Multimodality local consolidative treatment versus conventional care of advanced lung cancer after first-line systemic anti-cancer treatment: study protocol for the RAMON multicentre randomised controlled trial with an internal pilot

Abstract

Introduction

Lung cancer is the most common cause of cancer death worldwide and most patients present with extensive disease. One-year survival is improving but remains low (37%) despite novel systemic anti-cancer treatments forming the current standard of care. Although new therapies improve survival, most patients have residual disease after treatment, and little is known on how best to manage it. Therefore, residual disease management varies across the UK, with some patients receiving only maintenance systemic anti-cancer treatment while others receive local consolidative treatment (LCT), alongside maintenance systemic anti-cancer treatment. LCT can be a combination of surgery, radiotherapy and/or ablation to remove all remaining cancer within the lung and throughout the body. This is intensive, expensive and impacts quality of life, but we do not know if it results in better survival, nor the extent of impact on quality of life and what the cost might be for healthcare providers. The RAMON study (RAdical Management Of Advanced Non-small cell lung cancer) will evaluate the acceptability, effectiveness and cost-effectiveness of LCT versus no LCT after first-line systemic treatment for advanced lung cancer.

Methods and analysis

RAMON is a pragmatic open multicentre, parallel group, superiority randomised controlled trial. We aim to recruit 244 patients aged 18 years and over with advanced non-small-cell lung cancer from 40 UK NHS hospitals. Participants will be randomised in a 1:1 ratio to receive LCT alongside maintenance treatment, or maintenance treatment alone. LCT will be tailored to each patient’s specific disease sites. Participants will be followed up for a minimum of 2 years. The primary outcome is overall survival from randomisation.

Ethics and dissemination

The West of Scotland Research Ethics Committee (22/WS/0121) gave ethical approval in August 2022 and the Health Research Authority in September 2022. Participants will provide written informed consent before participating in the study. Findings will be presented at international meetings, in peer-reviewed publications, through patient organisations and notifications to patients.

Trial registration number

ISRCTN11613852.

Correspondence to Eric Lim; [email protected]

STRENGTHS AND LIMITATIONS OF THIS STUDY

• The study has a pragmatic design integrated into the standard care pathway at the majority of UK hospitals.

• A study for patients who present with extensive (poly-metastatic) disease that becomes oligometastatic (ie, induced oligometastatic) disease after initial systemic anti-cancer treatment.

• The study will assess a multimodal local consolidative treatment (surgery, radiotherapy, ablation) approach, with the potential to reduce radiation exposure in comparison to radiotherapy treatment alone.

• The study encourages the best practice of patients undergoing a restaging scan and discussions at multidisciplinary team meetings following initial systemic anti-cancer treatment, to inform further treatment options, which is not standard practice at all institutions.

• Some study treatments are offered off-site (ie, at another hospital), which can cause logistical challenges when obtaining data; however, we are addressing this by setting up data sharing agreements and facilitating communication between sites.

Introduction

Lung cancer is the most common cause of cancer death worldwide and the majority (57%) of patients in the UK present with advanced disease (defined as stage IIIB or IV). One-year survival is improving but remains low at 37%.¹

A number of phase 2 randomised controlled trials (RCTs) have focused on the prospect of radically (ie, with the intent of improving survival) treating patients with advanced lung cancer and oligometastatic disease (defined as less than five sites²) at presentation with systemic anti-cancer treatment (SACT) followed by radiotherapy to all remaining sites, a pathway known as local consolidative treatment (LCT). Two trials reported improvements with radiotherapy as LCT for overall survival and progression-free survival (PFS), respectively.^{3 4}

For a minority of patients with oligometastatic disease at presentation, further RCTs are underway evaluating radiotherapy alone as LCT, with the SARON trial (NCT02417662)⁵ in the UK, and the ROLE (NCT01796288) and CORE (NCT02759783)⁶ trials internationally. Based on published data, the inclusion criteria are widening from (arbitrarily defined) oligometastatic disease to extensive (polymetastatic) disease at presentation; the SABR-COMET-10 trial (NCT03721341)⁷ is investigating radiotherapy as LCT for patients with up to 10 sites of disease. However, there are no trials for the majority of patients who present with extensive disease that becomes oligometastatic disease (ie, all residual sites amenable to radical treatment) after SACT (more recently defined as ‘induced’ oligometastatic⁸ disease).

In the UK, LCT is multimodal including radiotherapy, surgery and local ablation, tailored to each patient’s specific disease site. A multimodality approach has the advantage of reducing total radiation dosage. Inclusion of surgery has additional advantages of providing tissue (to evaluate treatment response), refine staging (eg, lymph node status) and may achieve complete cancer clearance in a single episode of care. To date, only one trial has included surgery as an option alongside radiotherapy for LCT.⁹ The trial was stopped early for efficacy after 49 patients had been enrolled.⁹

LCT is intensive, impacts health-related quality of life (HRQoL) and is expensive but most importantly it is not known if it results in a better outcome for patients. Current trials are not addressing the question of the clinical and cost effectiveness of multimodality LCT in patients with the more common presentation of extensive disease, reduced to LCT eligible disease (defined as all disease sites amenable to radical treatment) after highly efficacious contemporary SACT such as immunotherapy and molecular targeted agents.

The RAMON study aims to evaluate the clinical and cost effectiveness of multimodality LCT in patients with advanced lung cancer, rendered LCT eligible metastatic disease, after contemporary standard-of-care SACT in comparison to symptom management treatment alone.

The trial will evaluate the acceptability, effectiveness and cost effectiveness of LCT versus no LCT after first-line systemic treatment for advanced lung cancer. Recruiting centres will be supported with an integrated QuinteT Recruitment Intervention (QRI)^10–12 and patients will be followed up at various time points over a 2-year period.

Method and analysis

Study design and population

RAMON is a pragmatic open multicentre, parallel group, superiority RCT in NHS hospitals. In total, 244 participants will be recruited to the study from at least 40 UK NHS hospitals, by their clinical care teams and will provide written informed consent before undertaking any study procedures (figure 1).

Figure 1. Study schema. SACT, systemic anti-cancer treatment.

An internal pilot phase will determine the feasibility of recruitment and adherence to the protocol and will be reviewed by the Trial Steering Committee (TSC) and Funder (NIHR131306) after 12 months of recruitment. Progression from the pilot phase will be determined if the following apply, or a feasible plan to satisfy any shortfall is in place:

• 25 centres open to recruitment.

• At least 45 participants are recruited.

• At least 95% of randomised participants adhered to the allocated treatment pathway.

The study opened to recruitment, 9 months behind target, on 10 January 2023 following delays experienced gaining regulatory approvals. Recruitment is scheduled to end in January 2025, with end of follow-up in January 2027 and full study completion, including reporting of results, in July 2027.

QuinteT Recruitment Intervention

The study has an embedded QRI to optimise informed consent and recruitment.^{10 11} A multifaceted, flexible approach will be used to investigate site-specific and wider recruitment obstacles as recruitment is underway¹¹. Action plans, grounded in these findings, will be formulated and implemented to improve recruitment and information provision, with format dependent on the nature of recruitment barriers identified.

Sub-study

The substudy, AQUA lung, aims to evaluate the use of a mobile phone based healthcare app (My Cancer Companion) to determine the agreement between patient’s self-reporting of HRQoL outcomes compared with completion of HRQoL scales at prespecified time points within the RAMON study. Participants involvement will include using the mobile phone app to record HRQoL and physical activity throughout the study. Clinic appointments can also be recorded, and useful articles will be available to read within the app. The information collected via the app will be compared with data collected through questionnaires as part of the main study, to see if the app could be used in place of questionnaires in future studies.

Health economic evaluation

The health economic evaluation will compare the costs and effects of LCT compared with conventional care, to assess whether LCT represents good value for money. The within-trial cost-effectiveness analysis will be conducted from an NHS and personal social services perspective, with a time horizon from randomisation to 2 years. The primary outcome for the economic evaluation will be quality-adjusted life years (QALYs), estimated using the EQ-5D-5L,^{13 14} which will be administered at baseline (pre-randomisation), and five timepoints post-randomisation (see table 1) via post or online. Resource use data collection will be integrated into the study case report forms for systemic treatment and surgery, and collected at each follow-up from participants on treatments, hospital admissions and further contact with health professionals in primary or secondary care.

Table 1

Schedule of data collection for primary and secondary outcomes

Data item	Baseline	LCT treatments*	Post randomisation
			6 w	6 m	12 m	18 m	24 m	Every 6 m to end of trial	End of trial
Demography, medical history, initial systemic treatment	✓
HRQoL questionnaires	✓		✓	✓	✓	✓	✓
LCT treatment and in-hospital postoperative data †		✓	✓	✓	✓	✓	✓
Serious adverse events		✓	✓	✓	✓	✓	✓	✓	✓
Patient-reported resource use			✓	✓	✓	✓	✓	✓
Disease progression/new cancer			✓	✓	✓	✓	✓	✓
Survival ‡			✓	✓	✓	✓	✓	✓	✓
HRQoL app§	✓	✓	✓	✓	✓	✓	✓	✓	✓

*Patients allocated to LCT and/or receiving surgery only.

†Including resource use.

‡All participants will be checked for survival at the end of the trial using summary care records.

§Participants encouraged to complete it regularly throughout the trial, but frequency and time points are not mandated.

HRQoL, health-related quality of life; LCT, local consolidative treatment.

Eligibility criteria

A patient may take part in the study if all the following apply:

• 18 years of age or over.

• Tissue confirmed non-small-cell lung cancer pretreatment clinical stage IV.

• Lung cancer treatment naïve prior to initial study systemic anti-cancer treatment (with the exception of radical treatment of solitary brain metastasis as standard of care).

• Completed standard of care SACT, defined as one of:

  • at least four cycles of platinum doublet chemotherapy or

  • at least 3 months of approved first-line molecular targeted treatment (a) epidermal growth factor receptor (EGFR) inhibitor in patients with EGFR mutant tumours or (b) anaplastic lymphoma kinase (ALK) inhibitor for patients with ALK rearranged tumours or

  • at least 3 months of approved first-line immunotherapy or combination immunochemotherapy.

• LCT eligible disease, defined as all disease sites amenable to radical treatment (eg, surgery, radiotherapy or ablation)

• Performance status 0 (ie, asymptomatic) or performance status 1 (ie, symptomatic but completely ambulatory) as per Eastern Cooperative Oncology Group definitions. A patient is ineligible if any of the following apply:

A patient is ineligible if any of the following apply:

• Serious concomitant disorder that would compromise patient safety during LCT.

• Complications from initial SACT that precludes maintenance SACT.

• Patient unable/unwilling to adhere to study procedures.

• Patient unable to give written informed consent.

• Women who are pregnant or breast feeding.

• Currently enrolled in another trial if either: an interventional trial that aims to improve survival, not permitted by other trial, would result in too much participant burden.

Patient approach and consent

Potential participants with advanced stage non-small-cell lung cancer (stage IV), who have undergone a course of initial SACT (and restaging as per that of local standard of care), will be identified through review of medical records and at multidisciplinary team (MDT) meetings by staff at the participating hospital site. Patients who meet all eligibility criteria will be introduced to the study by a member of the site research team who will also provide the patient with a copy of the patient information leaflet (PIL) which includes information on the potential risks and benefits of study participation, and any other relevant information. Participants will have the opportunity to ask questions before written informed consent is sought.

Details of all patients approached and reasons for non-participation will be documented. Participants will also be given the option for their data to be stored for potential use in future research and/or training. Participants can withdraw at any time and will be treated according to standard care for their hospital site. Data collected up until the point of withdrawal will be included in the analysis and the participant may give permission for passive data collection (eg, from hospital records) to continue.

Randomisation

Eligibility will be confirmed by the principal investigator or delegated medically qualified clinician at the hospital site. Participants will be randomised after initial SACT, confirmed eligibility, written informed consent given and completion of baseline assessments and data collection, to receive either LCT alongside maintenance treatment (intervention) or maintenance treatment alone (comparator) in a 1:1 ratio. Randomisation will be performed using a secure internet-based randomisation system ensuring allocation concealment. Randomisation will be stratified by centre, type of initial SACT received (molecular targeted treatment, immunotherapy or chemotherapy) and whether solitary brain metastases were treated prior to randomisation.

Blinding

It is not possible to blind participants or the clinical care team to the randomised allocation so the study will be at risk of measurement outcome bias; however, the study has been designed to protect against bias as follows:

• Selection bias will be prevented by allocation concealment. The allocation will not be revealed until sufficient information to uniquely identify the participant has been entered into the randomisation database.

• Performance bias will be minimised by (1) defining the interventions; (2) defining procedures for follow-up; (3) monitoring adherence to the protocol. The PIL and the process of obtaining informed consent will describe the uncertainty about the benefits of LCT versus no LCT in terms of quality and quantity of life. Patient-reported outcomes will be susceptible to bias although we believe that expectations about the alternative care pathways are likely to wane with follow-up.

• Detection bias will be minimised by using an objective primary outcome measure (survival) and by providing clear unambiguous definitions for each of the secondary outcome measures.

• Attrition bias will be minimised by using established methods developed in the Bristol Trials Centre to maximise the quality and completeness of the data, for example, regular monitoring of data, detailed querying of data inbuilt into the study database, offering alternative methods for participating in follow-up (eg, postal, online or telephone if unable to attend in person). Instances of non-adherence will be documented and reviewed at study meetings and an action plan for maximising compliance drawn up as appropriate. Data will be analysed by intention to treat irrespective of future management and events and every effort will be made to include all randomised participants.

• Reporting bias will be minimised by having prespecified outcomes and following a detailed analysis plan which will be prepared in advance of any comparative analyses.

Intervention

The intervention is LCT in the form of surgical resection, radiotherapy and/or ablation with radical intent (aim to improve survival) to all sites of residual disease alongside maintenance SACT, after the completion of initial SACT. The MDT caring for the participant will decide on the most appropriate type and sequence of LCT.

For participants randomised into LCT, the treatment duration is the time required to treat each disease site. As new sites of disease develop, it is expected that all new sites are treated (when feasible). When the disease site exceeds the threshold for continuing radical treatment (as decided by the MDT), the participant will be considered to be in a palliative (maintenance only) pathway and the date for this decision will be recorded.

Comparator

The comparator intervention is usual care of maintenance SACT. No restriction will be placed on the management of the primary or secondary sites of disease for the purposes of palliation of symptoms.

Outcomes

The primary outcome is overall survival defined as the time from randomisation to death from any cause (minimum follow-up 2 years after randomisation for survivors). Secondary outcomes are:

• Disease PFS defined as the time from randomisation to documented disease progression, as evaluated by site radiologist from CT scan or positron emission tomography-CT (PET/CT) scan (eg, CT of the head, chest, abdomen, pelvis and other anatomical sites); bone scan or MRI scan, carried out as part of the participants’ standard care (minimum follow-up 2 years after randomisation for survivors) or death from any cause.

• Serious adverse health events from randomisation to the end of the study (minimum of 2 years).

• Patient reported HRQoL captured using the following measures from randomisation to the end of the study (see table 1 for frequency of questionnaire completion):

  • The European Organisation for Research and Treatment of Cancer’s Quality of Life Questionnaire-C30 (EORTC QLQ-C30).

  • EORTC QLQ-LC13.

  • EQ-5D-5L questionnaire.

Data handling, storage and sharing

Data will be stored in a bespoke-designed database hosted on the NHS network with the exception of HRQoL questionnaire data which will be held on a separate database, hosted on the University of Bristol server. Access to both databases will be via secure password-protected web interfaces. The schedule for data collection is shown in table 1.

All study documentation will be retained in a secure location during the conduct of the study and for 5 years afterwards, when all participant identifiable paper records will be destroyed by confidential means. Data generated from the QRI (eg, audio recordings of consultations and interviews) will be stored indefinitely at the University of Bristol for teaching and training purposes. Transcripts will be labelled with a study-assigned participant number, edited to ensure anonymity of respondents and stored securely adhering to the University of Bristol’s data storage policies. Where trial related information is documented in the medical records, these records will be identified by a label bearing the name and duration of the trial. In compliance with the Medical Research Council Policy on Data Sharing, and with participant agreement, relevant ‘meta’-data about the trial and the full dataset, but without any participant identifiers other than the unique study identifier, will be held indefinitely. These will be retained because of the potential for the raw data to be used subsequently for secondary research and/or training.

Sample size

The study hypothesis is that LCT in addition to maintenance SACT improves overall survival by an absolute 20% at 2 years compared with maintenance SACT alone. The minimum clinically important difference, namely an absolute survival improvement of the order of 20% at 2 years, was chosen by the study’s patient and public involvement (PPI) group and agreed by the Trial Management Group (TMG).

The target sample size of 244 participants, 122 per group, is sufficient to detect an 18% improvement in survival (HR 0.55) with 90% power and a 15% improvement in survival (HR 0.6) with 80% power at 5% statistical significance, both of which are lower than the target 20%. These estimates assume that 2 year survival in patients with advanced lung cancer eligible for immunotherapy is 52%.¹⁵ They are also consistent with the target effect size of the phase 2 trial reported by Gomez et al.⁹ The possibility that survival could be worse with LCT was discussed and therefore a two-tailed test was agreed.

This sample size allows for 5% crossover. Allowance for drop-out has not been included as participant consent will be sought for study centres to determine the survival status for all participants, including any who choose to withdraw from active follow-up, at the end of the study, using summary care records.

Statistical analysis

Analyses will follow Consolidated Standards of Reporting Trials guidelines and will be directed by a prespecified statistical analysis plan. Primary analyses will be performed on an intention-to-treat basis. Analyses will be adjusted for stratification factors (eg, initial SACT and whether solitary brain metastases were treated prior to randomisation) and hospital site where possible.

Survival and progression-free-survival will be compared using survival methods (eg, Cox regression or restricted mean survival time to 2 years if the hazards are non-proportional). Patient-reported HRQoL (EORCT QLQ-C30, QLQ-LC13 and EQ-5D-5L) will be compared using a mixed regression model adjusting for baseline scores. Changes in treatment effect with time will be assessed by adding a time x treatment interaction to the model and comparing models using a likelihood ratio test. For EQ-5D-5L, a score of zero will be imputed after death; for other HRQoL outcomes, death will be accounted for by modelling survival and HRQoL jointly. Model fit will be assessed using standard methods and transformations and/or alternative models will be explored if appropriate. Treatment effects will be reported with 95% CIs. Safety outcomes will be graded using Common Terminology Criteria for Adverse Events criteria and will be described by Medical Dictionary for Regulatory Activities system organ class and preferred term. The proportion of patients experiencing one or more serious adverse events will be compared using a generalised linear model.

Three subgroup analyses of the primary outcome are planned: (1) by initial SACT (molecular targeted treatment, immunotherapy, or chemotherapy), (2) by the number of secondary disease sites, and (3) by the location site of residual disease (brain, visceral, bone, other). Subgroups will be compared by adding a treatment × subgroup interaction to the survival model. To account for non-adherence with the intervention, secondary instrumental variable analyses for the primary outcome will be performed.

Physical and mental health scores collected via the app used in the AQUA lung substudy will be compared with those from the RAMON questionnaire booklet using Bland and Altman plots to estimate limits of agreement. Correlation will be used to compare QLQ-C30 physical functioning and pedometry data collected via the app, and the Kappa statistic will be used to compare agreement between not selecting optional items in the app and reporting zero values in the RAMON questionnaires.

For the economic evaluation, unit costs will be derived from nationally published sources and attached to resource use data, and the total costs per participant calculated. Responses to the EQ-5D-5L will be assigned valuations according to National Institute for Health and Care Excellence guidance at the time of analysis and combined with survival to calculate QALYs gained per participant. Missing resource use and EQ-5D-5L data will be handled using multiple imputation methods.¹⁶ From average costs and QALYs associated with each group, the incremental cost-effectiveness ratio will be derived, producing the incremental cost per QALY gained with LCT compared with conventional care. If there are differences in mortality between groups, then costs and outcomes will be extrapolated to a longer time horizon. Results will be expressed in terms of a cost-effectiveness acceptability curve, which indicates the likelihood that LCT is cost-effective for different levels of willingness to pay for health gain, to help decision-makers assess whether LCT is likely to represent value for money.

Patient and public involvement

Patients have been involved from the inception of the RAMON study. The RAMON funding application was developed in collaboration with the thoracic surgery RESearch cOLlaborative patient and public involVEment group (RESOLVE PPI GROUP) of patients and carers who have undergone surgery for lung cancer, based at Heart of England NHS Foundation Trust. The RESOLVE PPI group advised on trial design, recruitment pathway and choice of the primary outcome. They also defined the minimally important difference in survival to support LCT as a treatment and reviewed the plain English summary of the study.

During the set-up phase of the study, the Bristol Trials Centre Patient Advisory Group (PAG) was consulted to review patient documents as the RESOLVE group did not have a meeting scheduled for a number of months. The PAG gave no major comments and fed back that documents were clear and understandable.

There is an active PPI coapplicant involved in the study who attended planning meetings and helped to draft the study applications. This coapplicant is also a member of the TMG and is consulted on any changes to patient-facing documents, as well as attending regular meetings with other members of the TMG. The RAMON study TSC also includes PPI member(s).

Ethics and dissemination

Ethics approval was obtained from the West of Scotland Research Ethics Committee (22/WS/0121) in August 2022 and the Health Research Authority (HRA) in September 2022. The RAMON study is sponsored by Royal Brompton and Harefield Hospitals, part of Guy’s and St Thomas’ NHS Foundation Trust and is overseen by an independent TSC and independent Data Monitoring and Safety Committee. The study was designed and is being delivered in collaboration with the Bristol Trials Centre, a UKCRC registered Clinical Trials Unit (CTU) which was in receipt of National Institute for Health Research CTU support funding until August 2023. All participants are required to provide written informed consent (included online supplemental material) before participating in the study. Information will be given to patients in advance of recruitment and patients will be given at least 24 hours to consider the study. Consent will be obtained by the principal investigator or a delegated member of the research team who has been trained in the study and completed GCP training in the last 3 years. Consent will be obtained either face-to-face or via post.

The study will be conducted in accordance with Good Clinical Practice guidelines, the Data Protection Act, General Data Protection Regulation UK and the UK Policy Framework for Health and Social Care Research.

The findings will be disseminated by usual academic channels, that is, presentation at international meetings and peer-reviewed publications, as well as through patient organisations and notifications to patients, where available.

Changes to the protocol since REC/HRA approval

Following REC and HRA initial approvals, the only major change to the protocol was an update to the eligibility criteria to allow inclusion of patients who have received radical treatment to solitary brain metastases as this is standard of care for this patient population. There is no evidence base to justify excluding these patients and it was agreed by the TMG and hospital site teams that exclusion criteria as previously written (lung cancer treatment naïve prior to initial study SACT) did not reflect usual care in UK hospitals; therefore, patients who have received this standard of care treatment should be considered for the study.

The current approved protocol version is v5.0 (20 September 2023). A full study protocol is available in the online supplemental material.

The RAMON study is sponsored by Royal Brompton and Harefield Hospitals, part of Guy’s and St Thomas’ NHS Foundation Trust. The sponsor takes responsibility for the quality and conduct of the research study. The authors thank all of the research and clinical team members at participating sites; members of the independent TSC and DMSC; and members of the patient and public involvement group.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

Twitter @NicolaMillsPhD2

Contributors EL is the chief investigator, identified the funding opportunity and codesigned the study. CB set up and manages the day-to-day running of the study and assembled the manuscript from the study protocol. CAR co-designed the study with EL and leads on methodology and statistics for the trial. RH drafted the statistical analysis plan, will prepare reports for the study team and independent oversight committee review and will complete the statistical analysis. NM leads the Quintet Recruitment Intervention within the study. LF has assisted with set up and delivery of the study. EAS is the health economics lead on the study. SB provides senior trial management oversight and advice. TN-D, ME, TBarwick, TBatchelor, JC and PDS provide clinical advice as part of the Trial Management Group. JR is the PPI lead in the trial. All authors were involved in preparation of the study protocol and have read and approved the final manuscript.

Funding This study is funded by the NIHR Health Technology Assessment Programme (project reference NIHR131306).

Competing interests All authors received support from the National Institute for Health and Care Research for the project associated with this manuscript, which was paid to their employing institution. EL reports personal fees from Abbott Molecular, AstraZeneca, Glaxo Smith Kline, Pfizer, Norvatis, Covidien, Roche, Lily Oncology, Boehringer Ingelheim, Medela, Ethicon, and AstraZeneca, and grants from ScreenCell, Clearbridge Biomedics, Illumina, and Guardant Health. PDS reports personal fees from Vitae Professionals. JR reports personal and travel fees from NCRI Lung Advanced disease subgroup, ELF lung cancer patient advisory group, BTOG, Clinical expert group lung cancer, WM Cancer Alliance lung cancer and mesothelioma EAG (as a patient representative). TND reports personal fees from AstraZenca, BMS, Boehringer Ingelheim, Lilly, MSD, Otsuka, Roche, Takeda, BMS, Eli-Lilly, Novartis, and Pfizer.

Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

Provenance and peer review Not commissioned; peer reviewed for ethical and funding approval prior to submission.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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