VICTORION-Spirit: Phase IIIb, multicentre, randomised controlled study to evaluate the implementation of inclisiran sodium in participants with, or at risk of, Atherosclerotic Cardiovascular Disease and elevated Low Density Lipoprotein Cholesterol using a vaccine model in an NHS primary care setting

The primary objective of this study is to demonstrate superiority of inclisiran +/- behavioural support compared to the patient’s usual lipid lowering drugs + behavioural support in a primary care setting (i.e. the 3 groups of patients described in point 1 above), in reducing the percentage change in LDL-C from baseline to Day 270 in adults with elevated LDL-C.

The secondary objectives of this study are to evaluate user satisfaction/experience and process evaluation for the 3 groups of patients by means of:

- Validated questionnaires to measure patient satisfaction, patient activation and empowerment, and patient adherence to cardiovascular disease self-management

- A process evaluation conducted using the Consolidated Framework for Implementation Research (CFIR) which will explore inclisiran delivery at three levels

- Feasibility and acceptability of delivery models for inclisiran to patients

- Feasibility and acceptability of delivery models for inclisiran to providers

- Wider use of the proposed delivery models across the NHS (outer setting)

- The service costs of each delivery model

- The acceptability and perceived sustainability of patient identification and referral routes

- Serious adverse event profile

NB. Patient activation is a measure of a person's knowledge, skills, and confidence to manage their own health and wellbeing. Patient empowerment is a process through which people gain greater control over decisions and actions affecting their health.

The exploratory objectives of this study are to compare the 3 groups of patients on the following assessments:

- Total lipid profile (total cholesterol, HDL-C, triglycerides), blood pressure, weight, BMI from baseline to end of study visit.

- Healthcare resource utilisation during the period of the study taken from the primary and secondary care EMR e.g. number of outpatient visits, number of hospital admissions, number of A&E visits, number of primary care visits.

- Assessments of treatment simplicity, resources used for treatment, and treatment impact will be made from bespoke questionnaires based on standard questionnaires used in the assessment of diabetes treatments.

Secondary care data from HES is crucial for the complete analysis of the service costs of each model, Healthcare Resource Utilisation (HRU) analysis, and serious adverse event profile for all patients participating in the study.

The project is now complete. Novartis Pharmaceuticals UK Limited would like to retain this Data to ensure reconstruction of the study analysis is possible if required.

No additional data will be requested from NHS England.

This Data Sharing Agreement (DSA) permits processing of the Data for the purpose of secure storage and back up.

This DSA does not permit any further processing that involves analysis or linkage other than for the purpose of verifying findings in line with the original objectives of the study by repeating previous analyses described in this DSA.

Following publication of the study findings, it is possible that the findings will be questioned or challenged by third parties through direct contact with Novartis Pharmaceuticals UK Limited, contact via the publishing journal or an open letter. In such circumstances, Novartis Pharmaceuticals UK Limited may repeat the previously analyses undertaken to verify that the published results were accurate and may write a response to be issued directly to the challenger or published.

Novartis Pharmaceuticals UK Limited may not undertake different analyses to those undertaken during the original analysis.

This DSA does not permit any onward sharing of the Data.

This DSA permits the necessary processing of the Data for the purposes of permanently destroying, deleting or erasing the Data once it is no longer required for the purpose for which it was collected. Once destroyed/deleted or erased, Novartis Pharmaceuticals UK Limited must confirm destruction to NHS England.

If any further data processing is required in addition to the above purposes or if the data needs to be moved to a different location/organisation Novartis Pharmaceuticals UK Limited must submit an Amendment request to NHS England before Data is accessed.

Data from the following NHS England Data will be retained:

- Emergency Care Data Set (ECDS)

- Hospital Episode Statistics (HES) Outpatients (OP)

- HES Admitted Patient Care (APC)

- HES Accident & Emergency (A&E)

The level of the Data being retained will be identifiable. Although the data fields requested are pseudonymised, NWEH hold the personal identifiers for the cohort, and therefore, though no attempt will be made to identify participants, NWEH have the technical ability to identify participants.

The data was minimised as follows:

- Limited to participating patients based on basic demographics (e.g. month and year of birth – to cross reference to primary care data), appointments/attendance/admissions/discharges/periods of care, treatment, diagnoses, and healthcare resource groups. A significant number of events for patients with ASCVD which occur in secondary care are not coded in primary care. These data are required for the calculation of HRU; without secondary care data the full HRU analysis could not be performed. All participating patients have given informed consent.

- The population of 300 patients per arm of the study was chosen as this is the sample size necessary to detect statistically significant differences in outcomes between the three groups.

- Study participants are aged 18 years or older. To apply any further age restriction would undermine the real-world principles of the study.

Data from 5 years prior to enrolment on the study and up to the end of the study is sought to allow a meaningful comparison of pre- and post-enrolment HRU. ECDS does not contain data for the full 5 years, so data from the HES A&E data set is being requested to provide this.

Only basic demographics (e.g. month and year of birth – to cross reference to primary care data), attendance, treatment, diagnoses, investigations, and conditions have been requested. The full range of these data are necessary for a complete HRU analysis.

- Only data for the period 5 years prior to the patient’s date of consent and throughout the course of the study will be required. The first patient was recruited onto the study in July 2021, so HES data sets back to 2016/17 have been selected in this application to accommodate this (i.e. back to at least July 2016). Date of consent will be provided to NHS England, only 5-years of ‘pre-consent’ data for each patient can be delivered. This option is requested in the interest of further data minimisation.

- The patients consented onto the study are from the Greater Manchester (GM) area and are registered with GPs in that area. Secondary care data is, therefore, likely to come from GM hospitals but could come from hospitals in other areas if, for example, patients had unscheduled visits while travelling or had to attend specialist clinics outside GM. Part of the rationale of using patient’s electronic records in a Real-World study such as this is to minimise interaction with patients and reduce any intrusion. No further reduction in the data requested can be made based on geography.

Novartis Pharmaceuticals UK Ltd is the research sponsor and the Controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(f) - processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party.

Novartis Pharmaceuticals UK Ltd has determined the processing is necessary for its legitimate interests in trying to understand the safety

and efficacy of medicines in development.

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

The funding is provided by Novartis Pharmaceuticals UK Ltd.

There is an ongoing collaboration between Novartis and NHS England to improve lipid management in England. The funding for this study is coming from a budget agreed between Novartis and NHSE as part of the collaboration. For regulatory purposes Novartis is the study sponsor and responsible for setting the objectives and the conduct of the study. NHSE had no responsibility or accountability in the development of the study protocol and have had no involvement in the conduct of the study. However, as collaborators NHS E will receive outputs of the study ((e.g., publications, clinical study report and process evaluation reports)” and are disseminated data under Health and Social Care Act 2012 – s261(2)(c).

NorthWest EHealth Limited (NWEH) is a processor acting under the instructions of Novartis Pharmaceuticals UK Ltd. NWEH's role is limited to linking data from the eCRF, HES, and GP systems and delivering it to Novartis in a format specified by Novartis for them to perform their own analysis.

Microsoft Limited provides IT hosting services to NWEH and will store the data as contracted by NWEH.

Restore PLC provides IT back up services and will store copies of the data.

Wellbeing provides a 3rd party primary care data extraction service which extracts data from GP EMR systems and delivers it to NWEH. It does not process the GP data in any other way and will not process the data requested from NHS England in any way whatsoever.

Novartis are a pharmaceutical company who have an interest in developing therapies for treating and preventing coronary heart disease. Novartis are interested in understanding how best to deliver their proven therapy for lowering LDL-C in a way that increases uptake and improves public health. Access to primary care data from GP EMR systems and secondary care data from HES data sets will allow for a full statistical analysis of HRU. This analysis will a) inform the evaluation of the superiority of inclisiran when delivered using the described model and, hence, support the primary objective of the study, and b) allow evaluation of the service costs of each delivery model and, hence, support this aspect of the secondary objectives of the study.

There are several planned reports and publications from this study. The planned activities are outlined below:

- Documents shared by Novartis with NHS England and Academic Health Science Networks (AHSNs) - textual reports with no patient details

- Patient report #1: report on number of patients meeting broad ‘at risk’ criteria who may be eligible for treatment with inclisiran in the study. Completed January 2022

- Process evaluation #1: early insights report based on feed-back from commissioners, patients, and healthcare professionals. Completed January 2022

- Patient report #2: report on number of patients who meet the full inclusion criteria (i.e. are eligible for inclisiran in the study). Completed June 2022

(Note: the above reports haven't used NHS England data, but they do feed into the research as they add background to the research).

- Process evaluation #2: in-depth report based on feed-back from commissioners, patients, and healthcare professionals.

- Full Clinical Study Report: inclisiran efficacy, patient reported outcomes, safety outcomes, patient demographics, process evaluation summary, and HRU (cost) analysis across the delivery methods

- Peer reviewed publications - aggregate data with small numbers suppressed

- Patient Identification and SNOMED codes / national case findings. Submission to Cardiovascular Research

- Study Methodology publication. Submission to British Medical Journal Open

- Patient engagement: Prior to commencement of the trial a patient focus group was set up by NWEH (on behalf of Novartis) to involve patients at the development stage of the process, to help improve and inform the study, as well as providing an opportunity to gain a better understanding of the patient’s needs. In addition, it offered a chance for the protocol to be tested, issues to be identified, and problems to be resolved before a study opened for recruitment. The study concluded overwhelmingly that participants had a positive opinion about the study. In fact, all those interviewed stated they would be interested in taking part in the study if they were offered the opportunity. When discussed with the researcher, the vaccine like model was perceived as a good alternative to their current medications. From questioning, no participants had any major concerns regarding the study design or the drug administration. Novartis will also be sending participants a summary of findings at the conclusion of the study to keep study participants up to date with the study outcomes.

- Data output: Northwest EHealth will produce a dataset of linked data from the eCRF, GP EMR systems, and the HES datasets. This data will be transformed into the standard format required for submission to regulatory authorities for analysis by Novartis. The data will be patient level and pseudonymised but Novartis will not have access to the pseudonymization key or identifiers and cannot re-identify the patients (see ‘Linked data’ under ‘Processing Activities’). This linked data is necessary for the subsequent production of the Full Clinical Report by Novartis (including HRU analysis) for dissemination to NHS England.

To date, three outputs from the SPIRIT program have been published, including two in peer-reviewed journals and one poster at the British Cardiovascular Society.

Findings have been used so far to better understand POCT (point of care testing) and its limitations in trials and routine clinical practice. The use of routine clinical data for trial data capture also produced learnings for the broader health and social care ecosystem.

Background

Elevated low-density lipoprotein associated cholesterol (LDL-C), is one of the major risk factors for coronary heart disease (CHD). Despite advances in treatment, atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability worldwide. Despite the proven efficacy of statins, there is still a considerable variability in individuals to these drugs, even when being treated with a high intensity regime. Furthermore, not all people tolerate statins or are able to take statins at sufficient intensive doses. Therefore, there is a clear unmet medical need for additional options beyond current available oral treatments for the lowering of LDL-C.

Inclisiran is a medicine used to lower LDL-C. Raised LDL-C is generally accepted to be an independent risk factor for the development and progression of atherosclerotic cardiovascular disease. Novartis Pharmaceuticals UK Limited holds the UK marketing authorisation for Inclisiran and there is a collaboration agreement in place between Novartis and NHS England. In accordance with the collaboration agreement, it is aimed that 300,000 patients with raised LDL-C will be prescribed Inclisiran over three years so they may benefit from its LDL-C lowering effects. The SPIRIT study, sponsored and funded by Novartis, will inform the national roll out of Inclisiran within a UK primary care setting. While Novartis could benefit financially if Inclisiran is widely prescribed within the NHS, it is expected that this large number of patients will derive benefit in terms of LDL-C reduction.

Inclisiran is a treatment for elevated low-density lipoprotein associated cholesterol and can be given in primary care settings as a twice-yearly injection to people with high cholesterol who have already had a previous cardiovascular event to reduce the chances of them having another. It can be used on its own or alongside statins or other cholesterol lowering drugs. Inclisiran works in a new way. It is the first of a new type of cholesterol-lowering treatment which uses ribonucleic acid (RNA) interference (RNAi) to boost the liver’s ability to remove harmful cholesterol from the blood. Ribonucleic acid is a nucleic acid present in all living cells. RNAi refers to a phenomenon where small pieces of RNA can shut down protein translation by binding to and causing the destruction of messenger RNAs that code for those proteins.

The efficacy of inclisiran has already been evaluated in three phase III studies (ORION-9, -10, and -11; conducted between November 2017 and September 2019 by The Medicines Company, which was subsequently acquired by Novartis Pharmaceuticals) in patients with ASCVD or ASCVD risk equivalents (e.g. type 2 diabetes mellitus) and/or familial hypercholesterolaemia. These preliminary observations are consistent with the general concept that however LDL-C is lowered, it is thought to result in reduced risk of future cardiovascular events. The overall safety and tolerability profile was generally similar between the inclisiran and placebo groups.

However, it is acknowledged that randomised clinical trials, by definition, are highly controlled and enrol a more select patient population than is expected to be prescribed the medicine post-approval. The impact of a new treatment on patient healthcare seeking behaviour and utilisation of local healthcare services is hard to measure from clinical studies with their own schedule of defined visits and procedures, whereby the clinician and patient are following a prescriptive protocol rather than the usual clinical practice. This study seeks to study the effectiveness of inclisiran in a real-world setting, rather than just the efficacy as measured in the previous phase III studies.

Study Design

This is an implementation research study, the aim of which is to evaluate the practicality and acceptability of administering inclisiran subcutaneously (via injection) in GP practices (in a vaccine-like programme) to consenting participants who have elevated LDL-C and are on established lipid lowering medication or have been recommended lipid lowering therapy by their healthcare provider but are unable to tolerate treatment. 889 participants were randomised onto the trial between July 2021 and March 2022 within the Greater Manchester Area. Recruitment is complete. Participants are split evenly per treatment group into the 3 groups described below at up to 30 primary care centres will be recruited.

For clarity, implementation research is commonly defined as the study of methods and strategies to promote the uptake of interventions that have proven effective into routine practice, with the aim of improving population health; how to organise, deliver and maintain an innovative treatment for ASCVD in a primary care setting in a sustainable way. Implementation research seeks to understand and work within real world conditions and is especially concerned with the users of the research and not purely the production of knowledge. In the case of this study, the users are patients and healthcare providers who are, respectively, receiving and administering inclisiran (or managing the administration thereof) within GP practices.

The study is based on the following principles:

- It is run in the setting where inclisiran is intended to be implemented in clinical practice, with the intention of understanding the effects of innovations within the real-world conditions of everyday clinical practice

- Inclusion / exclusion criteria reflect the patient population for whom inclisiran is intended to be used, rather than selecting patients who are suitable for a standard clinical trial

- Health delivery context: taking account of institutional and health system contexts – including the viewpoints of various stakeholder including commissioners, system managers and clinicians

This study will be conducted using North West E Health’s (NWEH’s) ConneXon clinical trials platform which integrates patient level electronic healthcare record data from primary care, secondary care, and national data sources, to support the integration of ‘real-world evidence’ from individually consented participants. ConneXon has been validated for use in clinical studies.

Most of the study data will be extracted directly from the patient electronic medical record (EMR) in order to minimise direct participant contact and maximise the outcomes of interest related to implementation (patients consent to data from their GP and hospital records to be collected). Some study specific data not routinely collected will also be reported by the investigator or delegate in an integrated Electronic Case Report Form (e-CRF) for accuracy and in compliance with regulatory standards.

The study is divided into three elements:

1. A prospective phase IIIb intervention with 3 groups of patients:

a. Group 1: Participants will continue to receive their existing lipid lowering therapy plus behavioural support

b. Group 2: Participants will continue to receive their existing lipid lowering therapy, plus inclisiran injection

c. Group 3: Participants will continue to receive their existing lipid lowering therapy, plus inclisiran injection, plus behavioural support. (Behavioural support consists of a regular support telephone call to motivate patients to make effective choices for self-management including behavioural change, goal setting, and empowerment)

2. An observational data assessment utilising the EMR held in primary and secondary care, and analysing data collected within these records during normal clinical practice to examine ongoing healthcare resource utilisation (HRU) and outcomes in the patient cohort

3. A process evaluation that will ascertain the views of patients and healthcare providers about the service they have received or provided and its potential for wider use across the NHS

Objective for Processing

The primary objective of this study is to demonstrate superiority of inclisiran +/- behavioural support compared to the patient’s usual lipid lowering drugs + behavioural support in a primary care setting (i.e. the 3 groups of patients described in point 1 above), in reducing the percentage change in LDL-C from baseline to Day 270 in adults with elevated LDL-C.

The secondary objectives of this study are to evaluate user satisfaction/experience and process evaluation for the 3 groups of patients by means of:

- Validated questionnaires to measure patient satisfaction, patient activation and empowerment, and patient adherence to cardiovascular disease self-management

- A process evaluation conducted using the Consolidated Framework for Implementation Research (CFIR) which will explore inclisiran delivery at three levels

- Feasibility and acceptability of delivery models for inclisiran to patients

- Feasibility and acceptability of delivery models for inclisiran to providers

- Wider use of the proposed delivery models across the NHS (outer setting)

- The service costs of each delivery model

- The acceptability and perceived sustainability of patient identification and referral routes

- Serious adverse event profile

NB. Patient activation is a measure of a person's knowledge, skills, and confidence to manage their own health and wellbeing. Patient empowerment is a process through which people gain greater control over decisions and actions affecting their health.

The exploratory objectives of this study are to compare the 3 groups of patients on the following assessments:

- Total lipid profile (total cholesterol, HDL-C, triglycerides), blood pressure, weight, BMI from baseline to end of study visit.

- Healthcare resource utilisation during the period of the study taken from the primary and secondary care EMR e.g. number of outpatient visits, number of hospital admissions, number of A&E visits, number of primary care visits.

- Assessments of treatment simplicity, resources used for treatment, and treatment impact will be made from bespoke questionnaires based on standard questionnaires used in the assessment of diabetes treatments.

Secondary care data from HES is crucial for the complete analysis of the service costs of each model, Healthcare Resource Utilisation (HRU) analysis, and serious adverse event profile for all patients participating in the study.

Legal Bases

Processing of the data is justified under the following UK GDPR Articles:

9(2)(j)– Scientific research. Also, improvement in public health due to increased uptake of inclisiran is in the public interest

6(1)(f) – It is a legitimate interest of Novartis to investigate means of most effectively delivering a proven therapy. The outcome of a Legitimate Interest Assessment conducted by Novartis: The processing may be within the public interest, as it assists with achieving the clinical study aim of providing new and innovative medicines to patients and improving population health. All parties involved in the processing have an interest in this aim.

Novartis are a pharmaceutical company who have an interest in developing therapies for treating and preventing coronary heart disease. Novartis are interested in understanding how best to deliver their proven therapy for lowering LDL-C in a way that increases uptake and improves public health. Access to primary care data from GP EMR systems and secondary care data from HES data sets will allow for a full statistical analysis of HRU. This analysis will a) inform the evaluation of the superiority of inclisiran when delivered using the described model and, hence, support the primary objective of the study, and b) allow evaluation of the service costs of each delivery model and, hence, support this aspect of the secondary objectives of the study.

All participating patients have given informed consent and the study has been approved by an independent Research Ethics Committee. This study does not present any harm to the public.

Data Requested

Emergency Care DataSet (ECDS), Hospital Episode Statistics (HES) Outpatients, Admitted Patient Care, and A+E data is requested so that the patient’s journey across the whole secondary care setting can be analysed. This information, along with primary care data from GPs, will be used to compare the total primary and secondary healthcare resources used by the three patient cohorts and establish if inclisiran and/or behavioural support reduces HRU.

Record level data is required, but no identifiable or sensitive data are being requested. The data requested is minimised to only that of participating patients based on basic demographics (e.g. month and year of birth – to cross reference to primary care data), appointments/attendance/admissions/discharges/periods of care, treatment, diagnoses, and healthcare resource groups. A significant number of events for patients with ASCVD which occur in secondary care are not coded in primary care. These data are required for the calculation of HRU; without secondary care data the full HRU analysis could not be performed.

To address the UK GDPR principle of minimisation, only data for the period 5 years prior to the patient’s date of consent and throughout the course of the study will be required. The first patient was recruited onto the study in July 2021, so HES data sets back to 2016/17 have been selected in this application to accommodate this (i.e. back to at least July 2016). Date of consent will be provided to NHS England, only 5-years of ‘pre-consent’ data for each patient can be delivered. This option is requested in the interest of further data minimisation.

Only pseudonymised data is being sought from NHS England, although NWEH supply NHS England with NHS number and date of birth to allow the correct patient cohort to be identified. No sensitive data is requested.

The population of 300 patients per arm of the study was chosen as this is the sample size necessary to detect statistically significant differences in outcomes between the three groups.

The geography of the study is already restricted to the Greater Manchester area. No further reduction in the data requested can be made based on geography.

Study participants are aged 18 years or older. To apply any further age restriction would undermine the real-world principles of the study.

Data from 5 years prior to enrolment on the study and up to the end of the study is sought to allow a meaningful comparison of pre- and post-enrolment HRU. ECDS does not contain data for the full 5 years, so data from the HES A&E data set is being requested to provide this.

Only basic demographics (e.g. month and year of birth – to cross reference to primary care data), attendance, treatment, diagnoses, investigations, and conditions have been requested. The full range of these data are necessary for a complete HRU analysis.

The patients consented onto the study are from the Greater Manchester (GM) area and are registered with GPs in that area. Secondary care data is, therefore, likely to come from GM hospitals but could come from hospitals in other areas if, for example, patients had unscheduled visits while travelling or had to attend specialist clinics outside GM. Part of the rationale of using patient’s electronic records in a Real-World study such as this is to minimise interaction with patients and reduce any intrusion.

Organisations involved and their roles:

Novartis Pharmaceuticals UK Ltd

- Study Sponsor/funding body

- Data Controller

- Data Processor

NorthWest EHealth Limited (NWEH)*

- Data Processor

Northern Care Alliance NHS Foundation Trust (NCA)

- Data Processor

- Provide Azure cloud hosting service for NWEH

Microsoft Limited

- Data Processor

- Provide Azure cloud from NCA

Restore PLC

- Used for data storage / archiving

Wellbeing Ltd**

- Data Processor

NHS England (NHSE)

- There is an ongoing collaboration between Novartis and NHSE to improve lipid management in England. The funding for this study is coming from a budget agreed between Novartis and NHSE as part of the collaboration. For regulatory purposes Novartis is the study sponsor and responsible for setting the objectives and the conduct of the study. NHSE had no responsibility or accountability in the development of the study protocol and have had no involvement in the conduct of the study. However, as collaborators NHS E will receive outputs of the study ((e.g., publications, clinical study report and process evaluation reports)” and are disseminated data under Health and Social Care Act 2012 – s261(2)(c).

*NWEH is wholly directed by Novartis on all aspects of data processing. The eCRF was developed by NWEH based on Novartis' study protocol. The data requested from NHS England and from GPs was that which will allow the objectives of the protocol to be fulfilled. NWEH will link data from the eCRF, HES, and GP systems and deliver it to Novartis in a format specified by Novartis for them to perform their own analysis.

**Wellbeing provides a 3rd party primary care data extraction service which extracts data from GP EMR systems and delivers it to NWEH. It does not process the GP data in any other way and will not process the data requested from NHS England in any way whatsoever.

There are several planned reports and publications from this study. The planned activities are outlined below:

- Documents shared by Novartis with NHS England and Academic Health Science Networks (AHSNs) - textual reports with no patient details

- Patient report #1: report on number of patients meeting broad ‘at risk’ criteria who may be eligible for treatment with inclisiran in the study. Completed January 2022

- Process evaluation #1: early insights report based on feed-back from commissioners, patients, and healthcare professionals. Completed January 2022

- Patient report #2: report on number of patients who meet the full inclusion criteria (i.e. are eligible for inclisiran in the study). Completed June 2022

(Note: the above reports haven't used NHS England data, but they do feed into the research as they add background to the research).

- Process evaluation #2: in-depth report based on feed-back from commissioners, patients, and healthcare professionals. Estimated Q2 2023

- Full Clinical Study Report: inclisiran efficacy, patient reported outcomes, safety outcomes, patient demographics, process evaluation summary, and HRU (cost) analysis across the delivery methods

- Peer reviewed publications - aggregate data with small numbers suppressed

- Patient Identification and SNOMED codes / national case findings. Submission to Cardiovascular Research estimated May 2023

- Study Methodology publication. Submission to British Medical Journal Open estimated May 2023

- Patient engagement: Prior to commencement of the trial a patient focus group was set up by NWEH (on behalf of Novartis) to involve patients at the development stage of the process, to help improve and inform the study, as well as providing an opportunity to gain a better understanding of the patient’s needs. In addition, it offered a chance for the protocol to be tested, issues to be identified, and problems to be resolved before a study opened for recruitment. The study concluded overwhelmingly that participants had a positive opinion about the study. In fact, all those interviewed stated they would be interested in taking part in the study if they were offered the opportunity. When discussed with the researcher, the vaccine like model was perceived as a good alternative to their current medications. From questioning, no participants had any major concerns regarding the study design or the drug administration. Novartis will also be sending participants a summary of findings at the conclusion of the study to keep study participants up to date with the study outcomes.

- Data output: Northwest EHealth will produce a dataset of linked data from the eCRF, GP EMR systems, and the HES datasets. This data will be transformed into the standard format required for submission to regulatory authorities for analysis by Novartis. The data will be patient level and pseudonymised but Novartis will not have access to the pseudonymization key or identifiers and cannot re-identify the patients (see ‘Linked data’ under ‘Processing Activities’). This linked data is necessary for the subsequent production of the Full Clinical Report by Novartis (including HRU analysis) for dissemination to NHS England.

Data has not yet flowed from NHS England, therefore analysis has not started and there are no yielded benefits.

Background

Elevated low-density lipoprotein associated cholesterol (LDL-C), is one of the major risk factors for coronary heart disease (CHD). Despite advances in treatment, atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability worldwide. Despite the proven efficacy of statins, there is still a considerable variability in individuals to these drugs, even when being treated with a high intensity regime. Furthermore, not all people tolerate statins or are able to take statins at sufficient intensive doses. Therefore, there is a clear unmet medical need for additional options beyond current available oral treatments for the lowering of LDL-C.

Inclisiran is a medicine used to lower LDL-C. Raised LDL-C is generally accepted to be an independent risk factor for the development and progression of atherosclerotic cardiovascular disease. Novartis Pharmaceuticals UK Limited holds the UK marketing authorisation for Inclisiran and there is a collaboration agreement in place between Novartis and NHS England. In accordance with the collaboration agreement, it is aimed that 300,000 patients with raised LDL-C will be prescribed Inclisiran over three years so they may benefit from its LDL-C lowering effects. The SPIRIT study, sponsored and funded by Novartis, will inform the national roll out of Inclisiran within a UK primary care setting. While Novartis could benefit financially if Inclisiran is widely prescribed within the NHS, it is expected that this large number of patients will derive benefit in terms of LDL-C reduction.

Inclisiran is a treatment for elevated low-density lipoprotein associated cholesterol and can be given in primary care settings as a twice-yearly injection to people with high cholesterol who have already had a previous cardiovascular event to reduce the chances of them having another. It can be used on its own or alongside statins or other cholesterol lowering drugs. Inclisiran works in a new way. It is the first of a new type of cholesterol-lowering treatment which uses ribonucleic acid (RNA) interference (RNAi) to boost the liver’s ability to remove harmful cholesterol from the blood. Ribonucleic acid is a nucleic acid present in all living cells. RNAi refers to a phenomenon where small pieces of RNA can shut down protein translation by binding to and causing the destruction of messenger RNAs that code for those proteins.

The efficacy of inclisiran has already been evaluated in three phase III studies (ORION-9, -10, and -11; conducted between November 2017 and September 2019 by The Medicines Company, which was subsequently acquired by Novartis Pharmaceuticals) in patients with ASCVD or ASCVD risk equivalents (e.g. type 2 diabetes mellitus) and/or familial hypercholesterolaemia. These preliminary observations are consistent with the general concept that however LDL-C is lowered, it is thought to result in reduced risk of future cardiovascular events. The overall safety and tolerability profile was generally similar between the inclisiran and placebo groups.

However, it is acknowledged that randomised clinical trials, by definition, are highly controlled and enrol a more select patient population than is expected to be prescribed the medicine post-approval. The impact of a new treatment on patient healthcare seeking behaviour and utilisation of local healthcare services is hard to measure from clinical studies with their own schedule of defined visits and procedures, whereby the clinician and patient are following a prescriptive protocol rather than the usual clinical practice. This study seeks to study the effectiveness of inclisiran in a real-world setting, rather than just the efficacy as measured in the previous phase III studies.

Study Design

This is an implementation research study, the aim of which is to evaluate the practicality and acceptability of administering inclisiran subcutaneously (via injection) in GP practices (in a vaccine-like programme) to consenting participants who have elevated LDL-C and are on established lipid lowering medication or have been recommended lipid lowering therapy by their healthcare provider but are unable to tolerate treatment. 805 participants were randomised onto the trial between July 2021 and March 2022 within the Greater Manchester Area. Recruitment is complete. Participants are split evenly per treatment group into the 3 groups described below at up to 30 primary care centres will be recruited.

For clarity, implementation research is commonly defined as the study of methods and strategies to promote the uptake of interventions that have proven effective into routine practice, with the aim of improving population health; how to organise, deliver and maintain an innovative treatment for ASCVD in a primary care setting in a sustainable way. Implementation research seeks to understand and work within real world conditions and is especially concerned with the users of the research and not purely the production of knowledge. In the case of this study, the users are patients and healthcare providers who are, respectively, receiving and administering inclisiran (or managing the administration thereof) within GP practices.

The study is based on the following principles:

- It is run in the setting where inclisiran is intended to be implemented in clinical practice, with the intention of understanding the effects of innovations within the real-world conditions of everyday clinical practice

- Inclusion / exclusion criteria reflect the patient population for whom inclisiran is intended to be used, rather than selecting patients who are suitable for a standard clinical trial

- Health delivery context: taking account of institutional and health system contexts – including the viewpoints of various stakeholder including commissioners, system managers and clinicians

This study will be conducted using North West E Health’s (NWEH’s) ConneXon clinical trials platform which integrates patient level electronic healthcare record data from primary care, secondary care, and national data sources, to support the integration of ‘real-world evidence’ from individually consented participants. ConneXon has been validated for use in clinical studies.

Most of the study data will be extracted directly from the patient electronic medical record (EMR) in order to minimise direct participant contact and maximise the outcomes of interest related to implementation (patients consent to data from their GP and hospital records to be collected). Some study specific data not routinely collected will also be reported by the investigator or delegate in an integrated Electronic Case Report Form (e-CRF) for accuracy and in compliance with regulatory standards.

The study is divided into three elements:

1. A prospective phase IIIb intervention with 3 groups of patients:

a. Group 1: Participants will continue to receive their existing lipid lowering therapy plus behavioural support

b. Group 2: Participants will continue to receive their existing lipid lowering therapy, plus inclisiran injection

c. Group 3: Participants will continue to receive their existing lipid lowering therapy, plus inclisiran injection, plus behavioural support. (Behavioural support consists of a regular support telephone call to motivate patients to make effective choices for self-management including behavioural change, goal setting, and empowerment)

2. An observational data assessment utilising the EMR held in primary and secondary care, and analysing data collected within these records during normal clinical practice to examine ongoing healthcare resource utilisation (HRU) and outcomes in the patient cohort

3. A process evaluation that will ascertain the views of patients and healthcare providers about the service they have received or provided and its potential for wider use across the NHS

Objective for Processing

The primary objective of this study is to demonstrate superiority of inclisiran +/- behavioural support compared to the patient’s usual lipid lowering drugs + behavioural support in a primary care setting (i.e. the 3 groups of patients described in point 1 above), in reducing the percentage change in LDL-C from baseline to Day 270 in adults with elevated LDL-C.

The secondary objectives of this study are to evaluate user satisfaction/experience and process evaluation for the 3 groups of patients by means of:

- Validated questionnaires to measure patient satisfaction, patient activation and empowerment, and patient adherence to cardiovascular disease self-management

- A process evaluation conducted using the Consolidated Framework for Implementation Research (CFIR) which will explore inclisiran delivery at three levels

- Feasibility and acceptability of delivery models for inclisiran to patients

- Feasibility and acceptability of delivery models for inclisiran to providers

- Wider use of the proposed delivery models across the NHS (outer setting)

- The service costs of each delivery model

- The acceptability and perceived sustainability of patient identification and referral routes

- Serious adverse event profile

NB. Patient activation is a measure of a person's knowledge, skills, and confidence to manage their own health and wellbeing. Patient empowerment is a process through which people gain greater control over decisions and actions affecting their health.

The exploratory objectives of this study are to compare the 3 groups of patients on the following assessments:

- Total lipid profile (total cholesterol, HDL-C, triglycerides), blood pressure, weight, BMI from baseline to end of study visit.

- Healthcare resource utilisation during the period of the study taken from the primary and secondary care EMR e.g. number of outpatient visits, number of hospital admissions, number of A&E visits, number of primary care visits.

- Assessments of treatment simplicity, resources used for treatment, and treatment impact will be made from bespoke questionnaires based on standard questionnaires used in the assessment of diabetes treatments.

Secondary care data from HES is crucial for the complete analysis of the service costs of each model, Healthcare Resource Utilisation (HRU) analysis, and serious adverse event profile for all patients participating in the study.

Legal Bases

Processing of the data is justified under the following UK GDPR Articles:

9(2)(j)– Scientific research. Also, improvement in public health due to increased uptake of inclisiran is in the public interest

6(1)(f) – It is a legitimate interest of Novartis to investigate means of most effectively delivering a proven therapy. The outcome of a Legitimate Interest Assessment conducted by Novartis: The processing may be within the public interest, as it assists with achieving the clinical study aim of providing new and innovative medicines to patients and improving population health. All parties involved in the processing have an interest in this aim.

Novartis are a pharmaceutical company who have an interest in developing therapies for treating and preventing coronary heart disease. Novartis are interested in understanding how best to deliver their proven therapy for lowering LDL-C in a way that increases uptake and improves public health. Access to primary care data from GP EMR systems and secondary care data from HES data sets will allow for a full statistical analysis of HRU. This analysis will a) inform the evaluation of the superiority of inclisiran when delivered using the described model and, hence, support the primary objective of the study, and b) allow evaluation of the service costs of each delivery model and, hence, support this aspect of the secondary objectives of the study.

All participating patients have given informed consent and the study has been approved by an independent Research Ethics Committee. This study does not present any harm to the public.

Data Requested

Emergency Care DataSet (ECDS), Hospital Episode Statistics (HES) Outpatients, Admitted Patient Care, and A+E data is requested so that the patient’s journey across the whole secondary care setting can be analysed. This information, along with primary care data from GPs, will be used to compare the total primary and secondary healthcare resources used by the three patient cohorts and establish if inclisiran and/or behavioural support reduces HRU.

Record level data is required, but no identifiable or sensitive data are being requested. The data requested is minimised to only that of participating patients based on basic demographics (e.g. month and year of birth – to cross reference to primary care data), appointments/attendance/admissions/discharges/periods of care, treatment, diagnoses, and healthcare resource groups. A significant number of events for patients with ASCVD which occur in secondary care are not coded in primary care. These data are required for the calculation of HRU; without secondary care data the full HRU analysis could not be performed.

To address the UK GDPR principle of minimisation, only data for the period 5 years prior to the patient’s date of consent and throughout the course of the study (i.e. up to the end of December 2022) will be required. The first patient was recruited onto the study in July 2021, so HES data sets back to 2016/17 have been selected in this application to accommodate this (i.e. back to at least July 2016). Date of consent will be provided to NHS Digital, only 5-years of ‘pre-consent’ data for each patient can be delivered. This option is requested in the interest of further data minimisation.

Only pseudonymised data is being sought from NHS Digital, although NWEH supply NHS Digital with NHS number and date of birth to allow the correct patient cohort to be identified. No sensitive data is requested.

The population of 300 patients per arm of the study was chosen as this is the sample size necessary to detect statistically significant differences in outcomes between the three groups.

The geography of the study is already restricted to the Greater Manchester area. No further reduction in the data requested can be made based on geography.

Study participants are aged 18 years or older. To apply any further age restriction would undermine the real-world principles of the study.

Data from 5 years prior to enrolment on the study and up to the end of the study (end December 2022) is sought to allow a meaningful comparison of pre- and post-enrolment HRU. ECDS does not contain data for the full 5 years, so data from the HES A&E data set is being requested to provide this.

Only basic demographics (e.g. month and year of birth – to cross reference to primary care data), attendance, treatment, diagnoses, investigations, and conditions have been requested. The full range of these data are necessary for a complete HRU analysis.

The patients consented onto the study are from the Greater Manchester (GM) area and are registered with GPs in that area. Secondary care data is, therefore, likely to come from GM hospitals but could come from hospitals in other areas if, for example, patients had unscheduled visits while travelling or had to attend specialist clinics outside GM. Part of the rationale of using patient’s electronic records in a Real-World study such as this is to minimise interaction with patients and reduce any intrusion.

Organisations involved and their roles:

Novartis Pharmaceuticals UK Ltd

- Study Sponsor/funding body

- Data Controller

- Data Processor

NorthWest EHealth Limited (NWEH)*

- Data Processor

Northern Care Alliance NHS Foundation Trust (NCA)

- Data Processor

- Provide Azure cloud hosting service for NWEH

Microsoft Limited

- Data Processor

- Provide Azure cloud from NCA

Restore PLC

- Used for data storage / archiving

Wellbeing Ltd**

- Data Processor

NHS England (NHSE)

- There is an ongoing collaboration between Novartis and NHSE to improve lipid management in England. The funding for this study is coming from a budget agreed between Novartis and NHSE as part of the collaboration. For regulatory purposes Novartis is the study sponsor and responsible for setting the objectives and the conduct of the study. NHSE had no responsibility or accountability in the development of the study protocol and have had no involvement in the conduct of the study. However, as collaborators, NHSE will receive outputs of the study (e.g., publications, clinical study report and process evaluation reports).

*NWEH is wholly directed by Novartis on all aspects of data processing. The eCRF was developed by NWEH based on Novartis' study protocol. The data requested from NHS Digital and from GPs was that which will allow the objectives of the protocol to be fulfilled. NWEH will link data from the eCRF, HES, and GP systems and deliver it to Novartis in a format specified by Novartis for them to perform their own analysis.

**Wellbeing provides a 3rd party primary care data extraction service which extracts data from GP EMR systems and delivers it to NWEH. It does not process the GP data in any other way and will not process the data requested from NHS Digital in any way whatsoever.

There are several planned reports and publications from this study. The planned activities are outlined below:

- Documents shared by Novartis with NHS England and Academic Health Science Networks (AHSNs) - textual reports with no patient details

- Patient report #1: report on number of patients meeting broad ‘at risk’ criteria who may be eligible for treatment with inclisiran in the study. Completed January 2022

- Process evaluation #1: early insights report based on feed-back from commissioners, patients, and healthcare professionals. Completed January 2022

- Patient report #2: report on number of patients who meet the full inclusion criteria (i.e. are eligible for inclisiran in the study). Completed June 2022

(Note: the above reports haven't used NHS Digital data, but they do feed into the research as they add background to the research).

- Process evaluation #2: in-depth report based on feed-back from commissioners, patients, and healthcare professionals. Estimated Q2 2023

- Full Clinical Study Report: inclisiran efficacy, patient reported outcomes, safety outcomes, patient demographics, process evaluation summary, and HRU (cost) analysis across the delivery methods

- Peer reviewed publications - aggregate data with small numbers suppressed

- Patient Identification and SNOMED codes / national case findings. Submission to Cardiovascular Research estimated May 2023

- Study Methodology publication. Submission to British Medical Journal Open estimated May 2023

- Patient engagement: Prior to commencement of the trial a patient focus group was set up by NWEH (on behalf of Novartis) to involve patients at the development stage of the process, to help improve and inform the study, as well as providing an opportunity to gain a better understanding of the patient’s needs. In addition, it offered a chance for the protocol to be tested, issues to be identified, and problems to be resolved before a study opened for recruitment. The study concluded overwhelmingly that participants had a positive opinion about the study. In fact, all those interviewed stated they would be interested in taking part in the study if they were offered the opportunity. When discussed with the researcher, the vaccine like model was perceived as a good alternative to their current medications. From questioning, no participants had any major concerns regarding the study design or the drug administration. Novartis will also be sending participants a summary of findings at the conclusion of the study to keep study participants up to date with the study outcomes.

- Data output: Northwest EHealth will produce a dataset of linked data from the eCRF, GP EMR systems, and the HES datasets. This data will be transformed into the standard format required for submission to regulatory authorities for analysis by Novartis. The data will be patient level and pseudonymised but Novartis will not have access to the pseudonymization key or identifiers and cannot re-identify the patients (see ‘Linked data’ under ‘Processing Activities’). This linked data is necessary for the subsequent production of the Full Clinical Report by Novartis (including HRU analysis) for dissemination to NHS England.

Yielded Benefits is not a requirement for new applications.