Saxenda in Obesity Services (STRIVE Study)

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.

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.

Eligibility Criteria:
Inclusion Criteria:

* be aged between 18-75 years old (inclusive)
* understand written and spoken English
* be able to give in informed consent
* a body mass index ≥35 kg/m2,
* have been referred to Tier 3 weight management or equivalent service in one of the five participating sites,
* have a stable body weight (less than 5kg self-reported change during the previous 12 weeks),
* Participant must be able to meet at least one of the inclusion criteria listed below:

  1. 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) and/or
  2. type 2 diabetes \[defined as established diagnosis of Type II diabetes from GP and/or HbA1C ≥48 mmol/mol (\>6.5%) at a blood test during the last 6 months\] being treated with any combination of lifestyle, metformin, sulphonylureas, thiazolidinediones (TZDs) or SGLT-2, and/or
  3. hypertension treated (defined as being on antihypertensive treatment with or without a diagnosis of hypertension from GP) or untreated (defined as Systolic Blood Pressure (SBP) ≥140 mmHg at two consecutive visits at the Tier 3 clinic), and/or
  4. obstructive sleep apnoea (on CPAP or established diagnosis of Apnoea Hypopnoea Index ≥15 at sleep studies during the last 12 months)

Exclusion Criteria:

* Diagnosis of Type 1 diabetes
* Type 2 diabetes with treatment on DPP-IV or insulin currently
* 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 the last 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 during the study period
* Have terminal illness
* Are not primarily responsible for their own care
* Not willing or able to give informed consent
* 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 \>6 mIU/liter or \<0.4 mIU/liter
* 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 screening, 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)
* History of major depressive episode during the last 2 years
* History of initiation of antidepressants during the last 12 weeks
* Simultaneous participation in other clinical trials of investigational drugs, lifestyle or physical activity interventions.
* Previous surgical treatment for obesity (excluding liposuction if performed \>1 year before trial entry)
* 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.