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Trial registered on ANZCTR


Registration number
ACTRN12616000233426
Ethics application status
Approved
Date submitted
5/02/2016
Date registered
19/02/2016
Date last updated
11/03/2020
Date data sharing statement initially provided
25/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
INtegrated combination Therapy, Electronic General practice support tool, phaRmacy led intervention And combination Therapy Evaluation (INTEGRATE): An integrated general practice and pharmacy-based intervention to promote the prescription and use of appropriate preventive medications among individuals at high cardiovascular risk
Scientific title
INTEGRATE Study: A pragmatic cluster randomised controlled trial of an integrated general practice and pharmacy-based intervention to promote the prescription and use of appropriate preventive medications among individuals at high cardiovascular risk.
Secondary ID [1] 288486 0
None
Universal Trial Number (UTN)
Trial acronym
INTEGRATE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiovascular disease and their risk factors
 297591 0
Condition category
Condition code
Cardiovascular 297788 297788 0 0
Other cardiovascular diseases
Public Health 297789 297789 0 0
Other public health

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Using a randomised controlled trial design, 70 Australian General Practice and Pharmacy pairs (35 intervention and 35 control) will be recruited. Each GP/Pharmacy pair in the intervention group will be exposed to three interventions (HealthTracker, CVD polypills and PASS). Each GP/pharmacy pair in the intervention arm will be encouraged to continue with the intervention 18 months from the time the last practice is recruited (based on results from the TORPEDO study1). At the end of this period, data will be collected from the GP/Pharmacy pairs in both study arms.
1 Peiris D, Usherwood T, Panaretto K, Harris M, Hunt J, Redfern J, et al. Effect of a Computer-Guided, Quality Improvement Program for Cardiovascular Disease Risk Management in Primary Health Care: The Treatment of Cardiovascular Risk Using Electronic Decision Support Cluster-Randomized Trial. Circulation: Cardiovascular Quality and Outcomes. 2015; 8(1): 87-95.

The integrated intervention comprises of the following three elements: (1) HealthTracker, (2) availability of the Polypills and (3)Pharmacy Adherence Support Service (PASS).

(1) HealthTracker is an electronic decision support tool that aims to assist general practitioners in the management of cardiovascular disease (CVD) risk. It aims to promote best practice care by giving management advice to health care providers based on national guidelines. HealthTracker incorporates a single, extensively validated screening and management algorithm, based on a synthesis of recommendations from several guidelines for CVD, kidney disease and diabetes prevention and management. HealthTracker interfaces with Medical Director (MD) and Best Practice (BP), two clinical practice software systems that together comprise around 80% of general practice record systems in Australia. Data from the patient records in MD or BP pre-populate HealthTracker which then provides the GP point-of-care recommendations on optimal use of CVD risk preventive medications (including option of polypill), based on that patient’s absolute CVD risk estimate.

(2). Eight CVD polypills will be available and they are:
(i) Name: PolyPill Hydrotelmi; Components: Telmisartan (40mg) + hydrochlorothiazide (12.5mg) + rosuvastatin (10mg)
(ii) Name: PolyPill Hydrotelmi Asp; Components: Telmisartan (40mg) + hydrochlorothiazide (12.5mg) + rosuvastatin (10mg) + aspirin (100mg)
(iii) Name: PolyPill Amtelmi; Components: Telmisartan (40mg) + amlodipine (5mg) + rosuvastatin (10mg)
(iv) Name: PolyPill Amtelmi Asp; Components: Telmisartan (40mg) + amlodipine (5mg) + rosuvastatin (10mg) + aspirin (100mg)
(v) Name: PolyPill Perindap; Components: Perindopril (4mg) + indapamide (1.25mg) + atorvastatin (40mg
(vi) Name: PolyPill Perindap Asp; Components: Perindopril (4mg) + indapamide (1.25mg) + atorvastatin (40mg) + aspirin (100mg)
(vii) Name: PolyPill Peramlo; Components: Perindopril (4mg) + amlodipine (5mg) + atorvastatin (40mg)
(viii) Name: PolyPill Peramlo Asp; Components:Perindopril (4mg) + amlodipine (5mg) + atorvastatin (40mg) + aspirin (100mg)

(3) Pharmacy Adherence Support Service (PASS): This intervention involves supporting patients with their “medication journey” by a trained pharmacist. Patients who have been prescribed a Polypill or a new CVD preventative medication will be referred by the GP to a partner Pharmacist who will firstly administer the 7 item Adherence to Refills and Medications Scale (ARMS-7) for assessing medication adherence in patients presenting with new CVD preventative medication prescriptions. A score of greater than 7 indicates unsatisfactory adherence to their medication regimen and the patient is recommended to participate in PASS. PASS, is a customised adherence program which involves a structured clinical interview (approximately 20 minutes) focused on: (i) understanding how the patient actually ‘uses’ their medications; (ii) understanding patient beliefs about their medications; and (iii) capturing patient-reported barriers to adherence. The structured interview is based on a modified version of the Brief Medication Questionnaire 1 (BMQ1), which will be used to systematically review and collect adherence data. Depending on the individualised recommendations, pharmacists may see enrolled patients at approximately 2 weeks (telephone discussion, 5 minutes), and during scheduled pharmacy visits at approximately 1, 3, 6 and 12 months after enrolment, to coincide with prescription re-fills (patients may however present each month for a regular re-fill of their medications). Adherence issues and barriers to medication taking will be reviewed at each visit (10 minutes). An electronic software (PASS Application) has been developed to deliver the ARMS-7 and the PASS via a Tablet/Ipad provided to Pharmacists.

The use of HealthTracker will be monitored centrally by the research team. The use of PASS will be monitored by Project Officers who will contact and visit pharmacies regularly. Fidelity measures (e.g. number of times a recommendation was clicked or the PASS intervention was delivered) will be collected throughout the study.
Intervention code [1] 293838 0
Prevention
Intervention code [2] 293844 0
Treatment: Other
Comparator / control treatment
General Practices allocated to the control arm will continue usual practice with their current systems and without access to the integrated intervention.
Control group
Active

Outcomes
Primary outcome [1] 297271 0
Proportion of high-risk patients who were not on full treatment at baseline achieving recommended target BP and LDL-C target levels at study end.
Definitions used for the primary outcome are based on current Australian guidelines:

1. High CVD risk: either (i) history of CVD (diagnosis of coronary heart disease, ischaemic stroke, OR peripheral vascular disease); (ii) presence of any guideline-stipulated clinically high risk conditions (diabetes and age greater than 60 years, diabetes and albuminuria, stage3B chronic kidney disease (CKD), or extreme risk factor elevations, systolic BP greater than or equal to 180mmHg, diastolic BP greater than or equal to 110 mmHg, total cholesterol greater than 7.5 mmol); or (iii) a calculated 5-year CVD risk of greater than 15% using the 1991 Anderson Framingham equation. In the TORPEDO study, this comprised 27% of the study population.
TORPEDO Study Reference: Welfare AIoHa. Cardiovascular disease: Australian facts 2011 2011. p. Cardiovascular disease series. Cat. no. CVD 53. Canberra: AIHW.
2.. BP and LDL-C target levels: BP less than or equal to 140/90 mmHg in general or people with CKD less than or equal to 130/80 mmHg in all people with diabetes; less than or equal to 130/80 mmHg if albuminuria present (UACR greater than 2.5 mg/mmol in men and greater than 3.5 mg/mmol in women); and LDL-C less than 2.0 mmol/L in all high risk individuals.

3. Full treatment: at least 1 BP-lowering drug and a statin for patients without established CVD; for those with CVD, full treatment will additionally require at least 1 antiplatelet drug.

Diabetes status will be cross checked with HbA1c and GTT measurements. According to Australian guidelines, HbA1c greater than 6.5% or GTT greater than 11.1 is diagnostic of diabetes.
CKD status will be also cross checked with eGFR measurement. Stage3B chronic kidney disease (CKD) is defined as either recorded CKD at baseline or eGFR less than 45 at both baseline and EOS in this study.
Full treatment: at least 1 BP-lowering drug and a statin for patients without established CVD; for those with CVD, full treatment will additionally require at least 1 antiplatelet drug.
Missing data approach for derivation of primary outcome:
To calculate the BP and LDL-C target at study end, target variable will be coded as missing if any of LDL-C, SBP/DBP are missing. Only available UACR is considered in calculating the BP target.
Clinical high risk patients will be derived based on available non-missing data and any missing value will be treated as “negative” status. For example, patients with no history of diabetes and missing age value will be coded as not in clinical high risk; patient with missing BP or missing LIPID value will be treated as not in high risk; patients with missing UACR will be considered as no albuminuria.
Timepoint [1] 297271 0
At end of study (when a median of 18 months follow-up has ended).
Secondary outcome [1] 320540 0
1. Proportion of high-risk patients who were not on full treatment at baseline achieving recommended target BP levels at study end.
Denominator: high CVD risk patients who were not on full treatment at baseline in the cohort. Same definitions as primary outcome for high risk patients, full treatment and BP target.
Numerator: patients who achieved recommended target BP levels at the end of study.
Data was extracted from the general practice software systems using CAT4..
Timepoint [1] 320540 0
At end of study (when a median of 18 months follow-up has ended).
Secondary outcome [2] 320696 0
2. Proportion of high-risk patients who were not on full treatment at baseline achieving recommended BP or LDL-C targets at study end;
Denominator: high CVD risk patients who were not on full treatment at baseline in the cohort. Same definitions as primary outcome for high risk patients, full treatment and BP and LDL-C target.
Numerator: patients who achieved recommended target BP level or LDL-C levels at end of study.
Data was extracted from the general practice software systems using CAT4.
Timepoint [2] 320696 0
At end of study (when a median of 18 months follow-up has ended).
Secondary outcome [3] 320697 0
3. Proportion of all high-risk patients achieving BP and LDL-C targets at the end of study;
Denominator: High CVD risk patients identified in the cohort. Same definitions as primary outcome for high risk patients and BP and LDL-C target.
Numerator: patients who achieved recommended target BP level and LDL-C levels at end of study.
Data was extracted from the general practice software systems using CAT4..
Timepoint [3] 320697 0
At end of study (when a median of 18 months follow-up has ended).
Secondary outcome [4] 320698 0
4. Proportion of high risk patients achieving BP and LDL-C targets and prescribed antiplatelet (if relevant) at the end of study;
Denominator: High CVD risk patients at baseline identified in the cohort.
Numerator: patients who achieved recommended target BP level and LDL-C levels (for non-established CVD) and target BP, target LDL and antiplatelet use (if established CVD) at end of study.
Data was extracted from the general practice software systems using CAT4..
Timepoint [4] 320698 0
At end of study (when a median of 18 months follow-up has ended).
Secondary outcome [5] 320699 0
Risk factor measurement and mean levels at the end of study;
1) Proportion of patients who were >=35 years if ATSI background or otherwise >=45 years at baseline who received appropriate screening of CVD risk factors by the end of study. Appropriate screening is defined as: having recorded smoking status at least once, systolic blood pressure (BP) in the previous 12 months, total cholesterol and high density lipoprotein cholesterol in the previous 24 months.
The three components of appropriate screening will be also reported separately.
2) For high risk patients who were not on full treatment at baseline, change from baseline of SBP, DBP, LDL-C and other lipid measurements.

Data was extracted from the general practice software systems using CAT4..
Timepoint [5] 320699 0
At end of study (when a median of 18 months follow-up has ended).
Secondary outcome [6] 320702 0
Treatment intensification in high-risk patients who were not on full treatment at baseline defined as proportion of high-risk undertreated patients who were newly prescribed or had additional numbers of antiplatelet, BP-lowering and/or lipid-lowering agents added during the intervention period. Done together and separately.
Data was extracted from the general practice software systems using CAT4..
Timepoint [6] 320702 0
At end of study (when a median of 18 months follow-up has ended).
Secondary outcome [7] 320703 0
7. Polypill prescriptions - will be assessed from the number of consent forms signed for the polypill and the supply of polypills.
Timepoint [7] 320703 0
At end of study (when a median of 18 months follow-up has ended).
Secondary outcome [8] 320704 0
8. Participation in pharmacy adherence support programs. Will be assessed from the number of consent forms for the PASS.
Timepoint [8] 320704 0
At end of study (when a median of 18 months follow-up has ended).
Secondary outcome [9] 320705 0
Proportion of non-high risk patients receiving new prescription or escalation of BP lowering, Statin and anti-platelet therapy during the study period.
Denominator is all non-high risk patients with calculated CVD risk <15% (including <10% ‘low’ risk and 10-15% ‘medium’ risk) at both baseline and end of study visit, excluding subjects with missing value of CVD risk.
Numerator is proportion of non-high-risk patients who were newly prescribed or had additional numbers of antiplatelet, BP-lowering and/or lipid-lowering agents added during the intervention period (i.e. new or additional numbers of medications prescribed at EOS but not present at baseline). Done together and separately
Data was extracted from the general practice software systems using CAT4..
Timepoint [9] 320705 0
At end of study (when a median of 18 months follow-up has ended).
Secondary outcome [10] 381129 0
Proportion of high-risk patients who were not on full treatment at baseline achieving recommended target LDL-C levels at study end.
Denominator: high CVD risk patients who were not on full treatment at baseline in the cohort. Same definitions as primary outcome for high risk patients, full treatment and LDL-C target.
Numerator: patients who achieved recommended target LDL-C levels at end of study.
Data was extracted from the general practice software systems using CAT4..
Timepoint [10] 381129 0
At end of study

Eligibility
Key inclusion criteria
General Practice eligibility:
1. Use of either Medical Director or Best Practice for electronic health record (EHR) management.
2. Predominant use of these systems to record risk factors and prescribe drugs.
4. Agreement that a majority of GPs and other designated staff are willing to use the integrated intervention.
5. Agreement to encourage patients to fill prescriptions at a designated partner pharmacy and consider enrolment in the pharmacy adherence program.

Pharmacy eligibility:
1. Agreement to stock and dispense the polypill formulations.
2. Agreement to conduct the pharmacy adherence program.

Patient eligibility:
1. All adult patients (18 years) attending the GP will be potentially be eligible to receive the HealthTracker intervention.
2. All adult patients who are recommended for the component medications according to current guidelines are eligible to be prescribed the polypill therapy.
3. All adult patients attending the paired pharmacy with a new prescription for a CVD prevention medication (either for an existing medication or a new medication), from the partner GP, will be eligible to receive the pharmacy intervention.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
General practice:
1. Not using either Medical Director or Best Practice

Pharmacy:
1. Unwilling to stock and dispense the polypill formulation
2. Unwilling to conduct PASS

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Using a cluster randomised controlled design, health services will be centrally randomised using a web-based platform.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Randomisation of 70 practices (35 per arm) will provide 90% power (2a=0.05) with a mean cluster size of 60 to detect:
1. Relative risk of greater than or equal to 1.15 in the proportion achieving BP targets for intervention vs. usual care. This assumes an ICC=0.03 and 55% of relevant patients from usual care practices will have BP levels at or below target by the end of follow-up.
2. Relative risk of greater than or equal to 1.25 in the proportion achieving LDL-C targets for intervention vs. usual care. This assumes an ICC=0.05 and 40% of relevant patients from usual care practices will have LDL-C levels at or below target by the end of follow-up.
3. Relative risk of greater than or equal to 1.35 in the proportion achieving BP and LDL-C targets for intervention vs. control. This assumes an ICC=0.02 and 14% of relevant patients from usual care practices will have BP and LDL-C levels at or below target by the end of follow-up.
Patient-level data analysis will be used performed on an intention-to-treat basis using generalised estimating equations with an exchangeable correlation structure to account for clustering of patients within services. The population for the primary analyses will be the cohort of eligible patients whose health record data are extracted at both randomisation and end-of-study periods.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/03/2017
Actual
15/12/2016
Date of last participant enrolment
Anticipated
30/09/2019
Actual
28/06/2019
Date of last data collection
Anticipated
30/06/2019
Actual
13/09/2019
Sample size
Target
4200
Accrual to date
Final
7165
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC

Funding & Sponsors
Funding source category [1] 292835 0
Government body
Name [1] 292835 0
National Health and Medical Research Council (NHMRC)
Country [1] 292835 0
Australia
Primary sponsor type
Other
Name
The George Institute of Global Health
Address
The George Institute for Global Health | AUSTRALIA
Level 5, 1 King St | Newtown NSW 2042 Australia
Postal Address: PO Box M201 | Missenden Rd | NSW 2050 Australia
Country
Australia
Secondary sponsor category [1] 291578 0
None
Name [1] 291578 0
None
Address [1] 291578 0
None
Country [1] 291578 0
Other collaborator category [1] 278807 0
University
Name [1] 278807 0
The University of New South Wales
Address [1] 278807 0
UNSW Sydney
High St
Kensington, NSW 2052
Australia

Postal Address:
UNSW Sydney, NSW 2052
Australia
Country [1] 278807 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294340 0
The University of Sydney
Ethics committee address [1] 294340 0
The University of Sydney
NSW 2006
Australia
Ethics committee country [1] 294340 0
Australia
Date submitted for ethics approval [1] 294340 0
30/04/2015
Approval date [1] 294340 0
03/11/2015
Ethics approval number [1] 294340 0
2015/616

Summary
Brief summary
Despite the strength of evidence about the benefits of medicines for the prevention of cardiovascular events, particularly in those at high-risk, there are substantial evidence-practice gaps. This study will test the hypothesis that an integrated intervention combining three evidence based approaches: (1) a CVD polypill (fixed dose-combination of generic blood pressure lowering and lipid modifying, with or without antiplatelet drugs), (2) a GP focused point-of-care electronic decision support and (3) a pharmacy-led medication adherence intervention will increase prescription and long-term use of recommended medications, leading to improvements in CVD risk factor levels compared to usual care. This will be done using a pragmatic cluster randomised control trial of 70 general medical practices.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 63330 0
Prof Anushka Patel
Address 63330 0
The George Institute for Global Health Level 10, King George V (KGV)
Building Missenden Rd Camperdown NSW 2050
Country 63330 0
Australia
Phone 63330 0
+61 2 9993 4500
Fax 63330 0
+61 2 9993 4501
Email 63330 0
[email protected]
Contact person for public queries
Name 63331 0
Anushka Patel
Address 63331 0
The George Institute for Global Health Level 10, King George V (KGV)
Building Missenden Rd Camperdown NSW 2050
Country 63331 0
Australia
Phone 63331 0
+61 2 9993 4500
Fax 63331 0
+61 2 9993 4501
Email 63331 0
[email protected]
Contact person for scientific queries
Name 63332 0
Anushka Patel
Address 63332 0
The George Institute for Global Health Level 10, King George V (KGV)
Building Missenden Rd Camperdown NSW 2050
Country 63332 0
Australia
Phone 63332 0
+61 2 9993 4500
Fax 63332 0
+61 2 9993 4501
Email 63332 0
[email protected]

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 data is potentially available for sharing pending relevant ethics approvals and sign off from the principle investigator.
When will data be available (start and end dates)?
Data will be available 3 years following the closure of the study, estimated to be available from January 2023.
Available to whom?
Requesters should be employees of a recognised academic institution, health service organisation, commercial research organisation or from pharmaceutical industry. Requesters must have experience in medical research. Requesters must be able to demonstrate through their peer review publications in the area of interest their ability to carry out the proposed use of requested data.
Available for what types of analyses?
The data sharing will be only for the purposes of health and medical research and within the constraints of the consent under which the data were originally gathered.
How or where can data be obtained?
In the first instance, potential requesters are strongly encouraged to approach the relevant study investigators informally to discuss feasibility of data sharing. Study investigators can refer such requests to the Institute’s Data Access Coordinator (Director, Research Strategy and Services). A formal outline of the proposed study is to be submitted to the Data Access Coordinator for consideration by the data Custodian. The proposal (max 3 pages) must include a clear statement of the background to the data use, the objectives and details of the methodology proposed, relevant references. In the outline, requesters must demonstrate through their peer review publications in the area of interest their ability to carry out the proposed study.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
7337Study protocolHayek, A., Joshi, R., Usherwood, T. et al. An integrated general practice and pharmacy-based intervention to promote the use of appropriate preventive medications among individuals at high cardiovascular disease risk: protocol for a cluster randomized controlled trial. Implementation Sci 11, 129 (2015) doi:10.1186/s13012-016-0488-1https://implementationscience.biomedcentral.com/articles/10.1186/s13012-016-0488-1 
7338Statistical analysis plan  [email protected]



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbasePutting polypills into practice: challenges and lessons learned.2017https://dx.doi.org/10.1016/S0140-6736%2817%2930558-5
EmbaseAn electronic decision support-based complex intervention to improve management of cardiovascular risk in primary health care: a cluster randomised trial (INTEGRATE).2021https://dx.doi.org/10.5694/mja2.51030
N.B. These documents automatically identified may not have been verified by the study sponsor.