 
 
 60 
17. PUBLICATION POLICY   
 
 
 
 
 
 
 
 
 60 
18. REFERENCES   
 
 
 
 
 
 
 
 
 
 61 
19. APPENDICES   
 
 
 
 
 
 
 
 
 
 62 
20. Appendix 1: King’s College Obesity Staging System    
 
 
 
 
 62 
Appendix 2: Participant Flow Chart   
 
 
 
 
 
 
 63 
Appendix 3: Table 2 Study Schedule for Measurements   
 
 
 
 
 64 
Figure 1: Study Design  
 
 
 
 
 
 
 
 
 16 
Table 1: Variables collected in this study and whether these measurements are routinely 
collected as part of the Tier 3 service or whether they will be additional as part of the study   23 
 


 
 
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1. 
AMENDMENT HISTORY 
Amendment 
No. 
Protocol 
Version No. 
Date 
Issued 
Author(s)  
of Changes 
Details of Changes Made 
Initial 
V2.0 
 
03/08/17 
Siân Hill 
Emer Brady 
REC Favourable Opinion granted for this version 
of protocol 
SA1-UK 
(SA2-IRE) 
V3 
(v6) 
27/03/18 
Sarah Edwards 
Emer Brady 
(Siân Hill) 
 
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. 
 
SA2-UK 
V4 
08/06/18 
Emer Brady 
Siân Hill 
(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. 
SA3-IRE 
N/A 
20/02/20
19 
Sarah Clarke 
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. 
SA3-UK 
(SA4-IRE) 
 
V5-UK 
V7-IRE 
07/01/20
19 
Sarah Clarke 
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 


 
 
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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. 
 
NSA02 
(UK 
only) 
IRE 
added as part 
of below SA5-
IRE 
UK 5.1 
 
26/03/20
20 
Sarah Clarke 
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. 
SA4-UK 
(SA5-IRE) 
UK V6.0 
IRE V8.0 
19/05/20
20 
Sarah Clarke 
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 


 
 
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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). 
SA5-UK 
(SA6-IRE) 
V7.0 
V9.0 
29/01/20
21 
Sarah Clarke 
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. 
  
 
 
 
 
 
 
 


 
 
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2. 
PROTOCOL SYNOPSIS 
Study Title 
Effectiveness and cost of integrating a protocol with use of Liraglutide 3.0mg 
into an obesity service (STRIVE Study) 
Clinical Phase  
Phase IV 
Study Setting 
The study will be co-ordinated by the appointed research team based at the 
Leicester Diabetes Centre (LDC). The Leicester Clinical Trials Unit (LCTU) will 
provide statistical input, and database management for this study. The study 
will include 5 sites in the UK and Ireland (Leicester, London, Liverpool, 
Glasgow, and Dublin (to include selected PIC’s)). 
Trial Design 
A 26 month, parallel, two group, open-label, real-world randomised 
controlled trial (RCT) design for subjects with severe and complex obesity who 
are referred to a Tier 3 or equivalent specialist weight management/obesity 
service. Participants will be randomised to receive 1) standard care (obesity-
specialist care), or 2) targeted prescribing pathway (obesity-specialist care 
plus targeted use of Liraglutide 3.0mg [LIRA 3mg] with pre-specified stopping 
rules for the medication). The aim of the study is to compare the 
effectiveness, budget impact, and cost-effectiveness between the two groups 
in a real-world setting among otherwise largely unselected patients.   
Trial Participants 
Eligibility criteria: 
 
Body mass index ≥35 kg/m2 
 
Referred to Tier 3 weight management or equivalent service  
 
Stable body weight (less than 5 kg self-reported change during the 
previous 12 weeks) 
 
Aged between 18-75 years old (inclusive)  
 
Diagnosed with at least one or more obesity-related co-morbidity (i.e. 
at least one of prediabetes, diabetes, hypertension, or obstructive 
sleep apnoea) 
 
Able to understand written and spoken English 
 
Able to give informed consent 
Planned Sample Size 
392 participants in total (131 in standard care; 261 in targeted prescribing 
pathway). This sample size allows for a 25% drop-out rate and will have 80% 
power to detect an absolute difference of 11% between the two groups 
(based on 5% of the participants achieving ≥15% weight loss in the standard 
care group and 16% of the participants achieving ≥15% weight loss in the 
targeted prescribing pathway group). 
Follow-up duration 
Up to 24 months (104 weeks) 
Primary Outcome 
Binary outcome indicating whether weight loss of ≥15% was achieved at 52 
weeks 
 
Secondary Outcomes 
Compare the targeted prescribing pathway and standard care groups in terms 
of: 
1. Improving obesity-related co-morbidities (obstructive sleep apnoea, 
prediabetes, diabetes, hypertension, dyslipidaemia, depression) 
2. Referral rates to other obesity interventions 
3. 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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4. Budget impact on a Tier 3 weight-management service 
5. Long-term cost-effectiveness 
6. Direct healthcare costs in terms of admissions, frequency, and cost of 
appointments 
7. Safety-related outcomes 
8. Adherence  
9. Patient satisfaction 
Investigational 
Medicinal Products 
Liraglutide (Saxenda) 6 mg/mL solution for injection in pre-filled pen, which 
will be administered by subcutaneous injection. This product forms part of the 
targeted prescribing pathway in the treatment group. 
Dose 
Dose escalation from 0.6 to 3.0 mg daily  


 
 
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3. 
ABBREVIATIONS 
ACR: Albumin Creatinine Ratio 
AE: Adverse Events 
AHI: Apnoea Hypopnoea Index 
BMI: Body Mass Index 
CRF: Case Report Form 
CI: Chief Investigator 
CPAP: Continuous Positive Airway Pressure machine 
COVID-19: Coronavirus – SARS-CoV-2 
DSMC: Data Safety Monitoring Committee 
eGFR: Estimated Glomerular Filtration Rate 
EMA: European Medicines Agency 
EQ-5D: European Quality of Life -5 Dimensions 
FBC: Full Blood Count 
FDA: Food and Drug Administration  
ICH GCP: International Conference on Harmonisation Good clinical practice 
GP: General Practitioner 
HbA1c: Glycated Haemoglobin 
HSRUQ: Health Services and Resources Use Questionnaire 
HCP: Health Care Professional 
IPAQ-Long: International Physical Activity Questionnaire 
ITT: Intention to treat 
IWQOL –Lite: Impact of Weight on Quality of Life – Lite 
LCTU: Leicester Clinical Trials Unit 
LDC: Leicester Diabetes Centre 
LFT: Liver Function Test 
LIRA 3mg: Liraglutide 3.0 mg (Saxenda)  
MDT: Multidisciplinary Team 
PCOS: Polycystic Ovarian Syndrome 
PHQ-9: Patient Health Questionnaire-9 
PI: Principal Investigator 
PP: Per Protocol  
QoL: Quality of Life  
REC: Research Ethics Committee 
SAE: Serious Adverse Event  
SAR: Serious Adverse Reaction 
BP: Blood Pressure 
RCT: Randomised Controlled Trial 
SOP: Standard Operating Procedure 
SUSAR: Serious Unexpected Suspected Adverse Reaction 
TFT: Thyroid Function Test 
TSC: Trial Steering Committee  
TSQM: Treatment Satisfaction Questionnaire for Medication 
T2DM: Type 2 Diabetes Mellitus 
U+Es: Urea, creatinine and Electrolytes 
UAR: Unexpected Adverse Reaction 
WL: Weight Loss 
 


 
 
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4. 
BACKGROUND AND RATIONALE 
‘Severe and complicated obesity’ (previously referred to as ‘morbid 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 [1]. Approximately 10% of the adult population in England now 
has a BMI ≥35kg/m2 [2]. In this group, 8-16% have type 2 diabetes mellitus (T2DM), imposing colossal 
direct and indirect healthcare costs [2, 3].  
 
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 [4]. 
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.  
 
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 [5-7].   
 
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 [5-7]. 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 [5], a reduction which is likely to 
generate major health benefits and long-term cost-savings, especially if weight loss can be 
maintained [7]. Among obese patients with T2DM, weight loss is less, but the potential cost-savings 
are greater [6].  
 
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 [8]. 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 [7]. 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.  


 
 
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As outlined above, 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.  
 
The targeted prescribing pathway directs the use of LIRA 3mg to patients likely to be “good” 
responders and aims to optimise health economic outcomes by initially starting all patients (in the 
targeted prescribing pathway group) on LIRA 3mg and then applying pre-specified rules for stopping 
LIRA 3mg at different time points for patients who do not achieve substantial weight loss. As part of 
the targeted prescribing pathway, patients who stop receiving LIRA 3mg would still receive standard 
care from the specialist-obesity service. The implementation of stopping rules for LIRA 3mg is 
expected to optimise the use of this medication and decrease the exposure and potential adverse 
side effects in non-responders. It is also expected that the cost-effectiveness and the budget impact 
would be improved by only treating patients with LIRA 3mg if they are “early and good” responders, 
whilst continuing to treat the remaining patients in the targeted pathway as per standard care.  
 
The study will be an open label, randomised controlled trial of standard care (i.e. the care usually 
provided by the relevant Tier 3 or specialist weight management service) versus the targeted 
prescribing pathway (i.e. standard care plus LIRA 3mg with pre-specified stopping rules). The aims of 
this study are to: 
 
a) compare effectiveness between the two groups, by comparing the proportion of participants 
achieving weight loss of ≥15% at 52 weeks after randomisation  
b) compare long-term maintenance between the two groups, by comparing the proportion of 
participants maintaining weight loss of ≥15% at 104 weeks among those who achieved ≥15% 
weight loss at 52 weeks  
c) evaluate the budget impact and cost-effectiveness of the targeted prescribing pathway over 
the 104 weeks of the study. 


 
 
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5. 
OBJECTIVES  
5.1 Primary Objectives 
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.  
 
5.2 Secondary Objectives 
The secondary objectives are to compare the targeted prescribing pathway and standard care in 
terms of: 
1. improving obesity-related co-morbidities (obstructive sleep apnoea, prediabetes, diabetes, 
hypertension, dyslipidaemia, depression) 
2. referral rates to other obesity interventions 
3. long-term maintenance (defined as the proportion of participants maintaining weight loss of 
≥15% at 104 weeks among those who achieved ≥15% weight loss at 52 weeks) 
4. budget impact on a Tier 3 weight management service 
5. long-term cost-effectiveness 
6. direct healthcare costs in terms of admissions, frequency, and cost of appointments 
7. safety-related outcomes 
8. adherence  
9. patient satisfaction. 
 


 
 
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6. 
STUDY DESIGN 
6.1 Summary of Trial Design 
A 26 month, parallel, two group, open-label, real-world, RCT design for patients with severe and 
complex obesity who are referred to a Tier 3 obesity service (including patients who are referred to a 
Tier 3 service as part of the bariatric surgery pathway). The total duration of participation will be 104 
weeks (+/-2 weeks).  
 
The first 52 weeks of the study (after randomisation) will determine whether using the targeted 
prescribing pathway in a Tier 3 setting will result in more participants attaining ≥15% weight loss 
compared with standard care. The second 52 weeks of the study will assess whether patients who 
lose ≥15% of their baseline weight by the first 52 weeks are more likely to maintain ≥15% weight loss 
for another 52 weeks in the targeted prescribing pathway compared with standard care. Further, 
budget impact, cost-effectiveness, improvement in obesity-related co-morbidities, complementary 
aspects of safety, effectiveness, adherence, and treatment satisfaction of both treatment groups will 
be assessed and compared (see Section 6.4.2).  
 
 
Participants will be randomised in a 2:1 fashion to either the intervention (targeted prescribing 
pathway + standard care) or control (standard care) group (2 intervention: 1 control). The control 
group will receive standard care in a specialist obesity service (Tier 3 or equivalent), according to the 
best practice in each site and can include total or partial meal replacement strategies. The 
intervention group will receive the same standard care as the control group (i.e. according to the 
best practice in each site) plus all participants will initially receive LIRA with pre-specified stopping 
rules. The targeted prescribing pathway is described in detail (including descriptions on stopping 
rules) below in Section 6.2 (see also Figure 1), but in brief, participants who do not meet the 
definition of a ‘early and good responder’ (defined as achieving ≥5% weight loss at 16 weeks, ≥10% 
weight loss at 32 weeks and ≥15% weight loss at 52 weeks) will have their LIRA 3mg treatment 
stopped. It is important to note that all participants will be analysed in the group to which they are 
randomised; in particular, participants in the intervention group who stop receiving LIRA 3mg will 
remain in the intervention group and will continue to receive standard care for the remainder of the 
study as per the targeted prescribing pathway (albeit, the part of the pathway where LIRA 3mg is not 
prescribed; see Figure 1). 
 
The study is intentionally designed to reflect a pragmatic “real-world” scenario and each Tier 3 
provider may require a different number of visits for their programme. However, study 
appointments for data collection, titration reviews, application of the stopping rules of LIRA 3mg, 
and dispensing will be standardised for all of the five sites (see Appendix 3 for outcome measures 
table).Should the study team be unable to contact a participant to invite them to attend study visits 
(lost to follow up) or for any reason a participant has had to miss a study visit (non attendance), the 
study team will ask that we are able to access data from existing hospital, GP or health records, 
where study visit data may exist in lieu of attendance at these study visits. Participants will be given 
the 
option 
to 
opt 
in 
or 
out 
of 
this 
on 
the 
consent 
form.


 
 
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6.2 Intervention (Targeted Prescribing Pathway) 
The NHS Weight Management pathway is divided into four distinct tiers: 
Tier 1: health promotion  
Tier 2: lifestyle interventions 
Tier 3: specialist multidisciplinary weight management services 
Tier 4: bariatric surgery 
 
Across the UK, each region has a specialist Tier 3 obesity and/or weight management service or 
equivalent, usually referred to as Tier 3. This includes a clinician led multidisciplinary team approach, 
potentially including a specialist physician, nurse, dietician, psychologist, physiotherapist, etc. From 
this point forwards, Tier 3 specialist weight management and/or equivalent services will be referred 
to as ‘Tier 3’ throughout the remainder of this protocol. 
 
Participants in the intervention group will receive the same standard care as those in the control 
group, i.e. the best medical practice delivered by the Tier 3 service at each site. Additionally, at 
baseline, LIRA 3mg will be prescribed to all of the participants in the intervention group at a starting 
dose of 0.6mg daily. Dose escalation of Liraglutide will occur according to a pre-specified titration 
protocol, from 0.6mg to a maximum of 3.0mg daily. Liraglutide dose will be 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 intervention group will be aware that the LIRA 3mg treatment may be stopped at 
various time points throughout the duration of the study and that continued use of LIRA 3mg is 
based upon their response to the treatment in terms of them achieving pre-defined weight loss 
targets at 16, 32 and 52 weeks.. Specifically, participants in the intervention group will continue to 
be prescribed LIRA 3mg for the 104 week duration of the study, unless one of the following stopping 
rules applies: 
 
1st stopping rule:  
After 16 weeks (± 14 days) on the medication, only those participants who have lost ≥5% of their 
baseline weight will be offered further treatment with LIRA 3mg for another 16 weeks. Participants 
who have not met this weight loss target will have their LIRA 3mg treatment stopped but will still 
continue in the targeted prescribing pathway but will receive standard care only during the 
remainder of the study. 
 
2nd stopping rule: 
After 32 weeks (± 14 days) on the medication, only those participants who have lost ≥10% of their 
baseline weight and are still on treatment with LIRA 3mg will be offered another 20 weeks on LIRA 
3mg. Participants who have not met this weight loss target will have their LIRA 3mg treatment 
stopped but will still continue in the targeted prescribing pathway but will receive standard care only 
during the remainder of the study. 
 
3rd stopping rule: After the first year of treatment (week 52; ± 14 days), only those participants who 
have lost ≥15% of their baseline weight and are still on treatment with LIRA 3mg will be offered 
another 52 weeks on LIRA 3mg. Participants who have not met this weight loss target will have their 


 
 
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LIRA 3mg treatment stopped and will still continue in the targeted prescribing pathway but will 
receive standard care only during the remainder of the study. 
 
Participants who fail to reach the pre-defined weight-loss targets to continue LIRA 3mg treatment, 
or who choose to stop receiving LIRA 3mg, will continue to be offered the standard care provided by 
the Tier 3 service. These participants will still attend the Clinical Review Visits but not the additional 
visits for participants who are still on LIRA 3mg (e.g. Weeks 65 & 91) because these visits will not be 
relevant to them; visits at Weeks 65 and 91 are intended to provide a new prescription of LIRA 3mg 
and to discuss adherence and any side effects; see Appendices 2 & 3).  
 
Participants will remain routinely in the Tier 3 service in-line with NICE guidance throughout the 
duration of the research study. Participants may be offered treatment options within the duration of 
the study, including bariatric surgery, as per NICE guidance and according to the decision of the local 
Tier 3 Multidisciplinary Team. Participants who have undergone bariatric surgery after 
randomisation will only be included in the intention to treat (ITT) analysis. This decision was made 
because the proportion of participants undergoing bariatric surgery is likely to be unbalanced 
between the treatment groups (i.e. more participants in the control group are expected to have 
bariatric surgery than in the targeted prescribing pathway treatment group), and thus weight loss in 
these individuals could unduly influence the study results. Participants who have been prescribed 
and start anti-obesity medication (such as Orlistat) will be ineligible for LIRA 3mg treatment.  
 
6.3 Control (Standard Care) 
Participants in the control group will follow the best medical care provided by the Tier 3 service at 
the relevant site. This typically involves dietary advice to reduce energy intake (and may include a 
period of partial or total meal replacement), accompanied – if available – 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 (such as Orlistat) as per 
local Tier 3 service policy. As with the LIRA 3mg group 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 in line with 
NICE guidance throughout the duration of the research study. Participants may be offered treatment 
options within the duration of the study, including bariatric surgery, as per NICE guidance and 
according to the decision of the local Tier 3 Multidisciplinary Team. 
 
6.4 Primary and Secondary Outcomes 
 
6.4.1 Primary Outcome 
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.  


 
 
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6.4.2 Secondary Outcomes 
Unless stated, the secondary outcomes listed below will be assessed at 52 and 104 weeks. 
 
Anthropometric Outcomes 
 
Weight (kg), from which these secondary outcomes will be derived (also at 16 and 32 
weeks): 
o Absolute change in weight (kg) from baseline  
o Relative change in weight (%) from baseline  
o Proportion of participants reaching weight loss of  ≥5%, ≥10% and ≥15%  
o 104 weeks only: Proportion of participants maintaining weight loss of ≥15% among 
those who lost ≥15% at 52 weeks 
 
Height (cm), from which this secondary outcome will be derived: 
o Change in BMI (kg/m2) from baseline 
 
Waist circumference (cm) 
 
Obesity-related co-morbidities and their treatments (General)  
 
King’s College Obesity Staging System assessment (a system to assess multiple co-
morbidities related to obesity and their severity, see Appendix 1) 
 
Quality of life (EQ5D) 
 
Impact of Weight on Quality of Life-Lite (IWQOL-Lite) 
 
Patient Health Questionnaire-9 (PHQ9) 
 
Obesity-related co-morbidities and their treatments (Obstructive Sleep Apnoea) 
 
Epworth Sleepiness Scale for all participants to determine levels of  daytime sleepiness 
 
Stop Bang questionnaire for all participants to identify undetected OSA  - it will  be 
administered by research team or taken from medical notes 
 
Proportion of participants on CPAP  
 
CPAP compliance (hrs/day) 
 
Apnoea Hypopnea Index (AHI) for participants with sleep apnoea who cannot tolerate CPAP 
or for participants on fixed pressures CPAP 
 
Oxygen desaturation index for participants with sleep apnoea who cannot tolerate CPAP or 
for participants on fixed pressures CPAP 
 
Obesity-related co-morbidities and their treatments (Prediabetes/Diabetes)  
 
HbA1C  
 
Proportion of participants with normoglycaemia (defined as HbA1C <42.0 mmol/mol without 
glucose lowering medications) 
 
Proportion of participants with prediabetes (defined as HbA1C 42.0-47.9 mmol/mol without 
glucose lowering medications)  
 
Proportion of participants with diabetes (defined as HbA1C ≥48 mmol/mol or on glucose 
lowering medications) 
 
Dose, class of medication, and number of agents for diabetes 


 
 
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 
Monitoring of microvascular complications for patients with diabetes [Albumin- Creatinine 
Ratio (ACR)] 
 
Obesity-related co-morbidities and their treatments (Hypertension)  
 
Blood pressure 
 
Proportion of participants with hypertension (defined as patients on antihypertensive 
medications or systolic blood pressure>140mmHg) 
 
Dose, class of medication, and number of agents for hypertension 
 
Obesity-related co-morbidities and their treatments (Dyslipidaemia)  
 
Lipids 
 
Dose, class of medication, and number of agents for dyslipidaemia 
 
Number of participants referred for other obesity intervention 
 
Number of participants referred to Tier 4 for bariatric surgery over the 104 weeks study 
period 
 
Direct healthcare cost 
 
Frequency and cost of contact with General Practitioner (GP) (type and duration of contact 
will be recorded to enable use of Tariff prices from http://www.pssru.ac.uk/project-
pages/unit-costs/2016/index.php?file=full to calculate accurate costings – accessed 
21/07/2017) 
 
Frequency and cost of contact with Healthcare Professionals (HCP) (type and duration of 
contact will be recorded to enable use of Tariff prices from http://www.pssru.ac.uk/project-
pages/unit-costs/2016/index.php?file=full to calculate accurate costings) 
 
Frequency of admissions, length of stay and cost of admissions to the hospital   
 
Frequency and cost of outpatient appointments with the hospital 
 
Prescription medication costs 
 
Health Service and Resources Use Questionnaire (HSRUQ) 
 
 Budget impact of Tier 3 service 
 
Cost of the proposed LIRA 3mg (as per protocol - e.g. actual dose taken = number of days 
taking study drug x daily cost of drug, or cost of total amount of study drug used) 
 
Cost of visits to clinician for assessment and medication prescription during Tier 3 
programme 
 
Cost of visits to dietician during Tier 3 programme 
 
Cost of visits to psychologist during Tier 3 programme 
 
Cost of exercise physiologist/physiotherapist during Tier 3 programme (if applicable) 
 
Cost of Multidisciplinary Team (MDT) discussion in Tier 3 service 
 
Cost of blood tests in Tier 3 service 
 
Cost of consumables and goods  
 
Cost of referral into Tier 4 
 


 
 
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Estimated cost-effectiveness of treatment over 2 years  
 
Length of treatment with LIRA 3mg 
 
Daily dose of LIRA 3mg (based on actual doses taken) 
 
Safety/adverse events  
 
Gastrointestinal symptoms (nausea, vomiting) 
 
Overall hypoglycaemia rate 
 
Overall AE/SAE rate 
 
Rates of severe hypoglycaemia 
 
Heart rate  
 
Blood pressure 
 
(See Section 10.4 for definitions of hypoglycaemia) 
 
Treatment satisfaction 
 
Treatment Satisfaction Questionnaire for Medication (TSQM) 
 
Compliance of patient with the treatment and patient related outcomes 
 
The number of participants who did or did not attend at least 70% of the scheduled 
appointments with the Tier 3 service (completers) 
 
The number of participants who had to stop treatment with LIRA 3mg because of adverse 
effects 
 
The adherence of participants with the LIRA 3mg (monitored through specific questionnaire 
and return of used pens) 
 
The number of participants who stopped LIRA 3mg at 16 weeks after randomisation 
 
The number of participants who stopped LIRA 3mg at 32 weeks after randomisation 
 
The number of participants who stopped LIRA 3mg at 52 weeks after randomisation 
 
The number of participants who completed 52 weeks of the Tier 3 service programme 
despite stopping LIRA 3mg at 16 weeks 
 
The number of participants who completed the 52 weeks of Tier 3 service programme 
despite stopping LIRA 3mg at 32 weeks 
 
The number of participants in the treatment group who had to stop treatment with LIRA 
3mg because of side effects 
 
The number of participants started on anti-obesity drugs 
 
Physical activity assessment 
 
International physical activity questionnaire (IPAQ- Long Form) 
 
 
 
 
 
 
 


 
 
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Table 1: Variables collected in this study and whether these measurements are routinely collected as 
part of the Tier 3 service or whether they will be additional as part of this study. 
 
Measurement 
Outcomes  
Standard 
Care 
Research 
Body weight 
-% Change (absolute change, relative change, proportion of 
participants reaching weight loss of  ≥5%, ≥10% and ≥15% 
[primary outcome], proportion of participants maintaining 
weight loss) 
X 
X 
 
Height 
 
X 
 
Waist 
circumference 
 
X 
 
Blood pressure 
-Proportion of participants with hypertension (defined as 
patients on antihypertensive medications or systolic blood 
pressure>140mmHg) 
-Dose, class of medication, and number of agents for 
hypertension 
X 
 
 
X 
 
Heart rate 
 
X 
 
Blood sample 
-HbA1c 
-Lipid profile (including LDL & HDL cholesterol & triglycerides) 
-Renal profile (including U&E’s, creatinine, eGFR) 
-Liver function test (LFTs) (including ALT, ALP, Bilirubin, 
Albumin) 
-Thyroid function test (TFTs) (including Free Thyroxine, Thyroid 
Stimulating hormone) 
-Haematology profile (including full blood count) 
-Amylase 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
Urine sample 
-ACR 
-Pregnancy testing 
 
X 
X 
Sleep apnoea  
-Epworth Sleepiness Scale  
- Stop Bang Questionnaire 
-CPAP pressures (proportion of participants on CPAP, AHI 
figures) 
-Sleep study (home based ambulatory sleep monitor) 
 
X 
X 
 
 
X 
Monitoring of 
adherence & 
compliance 
-To Tier 3 programme 
-With the LIRA 3mg (returned used pens)  
X 
 
X 
Questionnaires 
(Health status 
and obesity 
related co-
morbidities) 
-King’s College Obesity Staging System 
-Health Service and Resources Use Questionnaire (HSRUQ) 
-Treatment Satisfaction Questionnaire for Medication (TSQM) 
-EuroQol Five Dimensions Questionnaire (EQ5D) 
-Impact of Weight on Quality of Life-Lite (IWQOL-Lite) 
-International physical activity questionnaire (IPAQ-Long) 
-Patient Health Questionnaire-9 (PHQ9) 
 
X 
X 
X 
X 
X 
X 
X 


 
 
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Resource use 
-Frequency of contact with GP and HCP 
-Frequency of hospital admissions 
-Number of outpatient appointments 
-Medication use and costs 
-Estimation of direct healthcare costs and budget impact 
-Referrals to Tier 4 
 
X 
X 
X 
X 
X 
X 
Safety/adverse 
events 
-Gastrointestinal symptoms 
-Hypoglycaemic events 
-Hypertensive events 
 
X 
X 
X 


 
 
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7. 
TRIAL PARTICIPANTS 
7.1 
Participant Identification and Recruitment 
There will be a standard approach to identifying and recruiting eligible participants who have agreed 
to participate in the Tier 3 service. Patients will be identified and approached by their usual clinical 
care team. Five sites in different geographical areas, which are culturally and racially diverse, will be 
used to reflect Tier 3 service range across UK and Ireland. Each site will plan to recruit up to 77 
subjects over the recruitment period (up to 24 months or (equivalent to 4-6 patients per month. The 
study will also make use of Participant Identification Centres (PICs) within these five Tier 3 sites 
where applicable. For context, data from a local Tier 3 service (Leicester) showed that at least 90 
individuals who have been referred to the service in 2014 would potentially be eligible for this study 
(BMI ≥35 kg/m2 and diabetes or impaired glucose tolerance, hypertension or obstructive sleep 
apnoea). Further details on recruitment are given in Section 8.1. 
 
7.2 Inclusion Criteria 
To be considered eligible to participate in this study, a patient must: 
 
be aged between 18-75 years old (inclusive) 
 
understand written and spoken English 
 
be able to give informed consent 
 
have a BMI ≥35 kg/m2  
 
have been referred to the Tier 3 service in one of the participating sites 
 
have a stable body weight (less than 5kg self-reported change during the previous 12 
weeks) 
 
have at least one of prediabetes, diabetes, hypertension, and/or obstructive sleep apnoea, 
as defined below: 
 
prediabetes (defined as established diagnosis of impaired fasting glycaemia (IFG) 
from GP and/or established diagnosis of impaired glucose tolerance (IGT) from GP 
and/or HbA1C 42-47 mmol/mol (6-6.4%) without glucose lowering medications, at a 
blood test during the last 6 months) 
 
diabetes (defined as established diagnosis of Type 2 diabetes from GP and/or 
HbA1C ≥48 mmol/mol (>6.5%) at a blood test during the last 6 months] and/or 
being treated with any combination of lifestyle, metformin, sulphonylureas,  
Thiazolidinediones (TZDs) or SGLT-2) 
 
hypertension treated (defined as being on antihypertensive treatment with or 
without a diagnosis of hypertension from GP) or untreated (defined as Systolic 
Blood Pressure ≥140 mmHg at two consecutive visits at the Tier 3 clinic),  
 
obstructive sleep apnoea (on CPAP or established diagnosis of Apnoea Hypopnoea 
Index ≥15 at sleep studies during the last 12 months). 
 
7.3 Exclusion Criteria 
Patients who have met any of the following criteria will be excluded from the study: 
 
Diagnosis of Type 1 diabetes 
 
T2DM on treatment with DPP-IV or insulin currently 


 
 
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 
Treatment with GLP-1 receptor agonists within the last 6 months and/or have a history of 
GLP-1 receptor agonist intolerance 
 
Treatment with anti-obesity drugs within 12 weeks prior to randomisation 
 
eGFR ≤30ml/min/1.73m2 on serum testing over the last 26 weeks 
 
Females referred to the clinic because of fertility problem 
 
Females of child bearing potential who are pregnant, breast-feeding or intend to become 
pregnant or are not using or willing to use adequate contraceptive methods (as described in 
Section 8.3.1 
 
Have terminal illness 
 
Are not primarily responsible for their own care 
 
Any other significant disease or disorder which in the opinion of the investigator, may either 
put the participants at risk or may influence the result of the study or the participant’s ability 
to participate 
 
Untreated or uncontrolled hypothyroidism/hyperthyroidism defined as thyroid-stimulating 
hormone, as defined by local sites pathology laboratory reference ranges as outside the 
normal range; mIU/litre (see local site laboratory reference ranges)   
 
Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial 
medullary thyroid carcinoma (FMTC) 
 
Personal history of non-familial medullary thyroid carcinoma  
 
History of chronic pancreatitis or idiopathic acute pancreatitis  
 
Amylase levels three times higher than the upper normal range 
 
Obesity induced by other endocrinologic disorders (e.g. Cushing’s Syndrome)  
 
Current or history of treatment with medications that may cause significant weight gain, 
within 12 weeks prior to randomisation, including systemic corticosteroids (except for a 
short course of treatment, i.e. 7−10 days), atypical antipsychotic and mood stabilizers (e.g. 
clozapine, olanzapine, valproic acid and its derivatives, and lithium) 
 
Initiation of antidepressants during the last 12 weeks 
 
Previous surgical treatment for obesity <1 year before trial entry weight loss 
procedures/surgery including removal of a gastric band and/or gastric balloon  
 
History of other severe psychiatric disorders 
 
History of known or suspected abuse of alcohol and/or narcotics 
 
History of major depressive episode during the last 2 years 
 
Simultaneous participation in other clinical trials of investigational drugs, lifestyle or physical 
activity interventions. Patients will only be able to take part following participation in a 
previous clinical trial after a wash-out period of 16 weeks. 


 
 
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8. 
STUDY PROCEDURES 
8.1 Invitation of Eligible Patients 
Eligible patients will be mailed a brief invitation leaflet before they attend an appointment at their 
Tier 3 service or will be given the information leaflet during their appointment in the Tier 3 service 
by a member of the research team at the study site. Patients who are interested in participating in 
the study will return a completed reply slip to the study team indicating their interest. The study 
team will then contact the patient to provide further information, a full Participant Information 
Leaflet, and to invite them to attend a screening appointment. The patient will receive a letter 
confirming the details of the appointment. They will have at least 24 hours to consider participation 
before this appointment.  
 
Awareness and interest in the study will be generated through primary and secondary care services, 
as well as other local community services (such as but not limited to pharmacies and libraries) using 
leaflets, posters and marketing. We will also utilise electronic and digital marketing via websites 
including social media such as Facebook and Twitter, as well as promotional campaigns via 
local/national media (e.g. in print, radio) where applicable.  
 
8.2 Screening and Consent Visit (Day -42 to -1) 
The Screening and Consent Visit (Visit 1) is performed at least one day and up to 42 days prior to the 
Baseline Visit, depending upon the case record information relating to eligibility criteria (e.g. blood 
pressure measurement, renal function, thyroid function and sleep study [home based ambulatory 
sleep monitor] if specified).  
 
Patients will attend an appointment with a healthcare professional at the study site. The healthcare 
professional will check their eligibility to participate, explain in detail what the study involves and 
answer any questions they may have. Full written informed consent to participate will then be 
obtained. The person obtaining informed consent will be a suitably trained and competent 
healthcare professional who, in the opinion of the PI of each site, is able to give a full, unbiased 
explanation of the study (including benefits and risks) to the potential participant. The person 
obtaining consent will also have been named in the delegation log of staff as undertaking this duty 
and approved as study personnel by the relevant governance procedures.  
 
Each participant will also have a copy of the consent form and patient information leaflet; a copy will 
be placed in their hospital medical records and the original copy held in the site master file. This will 
also include explicit notice of their in-study medication and a standard label will be used on the front 
of the medical notes to highlight to any reviewer that this individual is taking part in the study and 
any issue regarding contra-indication of a procedure or medication outside of the study should be 
discussed with a study clinician. The standard label template is provided by the local Trust and 
should contain the following information; 
 
 
 
 
 


 
 
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PATIENT TAKING PART IN A CLINICAL TRIAL 
Study Name. . . . . . . . . . . . . . . . . . . . . . .  . . . . . . 
Patient ID No. . . . . . . . . . . . . . . . . . . . . . .  . . . . . . 
Investigator: . . . . . . . . . . . . . . . . . . . . . .  . . . . . . 
Telephone:  . . . . . . . . . . . . . . . . . . . . .  . . . . . . . .  
Date Consent Form Signed . . . . . . . . . . . . . . . . . . . . . . . . .  
TRIAL START _ _/_ _/_ _ _ _  TRIAL FINISH _ _/_ _/_ _ _ _ 
Don't destroy the records before (date) _ _/ _ _/ _ _ _ _ 
 
After consent has been obtained, a member of the research team will record participant 
demographics, medical/surgical history and perform measurement of anthropometrics (height, 
weight, waist circumference, blood pressure and pulse rate) for all the patients in line with study 
Standard Operating Procedures (SOPs) and arrange for standard laboratory testing (HbA1c, FBC, 
U+Es, lipids, LFTs, TFTs) and pregnancy test (for females of childbearing potential). A urine ACR will 
be performed for patients with prediabetes, diabetes and hypertension. The King’s College Obesity 
Staging assessment will be recorded in the CRF if it is available in the patient’s notes. A Stop Bang 
questionnaire will be undertaken (to capture any undetected OSA cases) and an Epworth Sleepiness 
Scale (to capture daytime sleepiness) will be undertaken by all participants. Participants with 
undetected (OSA) defined as a score between 5-8 on the Stop Bang, will be informed that they are at 
high risk of this sleep disorder and a referral to the sleep clinic from the local PI will be made so that 
the participant can be considered for investigation. All sleep related therapy will then be the 
responsibility of the local sleep clinic as per standard practice.  
Those participants that are already patients of the sleep clinic will have their notes reviewed to 
determine whether or not they are CPAP compliant and thus ‘successful’ against the below criteria.  
a.       CPAP usage >= 4 hrs/night = successful 
b.      CPAP usage < 4 hrs/night = struggling 
c.       CPAP usage < = 1 hrs/night = failure 
A repeat screening visit may take place if indicated for eligibility (for example, repeat blood pressure 
measurement for patients with undiagnosed hypertension). The study clinician will assess and 
decide when all the blood results and investigations are available whether a patient is eligible for 
randomisation or not.  
 
8.3 Data Collection Visits (Baseline, Weeks 52 and 104) 
Eligibility criteria for each participant will be re-checked at every visit. 
 
8.3.1 Baseline Visit (Day 0) – All Participants 
Only those patients who are eligible based on the data collected at the Screening and Consent Visit 
will proceed to the Baseline Visit (Day 0). Weight, waist circumference, blood pressure and pulse 
rate will be recorded for all the patients in line with study SOPs. The patient will also complete 
questionnaires to provide demographic and medical history details and additional data will be 
collected as indicated in Appendix 3 (e.g. self-reported physical activity using the International 
Physical Activity Questionnaire). Serious Adverse Event (SAE) and Adverse Event (AE) recording and 
documentation of changes in medication or diseases will be performed. Randomisation will be 


 
 
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performed and participants will be informed of their group allocation (see Randomisation Section 
8.3.1.1 below). Participants in both groups (standard care [control group] vs. standard care + LIRA 
3mg [targeted prescribing pathway]) will be counselled about the study visits and what they can 
realistically expect with each treatment option. Participants allocated to the targeted prescribing 
pathway will receive injection training, storage and dispensing. All participants will be informed that 
they may contact their GP or the study team at any time. 
 
Urine pregnancy tests will be performed for females of childbearing potential. Additional testing will 
also occur at any time during the trial if a menstrual period is missed or as required by local law. The 
test will be performed at the study site. Pregnancy testing will not be required for women who have 
undergone a hysterectomy or bilateral tubal ligation, or for women above the age of 50 years old, 
who have been without menses for at least 1 year. Participants will be given clear instructions 
regarding contraception throughout the study. Adequate contraceptive measures have been defined 
as sterilisation, intra-uterine device, oral contraceptives, consistent use of barrier methods, male 
sterilisation or true abstinence (when this is in line with the preferred and usual lifestyle of the 
participant) (www.hma.eu/fileadmin/dateien/Human_Medicines/01- 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
– 
accessed 
21/07/2017.  
 
8.3.1.1 Randomisation 
Randomisation will be conducted through a validated online system (sealedenvelope.com) provided 
through the LCTU. Eligible participants will be randomly assigned at their Baseline Visit (Day 0) in a 
2:1 ratio to participate in a Tier 3 service with:  
1) Targeted prescribing pathway - The use of once daily subcutaneous injections of 
Liraglutide (if they meet the pre-specified criteria), starting at a dose of 0.6 mg with 
gradual and pre-specified increments to 3.0mg 
or  
2) Control Group - No additional treatment. 
 
A 2:1 ratio will be used so that a sufficient number of responders will be available for responder 
analyses (see Section 11). Randomisation will be stratified by centre and BMI (>45kg/m2; <45kg/m2). 
Participants will be informed of their randomisation assignment during the Baseline Visit. A letter 
will be sent to the participant’s GP notifying them of their patient’s participation in the study. Both 
the participant and their GP will have the randomisation assignment confirmed by letter. 
 
8.3.1.2 Titration Protocol 
During the baseline visit, participants randomised to the targeted prescribing pathway group will be 
offered LIRA 3mg for the next 16 weeks and will be re-informed of the potential side effects of the 
medication. The research team will explain to participants in this group the titration protocol and the 
weight loss targets in order to continue receiving treatment with LIRA 3mg. All participants who will 
start on LIRA 3mg will be trained to self-administer the treatment injection once daily. Dose 
escalation of Liraglutide will occur according to a pre-specified titration protocol, from 0.6mg to a 
maximum of 3.0mg. Participants in the targeted prescribing pathway will continue to be prescribed 
LIRA 3mg for the duration of the study unless they do not meet the pre-defined weight loss targets 


 
 
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at each stopping point (after 16, 32 and 52 weeks – see Section 6.2 for stopping rules). Participants 
will be withdrawn from receiving LIRA 3mg if the doses are not tolerated during or following the 
titration period. Liraglutide dose will be initiated at 0.6mg and then steadily increased by the doses 
below. The up titration to maximum dose must be achieved by week 8. 
 
 
 0.6mg 
 
 1.2mg 
 
 1.8mg 
 
 2.4mg 
 
 3.0mg. 
 
Participants in the Targeted Prescribing Pathway will undergo titration reviews fortnightly during 
weeks 0-8. During these visits, there will be the option for telephone calls between weeks 1-3 and 
weeks 3-5 available to research team and for participants to counsel them on titration requirements. 
The titration protocol will be explained to the participants during the baseline visit and reviewed by 
the clinician at weeks 3, 5 and 8. 
 
8.3.2 Weeks 52 and 104 – All Participants 
The Data Collection Visits at Weeks 52 (± 3 months*) and 104 (± 14 days) will take place at the study 
site for all participants in both study groups. Weight, waist circumference, blood pressure and pulse 
rate will be recorded in line with study SOPs, any AEs/SAEs will be noted, and documentation of 
inclusion/exclusion criteria and changes in medication and/or diseases will be performed. Blood 
samples for standard laboratory testing of biochemical outcomes (HbA1c, FBC, U+Es, lipids, LFTs, 
TFTs, amylase) will be taken and participants will be requested to complete research questionnaires 
(see Appendix 3). A pregnancy test will take place for all female participants of child-bearing 
potential (in both standard care and LIRA 3mg targeted prescribing pathway groups). 
 
A urine ACR will be performed for participants with diabetes, prediabetes and hypertension.  
All participants will complete the Epworth Sleepiness Scale to capture any improvement/decline in 
daytime sleepiness during the course of the study and the Stop Bang questionnaire to capture any 
undetected OSA cases, at 3 data collection visits (Baseline, Weeks 52 and 104). OSA patients will be 
managed through their local sleep clinic as per standard care.  Those participants that are patients of 
the sleep clinic will have their notes reviewed to determine whether or not they are CPAP compliant 
and thus ‘successful’ against the below criteria.  
a.       CPAP usage >= 4 hrs/night = successful 
b.      CPAP usage < 4 hrs/night = struggling 
c.       CPAP usage < = 1 hrs/night = failure 
 
Additional procedures at Weeks 52 and 104 for the participants in the standard care group who 
have been prescribed and started anti-obesity medications (for example Orlistat) will be to ascertain 
whether they are still on the medication, their adherence, and any side effects. 
 
Additional procedures at the Week 52 visit for all participants who are on LIRA 3mg will include: 


 
 
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 
Identification of participants on LIRA 3mg who have lost ≥15% weight loss and meet the pre-
specified criteria to continue on LIRA 3mg. These participants will meet the study clinician in 
order to be offered LIRA 3mg for another 52 weeks, to receive a new prescription of LIRA 
3mg and to discuss adherence with the treatment and any side effects. Pregnancy testing 
will be undertaken as standard for this visit and clear instructions regarding contraception 
until the end of the study will be provided 
 
Participants on LIRA 3mg who did not reach the target of ≥15% weight loss will meet the 
study clinician who will explain to them that they cannot continue on the medication any 
longer and that they will instead continue in the study on the Tier 3 programme with 
standard care. These participants will remain in the intervention group (targeted prescribing 
pathway), but will not receive LIRA 3mg as per the pre-specified stopping rules. 
 
The purpose of the long-term (52-104 weeks) follow-up is to examine whether LIRA 3mg will help 
the “early and good” responders to maintain weight loss ≥15% in comparison with the control group 
over a longer period of time. Additional procedures at the Week 104 visit for all participants will 
include: 
 
The study clinician at each site will assess all the patients who participated in the study that 
have not been referred for bariatric surgery 
 
Participants who had significant weight regain during the second year in either treatment 
group will be discussed in Tier 3 MDT and may include a recommendation to their GP to 
refer them to Tier 4 service for bariatric surgery 
 
For participants who are on LIRA 3mg: the clinician will make a recommendation to the 
participant’s GP as to whether or not they should continue on the medication long-term, 
pending the local prescribing guidelines.  Please note: participants on LIRA 3mg targeted 
prescribing pathway will only receive study medication for a maximum of 106 weeks (4 
weeks titration, 100 weeks at 3mg, +/-2 weeks visit window). For those participants that 
achieve more than 15% weight loss or a BMI <35kg/m2 prior to the 104 weeks, treatment 
with LIRA 3mg will be continued unless the patient begins to experience side-effects. 
In an attempt to aid retention for the primary end point (week 52 – V11) all participants will be 
offered an incentive payment of £25 that will be paid on completion of the week 52 (visit 11) and 
dependant on us having weight data for that visit. 
In response to the COVID19 global pandemic an interim time point for the quality of life 
questionnaires has been added (HSRUQ, TSQM, EQ-5D, IWQOL-Lite, IPAQ-Long and PHQ-9). These 
will be sent out to all participants during the COVID19 pandemic. 
*Where possible the week 52 visit should continue to be scheduled within the (± 14 days) study visit 
window, however to aid retention and to help maximise data collection for the study primary end 
point, the week 52 visit window can be extended to ± 3 months. 
 
 
 
 


 
 
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8.4 Clinical Review (safety and retention) Visits (Weeks 2, 4, 8, 12, 16, 20, 32, 40 and 78) – All 
Participants 
 
The Clinical Review visits will take place with a member of the research team at the study site. 
Where appropriate, the Clinical Review visits will be arranged in conjunction with the standard Tier 3 
service appointments that participants will be scheduled to attend (e.g. appointments with the 
dietician). Additional study visits will be arranged in the event where this might not be possible. The 
participant appointment schedule will depend on the Tier 3 service schedule, the date of the 
required Clinical Review Visit, and the availability of participants. The participant’s adherence to the 
Tier 3 programme will also be reviewed. The research team will endeavour to maintain a low level of 
burden for these multiple visits. 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 for LIRA arm/13 for 
control arm) will be defined as ‘optional’ to reduce study burden and maximise participant 
retention, as per the visit schedule. Our experience in undertaking successful longitudinal research 
with multiple follow-ups will support these follow-up visits. The frequency of appointments for the 
Tier 3 service offered to the participants in both groups will continue as per the standard practice for 
each Tier 3 service. 
 
During these Clinical Review Visits, participant eligibility will be re-checked and consent for 
continuation in the study will be re-confirmed. Weight, waist circumference, blood pressure and 
pulse rate will be recorded in line with study SOPs, any AEs/SAEs will be noted, and documentation 
of inclusion/exclusion criteria and changes in medication and/or diseases will be performed. 
 
For patients on LIRA 3mg, monitoring of any problems and side effects, adherence with the injection, 
and advice on dose titration (at Weeks 2 and 4) as per the pre-specified protocol will take place 
during these visits. A pregnancy test will take place for all female participants of child-bearing 
potential who are in the targeted prescribing pathway and continue to be eligible to receive supply 
of LIRA 3mg. Clear instructions regarding contraception until the end of the study will be given at 
each visit. 
 
Additional procedures at the Week 16 visit for all participants who are on LIRA 3mg will include: 
 
Identification of participants on LIRA 3mg who have lost ≥5% weight loss and meet the pre-
specified criteria to continue on LIRA 3mg. These participants will meet the study clinician in 
order to be offered LIRA 3mg for another 16 weeks, to receive a new prescription of LIRA 
3mg and to discuss adherence with the treatment and any side effects. Pregnancy testing 
will be undertaken as standard for this visit and clear instructions regarding contraception 
until the end of the study will be provided. 
 
Participants on LIRA 3mg who did not reach the target of ≥5% weight loss will meet the 
study clinician who will explain to them that they cannot continue on the medication any 
longer and that they will instead continue in the study on the Tier 3 programme with 
standard care. These participants will remain in the intervention group (targeted prescribing 
pathway), but will not receive LIRA 3mg as per the pre-specified stopping rules. 
 
 


 
 
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Additional procedures at the Week 32 visit for all participants will include: 
 
Blood samples for standard laboratory testing of biochemical outcomes (HbA1c, FBC, U+Es, 
lipids, LFTs, TFTs, amylase) will be taken for all participants 
 
A urine ACR will be performed for participants with diabetes, prediabetes and hypertension 
for all participants 
 
Participants in the standard care group who have been prescribed and started on anti-
obesity medications (for example Orlistat) will be monitored to ascertain whether they are 
still on the medication, their adherence, and any side effects 
 
Participants on LIRA 3mg who have lost ≥10% weight loss and meet the pre-specified criteria 
to continue on LIRA 3mg. These participants will meet the study clinician in order to be 
offered LIRA 3mg for another 24 weeks, to receive a new prescription of LIRA 3mg and to 
discuss adherence with the treatment and any side effects. Pregnancy testing will be 
undertaken as standard for this visit and clear instructions regarding contraception until the 
end of the study will be provided 
 
Participants on LIRA 3mg who did not reach the target of ≥10% weight loss will meet the 
study clinician who will explain to them that they cannot continue on the medication any 
longer and that they will instead continue in the study on the Tier 3 programme with 
standard care. These participants will remain in the intervention group (targeted prescribing 
pathway) for the purpose of analysis, but will not receive LIRA 3mg as per the pre-specified 
stopping rules. 
 
8.4.1 Additional Clinical Review (safety and retention) Visits for LIRA 3mg group (Weeks 65 and 91) 
These two additional Clinical Review visits will take place with a member of the research team at the 
study site for only those participants in the intervention group who are still on treatment with LIRA 
3mg. The agenda for these visits will be identical to the other nine Clinical Review Visits as described 
above in Section 8.4. The purpose of these visits is to provide participants with a new prescription of 
LIRA 3mg and to discuss adherence with the treatment and any side effects. 
 
8.5 Co-morbidity related investigations 
For participants taking anti-hypertensive medication, it will be at the local Principal Investigator’s 
(PIs) discretion to make recommendations on anti-hypertensive drugs and diuretic in response to 
participants’ blood pressure and weight loss outcomes. Similarly, for participants taking anti-
depressant medication, it will be at the local PIs discretion to make recommendations to alter the 
participants’ 
anti-depressant 
medication 
if 
appropriate. 


 
 
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8.6 Source Data 
The CRF and study questionnaires are the primary data collection instruments. All data requested on 
the CRF will be recorded. All missing data will be explained. If the item is not applicable to the 
individual case then N/A will be written. All entries will be printed legibly in black ink. If any entry 
error has been made, to correct the error, a single line will be drawn through the incorrect entry and 
the correct data entered above it. All such changes will be initialled and dated. For clarification of 
illegible or uncertain entries, the clarification will be printed above the item and this will be initialled 
and dated. 
 
A copy of the signed patient consent form and patient information leaflet will be placed in the 
hospital notes of all participants and in the Investigator Site File.  A sticker will be placed on the 
cover of the notes (or inside cover) detailing the study title, contact details of the PI, participant ID 
and the fact that the notes should not be destroyed. All study visits and adverse events will be 
recorded in the hospital notes.   
 
The PI and his/her staff must ensure that these documents are pseudonymised.  Past medical history 
within the CRF required for inclusion in the study will be verified by participant hospital notes and/or 
GP medical history. 
 
8.7 Definition of End of Trial 
The end of the study is defined as the last participant’s last visit.  
 
8.8 Withdrawal of participants from the study and discontinuation of treatment 
Certain circumstances will necessitate the stopping of any or all the study medication for a particular 
participant. Adverse event review and other safety/acceptability assessments will provide the 
information for the study clinician to withdraw the participant and/or discontinue the treatment 
drug at any time during the trial.  
 
8.8.1 Withdrawal from the study 
Participants may withdraw consent from the study before study completion if they decide to do so, 
at any time and for any reason. If a participant decides to withdraw from the study, this will be 
recorded in the study records. They will be sent a letter thanking them for their participation, and 
informing them that the data collected up to the time point they withdrew will be included in the 
study analysis and that they will not be contacted again with regards to this study. They will not be 
asked to attend further visits. Furthermore, we will emphasise that their standard care will not be 
affected by their withdrawal from this study and that they will return to standard care.  
 
Participants will be withdrawn from this study by the research team as agreed by the PI if:  
 
They are diagnosed with a terminal illness  
 
The PI, Sponsor and or study clinician deem it unsafe for continuation in the study for 
medical, safety, regulatory, or other reasons consistent with applicable laws, regulations 
or Good Clinical Practice (GCP) 
 
They are considered to be lost to follow up as deemed by the clinician 
 
Loss of capacity during participation in research 


 
 
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 
Treatment with medications which the PI determines to require permanent withdrawal 
from the study (e.g. systemic corticosteroids). 
 
Again it will be emphasised that their standard care will not be affected by this withdrawal from the 
study and that they will return to standard care. 
 
For participants who fail to return to the site, the research team should make reasonable effort to 
re-contact the participants (e.g., contacting participant’s family or GP, reviewing available registries 
or health care databases) and to determine his/her health status, including at least his/her vital 
status. Attempts to contact such participants must be documented in the participant’s records (e.g. 
times and dates of attempted telephone contact, receipt for sending a registered letter). 
 
8.8.2 Treatment discontinuation (outside of the pre-specified stopping rules) 
Attempts will be made to assess the primary outcome on all participants whether or not they were 
compliant and in those who have who have discontinued the treatment (including those participants 
who have stopped the treatment outside of the pre-specified stopping rules). 
 
8.8.3 Permanent treatment discontinuation (outside of the pre-specified stopping rules) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the PI or the participant not to re-expose the participant to the LIRA 3mg 
treatment at any time. This definition is not the same as treatment discontinuation due to a 
participant not meeting the weight-loss targets at the pre-specified stopping rules as per the 
protocol. 
 
Participants may withdraw from treatment with the investigational drug if they decide to do so, at 
any time and for any reason. The PI may also decide to withdraw a participant from the study based 
on an inability of the subject to adhere to the obligations of the study or for the safety of the 
participant. Items that will lead to permanent discontinuation in the study include: 
 
Pregnancy 
 
Episode of acute pancreatitis (only for participants in LIRA 3mg group) 
 
Breast malignancy (only for participants in LIRA 3mg group) 
 
They repeatedly violate or are non-compliant with the protocol  
 
Where LIRA 3mg doses are not tolerated by the participant 
 
Any other contraindication to the study medication which the PI determines to 
require permanent treatment discontinuation.  
 
*Please note if a participant’s amylase result is within the normal range but the study clinician 
suspects acute pancreatitis a lipase test will be conducted. 
 
All efforts should be made to document the reasons for treatment discontinuation and this should 
be documented in the CRF and medical records. 
 


 
 
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Any abnormal laboratory value that in the opinion of the clinician may be an indication for 
discontinuing the treatment of a participant will be rechecked by the PI or second clinician if the first 
clinician is the PI for confirmation before making a decision of permanent discontinuation of the 
investigational drug for the concerned participant. Threshold values for the discontinuation of 
investigational drug use shall be defined in collaboration with the Sponsor representative. The 
values will be adapted to the population studied, as appropriate. 
 
8.8.4 Handling of participants after permanent treatment discontinuation 
This study observes the effect of a targeted prescribing pathway (i.e. the use of LIRA 3mg when 
stopping rules are applied in combination with standard care in a Tier 3 service for patients with 
severe and complex obesity) compared with standard care alone. In case the GP or PI stops 
treatment or a participant withdraws from treatment with LIRA 3mg, e.g. for safety reasons, the 
participant will be offered standard care and the observation will continue. 
 
If LIRA 3mg is stopped for other reasons not related to the applied stopping rules, it should be 
determined whether the stop can be made temporarily; permanent discontinuation of LIRA 3mg 
should be a last resort. Any discontinuation of the drug for reasons not related to the stopping rules 
should be fully documented in the CRF and medical records. 
 
Participants must be instructed to notify the Investigator immediately if they become pregnant 
during the trial. Pregnancy will result in permanent treatment discontinuation (this will apply to both 
the LIRA 3mg and the standard care groups).  The Investigator must report any pregnancy during the 
study to Novo Nordisk except for pregnancies occurring in the screening period prior to study 
treatment. Participants will give consent on enrolment that the Investigator will report any 
pregnancy during the study to Novo Nordisk and they will be asked to provide information about the 
pregnancy, delivery and the health of her infant until one month of age. Any AE in the child will be 
reported.  
 
Participants will be followed according to the study procedures as specified in this protocol up to the 
scheduled date of study completion. If possible, and after the permanent discontinuation of 
investigational drug, the participants will be assessed using the procedure normally planned for the 
last onsite visit, if appropriate. All cases of permanent treatment discontinuation should be recorded 
by a member of the research team in the appropriate pages of the CRF and medical records when 
considered as confirmed. Study Sponsor is to be informed. 
 
8.8.5 Handling of participants after temporary treatment discontinuation 
Temporary discontinuation of LIRA 3mg may be considered by the PI because of suspected Adverse 
Events (AEs). A rationale (e.g. severe nausea and vomiting, other gastrointestinal symptoms) must 
be given in writing by the PI.  
 
Re-initiation of treatment with LIRA 3mg may be done at a lower dose, under close and appropriate 
clinical/and or laboratory monitoring once the PI has considered, according to their best medical 
judgment, that the possible responsibility of the LIRA 3mg in the occurrence of the concerned event 
was unlikely and if the inclusion and exclusion criteria for the study are still met. 


 
 
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For all temporary treatment discontinuations, the duration of treatment discontinuation should be 
recorded by the research team when considered as confirmed. 
 
8.9 Continued provision of the intervention for participants (if appropriate) 
After the study, participants will be returned to the care of the weight management services where 
the local PI can make recommendations as to the continuation of the study treatment dependent on 
tolerance or side-effects (where applicable with regards to drug availability and local prescribing 
guidelines). Participants will be informed about the recommendation. For example, that they have 
been recommended to continue LIRA 3mg, but it will also be stressed that this will be down to the 
discretion of the GP and local prescribing guidelines. 
 
8.10 Response to the COVID19 global pandemic (Urgent Safety Measure) 
During the COVID19 global pandemic, a thorough risk assessment was conducted, and as a result the 
following appropriate adaptations have been made to the delivery of the study: 
 
Face to face study visits may be replaced with virtual consultations via telephone call or 
video call via the MyClinic application. Verbal consent will be sought from participants in 
advance of the video consultation (via MyClinic) and will be documented in the medical 
records. Face to face visits may continue at sites if this is in accordance with the local trust 
policy and appropriate risk mitigations are implemented at site to reduce the risk to 
participants.  Risk and mitigations will be detailed in the risk assessment. During this period 
both face to face visits and virtual ones may be conducted in line with the USM adaptations 
detailed below. 
 
Participants due a V11 (study primary endpoint) are asked to weigh themselves at home on 
scales provided by the study team.  A working instruction has been provided to participants 
to support them to record their weight in a standardised manner. During virtual 
consultations, the study nurse or doctor may witness the weight measurement process 
(following receipt of verbal consent from the participant).  In the absence of consent from 
the participant, the participant will report the weight measurement verbally and follow this 
up with a photo of the weight value (source data). . 
 
A courier service has been arranged for study drug deliveries to participants; some sites are 
using a drop off/collection service either on site or to participant’s homes. Participants on 
the Liraglutide arm will attend a virtual consultation and weigh themselves prior to 
additional study drug being dispensed. 
 
Participants in the Liraglutide arm who are of child bearing potential will receive a pregnancy 
test prior to their visit (to be used on the day of the visit) and the result reported either 
verbally to the study team during the video call  or via a photo (source data) following a 
telephone call. 
 
The study quality of life questionnaire packs (HSRUQ, TSQM, EQ-5D, IWQOL-Lite, IPAQ-Long 
and PHQ-9) will be mailed to participants, where applicable, to be completed at home and 
returned to the study team via the postal system. 
 


 
 
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As a result of conducting virtual consultations and telephone calls, the following procedures 
will not be performed during the COVID19 pandemic, therefore have been halted as an 
urgent safety measure: 
 
BP and Pulse measurements – Participants who are known to have hypertension have home 
BP monitoring machines and their BP measurements are being collected and assessed by the 
study team during remote visits. There is no undue risk for those who do not have 
hypertension, as Liraglutide is not related to BP, and participants are all established on the 
drug. 
 
Bloods (lipids, renal, LFTs, thyroid, FBC & HbA1c, amylase) at V9, 11 & 13/15 only - The 
amylase test usually taken at visits 9, 11 & 15 is a safety blood in relation to pancreatitis. 
During the remote visits, all participants will be monitored for any new symptoms which will 
be appropriately managed by the study clinical team. The small number of participants who 
have diabetes will regularly check their blood glucose at home as usual. All other bloods are 
taken to assess efficacy, therefore not conducting them will have no impact on participant 
safety. All participants will be asked to report AE/SAE during remote visits. 
 
ACR urine test – Not conducting this poses no additional risk to participants. 
Once restrictions due to the COVID19 pandemic have been lifted, a further risk assessment will be 
completed and in agreement with the Sponsor, Study team and NHS Host Organisations, face to face 
visits will be re-implemented.  For the avoidance of doubt, virtual consultations will still be an option 
for study visits, as preferred by the participant or recommended by the study clinician, to aid the 
retention of participants and study visit attendance and collection of primary outcome data (via self-
reported weight measurement data). 
 
 
9. 
TREATMENT OF TRIAL PARTICIPANTS 
9.1 Description of Study Treatment & Pharmacy Process 
Novo Nordisk will be supplying the LIRA 3mg which will be handled according to their in-house 
protocols and standard operating procedures. Study drug will be managed in accordance with the 
requirements of all applicable regulatory guidelines. 
 
LIRA 3mg will be provided to subjects as Saxenda® (manufacturer: Novo Nordisk). 
Delivery is to be via a subcutaneous injection. LIRA 3mg has been licensed across the European 
Union via the EMA, for treatment of obesity for patients with and without diabetes (February 2015, 
Procedure No EMEA/H/C/003780/0000, Marketing ID: EU/1/15/992/001-003) and was launched 
within the UK in January 2017. Patients in the LIRA 3mg group (i.e., the targeted prescribing 
pathway/intervention group) will titrate the drug dose and will stop the medication according to the 
pre-specified protocol.   
 
All study medication dosage will not exceed the stated recommendations of local guidelines and the 
British National Formulary. All contra-indications will be checked as part the eligibility criteria. 
 


 
 
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Study medication may be suspended or stopped by the study team if they become aware of the 
participant undergoing any contra-indicated procedure for out-of-study clinical care. This will be 
documented in the participant’s study and medical notes and a decision on any potential withdrawal 
from the study on this basis will reside with the PI of each site. Recommencing of the study drug will 
follow individual safety assessments in-line with the procedure in question.  
 
9.2 Dosage Information 
Liraglutide doses will be self-administered by the participant through daily subcutaneous injections. 
Liraglutide dose will be initiated at 0.6 mg and then increased to 1.2mg in week two, 1.8mg in week 
three, 2.4mg in week four and 3.0mg in week five. The dose will then be maintained at 3.0mg. A 
slow escalation of the LIRA 3mg dose should help reduce the dropout of participants due to side 
effects. Where LIRA 3mg doses are not tolerated by the participant they will be withdrawn from the 
treatment condition. 
 
9.3 Storage of Study Treatment 
Study medication will be stored in a refrigerator at 2 – 8 oc. It will not be frozen. Participants in the 
LIRA 3mg treatment group will be instructed to store the drug away from the freezer compartment 
and to store below 30°C or store in a refrigerator (2°C - 8°C) after first use. They will also be 
instructed to keep the cap on the pen in order to protect from light. 
 
The employment, dosing, handling, storage and destruction of LIRA 3mg will be conducted in 
accordance with the specified conditions of its approved labelling and in-line with pharmacy 
protocols and guidelines. 
 
The Co-PI or delegated individual/personnel in each site or other personnel allowed to store and 
dispense the investigational medication will be responsible for ensuring that the investigational drug 
is securely maintained as specified by the Sponsor and in accordance with applicable regulatory 
requirements. It is the co-PIs (or other delegated personnel’s) responsibility to ensure that an 
accurate record of investigational medications issued will be maintained.  
 
Any quality issue noticed with the receipt or use of an investigational medication (deficiency in 
appearance, pertaining documentation, labelling, expiration date) should be promptly reported to 
the Sponsor. Some deficiencies may be recorded through a complaint procedure. 
 
A potential defect in the quality of the investigational medication may be subject to initiation of a 
recall procedure by the Sponsor. In this case, the co-PIs will be responsible for promptly addressing 
any request made by the Sponsor, in order to recall investigational medication and eliminate 
potential hazards. 
 
Under no circumstances will the PIs supply investigational medication to a third party, allow the 
investigational drug to be used other than as directed by this clinical study protocol, or dispose of 
investigational device(s) in any other manner other than that directed by pharmacy. 
 


 
 
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9.4 Compliance with Study Treatment 
All participants in the study who have been prescribed LIRA 3mg should administer the drug daily. The 
participants will be instructed to return all unused, used or part-used medication/vials and packaging 
from used medication at each visit. Adherence questions will also be asked in follow-up visits for 
participants on LIRA 3mg. Examining medication returns and evaluating adherence will allow for an 
assessment of compliance and drug accountability.  All participants should report all events which 
they believe may have impact on dose adjustment (such as nausea, vomiting). The Investigator may 
withdraw the participants if they consider dose compliance is unsatisfactory. Participants will be 
defined as treatment compliant if they take 70% of planned doses. 
 
9.5 Accountability of the Study Treatment 
The study medication will be supplied by Novo Nordisk to the host pharmacy. The employment, 
dosing, handling, storage and destruction of study medication will be conducted in accordance with 
the specified conditions of its approved labelling and in-line with local pharmacy guidelines. 
 
Drug accountability will be the responsibility of the host pharmacy and will be fully documented.  
 
The participant will be asked to bring all used, part-used and unused medication and used 
vials/packaging back to the clinic at each visit where it will be returned to pharmacy. 
 
9.6 Concomitant Medication 
Participants are allowed to continue the use of concomitant medication, which will be recorded in 
the CRF. However, consideration will be given also to reducing polypharmacy especially where 
participants have achieved significant weight loss and improvements in obesity related co-
morbidities. If concomitant treatment has to be changed during the study period, this must be 
reported on the CRF provided (trade name and/or generic name) and in the participant’s medical 
records. If any changes in glucose, lipid and blood pressure lowering therapy is required (e.g. due to 
disease progression or improvement) during the study, this must also be documented on the CRF. 
Addition of any medication that will significantly influence weight, such as corticosteroids is reason 
for discontinuation of the participant in the treatment. 


 
 
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10. 
SAFETY REPORTING 
10.1 Definitions 
The reference safety information (RSI) for this study will be the Summary of Product Characteristics 
(SmPC). 
 
10.1.1 Adverse Event (AE) 
An AE or adverse experience is: 
Any untoward medical occurrence in a patient or clinical investigation participants administered a 
medicinal product, which does not necessarily have to have a causal relationship with this treatment 
(the study medication). 
 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of the study medication, whether 
or not considered related to the study medication. 
 
10.1.2 Adverse Reaction (AR) 
All untoward and unintended responses to a medicinal product related to any dose administered. 
The phrase "responses to a medicinal product" means that a causal relationship between a study 
medication and an AE is at least a reasonable possibility, i.e., the relationship cannot be ruled out. All 
cases judged by either the reporting medically qualified professional or the Sponsor as having a 
reasonable suspected causal relationship to the study medication qualify as adverse reactions.   
 
10.1.3 Severe Adverse Events (SAE) 
To ensure no confusion or misunderstanding of the difference between the terms "serious" and 
"severe", which are not synonymous, the following note of clarification is provided: 
The term "severe" is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache).  This is not the same as "serious," which is based on 
patient/event outcome or action criteria usually associated with events that pose a threat to a 
participant's life or functioning.  Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
 
10.1.4 Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) 
Is an AE, AR, or other untoward serious medical occurrence or effect that: 
 
Results in death, 
 
Is life-threatening*, 
 
Requires inpatient hospitalisation or prolongation of existing hospitalisation**, 
 
Results in persistent or significant disability/incapacity, or 
 
Is a congenital anomaly/birth defect. 
 
Is otherwise considered medically significant by the investigator**** 
* "Life-threatening" in the definition of "serious" refers to an event in which the participant was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 


 
 
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**Hospitalisation is defined as an unplanned, overnight, formal inpatient admission, even if the 
hospitalisation is a precautionary measure for continued observation. Thus hospitalisation for 
protocol treatment, elective procedures (unless brought forward due to worsening symptoms) or for 
social reasons are not regarded as a SAE. 
***Medical judgement should be exercised in deciding whether AE is serious in other situations. AEs 
that are not immediately life-threatening or do not result in death or hospitalisation but may 
jeopardise the participant or may require intervention to prevent one of the other outcomes listed 
in the SAE definition above, should be considered serious. Suspicion of transmission of infections 
agents must always be considered an SAE. 
If a participant dies as the result of an SAE, any post-mortem findings including histopathology must be 
provided. 
 
10.1.5 Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A serious adverse reaction, the nature or severity of which is not consistent with the applicable 
product information Summary of Product Characteristics for LIRA 3mg (Saxenda). 
 
Event Grade: 
 
Mild: Participant is aware of the event or symptom, but the event or symptom is easily 
tolerated. 
 
Moderate: Participant experiences sufficient discomfort to interfere with or reduce their 
usual level of activity. 
 
Severe: Significant impairment of functioning, participant is unable to carry out usual 
activities and/or the participant’s life is at risk from the event.  
 
 
After this initial evaluation the relationship of the AE to the study therapy/investigation medical 
therapy (IMP) will be assessed using the following definitions: 
Definitely: 
 
The AE starts a reasonable time after the study therapy/IMP administration. 
 
The AE stops/ improves when the study therapy/IMP has been stopped. 
 
The AE can reasonably be explained by known characteristics of the study therapy/IMP. 
Probably: 
 
A causal relationship is clinically/biologically highly plausible. 
 
There is a plausible time sequence between onset of the AE and administration of the study 
therapy/IMP. 
 
There is a reasonable response on withdrawal of the study therapy/IMP. 
 
It cannot be reasonably explained by known characteristics of the participant’s clinical state. 
Possibly: 
 
A causal relationship is clinically/biologically plausible. 
 
There is a plausible time sequence between onset of the AE and administration of the study 
therapy/IMP, however 
 
The AE could have been produced by the participant’s clinical state or other modes of 
therapy administered to the patient. 
Unlikely to be related: 


 
 
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 
The time association or the participant’s clinical state is such that the study therapy/IMP is 
not likely to have had an association with the observed effect. 
 
Another documented cause of the AE is most plausible. 
Unrelated: 
 
The AE is definitely not associated with the study therapy administered.  
 
Another documented cause of the AE is most plausible. 
 
10.2 Assessment periods 
All Adverse events (AEs) will be recorded throughout the study whether serious or not. Members of the 
research team will ask the participants about AEs at each study time point (see Appendix 3) and will 
complete the participant AE form, which will be a continuous log so as to capture end dates, and the 
study serious adverse event (SAE) log. This will be evaluated and classed according to the definitions in 
section 10.3 below (European Directive 2001/20/EC). 
 
10.3 Expected Serious Adverse Events/Reactions 
Rare side-effects (less than 1%) will be reported as SAEs.  The expected adverse events of renal 
impairment, cholecystitis and cholelithiasis will be reported as SAEs due to being medically 
significant. 
 
 
10.4 Definitions of hypoglycaemia  
A hypoglycaemic episode will be defined as treatment emergent if the onset of the episode is on or 
after the first day of randomised treatment and no later than 14 days after the last day of 
randomised treatment. Hypoglycaemic events will be defined as nocturnal if the time onset is 
between 00:01 and 05:59 (both included). 
A hypoglycaemic episode form and an Adverse Event (AE) form must be filled in for all 
hypoglycaemic episodes. Hypoglycaemic episodes requiring the assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative actions (i.e., ‘severe 
hypoglycaemic episodes’) will be qualified as an event of special interest. 
A different definition of hypoglycaemia will apply for patients with type 2 diabetes and a different 
definition will apply for patients without diabetes. 
 
10.4.1 Classification of hypoglycaemia for participants with type 2 diabetes 
All participants with diabetes will be supplied with a glucose meter and a diabetes diary for 
recording of hypoglycaemia, symptomatic episodes and routine blood glucose monitoring. Plasma 
glucose should always be measured from all participants with diabetes when there is the suspicion 
of a hypoglycaemic episode.  
 
All plasma glucose values ≤3.1 mmol/L (56mg/dL), as well as values >3.1 mmol/L (56mg/dL) when 
hypoglycaemic symptoms have occurred should be recorded by the participants in the diaries. 
Hypoglycaemic episodes will be recorded by the participant in his/her diary throughout the trial and 
must be transcribed into the CRF by the Investigator at each site visit throughout the trial.  
 


 
 
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Hypoglycaemic episodes will be summarised based on the American Diabetes Association (ADA) 
classification and Novo Nordisk’s definition. 
 
10.4.2 Novo Nordisk definition 
In normal physiology, hypoglycaemia symptoms occur at a blood glucose level of approximately < 
2.8 mmol/L (50 mg/dL)/plasma glucose level < 3.1 mmol/L (56 mg/dL). Therefore, Novo Nordisk has 
used this cut-off value to define minor hypoglycaemia. 
Minor hypoglycaemic episode is defined as: 
• An episode with symptoms consistent with hypoglycaemia with confirmation by plasma 
glucose < 3.1 mmol/L (56 mg/dL), or full blood glucose < 2.8 mmol/L (50 mg/dL) and which is 
handled by the subject himself/herself  
• Or any asymptomatic plasma glucose value < 3.1 mmol/L (56 mg/dL) or full blood glucose 
value < 2.8 mmol/L (50 mg/dL) Minor hypoglycaemic episodes will be summarised according 
to this definition, and can be subject to additional analysis. 
 
10.4.3 ADA hypoglycaemia classification 
According to ADA the definition of a hypoglycaemic episode is categorised as: 
 
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions. 
 
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤3.9 mmol/L. 
 
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of hypoglycaemia, 
but with a measured plasma glucose concentrations ≤3.9 mmol/L. 
 
Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia are not 
accompanied by a plasma glucose determination (but that was presumably caused by a plasma 
glucose concentration ≤3.9mmol/L). 
 
Relative hypoglycaemia: An episode during which the participant reports any of the typical 
symptoms of hypoglycaemia and interprets those as indicative of hypoglycaemia, but with a 
measured plasma glucose concentration >3.9 mmol/L. 
 
10.4.4 Classification of hypoglycaemia for participants without diabetes 
Participants without diabetes will not be routinely provided with blood glucose meters or diaries; 
hence blood glucose will not be measured in case of symptoms of hypoglycaemia unless it coincides 
with a clinic visit.  
 
The hypoglycaemia events for participants without diabetes will be reported spontaneously i.e., 
symptoms of hypoglycaemia (not biochemically confirmed) occurring outside of visits to the clinic; 
severe hypoglycaemia will be defined as an episode requiring assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative actions. In the event of severe or 


 
 
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symptomatic hypoglycaemia patients will be given a glucose monitor and asked to record their blood 
glucose whenever they feel symptomatic. 
 
10.5 Reporting Procedures for All Adverse Events 
All pregnancies, AEs, ARs, UARs, SAEs or SARs occurring during the study observed by the 
investigator or reported by the participant, whether or not attributed to study medication, will be 
recorded on the CRF and the medical notes. They will be reported in accordance with the Sponsor, 
host organisation, Novo Nordisk procedures, policies and requirements.   
 
The following information will be recorded: description, date of onset and end date, severity, 
assessment of relatedness to study medication, other suspect drug or device and action taken.  
Follow-up information should be provided as necessary.  
 
AEs considered related to the study medication as judged by a medically qualified investigator or the 
Sponsor will be followed until resolution or the event is considered stable.  All related AEs that result 
in a participant’s withdrawal from the study or are present at the end of the study, should be 
followed up until a satisfactory resolution occurs. 
 
It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient severity to 
require the participant’s removal from treatment (see section 10.1 and 10.2).  A participant may also 
voluntarily withdraw from treatment due to what he or she perceives as an intolerable AE.  If either 
of these occurs, the participant must undergo an end of study assessment and be given appropriate 
care under medical supervision until symptoms cease or the condition becomes stable. 
 
The severity of events will be assessed on the following scale:  1 = mild, 2 = moderate, 3 = severe.   
 
The relationship of AEs to the study medication will be assessed by a medically qualified investigator.  
 
10.6 Pregnancy 
Participants must be instructed to notify the Investigator immediately if they become pregnant 
during the trial. The Investigator must report any pregnancy during the trial to Novo Nordisk except 
for pregnancies occurring in the screening period prior to study treatment. Participants will give 
consent on enrolment that the Investigator will report any pregnancy during the trial to Novo 
Nordisk and they will be asked to provide information about the pregnancy, delivery and the health 
of her infant until one month of age. The Investigator must report information on pregnancy and 
follow-up according to Sponsor and local guidelines. If the pregnancy results in an abnormal 
outcome, such as congenital abnormalities, foetal death, spontaneous abortion, or SAE in the 
neonate, this should be regarded as an SAE with the same reporting requirements and timelines as 
for SAEs. If an SAE occurs in relation to a pregnancy, either to the mother or the newborn, then 
follow the same reporting requirements and timelines as for SAEs. 
 
10.7 Follow-up of Adverse Events 
During and following a patient’s participation in the study, the Investigator will ensure that adequate 
medical care is provided to the participant for any AEs, including clinically significant laboratory 


 
 
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values related to the trial. The Investigator will inform the participant when medical care is needed 
for AE(s) of which the Investigator becomes aware.  
 
The follow-up information will only include new (updated and/or additional) information that 
reflects the situation at the time of the Investigator’s signature.  
 
All serious AEs and all non-serious AEs classified as severe or possibly/probably related to the trial 
product will be followed-up until the participant has recovered, recovered with sequelae or fatal and 
until all queries have been resolved. For cases of chronic conditions or if the participant dies from 
another event, follow-up until the outcome category is “recovered” is not required, as these cases 
can be closed with an outcome of “recovering” or “not recovered”.  
 
The Sponsor guidance and processes for reporting SAEs will be adhered to.  
 
10.8 Reporting Procedures for Serious Adverse Events 
All SAEs must be reported to the Sponsor within 24 hours of discovery or notification of the event.  
The Sponsor will perform an initial check of the information and ensure that it is reviewed at the 
next R&I Management meeting.  All SAE information must be recorded on a current CTIMP SAE form 
and sent to the Sponsor. Additional information received for a case (follow-up or corrections to the 
original case) needs to be detailed on a new SAE form and sent to the Sponsor. All SAEs that are at 
least possibly related to the study treatment – Serious Adverse Reactions (SAR) – still present at the 
end of the study will be followed at least until the final outcome is determined. Even if it implies that 
the follow-up continues after the participants leave the trial and when appropriate until the end of 
the planned period of follow-up. 
 
The Sponsor will report all SUSARs to both the Competent Authorities (MHRA in the UK, HPRA in 
Ireland) and the Research Ethics Committee concerned. Fatal or life-threatening SUSARs must be 
reported within 7 days and all other SUSARs within 15 days. The CI will inform all investigators 
concerned of relevant information about SUSARs that could adversely affect the safety of 
participants. 
The CI will copy Novo Nordisk into communications about SAEs, SARs and SUSARs when expediting 
to the Sponsor, health and regulatory authorities. 
 
In addition to the expedited reporting above, within 90 days following the anniversary of the 
authorisation date for the study a Development Safety Update Reports (DSURs) will be sent by the 
Chief Investigator to the MHRA, HPRA and the Main Research Ethics Committee. A copy of the 
report will also be sent to Novo Nordisk (as the study funder), the University of Leicester (as the 
study Sponsor), and all host organisations.   
 
10.9 Reporting Serious Unexpected Suspected Adverse Reactions (SUSARs) 
In-line with the Medicines for Human Use (Clinical Trials) Regulations 2004, all relevant information 
about adverse drug reactions to the investigational medicinal product (LIRA 3mg, Saxenda®) in the 
proposed study, that are both serious and unexpected, will be subject to expedited recording to the 
appropriate Regulatory Authority and Research Ethics Committee (REC). 


 
 
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The University of Leicester, as Sponsor, will report all the relevant safety information previously 
described to the concerned competent authorities and to the Research Ethics Committee concerned. 
The Sponsor will inform all investigators concerned of relevant information about SUSARs that could 
adversely affect the safety of participants. 
 
A SUSAR that is fatal or life threatening will be reported to the relevant regulatory authority 
(MHRA/HPRA) and main REC within 7 working days after University of Leicester, the study Sponsor 
or their delegate becomes aware of the event. In each case relevant follow-up information will be 
sought and a report completed as soon as possible. It will be communicated to the MHRA/HPRA and 
the Ethics Committee within an additional eight calendar days. 
 
A SUSAR that is not fatal or life threatening will be reported to the relevant regulatory authority 
(MHRA/HPRA) and main REC within 15 working days after the University of Leicester, the study 
Sponsor or their delegate becomes aware of the event. Further relevant follow-up information will 
be given as soon as possible. 
 
Information on the final description and evaluation of an adverse reaction report may not be 
available within the required time frames for reporting. For regulatory purposes, initial expedited 
reports will be submitted within the time limits as soon as the minimum following criteria are met: 
 
a suspected investigational medicinal product, 
 
an identifiable subject (e.g. study subject code number), 
 
an adverse event assessed as serious and unexpected, and for which there is a reasonable 
suspected causal relationship, 
 
an identifiable reporting source and, when available and applicable a unique clinical trial 
identification (EudraCT number). 
 
In case of incomplete information at the time of initial reporting, all the appropriate information for 
an adequate analysis of causality will be actively sought from the reporter or other available sources. 
The University of Leicester, the study Sponsor or their delegate will report further relevant 
information after receipt as follow-up reports. 
 
In certain cases, it may be appropriate to conduct follow-up of the long-term outcome of a particular 
reaction. 
 
Electronic reporting will be the expected method for expedited reporting of SUSARs to the 
MHRA/HPRA. In that case, the format and content as defined by the Guidance 1 will be adhered to. 
 
 
 
 
 
 
 


 
 
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10.10 Reporting of Adverse Events to Novo Nordisk 
Adverse events related to the Novo Nordisk drug might potentially disclose important safety 
information. The investigator should copy Novo Nordisk into all communications when expediting 
SARs or SUSARs to the Sponsor, health and regulatory authorities and should report all SAR’s related 
to Novo Nordisk’s product (LIRA 3mg, Saxenda®) to the local Novo Nordisk affiliate safety 
department. The submission to Novo Nordisk must be within 15 days from the Investigator’s first 
knowledge about a valid case. 
 
 
 
 
 
 
 
The following events will be reported to Novo Nordisk: 
A. Serious Adverse Reaction or Suspected Unexpected Serious Adverse Reactions: as described 
in section 10.1. 
 
B. Serious Adverse Drug Reaction: An adverse drug reaction (ADR) is an adverse event for 
which a causal relationship (Possible/Probable relation) between the Novo Nordisk drug and 
the occurrence of the event is suspected. The ADR should be classified as serious if it fulfils 
one or more of the seriousness criteria (www.wikipedia; search: emea seriousness criteria) 
 
C. Pregnancies: where a foetus or embryo has been potentially exposed to the Novo Nordisk 
product. The outcome of such pregnancies must be reported and the child followed up for a 
period of 1 month after birth with any Adverse Events regarding the child reported. 
 
For any of these events the following parameters must be recorded as a minimum: 
 
Study name 
 
Patient identification (e.g. initials, sex, age) 
 
Event (preferably a diagnosis) 
 
Drug (e.g. Saxenda) 
 
Reported identification (e.g. Name, or initials) 
 
Causality 
 
Outcome 
 
All events should be recorded by the Investigator on standardised forms as follows: 
 
Serious Adverse Event Form (for SAE/SADR Safety Information) 
 
Pregnancy Form Part A 
 
Serious ADRs follow special reporting procedures as follows: 
 
Initial information must be forwarded to Novo Nordisk within 24 hours of obtaining 
knowledge about the serious ADR. 
 
Completed forms must be forwarded electronically/fax/courier within 5 calendar days of 
obtaining knowledge about the serious ADR. 
 
In addition to the above the reporting of SAE/SADR should also be submitted to local authorities 
according to national requirements. 
Therefore all UK cases will be reported to the 
UK affiliate Novo Nordisk UK on: 
Phone no:  0845 600 5055 
 
Fax no: 01293 611819 
Email: NNGB-safety@novonordisk.com 
All Ireland cases will be reported to: Donna 
Sexton, Clinical Medical & Regulatory Manager 
Phone no: (+353) 01 678 5989 
Fax no: Tel: (+353) 01 676 3259 
Email: complaintireland@novonordisk.com 


 
 
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11 STATISTICS 
11.1 Statistical methods and analysis 
A CONSORT diagram showing the flow of participants through the study will be produced. Baseline 
characteristics of the participants will be summarised by group using mean (standard deviation), 
median (interquartile range) or count (percentage) as appropriate.  
The primary analyses will compare the proportion of participants achieving ≥15% weight loss at 52 
weeks (primary outcome) after randomisation between the two study groups using a logistic 
regression model with adjustment for the stratification factors (site and BMI). The adjusted 
proportion (95% confidence interval) of participants achieving ≥15% weight loss will be estimated by 
group. The primary analyses will be based on the complete cases population, with intention to treat 
(ITT) and per protocol analyses as secondary analyses (see Sections 11.3 and 11.5). In all analyses, 
participants will be analysed in the group to which they were randomised at baseline; importantly, 
the participants in the intervention group who stop LIRA 3mg, because they meet a pre-specified 
stopping rule, will still be analysed in the intervention group. Participants who have undergone 
bariatric surgery during the period of the study will be excluded from the analysis for the primary 
outcome, because these participants are likely to have substantial weight loss, but are unlikely to be 
balanced between the groups (as it is expected that fewer participants in the intervention group will 
require bariatric surgery due to their expected weight loss). Missing primary outcome data will need 
to be imputed for the ITT analyses; this will be done by assuming that these participants did not 
achieve ≥15% weight loss at 52 weeks, which is a conservative approach. The characteristics of those 
with missing outcome data will be compared with those who have completed follow-up. The 
complete cases, ITT, and per protocol analyses will compare the two groups to demonstrate the 
effectiveness of the targeted prescribing pathway compared with standard care. 
 
Secondary outcomes measured at 52 weeks and 104 weeks will be analysed in a similar way, with 
binary outcomes compared using logistic regression models and summarised using proportion (95% 
confidence interval), and continuous outcomes compared using linear regression models and 
summarised using mean (95% confidence interval). If continuous outcomes are non-normally 
distributed then they will be transformed or a more suitable regression model will be selected. In all 
analyses, participants will be analysed in the group to which they were randomised at baseline. Only 
the complete cases population will be used for the secondary outcomes to reduce the number of 
models being fitted. Participants who have undergone bariatric surgery during the period of the 
study will be excluded from these analyses. Data on treatment adherence, safety (including adverse 
events), and treatment satisfaction will be summarised and tabulated.  
  
As additional secondary analyses, we will perform a responder analysis which will repeat the 
analyses of the secondary outcomes with the intervention group restricted to those participants who 
responded to the targeted prescribing pathway (i.e. had achieved ≥15% weight loss at 52 weeks 
after randomisation). The purpose of these analyses is to compare the outcomes of “early and good” 
responders to the targeted prescribing pathway with those who received standard care only. 
Therefore, all participants randomised to the standard care group will also be included in these 
responder analyses. 
 
 


 
 
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11.2 Sample Size 
Based on previous studies, it is expected that at one year approximately 5% of the participants in the 
standard care group will have achieved ≥15% weight loss (likely range: 3%-5%) [5, 7]. An achievable 
target for ≥15% weight loss at one year in the intervention group is 16% (likely range: 14%-20%) 
[5,7]. Based on these proportions, 25% drop out, 5% alpha and a 2:1 randomisation ratio with the 
higher proportion of participants being randomised to the intervention group, we would need to 
recruit 392 participants (261 intervention group; 131 standard care) to have 80% power to detect a 
significant difference between the groups at one year. With 261 participants randomised to the 
intervention group, and based on 16% achieving ≥15% weight loss at 12 months, an estimated 40 
participants in the intervention group will be eligible for the responder analyses. All 131 participants 
in the standard care group will be eligible for the responder analyses. 
 
11.3 Missing/unused/spurious data procedure 
Attempts will be made to assess the primary outcome on all participants including those who have 
withdrawn from treatment. The number of missing observations for each outcome will be reported. 
If missing outcome data are present then the initial analysis will be based on the complete cases. A 
sensitivity analysis will then be carried out repeating the analyses with the ITT population to assess 
the possible impact of the missing data on the results produced. Missing primary outcome data will 
need to be imputed for the ITT analyses; this will be done by assuming that these participants did 
not achieve ≥15% weight loss at 52 weeks, which is a conservative approach. We will also attempt to 
address bias by comparing the characteristics of those with missing outcome data to those who have 
completed follow-up. This strategy for dealing with missing outcome data has been recommended 
by White et al. [9]. 
 
11.4 Disposition of Patients 
Screened patients  
Screened patients are defined as any patient who met the inclusion criteria and signed the informed 
consent form.  
 
Treated patients  
Treated patients consist of all patients, who have been allocated to one of the two treatment 
groups, and have at least partially completed the Baseline Visit.  
 
Data from all randomised participants will be used in the study final report and analysis, with data 
analysed in the group to which the participant was randomised. Participants who have undergone 
bariatric surgery during the period of the study will be excluded from the complete cases, per 
protocol and responder populations. 
 
11.5 
Analysis Populations 
Complete cases population 
The complete cases population is defined as all randomised participants who have data available for 
the outcome being analysed, according to the study group to which they were randomised at 
baseline. Participants who had bariatric surgery during the study period will be excluded from this 
population. 


 
 
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ITT population 
The ITT population are all randomised participants and they will be analysed according to the 
treatment group to which they were randomised at baseline. Missing outcome data will be imputed. 
Participants who had bariatric surgery during the study period will be included in this population. 
 
Per protocol population 
The per protocol population is defined as all participants who were compliant with their randomised 
treatment group, analysed according to the treatment group to which they have randomised at 
baseline. Participants in the standard care group are defined as treatment compliant if they 
complete at least 70% of the planned contacts in the Tier 3 service. Participants in the intervention 
group are defined as treatment compliant if they complete at least 70% of the planned contacts in 
the Tier 3 service, and take at least 70% of their planned doses of LIRA 3mg as stipulated by the 
prescribing pathway. Participants who had bariatric surgery during the study period will be excluded 
from this population.  
 
Responder population 
The Responder population is defined as all participants in the intervention group who achieved ≥15% 
weight loss at 52 weeks, and all participants in the standard care group. Participants will be analysed 
according to the treatment group to which they were randomised at baseline. Participants who had 
bariatric surgery during the study period will be excluded from this population. 
 
11.6  
Health Economic Input 
A state-transition Markov cohort model has been developed, with health states encompassing the 
possible co-morbidities associated with obesity and documented to respond to weight loss. A 
thorough review of the literature was conducted to identify such conditions and inform transition 
probabilities in the model. 
 
The model projects  development of T2DM, myocardial infarction (MI), stroke, asthma cancer or 
mortality in the long term (up to lifetime horizon) based on short term effects of interventions in 
surrogate outcomes – body mass index (BMI), systolic blood pressure (SBP) , total cholesterol, high-
density lipoprotein (HDL) cholesterol and (for patients with T2DM) glycated haemoglobin (HbA1c). 
Effects on surrogate outcomes are translated into lifetime risks through risk-prediction models.  
 
Treatment effects are applied incrementally to the efficacy of the targeted prescribing pathway 
group. Effect on weight, in terms of BMI % reduction, is applied at every subsequent cycle starting 
from 3 months after treatment start for as long as the cohort remains on treatment and over the 
predefined catch-up time post-treatment. Note that a natural increase in weight is applied each year 
to all interventions considered, including no treatment.   
 
Treatment can be discontinued at 16 weeks, 32 weeks [note: the current version of the model does 
not include the functionality for a 32 week stopping rule, but that will be added] (based on the pre-
specified stopping rule) or at 52 weeks. Discontinuation at 3 months causes the cohort to move to 
the control group, and subsequently follow the clinical pathway of this treatment group who will be 


 
 
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receiving the standard care providing via the Tier 3 service. Thus, if the discontinuation is allowed at 
16 weeks, non-responders will have the same effect of the cohort in the control group, and 
responders will have the effect of the targeted prescribing pathway in the clinical trial. 
 
Discontinuation beyond 52 weeks causes BMI, and other cardio-metabolic risk factors, to revert to 
the levels projected under the no treatment option. Reversal takes place over a given number of 
cycles (years) – catch-up time – as defined by the user. Costs and quality of life outcomes are applied 
to the health state in which the cohort resides at each particular moment in time or once-off to 
events. Costs and health benefits (life years, quality-adjusted life-years, years T2DM free, years 
cancer free etc.) are summed-up for the time horizon of the model and results reported as 
incremental cost-effectiveness ratios. The risk of acquiring obesity-related co-morbidities have been 
taken from published epidemiological studies. 


 
 
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12 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
All source data, study documents, and participant notes will be made available for the Sponsor 
monitoring, and indeed any external audits and inspections by the Ethics Committee, Regulatory 
Authorities, Sponsor, LCTU and host institution.   
 
 
13.   
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
The study will be conducted in accordance with the current approved protocol, ICH GCP, relevant 
regulations and the SOPs and quality management procedures of Sponsor, host organisations and 
for those services provided by LCTU, the Unit’s SOPs.  
 
As part of the quality management process a risk assessment will be carried out and a monitoring 
plan will be developed by the Sponsor. The Sponsor will carry out all study monitoring. The Leicester 
Diabetes Centre will be responsible for all elements of trial management and carry out quality checks 
as identified within a quality management plan. A documented monitoring log and audit trail will be 
maintained throughout the lifetime of the study. 
 
 
All study documentation containing identifiable patient data will be managed in accordance with 
ICH-GCP,  UK Policy Framework for Health and Social Care Research, General Data Protection 
Regulation and the Data Protection Act as amended from time to time. 
 
13.1 Responsibilities of the Principal Investigator(s) 
The Investigator and delegated Investigator staff undertake to perform the clinical study in 
accordance with this clinical study protocol, ICH guidelines for Good Clinical Practice and the 
applicable regulatory requirements. 
 
The PIs are required to ensure compliance with all procedures required by the clinical study protocol 
and with all study procedures provided by the Sponsor (including security rules). The PIs agree to 
provide reliable data and all information requested by the clinical study protocol (with the help of 
the CRF or other appropriate instrument) in an accurate and legible manner according to the 
instructions provided and to ensure direct access to source documents by Sponsor representatives. 
With any data transfer, particular attention should be paid to the confidentiality of the subject’s 
data. 
 
The PIs may appoint such other individuals as he/she may deem appropriate as co-investigators to 
assist in the conduct of the clinical study in accordance with the clinical study protocol. All co-
investigators shall be appointed and will have been delegated by the PI and will have signed the 
delegation log prior to commencing work on the study. The co-investigators will be supervised by 
and work under the responsibility of the PI. The PI will provide them with a copy of the clinical study 
protocol and all necessary information. 
 
13.2 Responsibilities of the Sponsor 


 
 
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The Sponsor of this clinical study is responsible to health authorities for taking all reasonable steps 
to ensure the proper conduct of the clinical study protocol as regards ethics, clinical study protocol 
compliance, and integrity and validity of the data recorded on the CRFs.  
 
Following a risk assessment, the Sponsor will prepare and put into place a risk adaptive monitoring 
plan, detailing the frequency and type of monitoring visits. This may be by one or more of the 
following methods – remote data monitoring, site visits and in-house day-to-day to review study 
progress, Investigator and subject adherence to clinical study protocol requirements and any 
emergent problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, signature logs, version 
control, SAE documentation and reporting, AE documentation, subject compliance with the 
investigational drug, investigational drug accountability, concomitant therapy use and quality of 
data. The LCTU will undertake its own study audit as part of its trial management procedures. 
 
13.3 Deviation Procedures 
A deviation is a change or departure from the clinical trial protocol and/or Good Clinical Practice 
(GCP) that does not result in harm to the study participants or significantly affect the scientific value 
of the reported results of the study.  
 
Deviations may be identified by routine quality control procedures, or may be reported directly from 
the PI or other site staff, as a spontaneous written notification or by submission of a protocol 
deviation form included as part of the CRF. All such deviations should be documented in-line with 
Sponsor SOP’s and retained within the Trial Master File and notification sent to Sponsor when 
serious breaches occur (as detailed in Sponsor SOPs). An assessment will be made by the PI as to 
whether the deviation is deemed to be serious or substantial (see below). 
 
The deviation report should include: 
 
The title (full or accepted abbreviation) of the clinical trial 
 
The name of the CI and the PI  
 
A brief explanation of how the deviation was identified 
 
Details of initial corrective actions 
 
Actions that result from a deviation may include: 
 
Alerting the investigator and asking for further explanation or data verification 
 
Audit of the investigator site or the clinical trial database (as applicable) 
 
Examination of data from the site by a statistician as a central monitoring procedure 
 
Review of other study data  
 
Involvement of an DSMC or the TSC 
 
 


 
 
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13.4 Misconduct or Serious Breaches of GCP/Protocol 
If research misconduct or a serious breach is confirmed by clear and unequivocal evidence, it is the 
responsibility of the Sponsor (or delegate) to notify the MHRA and the main REC in the UK or the 
HPRA and EUREC in Ireland in writing within 7 days of the Sponsor becoming aware of the breach 
using the Serious Breach Notification Form and to investigate or take action simultaneously or after 
initial notification. 
 
Deviations from the protocol and/or GCP that are assessed as serious are to be reported to the 
MHRA/HPRA as a serious breach by the study Sponsor (or delegate). 
 
A serious breach is a violation or deviation that is likely to affect to a significant degree: 
(a) the safety or physical or mental integrity of the subjects of the study 
(b) the scientific value of the study 
 
Research misconduct is the deliberate reporting of false or misleading data or the withholding of 
reportable data. Concluding that an individual is responsible for misconduct in research relies on a 
judgement that there was an intention to commit the misconduct and/or recklessness in the 
conduct of any aspect of a research project. Misconduct includes: fabrication; falsification; 
misrepresentation of data and/or interests and or involvement; and plagiarism. It also includes a 
failure to follow accepted procedures or to exercise due care in carrying out responsibilities to avoid 
unreasonable risk or harm to participants in research, and/or a failure in the proper handling of 
information on individuals collected during the research. 
 
 
14.  
CODES OF PRACTICE AND REGULATIONS 
14.1 Clinical Trials Authorisation (CTA) 
Approval for the protocol (and any subsequent substantial amendments) will be sought from the 
MHRA (UK Competent Authority) and HPRA (Irish Competent Authority).  
 
14.2 Ethics 
This protocol and any amendments will be submitted to the Health Research Authority (HRA) and 
Research Ethics Committee (REC) for ethical approval (or to EUREC for sites in Ireland). 
 
This clinical study will be conducted in accordance with the principles laid down by the 18th World 
Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies. All staff working on this study will have an up to date ICH-GCP certificate. Ethical and 
research governance approval will be sought for this study through the HRA, appropriate regulatory 
bodies and NHS Trusts prior to any participant activity. 
 
In compliance with Novo Nordisk public disclosure commitments, this clinical study will be recorded 
in the public registry website clinicaltrials.gov before the enrolment of the first participant. The 
registry will contain basic information about the study sufficient to inform interested patients (and 
their healthcare practitioners) how to enrol in the study. 


 
 
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14.3 HRA 
HRA approval will be sought concurrently with MHRA and REC approval for those sites in NHS 
England, which will perform an assessment of governance and legal compliance prior to any local 
NHS checks and approvals being completed.  
 
For those sites that are not part of NHS England alternative appropriate regulatory approvals will be 
sought (e.g. Ireland approvals will be sought from the Health Products Regulatory Authority (HPRA) 
concurrently with English sites). 
 
14.4 Sponsorship and Indemnity 
Sponsorship and insurance for the study will be provided by the University of Leicester. 
 
If a patient is harmed due to negligence, this would be covered by the local NHS Trust(s) indemnity 
arrangements for all participants in clinical trials. If a study participant wishes to make a complaint 
about any aspects of the way they have been treated or approached during the research project, the 
standard National Health Service complaint system will be available to them. 
 
14.5 Host Organisation (R&I) Approvals 
In accordance with the Research Governance Framework, R&I approval for the study will be 
obtained from each participating Trust once all other approvals have been confirmed (REC, MHRA, 
HRA, HPRA).  The University of Leicester will undertake the role and responsibility of the research 
Sponsor and Sponsor greenlight will be obtained prior to any study activities commencing.   
 
For all amendments Sponsor will review this prior to submission by the Investigator to the required 
regulatory body/bodies, and all approvals will be confirmed prior to commencement at the site.  
 
14.6 Sponsor Standard Operating Procedures 
All relevant current Sponsor SOPs will be followed to ensure that this study complies with all 
relevant legislation and guidelines. 
 
14.7 Declaration of Helsinki 
The Investigator will ensure that this study is conducted in full conformity with the current revision of 
the Declaration of Helsinki (last amended October 2000, with additional footnotes added 2002 and 
2004). 
 
14.8 ICH Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in full conformity with relevant regulations 
and with the ICH Guidelines for Good Clinical Practice (CPMP/ICH/135/95) June 1996. 
 
14.9 Laws and Regulations 
This study will be conducted in compliance with all international guidelines, national laws and 
regulations of the country in which the study is performed, and any applicable guidelines.  


 
 
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14.10  
Other Ethical Considerations 
 
14.10.1 Known and potential risks 
LIRA 3mg is administered as a one daily subcutaneous injection and is available in a prefilled, 
disposable pen device comprising a pen injector and cartridge. There may be some anxiety and 
concern to starting treatment using a needle-based device and this will be discussed at length with 
their clinician. It can be taken at any time of the day and is meal independent. The pros and cons of 
LIRA 3mg will be explained to each participant during the initial consultation for study consent.  
LIRA 3mg has a good tolerability profile; however the most frequently reported adverse effects of 
LIRA 3mg are gastrointestinal, including nausea, diarrhoea, vomiting, constipation, abdominal pain, 
and dyspepsia. These gastrointestinal adverse effects may occur more frequently at the start of 
treatment with LIRA 3mg, and usually diminish within a few days or weeks on continued treatment.  
Hypoglycaemia is considered low risk with this treatment because its action is glucose dependent. 
However, participants suffering with diabetes on treatment with sulphonylureas may be at higher 
risk for hypoglycaemic episodes compared to the other participants. 
 
Rare serious adverse events may include hepatobiliary diseases such as associated with gallstone 
formation and pancreatitis. An increase incidence of breast malignancies previously reported may be 
due to reduced adipose tissue in the breast and earlier detection. 
 
14.10.2 Known and potential benefits 
Multiple randomised controlled trials in different populations have demonstrated that LIRA 3mg is 
an effective treatment for obesity and obesity-related co-morbidities. Moreover, intensive lifestyle 
programmes offered as part of the Tier 3 service have been shown to be effective in promoting 
weight loss in subjects with severe and complex obesity [10, 11].  
 
SCALE Obesity trial demonstrated that the combination of lifestyle changes and administration of 
LIRA 3mg from the beginning of treatment can lead to ≥ 15% weight loss in 14% of participants 
compared to just 3% in the placebo group at one year after treatment [5]. Moreover, the SCALE-
maintenance trial showed that LIRA 3mg in combination with advice for lifestyle change after an 
initial weight loss of 5% with low calorie diet and meal replacements, could result in an additional 
6.1 kg weight loss compared to placebo over the next year [7]. Overall, the SCALE-maintenance 
study resulted in a maintained weight loss of 12.2 kg for patients on LIRA 3mg and 26% of them 
achieved ≥15% weight loss [7].  
 
Additionally, the SCALE Obesity study showed that the prevalence of prediabetes was lower one 
year after treatment with LIRA 3mg compared with the placebo group [5]. The SCALE Diabetes study 
demonstrated that LIRA 3mg could result in greater weight loss and HbA1C control in patients with 
diabetes compared with placebo [6]. All the phase 3 studies with LIRA 3mg have shown 
improvements in systolic blood pressure, markers of inflammation and cardiovascular health [5-7]. 


 
 
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15. 
DATA MANAGEMENT 
15.1 CRF/Data collection sheet management 
Paper Case Report Forms (CRF) and study questionnaires are the primary data collection instruments 
and treated as source data. All data requested in the CRF will be recorded. All missing data will be 
explained. If the item is not applicable to the individual case, N/A will be written. All entries will be 
printed legibly in black ink. If any entry error has been made, to correct the error, a single line will be 
drawn through the incorrect entry and the correct data entered above it. All such changes will be 
initialled and dated. For clarification of illegible or uncertain entries, the clarification will be printed 
above the item and this will be initialled and dated. 
 
Data captured in the paper CRFs will then be entered into a validated database under the 
management of the LCTU. A copy of the patient consent form and information sheet will be placed 
in the hospital notes of all participants and in the Investigator Site File. A sticker will be placed on the 
cover of the notes (or inside cover) detailing the study title, contact details of the PI and the fact that 
the notes should not be destroyed. All study visits and AEs will be recorded in the hospital notes.  
 
All CRFs will be stored in a secure area. Each enrolled participant will be allocated a unique study ID 
so that the CRFs and electronic database remains anonymous. 
 
According to the ICH guidelines for Good Clinical Practice, the monitoring team must check the CRF 
entries against the source documents, except for the pre-identified source data directly recorded in 
the CRF. The informed consent form will include a statement by which the patient allows the 
Sponsor or duly authorised personnel, the Ethics Committee, and the regulatory authorities to have 
direct access to original medical records which support the data on the CRFs (e.g., subject’s medical 
file, appointment books, original laboratory records, etc.). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
 
15.2 Documentation storage, access, security 
All study documentation containing identifiable patient data will be managed in accordance with 
ICH-GCP, the UK Policy Framework for Health and Social Care Research and the Data Protection Act 
(or its subsequent legislation) and made available for inspection, monitoring or audit purposes by 
the Sponsor, host, regulatory authorities or the funder. 
 
Information will only be obtained from the patient if necessary for the study. 
 
All electronic data will be stored on secure network drives, to which only the relevant study staff 
have access, which is granted by the IT services or the research team.  This drive is backed up daily 
by the University of Leicester IM&T. 
 
All study documents and data will be kept for 15 years or the minimum determined by the 
regulatory authorities, whichever is the longer. Archived files will kept in a secure location. 
 
 


 
 
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15.3 Database management 
Paper CRF data will be entered by trained member(s) of the research team at site into a 
commercially available web based CDMS provided by the LCTU. On-entry validation checks will be 
applied where required and data entered will be checked for completeness, accuracy and timeliness 
by the study team/trial manager/data manager, with queries managed using the data clarification 
functionality within the CDMS system. 
 
The contacts database (which contains participant contact details) will be held separately from the 
study database. This will be password protected and managed at site by the research team. 
 
15.4 Data Confidentiality 
Each participant will be assigned a unique identification number upon recruitment. Participant’s 
contact details will be held on a database separate to the study visit data and used to arrange data 
collection visits at their local site. The database will be password protected and only researchers 
collecting data will have access. All data collected during the study will be stored pseudonymously 
on a separate database. Again access will be password protected and restricted to relevant members 
of the research team.  
 
Paper copies of the case report forms and questionnaires will be stored in a locked filing cabinet in 
the relevant research office. Neither hard copies nor electronic files containing personal information 
will be removed from the research office. Quality control checks will be conducted by the lead site 
(Leicester) these electronic documents will be pseudonymised and stored  in a secure manner. The 
study research team will comply with the Data Protection Policy of the University of Leicester and 
local NHS Trusts. 
 
16.  
STUDY GOVERNANCE 
The study will be conducted in accordance with the UK Policy Framework for Health and Social Care 
Research  and Medicines for Human Use (Clinical Trials) Regulations, 2004 and its subsequent 
iterations. The Sponsor responsible for checking research governance arrangements will be the 
University of Leicester. 
 
16.1 Trial Steering Committee (TSC) 
The TSC will comprise of the Chief Investigator and Co-Principal Investigators, with an Independent 
Chair, with at least one other independent clinician with expertise in a relevant field and a 
nominated representative from Novo Nordisk. The statistical team, and the trial management team 
may attend as required. This committee will be responsible for the overall management and 
oversight of the study and will meet once prior to start up and then every 6 months, normally within 
2 months of the Data Safety Monitoring Committees (DSMCs) (although additional meetings may be 
called by the CI, TSC or DSMC chair) to review and approve protocol amendments and any sub-study 
proposals, review recruitment rates, protocol adherence, retention, compliance, safety issues, 
planned analyses and reports and act on recommendations of the DSMC. Minutes from the TSC will 
be copied to the Sponsor. 
 


 
 
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16.2 Trial Management Group (TMG) 
The TMG will report to the TSC and will include the PI and the day-to-day project management team 
onsite, representatives from other sites, statistician(s), IT/Data Management, and research nurses as 
required. TMG meetings will be held at each site on a monthly or bi-monthly basis depending on 
need, either face-to-face or by teleconference, to discuss set-up, recruitment and retention, follow-
up data collection and any other day-to day practical issues. 
 
16.3 Data Safety and Monitoring Committee (DSMC) 
The DSMC will meet every six months and report to the TSC. The DSMC will be appointed by the CI 
and the LCTU Statistical Team and will comprise members who are independent of the study, to 
include at least one statistician and at least one clinician. The CI and/or trial statistician may be 
invited to attend to provide specific input by the DSMC Chair. The DSMC will review safety data 
regularly and make recommendations as to whether the study should continue, be modified or 
terminated.  A log of all AEs will be provided to the DSMC for this purpose. The DSMC will also 
review any statistical analysis plans. 
 
16.4 Premature discontinuation of the study  
Decided by the Sponsor 
Decided by the Sponsor in the following cases: 
 
If the information on the product leads to doubt as to the benefit/risk ratio 
 
If the CI has received from the Sponsor all (N)IMP, means and information necessary to 
perform the clinical trial and has not included any patient after a reasonable period of time 
mutually agreed upon 
 
In the event of breach by the CI of a fundamental obligation under this agreement, including 
but not limited to breach of the clinical trial protocol, breach of the applicable laws and 
regulations or breach of the ICH guidelines on GCP 
 
If the total number of patients is included earlier than expected. 
 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
 
Decided by the CI 
The CI must notify (30 days’ prior notice) the Sponsor of his/her decision and give the reason in 
writing. 
 
In all cases (decided by the Sponsor or by the CI), the appropriate Research Ethics Committee(s) and 
NHD Trusts should be informed according to applicable regulatory requirements. 
 
17.  
PUBLICATION POLICY 
It is envisaged that the results of the study will be published in the relevant Obesity/General Medical 
peer-reviewed journals. Acknowledgement of any supporting organisations, including funders, 
University of Leicester and the LCTU, will be included. 


 
 
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18. 
REFERENCES 
 
1. UK Government Reports. About Obesity. Retrieved from: 
http://www.noo.org.uk/NOO_about_obesity/severe_obesity 
2. Ahmad A, Laverty AA, Aasheim E, Majeed A, Millett C, Saxena S. Eligibility for bariatric surgery 
among adults in England: analysis of a national cross-sectional survey. JRSM Open. 2014; 7:5. 
3. Public Health England. Adult obesity and type 2 diabetes. Retrieved from: 
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/338934/Adult
_obesity_and_type_2_diabetes_.pdf  
4. National Institute for Health and Care Excellence. Obesity: identification, assessment and 
management. Retrieved from: https://www.nice.org.uk/guidance/cg189/chapter/1-
recommendations  
5. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, Lau DC, le Roux CW, Violante 
Ortiz R, Jensen CB, Wilding JP; SCALE Obesity and Prediabetes NN8022-1839 Study Group. A 
Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med. 
2015; 373:11-22. 
6. Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, Andreasen AH, Jensen CB, 
DeFronzo RA; NN8022-1922 Study Group. Efficacy of Liraglutide for Weight Loss Among Patients 
With Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial. JAMA. 2015; 314:687-99. 
7. Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM, Aronne L; NN8022-1923 
Investigators. Weight maintenance and additional weight loss with Liraglutide after low-calorie-
diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2013; 
37:1443-51. 
8. Blüher F, Hermansen K, Greenway F, et al. Early weight loss with liraglutide 3.0 mg is a good 
predictor of clinically meaningful weight loss after 56 weeks. Abstract #645 - 51st EASD Annual 
Meeting 2015. 
9. White IR, Horton NJ, Carpenter J, Pocock SJ. Strategy for intention to treat analysis in 
randomised trials with missing outcome data. BMJ. 2011;342:d40. 
10. Logue J, Allardice G, Gillies M, Forde L, Morrison DS. Outcomes of a specialist weight 
management programme in the UK National Health Service: prospective study of 1838 patients. 
BMJ Open. 2014; 1:4. 
11. Jennings A, Hughes CA, Kumaravel B, Bachmann MO, Steel N, Capehorn M, Cheema K. 
Evaluation of a multidisciplinary Tier 3 weight management service for adults with morbid 
obesity, or obesity and comorbidities, based in primary care. Clin Obes. 2014; 4:254-66.  
12. Leslie WS, Ford I, Sattar N, Hollingsworth K, Taylor R, Lean MEJ et al. The Diabetes Remission 
Clinical Trial (DiRECT): protocol for cluster randomised trial. BMC Family Practice. 2016; 17-20. 
 
 


 
 
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19. APPENDICES 
 
APPENDIX 1: King’s College Obesity Staging System 
 
 
Stage 0 
Normal Health 
Stage 1 
At risk of disease 
Stage 2 
Established disease 
Stage 3 
Advanced disease 
Airways 
Normal 
Snoring 
CPAP therapy 
Cor pulmonale 
BMI 
<35kg/m2 
35-40 kg/m2 
40-60 kg/m2 
>60 kg/m2 
Cardiovascular 
<10% risk 
10-20% risk 
Heart disease 
Heart failure 
Diabetes 
Normal 
Impaired fasting 
glucose 
Type 2 diabetes 
Uncontrolled type 2 diabetes 
Economic 
Normal 
Increased expense 
for clothes and travel 
Workplace 
discrimination 
Unemployment due to 
obesity 
Functional 
Can walk three 
flights of stairs 
Can walk one or two 
flights of stairs 
Requires mobility aid 
Housebound 
Gonadal 
Normal 
PCOS/erectile 
dysfunction 
Subfertility 
Sexual dysfunction leading to 
relationship breakdown 
Health status 
(perceived) 
Normal 
Low mood or QoL 
Depression or poor 
QoL 
Severe depression 
Image (body) 
Normal 
Dislikes body 
Body image 
dysphoria 
Eating disorder 
 
CPAP: Continuous Positive Airway Pressure, PCOS: Polycystic Ovarian Syndrome, QoL: Quality of Life 
 
 
 


 
 
 
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APPENDIX 2: Participant flowchart 
1st stopping rule for 
LIRA (≥5%WL) 
2nd stopping rule for 
LIRA 3 mg (≥10%WL) 
3rd stopping rule for 
LIRA 3 mg (≥15%WL) 
Clinical Review (safety and retention) Visit 
LIRA 3mg ONLY - Weeks 65 (±14 days) 
Clinical Review (safety and retention) Visits  
Weeks 2 (optional), 4 (optional), 8, 12 (optional) (±7 days) 
Clinical Review (safety and retention) Visit  
Week 16 visit (± 14 days)                    
Clinical Review (safety and retention) Visit 
Weeks 20 (optional) (±14 days) 
Clinical Review (safety and retention) Visit  
Week 32 visit (± 14 days)                    
Clinical Review (safety and retention) Visit 
Weeks 40 (optional) (±14 days) 
Data Collection Visit 
Week 52 visit (± 3 months)                   
Clinical Review (safety and retention) Visit 
Weeks 78 (optional) (±14 days) 
Data Collection Visit 
Weeks 104 (±14 days) 
Clinical Review (safety and retention) Visit 
LIRA 3mg ONLY - Weeks 91 (±14 days) 
Screening Visit 
Screened for eligibility and informed consent (day -42 to -1) 
Data Collection Visit 1 - Baseline Visit 
Baseline measurements, randomisation and initiation of 1st phase of the 
study with standard care at both groups (day 0) 
Excluded 
Declined to 
participate 
Approached at Tier 3 service 
Randomised 
Targeted prescribing pathway (n= 261)  
Standard care in Tier 3 service (n= 131) 
Key:  
Targeted prescribing pathway (LIRA 3mg) 
Standard care provided in Tier 3 service 


 
 
 
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APPENDIX 3: Study schedule for measurements. 
Table 2. Outcome measures and planned visits during the enrolment and control visits.  
WEEKS 
-6 to  
-1/52 
0/52 
2/52 
4/52 
8/52 
12 
/52 
16 
/52 
20 
/52 
32 
/52 
40 
/52 
52 
/52 
65 
/52* 
78 
/52 
91 
/52* 
104/5
2 
VISIT WINDOW 
Scree
ning^^ 
Base-
line 
+/- 
3dys 
+/- 
3dys 
+/- 
7dys 
+/- 
7dys 
+/- 
14dys 
+/- 
14dys 
+/- 
14dys 
+/- 
14dys 
+/- 3 
mths*
***
+/- 
14dys 
+/- 
14dys 
+/- 
14dys 
+/- 
14dys 
Visit No. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12* 
13* 
/12
14* 
15* 
/13
STUDY PROCEDURES 
Inclusion/ 
exclusion criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection 
training* 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Titration/ Review 
Visit* (dose$) /or 
telephone call)$$ 
 
X  
X 
 
 
X 
 
X$$ 
3.0$ 
 
 
 
 
 
 
 
 
 
 
Other HCP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Glucose self-
monitoring 
training/ 
education 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensing (or 
unsched visit)### 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DATA COLLECTION 
Subject 
demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Changes              
in med/diseases 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Waist 
Circumference 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood 
Pressure^^^^ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse rate^^^^ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver function 
tests^^^^ 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Renal function 
tests^^^^ 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Thyroid function 
tests^^^^ 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Haematology 
profile^^^^ 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Lipids^^^^ 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
HbA1C^^^^ 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Amylase^^^^ 
X 
 
 
 
 
 
 
 
X* 
 
X* 
 
 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Key: 
      Optional visits (both arms) 
      Stopping rules apply 
      Extra visits for LIRA 3mg group only 
      End of study 
$$ 
$$ 


 
 
 
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Page 65 of 65 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WEEKS 
-6 to  
-1/52 
0/52 
2/52 
4/52 
8/52 
12 
/52 
16 
/52 
20 
/52 
32 
/52 
40 
/52 
52 
/52 
65 
/52* 
78 
/52 
91 
/52* 
104/5
2 
VISIT WINDOW 
Scree
ning^^ 
Base-
line 
+/- 
3dys 
+/- 
3dys 
+/- 
7dys 
+/- 
7dys 
+/- 
14dys 
+/- 
14dys 
+/- 
14dys 
+/- 
14dys 
+/- 
3mth
s****
+/- 
14dys 
+/- 
14dys 
+/- 
14dys 
+/- 
14dys 
Visit No. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12* 
13* 
/12
14* 
15* 
/13
King’s Obesity 
Staging System 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Epworth 
Sleepiness 
Scale  
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Stop Bang 
Questionnaire 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
CPAP 
compliance ** 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Pregnancy test 
X 
X 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X 
X* 
X* 
X* 
X 
ACR***^^^^ 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
AE/SAE 
recording 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence with 
injection* 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence with 
other anti-
obesity 
medications# 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
X 
Adherence to 
Tier 3 (or 
equivalent) 
Service 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contacts with 
GP/HCP 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inpatient and 
Outpatient apt’s 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medications cost 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
QUESTIONNAIRES^^^ 
HSRUQ 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
TSQM### 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
IWQOL-Lite 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
IPAQ-Long 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
PHQ-9 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
*Only for participants at the LIRA 3mg group who are on active treatment 
$Target dose by week 8. $$Optional Telephone calls to check tolerance and up-titrate at weeks 1, 3 & 5. 
**As required for participants with identified risk OSA of or current OSA based on CPAP use and type of CPAP (variable or fixed pressures CPAP) 
*** Only for prediabetic, diabetic and hypertensive individuals 
****Where possible the week 52 visit should continue to be scheduled within the (± 14 days) study visit window, however to aid retention 
and to help maximise data collection for the study primary end point, the week 52 visit window can be extended to ± 3 months. 
# Only for participants in the standard care group on treatment with anti-obesity drugs 
##Only for participants with diagnosis of T2DM 
### For participants on treatment either with LIRA 3mg or other anti-obesity medication 
^ Only participants who report problems with injection and/or side-effects may be reviewed by study clinician 
^^A repeat screening visit may take place to assess eligibility 
Drug dispensing unscheduled visits may occur at any point within the study period for participants in LIRA3 mg group as required (not depicted above) 
^^^In response to the COVID19 global pandemic, an interim time point for the quality of life questionnaires has been added (HSRUQ, TSQM, EQ-5D, IWQOL-Lite, IPAQ-
Long and PHQ-9). These will be sent out to all participants during the COVID19 pandemic. 
^^^^ These activities will not be completed during the COVID19 pandemic restriction period, however once restrictions are lifted participants that resume face to face 
visits will be completed as per the original protocol. 
 

SAP_001.pdf: