Improving Medicines use in People with Polypharmacy in Primary Care (IMPPP)

Prescribing medicines is one of the most important things doctors do to treat illness and improve peoples’ health. The UK population is steadily ageing and people often have more than one health problem. This means more people are taking multiple medicines, which is called polypharmacy. Polypharmacy is common. It is often necessary to help a person keep well, but polypharmacy can also cause problems such as side effects or confusion about exactly what medicines are to be taken when. The UK needs to find ways of improving the use of medicines in people with polypharmacy so it can reduce some of these problems. However, there is no good scientific evidence to help health care professionals decide how to most effectively do this. The aim of this study is to create an effective approach for improving the use of medicines in people with polypharmacy attending general practice.

The aim of the study is to enable objective assessment of health service utilisation (such as unplanned hospital admissions and secondary care health service utilisation) and medication safety outcomes and associated costs in a cohort of patients recruited to Phase 3 of the Improving Medicines in People with Polypharmacy in Primary Care (IMPPP) study. This agreement requests linkage and data extraction using Hospital Episode Statistics (HES) and Emergency Care Data Set (ECDS) data from NHS England. Specifically, data related to accident and emergency attendances, inpatient and outpatient care is being sought.

Briefly, the IMPPP study will establish whether and how a complex intervention to improve medicines use in patients with polypharmacy in Primary Care (the IMPPP intervention) is clinically effective and cost effective.

The proposed project under this agreement fits within Phase 3 of the IMPPP study (see below). The IMPPP Phase 3 study requires objective data related to hospital episodes to enable comparison of medication safety and utilisation of secondary care inpatient, outpatient and accident and emergency services outcomes across the two IMPPP study groups (i.e. intervention versus control ‘usual care’). The data requested from NHS England will contribute to the evaluation of the clinical and cost effectiveness of the IMPPP intervention in comparison with usual care.

OVERARCHING STUDY

The data requested in this agreement is to support the delivery of phase 3 of the IMPPP trial only (i.e. the cluster randomised controlled trial on 37 general practices. The IMPPP study is a three-phase programme of work to develop, implement and evaluate an intervention to optimise medication use for patients with polypharmacy in a general practice setting. This programme of work, funded by the National Institute for Health Research, Health Service and Delivery Research, commenced December 2018. Phase 1 has been completed (end date November 2019) and Phase 2 is currently underway in participating general practices in Bristol (the end date was originally to be June 2020 , but due to COVID this had been pushed back and was completed 31/07/2021..

This agreement relates to IMPPP Phase 3 which commenced March 2020 and runs until the end of September 2023. The end date for the full research programme (that is Phase 1, 2 &3) is 30th September 2023.

The aim of the IMPPP study is to develop, implement and evaluate an intervention to optimise medication use for patients with polypharmacy in a general practice setting. The study objectives are:

Development study (Phase 1):

• To learn from NHS work in Scotland in order to develop a complex organisational intervention to improve medication review for people with polypharmacy.

Pilot-feasibility study (Phase 2):

• To optimise the implementation of the IMPPP intervention for use in the NHS in England in a pilot-feasibility study.

Main trial (Phase 3):

• To evaluate the clinical effectiveness and cost effectiveness of the intervention in a cluster randomised controlled trial.

• To examine the implementation of the intervention in the trial using a mixed methods process evaluation.

Phase 1 (intervention development)

Mixed-methods study in two Scottish Health Boards that are implementing novel informatics tools to support NHS polypharmacy reviews in a range of ways. Interviews with healthcare professionals (HCPs) plus patient focus groups will be used to understand implementation and experience of polypharmacy review, and the strengths and limitations of the various intervention components implemented. Descriptive epidemiological analysis of practice data will be undertaken to explore the prevalence, variation and amenability to change in potentially inappropriate prescribing (PIP). These findings will inform a detailed draft design of the intervention components, which will then be refined in consultation with Health Care Professionals and patient groups in England.

Phase 2 (implementation/pilot)

Pilot-feasibility study in five Bristol-area general practices (three intervention and two control), to optimise the intervention in the English NHS. Each practice is recruiting 25 patients. A formative qualitative process evaluation will examine initial adoption and intervention implementation, including likely barriers/facilitators to implementation which will be addressed prior to the main trial. The study team will also pilot and evaluate trial processes including collecting quantitative data on patient recruitment/retention.

Phase 3 (evaluation)

Multicentre cluster-Randomised Clinical Trial (RCT) comparing intervention vs usual care in the Bristol area and the West Midlands. GP practices will be randomised to the intervention or treatment as usual. Randomisation will be conducted at GP practice level, stratified by area. GP practices will be randomised on a 1:1 basis to receive either the intervention or treatment as usual, with 37 GP practices recruited (i.e. 18 GP Practices will receive treatment as usual, 19 will receive intervention). Randomisation of GP practices will be carried out by the trial team using a computer algorithm. Each practice will recruit 50 patients. A total of 1850 patients from 37 GP practices will be recruited into the trial, this is the total of the cohort that will be submitted to NHS England.

The primary outcome of IMPPP Phase 3 is the mean number of potentially inappropriate prescribing indicators triggered per patient at 6 months following the pre review eligibility check, which occurs in both the control/usual care and intervention practices (i.e. it is not at a fixed date point or related to the actual time of the scheduled review). The primary outcome applies to consented participants in both arms and not the wider practice population. The primary outcome will be captured using data collected and extracted from the general practice records by the study IT tool installed within each of the participating practices.

**Since the original proposal an amendment to the practice recruitment target for the Phase 3 RCT has been discussed and agreed with the Trial Steering Committee (TSC), Data Monitoring Committee (DMC) and funder. The initial target was 54 practices, which provided approximately 92% power based on our previous estimates of variance in outcome. However, pilot work has shown less variance and similar power can be achieved from 40 practices, with 37 sites required to reach our original aim of 90% power. TSC and  DMC agreed that a revised recruitment target of 37 practices is justified and sufficient to achieve the stated aim of 90%. As such our patient recruitment target has been reduced to 1850.

Due to several delays in both practice and participant recruitment the IMPPP trial will need to continue until end of September 2023 to allow all sites to complete the 6-month intervention delivery period and the 6-month follow-up period.**

Outcome measures:

• Patient experience:

o Quality of life (measured via administration of the EuroQol validated questionnaire on 5 domains of quality of life and the SF-12 validated questionnaire of 12 questions of health-related-quality of life [a]**

o Medication adherence Rating Scale (MARS)

o Burden of treatment (Multimorbidity Treatment Burden Questionnaire, developed for 3D study)

o Medicines literacy (categorical)

• Health service utilisation

o Unplanned acute hospital admission rate (all admission types) over previous 6 months

• Patient/medication safety

o Number of medication-related admissions (derived from ICD10 codes [b]** T36-T50, X40-44, Y40-Y84 in primary diagnostic position) over previous 6 months

o Inappropriate Polypharmacy Score (an automated score based on routine data being developed by the team as part of an ongoing project [NIHR SPCR FR12/330], based on composite of several factors (for example, medication adherence, presence of contraindications, drug-drug interactions, complexity)

o All-cause mortality

**[a] EuroQol-5D (EQ-5D) is an instrument which evaluates the generic quality of life developed in Europe and widely used. The EQ-5D descriptive system is a preference-based HRQL measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The SF-12v2 is a health-related quality-of-life questionnaire consisting of twelve questions that measure eight health domains to assess physical and mental health. Physical health-related domains include General Health (GH), Physical Functioning (PF), Role Physical (RP), and Body Pain (BP).

**[b] ICD-10 codes - ICD stands for the International Classification of Disease. The ICD provides a method of classifying diseases, injuries, and causes of death.

T36-T50 - Poisoning by, adverse effect of and underdosing of drugs, medicaments and biological substances

X40-44 - Accidental poisoning - opioid-related overdose deaths

Y40-Y84 - Complications of medical and surgical care

Cost effectiveness based upon Quality adjusted life years (QALY) and Service utilisation determined over previous 6 months. Secondary outcome data will be captured using patient-reported questionnaire data and from Hospital Episodes Statistics data released by NHS England. A parallel mixed-methods process evaluation will be undertaken to examine the implementation of the intervention to help explain the success, or otherwise, of the intervention, and to inform subsequent implementation in practice.

The study will provide valuable insights into how to best implement case-finding and prioritisation for medication review in patients with polypharmacy, how GPs and pharmacists can best collaborate to meet patients’ needs, and the role of informatics in supporting case-finding and focused review. The IMPPP intervention has the potential to improve health related quality of life and prescribing and reduce adverse medication effects and treatment burden in a growing and highly vulnerable population.

The University Charter gives Universities the power to make provision for research and for the enhancement and dissemination of knowledge. The personal data for this study is processed under UK GDPR Article 6 (1)(e) - Public Task - for academic medical research carried out as a task in the public interest. The processing is necessary for the University of Bristol ( as a public authority for the purposes of data protection legislation) to perform a task in the public interest. The task has a clear basis in law and the special category personal data for this study is processed under UK GDPR Article 9(2)(j) 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 right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. The public interest lies in the improved evidence on the assessment of health service utilisation (such as unplanned hospital admissions and secondary care health service utilisation) and medication safety outcomes and associated costs for people who are taking multiple medicines, which is called polypharmacy. For these reasons, the processing also meets the conditions of Schedule 1 Part 1 paragraph 4 of the Data Protection Act 2018.

Consent will be sought from study participants for identifying data to flow to NHS England in the form of a cohort to enable matching to NHS England data sets. The Participant Information Sheet explains that participation in the study involves sharing of the following identifying data: Date of Birth, NHS Number, Post Code and Gender with NHS England to enable data linkage and extraction of data from hospital records.

The main risk issues arising from the proposed dissemination relates to identification of data subjects. To mitigate this risk each participant will be assigned a unique study identification code (ID) at baseline. The unique study ID will only be linkable to the participants name via a ‘code breaker’ database, which will be password protected and stored in a restricted access folder on the University of Bristol network.

To avoid dissemination of identifiable data by NHS England, the released dataset will include the unique study ID only (date of birth, NHS Number, postcode and Gender, Date of Randomisation and Date of End of Follow up will be removed from the dataset released by NHS England). The unique study identification code will be used by the studies analytic team to enable linkage of data released by NHS England to data held at the University of Bristol for the purposes of data analysis. Linkage of the data released by NHS England with the study data held at the University of Bristol is necessary to ensure that the participants’ data is analysed within the group (i.e. intervention or control group) to which they have been randomly assigned. No identifiers will be used to re-identify participants and no attempt will be made to reidentify individuals.

Prior to analysis of outcomes, study data ascertained from participant self-report and the practice based medical record will be stripped of identifying data. Gender will not be removed during processing however will be presented as grouped data in study outputs. All study outputs will report data aggregated and suppressed according to the HES analysis guide by study arm (i.e. intervention versus usual care groups). Data in record level form will not be reported in any of the study outputs.

Data on Emergency Services Data Set (ECDS), Outpatients (OP) and Admitted Patient Care (APC) care for all participants who have consented to take part in Phases 3 of the IMPPP study is being sought to objectively determine secondary care health service usage, this will inform the secondary outcomes and the cost-effectiveness.

Data will be requested for the approximate period July 2021 - September 2023 to cover a period of 6-month pre-randomisation and 12-months leading up to end of follow-up for all IMPPP trial participants (i.e. recruitment of participants will take place between January - September 2022).

The total period of data required for each patient is a maximum of 18 months (as per the patient information sheet), but this is not necessarily continuous for each patient participant. This is because the 6-month baseline period is fixed for any given practice and determined by randomisation date (to ensure blinding) but the 12 months is determined by the start date of intervention delivery at the practice not the randomisation date. Intervention delivery at practices starts following their completion of the IMPPP trial training programme. Intervention delivery continues for a period of 6-months. Each patient participant is then followed up for a period of 6 months from the point at which they receive the intervention.

These data will be used in the evaluation of the clinical and cost effectiveness of the IMPPP intervention in comparison with routine care. Specifically, with respect to the secondary outcomes of health service utilisation and medication safety. HES contains records of all admissions, appointments, and attendances for patients at NHS hospitals in England.

The data subjects are research participants that have provided their consent to take part in IMPPP Phase 3 (i.e. the cluster randomised controlled trial).

A total of 1850 participants will be recruited to Phase 3, 950 to the intervention group and 900 to the usual care group. Participants will have been identified at their General Practice by the studies IT tool as being potentially eligible for inclusion in the study based upon the following inclusion criteria: -

 Aged ≥ 18 years

 Multiple medicines, defined as taking at least four regular medicines; this will be based on medicines 1) being currently available on the repeat prescribing system and 2) having been prescribed at least once in the previous 3 months

 Be identified by the case-finding function of the studies IT tool. The IT tool applies 121 prescribing indicators to the clinical records of patient registered at participating practices. Patients who trigger at least one of the prescribing indicators are potentially eligible to take part.

Following case-finding via the IT tool installed at the practice, the General Practitioner (GP) screens the list of potentially eligible participants to identify people to be invited to take part. Screening of the medical records of potentially eligible patients will be conducted to exclude people with the following characteristics: -

• Individuals receiving end-of-life care

• Patients judged by their GP to have particularly poor compliance with their prescription medicines and/or a history of drug or alcohol misuse.

• The GP deems contact to be inappropriate, for example, due to severe mental health problems, terminal illness, recent bereavement

• Participant is unable to complete the study questionnaires or medication review appointment (either themselves or with the help of carers)

• Individuals planning to move GP practice within the 6-month follow up period

A recent medication review outside the trial setting will not be considered an exclusion criterion, although it will be left to the GP screening for inclusion in the study to decide if a second review in a short time as part of the study would be inappropriate.

Potential participants deemed to be eligible by the GP are mailed an invitation pack containing the study invitation letter from the GP, a participant information leaflet, a consent form, a contact details form, a study baseline questionnaire and two return addressed freepost envelopes for return of completed documents to the research team based at the University of Bristol.

General practice and participant recruitment will be staggered for logistical reasons. Phase 3 participant recruitment will take place across 37 general practices in the West of England and West Midlands regions between January 2022 - September 2022. The trial closed to patient participant recruitment at the end of September 2022. The staggered nature of the participant recruitment process means that completion and return of the consent forms will take place over a period of 7 months. Hospital Episodes data for each study participant is being requested for a total period of up to 18 months to include the 6-month period before the date upon which the practice was randomised up until the date upon which the participant is sent the final study questionnaire.

University of Bristol are requesting only personal health data, which is adequate, relevant and limited to what is necessary in relation to the purposes for which they are processed. The study team will set up one cohort to minimise the amount of data being returned by NHS England and will provide NHS England with one data document for the cohort containing the participants Date of Birth, NHS Number, Post Code and Gender to enable linkage with HES IDs. The University of Bristol will additionally supply the practice randomisation date and the date of end of follow-up.

After careful consideration the study team have been unable to identify an alternative, less intrusive way of achieving the purpose of objectively determining secondary care health service utilisation for IMPPP participants. Study participants in both arms of the study will receive three questionnaires (one questionnaire will be administered at each of the following timepoints; T1, T2; and T4). Each questionnaire will take around 30 minutes to complete. Inclusion of questions to capture secondary care health service utilisation would substantially increase the length of these questionnaires and burden of the research on participants. In order to minimise the amount of data being released by NHS England the study team have chosen only those fields which are required to achieve the purpose (maternity episodes, for example, are not being requested as they do not fit with the purpose of this agreement). To further reduce the risk of intrusion, identifiable or sensitive fields are not being requested.

The IMPPP research programme (comprising IMPPP phase 1, 2 & 3) is being conducted by the University of Bristol in collaboration with the Universities of Dundee and Keele. The University of Bristol is the sole data controller and data processor for this agreement with NHS England. The Bristol team have solely developed the element of the protocol that requires the NHS England data. The Bristol team made the decision to request data from NHS England, have decided on which aspects of NHS England data to collect and how data provided by NHS England will be processed. The Bristol team will be solely responsible for processing the data released by NHS England and hold the consent forms completed by the data subjects. Researchers and investigators from the Universities of Keele and Dundee were not involved in developing the element of the protocol that requires the NHS England data and will have no role in determining the means and purpose of the processing of the data requested from NHS England.

The University of Dundee has provided research sponsorship for Phase 1 of the IMPPP study. Investigators and researchers based at the University of Dundee were responsible for the conduct and delivery pf phase 1 IMPPP (intervention development phase). This phase of the research has been completed (end date November 2019). Investigators and researchers from all three universities (Bristol, Keele and Dundee) have had input from the start of the IMPPP research programme as members the Trial Management Group. This group meets monthly to discuss study progress and processes. Members of the group provide expert clinical advice and methodological guidance to the IMPPP Chief Investigator, to support decision making in relation to the conduct of the Phase 3 IMPPP trial The investigators will continue in their membership of the Trial Management Group going forward and as such will be responsible for the oversight and delivery of the phase 3 research protocol.

The University of Keele will have a role in IMPPP Phase 3 taking responsibility for recruitment of practices and patients within the West Midlands region. A total of 37 practices will be recruited to the trial. Practices will be based within the South West and West Midlands areas.

The study's Chief Investigator and analytic team based at the University of Bristol, Bristol Medical School, School of Population Health Sciences, will be responsible for data storage, cleaning, processing and analysis of all study outcomes (to include secondary outcomes for which NHS England data is requested). Analysis will be conducted in a blinded manner (i.e. without knowledge of which group is the intervention group and which group is the usual care group). The research team based at the University of Bristol will be responsible for the extraction of primary outcome data from the general practice records and for storage, processing and analysis of these data and the pseudonymised hospital episodes data received from NHS England. Investigators and researchers based at the Universities of Keele and Dundee will not have access to record level data provided by NHS England.

Commissioners (specifically the Bristol, North Somerset and South Gloucestershire Commissioning Care Group (BNSSG CCG)) are supporting the conduct and the delivery of the IMPP Study as administrators of the research grant. The BNSSG CCG has had no involvement in the development of the research protocol and no role in determining the means and purpose of the data processing. Therefore the CCG is therefore not considered a data controller for this agreement.

This programme of work is funded by the National Institute for Health Research, Health Service and Delivery Research (Ref 16/118/14).

University of Bristol are planning a range of outputs from the IMPPP study (Phases 1, 2 & 3); most of these are planned to be produced in the final 6-month dissemination period (unless otherwise stated):

• Academic papers, including: intervention development (produced after Phase 1); trial-based effectiveness and cost-effectiveness; patient experience of the intervention and usual care; and process evaluation

• NIHR final report including executive and Plain English summaries (completion date March 2024)

• Printed and electronic promotional material targeting NHS managers, commissioners and policy makers within Clinical Commissioning Groups across England (to include medicines management teams, regional medicines optimisation groups, NHS England’s Clinical Pharmacist in General Practice programme, Primary Care Networks)

• Policy briefing documents, drawing upon research findings plus feedback from stakeholder engagement exercise at a national workshop

• IMPPP informatics tool for practices, including remote dashboards for CCGs. The system will be readily scalable, so easily distributed to other EMIS Web practices in the short term, and in the longer term to practices using other computer systems

• Educational materials on polypharmacy for clinicians, including students will be provided to Medicines Management Groups within Clinical Commissioning Groups across England and to UK Universities delivering undergraduate and post graduate programmes in medicines optimisation via email and oral presentation.

• Information leaflets for patients about polypharmacy and medication review*.

• The maintenance of an IMPPP study website (providing patient information, and research updates throughout project including final results).

http://www.bristol.ac.uk/primaryhealthcare/researchthemes/imppp/

*The research question and study design were discussed with Personal and Public Involvement (PPI) advisors prior to the funding application being submitted. Since the funding has been secured, PPI advisors have been involved in the development of the plain English summary for the protocol and ethics application and the patient-facing documents (to include participant information sheets, consent forms, interview topic guides, questionnaires and the invitation letter and supporting documents sent to participants prior to the medication review appointment). The study team aim to work closely with public and other patient groups when publicising the findings.

No data has been disseminated under the pervious version of this agreement as such their are no yielded benefits to date.

Prescribing medicines is one of the most important things doctors do to treat illness and improve peoples’ health. The UK population is steadily ageing and people often have more than one health problem. This means more people are taking multiple medicines, which is called polypharmacy. Polypharmacy is common. It is often necessary to help a person keep well, but polypharmacy can also cause problems such as side effects or confusion about exactly what medicines are to be taken when. The UK needs to find ways of improving the use of medicines in people with polypharmacy so it can reduce some of these problems. However, there is no good scientific evidence to help health care professionals decide how to most effectively do this. The aim of this study is to create an effective approach for improving the use of medicines in people with polypharmacy attending general practice.

The aim of the study is to enable objective assessment of health service utilisation (such as unplanned hospital admissions and secondary care health service utilisation) and medication safety outcomes and associated costs in a cohort of patients recruited to Phase 3 of the Improving Medicines in People with Polypharmacy in Primary Care (IMPPP) study. This agreement requests linkage and data extraction using Hospital Episode Statistics (HES) and Emergency Care Data Set (ECDS) data from NHS Digital. Specifically, data related to accident and emergency attendances, inpatient and outpatient care is being sought.

Briefly, the IMPPP study will establish whether and how a complex intervention to improve medicines use in patients with polypharmacy in Primary Care (the IMPPP intervention) is clinically effective and cost effective.

The proposed project under this agreement fits within Phase 3 of the IMPPP study (see below). The IMPPP Phase 3 study requires objective data related to hospital episodes to enable comparison of medication safety and utilisation of secondary care inpatient, outpatient and accident and emergency services outcomes across the two IMPPP study groups (i.e. intervention versus control ‘usual care’). The data requested from NHS Digital will contribute to the evaluation of the clinical and cost effectiveness of the IMPPP intervention in comparison with usual care.

OVERARCHING STUDY

The data requested in this agreement is to support the delivery of phase 3 of the IMPPP trial only (i.e. the cluster randomised controlled trial on 54 general practices. The IMPPP study is a three-phase programme of work to develop, implement and evaluate an intervention to optimise medication use for patients with polypharmacy in a general practice setting. This programme of work, funded by the National Institute for Health Research, Health Service and Delivery Research, commenced December 2018. Phase 1 has been completed (end date November 2019) and Phase 2 is currently underway in participating general practices in Bristol (the end date was originally to be June 2020 , but due to COVID this has been pushed back to approximately end of July 2021).

This agreement relates to IMPPP Phase 3 which commenced March 2020 and runs until the end of August 2022. The end date for the full research programme (that is Phase 1, 2 &3) is 30th August 2022.

The aim of the IMPPP study is to develop, implement and evaluate an intervention to optimise medication use for patients with polypharmacy in a general practice setting. The study objectives are:

Development study (Phase 1):

• To learn from NHS work in Scotland in order to develop a complex organisational intervention to improve medication review for people with polypharmacy.

Pilot-feasibility study (Phase 2):

• To optimise the implementation of the IMPPP intervention for use in the NHS in England in a pilot-feasibility study.

Main trial (Phase 3):

• To evaluate the clinical effectiveness and cost effectiveness of the intervention in a cluster randomised controlled trial.

• To examine the implementation of the intervention in the trial using a mixed methods process evaluation.

Phase 1 (intervention development)

Mixed-methods study in two Scottish Health Boards that are implementing novel informatics tools to support NHS polypharmacy reviews in a range of ways. Interviews with healthcare professionals (HCPs) plus patient focus groups will be used to understand implementation and experience of polypharmacy review, and the strengths and limitations of the various intervention components implemented. Descriptive epidemiological analysis of practice data will be undertaken to explore the prevalence, variation and amenability to change in potentially inappropriate prescribing (PIP). These findings will inform a detailed draft design of the intervention components, which will then be refined in consultation with Health Care Professionals and patient groups in England.

Phase 2 (implementation/pilot)

Pilot-feasibility study in five Bristol-area general practices (three intervention and two control), to optimise the intervention in the English NHS. Each practice is recruiting 25 patients. A formative qualitative process evaluation will examine initial adoption and intervention implementation, including likely barriers/facilitators to implementation which will be addressed prior to the main trial. The study team will also pilot and evaluate trial processes including collecting quantitative data on patient recruitment/retention.

Phase 3 (evaluation)

Multicentre cluster-Randomised Clinical Trial (RCT) comparing intervention vs usual care in the Bristol area and the West Midlands. GP practices will be randomised to the intervention or treatment as usual. Randomisation will be conducted at GP practice level, stratified by area. GP practices will be randomised on a 1:1 basis to receive either the intervention or treatment as usual, with 27 GP practices recruited in each arm (i.e. 27 GP Practices will receive treatment as usual, 27 will receive intervention). Randomisation of GP practices will be carried out by the trial team using a computer algorithm. Each practice will recruit 50 patients. A total of 2,700 patients from 54 GP practices will be recruited into the trial, this is the total of the cohort that will be submitted to NHS Digital.

The primary outcome of IMPPP Phase 3 is the mean number of potentially inappropriate prescribing indicators triggered per patient at 6 months following the pre review eligibility check, which occurs in both the control/usual care and intervention practices (i.e. it is not at a fixed date point or related to the actual time of the scheduled review). The primary outcome applies to consented participants in both arms and not the wider practice population. The primary outcome will be captured using data collected and extracted from the general practice records by the study IT tool installed within each of the participating practices.

Outcome measures:

• Patient experience:

o Quality of life (measured via administration of the EuroQol validated questionnaire on 5 domains of quality of life and the SF-12 validated questionnaire of 12 questions of health-related-quality of life [a]**

o Medication adherence Rating Scale (MARS)

o Burden of treatment (Multimorbidity Treatment Burden Questionnaire, developed for 3D study)

o Medicines literacy (categorical)

• Health service utilisation

o Unplanned acute hospital admission rate (all admission types) over previous 6 months

• Patient/medication safety

o Number of medication-related admissions (derived from ICD10 codes [b]** T36-T50, X40-44, Y40-Y84 in primary diagnostic position) over previous 6 months

o Inappropriate Polypharmacy Score (an automated score based on routine data being developed by the team as part of an ongoing project [NIHR SPCR FR12/330], based on composite of several factors (for example, medication adherence, presence of contraindications, drug-drug interactions, complexity)

o All-cause mortality

**[a] EuroQol-5D (EQ-5D) is an instrument which evaluates the generic quality of life developed in Europe and widely used. The EQ-5D descriptive system is a preference-based HRQL measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The SF-12v2 is a health-related quality-of-life questionnaire consisting of twelve questions that measure eight health domains to assess physical and mental health. Physical health-related domains include General Health (GH), Physical Functioning (PF), Role Physical (RP), and Body Pain (BP).

**[b] ICD-10 codes - ICD stands for the International Classification of Disease. The ICD provides a method of classifying diseases, injuries, and causes of death.

T36-T50 - Poisoning by, adverse effect of and underdosing of drugs, medicaments and biological substances

X40-44 - Accidental poisoning - opioid-related overdose deaths

Y40-Y84 - Complications of medical and surgical care

Cost effectiveness based upon Quality adjusted life years (QALY) and Service utilisation determined over previous 6 months. Secondary outcome data will be captured using patient-reported questionnaire data and from Hospital Episodes Statistics data released by NHS Digital. A parallel mixed-methods process evaluation will be undertaken to examine the implementation of the intervention to help explain the success, or otherwise, of the intervention, and to inform subsequent implementation in practice.

The study will provide valuable insights into how to best implement case-finding and prioritisation for medication review in patients with polypharmacy, how GPs and pharmacists can best collaborate to meet patients’ needs, and the role of informatics in supporting case-finding and focused review. The IMPPP intervention has the potential to improve health related quality of life and prescribing and reduce adverse medication effects and treatment burden in a growing and highly vulnerable population.

The University Charter gives researchers the power to make provision for research and for the enhancement and dissemination of knowledge. The GDPR legal basis the processing of Personal data is Article 6 (1)(e) processing is necessary for the performance to a task carried out in the public interest and the legal basis for health data (a special category of Personal data) is Article 9 (2)(j) processing is necessary for reasons of public interest in the area of research.

consent will be sought from study participants for identifying data to flow to NHS Digital in the form of a cohort to enable matching to NHS Digital data sets. The Participant Information Sheet explains that participation in the study involves sharing of the following identifying data: Date of Birth, NHS Number, Post Code and Gender with NHS Digital to enable data linkage and extraction of data from hospital records. The Date of Consent will mean that the datasets requested will be filtered to the exact data periods required for the study.

The main risk issues arising from the proposed dissemination relates to identification of data subjects. To mitigate this risk each participant will be assigned a unique study identification code (ID) at baseline. The unique study ID will only be linkable to the participants name via a ‘code breaker’ database, which will be password protected and stored in a restricted access folder on the University of Bristol network.

To avoid dissemination of identifiable data by NHS Digital, the released dataset will include the unique study ID only (date of birth, NHS Number, postcode and Gender and Date of Consent will be removed from the dataset released by NHS Digital). The unique study identification code will be used by the studies analytic team to enable linkage of data released by NHS Digital to data held at the University of Bristol for the purposes of data analysis. Linkage of the data released by NHS Digital with the study data held at the University of Bristol is necessary to ensure that the participants’ data is analysed within the group (i.e. intervention or control group) to which they have been randomly assigned. No identifiers will be used to re-identify participants and no attempt will be made to reidentify individuals.

Prior to analysis of outcomes, study data ascertained from participant self-report and the practice based medical record will be stripped of identifying data. Gender will not be removed during processing however will be presented as grouped data in study outputs. All study outputs will report data aggregated and suppressed according to the HES analysis guide by study arm (i.e. intervention versus usual care groups). Data in record level form will not be reported in any of the study outputs.

Data on Emergency Services Data Set (ECDS), Outpatients (OP) and Admitted Patient Care (APC) care for all participants who have consented to take part in Phases 3 of the IMPPP study is being sought to objectively determine secondary care health service usage, this will inform the secondary outcomes and the cost-effectiveness.

Data will be requested for the approximate period December 2020 - August 2022 to cover a period of 6-month pre-consent and 12-months post-consent for all IMPPP trial participants (i.e. recruitment of participants will take place between April - August 2021). The exact data period covered will vary from participant to participant as exact extraction will be based on the participant's Date of Consent.

These data will be used in the evaluation of the clinical and cost effectiveness of the IMPPP intervention in comparison with routine care. Specifically, with respect to the secondary outcomes of health service utilisation and medication safety. HES contains records of all admissions, appointments, and attendances for patients at NHS hospitals in England.

The data subjects are research participants that have provided their consent to take part in IMPPP Phase 3 (i.e. the cluster randomised controlled trial).

A total of 2,700 participants will be recruited to Phase 3, 1,350 to the intervention group and 1,350 to the usual care group. Participants will have been identified at their General Practice by the studies IT tool as being potentially eligible for inclusion in the study based upon the following inclusion criteria: -

 Aged ≥ 18 years

 Multiple medicines, defined as taking at least four regular medicines; this will be based on medicines 1) being currently available on the repeat prescribing system and 2) having been prescribed at least once in the previous 3 months

 Be identified by the case-finding function of the studies IT tool. The IT tool applies 121 prescribing indicators to the clinical records of patient registered at participating practices. Patients who trigger at least one of the prescribing indicators are potentially eligible to take part.

Following case-finding via the IT tool installed at the practice, the General Practitioner (GP) screens the list of potentially eligible participants to identify people to be invited to take part. Screening of the medical records of potentially eligible patients will be conducted to exclude people with the following characteristics: -

• Individuals receiving end-of-life care

• Patients judged by their GP to have particularly poor compliance with their prescription medicines and/or a history of drug or alcohol misuse.

• The GP deems contact to be inappropriate, for example, due to severe mental health problems, terminal illness, recent bereavement

• Participant is unable to complete the study questionnaires or medication review appointment (either themselves or with the help of carers)

• Individuals planning to move GP practice within the 6-month follow up period

A recent medication review outside the trial setting will not be considered an exclusion criterion, although it will be left to the GP screening for inclusion in the study to decide if a second review in a short time as part of the study would be inappropriate.

Potential participants deemed to be eligible by the GP are mailed an invitation pack containing the study invitation letter from the GP, a participant information leaflet, a consent form, a contact details form, a study baseline questionnaire and two return addressed freepost envelopes for return of completed documents to the research team based at the University of Bristol.

General practice and participant recruitment will be staggered for logistical reasons. Phase 3 participant recruitment will take place across 54 general practices in the West of England and West Midlands regions between April 2021 - August 2021. The staggered nature of the participant recruitment process means that completion and return of the consent forms will take place over a period of 4 months. Hospital Episodes data for each study participant is being requested for a total period of up to 18 months to include the 6-month period before the date upon which the person provided consent to participant up until the date upon which the participant is sent the final study questionnaire (i.e. at time-point 4 which maybe up to 9 months after the date of consent due to the study design requiring invitation and consent form mailout prior to randomisation of practices and training in intervention delivery for practices).

University of Bristol are requesting only personal health data, which is adequate, relevant and limited to what is necessary in relation to the purposes for which they are processed. The study team will set up one cohort to minimise the amount of data being returned by NHS Digital and will provide NHS Digital with one data document for the cohort containing the participants Date of Birth, NHS Number, Post Code and Gender to enable linkage with HES IDs. The University of Bristol will additionally supply the participant's Date of Consent.

After careful consideration the study team have been unable to identify an alternative, less intrusive way of achieving the purpose of objectively determining secondary care health service utilisation for IMPPP participants. Study participants in both arms of the study will receive three questionnaires (one questionnaire will be administered at each of the following timepoints; T1, T2; and T4). Each questionnaire will take around 30 minutes to complete. Inclusion of questions to capture secondary care health service utilisation would substantially increase the length of these questionnaires and burden of the research on participants. In order to minimise the amount of data being released by NHS Digital the study team have chosen only those fields which are required to achieve the purpose (maternity episodes, for example, are not being requested as they do not fit with the purpose of this agreement). To further reduce the risk of intrusion, identifiable or sensitive fields are not being requested.

The IMPPP research programme (comprising IMPPP phase 1, 2 & 3) is being conducted by the University of Bristol in collaboration with the Universities of Dundee and Keele. The University of Bristol is the sole data controller and data processor for this agreement with NHS Digital. The Bristol team have solely developed the element of the protocol that requires the NHS Digital data. The Bristol team made the decision to request data from NHS Digital, have decided on which aspects of NHS digital data to collect and how data provided by NHS Digital will be processed. The Bristol team will be solely responsible for processing the data released by NHS Digital and hold the consent forms completed by the data subjects. Researchers and investigators from the Universities of Keele and Dundee were not involved in developing the element of the protocol that requires the NHS Digital data and will have no role in determining the means and purpose of the processing of the data requested from NHS Digital.

The University of Dundee has provided research sponsorship for Phase 1 of the IMPPP study. Investigators and researchers based at the University of Dundee were responsible for the conduct and delivery pf phase 1 IMPPP (intervention development phase). This phase of the research has been completed (end date November 2019). Investigators and researchers from all three universities (Bristol, Keele and Dundee) have had input from the start of the IMPPP research programme as members the Trial Management Group. This group meets monthly to discuss study progress and processes. Members of the group provide expert clinical advice and methodological guidance to the IMPPP Chief Investigator, to support decision making in relation to the conduct of the Phase 3 IMPPP trial The investigators will continue in their membership of the Trial Management Group going forward and as such will be responsible for the oversight and delivery of the phase 3 research protocol.

The University of Keele will have a role in IMPPP Phase 3 taking responsibility for recruitment of practices and patients within the West Midlands region. A total of 54 practices will be recruited to the trial. Practices will be based within the South West and West Midlands areas.

The study's Chief Investigator and analytic team based at the University of Bristol, Bristol Medical School, School of Population Health Sciences, will be responsible for data storage, cleaning, processing and analysis of all study outcomes (to include secondary outcomes for which NHS Digital data is requested). Analysis will be conducted in a blinded manner (i.e. without knowledge of which group is the intervention group and which group is the usual care group). The research team based at the University of Bristol will be responsible for the extraction of primary outcome data from the general practice records and for storage, processing and analysis of these data and the pseudonymised hospital episodes data received from NHS Digital. Investigators and researchers based at the Universities of Keele and Dundee will not have access to record level data provided by NHS Digital.

Commissioners (specifically the Bristol, North Somerset and South Gloucestershire Commissioning Care Group (BNSSG CCG)) are supporting the conduct and the delivery of the IMPP Study as administrators of the research grant. The BNSSG CCG has had no involvement in the development of the research protocol and no role in determining the means and purpose of the data processing. Therefore the CCG is therefore not considered a data controller for this agreement.

This programme of work is funded by the National Institute for Health Research, Health Service and Delivery Research (Ref 16/118/14).

University of Bristol are planning a range of outputs from the IMPPP study (Phases 1, 2 & 3); most of these are planned to be produced in the final 6-month dissemination period (unless otherwise stated):

• Academic papers, including: intervention development (produced after Phase 1); trial-based effectiveness and cost-effectiveness; patient experience of the intervention and usual care; and process evaluation

• NIHR final report including executive and Plain English summaries (completion date March 2023)

• Printed and electronic promotional material targeting NHS managers, commissioners and policy makers within Clinical Commissioning Groups across England (to include medicines management teams, regional medicines optimisation groups, NHS England’s Clinical Pharmacist in General Practice programme, Primary Care Networks)

• Policy briefing documents, drawing upon research findings plus feedback from stakeholder engagement exercise at a national workshop

• IMPPP informatics tool for practices, including remote dashboards for CCGs. The system will be readily scalable, so easily distributed to other EMIS Web practices in the short term, and in the longer term to practices using other computer systems

• Educational materials on polypharmacy for clinicians, including students will be provided to Medicines Management Groups within Clinical Commissioning Groups across England and to UK Universities delivering undergraduate and post graduate programmes in medicines optimisation via email and oral presentation.

• Information leaflets for patients about polypharmacy and medication review*.

• The maintenance of an IMPPP study website (providing patient information, and research updates throughout project including final results).

http://www.bristol.ac.uk/primaryhealthcare/researchthemes/imppp/

*The research question and study design were discussed with Personal and Public Involvement (PPI) advisors prior to the funding application being submitted. Since the funding has been secured, PPI advisors have been involved in the development of the plain English summary for the protocol and ethics application and the patient-facing documents (to include participant information sheets, consent forms, interview topic guides, questionnaires and the invitation letter and supporting documents sent to participants prior to the medication review appointment). The study team aim to work closely with public and other patient groups when publicising the findings.

Yielded Benefits is not a requirement for new applications.