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Trial registered on ANZCTR


Registration number
ACTRN12613001204730
Ethics application status
Approved
Date submitted
8/10/2013
Date registered
4/11/2013
Date last updated
15/08/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Opti-Med: A randomised controlled trial of deprescribing to optimise health outcomes for frail older people.
Scientific title
A randomised double-blind placebo-controlled trial (with an additional open intervention arm) to determine whether deprescribing is safe and optimises health outcomes among frail older adults living in residential aged care facilities (RACF) in WA and NSW.
Secondary ID [1] 283327 0
NIL
Universal Trial Number (UTN)
U1111-1148-6094
Trial acronym
Opti-Med
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Medication use in older adults who are often frail with complex co-morbidity (co-existing medical conditions). 290219 0
Condition category
Condition code
Other 290609 290609 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Testing a deprescribing intervention (medication withdrawal algorithm) in which some/all of a the study participant's medications are targeted for withdrawal. One of the two (2) intervention groups will have their medicines over-encapsulated (this will be the BLINDED INTERVENTION group). The other intervention group will have their medicines withdrawn over time without over-encapsulation - ie they will not be blinded (this will be the OPEN INTERVENTION group). Each participant will be enrolled in the study for 12 months and clinical care for all participants will continue under their usual GP/specialists.

Both the BLINDED INTERVENTION and OPEN INTERVENTION groups will be treated in the same manner with respect to medication withdrawal. The Medication withdrawal algorithm will be applied by research pharmacists to develop a Medication Withdrawal Plan (MWP) for each participant prior to their allocation to a study group. The MWP is unique for each participant (because of the unique mix of medications each person is taking at baseline). The method used to determine each participant’s MWP will be consistent. Medicines least likely to be of benefit to the participant and least likely to cause adverse drug withdrawal events (ADWE) will be ceased first and those most likely to cause ADWE and/or most likely to provide symptomatic benefit will be tapered slowly and withdrawn last. Up to three medications will be withdrawn simultaneously if unlikely to cause ADWE or if withdrawal effects would be clearly ascribable to the individual drugs. When tapering is required, doses will generally be halved at fortnightly intervals until a dose of half the lowest dose form is reached, following which the medication will be ceased. Some medications with longer half-lives may be tapered to every second and/or every third day dosing until ceased. The total duration of medication withdrawal will depend on the complexity of the participant’s medication regimen and the number of target medicines that are identified.

Encapsulation:
In the BLINDED INTERVENTION group, we will cease target medications according to the consensus withdrawal plan, as for the OPEN INTERVENTION group. However, medications that can be stopped without dose reduction (e.g. statins, aspirin, vitamins, mineral supplements, bisphosphonates) will be replaced with an (empty) inert placebo capsule. Medications that need to be tapered (e.g., antidepressants, anti-hypertensives, anti-reflux agents) will be encapsulated to maintain blinding. Once the dose has been tapered to zero, an empty inert capsule will continue to be supplied to the participant so that blinding is not compromised.

In the BLINDED CONTROL group, the usual dose forms that have been identified as target medicines will be encapsulated at the intervals indicated in the medication withdrawal plan.

As this is a residential care population the majority of participants will have their medicines administered by a staff member, promoting adherence to intervention protocols.

Adherence and compliance:
Contemporaneous, and previous, medication charts will be copied at each participant review to provide a complete medication administration record.

Upon trial completion, community pharmacies and RACF will be asked to return any remaining trial medication to the pharmacy supplier.
Adherence, compliance, and effectiveness of blinding will be measured by
i) counting of unused medicines
ii) reconciliation of withdrawal plans with administration records
iii) asking cognitively intact participants which group they believe they were allocated to at the conclusion of the twelve month follow up
iv) asking RACF nursing staff, the usual treating doctor and blinded research staff which group they believe participants were allocated at the time of the 12 month follow-up.

Monitoring of Encapsulation Process and Supply of Study Medications:
The research staff will closely monitor for any errors in the supply of usual or study medications at each regular review, and for any errors in medication administration by visual inspection of the administration record to detect omitted or delayed medicines. The DMC will review these at prescribed intervals (the exact intervals will be determined by the DMC once it convenes and ratifies its charter).
Intervention code [1] 288049 0
Treatment: Other
Intervention code [2] 288050 0
Other interventions
Comparator / control treatment
Participants in the CONTROL group will not have the medicines which were targeted for withdrawal actually withdrawn, but will be blinded to this through over-encapsulation of their usual medicines (this will be the BLINDED CONTROL group). Normal clinical care of participants will continue under their usual GP/specialists.
Control group
Active

Outcomes
Primary outcome [1] 290623 0
Survival of participants at 12 months post-randomisation

As well as the 3,6,12 month assessments, regular visits to monitor participants will occur as part of the MWP monitoring and safety measures.

Participants will be reviewed by research staff for potential drug withdrawal adverse effects (ADWE) one week after each medication adjustment. Information will be obtained in systematic way from the following sources: i) the participant, ii) the RACF staff, iii) participant’s RACF notes and iv) NOK/person responsible (when consent has been given). The research staff will ask about possible ADWE (e.g., bowels not open in participants tapering aperients, increased agitation or insomnia in participants tapering antidepressants or analgesics, etc) and/or ask nursing staff about any specific suspected ADWE. They will also visit the participant, ask about possible ADWE and check for any withdrawal-related symptoms (e.g. elevated blood pressure after cessation of an antihypertensive agent, increased shortness of breath and/or elevated JVP and/or ankle oedema after cessation of a diuretic).

If the participant has died since last visited by the research team, the date, place and cause of death will be recorded, as well as autopsy results (if performed and available). Information will be collated from the Residential Aged Care Facilities (RACFs) & hospital records, and the treating General Practitioner (GP). Permission for this access, including after the 12 month study period, is included in the pre-enrolment consent/assent process which is completed with participants/NOK, GPs and RACFs.

Ongoing monitoring of mortality for up to 5 years (subject to adequate resourcing) is envisaged.
Timepoint [1] 290623 0
measured at 3, 6, 12 months post randomisation
Secondary outcome [1] 304924 0
Quality of life

will be assessed using the EQ-5D-5L, a quality of life tool. Participants with MMSE >23 will complete the EQ-5D-5L (ie. self-rated).
For participants with an MMSE score of <= 23, a staff proxy (staff appropriate informant) will be asked to fill in the questionnaire.
Timepoint [1] 304924 0
baseline (= 0 months ie. time of first assessment after enrolment & post randomisation), 3, 6, 12 months
Secondary outcome [2] 305124 0
Anticholinergic and sedative drug exposure

Information about medications (and dose, strength etc information) will be gathered and recorded at each assessment and monitoring visit. Information will be collected from the participant/RACF/hospital records. Permission for this access will have already been granted as part of the pre-enrolment consent/assent process with participants/NOK, GPs and RACFs
Anticholinergic and sedative drug exposure will be calculated using the Drug Burden Index (DBI).
Timepoint [2] 305124 0
Baseline, 3, 6, 12 mths post randomisation
Secondary outcome [3] 305125 0
Number of potentially inappropriate medicines based on published criteria (modified Beers Criteria)

Information about medications (and dose, strength etc information) will be gathered and recorded at each assessment and monitoring visit. Information will be collected from participant/RACF/hospital records. Permission for this data collection will have already been granted as part of the pre-enrolment consent/assent process with participants/NOK, GPs and RACFs.
Timepoint [3] 305125 0
baseline, 3, 6, 12 months post randomisation
Secondary outcome [4] 305126 0
Number of regular and PRN prescription medicines

Information about medications (and dose) will be gathered and recorded at each assessment and monitoring visit. Information will be collected from participant/RACF/hospital records. Permission for this data collection will have already been granted as part of the pre-enrolment consent/assent process with participants/NOK, GPs and RACFs.
Timepoint [4] 305126 0
Baseline, 3, 6, 12 months post randomisation
Secondary outcome [5] 305127 0
Hospital admissions

Information about hospital admissions will be gathered and recorded at each assessment and visit. Information will be collected from participant/RACF incident reports/hospital records. Permission for this data collection will have already been granted as part of the pre-enrolment consent/assent process with participants/NOK, GPs and RACFs.
Timepoint [5] 305127 0
3, 6 & 12 months post randomisation
Secondary outcome [6] 305128 0
Independence in activities of daily living

Assessed using the Modified Barthel Index (MBI)
Timepoint [6] 305128 0
baseline, 3, 6 & 12 months post randomisation
Secondary outcome [7] 305129 0
Cognitive function

Assessed using the Mini-Mental State Examination (MMSE)
Timepoint [7] 305129 0
baseline, 3, 6 & 12 months post randomisation
Secondary outcome [8] 305130 0
Falls

Information about falls will be gathered and recorded at each assessment visit. Information will be collected from participant/RACF incident reports/hospital records. Permission for this data collection will have already been granted as part of the pre-enrolment consent/assent process with participants/NOK, GPs and RACFs.
Timepoint [8] 305130 0
3, 6, 12 months post randomisation
Secondary outcome [9] 305131 0
Fractures

Information about falls will be gathered and recorded at each assessment visit. Information will be collected from participant/RACF incident reports/hospital records. Permission for this data collection will have already been granted as part of the pre-enrolment consent/assent process with participants/NOK, GPs and RACFs.
Timepoint [9] 305131 0
3, 6, 12 mths post randomisation
Secondary outcome [10] 305132 0
Frailty

Measured using the Frailty Index (FI)
Timepoint [10] 305132 0
baseline, 3, 6 & 12 month post randomisation.
Secondary outcome [11] 305133 0
Neuropsychiatric symptoms

Behavioural and Psychological symptoms of dementia assessed by Neuro Psychiatric Inventory (NPI) at baseline, 3, 6 & 12 month assessments.
Timepoint [11] 305133 0
baseline, 3, 6 & 12 month post randomisation
Secondary outcome [12] 305134 0
Medication Side Effects

assessed by Medication Side Effects Questionnaire
Timepoint [12] 305134 0
3,6,12 months post randomisation

Eligibility
Key inclusion criteria
- living in a residential aged care facility.
- not moribund/terminal phase of illness
- taking regular medication (prescribed or other)
Minimum age
65 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria
i) Not taking any regular medication;
ii) Moribund or otherwise in the terminal phase of illness;
iii) Usual doctor does not agree to participation;
iv) RACF manager does not agree to participation; or
v) Participant/next of kin (if participant lacks capacity to consent) does not agree to participation.
vi) Non-English Speaking (In the first phase of recruitment only those people who are able to understand English will be recruited. If subsequently necessary, an amendment to recruit participants who do not understand English will be proposed).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
- residential aged care facilities in two Australian states (WA & NSW)
- if meet eligibility criteria, approached with study information
- participant and/or next of kin (NOK) or "person responsible" provide written consent/assent to participate
- GP/treating doctor also provides written assent for patient's participation
- application of a structured deprescribing protocol to generate and implement a Medication Withdrawal Plan (MWP) is done by 2 study pharmacists who then reach consensus on final(MWP) prior to randomisation
- GP reviews MWP & has right of 'veto' on any/all medications proposed for withdrawal
- after MWP confirmed, randomisation is carried out
- blinding (except in OPEN INTERVENTION group) is maintained by over-encapsulation of medications

Because randomisation of Opti-Med participants is carried out AFTER recruitment to the study and AFTER all consents/assents have been completed and the MWP generated and signed-off by the attending GP, the research personnel will not know which group a participant will be allocated to at the time at which they are recruiting participants and will therefore remain unbiased in their treatment of each participant. This blinding will continue through the 12 months of a participant's enrolment.

Randomisation/allocation will be carried by pharmacy, using computer generated tables made available by the OM study biostatistician, who has no involvement in the recruitment process, and no contact with the participants at any time during the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation stratified by number of regular medications (>10), gender & frailty index (>10).

Our bio-statistician will create computer-generated randomisation tables. The randomisation will be carried out by the study pharmacist or community pharmacists who have been authorised to do this.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
3 groups
1. BLINDED INTERVENTION arm
2. BLINDED CONTROL arm
3. additional OPEN INTERVENTION arm
Phase
Not Applicable
Type of endpoint(s)
Safety
Statistical methods / analysis
Intention-to-treat comparisons of the BLINDED & OPEN INTERVENTION groups with the control group using Cox proportional hazards regression, controlling for baseline variables if necessary.
Economic evaluation: cost-effectiveness and cost-utility analyses.

Sample size rationale

We have chosen to power the study for mortality to establish that the intervention is safe (i.e. no significant reduction in survival). A sample size of 954 (3 groups of 318) has been chosen to balance feasibility of recruitment with power to detect any clinically important treatment effect. In the primary analysis we will seek to confirm mortality is not significantly increased in the intervention groups (compared to the control group) and will have 80% power at the 0.05 level of significance to exclude an increase in one-year mortality of greater than or equal to 9%.

We anticipate needing to screen ~4000 residents to enrol our target of ~1000 participants

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,WA

Funding & Sponsors
Funding source category [1] 288062 0
Government body
Name [1] 288062 0
National Health and Medical Research Council
Address [1] 288062 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601

Postal:
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 288062 0
Australia
Primary sponsor type
University
Name
University of Western Australia
Address
University of Western Australia
35 Stirling Highway
Crawley WA 6009

Country
Australia
Secondary sponsor category [1] 286784 0
University
Name [1] 286784 0
University of Sydney
Address [1] 286784 0
University of Sydney
NSW 2006

Attention: A/Professor Vasi Naganathan
Centre for Education and Research on Ageing (CERA)
Concord Repatriation General Hospital (CRGH)
Hospital Rd,
Concord NSW 2139

Country [1] 286784 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289987 0
University of Western Australia Human Research Ethics Office
Ethics committee address [1] 289987 0
University of Western Australia
35 Stirling Highway
Crawley WA 6009
Ethics committee country [1] 289987 0
Australia
Date submitted for ethics approval [1] 289987 0
Approval date [1] 289987 0
19/03/2013
Ethics approval number [1] 289987 0
RA/4/1/5930
Ethics committee name [2] 289988 0
Human Research Ethics Committee – Concord Repatriation General Hospital (CRGH) of the Sydney Local Health District.
Ethics committee address [2] 289988 0
Sydney Local Health District Human Research Ethics Committee - CRGH
CRGH
Hospital Rd
Concord NSW 2139
Ethics committee country [2] 289988 0
Australia
Date submitted for ethics approval [2] 289988 0
Approval date [2] 289988 0
21/08/2013
Ethics approval number [2] 289988 0
HREC/13/CRGH/77 CH62/6/2013-051

Summary
Brief summary
Frail older people living in residential care are often prescribed unnecessary medications. We want to test whether stopping some of their drugs will improve their life expectancy, quality of life & independence & reduce their risk of falling. We will stop medications thought to cause harm in older people and medications that may not provide any overall benefit. The primary aim is to determine whether deprescribing is safe among older people living in residential aged care facilities (RACF). The secondary aims are to determine whether medication reduction improves physical health, cognitive function, and quality of life.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 43294 0
Prof Christopher Etherton-Beer
Address 43294 0
University of Western Australia
35 Stirling Highway
Crawley WA 6009
Country 43294 0
Australia
Phone 43294 0
61 8 9224 1633
Fax 43294 0
61 8 9224 8001
Email 43294 0
christopher.etherton-beer@uwa.edu.au
Contact person for public queries
Name 43295 0
Prof Christopher Etherton-Beer
Address 43295 0
University of Western Australia
35 Stirling Highway
Crawley WA 6009
Country 43295 0
Australia
Phone 43295 0
61 8 9224 1633
Fax 43295 0
61 8 9224 8001
Email 43295 0
christopher.etherton-beer@uwa.edu.au
Contact person for scientific queries
Name 43296 0
Prof Christopher Etherton-Beer
Address 43296 0
University of Western Australia
35 Stirling Highway
Crawley WA 6009
Country 43296 0
Australia
Phone 43296 0
61 8 9224 1633
Fax 43296 0
61 8 9224 8001
Email 43296 0
christopher.etherton-beer@uwa.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary