Medication Monitoring in General Practice: Clinical Impact of Implementing a Nurse-led Adverse Drug Reaction (ADRe) Profile in Older Adults With 5 or More Prescribed Medicines
Phase: NA
Conditions: Polypharmacy
Sponsor: Swansea University

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TITLE OF THE PROTOCOL: Medication monitoring in general practice: clinical 
impact of implementing a nurse-led Adverse Drug Reaction (ADRe) Profile in older 
adults with 5 or more prescribed medicines 
 
Short title/Acronym: Medication monitoring in general practice/ADReGP 
 
Chief Investigator   
 
Prof. Sue Jordan 
 
Faculty  
Faculty of Health and Life Sciences  
 
Date  
20/11/2020  
 
SU Sponsor reference: 
RIO 034-20 
IRAS Number 
292693 
NHS REC reference: 
21/WA/0042 
Clinicaltrials.gov number: 
NCT04663360 
 
Sponsor: 
Swansea University 
 
Representative of the Sponsor: 
 
Mr Ceri Jones  
Academic Lead for Research Integrity 
Research Engagement & Innovation Services 
Swansea University 
Swansea SA2 8PP 
Tel: 01792 513849 
Email: researchgovernance@swansea.ac.uk  
This is the SU authorised signatory 
 
NHS R&D Trust Lead 
 
1) Swansea Bay UHB: Jemma Hughes 
                                                      Swansea Bay University Health Board  
                                                    1st floor, Institute of Life Science 2  
                                                    Swansea University  
                                                    Singleton Park 
                                                    SA2 8PP 
 
                                                    Contact details  
                                                    01792 530890 | |01792 530887 
                                                    jemma.hughes@wales.nhs.uk  
 
                                                      

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 2) Hywel Dda UHB:  Chris Tattersall 
Research & Development Manager (Study set-up & data)  
Hywel Dda University Health Board  
2nd Floor, Sealyham Block  
Withybush Hospital  
Fishguard Road  
Haverfordwest  
Pembrokeshire  
SA61 2PZ 
 
Contact details 
Email / e-bost: chris.tattersall@wales.nhs.uk 
Tel / Rhiff ffôn: 01437 773813 (EXT 3813) or 01437 773823 (EXT 3823) 
 
3) Cardiff and Vale UHB: TBC 
 

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STUDY SUMMARY/SYNOPSIS 
 
TITLE 
Medication monitoring in general practice: 
clinical impact of implementing a nurse-led 
Adverse Drug Reaction (ADRe) Profile in older 
adults with 5 or more prescribed medicines 
SHORT 
TITLE/Acronym 
Medication monitoring of older adults with 
polypharmacy in primary care/ADReGP 
 
Protocol Version 
Number and Date 
 
V2 08/01/2021 
Methodology 
 
Multiple-site parallel arm randomised controlled trial 
 
Study Duration 
 
Jan 2021 – Oct 2022 
22 months 
 
Study Centre 
 
GP practices or community nurse-led clinics 
(Swansea Bay UHB, Hywel Dda UHB and Cardiff & 
Vale UHB) 
Objectives 
 
• To establish the suitability/effectiveness of 
ADRe Profile for video call completion  
• To establish whether patients could complete 
parts of ADRe Profile themselves 
• To explore whether the ADRe Profile identifies 
health problems that could be attributable to 
polypharmacy and ameliorated (and record 
any changes to care, benefits or harms to the 
patients) 
• To explore whether routinely collected data 
could be used to populate the ADRe Profile 
 
Number of 
Subjects/Patients 
131 (35 – validity testing, 80 – patients, 16 – 
healthcare professionals) 
 
Main Inclusion 
Criteria 
 
Phase 1 
• Content validity index respondents: 
healthcare professionals (current or retired, 
working full-time or part-time, willing to 

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participate), service users (age > 64, willing to 
participate) 
• Cognitive interview respondents: 
healthcare professionals (current or retired, 
working full-time or part-time, willing to 
participate), service users (age > 64, willing to 
participate) 
• Contrast group validity respondents: group 
A (people, age >64, no daily prescribed 
medicines - vitamin and nutritional 
supplements and moisturising skin 
preparations will not be counted as 
‘medicines’, willing to participate), group B (as 
below) 
• Inter-rater reliability and feasibility 
participants: service users (age > 64 years, 
with a long-term condition, prescribed > 5 
medications daily. (Vitamin and nutritional 
supplements and moisturising skin 
preparations will not be counted as 
‘medicines’.), Willing and able to give 
informed, signed consent themselves, or 
where capacity is lacking in the opinion of their 
nurses, a consultee/representative 
accompanying the patient who is willing to 
give advice and assent to the service user 
participating and sign on their behalf. 
Phase 2 
Service users: 
• age > 64 years  
• with a long-term condition 
• prescribed > 5 medications daily. (Vitamin and 
nutritional supplements and moisturising skin 
preparations will not be counted as 
‘medicines’.) 
• Willing and able to give informed, signed 
consent themselves, or where capacity is 

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lacking in the opinion of their nurses, a 
consultee/representative accompanying the 
patient who is willing to give advice and 
assent to the service user participating and 
sign on their behalf. 
Nurses: 
• Working in or alongside a general practice and 
expected to work there for the next 6 months 
Pharmacists and GP’s: 
• Aligned with the general practice, expected to 
stay in employment for the next 6 months 
Phase 3 
No new participants, we shall approach people who 
took part in Phase 2. 
 
Statistical 
Methodology and 
Analysis 
 
We are combining  quantitative and qualitative 
methods of analysis to capitalize on the respective 
strengths of each of the approaches. The mixed 
methods will help to evaluate the intervention effect 
from a patient perspective, as well illustrate the 
conclusions derived from the quantitative data with 
stakeholder insight (Bharmal et al., 2018).  
The overall design is sequential: QUAN Phase 1 
informs QUAN + QUAL Phase 2, which informs 
convergent design Phase 3 (QUAN + QUAL), 
Itemised methods of analysis are described below: 
Content Validity Index (CVI) 
To be measured using Lynn’s (1986) method: 
Experts will rate each item using a four-point ordinal 
scale (1 = not relevant, 2 = somewhat relevant, 3 = 
quite relevant, and 4 = highly relevant) 
Number of experts rating the item 3 or 4 will be 
divided by total number of experts 
Result of 0.78 or above will be accepted as having 
met the validity threshold.  
Scale content validity ratio will be calculated as a 
proportion of total items judged against content valid 
items. 
 

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Cognitive interviews 
Think aloud technique combined with participant 
confidence rating (the degree of confidence 
participant has in their answer) and observation (eg. 
To find out where people start reading, whether they 
look for instructions, whether they take longer to 
answer any particular questions) 
 
Contrast group construct validity 
Numerical value will be added to ADRe responses (0 
for ‘no’ answers and 1 for ‘yes’ or ‘worse’ answers. 
Numbers of problems will be compared for the group 
(n=20) without prescribed medicines and the group 
(n=20) that is prescribed > 4 medicines (these are 
participants of 1.2 ADRe testing). 
 
Inter-rater Reliability (IRR) 
Cohen’s Kappa will be calculated (Cohen, 1960) to 
compare patient and researcher completion. 
 
Randomised Controlled Trial 
Data will be entered into excel via the electronic 
version of ADRe, imported into SPSS and described 
for the before and after ADRe administrations. 
Statistical analysis: differences between before and 
after the intervention will be calculated for: number 
and nature of problems addressed, prescription 
regimens, NHS use. The impact of GP practice, age, 
diagnoses, and medicines’ use (numbers and types 
of medicines prescribed) will be described and 
accounted for.  To explore the recorded changes and 
potential for further clinical gains, putative aetiologies 
of service users’ signs and symptoms will be 
ascribed, using clinical information from medical and 
nursing records, including, but not restricted to, 
information on ADRe, and the list of medications 
prescribed (and over the counter) The ascription will 
be checked by supervisors  using manufacturers’ 
literature and formularies. Juxtaposition of ADRe and 
medication lists will generate suggestions for 
changes to improve the processes and possibly the 

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outcomes of care. The prevalence of problems on 
the before and after profiles will be compared with 
two by two contingency tables, using McNemar’s test 
for related dichotomous variables (Altman 1991).  
 
Survey 
Data will be described using the Statistical Package 
for Social Sciences (SPSS) and later combined with 
the interview results. 
 
Interviews and recorded ADRe consultations 
All interviews (and relevant parts of ADRe 
consultations) will be transcribed verbatim by the 
researcher/professional transcriber and anonymised.  
Transcripts will be coded, categorised, analysed and 
interpreted alongside the data of all completed 
cases, to identify, analyse and report patterns within 
data (Braun and Clark, 2006). The transcripts will be 
analysed by the team using the constant comparative 
method which will provide a systematic, re-iterative 
way of comparing and contrasting emerging codes, 
categories and concepts and ensure that theoretical 
perspectives are embedded in the description of 
change. Two researchers (VL, SJ) will ensure validity 
of the analysis and verify interpretation.  
Disagreements will be resolved through discussion at 
team meetings. Diaries/logs will also be analysed in 
association with interview transcripts.  
Triangulation 
Survey and interview data will be integrated with the 
outcome measures documented on the ADRe 
Profile, taking a pragmatic perspective of 
complementary triangulation (Östlund et al., 2011). 
Resulting cross-cutting themes derived from the data 
should enhance understanding and validity, and 
contextualise the ADRe data (Foss & Ellefsen, 2002; 
Denzin, 2012).   
 
Costs  
Resource use, costs, and health economic outcome 
measures will be described using  the Personal 

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Social Services Research Unit (PSSRU) unit costs of 
health workers (www.pssru.ac.uk) and the National 
Tariff Payment Systems.   
 
The regulatory and governance requirements will be 
met through gaining approval from the relevant 
review bodies to conduct the project.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Agreement Page 
 
The clinical study as detailed within this research protocol  
 
(Version 2, dated 8th January, 2021),  
 
or any subsequent amendments will be conducted in accordance with the  
• 
UK Policy Framework for Health and Social Care Research (2017) 
• 
Medicines for Human Use (Clinical Trials) Regulations (2004) 
• 
Medical Devices Regulations (EU MDR/IVDR 2017) 
World Medical Association Declaration of Helsinki (1996)  
and the current applicable regulatory requirements and any subsequent 
amendments of the appropriate regulations. 
 
Chief Investigator Name: Prof. Sue Jordan 
Chief Investigator Site: Swansea University 
Contact details:  
 
Tel No: 01792 518541 
 
 
 
Email: S.E.Jordan@swansea.ac.uk 
 
 
 
Fax: 
Signature and Date: 
………………
………………………. 
 
Principal Investigator Name: Vera Logan 
Contact details:  
 
Tel No: 01792 604721 
 
 
 
Email: vera.logan@swansea.ac.uk 
 
 
 
Fax: 
Signature and Date: 
            08/01/2021 
 
Statistician Name: Prof. Sue Jordan 
 
Principal Investigator Site: Swansea University 
Contact details:  
 
Tel No: 01792 518541 
 
 
 
Email: S.E.Jordan@swansea.ac.uk 
 
 
 
Fax: 
Signature and Date: 08/01/2021 
 

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Glossary of Terms and Abbreviations 
 
AE 
 
 
Adverse Event 
 
 
 
AR 
 
 
Adverse Reaction 
ASR  
 
Annual Safety Report 
CA 
 
 
Competent Authority 
CI 
 
 
Chief Investigator 
CRF  
 
Case Report Form 
CRO  
 
Contract Research Organisation 
DMC  
 
Data Monitoring Committee 
EC 
 
 
European Commission 
GAfREC 
Governance Arrangements for NHS Research Ethics 
Committees 
ICF 
 
 
Informed Consent Form 
ISRCTN 
 
International Standard Randomised Controlled Trial Number 
MA 
 
 
Marketing Authorisation 
MS 
 
 
Member State 
Main REC 
 
Main Research Ethics Committee 
NHS R&D 
 
National Health Service Research & Development   
PI 
 
 
Principle Investigator 
QA 
 
 
Quality Assurance 
QC 
 
 
Quality Control 
Participant 
 
An individual who takes part in a clinical trial 
RCT  
 
Randomised Controlled Trial 
REC  
 
Research Ethics Committee 
SAE  
 
Serious Adverse Event 
SDV  
 
Source Document Verification 
SOP  
 
Standard Operating Procedure  
SSA  
 
Site Specific Assessment 
TMG  
 
Trial Management Group 
TSC  
 
Trial Steering Committee 

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Protocol Description/Guidelines 
 
Index  
 
 
 
 
 
 
Insert  Page Number 
 
1. 
Introduction ..................................................................................................... 14  
1.1 Background ....................................................................................................... 14 
1.2 Preclinical Data ................................................................................................. 14 
1.3 Clinical Data ...................................................................................................... 15 
1.4 Rationale and Risks/Benefits ............................................................................ 16  
 
2.      Trial Objectives and Design .......................................................................... 19 
2.1    Trial Objectives ................................................................................................. 19  
2.2    Trial Design ...................................................................................................... 21 
2.3    Study Scheme Diagram ................................................................................... 22  
 
3.      Subject Selection ........................................................................................... 24 
3.1 Number of Subjects and Subject Selection ....................................................... 24  
3.2    Inclusion Criteria ............................................................................................... 26 
3.3 Exclusion Criteria .............................................................................................. 27  
3.4 Criteria for Premature Withdrawal ..................................................................... 29  
 
4.      Study Procedures ........................................................................................... 29  
4.1    Informed Consent Procedures .......................................................................... 29 
4.2    Screening Procedures ...................................................................................... 30  
4.3    Randomisation Procedures (if applicable) ........................................................ 31  
4.4    Schedule of Treatment for each visit ................................................................ 31  
4.5    Schedule of Assessment (in Diagramatic Format) ........................................... 33  
4.6    Follow up Procedures (if applicable) .............................................................. N/A 
4.7    Laboratory Assessments (if applicable) .......................................................... N/A  
4.8 Radiology Assessments (if applicable) ............................................................ N/A  
4.9 Medical Device (if applicable) ............................................................................ 34 
4.10 End of Study Definition ...................................................................................... 34 
4.11  Procedures for unblinding (if applicable) ........................................................ N/A 
4.12  Subject Withdrawal ........................................................................................... 35  
4.13  Data Collection and Follow up for Withdrawn Subjects .................................... 35  
 
5.      Laboratories (if applicable).......................................................................... N/A 
5.1 Central/Local Laboratories  
5.2    Sample Collection/Labeling/Logging  
5.3    Sample Receipt/Chain of Custody/Accountability  
5.4    Sample Analysis Procedures  

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5.5    Sample Storage Procedures (if applicable)  
5.6    Data Recording/Reporting.  
 
6.      Safety Reporting ............................................................................................. 35 
 
6.1    General Definitions ........................................................................................... 35 
6.1.1 
Adverse Event (AE)  
6.1.2 
Serious Adverse Event (SAE) 
6.2    Investigators Assessment  
 
6.2.1 
Seriousness 
6.2.2       Causality 
6.2.3       Expectedness 
6.2.4       Severity 
6.3  Notification and reporting Adverse Events  
6.4    Notification and Reporting of Serious Adverse Events ..................................... 37  
6.4.1       Serious Adverse Event (SAEs) that are ‘related and unexpected’ 
6.5 Urgent Safety Measures 
6.6 Annual Safety Reporting  
6.7    Overview of the Safety Reporting Process/Pharmacoviligance responsibilities 
 
7.      Statistical Considerations ............................................................................. 37 
7.1    Primary Endpoint Efficacy Analysis .................................................................. 37  
7.2   Secondary Endpoint Efficacy Analysis  
7.3   Safety Endpoints  
7.4   Sample Size ...................................................................................................... 38  
7.5   Statistical Analysis ............................................................................................. 38  
 
8.      Data Handling & Record Keeping ................................................................. 41 
8.1    Confidentiality ................................................................................................... 41 
8.2    Study Documents ............................................................................................. 42  
8.3    Case Report Form ............................................................................................ 43   
8.4    Record Retention and Archiving ....................................................................... 44 
8.5    Compliance ...................................................................................................... 44 
8.6    Clinical Governance Issues .............................................................................. 44 
8.6.1       Ethical Considerations 
8.7    Quality Control and Quality Assurance ............................................................. 45 
8.7.1       Summary Monitoring Plan 
         8.7.2      Audit and Inspection 
8.8   Non-Compliance ................................................................................................ 45       
 
 

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9.    Trial Committees .............................................................................................. 45  
 
10.    Publication Policy .......................................................................................... 46 
 
11.    References ...................................................................................................... 46 
 
12.    Appendices ..................................................................................................... 47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. 
Introduction  
 
1.1    Background  
Medicines’ management, especially monitoring therapeutic and adverse effects for 
older adults, is an area of growing importance (Care Quality Commission, 2019; 
NHS Scotland, 2018; NICE, 2015; Oscanoa et al., 2017; WHO, 2017, 2019). 
Medicines prescribed for the older population can lead to medicine-related frailty 
(Saum et al., 2017) and adverse drug reactions due to polypharmacy and altered 
pharmokinetics (Chetty et al., 2018). Adverse drug reactions cause around 5-8% of 
unplanned hospital admissions in the UK, costing the NHS £1.5-2.5bn pa (NICE, 
2015), apart from the avoidable patient harm. 
GP’s are increasingly prescribing more medications that would have been prescribed 
by specialists in the past (Wood, 2020). GMC published in its report Investigating the 
prevalence and causes of prescribing errors in general practice that 1 in 20 
prescriptions contained an error in terms of medication or monitoring, affecting 1 in 8 
patients (2012). It is well known that the number of people with multiple conditions is 
increasing, with older people more likely to live with a long-term disease (Health 
Foundation, 2018). The problems persist, and polypharmacy presents a major threat 
to patient safety internationally (WHO, 2019). 
 Many adverse drug reactions could be prevented with improved monitoring (Gabe et 
al., 2011). Doctors, pharmacists and nurses are regularly involved with aspects of 
medicine management, yet there is often a lack of clarity in who should monitor for 
the side effects and both doctors and nurses think that the other profession monitors 
patients for adverse effects of prescribed medicines (Logan et al 2020). ADRe Profile 
(Jordan et al 2014; Jordan et al 2015) represents an innovative nurse-led tool, which 
collates patient observation and self-reported data to identify a potential link of any 
problems with the medicines prescribed.  
 
1.2    Preclinical Data  
The study population are older people who are prescribed 5 or more medications 
daily. Implied is the presence of one or more long-term conditions, particularly 
cardiovascular, respiratory, endocrine, neurological, mental health and 
musculoskeletal conditions. Implementation of guidelines for management of these 
conditions results in prescriptions. An increase in the number of long-term conditions 
increases the complexity of therapeutic and pharmacological management and is 
associated with the use of multiple medications. Globally, the numbers of older 
people are growing and more live with multimorbidity (WHO, 2016). The UK 
incidence of long-term health problems in people older than 65 years was 8.75 
million in 2019 (Office for National Statistics [ONS], 2020). This translates to over 2 
in 3 people over 65 having a long-term condition. In England, simulation projections 
estimate that between 2015 and 2035, the number of older people with more than 4 

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diseases will double and a third of these will have mental health problems (Kingston 
et al., 2018). Polypharmacy is hence a phenomenon that likely to increase (Duerden 
et al., 2013) and medication safety has been identified as the theme of the WHO 
third global safety challenge (WHO, 2017).    
 
1.3    Clinical Data  
          Medication monitoring and monitoring patients for potential adverse drug reactions 
has been described as an ‘orphan task’ in the past due to its position on the 
interprofessional boundary between pharmacy, medicine and nursing and the 
subsequent deficiency in ownership (Jordan, 2002, Jordan et al., 2016). Recent 
studies confirm the lack of clarity of the nurses’ roles in medication management (De 
Baetselier et al., 2019) and effective teamwork has been affirmed as a facilitator of 
safe management of polypharmacy (WHO, 2019), and medication management 
overall (WHO, 2017). ADRe Profile is an instrument that involves nurses, 
pharmacists, prescribers and patients in monitoring for adverse drug reactions to 
medicines. Nurses and patients identify the problems and may solve some of them, 
pharmacists review the medicines and prescribers may be provided with 
recommendations to consider adjustment of the prescriptions.  
 
To date, two randomised controlled trials and five observational/before and after 
studies have investigated the clinical impact of the ADRe Profile. In total, 168 study 
participants had the ADRe Profile implemented. Majority of the participants were 
prescribed mental health medicines (antipsychotics, antidepressants or anti-
epileptics), one study included patients with respiratory diseases, taking 
bronchodilators, corticosteriods or leukotriene receptor antagonists. The setting was 
mostly in the community, with 3 nursing homes, 3 community mental health settings 
and one outpatient respiratory clinic.  
 
In two of the community mental health settings, the mean number of problems 
actioned increased from 0.35 with no ADRe Profile to 3 with ADRe Profile (Jordan et 
al., 2002; Jordan, 2002). Little change in the number of problems actioned was noted 
in the comparator groups. The mean number of problems detected increased from 2 
without the Profile to 9 with the Profile in one of the studies (Jordan, 2002), no 
information was offered in the other study. Most actions taken were to alleviate 
physical health problems.   
 
Another study from an acute mental health service setting identified and addressed 
health problems for all participants (the mean increase of actions taken was 11.9, SD 
= 4.7, range 2-20) (Jones et al., 2016). Some of the problems identified were 
orthostatic hypotension, hypertension, constipation or inadequate diet, two of the 

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problems were potentially life-threatening (cardiac arrhythmia with chest pain and 
breathlessness and valproate-induced pancreatitis).  
 
The findings of the three studies from care homes are consistent with the above. 11 
participants in a private sector nursing home had at least one problem ameliorated 
(mean = 4.9, SD = 3.6, range = 1-11), for example previously un-noticed abnormal 
movements, postural hypotension and pain (Jordan et al., 2014). Majority of 
residents in the other two care home studies had at least one problem ameliorated. 
The use of the Profile prompted documentation and treatment of pain, balance, 
cognitive decline, irritability and other problems (Jordan et al., 2015) and resulted in 
effective analgesia (7 out of 8 residents with reported pain), amelioration of sedation, 
confusion or hallucinations (on discontinuation of antipsychotics), changes to care to 
prevent further falls (5 out of 9 residents with identified falls) (Jordan et al., 2019). 
Jordan and colleagues (2015) also report a reduction in mental health prescriptions 
associated with the use of the Profile (aOR 4.45, 1.15-17.22), even though total 
number of medicines prescribed has not changed, partly due to increase in 
analgesia.  
 
A trial in a nurse-led respiratory outpatient clinic (Gabe et al., 2014) reported more 
problems identified and actions taken to ameliorate the problems for the ADRe 
Profile intervention arm. Examples of problems identified was muscular weakness 
and pain, dry mouth/dental/oral problems, tendency to bruising and others.  
 
In all studies, the use of ADRe Profile resulted in identification of previously 
unattended problems and empowerment of the nurse to initiate actions to address 
the problems. No harm from completing the checklist has been recorded. The ADRe 
Profile positively contributed to the quality and safety of care. 
 
 
1.4    Rationale and Risks/Benefits  
 
 
This study concerns optimisation of medicines monitoring and multidisciplinary team 
involvement in medicines management and optimisation. Similar projects have not 
encountered major ethical, legal or management issues, and we do not envisage any 
here. The Adverse Drug Reaction (ADRe) Profiles for nurse-led medicines 
monitoring have benefitted patients in all previous trials and observation studies and 
no harms have been reported. In this study, the instrument will be adapted for use in 
general practices and the feasibility of its adoption will be explored by the 
researchers. The ADRe Profile has recently been endorsed by the Royal 
Pharmaceutical Society and All Wales Medicines Strategy Group (AWMSG). 
Embedding the ADRe Profiles thus represents an addition of an established 

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instrument to the nursing documentation and the risk of physical and emotional harm 
from the instrument is predicted to be minimal, and no more than in routine clinical 
interviews. Vital signs will be recorded. Results of ECGs, lung function tests and 
laboratory results will be noted as ‘present / absent’: these tests are not part of the 
study. 
 
 
Risks and burdens according to study participants: 
Content validity index and construct validity respondents: we foresee no 
potential risk of physical or emotional harm to competent adult respondents 
completing an electronic document from their own computers in their own time.  
Cognitive interview participants: we foresee no potential risk of physical or 
emotional harm to competent adult respondents reading through a draft instrument 
with a trained research fellow in their own time. Respondents will be asked questions 
on validity and interpretation of the instrument. They will not be asked any questions 
about themselves or expected to divulge any personal information. No identifiable 
data will be collected.  
Service users – ADRe Profile completion: Previous work in the nursing homes 
and a respiratory clinic indicates that no physical or emotional harms emanate from 
this intervention, and the physical health of all participants has benefitted (Gabe et 
al., 2014; Jordan et al., 2015; Jones et al., 2016; Jordan et al., 2019).  We do not 
foresee any risks of physical or emotional harm in this or future studies. We foresee 
no legal or organisational risk from this study. Any changes to patient management 
will be based on the professional judgment of staff delivering routine care, and not 
directed by the study procedures. The intervention only aims to enhance patient 
monitoring to inform professional judgement. All questions and observations are of a 
nature that should be pursued under routine care. Time will be required by nurses to 
complete the ADR profiles; however, the clinical gains reported in care home studies 
are likely to outweigh any diversion of resources (Jordan et al., 2015, 2014, 2019). 
Should any answers in the ADRe Profile raise the nurse-researcher’s concern about 
physical or mental health and well-being of the participant, clinical judgment will be 
applied and the participant will be advised or referred to their general practitioner. 
Completed ADRe profiles will be passed to the pharmacist associated with the GP 
practice and academic pharmacists and thence prescribers.  

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Balance of risks and benefits of participation in the ADRe Profile completion: 
Risk 
Benefit 
- 
Breach of confidentiality 
- 
Adjustment of medicines, 
additional prescriptions or de-
prescribing 
- 
Possible additional health service 
contacts 
- 
Possible misunderstanding (esp. 
people who have difficulty 
speaking or understanding 
English) 
- 
Additional medication review 
- 
Potential identification and 
amelioration of health and well-
being problems 
- 
Opportunity to discuss therapeutic 
regimen with academic clinicians, 
and access ADRe’s supporting 
information. 
 
Survey and semi-structured interviews: stakeholder perspectives will be sought 
from service users, nurses, pharmacists and GP’s. There are no significant risks 
attached to these interviews, however; should any participant become 
upset/distressed during the interviews, the researcher, who is experienced at de-
escalating difficult/emotional situations, will deal with the situation. Potential risks and 
burdens will be described in the participant information sheet in such a way that 
participants can clearly understand what will be involved if they consent to take part. 
The principles of GCP training and the standard operating procedures of the 
Swansea Clinical Trials Unit will be followed throughout. The trials unit has granted 
access to their standard operating procedures. 
Covid 19 pandemic: The researchers will ensure compliance with health and safety 
requirements in the context of the pandemic, and measures that adhere to current 
infection control guidelines (e.g. protective equipment, social distancing). Alternative 
arrangements have been planned to protect the potentially vulnerable participants 
from the effects of Covid 19. If by the time the trial is taking place it would be 
deemed that in-person exposure would increase the participants’ risk of contracting 
Covid 19, all contact will be only electronic, through video calls, phone calls or by 
post. We will be guided by Welsh government responses to the pandemic.  

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2.      Trial Objectives and Design 
 
2.1    Trial Objectives  
 
 
Primary Objectives  
• 
To establish the suitability/effectiveness of ADRe Profile for video call 
completion  
• 
To establish whether patients could complete parts of ADRe Profile themselves 
• 
To explore whether the ADRe Profile identifies health problems that could be 
attributable to polypharmacy and ameliorated (and record any changes to care, 
benefits or harms to the patients) 
• 
To explore whether routinely collected data could be used to populate the 
ADRe Profile 
 
         Secondary Objective  
• To establish the validity and reliability of the ADRe Profile 
• To explore the feasibility of linking the electronic ADRe Profile to GP 
electronic records 
• To report how ADRe Profile contributes to efficient collaboration of the 
multiprofessional team (nurses, care assistants, pharmacists, GP’s) in 
monitoring the effects of patients’ medications  
• To report how ADRe contributes to patient-centered care 
• To estimate costs associated with ADRe implementation 
 
         Primary Endpoint  
Phase 1 
• 
Content validity index (overall assessment of validity of the instrument) 
• 
Construct validity (overall assessment of validity of the instrument) 
• 
Cognitive interviews: Enhanced understanding how participants answer the 
ADRe questions. 
• 
Inter-rater reliability of patient versus nurse-researcher completed ADRe Profile 
(Cohen's Kappa) - (To determine how much of the potential variability of the 
records is due to errors in measurement, to estimate a degree to which service 
users accurately evaluate their symptoms when compared with a nurse 
researcher, to determine suitability of ADRe for patient self-completion. Cohen's 
Kappa will be calculated.)  [Time Frame: 4 months from the start of the study] 
• 
Level of completion of all items in the video call-completed ADRe Profile. 
(Comparison of completeness of the ADRe Profile completed through a video 

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call with ADRe Profiles previously completed in person, suitability of ADRe 
Profile for video call completion.)   [Time Frame: 4 months from the start of the 
study] 
• 
Calculated percentage and described nature of items on the ADRe Profile that 
can be populated from accessing the nursing and medical notes. (Establishing 
the overlap of information - the number and nature of the ADRe items that have 
previously been collected and recorded in the patients' nursing and medical 
notes.) [Time Frame: 16 months from the start of the study] 
Phase 2 
• 
Clinical impact on service users, including new problems identified (number and 
nature) and problems addressed (number and nature). [Time Frame: 16 months 
from the start of the study] 
• 
Number of patients with a change in signs and symptoms related to adverse 
effects of prescribed medicines. Care quality/ clinical gain/ benefit to patients as 
recorded in notes and on the Profile by the number and nature of all health 
problems addressed, particularly serious adverse events. [Time Frame: 16 
months from the start of the study] 
• 
Prescription changes (number of patients with changes in prescription 
regimens: drug or dose. Number and nature of changes). [Time Frame: 16 
months from the start of the study] 
Phase 3 
• 
Description of stakeholder views on ADRe Profile implementation effectiveness 
(survey rating of the ADRe Profile - Likert scale). A brief survey will be 
distributed to the main stakeholders (patients, nurses, GP's and pharmacists) 
following completion of Randomised Controlled Trial. [Time Frame: 22 months 
from the start of the study] 
• 
Description of stakeholder views on ADRe Profile implementation feasibility 
(eliciting interview themes). Semi-structured interview with the main 
stakeholders (patients, nurses, GP's and pharmacists) to explore their views on 
feasibility of ADRe Profile integration in GP practices. [Time Frame: 22 months 
from the start of the study]. 
 
         Secondary Endpoint  
• 
Calculation of the average nurses', GP's and pharmacists' length of time per 
one ADRe Profile completion. Average length of the health professionals' time 
involvement with one ADRe Profile. [Time Frame: 16 months from the start of 
the study]. Phase 2 
• 
Calculation of the cost of nurses', GP's and pharmacists' time, based on 
average national salary cost per hour. Estimated costs of ADRe implementation 
in GP practices. [Time Frame: 16 months from the start of the study] Phase 2 

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• 
Description of the main stakeholders' views on multidisciplinary collaboration 
(eliciting interview themes). Semi-structured interview with the main 
stakeholders (patients, nurses, GP's and pharmacists) to explore their views on 
whether and how ADRe Profile contributed to multidisciplinary collaboration 
between nurses, doctors and pharmacists. [Time Frame: 22 months from the 
start of the study] Phase 3 
• 
Description of the patients' views on the contribution of ADRe Profile to patient-
centered care (eliciting interview themes). Semi-structured interview with the 
patients to seek their views on whether and how ADRe Profile contributes to 
patient-centered care. [Time Frame: 22 months from the start of the study] 
Phase 3 
 
 
2.2    Trial Design  
 
Phase 1 
• Validity testing: content validity index (CVI), cognitive interviews, construct 
validity testing 
• Feasibility trial 
• Reliability testing (inter-rater reliability) 
Phase 2 
• Randomised controlled trial (cluster group randomization by GP practice, 
intervention arm (ADRe Profile implementation), control arm (standard of 
care) 
Phase 3 
• Interviews and survey with participants of phase 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.3    Study Scheme Diagram  
 
 
 
 

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3.      Subject Selection 
 
3.1    Number of Subjects and Subject Selection  
   
Content Validity Index sample size n = 10 
Participants: a convenience sample of 2 GPs, 2 pharmacists, 2 nurses working in 
general practice/community and 2 care assistants working in general 
practice/community and 2 patients 
Recruitment strategy: advertise in research networks and the university 
 
Contrast group sample size n = 2x20 
Participants: a convenience sample of up to 20 service users > 64 who do not take 
prescribed medicines daily. 
Recruitment strategy: Advertise in research networks and the university 
 
Cognitive interview sample size n = 5 
Participants: a convenience sample of 1 patient, 1 nurse working in general 
practice/community, 1 care assistant working in general practice/community, 1 GP + 
1 pharmacist 
Recruitment strategy: Advertise in research networks and the university 
 
Inter-Rater Reliability sample size n = 20 + 30 = 50 
Participants: 20 service users from 2 general practices, >64, with >4 prescribed 
medicines. 
Recruitment strategy: Approach cluster areas in Swansea Bay UHB and Hywel Dda 
UHB. Invitation by letter and/or email. General practice to identify suitable patients 
and approach them to invite for participation. 
 
Randomised Controlled Trial sample n = 60 
Participants: 6 new general practices x 10 patients and practice / district nurses or 
nurse assistants 
 

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Recruitment strategy:  approach all 8 GP clusters in Swansea Bay UHB and 7 
clusters in Hywel Dda UHB by post and/or email. General practice to identify suitable 
patients and approach them to invite for participation. 
Calculation of the sample size: 
RCT (sample = 60): Previously, in a ‘before and after’ single arm intervention study, 
with participants acting as their own controls, 17/19 (89%) had improvement in at 
least 1 clinical problem when ADRe Profiles for polypharmacy were used (Jordan et 
al submitted). We hypothesised that 9/19 (47%) would have shown some 
improvement without intervention, necessitating an effective sample of 40 patients 
(20 in each arm), with 5% significance and 90% power (Uitenbroek 1997). Based on 
the reported intra-cluster coefficient (0.02), (Jordan et al 2015), and a design effect 
of 1.18, to achieve an effective sample size of 40, we need an actual sample size of 
48 (Killip et al 2004). 10 patients in each of 6 clusters (GP practices) allows for 20% 
loss to follow up, which is realistic in general practice, where either patient or nurse 
may be unavailable for follow up. 
 
Survey sample size: up to 3 nurses, 3 pharmacists, 3 GP’s and up to 30 service 
users. 
For the survey, all health professionals involved with the intervention arm (n=9) and 
all service users in the intervention arm (n=30) will be included. The aim is to gain 
stakeholder views on the intervention. 
 
Qualitative semi-structured interviews sample size - 3 nurses, 3 pharmacists, 3 
GP’s and 3 service users  
For the qualitative interviews, a convenience sample of 12 participants will be 
selected. This will include all nurses, GP’s and pharmacists in the intervention arm, 
as well as a purposive sample of 3 patients. The patients will be selected based on 
the most positive and most negative responses in the survey. The aim is to gain 
stakeholder views on the intervention and to supplement and illustrate the RCT data.  
 
 
 
 

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3.2    Inclusion Criteria  
Phase 1 
• Content validity index respondents: healthcare professionals (current or 
retired, working full-time or part-time, willing to participate and sign informed 
consent), service users (age > 64, willing to participate) 
• Cognitive interview respondents: healthcare professionals (current or 
retired, working full-time or part-time, willing to participate), service users (age 
> 64, willing to participate and sign informed consent) 
• Contrast group validity respondents: group A (people, age >64, no daily 
prescribed medicines - vitamin and nutritional supplements and moisturising 
skin preparations will not be counted as ‘medicines’, willing to participate and 
sign informed consent), group B (as below) 
• Inter-rater reliability and feasibility participants: service users (age > 64 
years, with a long-term condition, prescribed > 5 medications daily. (Vitamin 
and nutritional supplements and moisturising skin preparations will not be 
counted as ‘medicines’.), Willing and able to give informed, signed consent 
themselves, or where capacity is lacking in the opinion of their nurses, a 
consultee/representative accompanying the patient who is willing to give 
advice and assent to the service user participating and sign on their behalf. 
 
Phase 2 
Service users: 
• age > 64 years  
• with a long-term condition 
• prescribed > 5 medications daily. (Vitamin and nutritional supplements and 
moisturising skin preparations will not be counted as ‘medicines’.) 
• Willing and able to give informed, signed consent themselves, or where 
capacity is lacking in the opinion of their nurses, a consultee/representative 
accompanying the patient who is willing to give advice and assent to the 
service user participating and sign on their behalf. 
Nurses: 

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• Working in or alongside a general practice and expected to work there for the 
next 6 months, willing to participate and sign informed consent 
Pharmacists and GP’s: 
• Aligned with the general practice, expected to stay in employment for the next 
6 months, willing to participate and sign informed consent 
Phase 3 
No new participants, we shall approach people who took part in Phase 2. 
 
 
3.3    Exclusion Criteria  
Phase 1 
• Content validity index respondents: not willing to participate 
• Cognitive interview respondents: not willing to participate 
• Contrast group validity respondents: not willing to participate 
• Inter-rater reliability and feasibility testing respondents: age < 64 years, 
without any long-term conditions, prescribed < 5 medications daily, not willing 
to participate, unable to consent and no consultee/representative present, not 
fluent in English or Welsh (unless a family member can assist with 
translation), receiving palliative care, expected to remain in the practice for the 
next 12 months 
 
Phase 2 
Service users: 
• Age < 64 years 
• Without any long-term conditions 
• Prescribed < 5 medications daily 
• Not willing to participate 
• Unable to consent and no consultee/representative present 
• Not fluent in English or Welsh (unless a family member can assist with 
translation) 
• Receiving palliative care 

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• Expected to remain in the practice for the next 12 months 
Nurses: 
• Unwilling to participate, unwilling to administer ADRe Profile 
Pharmacists and GP’s: 
• Unwilling to participate, unwilling to review ADRe Profile 
Phase 3 
No new participants. 
 
Recruitment and identification of personal Consultees:  In the event that a 
participant lacks decision-making capacity regarding participation in the study a 
personal consultee will be identified to provide advice.  The Consultee may be their 
next of kin, family member, a friend, an unpaid carer, other relative in regular 
contact. The Personal Consultee will have an unpaid or non-professional role in 
caring for the person. 
The consultee will be identified by the practice nurse as they will likely accompany 
the service user to the GP practice or respond to the invitation to participate on 
behalf of the service user. The consultee will be contacted to provide a information 
about the study (Participant Information Sheet for consultees) and they will be asked 
for their advice regarding the inclusion of the person and what the person’s views 
would have been regarding inclusion in the research if they had capacity to make the 
decision for themselves.  If they are happy to be a Personal Consultee, they will sign 
the consent form for consultees. 
In the event that a Personal Consultee cannot be identified, or is not willing or able to 
act (for example due to their own illness or infirmity), the service user will not be 
included in the study.  
The Consultees will have as much time as they need to consider the study and will 
have the opportunity to ask the practice nurse/or the researcher questions before 
giving their advice regarding the inclusion of the person lacking capacity.   
The practice nurse/researcher will obtain written confirmation that the Consultee has 
provided consent by means of a Consultee dated signature on the Consultee 
Declaration Form, and dated signature of the person who presented and obtained 
the declaration.  
The original signed form will be retained in the participant’s medical records, a copy 
will be provided to the researcher for the ADRe Study site file in the ADRe office, and 
copies will be offered to the participant or his/her family and the consultee. 
 
 

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3.4    Criteria for Premature Withdrawal  
 
Parts of the study involve single contact with researcher, so there is little scope for 
non-compliance (content validity index, cognitive interviews, construct validity, 
survey, interviews). The feasibility trial (n=20) and the intervention arm of the trial 
(n=30) involve 3 and 5 points of contact (in person or virtual), respectively. If the 
participant becomes too unwell to respond to ADRe, and there is no consultee 
available, they will not be asked to complete a 2nd ADRe. However, unless informed 
otherwise, we shall retain collected data and collect information from patients’ notes 
as originally planned. 
 
4.      Study Procedures  
 
4.1    Informed Consent Procedures 
 
Informed consent will be gained from all research participants. Principal investigator 
or the practice nurse will take consent,  
Arrangements for seeking consent: 
In designing the consent process, we aimed for transparency and clarity, and we 
chose wording that we think reduces the possibility that potential participants feel 
pressured to join the study due to a sense of moral responsibility. 
Consent for the validity and reliability testing will be sought electronically. 
Procedure for seeking consent for the feasibility testing, RCT, survey and interview: 
when expressions of interest are received from potential participants, we shall 
approach the individuals and arrange a time and format (i.e. virtual or face-to-face) 
that is preferred and convenient for them and in line with Covid 19 pandemic 
guidelines. All potential participants will be given an information sheet outlining the 
purpose of the project and interview and given time to reflect on the study. Help and 
clarification will be given as needed. During this process the nurse-researcher will 
make judgements whether the potential participant is able to understand the 
information relevant to the decision, retain that information, use or weigh up that 
information as part of the process of making the decision, and communicate their 
decision. Participants appearing to be competent will be asked to sign a consent 
form (electronic signature will be accepted). If any doubts arise with regards to 
competence, the service user’s consultee will be approached, if available, or the 

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decision will be postponed. The service user will not be included in the study if not 
competent and no consultee/representative available. Consent will be recognised as 
a continuously negotiated process, which provides opportunities for ongoing 
communication between the researcher and participant ensuring voluntary and 
informed participation. For consenting participants, a copy of the consent will be 
retained in the patient’s notes, a copy will be offered to the participant and a copy will 
be securely stored by the researchers (chief investigator’s locked office). 
Participant Information Sheets (PIS): 
Participant information sheets will clearly explain the study in plain language. A copy 
given to participants will be kept for future reference. GDRP leaflet and Summary 
information will be included in PIS. The date PIS has been given to the participant 
will be recorded in the notes along with the consent form to ensure sufficient length 
of time for participants to decide on their involvement.  
Participants will have as long as needed to decide whether or not they want to take 
part, maximum of 14 days. 
 
4.2    Screening Procedures  
 
Initial screening will be performed by a member of the potential participant’s usual 
clinical care team. This healthcare professional will keep a screening log record. 
 
 
 
4.3     Randomisation Procedures (if applicable)  
 
Randomisation of participants in Phase 2 will be performed to promote internal 
design validity and minimise the effects of confounding. To avoid selection bias and 
enable allocation concealment, GP practices will be selected and patients consented 
before randomization. While masking is not possible due to the design of the study, 
ascertainment bias will be lowered by researchers not being aware of the 
randomization results until after they have accessed the nursing and medical notes 
and elicited necessary data. Cluster randomization will allow each practice its own 
care as an independent entity and will minimize contamination. The cluster design 
has been accounted for in the sample size.  

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4.4    Schedule of Treatment for each visit  
 
Procedure 
Number 
of 
interve
ntions 
Routine Averag
e time 
Who will 
conduct 
Place 
PHASE 1 
Consent for 
CVI 
1 
no 
5 mins 
researcher 
Electronic 
Content 
validity index 
1 
0 
10 mins  researcher 
Electronic  
Consent for 
cognitive 
interview 
1 
0 
5 mins 
researcher 
Electronic 
Cognitive 
interviews 
1 
0 
1 hour 
researcher 
Virtual (video call) 
Consent for 
construct 
validity 
testing 
1 
0 
5 mins 
researcher 
Electronic 
Construct 
validity 
testing 
1 
0 
10 mins 
researcher 
Electronic 
Consent (+ 
reading PIS) 
for service 
users – 
PHASE 1 
1 
0 
15 mins 
– as 
long as 
the 
participa
nt 
needs 
Researcher
s or nurses 
Virtual/GP 
surgery 
ADRe Profile 
self-
completion 
1 
1 
10 – 25 
mins 
service 
users 
Virtual 
ADRe Profile 
completion 
with nurse 
1 
1 
10 – 25 
mins 
Nurse-
researchers 
Virtual/GP 
surgery 

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researcher 
Debrief 
1 
0 
15 mins 
researchers 
Virtual/GP 
surgery 
PHASE 2 
Consent (+ 
reading PIS) 
1 
0 
15 mins 
– as 
long as 
the 
participa
nt 
needs 
Researcher
s or nurses 
Virtual/GP 
surgery/patient’s 
home 
Introductory 
training for 
nurses 
1 
0 
15 mins 
Researcher 
Virtual/GP 
surgery 
ADRe Profile 
self-
completion 
2 
1 
10 – 25 
mins 
service 
users 
electronically or 
by post 
ADRe Profile 
completion 
with a 
nurse/nurse-
researcher 
2 
1 
10 – 25 
mins 
nurse/resea
rchers 
Virtual/GP 
surgery/patient’s 
home 
Debrief 
1 
0 
15 mins 
researchers 
Virtual/GP 
surgery/patient’s 
home 
PHASE 3 
Survey – 
service users 
1 
0 
10 mins 
researchers 
Electronic/by post 
Survey – 
GP’s 
1 
0 
10 mins 
researchers 
Electronic/by post 
Survey - 
pharmacists 
1 
0 
10 mins 
researchers 
Electronic/by post 
Survey – 
nurses/care 
assistants 
1 
0 
10 mins 
researchers 
Electronic/by post 
Interview  - 
1 
0 
1 hour 
researchers 
Virtual/GP 
surgery/patient’s 

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service users 
home 
Interview – 
GP’s 
1 
0 
1 hour 
researchers 
Virtual/GP 
surgery 
Interview - 
pharmacists 
1 
0 
1 hour 
researchers 
Virtual/GP 
surgery 
Interview – 
nurses/care 
assistants 
1 
0 
1 hour 
researchers 
Virtual/GP 
surgery 
Debrief 
/feedback 
1 
1 
10 mins 
researcher 
Virtual/GP 
surgery 
 
4.5    Schedule of Assessment (in Diagramatic Format)  
 
Phase of study 
Intervention arm 
Control arm 
Phase 1 - feasibility 
Medical notes accessed 
for items to populate 
ADRe Profile 
No control  
 
Self-completed ADRe 
Profile 
 
 
Researcher-completed 
ADRe Profile 
 
Phase 2 – RCT step 1 
Medical notes accessed 
for items to populate 
ADRe Profile 
Medical notes accessed 
for items to populate 
ADRe Profile 
 
Self-completed ADRe 
Profile 
Standard of care 
 
Nurse or researcher-
completed ADRe Profile 
Standard of care 
Phase 2 – RCT step 2 
Medical notes accessed 
for items to populate 
ADRe Profile 
Medical notes accessed 
for items to populate 
ADRe Profile 
 
Self-completed ADRe 
Profile 
Standard of care 
 
Researcher-completed 
ADRe Profile 
Standard of care 
Phase 3 – Survey and 
interviews 
Survey administered to 
service user participants 
 
 
Interviews performed 
with  selected 
 

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participants (3 service 
users, 3 nurses, 3 GP’s, 
3 pharmacists) 
 
4.6    Follow up Procedures (if applicable)  
N/A 
 
4.7    Laboratory Assessments (if applicable)  
N/A 
 
4.8     Radiology Assessments (if applicable)  
N/A 
 
4.9 Medical Devices (if applicable) 
        ADRe Profile is designed to help healthcare professionals detect possible adverse 
side effects caused by service users’ primary care medicines, and review their 
general health and well-being, in case this has worsened as a result of these 
medicines. It brings together relevant information and gives the prescriber or 
pharmacist reviewer a picture of all possible adverse effects and all medicines 
prescribed.  
 
4.9    End of Study Definition  
 
        End of a clinical trial will be the last visit (or virtual visit) of the last subject to 
complete the ADRe Profile. End of the whole study will be the interview with the last 
interviewee. The end of the study is estimated to be October 2022 and no later than 
July 2023. 
Criteria for stopping the study early: 
- inability to access GP service users, recruit participating GP practices 
- serious event precluding principle or chief investigator from finishing the research 
- results from phase 1 show no justification for continuing with phase 2, results from 
phase 2 show no justification for continuing with phase 3. 
 
        Once the end of study has been declared, no further substantial amendments will be 
made and a Clinical Trial Summary Report will be produced. The HRA ethics 
committee (The ‘Declaration of the End of Trial Form’ will be completed) and the 
NHS R&D offices will also be notified within 3 months of the end of the study. 
 
4.11  Procedures for unblinding (if applicable)  
N/A 
 

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4.12  Subject Withdrawal  
Criteria for participant withdrawal: 
- participant's /consultee's wishes 
- physical deterioration, where continuing with the research would represent a 
burden on the participant 
- failure to engage in participation 
- move into long-term care facilities 
- prolonged hospitalisation 
 
4.13 Data Collection and Follow up for Withdrawn Subjects  
Unless requested otherwise, data that has been already collected will be kept for 
withdrawn participants. 
 
 
5.      Laboratories (if applicable) 
N/A 
 
6.      Safety Reporting  
 
6.1    General Definitions 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a subject to whom a medicinal product 
has been administered, including occurrences which are not necessarily caused by 
or related to that product. An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom or disease temporarily 
associated with study activities. 
Serious Adverse Event (SAE) 
An SAE fulfils at least one of the following criteria: 
· Is fatal – results in death (NOTE: death is an outcome, not an event) 
· Is life-threatening 
· Requires inpatient hospitalisation or prolongation of existing hospitalisation 
· Results in persistent or significant disability/incapacity 
· Is a congenital anomaly/birth defect 
· Is otherwise considered medically significant by the Investigator 
 
6.1.1 
Adverse Event (AE) 
If an adverse event is identified or reported, it will be recorded in the participant’s 
medical records. Any adverse events will be assessed by the clinical team and the 
chief investigator. Any adverse events arising as a result of the ADRe checklist will 
be passed to the sponsor’s representative and the participant’s responsible clinician 
for assessment. No adverse events have arisen as a result of using the ADRe 

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checklists in 2 trials and 3 observation studies. Previous research has not identified 
any harm resulting from completing the ADRe Profile checklist. We are not planning 
on establishing a Data Monitoring Committee.  
 
6.1.2       Serious Adverse Event (SAE) 
Previous research has not identified any harm resulting from completing the ADRe 
Profile checklist. We are not planning on establishing a Data Monitoring Committee. 
 
6.2    Investigators Assessment  
 
6.2.1 
Seriousness 
The Chief/Principal Investigator or the clinical team responsible for the care of the 
patient will assess whether the event is serious. 
 
6.2.2       Causality 
The Chief Investigator will be responsible for assessing the causality. 
 
6.2.3       Expectedness 
It is unlikely that completing a checklist should cause any serious adverse events.  
 
6.2.4       Severity 
The Chief Investigator will assess the severity of the event according to the following 
definitions: 
Mild: Some discomfort noted but without disruption of daily life 
Moderate: Discomfort enough to affect/reduce normal activity 
Severe: Complete inability to perform daily activities and lead a normal life 
 
 
6.3  Notification and reporting Adverse Events or Reactions 
Any Adverse Event will be recorded in the study file and the participant will be 
followed up the research team. The Adverse Event will be documented in the 
participant’s medical notes and the CRF. 
 
6.4    Notification and Reporting of Serious Adverse Events  
 
6.4.1        
Related and unexpected Serious Adverse Events will be reported to the sponsor 
within 24 hours of learning of the event and to the Main REC within 15 days. 
 
6.5 Urgent Safety Measures 
 

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Should the Chief Investigator need to take any urgent safety measures to ensure the 
safety and protection of the trial participants from any immediate hazard to their 
health and safety, any such measures will be taken immediately. The Sponsor and 
the Main Ethics Committee will be informed immediately via telephone and in writing 
within 3 days (in a form of a substantial amendment). The Sponsor will be sent a 
copy of all correspondence. 
 
 
6.6 Annual Safety Reporting  
The Chief Investigator will send the Annual Progress Report to the main REC (using 
NRES template).  
 
6.7    Procedures for reporting blinded ‘ unexpected’ and related’ SAEs 
N/A 
 
6.8    Overview of the Safety Reporting Process/Pharmacoviligance responsibilities 
It is extremely unlikely that the implementation of the ADRe Profile (checklist) should 
cause any harm. The ADRe Profile has been developed to identify and support 
amelioration of potential side effects from commonly prescribed medicines. As part 
of the study protocol, the completed ADRe Profile and the list of patient’s medicines 
is reviewed by the study pharmacist and, if needed, the patient’s GP. 
 
 
7.      Statistical Considerations 
7.1    Primary Endpoint Efficacy Analysis  
Differences between before and after the intervention will be calculated for: problems 
addressed, prescription regimens, NHS use, and compared, adjusting for site. The 
impact of age, diagnoses, and medicines’ use (numbers and types of medicines 
prescribed) will be accounted. 
 
7.2    Secondary Endpoint Efficacy Analysis  
N/A 
 
7.3    Safety Endpoints  
N/A 
 
7.4    Sample Size  
 
RCT (sample = 60): Previously, in a ‘before and after’ single arm intervention study, 
with participants acting as their own controls, 17/19 (89%) had improvement in at 
least 1 clinical problem when ADRe Profiles for polypharmacy were used (Jordan et 

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al submitted). We hypothesised that 9/19 (47%) would have shown some 
improvement without intervention, necessitating an effective sample of 40 patients 
(20 in each arm), with 5% significance and 90% power (Uitenbroek 1997). Based on 
the reported intra-cluster coefficient (0.02), (Jordan et al 2015), and a design effect 
of 1.18, to achieve an effective sample size of 40, we need an actual sample size of 
48 (Killip et al 2004). 10 patients in each of 6 clusters (GP practices) allows for 20% 
loss to follow up, which is realistic in general practice, where either patient or nurse 
may be unavailable for follow up. 
For the survey, all health professionals involved with the intervention arm (n=9) and 
all service users in the intervention arm (n=30) will be included. The aim is to gain 
stakeholder views on the intervention. 
For the qualitative interviews, a convenience sample of 12 participants will be 
selected. This will include all nurses, GP’s and pharmacists in the intervention arm, 
as well as a purposive sample of 3 patients. The patients will be selected based on 
the most positive and most negative responses in the survey. The aim is to gain 
stakeholder views on the intervention and to supplement and illustrate the RCT data.  
 
7.5    Statistical Analysis  
 
We are combining  quantitative and qualitative methods of analysis to capitalize on 
the respective strengths of each of the approaches. The mixed methods will help to 
evaluate the intervention effect from a patient perspective, as well illustrate the 
conclusions derived from the quantitative data with stakeholder insight (Bharmal et 
al., 2018).  
The overall design is sequential: QUAN Phase 1 informs QUAN + qual Phase 2, 
which informs convergent design Phase 3 ( QUAL + quan), Itemised methods of 
analysis are described below: 
Content Validity Index (CVI) 
To be measured using Lynn’s (1986) method: 
Experts will rate each item using a four-point ordinal scale (1 = not relevant, 2 = 
somewhat relevant, 3 = quite relevant, and 4 = highly relevant) 
Number of experts rating the item 3 or 4 will be divided by total number of experts 
Result of 0.78 or above will be accepted as having met the validity threshold.  
Scale content validity ratio will be calculated as a proportion of total items judged 
against content valid items. 
 
Cognitive interviews 

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Think aloud technique combined with participant confidence rating (the degree of 
confidence participant has in their answer) and observation (eg. To find out where 
people start reading, whether they look for instructions, whether they take longer to 
answer any particular questions) 
 
 
Contrast group construct validity 
Numerical value will be added to ADRe responses (0 for ‘no’ answers and 1 for ‘yes’ 
or ‘worse’ answers. Numbers of problems will be compared for the group (n=20) 
without prescribed medicines and the group (n=20) that is prescribed > 4 medicines 
(these are participants of 1.2 ADRe testing). 
 
Inter-rater Reliability (IRR) 
Cohen’s Kappa will be calculated (Cohen, 1960) to compare patient and researcher 
completion. 
 
Randomised Controlled Trial 
Data will be entered into excel via the electronic version of ADRe, imported into 
SPSS and described for the before and after ADRe administrations. Statistical 
analysis: differences between before and after the intervention will be calculated for: 
number and nature of problems addressed, prescription regimens, and NHS use. 
The impact of GP practice, age, diagnoses, and medicines’ use (numbers and types 
of medicines prescribed) will be described and accounted for in exploratory bivariate 
and multivariate regression analyses.  To explore the recorded changes and 
potential for further clinical gains, putative aetiologies of service users’ signs and 
symptoms will be ascribed, using clinical information from medical and nursing 
records, including, but not restricted to, information on ADRe, and the list of 
medications prescribed (and over the counter) The ascription will be checked by 
supervisors  using manufacturers’ literature and formularies. Juxtaposition of ADRe 
and medication lists will generate suggestions for changes to improve the processes 
and possibly the outcomes of care. The prevalence of problems on the before and 
after profiles will be compared with two by two contingency tables, using McNemar’s 
test for related dichotomous variables (Altman 1991).  
 
Survey 
Data will be described using the Statistical Package for Social Sciences (SPSS) and 
later combined with the interview results. 
 
Interviews and recorded ADRe consultations 
All interviews (and relevant parts of ADRe consultations) will be transcribed verbatim 
by the researcher/professional transcriber and anonymised.  Transcripts will be 

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coded, categorised, analysed and interpreted alongside the data of all completed 
cases, to identify, analyse and report patterns within data (Braun and Clark, 2006). 
The transcripts will be analysed by the team using the constant comparative method 
which will provide a systematic, re-iterative way of comparing and contrasting 
emerging codes, categories and concepts and ensure that theoretical perspectives 
are embedded in the description of change. Two researchers (VL, SJ) will ensure 
validity of the analysis and verify interpretation.  Disagreements will be resolved 
through discussion at team meetings. Diaries/logs will also be analysed in 
association with interview transcripts.  
Triangulation 
Survey and interview data will be integrated with the outcome measures documented 
on the ADRe Profile, taking a pragmatic perspective of complementary triangulation 
(Östlund et al., 2011). Resulting cross-cutting themes derived from the data should 
enhance understanding and validity, and contextualise the ADRe data (Foss & 
Ellefsen, 2002; Denzin, 2012).   
 
Costs  
Resource use, costs, and health economic outcome measures will be described 
using  the Personal Social Services Research Unit (PSSRU) unit costs of health 
workers (www.pssru.ac.uk) and the National Tariff Payment Systems.   
 
The regulatory and governance requirements will be met through gaining approval 
from the relevant review bodies to conduct the project.  
 
 
8.      Data Handling & Record Keeping 
 
8.1     Confidentiality  
The Caldicott principles have been followed as an ethical framework for use of 
identifiable data. 
We will only collect data that is necessary for answering the research question and 
all data will be de-identified and patient numbers/codes used. 
Participants will be informed in the Participant Information Sheet about how their 
data will be handled and processed. They will also be informed of who will have 
access to the data. 
The research involves access to patient data: we shall remain mindful of the risks for 
patients associated with any breach of confidence or failure to maintain data 
security. The study team will respect confidentiality of personal data and meet the 

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requirements of the GDPR regulations and the Data Protection Act, 2018. The 
research fellow is a registered nurse, recognises the common law duty of 
confidentiality and is bound by professional code of conduct (NMC, 2018).  
Completed ADRe Profiles will be either collected electronically (with access secured 
using the University’s login system), or will be returned by post. No identifiable data 
will be collected on the Profile, only a code number, m/f and age. All data files and 
transcripts of the interviews/relevant parts of ADRe consultations will be 
pseudonymised and de-identified before analysis.    All data analysis will be 
performed by the research team.  
In interviews and ADRe consultations, we shall try not to collect or transcribe, and 
will delete from recordings and transcripts, all names, addresses, postcodes, birth 
dates, ages, salaries, identification numbers, location data of interviews and 
organisations, online identifiers or references to factors specific to the physical, 
physiological, genetic, mental, economic, cultural or social identity of respondents or 
organisations. Omissions and redactions will be marked []. Digital recordings from 
the recording devices will be transferred to a password-protected single user PC for 
anonymization, transcription and storage. Any transcriptions of interviews and 
relevant parts of ADRe consultations will be performed by the research 
team/professional transcriber. Interviews will be assigned numbers and pseudonyms 
will be used if necessary. Transcripts will be anonymised and de-identified in 
accordance with the ICO (2012) guidelines (A38). Every interview that has been 
anonymised and analysed will be saved in a separate Word file. During the analysis, 
code labels will be applied to the text. The chief investigator will keep an anonymised 
code table in a Word file on the work computer (secured with password). 
In addition, we shall not, for all participants, collect genetic data, biometric data, 
tissue samples, or data concerning a natural person's sex life or sexual orientation. 
Data concerning health will not be collected from healthcare professionals and 
patients responding to CVIs and cognitive interviews (ICO 2012, MRC 2018).  
Any disclosures at interview will be treated in strict confidence. We shall avoid 
disclosure of attributable data in publications. Study numbers will be used 
throughout. All research participants will be given an information sheet detailing the 

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use of their data. They will also be asked to sign consent forms when they have read 
and considered the information sheets. 
A log of changes made to anonymise the data will be kept on password protected 
single user PCs of the chief investigator.  
The researchers accept the professional, public, institutional and personal 
responsibility associated with conducting research. The sponsor of the study – 
Swansea University – is a signatory to the Concordat to Support Research Integrity 
(2019), and the expected ethical and procedural standards will be observed. The 
research fellow is further bound by professional code of conduct (NMC, 2018) and 
completed Swansea University statutory research training and GCP training (training 
file available on request). 
 
 
8.2    Study Documents  
• A signed protocol and any subsequent amendments 
• Current Summary of Product Characteristics/ Investigator’s Brochure 
• Sponsor Self-Monitoring template for the trial team to complete on a regular    
basis as detailed by the Monitoring section 
• Current/Superseded Patient Information Sheets (as applicable) 
• Current/Superseded Consent Forms (as applicable) 
• Indemnity documentation from sponsor 
• Conditions of Sponsorship from sponsor 
• Conditional/Final R&D Approval  
• Signed site agreement 
• Ethics submissions/approvals/correspondence 
• CVs of CI and site staff 
• Laboratory accreditation letter, certification and normal ranges for all 
laboratories to be utilised in the study 
• Delegation log 
• Staff training log 
• Site signature log 
• Patient identification log 
• Screening log 
• Enrolment log  
• Monitoring visit log 
• Protocol training log 
• Correspondence relating to the trial 

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• Communication Plan between the CI/PI and members of the study team 
• SAE reporting plan for the study 
 
 
 
 
 
8.3    Case Report Form  
Swansea Trials Unit’s forms will be adapted for use in CRF (with permission) 
1 List of ADReGP Case Report Forms  
Number 
Title 
FORM 01 
Inclusion Criteria 
FORM 02 
Exclusion Criteria 
FORM 03 
Eligibility review 
FORM 04 
Randomisation/Enrolment 
FORM 05 
Patient Details (age and gender) 
FORM 06 
Baseline Medical Conditions 
FORM 07 
Baseline Medication list  
FORM 08 
Baseline ADRe Profile from available medical notes  
FORM 09 
Baseline Self-completed ADRe Profile 
FORM 10 
Baseline Nurse/researcher-completed ADRe Profile 
FORM 11 
Endpoint Medical Conditions 
FORM 12 
Endpoint Medication list 
FORM 13 
Endpoint ADRe Profile from available medical notes 
FORM 14 
Endpoint Self-completed ADRe Profile 
FORM 15 
Endpoint Nurse/researcher-completed ADRe Profile 
FORM 16 
Adverse Events 
FORM 17 
Serious Adverse Events 
FORM 18 
End of Treatment 
FORM 19 
Details of Death 
FORM 20 
Consent Withdrawal 
FORM 21 
PI Declaration 
QUESTIONNAIRES 
Patient survey 
Nurse survey 
GP survey 
Pharmacist survey 
 
 
8.4    Record Retention and Archiving 
Upon completion of the study, data will be stored for a period of 10 years and 
securely destroyed after that period. 
 

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8.5    Compliance 
The CI will ensure that the trial is conducted in compliance with the principles of the 
Declaration of Helsinki (1996), and in accordance with all applicable regulatory 
requirements including but not limited  
 
• UK Policy Framework for Health and Social Care Research (2017)  
• Medicines for Human Use (Clinical Trials) Regulations (2004) 
• Medical Devices Regulations (EU MDR/IVDR 2017) 
and SU policies and procedures and any subsequent amendments. 
 
8.6    Research Governance Issues 
 
8.6.1       Ethical Considerations 
Permission to carry out this study will be given by an NHS Research Ethics 
Committee.  Following approval, any subsequent amendments will be communicated 
to the Ethics Committee as well as the Sponsor, the investigators, the study 
participants, and the trial registry. 
 
Participation in the study is voluntary.  All those participating will receive a participant 
information sheet (PIS) and will need to sign a consent form indicating their 
understanding of their role in the study.  The researcher will also be available to 
discuss with the participants any questions that they may have.   
 
All participants will be given sufficient time to decide whether they wish to take part.  
They will be informed that their participation in voluntary and that they are free to 
withdraw at any time without giving a reason for doing so. Those participants 
agreeing to be interviewed will be informed that their anonymised data and quotes 
may be used in any relevant publications.  
 
Service user participants or their representatives will be informed that if they chose 
to withdraw from the study, their medical care or legal rights will not be affected.   
They will also be informed that  
• 
sections of their medical records may be looked at by individuals from 
Swansea University and from regulatory authorities 
• 
the completed ADRe Profile will be shared with the study pharmacist, together 
with a copy of their medication record 
• 
their GP will be informed of their participation and may review or adjust their 
prescribed medicines. 
 
The research team will at all times use their judgement to identify any problems that 
may arise during the study.  If they feel that improper or unprofessional behaviour is 

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being carried out relating to the study or in care delivery, then they can highlight the 
problem to the representative of the Sponsor of the ADRe Study, and R&D 
representative at Swansea Bay/Hywel Dda University Health Board.   
 
If, at any time, the participant or their Consultee feels that abuse, malpractice or sub-
optimal care is being carried out, then they will have the opportunity to speak to their 
GP surgery team, who will investigate further.   
 
Declaration of interests:  The chief investigator, principal investigator and all 
collaborators state they have no financial interests to declare in relation to the study. 
 
8.7    Quality Control and Quality Assurance 
 
8.7.1       Summary Monitoring Plan 
A steering group committee will provide oversight of the progress and ensure 
delivery of the project outputs and achievement of the outcomes. 
 
         8.7.2      Audit and Inspection 
Internal audits will be conducted by a sponsor’s representative 
 
8.8    Non-Compliance        
 
Non-compliance may be captured from a variety of different sources including 
monitoring visits, CRFs, communications and updates. The sponsor will maintain a 
log of the non-compliances to ascertain if there are any trends developing which to 
be escalated. The sponsor will assess the non-compliances and action a timeframe 
in which they need to be dealt with. Each action will be given a different timeframe 
dependant on the severity. If the actions are not dealt with accordingly, the Research 
Governance Office will agree an appropriate action, including an on-site audit. 
 
9.    Trial Committees  
A steering committee will provide oversight of the progress and ensure delivery of 
the project outputs and achievement of the outcomes. 
 
10.    Publication Policy  
Only anonymized and de-identified data (or quotes from interviews) will be published 
or otherwise disseminated. This is also outlined in the Participant Information 
Sheet. 
 
11.    References 

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• Altman D.G. (1991) Practical Statistics for Medical Research. Chapman & 
Hall: London. 
• Bharmal, Murtuza, Guillemin, Isabelle, Marrel, Alexia, Arnould, Benoit, 
Lambert, Jérémy, Hennessy, Meliessa, & Fofana, Fatoumata. (2018). How to 
address the challenges of evaluating treatment benefits-risks in rare 
diseases? A convergent mixed methods approach applied within a Merkel cell 
carcinoma phase 2 clinical trial. Orphanet Journal of Rare Diseases, 13(1), 
95–95.)20 
• Braun, V. & Clarke, V. (2006). Using thematic analysis in psychology. 
Qualitative Research in Psychology, 3, 77–101. 
• Denzin, N. K. (2012). (2012). Triangulation 2.0. Journal of Mixed Methods 
Research: 6(2), 80-88. 
• Foss C., Ellefsen B. (2002). The value of combining qualitative and 
quantitative approaches in nursing research by means of method 
triangulation. Journal of Advanced Nursing, 40(2), 242-8. 
• Information Commissioner’s Office (ICO). 2012. Anonymisation: managing 
data protection risk code of practice.  https://ico.org.uk/media/for-
organisations/documents/1061/anonymisation-code.pdf 
• Killip S, Mahfoud Z, Pearce K. What Is an Intracluster Correlation Coeffi 
cient? Crucial Concepts for Primary Care Researchers. Annals of Family 
Medicine 2004;2(3):204-08 
• MRC 2018 https://mrc.ukri.org/documents/pdf/gdpr-guidance-note-3-consent-
in-research-and-confidentiality/     
• Nursing and Midwifery Council (NMC). (2018). The Code:  Professional 
standards of practice and behaviour for nurses, midwives and nursing 
associates. In. London: Nursing and Midwifery Council. 
• Östlund, U., Kidd, L., Wengström, Y., & Rowa-Dewar, N. (2011). Combining 
qualitative and quantitative research within mixed method research designs: a 
methodological review. International journal of nursing studies, 48(3), 369–
383. https://doi.org/10.1016/j.ijnurstu.2010.10.005 
• The Concordat to Support Research Integrity, 
https://www.universitiesuk.ac.uk/policy-and-
analysis/reports/Documents/2019/the-concordat-to-support-research-
integrity.pdf (2019). 

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• Uitenbroek, D. G. (1997). SISA Binomial. Southampton: D.G. Uitenbroek. 
Retrieved January 01, 2016, from the World Wide Web: 
https://www.quantitativeskills.com/sisa/distributions/binomial.htm. 
 
 
 
12.    Appendices 
This section should contain the list (Do not copy and paste the documents 
(denoted by underlining) as you do not want to make a substantial 
amendment every time that a substantial amendment is made for these 
documents) of all pertinent documents that are associated with the 
management of the study.  
 
The following is a list of attachments, those with an asterisk* must be submitted 
to the Research Ethics Committee with the protocol. 
• Consent Form (versioned and dated appropriately)* 
• Patient Information Sheet (versioned and dated appropriately)* 
• GP letters/ advertisements/any other letters and documents to be given to 
the patient (versioned and dated appropriately)* 
• An SAE/SUSAR reporting Organogram – who will be the study members 
(including BACK UP STAFF for ALL individuals) involved in the 
identification/reporting of the SAE 
• Communication Plan Organogram – how will information be disseminated 
between the PI/CI and the members of the study team relating to the 
protocol and other trial related duties. This plan should ensure that there is 
always a physician (either PI/Sub-I) trained adequately on the study to 
ensure that a study trained medical physician is available to make any trial 
related decisions with regards to patient care, mainly with regards to 
adverse events or intercurrent illnesses. 
• Source Data Identification List 
 
 
 
 
 
Appendix  

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Appendix 1 – Information with regards to Safety Reporting in Non-CTIMP 
Research 
 
 
 
Who 
When 
How 
To Whom 
SAE 
Chief 
Investigator 
-Report to 
Sponsor within 
24 hours of 
learning of the 
event 
 
-Report to the 
MREC within 
15 days of 
learning of the 
event 
 
SAE Report 
form for Non-
CTIMPs, 
available from 
NRES website. 
Sponsor and 
MREC 
Urgent 
Safety 
Measures  
Chief 
Investigator  
Contact the 
Sponsor and 
MREC 
Immediately 
 
Within 3 days  
By phone 
 
 
 
 
Substantial 
amendment 
form giving 
notice in 
writing setting 
out the 
reasons for the 
urgent safety 
measures and 
the plan for 
future action. 
Main REC 
and Sponsor  
 
 
 
Main REC 
with a copy 
also sent to 
the sponsor. 
The MREC 
will 
acknowledge 
this within 30 
days of 
receipt.  
Progress 
Reports  
Chief 
Investigator  
Annually 
(starting 12 
months after 
the date of 
favourable 
opinion) 
Annual 
Progress 
Report Form 
(non-CTIMPs) 
available from 
the NRES 
Main REC 

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website 
Declaration 
of the 
conclusion 
or early 
termination 
of the study 
Chief 
Investigator  
Within 90 days 
(conclusion) 
 
Within 15 days 
(early 
termination) 
 
The end of 
study should be 
defined in the 
protocol 
End of Study 
Declaration 
form available 
from the NRES 
website 
Main REC 
with a copy to 
be sent to the 
sponsor  
Summary of 
final Report  
Chief 
Investigator 
Within one year 
of conclusion of 
the Research 
No Standard 
Format 
However, the 
following 
Information 
should be 
included:- 
Where the 
study has met 
its objectives, 
the main 
findings and 
arrangements 
for publication 
or 
dissemination 
including 
feedback to 
participants 
Main REC 
with a copy to 
be sent to the 
sponsor 
 
 
 
Please outline the process/organisation within the study team to ensure that all 
SAE reporting is conducted in accordance with the sponsor’s timelines. Display 
this information within an organogram to be located in the appendices in section 
15 to ensure that there is a clear and distinct reporting process outlined with the 
study members detailed within this process.