TITLE PAGE - KCE...TITLE PAGE FULL/LONG TITLE OF THE PILOT Pilot study of the OptiMEDs intervention: a complex intervention for multidisciplinary medication review (including nurses,

TITLE PAGE

FULL/LONG TITLE OF THE PILOT

Pilot study of the OptiMEDs intervention: a complex intervention for multidisciplinary medication review (including nurses, pharmacists, and physicians) in nursing homes, with ICT-support for the evaluation of the appropriateness of prescribing and for side-effect monitoring.

SHORT STUDY TITLE / ACRONYM

Pilot study of the OptiMEDs intervention

PROTOCOL VERSION NUMBER AND DATE

Protocol v1.3 20/08/2019

RESEARCH REFERENCE NUMBERS

SPONSOR Number: BC-2394

KCE Trial Number: KCE-17008

KCE Trials programme Version v1.3 20/08/2019

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TABLE OF CONTENTS

PERFORMANCE OF TASKS BY THE PROJECT MANAGER IN THE NURSING HOME’S ............................................................................................................................. 11

1 BACKGROUND ................................................................................................. 13

2 RATIONALE ....................................................................................................... 15

3 OBJECTIVES AND ENDPOINTS / OUTCOME MEASURES ............................. 16

PRIMARY OBJECTIVE OF THE PILOT STUDY ............................................................... 16

SECONDARY OBJECTIVES OF THE PILOT STUDY ...................................................... 16

PRIMARY ENDPOINT IN THE PILOT STUDY .................................................................. 16

Minimum criteria for advancing to the full trial study............................................ 17

SECONDARY ENDPOINTS IN THE PILOT STUDY ......................................................... 18

Regarding PIMs ................................................................................................... 18

Regarding the primary endpoint of the full trial .................................................... 18

Regarding other outcomes .................................................................................. 18

4 PILOT DESIGN .................................................................................................. 19

5 STUDY SETTING OF THE PILOT STUDY ......................................................... 19

6 ELIGIBILITY CRITERIA ..................................................................................... 21

INCLUSION CRITERIA ...................................................................................................... 21

EXCLUSION CRITERIA ..................................................................................................... 21

7 PILOT PROCEDURES ....................................................................................... 22

RECRUITMENT ................................................................................................................. 22

CONSENT .......................................................................................................................... 22

WITHDRAWAL AND REPLACEMENT OF RESIDENTS .................................................. 22

ASSIGNMENT TO THE INTERVENTION OR CONTROL ARM ....................................... 23

BASELINE DATA ............................................................................................................... 23

TRIAL ASSESSMENTS ..................................................................................................... 24

END OF PILOT INTERVENTION PERIOD ....................................................................... 25

8 THE INTERVENTION ......................................................................................... 26

THE OPTIMEDS TOOL ..................................................................................................... 26

8.1.2 Instructions for use/ intended use ............................................................................. 26

8.1.3 Delivery of the software ............................................................................................. 27

8.1.4 Storage of the medical device ................................................................................... 27

8.1.5 Known reactions/side effects of the medical device use .......................................... 27

PREPARATION OF THE PILOT INTERVENTION ............................................................ 27

FLOW OF THE INTERVENTION ....................................................................................... 28

ASSESSMENT OF DISCONTINUATION PROBLEMS AND REPORTABLE EVENTS ... 30

Discontinuation problems .................................................................................... 30

Reportable events ................................................................................................ 30

DATA COLLECTION FOR FEASIBILITY AND ACCEPTABILITY STUDY OF THE OPTIMEDS INTERVENTION ............................................................................................. 31

OVERVIEW OF THE DATA FLOW OF THE OPTIMEDS PILOT STUDY ......................... 32

Research data for the OptiMEDs trial .................................................................. 33

Data collection for the OptiMEDs tool .................................................................. 34

Data collection to study the feasibility and acceptability ...................................... 34


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Data collection for the GO/NO-GO decision ........................................................ 34

9 STATISTICS AND DATA ANALYSIS ................................................................. 37

SAMPLE SIZE CALCULATION ......................................................................................... 37

PLANNED RECRUITMENT RATE .................................................................................... 37

STATISTICAL ANALYSIS PLAN ....................................................................................... 37

Description of feasibility and acceptability investigations. ................................... 37

Flow of NH residents and descriptive analysis of baseline data ......................... 38

Exploratory analysis of primary outcome of the OptiMEDs intervention ............. 38

Exploratory analysis of the secondary outcomes of the OptiMEDs intervention . 39

DATA COLLECTION FOR ECONOMIC EVALUATION .................................................... 40

10 DATA HANDLING .............................................................................................. 41

DATA COLLECTION TOOLS AND SOURCE DOCUMENT IDENTIFICATION ............... 41

DATA HANDLING AND RECORD KEEPING .................................................................... 41

ACCESS TO DATA ............................................................................................................ 41

11 MONITORING, AUDIT & INSPECTION .............................................................. 42

12 ETHICAL AND REGULATORY CONSIDERATIONS ......................................... 42

ETHICS COMMITTEE (EC) REVIEW & REPORTS .......................................................... 42

1 COMPETENT AUTHORITY (CA) ....................................................................... 42

DATA PROTECTION AND NH RESIDENT CONFIDENTIALITY ...................................... 42

INDEMNITY ........................................................................................................................ 43

2 PROTOCOL COMPLIANCE ............................................................................... 43

3 EARLY TERMINATION ...................................................................................... 43

13 REFERENCES ................................................................................................... 44


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SIGNATURE PAGE The undersigned confirm that the following protocol has been agreed and accepted and that the Chief Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to the principles outlined in the requirements for the conduct of clinical trials in the EU under Council Directive

93/42/EEC on Medical Device and any subsequent amendments, GCP guidelines/ISO14155, the Belgian law of May 7th 2004 regarding experiments on the human person, the Sponsor’s SOPs, and other regulatory requirements as amended.

I agree to ensure that the confidential information contained in this document will not be used for any other purpose other than the evaluation or conduct of the clinical investigation without the prior written consent of the Sponsor

I also confirm that I will make the findings of the study publically available through publication or other dissemination tools without any unnecessary delay and that an honest accurate and transparent account of the study will be given; and that any discrepancies from the study as planned in this protocol will be explained.

For acknowledgement on behalf of the Study Funder

Signature: ......................................................................................................

Date: ....../....../......

Name:

Position:

For and on behalf of the Study Sponsor:

Signature: ......................................................................................................

Date: ....../....../......

Name: Patrick Wouters

Position: Head of department of fundamental and applied health sciences, UGent

Chief Investigator:

Signature: ......................................................................................................

Date: ....../....../......

Name: Thierry Christiaens

Position: Head of Clinical Pharmacology, UGent

Statistician:

Signature: ......................................................................................................

Date: ....../....../......

Name: (please print): Monique Elseviers

Position: Pharmaco-epidemiological researcher (currently Prof. emeritus working as consultant, before connected to UGhent as guest professor)


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CRA AGREEMENT

I have read this protocol and agree that it contains all necessary details for carrying out this study. I agree to conduct this trial in compliance with the approved protocol, GCP guidelines/ISO14155 and in accordance with the principles outlined in the Declaration of Helsinki

CRA

Signature: ......................................................................................................

Date: ....../....../......

Name:

Nursing Home:


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KEY TRIAL CONTACTS

Chief Investigator Thierry Christiaens [email protected]

Tel.: +32 (0)9 332 24 92

Co-investigator 1 Robert Vander Stichele [email protected] Tel: +32 (09) 332 00 40

Co-investigator 2 Monique Elseviers [email protected] Tel: +32 (0)9 332 00 40

Project Manager Maarten Wauters [email protected] +32 (0)9 332 00 40

Sponsor Ghent University

Rik Van de Walle, Rector Universiteit Gent

DOZA contractbeheer, [email protected]

Tel.: +32 (0) 9 264 30 36

Sint-Pietersnieuwstraat 25, Rect.2, 9000 Gent..

Funder(s) Belgian Health Care Knowledge Centre (KCE)

Administrative Centre Botanique, Doorbuilding, Boulevard du Jardin Botanique 55, B-1000 Brussels, Belgium

[email protected]

00 32 2 287 33 88

Clinical Trials Unit Health, Innovation & Research Institute

Ghent University Hospital, C.Heymanslaan 10 – 1K5 (ingang 81, route 812), 9000 Gent

[email protected]

Tel. +32 9 332 05 00

Statistician Monique Elseviers [email protected] Tel: +32 (9) 332 00 40

Data Manager Maarten Wauters [email protected] +32 (0)9 332 00 40

ICT Development RAMIT (Research in Advanced Medical Informatics and Technology) Geert Thienpont [email protected] Tel: +32 (0)9 332 40 67

mailto:[email protected]










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LIST OF ABBREVIATIONS

ADL: Activities of Daily Living

AE: Adverse Event

ATC: Anatomical Therapeutic Chemical classification

CRA: Coordinating and advizing physician (Coördinerend Raadgevend Arts in Dutch)

DP: Discontinuation Problems

eCRF: electronic Case Report Form

GP: General Physician

NH: Nursing Home

MMSE: Mini-Mental State Examination

PIM: Potentially Inappropriate Medication

QoL: Quality of Life

SAE: serious adverse event

SB: Safety Board

SUS: System Usability Scale

TMG: Trial Management Group


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TRIAL SUMMARY

Trial Title Pilot study of the OptiMEDs intervention: a complex intervention for multidisciplinary medication review (including nurses, pharmacists, and physicians) in nursing homes (NH), with ICT-support for the evaluation of the appropriateness of prescribing and for side-effect monitoring.

Internal ref. no. (or short title) KCE-17008 Pilot study of the OptiMEDs intervention

Trial Design Pilot study of a pragmatic cluster-randomized trial with the inclusion of two NHs where the feasibility and acceptability of the OptiMEDs intervention will be tested and one NH where the standard of care will be registered.

Trial Participants Residents of the participating NHs will be eligible for participation if they are 65 years or older and permanently residing in the NH. Residents will be excluded if they have a limited life expectancy (<3 months).

Planned Sample Size Using three NHs with at least 100 beds and an estimated inclusion rate of 50%, we expect to include at least a total of 150 residents (100 in the intervention group, 50 in the control group).

Treatment and follow-up duration

All residents will be recruited in a period of 1 month. For a resident, the duration of the study will be 5-6 months. After a preparatory phase of 1 month, the multidisciplinary medication review will be organized in the second month and follow-up is planned at ±1 week, ±1 month and 4 months after the medication review.

Planned Trial Period The total duration of the pilot study will be 18 months.

Objectives Endpoints

Primary To investigate the feasibility and acceptability of a full trial study demonstrating that in NH residents receiving the OptiMEDs, a standardized multidisciplinary medication review (prepared by ICT-support) will lead to a decrease in the use of inappropriate medications four months after the intervention in comparison with residents with standard care.

The OptiMEDs pilot study will be tested at the level of functionality (number of software problems, user problems), organization (extra workload for nurse, pharmacist, GP), participation (non-consenting residents or proxies, GPs) and acceptability (readiness for future use by nurses, GPs, pharmacists) using well-defined minimum criteria that need to be met before moving to a full trial study.

Secondary

To investigate the feasibility and acceptability to measure that the OptiMEDs intervention will lead to a more appropriate, safer, and more cost-effective pharmacotherapy in nursing home residents using the endpoints as defined for the full trial study.

The secondary endpoint of the pilot will be the proportion of NH residents who successfully discontinued use of at least 1 inappropriate medication after 4 months of follow-up (that is, without relapse symptoms or severe withdrawal effects leading to a re-start of the discontinued medication within the follow-up period of 4 months).


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For the full trial study we are looking for a more patient-related outcome as primary endpoint. We consider all secondary endpoints of the pilot as candidate for the primary endpoint in the full trial, particularly as part of a composite primary endpoint.

For secondary endpoints, we will evaluate the effect of the intervention compared to standard of care on medication related process factors (number of medications, anticholinergics, candidates for de-prescribing…), patient-related outcomes (pain, alertness, QoL, falls…) and on health care usage (consultations, hospitalization…) four months after the intervention.

Intervention(s) The intervention group (i.e. all eligible and consented residents of 2 NHs) will receive the OptiMEDs intervention: the combination of an electronic decision support tool (for the appraisal of potentially inappropriate medication use, anticholinergic use, or medications that can be de-prescribed in view of limited life expectancy) with focused nurse observations (using a list of potential medication-related symptoms based on the individual medication chart of the nursing home residents), that will serve as the basis during a multidisciplinary medication review with the input of GPs, trained community pharmacists and nurses.

The OptiMEDs tool is manufactured by RAMIT.

The control group (i.e. all eligible and consented residents of one control NH) will receive usual care .


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FUNDING AND SUPPORT IN KIND

FUNDER(S)

FINANCIAL AND NON FINANCIAL SUPPORT GIVEN

BELGIAN HEALTH CARE KNOWLEDGE CENTRE,

Administrative Centre Botanique (Doorbuilding) Boulevard du Jardin Botanique 55 B-1000 Brussels, Belgium

Financial support

ROLE OF STUDY SPONSOR AND FUNDER

Ghent University as mentioned in KEY TRIAL CONTACT shall act as sponsor of the Pilot Study, as defined in the Law of 2004, and shall assume all responsibilities and liabilities in connection therewith and procure the mandatory liability insurance coverage in accordance with the Law of 2004. Ghent University shall ensure that it shall be mentioned in the Protocol, the Informed Consent Forms and in other relevant communication with the Study Subjects or the Regulatory Authorities as sponsor of the Study. Ghent University acknowledges and agrees for the avoidance of doubt that KCE shall under no circumstances be considered as sponsor of the Study or assume any responsibilities or liabilities in connection therewith, and Ghent University shall make no representations whatsoever in this respect.


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ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITEES

Trial Management Group (TMG)

The day-to-day management of the study will be performed by the Trial Management Group (TMG). Members of the TMG will be the chief investigator and co-investigators, the project manager, the data manager, completed with other members and subcontractors of the trial as needed (e.g. RAMIT, Health Innovation and Research Institute, …, see list key trial contacts). Apart from their daily commitment in the management of the trial, the members of the TMG will meet on a bi-weekly base.

In the preparatory phase, the TMG will organize the selection of the nursing homes. The TMG will be involved in the development of the study material (software development in close collaboration with RAMIT and information material for NH residents, NH staff, GPs and pharmacists). The TMG will organize informative meetings with nurses, GPs, residents and their family and educational sessions for nurses and pharmacists.

During the trial, the TMG will monitor the recruitment of patients, the strict and timely conduct of the intervention in accordance with the protocol, the correctness and completeness of the data collection and the organization of a permanent communication service to solve the local problems.

After the data collection, the TMG will evaluate the preliminary results and will guide the scientific writing of the study results.

Additionally, the TMG will be responsible to report on the progress of the trial to the funder on a regular base.

Tasks performed by the TMG and project manager (PM) in the Nursing Homes

TMG & PM: Recruitment of NHs

TMG & PM: Preparation of intervention: o Educational sessions with GPs, pharmacists, nurses o Informative sessions for residents and their proxies o Generation of study protocols o Installation of the ICT platform

PM: the organization of a permanent communication service to solve the local problems.

PM: distribution of informative leaflets and the organisation of information sessions.

TMG & PM:training material and manuals for using the OptiMEDs tools will be developed and their acceptability will be tested.

PM:onsite help for nurses for practical problems regarding the data collection and data input.

PM:collection of feasibility and acceptability data

Safety Board (SB)

A Safety Board will be installed consisting of three members: a geriatrician (prof.dr. M. Petrovic), a clinical pharmacologist (prof.dr. S. Rottey) and a general practitioner with the function of CRA in a NH (not included in this pilot study; dr. H. Warie).

The Safety Board will receive all reported discontinuation problems and will evaluate if the reported problem can be considered as (1) a harm of ceasing medication use or (2) a drug withdrawal reaction and the SB will score the severity of the problem. Additionally, they will be informed about all SAEs including deaths of the intervention group to evaluate the possible relation with ceasing medication use or withdrawal reaction.

The members of the Safety Board are not involved in the development of the OptiMEDs pilot and full trial study enabling them to evaluate the safety issues completely independent from the Trial Management Group.


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TRIAL FLOW CHART

GANTT chart showing the study pathway

For the flowchart showing a residents pathway, see 7.6 Trial Assessment.

OptiMED GANTT chart Teams

involved

Preparatory Phase J J A S O N D J F M A M J J A S O N

Contract and subcontract negotiations and signment 1,2,3

Ethical commission approval 1,2

Development of the OptiMED intervention tools 1,3

Development of the Harms module 1,3

Development of eCRF 1,2

Development of study material (IC, questionnaires…) 1

Recruitment of participating nursing homes 1

Round table meeting with residents and family 1

Installation and test of ICT package in NH 1,3

Initation visits, Training of nurses 1,2,4

Information for GPs 1,6

Information and training of community pharmacists 1,5

Recruitment of participating residents 1,4

OptiMED Intervention Phase

ICT scoring (PIMs, Anticholinergics, Deprescribing) 1,3

Symptoms observation (Pharmanurse) 4

Comments of community pharmacist 5

Organization of medication chart reviews 4,6

Scientific Committee meeting 4,6

OptiMED Follow-up phase

Data collection 1w,1m&4m after medication chart review 4

Registration of potential harms 4,6

Data verification at entering 1

Analysis phase

Data cleaning 1,3

Database lock 1,2

Data analysis 1,2

Reporting Phase

Preparation of final pilot report 1

Preparation of scientific report for publication 1

Q = Quarter Coloured zone = timing of activity

TEAMS INVOLVED

1=Trial Management Group

2=Health, Innovation and Research Institute

3=Ramit

4=Nursing team NH

5=Community Pharmacist

6=GP

Q2 Q3 Q4

Year 2Year 1

Q1 Q5 Q6


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STUDY PROTOCOL

1 BACKGROUND

Worldwide and in Belgium the number of older adults (65+) and oldest old (80+) is increasing [1]. Also the population of older adults residing in nursing homes is increasing, despite increasing health services to keep elderly residents with decreased physical and cognitive function at home [2].

The older adults residing in a nursing home are a vulnerable, multi-morbid population, often with severe physical and cognitive dysfunction [3–5]. They often use a considerable amount of systemic medication on a chronic basis.

Older adults and certainly the oldest old are more sensitive to the effects and side-effects of medications due to pharmacokinetic and pharmaco-dynamic changes [6, 7]. This affects their functional and cognitive capabilities, their social life, and quality of life (3). Predominantly psychotropic agents, antiplatelet agents, hypoglycaemic medications and hypno-sedatives are related to Drug Related Problems (DRPs) [8]. DRPs can lead to unwanted symptoms (such as dry mouth, orthostatic hypotension, dizziness, sedation, confusion, hallucinations, bleeding) that will affect quality of life, but also lead to unwanted outcomes such as falls, hospitalisation and even premature death.

The Prescribing in Homes for the Elderly in Belgium (PHEBE) study confirmed the high level of polypharmacy (with a mean medication use of 8 drugs per resident), with a predominant intake of psychotropic medications (79% of all residents took at least 1 psychotropic drug) [3, 9].

Medication prescribers face a complex medication choice process in older residents who have a lot of diseases and other medications. They also encounter the problem of a lack of specific evidence in this particular age group with regard to efficacy and safety of medications [10]. Changing treatment goals and limited life-expectancy may alter the traditional and documented balance of benefit and harm in this frail population.

In Belgium, as in most European countries, the nursing home setting is part of primary care, and medical assistance is mainly provided by visiting general practitioners, with a coordinating NH physician (CRA).

Communication with the pharmacists who supply the medicines to the nursing homes is limited. Pharmaceutical care activities of pharmacists in support of the appropriateness of prescribing are only emerging and not standardized. Nurses have a more intense and constant contact with the residents, but their observations are not systematically collected.

In Belgium, a number of initiatives were taken to improve the quality of pharmacotherapy to residents of nursing homes. A central formulary with evidence-based guidance on pharmacotherapy in nursing homes is produced by an independent drug information organization (Farmaka, now BCFI). The COME-ON is conducting a field study to explore the feasibility and barriers for holding medication reviews in nursing homes, with regard to sleeping pills and statins [11]. In Flanders, the Leiehome project is another field study aiming to reduce the use of psychotropic drugs in nursing homes [12].

Although general practitioners are invited to perform medication reviews, this is not implemented comprehensively and performed regularly. Little state-of-the art ICT support is available, to exploit the emerging capabilities of e-Health investments.

A limited number of randomized controlled trials to reduce potentially inappropriate prescribing have been conducted. Potentially inappropriate medications (PIMs) are medications that are considered as having more risks than benefits in old age and that are related to increased risks of side-effects. In general, PIMs are not favourable to be prescribed in old age, albeit that in specific cases these medications remain the best choice. Recently, PIMs were listed in an international repository [13]. In this repository, explicit criteria from three international reference studies on PIMs were selected and operationalized (e.g. translated into usable codes and syntaxes). In this repository, a total of 650 criteria are present.

There is existing and still growing evidence that PIMs are related to increased health care usage (hospitalizations, mortality) and health-related costs. Of those interventions focusing on the reduction of PIM use, single interventions such as computerized decision-support systems, educational interventions, and pharmacists-led interventions have produced inconsistent effects [14, 15]. Multifaceted complex interventions involving all actors in the medication management process (NH resident, nurse, pharmacist, GP) may be more likely to improve prescribing than single interventions [16–19].


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Also in Belgium, there have been initiatives to improve the geriatric pharmacotherapy. For now, it has been strongly advised to hold medication reviews, but it is not yet implemented, nor mandatory. It was not detailed who should participate, what needs to be collected and discussed, and how frequent it should take place.

There are some other initiatives aiming to reduce potentially inappropriate medications. However, not one of these initiatives is automated, electronically available, tailored to the NH setting, and designed to appraise the total medication intake of older adults.

The WZC Formularium by FARMAKA serves as a guiding tool for medication prescribers for older patients, in nursing homes. It lists the indications, the side-effects per medication, and also per (relevant) indication suggested medications. It is however not automated, nor directly electronically available.

Other initiatives include the Leiehome project (published as ‘A quality improvement initiative on the use of psychotropic drugs in nursing homes in Flanders’). Through the transition towards more patient-centered care (tailoring the care for older adults to their needs by stimulating multidisciplinary collaboration, offering non-pharmacological alternatives for sleeping problems, etc.), reductions in the psychotropic medication use have been noted. The medications were manually reviewed [12].

In the COME-ON study, a multicenter cluster controlled trial in 63 nursing homes, under the initiative of the RIZIV/IMAMI. The COME-ON is exploring the feasibility and barriers of all structural components for holding medication reviews in nursing homes. The components were however not automated, leading to a time-invasive intervention. The focus was also on a limited number of medication groups (statins and antidepressants). The intervention was not pragmatic in terms of availability of data (medical history is not automatically captured in the NH software systems) and in terms of the role of a pharmacist (who does not visit the NH) [11].

The GheOP³S tool is a tool used in a number of community pharmacies, and is able to automatically detect potentially inappropriate medications. However, the PIMs are adapted for use in a community-pharmacy and for ambulatory patients. In the NH specialized firms are responsible for delivering the medications (in uni-doses), meaning that the GheOP³S tool is not adapted to the setting.


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2 RATIONALE

The interest in improving the pharmacotherapy of older adults in nursing homes is growing. However, only performing a medication review may not lead to improved pharmacotherapy, and is time consuming certainly if it is not structured [20, 21].

We propose a method that could investigate the medication use, on the level of the active substance of a medication, and supported by evidence based knowledge, in order to support the decision of GPs regarding the pharmacotherapy of older adults. First, we want to aid GPs by supporting them in their medication decisions using an electronic tool. Second, we want to involve different stakeholders (GPs, nurses and pharmacists) in the multidisciplinary medication review by offering them tools to strengthen their role.

To achieve this, we propose the OptiMEDs intervention: the combination of an electronic decision support tool (for the appraisal of potentially inappropriate medication use, anticholinergic use, or medications that can be de-prescribed in the medication chart of nursing home residents) with focused nurse observations (derived from the Pharmanurse [22] component in the OptiMEDs software, where potential medication-related symptoms are listed based on the individual medication chart of the nursing home residents), that will serve as the basis during a multidisciplinary medication review with the input of GPs, pharmacists and nurses (for a full description of this intervention, see chapter 8. The Intervention).

By using the OptiMEDs intervention, we expect to obtain a more appropriate, safer, and more cost-effective pharmacotherapy in nursing home residents (e.g. less medication-related symptoms, less potentially inappropriate prescribing, a better quality of life, less hospitalizations, health care usage, or mortality).

In comparison with the other ongoing initiatives (see 1. BACKGROUND), the OptiMEDs may offer some strengths

The feedback is Individualized The basis is the individual medication list of a specific patient

The feedback is automated & quick

The feedback is integrated in the current practice patterns & User-friendly Nurse, pharmacist,

and physician will receive an automated guidance about the intervention notifying when a particular

task is due for a particular patient.

The feedback is tailored to the setting Using available resources (based on the existing

medication chart of each resident), for residents with and without mental problems. The nurse has

a central role, the pharmacist (who is rarely in the NH) gives feedback from a distance.

The system is dynamic & flexible The system allows easy updating of the underlying rules for

decision support, to enable incorporation of evolving new insights. In addition, integration of other

evidence-based components is feasible and easy. Further integration of these software tool in the

EHRs of nursing homes, hospitals or in general practices is possible


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3 OBJECTIVES AND ENDPOINTS / OUTCOME MEASURES The overall final objective of the OptiMEDs project is to provide a feasible, evidence-based, and ICT-enabled method of regular multidisciplinary medication review in Belgium aiming to obtain a more appropriate, safer, and more cost-effective pharmacotherapy in nursing home residents (e.g. less medication-related symptoms, less potentially inappropriate prescribing, a better quality of life, less hospitalizations or mortality).

To achieve this overall objective, we propose the OptiMEDs intervention involving NH residents, nurses, pharmacists, and physicians and guiding them in making a rational pharmacotherapeutic choice for older adults. The inclusion of nurses in the intervention is crucial, as they will be responsible for the main observation of side-effects, and will be responsible to be the NH resident’s voice in the multidisciplinary medication review. We also want to involve pharmacists in an approach that is feasible and relatable to the Belgian health care setting.

The OptiMEDs intervention is a multi-faceted intervention combining:

an ICT platform: o automatic and secure capture of individual prescribing information from the electronic

medication administration records in the nursing home o a tool for structured nurse observations of side effects, derived from the existing

Pharmanurse application (20) (used to list potential medication side effects, based on the individual medication chart of the nursing home residents) to support monitoring of medication safety by nurses.

o an electronic decision support tool for the appraisal of potentially inappropriate medication (explicit criteria of misuse and underused of medication, based on existing lists of explicit criteria (PIMs)), use of medication with anticholinergic properties and medication inappropriate in view of the limited life expectancy.

a multidisciplinary medication review with the input of GPs, trained community-pharmacists and nurses.

For a full description of the flow and components of the OptiMEDs intervention, see 8. The Intervention.

Based on the decision of the KCE Trials Board, the OptiMEDs intervention will first be tested in a limited number of nursing homes as a pilot study

Primary objective of the pilot study

Before conducting a cluster-randomized controlled pragmatic trial of this complex intervention, all components in the OptiMEDs intervention need to be evaluated for feasibility and acceptability

The primary objective of the pilot study is to test feasibility and acceptability:

1. at the functionality level (the practical operation of the ICT-platform, the usability of the tools for nurses and pharmacists)

2. at the organizational level (workload for nurses, pharmacists and GPs, practical problems for organizing the medication chart review)

3. at the participation level (participation rate of GPs and of residents and their proxies) 4. at the level of acceptability (appreciation of the ICT-platform, the assessment and observation

tools and the multidisciplinary medication chart review)

Secondary objectives of the pilot study

To investigate the feasibility and acceptability of the measurements of the endpoints of the OptiMEDs full trial study. The OptiMEDs aims to a more appropriate, safer, and more cost-effective pharmacotherapy in nursing home residents.

Primary endpoint in the pilot study

The following endpoints are proposed for the evaluation of the level of feasibility and acceptability of the OptiMEDs intervention:

at the functionality level


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o monthly number of interventions for software problems (project manager, with assistance of RAMIT)

o number of extra interventions from the PM for user problems of the tool by nurses o number of extra interventions from the PM for user problems of the tool by pharmacists o listing of functionality problems encountered

at the organizational level o timing of workload for nurses regarding the use of OptiMEDs; e.g. for data in&output, observation

of symptoms, organization of the medication chart review o timing of workload to perform a medication chart review by the pharmacist o duration of a medication chart review by GP and nurse o listing of practical problems for organizing the medication chart review

at the participation level o number of GPs that refuse to participate / accept to participate o number of GPs that did not attend the medication chart review o Number of non-consenting eligible residents legally capable to give consent o Number of non-consenting proxies for eligible residents legally not capable to give consent o Number of medication reviews completed o Number of medication reviews completed on time (by pharmacists) o Number of nurse observations completed (on time)

at the level of acceptability o evaluation of the problems seen in the ICT-platform (nurses, pharmacists) o appreciation of the assessment and observation tools (nurses, pharmacists, GPs) o appreciation of the multidisciplinary medication chart review (nurses, pharmacists, GPs) o evaluation of the OptiMEDs intervention for future use (all health care workers, residents and

proxies) suggestions for improvement of the tool for the future trial and the future use of OptiMEDs (from all health care workers, residents and proxies)

Minimum criteria for advancing to the full trial study

Finally, we define the following minimum criteria that need to be met before moving to a full trial:

- Concerning Recruitment

• At least 80% of all eligible residents will be allowed to enter the study by their GPs

• At least 40% of all eligible residents participate in the trial giving IC for participation

- Concerning outcome

• At least 30% of all participating residents in the intervention arm have at least one

successfully discontinued PIM (see 3.4.1)

- Concerning process

• In at least 85% of participating residents the ICT application of the OptiMEDs intervention

functioned without any technical problem

• In at least 95% of the total participating NH residents (that have given consent, in either

intervention or control), it was possible to automatically extract their medication

administration chart and forward it to the OptiMEDs system.”

• At least 50% of the GPs, and nurses feel that this study is feasible, is beneficial, and want

to redo all processes.

- Concerning harms

• Not more than 10% of all participating NH residents that underwent a medication review

has encountered clinically significant withdrawal symptoms or adverse events from

discontinuing inappropriate medication

• Not more than 2% of all participating NH residents that underwent a medication review has

encountered a clinically serious withdrawal syndrome or serious adverse event from

discontinuing inappropriate medications.


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For a full overview of the numerator/denominator in each Go / No Go criterion, please see 8.6.4 Data

collection for the Go / No Go criteria.

Secondary endpoints in the pilot study

In this pilot study, we will investigate whether all data required can be collected to investigate that the OptiMEDs intervention may lead to a more appropriate, safer, and more cost-effective pharmacotherapy in nursing home residents using the endpoints as defined for the full trial study.

Regarding PIMs

The secondary endpoint of this pilot study will be the proportion of NH residents who successfully discontinued use of at least 1 potentially inappropriate medication after 4 months of follow-up (that is, without relapse symptoms or severe withdrawal effects leading to a re-start of the discontinued medication within the follow-up period of 4 months).The formulation of this endpoint is similar to the endpoint used in a study performed in the Netherlands by Wouters et al. and recently published in Annals of Internal Medicine [23].

The PIMs will be selected from the international repository by Ivanova et al. [13]. For use in this study, we will select those that are applicable in the nursing home context (e.g. the PIM criteria that can be assessed without clinical data; 64% of the total criteria in the repository).

We define the successful discontinuation of a PIM as follows:

When a PIM is present at baseline (e.g. as recognized by the software, before the pharmacist reviews the medication list), but not present at follow-up (4 months later), this will be a successful discontinuation. It will thus be used as an endpoint.

Medications that had to be tapered gradually (such as narcotics or steroids) because of the potential for severe withdrawal effects will not be excluded from the intervention and will be included in the count of successful discontinuations.

A switch of an inappropriate medication to another medication in the same Anatomical Therapeutic Chemical (ATC) group will not be considered a successful discontinuation, with the exception of a switch from a medication with anticholinergic properties to a medication in the same ATC group but without anticholinergic properties.

Regarding the primary endpoint of the full trial

We will consider more patient-related outcome as primary endpoint. We consider all secondary endpoints of the pilot as candidate for the primary endpoint in the full trial, particularly as part of a composite primary endpoint (e.g. pain, sedation … ).

Regarding other outcomes

The proposed secondary outcomes will focus on the effect of the intervention compared to standard of care on medication related process factors, NH resident-related outcomes, and on health care usage, four months after the intervention.

Medication related process outcomes o number of medications, the prevalence of polypharmacy, the PIM score, the anticholinergic

exposure score, the number of medications candidate for de-prescribing in view of limited life expectancy.

o number of recommendations taken by the trained pharmacists, number of recommendations taken by the GP/nurse, number of effective changes of medication at 1 week (±3days), 1 month (±3days) and 4 months (±5 days) after the medication chart review.

NH resident-related outcomes o number of medication related symptoms o level of pain


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o level of alertness o quality of life (as measured by the EQ-5D-5L), o cognitive function, as measured by the Mini Mental State Examination (MMSE) o the level of care dependency (ADL) o falls o hospitalization o mortality

Health care usage & expenditure outcomes o Data on the number of hospitalization days, fall incidents (with medical intervention), the

number of GP visits (planned/unplanned), and the direct medication costs will be used to estimate health care related expenditures.

4 PILOT DESIGN

In the pilot study the OptiMEDs intervention will be tested on his feasibility (both operational and organisational) and acceptability by the nursing home and by the GPs, Pharmacists, and nurses with two complete nursing homes in the intervention arm and one in the control arm.

5 STUDY SETTING OF THE PILOT STUDY

Three nursing homes (NH) will be recruited for participation in the pilot study: two to test the OptiMEDs intervention, one as control NH. NHs will be asked to participate with all their wards and all their eligible residents

Nursing homes will be eligible for participation with the following criteria fulfilled:

size: > 100 beds

mixed population of high care dependent and low care-dependent residents with and without dementia

software of Care Solutions or Farmad is used for electronic handling of the medication chart

the NH management as well as the responsible CRA and the community pharmacist who delivers the medication in the NH give their written agreement to participate

For this pilot study, the NHs will be recruited in East Flanders for practical reasons.

We will select NHs that are representative for the NHs in Belgium (NHs with different case mix (age, gender, proportion dementia, etc.) and from different organisations (private/public). More concretely, we will select one NH from the public sector, one from the non-profit private sector and one from a commercial organization (such as Armonea). One of them will be located in a rural, one in an urban and one in an area between both. All will have a mixed population of mentally fit residents and residents with dementia. We will carefully register the reaction of the NHs when we contact them for recruitment with the source of refusal (was it the NH direction, the CRA or the delivering pharmacist?) and the reason.

Our pledge is to select for the pilot study nursing homes where the current situation reflects usual care. In usual care, no structured medication reviews take place as of current. It has been strongly advised to hold medication reviews, but it is not yet implemented, nor mandatory. It was not detailed who should participate, what needs to be collected and discussed, and how frequent it should take place. Therefore, we will not include one of the few nursing homes that have been involved in other formal projects of medication review, more in detail the projects LEIEHOME and COME-ON [11, 12].

For this pilot study, we will limit our selection to NHs where the electronic handling of the medication chart belongs to the software package provided by Care Solutions or Farmad. These companies are the two most important IT providers (out of three) for NHs in Flanders. We will make our selection of NHs in a way that both providers will be included in this pilot study.

The role of the CRA is crucial in the OptiMEDs study. The CRA will be the go-between for optimization of the collaboration between the research team and the NH and GPs. Apart from the NH management team, the CRA will be first informed about the OptiMEDs study and will be asked to participate separately from the NH direction. The CRA will be asked to help motivating the direction to participate. He will be the one who will contact all visiting GPs to inform them about the OptiMEDs study and to ask for their active participation. He will also be involved in informing and motivating the NH staff and the residents and their proxies.


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We will ask the local community pharmacist who prepares and delivers the medication to a NH to participate in the multidisciplinary medication review of the residents. Therefore, selection of a NH will also depends on the consent of the delivering pharmacist. He will confirm his participation by mail. As yet, one of the biggest organizational problems to perform standardized multidisciplinary medication reviews is the fact that GPs, nurses and pharmacists have to be present in the NH on the same time, which is extremely difficult to organize. Therefore we plan to organize the medication review of the pharmacist separately. The pharmacist will receive a report of the assessment tool, perform his medication review and send his recommendations back to the NH for the further medication review by GP and nurse. His/her time spent to perform the review will be registered and he will be reimbursed for the time spent. To prepare the participating pharmacists for this task, they will be offered a specific training program during the preparatory phase of the intervention.

After complete agreement of the NH (i.e. NH direction, CRA and delivering pharmacist agreed to participate), we will ask the CRA of the NH to contact all visiting GPs with an information leaflet about the OptiMEDs intervention. In the leaflet, it will be explained that a participating GP will agree with the participation of his/her patients. A consenting GP will not actively participate in the OptiMEDs study. His/her task will be limited to the delivery of standard of care to his/her patients. GPs will be asked to participate in the OptiMEDs study by sending a reply mail to confirm their participation. GPs not willing to participate in the study will be asked to give the reason why.

Additionally, since GPs, pharmacists as well as nurses will be questioned about their experiences with the OptiMEDs intervention and tool, all will be asked to sign an Informed Consent Form (ICF) (see 8.5 Data collection for feasibility and acceptability study of the OptiMEDs intervention).


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6 ELIGIBILITY CRITERIA

Inclusion criteria

For nursing homes:

located in East Flanders

size: > 100 beds

mixed population of high care dependent and low care-dependent residents with and without dementia

software of Care Solutions or Farmad is used for electronic handling of the medication chart

the NH management as well as the responsible CRA and the community pharmacist who delivers the medication in the NH give their written agreement to participate

For residents: All residents of all wards of the participating nursing homes will be considered for inclusion if they meet the following inclusion criteria:

aged 65 years or older

mentally fit as well as cognitive impaired NH residents will be included after Informed Consent given by the resident (mentally capable residents) or his representative (cognitive impaired residents, defined as a sumscore of 6 or more on the KATZ items of disorientation in time and place).

Exclusion criteria

Residents will not be considered for inclusion if:

they have a limited life-expectancy (less than 3 months, as judged and documented by the treating GP)

they are residing in a short-stay / revalidation bed

GP refused to have his NH residents included in this pilot


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7 PILOT PROCEDURES

Recruitment

All residents of 65 and older, residing permanently in the NH and with a life-expectancy of >3 months are eligible for participation in the pilot study, regardless their mental status.

We will approach only a limited set of Nursing Homes, using a short list of nursing homes located in East Flanders, working with either Farmad or Care Solutions, with a mixed character (public sector, non-profit private sector and from a commercial organization), and a mixed location (rural, urban and between both). All will have a mixed population of mentally fit and demented residents.

Starting from this shortlist of NHs that meet the eligibility criteria, we will contact the NH directly through telephone until three agree to participate. Reasons for not participating will be carefully noted.

The management team of the NH will list up the eligible residents. All eligible residents (or the representative in case of mental impairment) from the intervention as well as from the control NH will be asked to participate and to give their written Informed Consent.

Consent

In the Intervention NHs, all residents and their proxies will be invited to attend a meeting before the start of the study where the objectives and procedures of the OptiMEDs intervention will be explained by the project manager of the sponsor. Additionally, information will be provided about potential harms of inappropriate medication and polypharmacy in old age.

Additionally, leaflets adapted to residents intellectual and reading capacities will be distributed to all residents and their proxies in order to prepare and facilitate the recruitment.

If the resident agrees to participate, written informed consent will be obtained from the resident by the responsible nurse in both the intervention and control NHs. For participants with mental incapacity, a representative (following the cascade described in the Law on Patients’ Rights) will be asked to sign the Informed Consent form. All Informed Consent forms will also be countersigned by the responsible nurse and the CRA (as soon as possible).

Resident will get ample time to ask questions and to decide whether or not to participate in the study. The right of a resident to refuse participation without giving reasons will be respected under all circumstances. The resident has the legal right to withdraw at any time from the study without giving reasons and without prejudicing his or her further treatment.

In a NH with a normal mixed population, we can expect that about half of the population will not be capable to give informed consent. It is however upmost important to include this population in the study, since previous observations showed that particularly in residents with dementia the quality of pharmacotherapy is suboptimal.

Withdrawal and replacement of residents

7.3.1 Criteria for withdrawal

Residents may prematurely discontinue from the study at any time. Premature discontinuation from the study is to be understood when the subject did not undergo the end of follow-up assessment (4 months (±1week) after the medication review for the intervention group, and six months (±1week) after the baseline data collection for the control group.

Residents can be withdrawn under the following circumstances:

at their own request

if the CRA or GP feels it would not be in the best interest of the resident to continue

if the subject violates conditions laid out in the informed consent form or disregards instructions by the NH personal


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if an end-of-follow-up occurs due to changing to another nursing home, hospitalization during the the study end assessment or death

In all cases, the reason why residents are withdrawn must be recorded in detail in the eCRF and in the subject’s medical records. Should the study be discontinued prematurely, the OptiMEDs software will be returned and the sponsor will notify the relevant regulatory authorities and ethical committees.

7.3.2 Replacement policy

Drop-outs will not be replaced.

Assignment to the intervention or control arm

In this pilot study, one nursing home as a whole will be assigned to the control arm, and two nursing homes to the intervention arm.

Since we agreed to test two software vendors (Farmad or Care Solutions), the intervention arm will consist in one nursing home using Farmad and one using Care Solutions. For the control arm, the software package in use can be either Farmad or Care Solutions.

No randomization at the level of the resident will be required.

Baseline data

From all consenting residents the following data will be collected at baseline:

- Automated extraction of the medication chart (see 8.2 Flow of the Intervention) - Data to be extracted from the administrative files of the NH:

o Age in years, o Gender, o Date of NH admission o KATZ variables (Activities of Daily living (ADL) and disorientation in time and place) o Recent (< 3 months) Mini Mental State Examination (MMSE scale) o Hospitalization in the last 4 months o GP consultations in the last 4 months o Fall incidents in the last 4 months

- Data to be collected by contacting the resident: o Quality of life (as measured by the EQ-5D-5L) o Cognitive function, as measured by the (MMSE) (if no recent assessment available)

From all consenting residents the following data will be collected in the CONTROL NH, 6 months after the first automated extraction of the medication chart and in the INTERVENTION NHs 4 months after the medication review:

- Automated extraction of the medication chart (see 8.2 Flow of the Intervention) - Data to be extracted from the administrative files of the NH:

o KATZ variables (Activities of Daily living (ADL) and disorientation in time and place) o Recent (< 3 months) Mini Mental State Examination (MMSE scale) o Planned and unplanned hospitalizations in the last 4 months o GP consultations in the last 4 months o Fall incidents in the last 4 months

- Data to be collected by contacting the resident: o Quality of life (as measured by the EQ-5D-5L), o Cognitive function, as measured by the (MMSE) (if no recent assessment available)

For a full overview of the data collection at baseline and at follow-up, please see table 8.7.1 (Research data for the OptiMEDs trial).

For non-consenting residents the following aggregated administrative data will be collected: year of birth, gender, MMSE, and KATZ variables (ADL and disorientation in time and place).


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Trial assessments

We will focus here on the assessments in the trial study. Assessments for feasibility and acceptability will be detailed in 8.6

The flow of a resident and his medication chart in the intervention arm is presented in figure 7.6.1. Differences with the assessment of residents in the control arm are mentioned by (*) and explained below.

Figure 7.6.1: Flowchart of a resident with associated assessments and data collection

Legend: In the flowchart, all actions and corresponding data collection marked with (*) are related to the OptiMEDs intervention and will only be performed in the intervention group. In the residents of the control arm, only extraction of the medication chart with automated assessment of appropriateness will be done, the first time after informed consent is given and the second time at the end of the observation period six months later.

For the Pharmanurse tool, a list with possible medication-related symptoms will be generated based on the extracted medication chart of each individual resident. The responsible nurse will use this list to perform focused observations of the suggested symptoms (=Pharmanurse) [20] . Her/his observations will be put into the system and a list of observed symptoms will be produced and a symptom-score (= sum score) will be given. Additionally and since it can be expected that medication changes intending to improve


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pharmaco-therapeutic care will have an important positive impact on alertness and on pain, both will be followed carefully during the study period in all participating residents. Nurses will assess alertness and pain using VAS scales (with the PAINAD tool for residents with dementia [32]).

After the automated extraction of the medication chart, an electronic assessment of the appropriateness of prescribing will be performed with the following results:

The total number of chronic systemic medication will be counted

Polypharmacy (>= 5 medications) and Extreme polypharmacy (>=10 medications) will be flagged

All medications considered as PIMs will be flagged [24, 25]

A total PIMscore (= sum score) will be given

All medications with anticholinergic properties will be flagged [26–28]

Based on dosage and potency, a total anticholinergic burden score will be given (based on the MARANTE scale) [26–28]

Medications candidate for de-prescribing in view of the limited life expectancy will be flagged [29–31]

After the medication chart review, the nurse will be responsible to put in the results of the discussion between GP and nurse, taking into account the written recommendations of the community pharmacist and to register all medication changes. For each medication on the list the nurse will note (1) keep unchanged or dose increase or dose reduction or stop, (2) rationale for change, (3) if applicable, planning of tapering. The start-up of new pharmaceutical treatments will also be registered. This medical review will be printed and signed by the GP.

Adverse Events (AEs) will be limited to discontinuation problems and will focus on harms of ceasing medication and drug withdrawal reactions after the medication review that needs a medical intervention (=contact with GP or specialist). There is a specific module in the eCRF where discontinuation problems can be reported by the nurse, together with actions taken by the GP to solve the problem.

Additionally, possible discontinuation problems will be monitored systematically by the responsible nurse in all residents of the intervention arm, one week (+3days) and four weeks (±3days) after the medication review. These systematic reports will be captured in OptiMEDs.

Apart from the pilot assessment and data collection described in this section, trial assessments and data collection will be repeated at the end of follow-up, 4 months (±1week) after the medication review for the intervention group, six months (±1week) after the baseline data collection for the control group.

End of Pilot intervention period

The pilot intervention period will end when

the last NH resident in the intervention arm will have had his last assessment four months after the medication review

and when the last NH resident in the control arm has his last medication chart extracted six months after the baseline medication extraction


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8 THE INTERVENTION

The literature states that successful interventions are based on interdisciplinary cooperation, and the combination of different methods is needed in order to obtain a more rational pharmacotherapy in older adults.

Based on these findings, we propose a multifaceted intervention, where the key is to hold a multidisciplinary medication review with input of nurses, pharmacists, and GPs. This medication review will be supported on the one hand by nurse observations, and on the other hand by the automated analysis of potentially inappropriate medications, anticholinergics, and medications that can be de-prescribed.

The OptiMEDs Tool

Description of the OptiMEDs Tool

The OptiMEDs intervention is a multi-faceted intervention combining:

1. an ICT platform: o automatic and secure capture of individual prescribing information from the electronic

medication administration records in the nursing home o a tool for structured nurse observations of side effects, derived from the existing

Pharmanurse application (20) (used to list potential medication side effects, based on the individual medication chart of the nursing home residents) to support monitoring of medication safety by nurses.

o an electronic decision support tool for the appraisal of potentially inappropriate medication (explicit criteria of misuse and underused of medication, based on existing lists of explicit criteria (PIMs)), use of medication with anticholinergic properties and medication inappropriate in view of the limited life expectancy.

2. a multidisciplinary medication review with the input of GPs, trained community-pharmacists and nurses.

The OptiMEDs tool is a web application developed by RAMIT. RAMIT vzw, a non-profit association, is a research platform established in 1992, with the support of the Ghent University. RAMIT’s main mission is performing and supporting International and National R&D in Medical Informatics and Telematics, nowadays called eHealth.

8.1.2 Instructions for use/ intended use

The OptiMEDs tool is developed by RAMIT.

It is a web application, accessible through a web browser. No installation is required, although hyperlinks will be installed on the laptops / pc’s / handheld devices (tablets) in the nursing homes.

The application is hosted on a secured website (Windows 2008 R2 Standard server). OptiMEDs uses IIS version 7.5 as a web server.

OptiMEDs is developed using the CF Wheels 2.0 framework which uses the Adobe Coldfusion 2016 CFML engine. As OptiMEDs is a web application standard Bootstrap and JQuery are used to visualise the application and provide client side functionality. All data is stored in an MS SQL database version using MS SQL Server 2005.

For more information on the privacy and security measures in the OptiMEDs software, we refer to the privacy and security document.

For more information on the instructions for use, we refer to the manual powerpoint (in Dutch).

OptiMEDs will not bear a CE marking.


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8.1.3 Delivery of the software

OptiMEDs is a web application, accessible through a web browser. No installation is required, although hyperlinks will be installed on the laptops / pc’s / handheld devices (tablets) in the nursing homes.

After the study, the hyperlinks will be removed from the laptops / pc’s / handheld devices in the nursing homes. The user rights of the nurses, GPs and pharmacists will be revoked, meaning users will not be able to log in to the website. The website will be put offline after the last data is collected from the last patient (4 months after the medication review). After the data has been analysed and reported, the database will be cleared, erasing all data.

8.1.4 Storage of the medical device

The OptiMEDs platform is a secured ICT platform, developed and processed by RAMIT for this study. It will be operating on a dedicated server in the secure environment of the ICT department of the Ghent University, protected by the university firewall. Access control of this dedicated server part is determined by the OptiMEDs security rules.

User roles and user rights will be defined (e.g. nurses from NH 1 can only view the residents assigned to her name, GPs can only view their patients). Credentials of the users are checked before determining access privileges to the OptiMEDs functions as required for good operation. When users migrate in or out of the organization there access rights are adjusted or revoked. Data stays within the protected environments of the OptiMEDs platform, until the end of the data collection period.

For more information, we refer to the Privacy & Security Document.

8.1.5 Known reactions/side effects of the medical device use

Technical problems with defaults in the functioning of the OptiMEDs tool will result in a lack of advices that are normally produced by the software. Without advices, side effects related to the fact that a GP might follow an advice, will not occur .

Since the OptiMEDs tool will provide only advices that CAN BE followed by a decision of the GP to change the medication during the medication review, direct side effects of the medical device use are unexpected.

What can be expected is that part of the residents whose medication is discontinued, will show discontinuation problems. The following(non-exhaustive list of) discontinuation problems can be related to the discontinuation of medications: nausea / vomiting, diarrhea, changes in appetite, heartburn, nervositas / agitation / aggression, anxiety, sleeplessness, changes in consciousness or cognition, delusion / hallucinations / psychosis, hyperglycaemia, hypoglycaemia, sweating, weight loss.

Only indirectly, the use of the OptiMEDs tool can cause these side effects/harms.

Although all advises included in the OptiMEDs tool are based on published lists of medications with possible negative effects in old age, these lists are intended for ‘in general’ use. This means that for a given patient with a given clinical condition, it could be that the discontinuation of a particular medication is not advisable. In that case, it is the GP who has to take the right decision. It is not the medical device who causes side effects.

Preparation of the Pilot intervention

The preparatory phase will consist of several actions, including and not limiting to - Recruitment of NHs - Recruitment of residents - Preparation of intervention:

o Educational sessions with GPs, pharmacists, nurses o Informative sessions for residents and their proxies o Generation of study protocols


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o Installation of the ICT platform During the preparatory phase of the intervention, motivational actions towards the GPs, the health care staff and the residents will consist in the distribution of informative leaflets and the organisation of information sessions. While in the intervention NHs part of the information sessions will be used for informative and motivational purposes, in the control NH the informative part will be more general and limited in time. During the pilot study, training material and manuals for using the OptiMEDs tools will be developed and their acceptability will be tested. Also in the control NH, data input will be required during the study period. In the control NH the same eCRF will be used for the collection of pilot related data. In the control NH, the OptiMEDs tool will only be used for extraction of the medication chart at baseline and after six months, for the automated assessment of the appropriateness of pharmacotherapy.

Flow of the intervention

The intervention starts with the extraction of the medication chart, and the transfer through a secured website by the responsible IT programmer of the NH software providers.

The medication chart will be processed electronically by our subcontractor RAMIT to yield on the one hand a checklist for focused observations of side-effects by nurses and on the other an automated assessment for the appraisal of the medication use.

The responsible nurse will perform the symptom observation within 2 weeks after receiving the observation list from RAMIT.

The pharmacist will perform his medication review within 2 weeks after receiving the feedback

The nurse and GP will perform the medication review within 4 weeks after receiving the feedback from the pharmacist.

We refer to figure 8.2.1 for a full overview. Numbers in the figure correspond with the numbers used in the following text, giving further explanation about each step of the intervention.


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Figure 8.2.1: Flow of the intervention from moment of data extraction to medication review

From the moment a resident consents, the GP and pharmacist will receive notice that his NH resident is involved in the study (through emails), and that approximately one month from that point, a medication review needs to take place.

1. The OptiMEDs intervention will start with the automated extraction of the medication chart (1) out of the electronic software system in the NH. This file is transferred using a secured website for further analysis.

2. Using the Pharmanurse tool (2), a checklist for possible medication-related symptoms will be produced based on the extracted medication list of each individual NH resident. Nurses will use this checklist to do focused observations per NH resident for actual medication-related side-effects. Additionally, they will observe alertness and pain. Results of the observations will be put in the Pharmanurse tool.

3. From the moment the medication chart is transferred, the extracted medication data will also be used as input for an automated assessment tool that will flag potential inappropriate medications (3) using the explicit criteria from the PIMM- repository (a combination of the most current version of EU(7)-PIM, START/STOPP-2 and the Beers’ list).

4. The extracted data from the individual medication chart will be also automatically scanned for the presence, potency and dosage of anticholinergic medication (4) using the MARANTE scoring system.

5. A list of medications for de-prescribing in old age (5) will be used to flag all medications on the medication chart that can be considered for de-prescribing in view of the old age and the limited life expectancy of the resident

6. The results of the OptiMEDs software will be summarized in a pharmacist report (6). The pharmacist will receive notice (through email) when nurses have performed their observations for one patient. The pharmacist can access the pharmacist report from home.


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7. The pharmacist will analyze this report and use a standard electronic input file (7) to return his comments, additional suggestions, and proposals for more cost-effective prescribing.

8. A review report (8) including all previous actions (1 to 7) will be produced by the IT system to serve as a guidance for the medication chart review by the GP and the responsible nurse. Once the review report is ready, the responsible nurse will invite the GP to come to the nursing home for the standardized medication chart review. The GP will be invited to take a look at the review report before the medication review takes place in order to prepare his review. During the medication review and using the review report, GP together with the nurse will decide about possible adaptations of the medication list and the way medication changes will be performed (e.g. tapering of medication before complete discontinuation). Conclusions of the review will be recorded using a standard electronic input file.

Assessment of discontinuation problems and reportable events

Discontinuation problems

In the OptiMEDs intervention, discontinuation problems (DP) will be (1) harms of ceasing medication use and (2) drug withdrawal reactions:

1. Ceasing medication can lead to a return of the condition treated by the discontinued medication. If the condition returns, medication can be re-initiated, by decision of the GP, at all times.

2. Possible reactions related to drug withdrawal can be expected for particular medication groups or in case of high doses. Drug withdrawal reactions can be minimized by proper planning (ie tapering) and careful monitoring after withdrawal. It will be the responsibility of the treating GP to prescribe a tapering schedule if needed and to monitor and possibly treat the withdrawal reactions.

If discontinuation problems occur necessitating to contact the GP or a specialist, a DP report will be filled by the nurse. There is a specific module in the eCRF where all DPs can be reported, together with actions taken by the GP to solve the problem. Also follow-up data on the evolution of the DP will be registered in the eCRF.

The Safety Board needs to evaluate the severity of the problem. The Safety Board consists of a geriatrician, a clinical pharmacologist and a GP with the function of CRA in a NH (not included in this pilot study), not linked with our research group. They will judge to flag the DP as ‘ a clinically significant withdrawal syndrome or adverse event from discontinuing inappropriate medication’ (see 3.3.1 Minimum criteria for advancing to the full trial study, last requirement).

Additionally, possible withdrawal reactions will be monitored systematically by the responsible nurse in all residents of the intervention arm, one week (+3days) and one month (±3days) after the medication review. Results of this systematic observations will be registered in the OptiMEDs tool.

Reportable events for all participating residents

For all participating residents of the intervention and the control arm, the following events occurring during the complete study period of six months will be collected and reported

1. All deaths giving the date and place of death and a short description of the cause of death. This data will be captured in the End-of-Observation (EoS) file of the eCRF.

2. All unplanned hospitalizations giving number of hospitalizations and number of hospitalized days. Hospitalizations for social reasons, for pre-existing conditions and planned surgery will not be considered as unplanned hospitalizations. This data will be extracted from the administrative data of the NH, collected at baseline for hospitalization in the 4-month period before the start of the study and at study end for the preceding 4 months. This data will be registered in the eCRF on the screens of administrative data.

Reportable events for residents of the intervention arm


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Only for those NH residents who have completed a medication review in the intervention arm also Serious

Adverse Events (SAEs) occurring until 4 months (±1week) after the medication review will additionally be

reported.

A serious Adverse Event (SAE) is an adverse event that:

a) led to a death, injury or permanent impairment to a body structure or a body function.

b) led to a serious deterioration in health of the subject, that either resulted in:

• a life-threatening illness or injury, or

• a permanent impairment of a body structure or a body function, or

• an in-patient hospitalization or prolongation of existing hospitalization, or

• a medical or surgical intervention to prevent life threatening illness.

This reporting will be done using a specific event form called ‘serious adverse event form’ capturing

description of the event, date of onset and end date, severity, assessment of relatedness with ceasing

medication and action taken. This form should be completed by the nurse and sent as soon as possible

but not later than 3 calendar days after NH personnel’s awareness of the event to:

1. The safety board committee and the CI by e-mail to [email protected]

2. HIRUZ by email [email protected] who will inform the EC Board and FAGG.

A printed copy of the SAE form needs to be signed off by the CRA within 1 week and send to the

research team

Follow-up information should be provided as necessary and registered until the problem is solved.

On the serious adverse event form the GP or CRA should assess the relatedness of the SAE with the

change in medication use and with the device use*. It is the responsibility of the Safety Board to review the

causality and relatedness to the medication review/discontinuation of medications.

*NOTE: Although the OptiMEDs tool has to be considered as medical device, direct negative effects related

to the use of this device are not expected to occur. Technical problems with defaults in the functioning of

the OptiMEDs tool will result in a lack of advices. Without advices, side effects related to the fact that a GP

might follow these advices, will not occur. The tool produces only general advices, no binding

recommendations. It remains the responsibility of the GP all or not to follow these advices.

Only indirectly, the use of the OptiMEDs tool can cause side effects/harms. Although all advises included

in the OptiMEDs tool are based on published lists of medications with possible negative effects in old age,

these lists are intended for ‘in general’ use. This means the for a given patient with a given clinical condition,

it could be that the discontinuation of a particular medication is not advisable. In that case, it is the GP who

has to take the right decision and not the medical device who causes side effects.

Data collection for feasibility and acceptability study of the OptiMEDs intervention

In this pilot study, extra data will be collected to explore the feasibility and acceptability of the OptiMEDs intervention:




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at the functionality level o For IT related software problems: date, problem, intervention, result o For user related problems: date, identification user, problem, intervention, result

o In case of IT related software problems or user related problems, the users in the NH can contact the project manager by phone or via [email protected]

at the organizational level o Timing of workload for nurses regarding the use of OptiMEDs(for data in&output, observation of

symptoms, organization of the medication chart review) will be registered noting start and end time for each of this actions by the nurse

o Timing of workload to perform a medication chart review by the pharmacist will be registered noting start and end time by the pharmacist

o Also for the duration of a medication chart review by GP and nurse start and end time will be noted o Practical problems for organizing the medication chart review will be registered by the nurse

at the participation level o Number of GPs refusing to participate o Number of participating GPs at the start of the study o Number of GPs that did not attend the medication chart review o Number of non-consenting eligible residents legally capable to give consent o Number of non-consenting proxies for eligible residents legally not capable to give consent

o Number of medication reviews completed on time (by pharmacists)

o Number of completed nurse observations

at the level of acceptability o A round table discussion will be organized with a selection of nurses of all participating NH handling

the following topics: (1) functionality of the ICT-platform, (2) readiness of the OptiMEDs intervention for further use, (3) suggestions for improvement of the tool, the full trial study and the potential future use of OptiMEDs

o During an interview with the participating pharmacists, the same topics will be handled using a structured questionnaire with open questions

o A structured questionnaire will be distributed to all participating health care workers to investigate the appreciation of the assessment and observation tools (nurses, pharmacists, GPs), appreciation of the multidisciplinary medication chart review (nurses, pharmacists, GPs) and readiness for future use. In this questionnaire, the 10 questions of the system usability scale (SUS) will be incorporated. The SUS is a validated scale providing an overall score, to determine if tools are feasible in current practice. The SUS can be divided into two separate factors, specifically representing the usability (8 items) and learnability (2 items)[33, 34].

For pharmacists we expect a full response rate since they will be contacted by telephone and interviewed about their experiences by the project manager.. For the nurses, the response rate is expected to be high and the profile of respondents can be compared with the general demographic profile of the entire nursing group of each NH. For the GPs, response rate is expected to be lower but can be improved by offering the questionnaire during the last of their medication reviews. Should the response rate be unacceptable low in this group, we will consider to perform a non-response investigation.

Overview of the data flow of the OptiMEDs pilot study

Within the OptiMEDs pilot study, 4 types of data collection can be distinguished:

1. Research data for the OptiMEDs trial

2. Data collection for the OptiMEDs tool



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3. Data collection to study the feasibility and acceptability of the OptiMEDs trial

4. Data needed for the GO/NO GO decision

Research data for the OptiMEDs trial

This data collection will be performed after Informed Consent is signed (i.e. in the preparatory month) and will be repeated four months after the medication review (i.e at the end of the observation period) (see 7.5 Baseline data).

All this data will be collected in ALL consenting residents (in intervention and control arm).

Except for the reportable events and the discontinuation events, only collected in the investigational arm (see 8.4.2).

Pain and alertness for the control arm

Table 8.6.1: Research data for the OptiMEDs Trial.

Data to be extracted from the administrative files of the NH: Baseline End Who?

o Age x A/NH

o Gender x A/NH

o Date of NH admission x A/NH

o KATZ variables (Activities of Daily living (ADL) and disorientation in time and place)

x x A/NH

o Recent (< 3 months) Mini Mental State Examination (MMSE scale) (if available)

x x A/NH

o Planned and unplanned hospitalization in the last 4 months

x x A/NH

o GP consultations in the last 4 months x x A/NH

o Fall incidents in the last 4 months x x A/NH

Data to be collected by observation of resident

o Reportable events (see section 8.4.2) x N

o Spontaneous reporting of discontinuation problems up to one month (±3days) after medication review (with confirmation of GP)

x GP+N

Data to be collected by contacting the resident:

o Quality of life (as measured by the EQ-5D-5L) x x N

o Cognitive function, as measured by the (MMSE) (if no recent assessment available)

x x N

o Pain and alertness (control arm) X X N

A/NH =Automated by Nursing Home administrator A/O tool=Automated by OptiMEDs tool

GP=General Practitioner N=Nurse R=Research team

In the three NHs, the following aggregated data will be collected from all the residents at time of the patient inclusion: year of birth, gender, latest MMSE and Katz scores.


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Data collection for the OptiMEDs tool

This part of the data will be collected within the OptiMEDs tool.

The medication data collection will be performed the first time in the preparatory month and will be repeated four months after the medication review (i.e. at the end of the observation period). Data collection on potential discontinuation problems will happen after 1week (+3days) and 4 weeks (±3days) after the medication review.

For the data collection of this part, there will be a clear distinction between intervention and control arm

Figure 8.6.2: Data collection for the OptiMEDs tool

Intervention NH

Control NH

Who?

Baseline Extraction of the medication chart x x

A/O tool

Symptom Observations x N

Pain and alertness score x N

Systematic reporting of discontinuation problems after about 1 week (±3days) by the nurse

x N

Systematic reporting of discontinuation problems after about 1 month (±3days) by the nurse

x N

Extraction of medication chart at study end x x

A/O tool

Symptom Observations x N

Pain and alertness score x N

A/NH =Automated by Nursing Home administrator A/O tool=Automated by OptiMEDs tool GP=General Practitioner

N=Nurse R=Research team

Note: Pain and alertness will be integrated in the symptom observation list. For the control group, it will be collected separately and reported via eCRF.

Data collection to study the feasibility and acceptability

This data will be collected on paper forms and not in the eCRF. The data will be collected in the NH of the intervention arm by the research team of the sponsor. For a complete description, see 8.5 Data collection for feasibility and acceptability study of the OptiMEDs intervention.

Data collection for the GO/NO-GO decision

Data for the GO/NO-GO decision before moving to a full trial will be collected at different stages of the pilot and input in the eCRF or OptiMEDs platform, using different sources and will be mainly collected in the NHs of the intervention arm.

Table 8.6.4: Data collection for the Go/No Go criteria.

Data source NH involved Numerator and Denominator


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Concerning Recruitment

At least 80% of all eligible residents will be allowed to enter the study by their GPs

Paper form Counting eligible residents with consenting GP

all N: All eligible residents that enter the study with approval by the GP

D: All Eligible residents: all residents that apply to the eligibility criteria /exclusion criteria

At least 40% of all eligible residents participate in the trial giving IC for participation

Paper form Counting eligible residents and participating residents

all N: All eligible residents that have given IC

D: All eligible residents

Concerning outcome

At least 30% of all participating residents in the intervention arm have at least one successfully discontinued PIM (see 3.4.1)

Comparison by the OptiMEDs tool on the medication chart at baseline and at study end

Intervention arm

N: all participating residents in the intervention arm with at least 1 successfully discontinued PIM

D: All participating residents in the intervention arm

Concerning process

In at least 85% of participating residents the ICT application of the OptiMEDs intervention functioned without any technical problem

Registration on paper form

All N: all participating residents without a functional problem that impedes the further use of this NH resident his data in the pilot

D: All participating residents

In at least 95% of the total participating NH residents (that have given consent, in either intervention or control), it was possible to automatically extract their medication administration chart and forward it to the OptiMEDs system.”

Registration on paper form

All N: all participating residents where data extraction was possible, so that further use of this NH resident his data in the pilot was possible

D: All participating residents

At least 50% of the GPs, and nurses feel that this study is feasible, is beneficial, and want to redo all processes.

Based on questionnaires at study end

Intervention arm

N: all nurses / GPs that participated in the study and have used the OptiMEDs software that have given positive feedback

D: all nurses / GPs that participated in the study and have used the OptiMEDs software

Concerning harms

Not more than 10% of all participating NH residents that underwent a medication review

Registration in the OptiMEDs tool and flagged by the safety

Intervention arm

N: All participating NH residents with an event related to the


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has encountered clinically significant withdrawal symptoms or adverse events from discontinuing inappropriate medication.

board as ‘clinically significant’

discontinuation of medications after a medication review

D: All participating NH residents of the intervention arm that underwent a medication review

Not more than 2% of all participating NH residents that underwent a medication review has encountered serious clinically significant withdrawal symptoms or adverse events from discontinuing inappropriate medication.

Registration in the OptiMEDs tool and flagged by the safety board as ‘clinically significant and serious’

Intervention arm

N: All participating NH residents with a serious event related to the discontinuation of medications after a medication review

D: All residents of the intervention arm that underwent a medication review


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9 STATISTICS AND DATA ANALYSIS

For this pilot study, the main objective is to explore the feasibility and acceptability of the OptiMEDs intervention. As secondary objective, it is also our intention to investigate feasibility and acceptability to measure the primary and secondary outcomes of the intervention.

Sample size calculation

Our sample will be limited to the three NHs that we are allowed to include at this stage of the study, with an expected inclusion of 150 residents.

Planned recruitment rate

Based on our experience in nursing homes (PHEBE, n=2077, Ageing@NH, n=741), a participation rate of 50% is expected, which can be considered as sufficient for this pilot study. For each NH with a minimum of 100 beds, we expect to include at least 50 resident [3, 35].

Below we explain in four steps how we reached this target.

First, recruitment rate depends on the rate of participation of the GPs. We want to maximize the

participation rate of GPs. All GPs will be informed prior to the study and receive a mail to confirm

their participation. We expect that GPs will not participate for about 10% of the residents.

(RESULT of the first step: 90/100 residents remaining)

Second, 10% of the residents will have a limited life expectancy of less than 3 months .

(RESULT: 81/100 residents remaining)

Third, we expect that in the remaining number of residents, half of the population will be

cognitively able and the other half cognitively impaired. Participation rates in the cognitively able

group is expected to be around 90%, in the cognitively impaired group, this will be around 50%

(also because no formal agreement from a proxy can be obtained). These are figures based on

previous studies with similar recruitment rates.

(RESULT: 37 + 20 = 57/100 residents remaining)

Fourth, it is expected that 10 % of the residents will be further lost because a GP did not opt out

of the study, but did not participate in the medication review (forgetfulness, late refusal)

(RESULT: 51/100 residents remaining)

In conclusion we expect to recruit a minimum of 50 residents per nursing home, reaching a total of 150 participating residents. To be on the safe side we will select slightly larger nursing homes.

NOTE: We consider this recruitment numbers as minimum criteria before moving to a full RCT. One has to realize however that the potential future use of the OptiMEDs intervention, while participation of the GP will still be formally required, the organization of the medication review guided by the OptiMEDs tool will no longer depends on the IC of the resident but will be considered as good clinical practice for all residents of the NH.

Statistical analysis plan

Description of feasibility and acceptability investigations.

Analysis of data collected to investigate the feasibility and acceptability of the intervention mainly consist of descriptive statistics.

at the functionality level o For IT related software problems: number of interventions and result


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o For user related problems: number of interventions and result

at the organizational level o workload of nurses (in median minutes (range) and with boxplot presentation) for data in&output,

observation of symptoms, organization of the medication chart review o workload of pharmacist to perform a review and report his recommendations (in median minutes

(range) and with boxplot presentation) o time used to perform a medication chart review by GP and nurse (in median minutes (range) and

with boxplot presentation)

at the participation level o

o Number and percentage of participating GPs at the start of the study o Number and percentage of GPs that refused participation o Number and percentage of GPs that did not attend the medication chart review o Number and percentage of non-consenting residents legally capable to give consent o Number and percentage of non-consenting proxies for residents legally not capable to give

consent o Number and percentage of medication reviews completed o Number and percentage of medication reviews completed on time (by pharmacists) o Number and percentage of nurse observations completed

at the level of acceptability o the appreciation of the assessment and observation tools and of the multidisciplinary medication

chart review will be calculated using a sumscore of the different items and will be compared between nurses, pharmacists and GPs. The 10 questions of the system usability scale (SUS) will be scored to determine if the OptiMEDs tools are feasible in current practice. The SUS can be divided into two separate factors, specifically representing the usability (8 items) and learnability (2 items)(29, 30).

Flow of NH residents and descriptive analysis of baseline data

A consort flow diagram will be produced

Comparison of baseline data at the level of the residents will include:

Demographic characteristics: age, gender, number of months residing in NH

Physical health: ADL score, falls, GP consultations and hospitalizations during the previous 4 months

Mental health: KATZ disorientation, MMSE, QoL

Comparison of baseline data at the level of the NH will include:

Percentage of residents with dementia

Number of visiting GPs

Number of (non)consenting GPs

Participation rate of residents

Continuous variables (most semi-quantitative score variables or skewed numbers) will be presented with median and range and will be compared using non-parametric statistics (Mann-Whitney-U-test). Categorical variables will be presented with percentage and will be compared using chi-square test

Exploratory analysis of primary outcome of the OptiMEDs intervention

Since in this pilot study the number of included residents will be limited to 150, we realize that the proposed outcome analysis will be underpowered and will be limited to an exploration of the expected results. First of all, the feasibility and acceptability to measure the defined outcomes will be studied (variation of the results, interpretation, sum scores, risk of bias, …). Second, more in-depth statistical analysis of the outcomes will be explored, keeping in mind that the samples size of the pilot study is too limited to obtain significant results.


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The primary outcome that will be explored is the proportion of NH residents who successfully discontinued use of at least 1 inappropriate medication after 4 months of follow-up. The definition of a successful discontinuation is given in 3.4 SECONDARY ENDPOINTS IN THE PILOT STUDY.

‘Successful discontinuation’ will be a dichotomous variable.

For each resident, all medications recognized as a PIM on the medication list at baseline (e.g. as recognized by the software, before the pharmacist reviews the medication list) will be ‘flagged’. The follow-up medication list 4 months after the medication review will be compared with the baseline list. If a ‘flagged’ medication at baseline is no longer present on the follow-up list (and no other medication of the same ATC group is added to the follow-up list), then the variable ‘successful discontinuation’ will become positive.

Percentage ‘successful discontinuation’ will be compared between intervention and control arm using a chi-square test. The percentages to compare can be based on all included residents at baseline or on all those still alive and included after 4 months of follow-up. In the particular situation of a NH where a mortality of about 10% during the observation period can be expected, both are worthwhile to consider.

To enable adjustment for confounding, a logistic regression analysis will be performed with ‘successful discontinuation’ as outcome, and intervention/control arm as independent variable. The primary outcome will be influenced by specific resident characteristics and subgroup analysis will be worthwhile to explore:

- Different age categories - Gender - ADL categories - Time after permanent admission in the NH - Mental status: dementia yes/no based on disorientation in time and place and the MMSE score

NOTE: Since the limited number of included residents in this pilot study, we realize that the proposed outcome analysis will be underpowered and will be limited to an exploration of the expected results.

Exploratory analysis of the secondary outcomes of the OptiMEDs intervention

Medication related process outcomes o Comparison within the intervention and the control arm will be made between the medication

used at baseline and at the end of the observation period (i.e. for the intervention group 4 months after medication review, for the control group six months after baseline) using paired analysis techniques (the non-parametric Wilcoxon paired rank test for continuous variables and the McNemar test for dichotomous categorical variables). The following parameters will be compared: number of medications, the prevalence of polypharmacy, the PIM score, the anticholinergic exposure score, the number of medications with discontinuation properties (i.e. medications candidate for de-prescribing in view of limited life expectancy )

o For the same variables, differences between baseline and after 4 months follow-up will be calculated and compared between intervention and control arm using the non-parametric Mann Whitney U-test and Chi-square test, respectively

o Additionally, within the intervention group the following results will be reported using descriptive statistics: number of recommendations taken by the trained pharmacists, number of recommendations taken by the GP/nurse, number of effective changes of medication at 1 week (±3days), 1 month (±3days) and 4 months (±5 days) after the medication chart review.

NH resident-related outcomes All NH residents related outcomes will be compared between baseline and 4 month follow-up and between intervention and control arm as described above

o quality of life (as measured by the EQ-5D-5L), o cognitive function, as measured by the Mini Mental State Examination (MMSE) o the level of care dependency (ADL) o falls o hospitalization o mortality o number of medication related symptoms (only in intervention arm) o level of pain o level of alertness


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Data collection for economic evaluation

Data collection in view of the feasibility of a future economic evaluation of the OptiMEDs intervention will include data pre- and post- intervention for:

QoL

Total expenditures for chronic medication per resident

Number of falls with medical intervention during 4 months

Number of GP consultations during 4 months

Number of hospitalization days during 4 months


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10 DATA HANDLING

Data collection tools and source document identification

Source documents will consist of: - Medication chart from resident’s medical file (Care Solutions or Farmad) - Resident’s demographics and physical/mental health from administrative files of the NH - GP visits, SAEs, hospitalization and mortality from administrative files of the NH - Questionnaire residents (paper form) and nurse/pharmacist/GP (electronic and paper form) - Data of falls frequency by residents and/or responsible nurse - Alertness VAS scale (nurse observation) and pain (VAS scale or PAINAD) (resident or nurse)

Since an important part of the data that need to be collected for this pilot study will be automatically collected as part of the intervention tool, we decided to collect all data through the OptiMEDs IT platform and the web-based electronic data capture (EDC) system REDCap. The eCRFs are to be completed within reasonable time by the responsible NH nurse. Data reported on each form should be consistent with the source data. The entries can be checked by trained personnel (Monitor).

Data handling and record keeping

Coded data will be transferred to the Sponsor over a secured (SSL) connection by data entry in REDCap. For each subject enrolled an eCRF must be completed and signed by the CRA. The CRA must verify that all data entries in the eCRFs are accurate and correct. eCRF entries and corrections will only be performed by study NH staff, authorized by the CRA. The subject identification code list will be safeguarded by the NH. The name and any other identifying details will not be included in the study database. Login in REDCap is password controlled, and access will be controlled with IP restriction. Each user will receive a personal login name and password and will have a specific role which has predefined restrictions on what is allowed in REDCap. Furthermore, users will only be able to see data of residents of their own NH. Any activity in this software is traced and transparent per audit trail and log files. Data validation rules will be added in the EDC system to maximize immediate validation of the data at entry. In addition, complex edit checks will be programmed by a data manager to check for inconsistencies within data. Any inconsistencies will be queried to the responsible nurse at the NH. Query management and reconciliation will be carried out in REDCap.

All data will be handled and all records will be kept in accordance with the REGULATION (EU) 2016/679 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation).

A study number will be given to each participating resident in the eCRF.

In the OptiMEDs data the Social Security Number will be collected for the medication list of the participating resident. At the end of the data collection period, data cleaning activities will be performed on the data collected so far on the platforms. The cleaned data from the OptiMEDs platform will be sent to the Trusted Third Party, over a secured line with secured protocol. The Trusted Third Party will then pseudonymise the data, by replacing the Social Security Number in the data, with the Study Number. The Trusted Third Party will then send these pseudonymised data to the study team for merger with the cleaned clinical data, with the study number as linking element.

The investigator and sponsor specific essential documents will be retained for at least 20 years. At that

moment, it will be judged whether it is necessary to retain them for a longer period, according to applicable

regulatory or other requirement(s).

Access to Data

The board of directors of the NH or the responsible Coordinating and Advisory Physician (CRA) will permit study-related monitoring, audits from the sponsor, EC review, and regulatory inspection(s), providing direct access to source data/documents.

The project manager of the sponsor will have access to the OptiMEDs platform and to the eCRF.


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11 MONITORING, AUDIT & INSPECTION

Regular on-site and remote monitoring will be performed by the sponsor’s CTU HEALTH INNOVATION

AND RESEARCH INSTITUTE according to ICH GCP. Prior to commencing recruitment, the monitor and

CI’s delegate will meet the NH’s personnel to review trial specific procedures such as the protocol, safety

reporting procedures, ICF procedures, eCRF completion guidelines and study timelines. Following written

standard operating procedures, the monitor will verify on-site whether the study is conducted and data are

generated, documented and reported in compliance with the protocol, GCP and the applicable regulatory

requirements. Data recorded in the eCRF can be evaluated for accuracy in relation to source documents.

The monitor will provide a monitoring report after each visit to the sponsor. The frequency, extent and

nature of monitoring will be defined in more detail in a monitoring plan. Depending on the quality of the

data, additional monitoring visits may be necessary at the sponsor’s discretion.

12 ETHICAL AND REGULATORY CONSIDERATIONS

Ethics Committee (EC) review & reports

This pilot can only be undertaken after full approval of the protocol and addenda has been obtained from

the central EC (and local EC if applicable). This document must be dated and clearly identify the protocol,

amendments (if any), the informed consent form and any applicable recruiting materials and compensation

programs approved.

During the pilot, the following documents will be sent by the sponsor to the central EC for their review:

Significant safety issue

All protocol amendments and revised informed consent form (if any).

Date of first inclusion of the pilot and last visit of last NH resident

Final progress report, including safety summary and deviations

Notification of end of pilot

Amendments should not be implemented without prior review and documented approval / favorable opinion form the central EC except when necessary to eliminate an immediate hazard to pilot subjects or when the change involves only logistical or administrative aspects of the pilot. At the end of the trial, the sponsor will notify the EC about the trial completion. Within one year after the final completion of the study, a full final report will be written by the sponsor and submitted to the ethical committee and competent authority.

Competent Authority (CA)

Before start of the pilot, the clinical investigation will be notified to the competent authority. During the course of the trial, all reports of serious adverse events and protocol amendments will be notified by the sponsor to the competent authorities within the timelines as defined by the national law. At the end of the trial, the sponsor will notify the CA about the trial completion.

Data protection and NH resident confidentiality

All involved study staff will comply with the requirements of the REGULATION (EU) 2016/679 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation). A study number will be assigned to participating residents. Data entry takes place at the NH and the eCRF will contain pseudonymised, depersonalized data. Access will be limited to the minimum number of individuals necessary for quality control, audit, and analysis.


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Indemnity

The sponsor will provide an insurance, even without fault, to cover its liability as the requesting party (as referred to in the Act of 7 May 2004 on clinical trials) in case of harm caused to the resident by participation in the study.

Protocol compliance

Prospective, planned deviations or waivers to the protocol are not allowed. Under emergency

circumstances, deviations from the protocol to protect the rights, safety or well-being of human subjects

may proceed without prior approval of the sponsor and the EC. Such deviations shall be documented and

reported to the sponsor and the EC as soon as possible. Accidental protocol deviations must be adequately

documented on the protocol deviation log. In case accidental protocol deviations are considered as critical

issues that significantly affect patient safety, data integrity and/or study conduct these should be reported

to the sponsor immediately. The sponsor will subsequently communicate and discuss this with the EC.

The following items will be documented on the protocol deviation log: date of deviation, description of

deviation, actions taken and classification of deviation. Deviations will be classified as minor or major. A

minor protocol deviation is a deviation that does not affect the safety, rights or well-being of subjects or the

quality of their data. A major protocol deviation is a deviation that affects safety, rights or well-being of

subjects or quality of their data.

Any deviation that potentially interferes with and/or affects the efficiency and/or quality conduct of the study

will be discussed by the monitor with the CRA and will be documented on the monitoring report including a

proposed plan of action for resolution if applicable.

Early termination

Early termination or suspension of the study or an investigational site may be necessary in case of major non-compliance, critical safety issues or premature trial discontinuation. This can occur at any time by the sponsor, the NH, EC or regulatory authority. In the event that the clinical investigation would be discontinued prematurely, the OptiMEDs software data will be returned, the terminating party shall justify its decision in writing and the sponsor will communicate early termination, including the reason for early termination, to EC and regulatory authority.


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