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Trial registered on ANZCTR


Registration number
ACTRN12618000034235
Ethics application status
Approved
Date submitted
30/11/2017
Date registered
12/01/2018
Date last updated
3/05/2021
Date data sharing statement initially provided
30/01/2019
Date results information initially provided
27/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Safer Prescribing and Care for the Elderly (SPACE): Cluster RCT in New Zealand General Practice
Scientific title
Safer Prescribing and Care for the Elderly (SPACE): Cluster RCT in New Zealand General Practice testing a complex intervention comprising audit and feedback plus triggering patient motivation
Secondary ID [1] 293377 0
None
Universal Trial Number (UTN)
Trial acronym
SPACE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
High-risk prescribing 305502 0
Public health 305503 0
Condition category
Condition code
Public Health 304753 304753 0 0
Health service research

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The SPACE intervention comprises a practice audit to identify people with high-risk prescribing for non-steroidal anti-inflammatory drugs (NSAIDs) and/or antiplatelet medicines; an one-off 15 minute outreach visit by a community pharmacist to deliver to doctors patient-specific feedback and educational material; a tick-box for doctors to indicate the action they will take in response to the feedback; a mail-out of the educational material to local community pharmacists; and, one month later, a mail-out from the practice to patients identified as having high-risk prescribing containing information about their medicines and a letter encouraging them to discuss their medicines when they next see their doctor.
All prescribing decisions will be made as usual by the doctor in discussion with the patient.
For doctors the intervention entails the one-off 15-minute meeting with the pharmacist to go through their list of patients identified as having high-risk prescribing, and then for each patient indicating in a tick-box the intended action (‘review medicines + patient letter’, ‘review medicines + no letter', ‘no action’).
The intervention does not target patients, but rather targets doctors. However, patients with high-risk prescribing that are selected by the doctor to receive a mail-out, will receive a mail-out from the practice containing a medicines information brochure and a letter encouraging the patient to talk about their medicines when they are next in at the practice seeing their doctor.
Thus in summary the intervention comprises practice prescribing audit to identify patients with high-risk prescribing and generate a list of such patients for each doctor; a 15-minute one-off outreach visit by the pharmacist to go through with each doctor their list of patients identified as having high-risk prescribing; a tick-box for the doctor to select for each patient the intended action; a mail-out to selected patients. As part of the intervention, the local pharmacist will be notified of the study.
The feedback to each doctor comprises their list of patients who fulfil the high-risk prescribing definition for this study; a one page summary of educational material about the safe prescribing of NSAIDs and anti-platelet medicines. This same educational material will be provided to local community pharmacists.
The mail-out to patients comprises a brief letter informing patients that the practice is reviewing the prescribing of some medicines and that they (the patient) is on the medicines of interest, and encouragement to discuss their medicines when they are next in at the practice seeing their doctor. The medicines information brochure provides basic information about NSAIDs and anti-platelet medicines.
The audit, feedback and tick-box occur at baseline; the pharmacist is informed at or as close as possible to baseline; the mail-out to the patient occurs at baseline (although the mail-out will take a couple of days in postal transit).
Intervention code [1] 299632 0
Treatment: Other
Comparator / control treatment
Practice as usual in the control practices. That is, all doctors in control practices will participate as usual in any quality improvement initiatives, audit activities, continuing medical education activities, and any other practice activities. All prescribing decisions will be made as usual by the doctor in discussion with the patient.
Control group
Active

Outcomes
Primary outcome [1] 303978 0
The primary outcome measure is:
The proportion of the participants receiving high-risk prescribing of NSAID and/or antiplatelet medicines. That is, the proportion of ‘vulnerable-at-baseline patients’ (with gastro-intestinal, renal or cardiac risk factors) receiving high risk prescribing of NSAID and/or antiplatelet medicines, in the 14 weeks prior to each time-point (baseline, 6 months and 12 months), according to the definitions listed in Table 2.
The primary outcome is assessed by analysing extracted practice prescribing data.
Table 2: Definition of high-risk prescribing of NSAID and/or antiplatelet medicines in different categories of potential adverse drug event (ADE)
Category of potential adverse drug event (ADE): High-risk prescribing
A. Gastrointestinal NSAID or aspirin without gastro-protection in patient with prior peptic ulcer
NSAID without gastro-protection in patient 75years and older
NSAID without gastro-protection in patient 65years and older taking aspirin
Clopidogrel without gastro-protection in patient 65years and older taking aspirin
NSAID without gastro-protection in patient taking an oral anticoagulant
Aspirin or clopidogrel without gastro-protection in patient taking an oral anticoagulant
B. Renal NSAID in patient taking both renin-angiotensin system blocker and diuretic
NSAID in patient with chronic kidney disease (eGFR <60)
C. Cardiac NSAID in patient with history of heart failure
Timepoint [1] 303978 0
Assessment time-points will be baseline, 6 months and 12 months. The primary time-point is considered to be at 6 months.
Secondary outcome [1] 340602 0
The proportion of study participants at increased risk of gastrointestinal ADEs receiving gastrointestinal high-risk prescribing of NSAID and/or antiplatelet medicines
The rate of high-risk prescribing will be assessed by analysis of extracted practice prescribing data.
Timepoint [1] 340602 0
Assessment time-points will be baseline, 6 months and 12 months. The secondary time-point is 12 months.
Secondary outcome [2] 341226 0
The proportion of study participants at increased risk of renal ADEs receiving renal high-risk prescribing of NSAID medicines.
The rate of high-risk prescribing will be assessed by analysis of extracted practice prescribing data.
Timepoint [2] 341226 0
Assessment time-points will be baseline, 6 months and 12 months. The secondary time-point is considered to be 12 months.
Secondary outcome [3] 341229 0
The proportion of total study participants (vulnerable patients) admitted (and number of admissions) for related adverse drug events (gastrointestinal ulcer or bleeding, acute kidney injury, and heart failure) during the 12 months after baseline for the intervention compared with the control group.
Hospitalisation data will be linked to primary care patient data by encrypted National Health Index (NHI) number.
Timepoint [3] 341229 0
The secondary timepoint is the 12 months following baseline
Secondary outcome [4] 341230 0
Overall practice rate of high-risk prescribing (in vulnerable patients). This would include newcomers to the practice at 6m or 12m, and practice patients who were not previously vulnerable but who have become so.
The rate of high-risk prescribing will be assessed by analysis of extracted practice prescribing data.
Timepoint [4] 341230 0
Assessment time-points will be baseline, 6 months and 12 months. The secondary time-point is considered to be 12 months.
Secondary outcome [5] 341231 0
Data will also be collected to enable a subsequent cost-effectiveness evaluation of the intervention from a societal and health funder perspective.
The cost-effectiveness of the intervention will be measured as the cost per reduction in high-risk prescribing, and cost per reductions in hospitalisations from the health funder (District Health Board) perspective.
The data collected will include the cost of delivering the intervention (including pharmacist and doctor time for the feedback outreach session, travel time and costs for the outreach visit, audit time and cost); cost of medicines; cost of hospitalisations.
Timepoint [5] 341231 0
The secondary time-point will be 12 months.

Eligibility
Key inclusion criteria
Inclusion criteria: Patients (‘vulnerable patients’) will be included in the study if, at baseline, they fulfil one or more of the following inclusion criteria:
• Gastrointestinal risk factors (and not on gastro-protective medication) - Prior peptic ulcer; 75y and older; 65y and older prescribed aspirin; Prescribed oral anticoagulant
• Renal risk factors - Prescribed both renin-angiotensin system blocker and diuretic; chronic kidney disease (eGFR <60)
• Cardiac risk factors - Heart failure
Where patients have baseline assessments included in one study practice and then move to a second study practice before baseline assessment at the second practice, they will be included as study participants in the second practice only.
Minimum age
No limit
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
All patients fulfilling inclusion criteria in participating practices will be included. If children fulfil the inclusion criteria they will be included. This is highly unlikely given the inclusion criteria. No children were identified in audits during the feasibility study. We see no reason to exclude children - if children are receiving high-risk prescribing then it makes sense for doctors to review their medicines as well. The intervention is designed to promote medicines review.

Study design
Purpose of the study
Educational / counselling / training
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Practices will be purposively sampled and recruited, aiming to include small (0-2999 enrolled patients), medium (3000-7999 enrolled patients) and large (8000-14999 enrolled patients) practices in the Auckland and Northland regions.
Practices will be randomised 1:1 to intervention or control. Randomisation will be stratified by practice location (Auckland vs Northland) and practice size (small (0-2999 enrolled patients), medium (3000-7999 enrolled patients) and large (8000-14999 enrolled patients)). Block randomisation will be carried out using randomly varying block sizes of 2 and 4. Random sequence generation and allocation of randomisation will be undertaken by a statistician not involved in recruitment or baseline data extraction.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple random sequence generation, using a randomisation table created by computer software, and allocation of randomisation will be undertaken by a statistician not involved in recruitment or baseline data extraction.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
The sample size calculation for this study is based on previous trials demonstrating a clinically relevant 25-45% relative risk reduction in the proportion of high-risk prescribing, one trial of which also demonstrated how such reduction (3.7% to 2.2%) in high risk prescribing can translate to significant reductions in hospitalisations due to bleeding complications. We estimated an average of 200 ‘vulnerable patients’ per practice, and an intracluster correlation coefficient (ICC) of 4.68 x 10-7 for the primary outcome based on a cluster randomised trial examining similar outcome of NSAIDs prescribed to patients with a history of peptic ulcer and not prescribed gastro-protection. We estimated an 8% high-risk prescribing rate, based on local feasibility study data.
Assuming approximately 12% of patients would be lost to follow-up over the 12 month study period, data from 8000 patients from 40 practices (20 practices in each group) with an average of 200 vulnerable patients per practice would be required to detect as statistically significant a difference of 6% in the intervention group and 8% in the control group of high-risk prescribing at 12 months (p=0.9, alpha=0.05).
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
Analyses will be performed according to the intention-to-treat principle, with the use of mixed-effect models to account for clustering in the data. ‘Intention to treat’ for the primary analysis will be according to practice allocation (intervention (I) or control (C)), regardless of adherence to components of the intervention. ‘Allocation’ of practices was according to random sequence for 33 of the 39 practices. However, due to a transcription error, the allocation of one random sequence of six practices was inverted (C,I,C,I,C,I instead of I,C,I,C,I,C), resulting in three practices randomised to intervention being allocated to control and vice versa. This transcription error was only identified after completion of the trial and all data collection when analysts were unblinded.
Sensitivity analyses will be undertaken by original random sequence and per protocol for the primary outcome.
The proportion of patients with high-risk prescribing will be analysed using random-effects logistic regression with the individual as the unit of analysis and the practice included as the random effect to control for the effects of clustering. GLIMMIX with Group*Time interaction will be used to assess the overall difference between intervention and control. The model will adjust for the stratification factors including practice location (Northland or Auckland) and practice size). Baseline covariates including (age, sex, and baseline number of long-term medicines) will be adjusted if appropriate. Random effects logistic regression analyses will be used to test the differences in drug-specific secondary outcomes (such as hospitalisations) between intervention and control groups.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
19/03/2018
Actual
22/02/2018
Date of last participant enrolment
Anticipated
31/05/2019
Actual
25/06/2019
Date of last data collection
Anticipated
29/07/2020
Actual
29/07/2020
Sample size
Target
8000
Accrual to date
Final
21877
Recruitment outside Australia
Country [1] 9364 0
New Zealand
State/province [1] 9364 0
Auckland and Northland

Funding & Sponsors
Funding source category [1] 298004 0
Charities/Societies/Foundations
Name [1] 298004 0
Auckland Medical Research Foundation
Country [1] 298004 0
New Zealand
Primary sponsor type
University
Name
The University of Auckland
Address
Tamaki campus
261 Morrin Road
Auckland 1142, New Zealand
Country
New Zealand
Secondary sponsor category [1] 297069 0
None
Name [1] 297069 0
Address [1] 297069 0
Country [1] 297069 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299040 0
University of Auckland Human Participants Ethics Committee
Ethics committee address [1] 299040 0
The University of Auckland Private Bag 92019 Auckland, New Zealand
Level 10, 49 Symonds Street, Auckland 1010, New Zealand
Ethics committee country [1] 299040 0
New Zealand
Date submitted for ethics approval [1] 299040 0
07/09/2017
Approval date [1] 299040 0
09/10/2017
Ethics approval number [1] 299040 0
020092

Summary
Brief summary
The SPACE Cluster Randomised Control Trial (RCT) will test the effect of an intervention designed to promote medicines review and support safer prescribing decisions in general practice.
In New Zealand (NZ) there were 15,254 hospital admissions for adverse drug events (ADEs) in 2005. Most ADE admissions are caused by commonly prescribed drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), antiplatelet medications and anticoagulants, which together account for one third of ADE admissions. The single greatest predictor of adverse drug events and ‘high-risk’ prescribing is the number of medicines a person is taking. With demographic trends, there are increasing numbers of older people who are prescribed multiple medications for co-exsiting medical conditions. In NZ, approximately 10% of older people are taking ten or more regular medicines, and high-risk prescribing is common, often involving NSAIDs.
We have developed the Safer Prescribing and Care for the Elderly (SPACE) intervention for NZ general practice, adapted from the successful Australian Veterans' MATES programme. The first SPACE module comprises a practice audit to identify high-risk prescribing of NSAIDs and antiplatelet medicines to ‘vulnerable’ patients (at least one existing risk factor for ADE), an outreach visit from the Primary Health Organisation (PHO) pharmacist to provide education and patient-specific feedback to general practitioners (GPs), and patient activation through a practice mail-out encouraging patients receiving ‘high-risk’ medication combinations to discuss their medicines when they next see their GP.
This cluster RCT is planned to assess whether the SPACE intervention can reduce the rate of ‘high-risk’ prescribing and related ADE hospital admissions over 12 months amongst predominantly older ‘vulnerable’ patients using existing PHO infrastructure and systems in every-day NZ primary care.
Methods: A cluster RCT design involving 8000 vulnerable patients from 40 practices (including 120 GPs), would be adequate to detect a 25% reduction in rate of ‘high-risk’ prescribing, allowing for a 12% loss to follow-up of patients over 12 months. Randomisation will be by practice.
Significance: The prevalence of high-risk prescribing and avoidable ADE admissions, and the unnecessary cost imposed on an already stretched health system, justify greater efforts to improve the safety of prescribing in general practice. The aging population with increasing polypharmacy mean the ADE rates and costs will only increase unless we can improve the safety of prescribing in general practice. If shown to be effective, the SPACE programme could be rolled out nationally and used routinely by PHOs, with further evidence-based SPACE modules developed to support safer prescribing in general practice and minimise avoidable ADE hospital admission
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 79082 0
Dr Katharine Wallis
Address 79082 0
Department of General Practice and Primary Health Care, University of Auckland, 261 Morrin Road, Auckland 1142
Country 79082 0
New Zealand
Phone 79082 0
+64 21794544
Fax 79082 0
Email 79082 0
k.wallis@auckland.ac.nz
Contact person for public queries
Name 79083 0
Dr Katharine Wallis
Address 79083 0
Department of General Practice and Primary Health Care, University of Auckland, 261 Morrin Road, Auckland 1142
Country 79083 0
New Zealand
Phone 79083 0
+64 21794544
Fax 79083 0
Email 79083 0
k.wallis@uq.edu.au
Contact person for scientific queries
Name 79084 0
Dr Katharine Wallis
Address 79084 0
Department of General Practice and Primary Health Care, University of Auckland, 261 Morrin Road, Auckland 1142
Country 79084 0
New Zealand
Phone 79084 0
+64 21794544
Fax 79084 0
Email 79084 0
k.wallis@uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial, after de-identification.
When will data be available (start and end dates)?
Beginning 3 months and ending 5 years following main results publication.
Available to whom?
Researchers who provide a methodologically sound proposal.
Available for what types of analyses?
Only to achieve the aims in the approved proposal.
How or where can data be obtained?
Access subject to approvals by Principal Investigator, and requirement to sign data access agreement.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
1194Study protocol    374006-(Uploaded-29-01-2019-13-43-14)-Study-related document.pdf
1195Ethical approval    374006-(Uploaded-29-01-2019-13-44-45)-Study-related document.pdf
1196Informed consent form    374006-(Uploaded-29-01-2019-13-45-58)-Study-related document.pdf



Results publications and other study-related documents

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