Implementation of a Decision Support System and Its Effect on Early Optimisation of Lipid-Lowering Therapies in Patients With Acute Coronary Syndrome: a Cluster Randomised Controlled Trial
Phase: NA
Conditions: Acute Coronary Syndrome, Myocardial Infarction
Sponsor: Imperial College London

ZODIAC 
Imperial College London 
V.3 17 JAN 24 
 
Confidential 
SOP_TEM_CR001 v6.0 Effective 01 Aug 2019  
 
 
Page 1 of 48 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
ICTU ADOPTED 
 
 
 
Full Study Title: Implementation of a Decision Support System and its effect on early 
optimisation of Lipid-Lowering Therapies in patients with Acute Coronary Syndrome: a 
cluster Randomised Controlled Trial 
 
Short Study title / Acronym: OptimiZation Of lipid lowering therapies using a Decision 
support system In patients with Acute Coronary syndrome (ZODIAC).  
 
 
 
Sponsor: 
 
 
 
Imperial College London 
 
Version no:                         
V3.0         
 
 
 
 
 
Protocol Date:  
 
  
17 Jan 2024 
 
Property of Imperial Clinical Trials Unit (ICTU) 
 
May not be used, divulged or published without the consent of ICTU 
 
This protocol has regard for the HRA guidance 
 
 
 
 
 
 
 

ZODIAC 
Imperial College London 
V.3 17 JAN 24 
 
Confidential 
SOP_TEM_CR001 v6.0 Effective 01 Aug 2019  
 
 
Page 2 of 48 
 
 
RESEARCH REFERENCE NUMBERS 
 
 
 
IRAS ID: 
317589 
Clinical trials.gov Number: 
NCT05844566 
Sponsor Protocol Number: 
22HH7982 
Funder reference: 
GM-2021-13502 
 
 
 
Keywords: 
 
Decision Support System; Lipid Lowering Therapies; Acute Coronary Syndrome 
 
 

ZODIAC 
Imperial College London 
V.3 17 JAN 24 
 
Confidential 
SOP_TEM_CR001 v6.0 Effective 01 Aug 2019  
 
 
Page 3 of 48 
 
 
CONTACT LIST 
 
Chief Investigator  
 
Professor Kausik K Ray 
Director ICTU Global 
Imperial Clinical Trials Unit, Stadium House, 68 Wood Lane, London, W12 7RH 
Tel: 
+44 (0)207 594 3341 
Email: k.ray@imperial.ac.uk  
 
Sponsor 
 
Research Governance and Integrity Team 
Imperial College London 
Address: Room 221, Medical School Building, St Marys Campus, Norfolk Place, London 
W2 1PG 
 
Tel: +44 020 7594 9480 
 
Email: RGIT@imperial.ac.uk  
 
EU Legal Representative  
 
Hippocrates Research S.r.l. 
Via XX Settembre 30/12, Genoa, Italy 
Tel: +39 010 545481 
Email: info@hippocrates-research.it  
 
Clinical queries 
 
Clinical queries should be directed to the Chief Investigator or ICTU Study Manager who will 
direct the query to the appropriate person. 
 
Funder  
 
SANOFI WINTHROP INDUSTRIE 
Address: 54 Rue de la Boétie 75008 Paris – France 
 
ICTU Study Manager 
 
Maria Moreno MoralesAddress: Imperial Clinical Trials Unit, Imperial College London 1st 
Floor, Stadium House, 68 Wood Lane, London W12 7RH 
Tel: 
+44 7935 352 902 
Email:  m.moreno-morales@imperial.ac.uk  
 
ICTU Operations Manager 
 
Dr Gaia Kiru 
Head of Operations ICTU Global 

ZODIAC 
Imperial College London 
V.3 17 JAN 24 
 
Confidential 
SOP_TEM_CR001 v6.0 Effective 01 Aug 2019  
 
 
Page 4 of 48 
 
 
Address: Imperial Clinical Trials Unit, Imperial College London 1st Floor, Stadium House, 
68 Wood Lane, London W12 7RH 
Tel: 
+44207 594 8974   
Email: g.kiru@imperial.ac.uk  
Jessica Smith  
Operations Manager  
Address: Imperial Clinical Trials Unit, Stadium House, 68 Wood Lane, London W12 7RH 
Tel: +44207 594 2594 
Email: jessica.smith1@imperial.ac.uk  
 
Senior Statisticians 
 
Professor Victoria Cornelius 
Head of Statistics 
Address: Imperial Clinical Trials Unit, Imperial College London, 
1st Floor, Stadium House, 68 Wood Lane, London W12 7RH  
Tel: 20 7594 1218 
Email: v.cornelius@imperial.ac.uk  
Dr Leila Janani 
Research Fellow and Senior Clinical Trials Statistician 
Address: Imperial Clinical Trials Unit, Imperial College London 1st Floor, Stadium House, 
68 Wood Lane, London W12 7RH 
Tel: 20 7594 1737 
Email: l.janani@imperial.ac.uk 
 
Trial Coordination 
 
 
 
 
Other Vendors/suppliers  
 
Decision Support System (DSS) Developer group 
Christophe Stevens 
Imperial College London, Primary Care & Public Health 
Address: 309, 3rd Floor, Reynolds Building, Charing Cross Campus 
Tel: +44 20 7594 8596  
Email: christophe.stevens@imperial.ac.uk  
 
 
This protocol describes an implementation trial which assesses whether availability and use 
of a Decision Support System (DSS) improve achievement of guideline recommended 
control of cholesterol levels in patients after an acute coronary syndrome (ACS). This 
protocol provides information about procedures for enrolling participants into the trial. The 
protocol should not be used as a guide for the treatment of other participants (not 
participating in the trial); every care was taken in its drafting, but corrections or amendments 
may be necessary. These will be circulated to investigators in the study, but centres enrolling 
Imperial Clinical Trials Unit, Imperial College London 
Address: 1st Floor, Stadium House, 68 Wood Lane, London W12 7RH 

ZODIAC 
Imperial College London 
V.3 17 JAN 24 
 
Confidential 
SOP_TEM_CR001 v6.0 Effective 01 Aug 2019  
 
 
Page 5 of 48 
 
 
participants for the first time are advised to contact the Trial Coordination centre to confirm 
they have the most recent version. Problems relating to this trial should be referred, in the 
first instance, to the Trial Coordination centre.  
 
This trial will adhere to the principles outlined in the International Conference on 
Harmonisation Good Clinical Practice (ICH GCP) guidelines. It will be conducted in 
compliance with the protocol, the Data Protection Act 2018 and other regulatory 
requirements as appropriate. 

ZODIAC 
Imperial College London 
V.3 17 JAN 24 
 
Confidential 
SOP_TEM_CR001 v6.0 Effective 01 Aug 2019  
 
 
Page 6 of 48 
 
 
ABBREVIATIONS  
 
ACS 
Acute Coronary Syndromes 
ADR 
Adverse Drug Reaction  
AE 
Adverse Event 
ASCVD 
Atherosclerotic Cardiovascular Disease 
CI 
Chief Investigator 
CV 
Cardiovascular  
CVD 
Cardiovascular Disease  
CRF 
Case Report Form 
DSS 
Decision Support System 
eCRF 
Electronic Case Report Form 
EAS 
European Atherosclerosis Society 
ESC 
European Society of Cardiology 
HRA 
Health Research Authority 
GPvP 
Good Pharmacovigilance Practice 
ICMJE 
International Committee of Medical Journal Editors 
ICTU 
Imperial Clinical Trials Unit 
ITT 
Intention to Treat 
LDL-C 
Low-density lipoprotein cholesterol  
LLT 
Lipid Lowering Therapy 
LMT 
Lipid Modifying Treatment 
MI 
Myocardial Infarction 
NSTEMI 
Non-ST segment elevation myocardial infarction 
QA 
Quality Assurance 
QC 
Quality Control  
REC 
Research Ethics Committee 
SAP 
Statistical Analysis Plan 
SoC 
Standard of Care 
SOP 
Standard Operating Procedure 
STEMI 
ST segment elevation myocardial infarction 
TEC 
Trial Executive Committee 
UA 
Unstable Angina 

ZODIAC 
Imperial College London 
V.3 17 JAN 24 
 
Confidential 
SOP_TEM_CR001 v6.0 Effective 01 Aug 2019  
 
 
Page 7 of 48 
 
 
Table of Contents  
RESEARCH REFERENCE NUMBERS 
2 
CONTACT LIST 
3 
ABBREVIATIONS 
6 
TRIAL SUMMARY 
9 
1.1 Clinical setting ................................................................................................................ 14 
1.2 Intervention details ......................................................................................................... 14 
2. OBJECTIVES AND ENDPOINTS 
16 
2.1  Primary Objective .......................................................................................................... 16 
2.2 Secondary Objectives..................................................................................................... 16 
2.3 Primary Endpoint ............................................................................................................ 16 
2.5. Exploratory analysis ...................................................................................................... 17 
3. STUDY DESIGN 
17 
3.1 Design ............................................................................................................................ 17 
4. PARTICIPANT ENTRY 
18 
4.1 Study setting and population .......................................................................................... 18 
5. PROCEDURES AND MEASUREMENTS 
19 
5.2 Identification and recruitment of participants ................................................................... 19 
5.3 Screening and Baseline evaluations ............................................................................... 20 
5.4 Visit Schedule ................................................................................................................ 20 
5.5 Follow-up ........................................................................................................................ 20 
6. WITHDRAWAL ................................................................................................................. 21 
6.1 Withdrawal from Study ................................................................................................... 21 
7. SAFETY REPORTING 
21 
8. STATISTICAL ANALYSES 
254 
8.1 Sample Size and power considerations ........................................................................ 254 
8.2 Planned recruitment rate .............................................................................................. 255 
8.3 Statistical Analysis ........................................................................................................ 255 
9. REGULATORY, ETHICAL AND LEGAL ISSUES 
288 
9.1 Declaration of Helsinki .................................................................................................. 288 
9.2 Good Clinical Practice .................................................................................................. 288 
9.3 Research Ethics Committee (REC) Approval ............................................................... 298 
9.4 HRA approval ............................................................................................................... 299 
9.5 Non-Compliance and Serious Breaches ....................................................................... 309 
9.6 Insurance and Indemnity and Sponsor ........................................................................... 30 
9.7 Trial Registration ............................................................................................................ 30 
9.8 Informed Consent ........................................................................................................... 30 
9.9 Participant Confidentiality ............................................................................................... 30 
9.10 Data Protection and Participant Confidentiality ............................................................. 30 
9.11 End of Trial ................................................................................................................... 31 
9.12 Study Documentation and Data Storage ....................................................................... 31 
10. DATA MANAGEMENT 
31 
10.1 Source Data ................................................................................................................. 31 
10.2 Language ..................................................................................................................... 31 
10.3 Database ...................................................................................................................... 31 
10.4 Data Collection ............................................................................................................. 31 
10.5 Archiving ...................................................................................................................... 32 
11. STUDY MANAGEMENT STRUCTURE 
32 
11.1 Trial Executive Committee ............................................................................................ 32 
11.2 Early Discontinuation of the Study ................................................................................ 32 
11.3 Risk Assessment .......................................................................................................... 32 
11.4 Monitoring .................................................................................................................... 32 
11.5 Quality Control and Quality Assurance ......................................................................... 32 

ZODIAC 
Imperial College London 
V.3 17 JAN 24 
 
Confidential 
SOP_TEM_CR001 v6.0 Effective 01 Aug 2019  
 
 
Page 8 of 48 
 
 
11.6 Peer review .................................................................................................................. 32 
11.7  Publication and Dissemination policy ........................................................................... 33 
12. REFERENCES 
34 
13. REVISION HISTORY 
36 
SIGNATURE PAGE 1 (CHIEF INVESTIGATOR) 
37 
SIGNATURE PAGE 2 (SPONSOR) 
398 
SIGNATURE PAGE 3 (STATISTICIAN) 
409 
SIGNATURE PAGE 4 (PRINCIPAL INVESTIGATOR) 
40 
14. APPENDICES 
41 

ZODIAC 
Imperial College London 
V.3 17 JAN 24 
 
Confidential 
SOP_TEM_CR001 v6.0 Effective 01 Aug 2019  
 
 
Page 10 of 48 
 
 
▪ Record of corresponding lipid-lowering therapy at the time the LDL-C is 
measured.  
▪ Estimated GFR (eGFR), e.g. available or derived using MDRD, or its 
component, the serum creatinine. 
Patient’s demographics (age, gender), prior clinical history (ASCVD, coronary artery 
disease, cerebrovascular disease, abdominal aortic aneurysm, peripheral artery disease, 
Diabetes Melitus), systolic blood pressure, smoking status.  
 
Participants: 
• Aged ≥18 to < 80 years old 
• Provide written informed consent 
• Presenting to a study site with ACS as LLT naïve, monotherapy or combination 
therapy (defined as more than one LLT agent) 
• Willing to take lipid lowering treatments for the secondary prevention of 
cardiovascular disease 
o Attending the same study site (or same clinical team) for ACS follow up to 
ensure follow up data can be collected; or ensure that follow up data can be 
collected from other clinical institutions as part of the clinical pathway.  
 
Exclusion criteria: 
Sites: 
• Unable to capture/ provide data on patients with ACS during admission and follow up 
• Unable or unwilling to use lipid lowering treatments other than statins for ACS care 
 
Participants:  
• Unable to provide written informed consent 
• LDL-C measurement < 1.8 mmol/L at admission  
 
MAIN STUDY PROCEDURES  
Those sites randomised to standard of care will continue with routine clinical practice. For 
those sites randomised to the DSS, there will be no patient intervention. The DSS generates 
a patient-specific recommendation on the value of initiation of add-on lipid lowering therapy 
for reducing the risk of recurrent Cardiovascular (CV) events. Based on the patient-specific 
profile and a benefit calculator plus other evidence-based tools, the DSS generates a 
patient-specific recommendation on the expected clinical benefit from combination therapy 
and is designed to support clinical decision making at the time of ACS in-line with EAS/ ESC 
guidelines. Implementing the patient-specific recommendation remains at the clinicians’ 
discretion.   
 
OUTCOME MEASURES 
 
PRIMARY ENDPOINT 
Proportion of patients treated with combination therapy, or who receive escalated 
monotherapy, or escalated combination therapy, within 16 weeks of the index ACS. 
Combination therapy is defined as two or more drug combination regimens using 
commercially available licenced LLTs (statins, selective cholesterol-absorption inhibitors, 
adenosine triphosphate-citrate lyase (ACL) inhibitors, bile acid sequestrants, PCSK9 
monoclonal inhibitors or PCSK9 siRNA therapy). Escalated therapy includes increase in 

ZODIAC 
Imperial College London 
V.3 17 JAN 24 
 
Confidential 
SOP_TEM_CR001 v6.0 Effective 01 Aug 2019  
 
 
Page 11 of 48 
 
 
statin potency, switching to a more potent combination regimen e.g. statin plus ezetimibe to 
statin plus PCSK9 Mab, or two drug combination therapy increased to triple therapy. 
 
SECONDARY ENDPOINTS 
1. Time to initiation of combination therapy or escalation of Lipid lowering therapy as 
defined in the primary endpoint.  
2. LDL-C by Week 16 
3. Proportion of patients reaching target LDL-C level (<1.4 mmol/L (<55 mg/dL) by Week 
16.  
EXPLORATORY ENDPOINTS  
1. Proportion of patients achieving a decrease from baseline LDL-C level of more than 
50% by Week 16 for LLT naïve patients 
2. Percent change from baseline in LDL-C by Week 16 for LLT naïve patients 
3. Percent change from baseline in non-HDL-C by Week 16 for LLT naïve patients 
4. Percent change from baseline in HDL-C by Week 16 for LLT naïve patients 
5. Percent change from baseline in triglycerides by Week 16 for LLT naïve patients 
6. Percent change from baseline in total cholesterol by Week 16 for LLT naïve patients 
7. Proportion of patients on combination therapy at Week 16 (for at least 4 weeks) 
achieving target LDL-C level <1.4 mmol/L (<55 mg/dL) and a decrease of baseline in 
LDL-C level of at least 50% by Week 16 for LLT naïve patients  
8. Proportion of all patients achieving target LDL-C level <1.8 mmol/L (<70 mg/dL) by 
Week 16 
9. Proportion of patients on combination therapies with three oral LLTs or 1 injectable 
therapy plus an oral LLT 
10. Proportion of patients with all-cause and CV mortality by Week 16 
11. Proportion of patients with myocardial infarction, stroke/TIA, admission for CV reasons 
and revascularisations (CABG and/or angioplasty) by Week 16 
12. Proportion of patients with goal achievement (LDL-C <1.4mmol/L by Week 16 or 
55mg/dl) in each trial arm stratified by institution setting (secondary/tertiary/mixed), 
country (UK/Spain/Italy) and by subpopulations defined by whether patients had 
experienced one or more CV events in the 2 years prior to admission. 
13. LDL-C levels by 16 weeks among LLT naïve (at ACS), monotherapy and combination 
therapy patients, within the DSS arm. 
14. Quantitative evaluation as evaluated by the DSS Evaluation Questionnaire of the DSS 
by the clinicians at DSS sites 
 
1. BACKGROUND  
Acute coronary syndromes (ACS) represent conditions compatible with acute myocardial 
ischemia and/or infarction. These include ST segment elevation myocardial infarction 
(STEMI), non-ST segment elevation myocardial infarction (NSTEMI), and unstable angina 
(UA). Following hospitalisation for an ACS, patients who survive to hospital discharge are at 
high-risk of recurrent non-fatal and fatal atherosclerotic cardiovascular disease (ASCVD) 
events, including myocardial infarction (MI), ischemic stroke, cardiovascular (CV) death, UA 
requiring hospitalisation, and coronary revascularization.1 Risk factors/markers which 

ZODIAC 
Imperial College London 
V.3 17 JAN 24 
 
Confidential 
SOP_TEM_CR001 v6.0 Effective 01 Aug 2019  
 
 
Page 12 of 48 
 
 
identify those at greater risk for recurrent ASCVD events include the characteristics of the 
index ACS event itself (e.g. whether MI or UA), management strategies (revascularization, 
use of preventive therapies), prior history of ASCVD or polyvascular disease, other 
comorbidities (e.g. diabetes), and demographic characteristics.1,2 
 
Low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for incident and recurrent 
risk of ASCVD events.3 Reduction in LDL-C with lipid-lowering therapy (LLT) reduces the 
risk of ASCVD events across broad group of patients, including those with a recent or a 
history of a prior ACS event.4 The relative risk reduction derived with sustained LDL-C 
lowering via LLT has been observed to be time-dependent in randomised controlled trials 
(RCTs) with the relative risk-reduction gradually improving over time with continued and 
persistent treatment with LLT over longer durations.4 This is consistent with data from 
Mendelian randomisation studies where a larger relative risk reduction is observed per 1 
mmol/L reduction in LDL-C (approximately 52% over 52 years) as compared to RCT data 
where over 5 years the benefit per 1mmol/L is approximately 22%, reinforcing the 
importance of longer-term cumulative reductions to benefit from LDL-C lowering.3 Moreover, 
as the benefit per 1mmol/L reduction in LDL-C is half (approx. 10-11%) in the first year of 
therapy versus later years, this underscores a strategy of immediate, intensive and 
sustained reduction in LDL-C in very high-risk individuals such as those with an ACS event. 
Furthermore, as the required reductions in LDL-C and the recommended goals are 
unachievable for the vast majority without use of combination therapy, recent expert 
consensus statements recommend combination LLT as first-line strategy in this population 
rather than a step-wise approach.5 
 
The 2019 European Society of Cardiology (ESC) and European Atherosclerosis Society 
(EAS) dyslipidaemia guidelines categorise patients with an ACS event as very-high risk and 
recommend an LDL-C goal of < 1.4 mmol/L (< 55 mg/dL) and >50% reduction in LDL-C in 
this population.1 Several studies of populations in Europe have highlighted gaps between 
clinical practice and implementation of recommended LLTs as compared with evidence 
based guideline recommendations. A national registry including several thousand 
individuals admitted to hospital with a MI in Sweden concluded that approximately 77% 
patients had no evidence of past statin treatment at the time of admission for the MI event.6 
In the 6-10 weeks after the MI event, there was insufficient treatment intensification. For 
instance ~25% of patients who were admitted saw little or no change in cholesterol levels, 
with LDL-C levels of about 2.1mmol/L at admission and ~ 2.3 mmol/L post discharge. Most 
of these patients were on statins, had prior history of ASCVD and high-risk comorbidities. 
The use of ezetimibe was 1% at the MI event increasing to 7% post event suggesting a 
shortfall in optimisation/ intensification of therapy beyond statin based monotherapy. Even 
among the 77% of patients newly initiated onto statins at the time of the ACS event, LDL-C 
levels ranged between 1.8-1.9 mmol/L with approximately 13% of those initiated onto statin 
therapy discontinuing at 8-12 months. In the DA VINCI study representing 5,888 patients 
prescribed LLT in 18 countries across Europe, LDL-C goal achievement in very-high risk 
patients per 2016 and 2019 ESC/EAS guidelines was 39% and 18%, respectively.7 Use of 
statin monotherapy and combination of statin and ezetimibe was 84% and 9.0 % 
respectively. Use of PCSK9 monoclonal antibodies in combination with oral LLTs were 1% 
Similar findings regarding gaps in treatment compared with guideline recommendations 
have been reported in several country-specific studies across Europe including the United 
Kingdom (UK), France, Italy, Germany, and the Netherlands, representing a collective failure 
of public health in implementing guidelines.8-13 
 

ZODIAC 
Imperial College London 
V.3 17 JAN 24 
 
Confidential 
SOP_TEM_CR001 v6.0 Effective 01 Aug 2019  
 
 
Page 13 of 48 
 
 
Barriers to achieving guideline recommendations for control of lipid-levels via LLT therapy 
are multi-factorial. These may include perceived side effects, health literacy (lack of patient 
education) relating to benefits of therapy for an essentially silent risk-factor, complexity of 
treatment regimens including polypharmacy in patients requiring multiple medications, and 
challenges related to reimbursement. Implementation of effective lipid lowering strategies in 
patients at highest risk, such as those with ACS, is poor globally, heterogeneous, and often 
relies on unwieldy multiple steps, delaying the time to optimisation of effective control of 
LDL-C. Moreover, to achieve guideline based lower LDL-C levels, combination therapy is 
required. Extensive contemporary data demonstrates that combination therapy will be 
essential in order for the vast majority of ACS patients to reach new guideline target of LDL-
C. A study based on patients with an ACS hospitalisation in Switzerland concluded that 
approximately 76% will require combination therapy to achieve LDL-C < 1.4 mmol/L (note 
the additional requirement of > 50% LDL-C reduction from baseline was not modelled in this 
analysis making this estimate relatively lower), with 35% requiring only statin + ezetimibe 
and 51% requiring an add-on PCSK9 inhibitor.14  
 
Another study based on the SWEDEHEART registry in Sweden representing individuals 
with hospitalization for an MI event indicated that 80% of the patients will require treatment 
with combination therapy (approximately 29% requiring only statin + ezetimibe and 
approximately 51% requiring an add-on PCSK9 inhibitor) to achieve 2019 ESC/EAS 
guideline recommendation of LDL-C level of < 1.4 mmol/L and ≥ 50% reduction in LDL-C.15 
Another study based on the INTERCATH registry in Germany representing a stable ASCVD 
population indicated that approximately 70%  of the patients will require statin and ezetimibe 
to achieve LDL-C goals with approximately 42% also requiring add-on PCSK9i in order to 
achieve the 2019 ESC/EAS guideline recommendations.11 These estimates predicting that 
approximately 70% to 80% of very high-risk patients will require combination LLT to achieve 
LDL-C levels < 1.4mmol/L are analogous to scenarios for antihypertensive therapies where 
approximately 75% to 80% of individuals are estimated to require combination therapy for 
achieving guideline recommended blood pressure control. Based in part on this rationale 
the 2018 European Society of Cardiology (ESC) and the European Society of Hypertension 
(ESH) guidelines for the management of arterial hypertension recommend initiating 
treatment with a combination therapy in most people with hypertension.17 
 
The aim of this trial is to assess whether the availability and use of a DSS system is more 
likely to result in implementation and achievement of EAS/ESC lipid lowering goals in ACS 
patients.  
 
The expected clinical benefit of treatment with combination LLT depends on: (1.) patient’s 
baseline risk representing existing clinical characteristics, (2.) baseline LDL-C level, (3.) 
absolute LDL-C reduction with LLT treatment regimens whether monotherapy or 
combination therapy, and (4.) duration of treatment.4 Although the baseline risk and LDL-C 
levels represent characteristics before treatment and vary by patients, a published risk-
reduction model combines these with potential treatment choices and treatment duration to 
provide reliable estimates of the magnitude of the expected clinical benefit. These estimates 
serve as a framework, helping provide scenarios where the choice and duration of different 
treatment regimens can be reliably estimated and visualised easily. This serves to inform 
the health-care professional and may help to better communicate to patients the clinical 
value of more intensive, continued therapy and relevance of consistent sustained LDL-C 
reductions over time. The estimation of the baseline risk can be further facilitated by use of 
the SMART risk prediction model which has been validated in multiple trials, epidemiological 

ZODIAC 
Imperial College London 
V.3 17 JAN 24 
 
Confidential 
SOP_TEM_CR001 v6.0 Effective 01 Aug 2019  
 
 
Page 15 of 48 
 
 
iv) A hypothetical alternative treatment strategy for which the clinical benefit must be 
estimated.  
v) 
The patient identifier and email address of the nurse / investigator responsible for 
entering the data into the “OpenClinica” study database. 
The DSS produces the following outputs over a period of 30 years starting from 0 years (on 
the x-axis in figures and in rows of tables): 
  
i) 
Estimated risk of ASCVD for current and alternative therapies, and no therapy, and 
by duration of treatment (or years without treatment).  
ii) 
Absolute reductions in ASCVD risk due to current and alternative therapies 
compared to no therapy, by duration of treatment. 
iii) Relative reductions in risk due to current or alternative therapies compared to no 
therapy, by duration of treatment. 
iv) Numbers Needed to Treat to prevent one composite endpoint outcome under 
current and alternative therapies by duration of treatment. 
The DSS has been developed with the Angular 10 JavaScript Framework and will be 
published in a web application that can be accessed on the Internet using the most common 
Web browsers, namely Google Chrome, Safari, Internet Explorer, Microsoft Edge, or Mozilla 
Firefox. The DSS has been tested on these web browsers and we cannot guarantee it will 
work on other unlisted web browsers. The DSS will be protected from unwanted use by 
asking its users to enter their OpenClinica credentials. 
All versions will be run within the users’ devices to enhance data privacy and reduce the risk 
of malfunctioning. At each use of the DSS, i) a limited amount of information will be collected, 
anonymised, and stored on a secure server for data and usage monitoring, and ii) the DSS 
inputs will be sent to the clinical research nurse responsible of inputting these data into 
OpenClinica, the study database. 
No personally identifiable information will be stored in or by the DSS directly, which will be 
described in a readily available Privacy Notice. The DSS will be accessible to visually 
impaired users, and this will be described in an accessibility statement. 
Prior to the trial taking place, the DSS will be functionally tested by an external software 
testing company to make sure the risk and benefit are accurate and reliable.  The DSS will 
be hosted on two servers from different cloud providers so if one is not working users will be 
asked to use the second domain name and access the working server. It is highly unlikely 
that two data providers are unavailable at the same time. No data will remain on the cloud 
but only transit for a brief moment until it reaches OpenClinica. 
The authors of the original publication23 have reviewed the implementation of their time-
dependent model within the DSS source code and have validated its accuracy. 
Once a site has been randomised to receive the DSS tool, study staff and clinicians utilising 
the DSS will receive training on the tool including a standardised training manual, as well as 
practical training and simulated clinical scenarios. A study version of the DSS tool will be 
created (in English) and distributed to site staff after allocation to the DSS and site training 
has been conducted. Access will be restricted to those site staff who are both trained on the 
DSS and are on the study delegation log.