Study on the Effect of Atorvastatin Co-administered With Omeprazole on Statin Lactone (SEACOL)
Phase: PHASE4
Conditions: Metabolite
Sponsor: National University Hospital, Singapore

Study Protocol Number <2023-00947>, Version <04>, Dated <7 May 2024> 
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STUDY PROTOCOL 
 
PROTOCOL TITLE: 
Study on the Effect of Atorvastatin Co-administered with Omeprazole on statin Lactone (SEACOL) 
 
PROTOCOL NUMBER:  
2023/00947 
 
PROTOCOL VERSION:  <Ver 04> 
PROTOCOL DATE:  
<7 May 2024> 
 
PRINCIPAL INVESTIGATOR:  
Dr. Chester Lee Drum, Senior Consultant, Department of Cardiology, National University Heart Centre, 
Singapore 
 
SITE PRINCIPAL INVESTIGATOR:  
Dr. Chester Lee Drum, Senior Consultant, Department of Cardiology, National University Heart Centre, 
Singapore 
 
CO-INVESTIGATOR: 
Junietta Lim Yuin Wenn, Pharmacist and PhD student, Department of Medicine, National University of 
Singapore, Singapore 
 
STUDY SITE: 
Main site: 
National University of Singapore (NUS) Center of Translational Medicine Cardiovascular Research 
Institute (CVRI) 
 
Sub-sites: 
National University Health System (NUHS) Investigational Medicine Unit (IMU) 
 
Collaborator: 
1. Jielin Yang, Research Associate, Department of Medicine, National University of Singapore, 
Singapore 
 
 
 
O F F I C I A L  U S E  O N L Y  
Doc Name : Protocol Template 
Doc Number : 207-002 
Doc Version : 03 
Date : 01 June  09 

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TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE ........................................................................................................................ 4 
1.1. 
GENERAL INTRODUCTION ........................................................................................................................................ 5 
1.2. 
RATIONALE AND JUSTIFICATION FOR THE STUDY ...................................................................................................... 5 
A. 
RATIONALE FOR THE STUDY PURPOSE ..................................................................................................................... 6 
B. 
RATIONALE FOR DOSES SELECTED ........................................................................................................................... 7 
C. 
RATIONALE FOR STUDY POPULATION ....................................................................................................................... 7 
D. 
RATIONALE FOR STUDY DESIGN .............................................................................................................................. 7 
2. 
HYPOTHESIS AND OBJECTIVES ......................................................................................................................... 7 
2.1. 
HYPOTHESIS ........................................................................................................................................................... 7 
2.4. 
POTENTIAL RISKS AND BENEFITS: ............................................................................................................................ 8 
A. 
END POINTS - EFFICACY ......................................................................................................................................... 8 
B. 
END POINTS - SAFETY ............................................................................................................................................ 8 
 
3.     STUDY POPULATION ...............................................................................................................................................5 
3.1. 
LIST THE NUMBER OF SUBJECTS TO BE ENROLLED. .................................................................................................... 9 
3.2. 
CRITERIA FOR RECRUITMENT .................................................................................................................................. 9 
3.3. 
INCLUSION CRITERIA .............................................................................................................................................. 9 
3.4. 
EXCLUSION CRITERIA .............................................................................................................................................. 9 
3.5. 
WITHDRAWAL CRITERIA .......................................................................................................................................... 9 
3.6. 
SUBJECT REPLACEMENT ......................................................................................................................................... 10 
4. 
TRIAL SCHEDULE ................................................................................................................................................... 10 
5.     STUDY DESIGN ..........................................................................................................................................................6 
5. 
STUDY DESIGN ................................................................................................................................................. 10 
5.1. 
SUMMARY OF STUDY DESIGN ................................................................................................................................ 10 
6. 
METHODS AND ASSESSMENTS ......................................................................................................................... 13 
6.1. 
RANDOMISATION AND BLINDING ........................................................................................................................... 13 
6.2. 
STUDY VISITS AND PROCEDURES ........................................................................................................................... 14 
7. 
TRIAL MATERIALS ................................................................................................................................................. 15 
7.1. 
TRIAL PRODUCT (S) .............................................................................................................................................. 15 
7.2. 
STORAGE AND DRUG ACCOUNTABILITY .................................................................................................................. 16 
8. 
TREATMENT ............................................................................................................................................................. 16 
8.1. 
RATIONALE FOR SELECTION OF DOSE .................................................................................................................... 16 
8.2. 
STUDY DRUG FORMULATIONS ................................................................................................................................ 16 
8.3. 
STUDY DRUG ADMINISTRATION ............................................................................................................................. 17 
8.4. 
SPECIFIC RESTRICTIONS / REQUIREMENTS ............................................................................................................ 17 
8.5. 
BLINDING ............................................................................................................................................................. 17 
8.6. 
CONCOMITANT THERAPY........................................................................................................................................ 17 
9. 
SAFETY MEASUREMENTS .................................................................................................................................... 17 
9.1. 
DEFINITIONS .................................................................................................. ERROR! BOOKMARK NOT DEFINED. 
9.2. 
COLLECTING, RECORDING AND REPORTING OF “UNANTICIPATED PROBLEMS INVOLVING RISK TO SUBJECTS OR 
OTHERS” – UPIRTSO EVENTS TO THE NHG DOMAIN SPECIFIC REVIEW BOARDS (DSRB) ................................................... 17 
9.3. 
COLLECTING, RECORDING AND REPORTING OF SERIOUS ADVERSE EVENTS (SAES) TO THE HEALTH SCIENCE 
AUTHORITY (HSA) ............................................................................................................................................................. 18 
9.4. 
SAFETY MONITORING PLAN ................................................................................................................................... 18 

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9.5. 
COMPLAINT HANDLING –....................................................................................................................................... 19 
10. DATA ANALYSIS ..................................................................................................................................................... 19 
10.1. 
DATA QUALITY ASSURANCE ................................................................................................................................... 19 
10.2. 
DATA ENTRY AND STORAGE .................................................................................................................................. 19 
11. SAMPLE SIZE AND STATISTICAL METHODS ................................................................................................ 19 
11.1. 
DETERMINATION OF SAMPLE SIZE ......................................................................................................................... 19 
11.2. 
STATISTICAL AND ANALYTICAL PLANS .................................................................................................................... 20 
12. ETHICAL CONSIDERATIONS .............................................................................................................................. 20 
12.1. 
INFORMED CONSENT ............................................................................................................................................. 20 
12.2. 
IRB REVIEW ......................................................................................................................................................... 20 
12.3. 
CONFIDENTIALITY OF DATA AND PATIENT RECORDS .............................................................................................. 21 
13. PUBLICATIONS ....................................................................................................................................................... 21 
14. RETENTION OF TRIAL DOCUMENTS ............................................................................................................... 21 

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STUDY PROTOCOL 
 
1. 
BACKGROUND AND RATIONALE 
 
Goh et al. 2023 found that the co-prescription of omeprazole is associated with increased 
atorvastatin lactone (ATVlac) levels and increased risk of MACE. Omeprazole’s role in inducing 
UGT1A activity has been previously studied and UGT1A is involved in the metabolism of 
statin to statin lactone. Although statin lactone production may independently reduce the 
benefit of statin in about 30% of patients, to date, there has not been any published 
interventional study investigating the combined effect of statin and proton pump inhibitor (ppi) 
on statin lactone levels. Thus, this study aims to investigate the effect of Atorvastatin co-
administered with Omeprazole versus Atorvastatin monotherapy on ATVlac level. We 
hypothesize that co-administration with Omeprazole results in a higher ATVlac level. 

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1.1. 
General Introduction 
 
Both drugs are US FDA and Singapore HSA approved drugs.  
 
(i) Atorvastatin is a synthetic lipid-lowering agent, which is an inhibitor of HMG-CoA 
reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and 
rate-limiting step in cholesterol biosynthesis.Atorvastatin is indicated as an adjunct to diet for 
reduction of elevated total-cholesterol (total-C), low density lipoprotein cholesterol (LDL-C), 
apolipoprotein B (apo B) and triglycerides (TG) in adults, adolescents and children aged 10 
years or older with primary hypercholesterolemia, heterozygous familial hypercholesterolemia or 
combined (mixed) hyperlipidaemia (Fredrickson Types IIa and IIb), elevated serum triglyceride 
(TG) levels (Fredrickson Type IV), and for patients with dysbetalipoproteinemia (Fredrickson 
Type III) when response to diet and other non-pharmacological measures is inadequate. 
Atorvastatin is also indicated to reduce total-C and LDL-C in adults with homozygous familial  
hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if 
such treatments are unavailable. Atorvastatin is also indicated to reduce the risk of myocardial 
infarction (MI) in adult hypertensive patients without clinically evident coronary heart disease 
(CHD), but with at least three additional risk factors for CHD such as age >55 years, male sex, 
smoking, left ventricular hypertrophy, other specified abnormalities on electrocardiogram 
(ECG), microalbuminuria or proteinuria, ratio of plasma total cholesterol (total-C) to HDL-
cholesterol >6, or premature family history of CHD. Atorvastatin is indicated in adults with 
type 2 diabetes and without clinically evident CHD, but with multiple risk factors for CHD such 
as retinopathy, albuminuria, smoking or hypertension, as well as in adults with clinically evident 
CHD. 
 
(ii) Omeprazole is a proton pump inhibitor which suppresses gastric basal and stimulated acid 
secretion by inhibiting the parietal cell H+/K+ ATP pump. Omeprazole is indicated for the 
treatment of gastroesophageal reflux disease (acute, healing or symptomatic), heartburn, 
helicobacter pylori eradication, peptic ulcer disease, duodenal or gastric ulcers and zollinger-
ellison syndrome.  
 
Rationale of the dose and schedule of administration: The proposed dosing used is 40mg/day 
for Atorvastatin and 20mg/day for Omeprazole, which are within approved therapeutic ranges 
(Atorvastatin 10 - 80mg, Omeprazole 20 - 360mg). The chosen doses are also the commonly 
prescribed doses for each drug based on clinical experience, with well-documented safety and 
efficacy profile. Since Atorvastatin is dosed once daily while Omeprazole can be dosed once or 
twice a day, for convenience and to improve compliance, we decided to schedule both drugs for 
once a day administration. Omeprazole should preferably be taken on an empty stomach, such 
as 30 - 60 mins before breakfast, while Atorvastatin can be administered without regard to food, 
hence, to standardize administration across all treatment arms, we will advise patients to take 
their assigned drugs 30 mins before breakfast. 
 
Manufacturing, Packaging and labeling: The investigational product (IP) will be packaged and 
labelled by the manufacturer before shipping to the study site. All the participants will receive 
identical-looking Atorvastatin tablets while half of the participants will also receive Omeprazole 
capsules. Each drug will be packaged in a separate bottle with labels containing information on 
the test product including the IP code, expiry, allergen instructions, directions for use and its 
purpose i.e. “for clinical use only”. They will contain instructions for the participant on how to 
appropriately administer the drugs. 
 

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Receipt, handling, storage and disposal of drugs: The drugs will be received directly from the 
manufacturers by the Co-I, who is a registered pharmacist. Once received, the drugs will be 
stored under lock and key, whereby only the PI and Co-I will have access to the drugs and hold 
the keys to the cabinet. When a participant is enrolled in the study, the PI or Co-I will retrieve 
the necessary drugs from the cabinet and the Co-I will pass the drugs directly to the participant, 
along with an explanation on how and when to consume the drugs. Participants will be 
requested to return any unused drugs to the PI or Co-I at the end of the study period. These 
unused drugs will be returned to the manufacturer for proper disposal.  
 
IP randomization: The pharmacist will dispense the IP once during the study period. Each 
patient is supplied either 30 tablets in 1 bottle (control arm) or 60 tablets / capsules in 2 
separate bottles (intervention arm). 30 Atorvastatin tablets will be packaged in 1 bottle and the 
other 30 Omeprazole capsules will be packaged in another bottle. An additional 5 surplus 
tablets / capsules of each drug will also be supplied in separate bottles to replace any damaged 
or missing tablets / capsules. We will provide the pharmacist with a code list. The pharmacist 
will dispense the drugs to the participants based on the unique randomisation code for that 
participant. Only trial pharmacy staff at the study site will be notified of the treatment allocation 
while all other site staff and research coordinators will be blinded. Delegated pharmacists will 
have access to an unbinding code list which they will use to cross reference the randomisation 
code in the email with the treatment allocations on the code list. To promote compliance to the 
study protocol, participants will be sent reminder texts before each visit. Compliance will be 
measured both by tablet / capsule counting (participants will be asked to return untaken tablets 
/ capsules at the second visit) and a self-reported compliance questionnaire.  
 
 
1.2. 
Rationale and justification for the Study 
 
a. 
Rationale for the Study Purpose 
A higher level of Atorvastatin lactone has been found to be associated with an increased risk of 
Major Adverse Cardiovascular Events (MACE) and the co-prescription of Omeprazole was 
found to be associated with a higher concentration of Atorvastatin lactone in the same study. 
However, the above study was conducted retrospectively and we think that it would be clinically 
important to conduct a prospective interventional trial to assess the effect of co-administration 
of Omeprazole with Atorvastatin on the concentration of Atorvastatin lactone. If it is indeed 
found that patients on both Omeprazole and Atorvastatin have a higher Atorvastatin lactone 
level, then an individualized risk-benefit assessment should be conducted to weigh the higher 
risk of MACE with co-prescription of Omeprazole against the benefit of Omeprazole for its 
prescribed indication. 
 

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b. 
Rationale for Doses Selected 
 
The proposed dosing used is 40mg/day for Atorvastatin and 20mg/day for Omeprazole, which 
are within approved therapeutic ranges (Atorvastatin 10 - 80mg, Omeprazole 20 - 360mg). The 
chosen doses are also the commonly prescribed doses for each drug based on clinical 
experience, with well-documented safety and efficacy profile. Since Atorvastatin is dosed once 
daily while Omeprazole can be dosed once or twice a day, for convenience and to improve 
compliance, we decided to schedule both drugs for once a day administration. Omeprazole 
should preferably be taken on an empty stomach, such as 30 - 60 mins before breakfast, while 
Atorvastatin can be administered without regard to food, hence, to standardize administration 
across all treatment arms, we will advise patients to take their assigned drugs 30 mins before 
breakfast. 
 
c. 
Rationale for Study Population 
 
Healthy volunteers will be selected for this study as we would like to prospectively study the 
effect of co-administration of Atorvastatin and Omeprazole on Atorvastatin lactone, so we 
would like to recruit subjects who are not currently taking a statin or ppi. Nonetheless, it may be 
difficult to identify such patients within the outpatient or inpatient setting, hence we feel that 
healthy volunteers may will be the most suitable. 
 
d. 
Rationale for Study Design 
 
A 2-arm trial was selected to allow us to compare the Atorvastatin lactone metabolite level 
across the participants in this study. The study duration of 30 days was selected in view of the 
study’s secondary endpoint to measure c-reactive protein (CRP) level. Atorvastatin induces a 
significant and extensive decrease in CRP level within the first 4 weeks of therapy but with no 
further decrease after 3 months [5]. This means that at the 30-days timepoint, we should be able 
to capture any significant changes in CRP. 
 
2. 
HYPOTHESIS AND OBJECTIVES 
 
2.1. 
Hypothesis 
 
Co-administration of Omeprazole results in higher atorvastatin lactone level 
2.2. 
Primary Objectives 
 
To investigate the effect of co-administration of Omeprazole with Atorvastatin versus 
Atorvastatin monotherapy on atorvastatin lactone level. 
 
Primary endpoint: Higher statin lactone level in intervention arm (Atorvastatin + 
Omeprazole) after 30 days 
 
2.3      Secondary Objectives 
 
Secondary endpoints: 
➢ Higher hs-CRP in intervention arm 

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➢ Lipid panel 
➢ Incidence of adverse drug side effects (e.g. muscle-related or elevated LFTs) 
 
For safety endpoint, if the principal investigator, study team member, or the patient's primary 
treating physician notices anything with potential medical significance in any of the tests (blood 
test and vital signs), the physician will assess the causality and seriousness of the adverse event 
(AE) / serious adverse event (SAE). If found, all AE/SAE will be immediately notified to the 
Sponsor, Research Ethics Committee (DSRB), HSA authority, and the drug manufacturer, and 
full report will be submitted within the time frame specified. Given the relatively low risk 
associated with Atorvastatin and Omeprazole and short study duration, the study does not have 
an independent data monitoring committee. In the unlikely event of a AE/SAE, medical 
treatment will be allocated to ensure patient safety 
 
2.4 
Potential Risks and benefits:  
 
We consider potentially minimal risk to the study participants. This study will involve (1) A 
demographics + medical + medication history survey, (2) Blood sampling (18mL per sample per 
subject, performed by a trained phlebotomist), and (3) A self-reported compliance questionnaire. 
 
Potential benefits: 
 
There is no direct individual benefits from participating in this study. However, the knowledge gained 
from this study may contribute to the medical field regarding the possible negative implications of co-
prescription of drugs. 
 
Potential risks: 
 
i) Breach of confidentiality may happen during the study, such as after collection of personal 
information  
 
ii) Subjects may primarily experience pain during the venipuncture blood draw when the needle goes 
through the skin. In less than 10% of cases, a small amount of bleeding under the skin will produce a 
bruise (minute hematoma). The puncture site may be visible and sore to the touch for a short period of 
time after the collection. Dizziness or light-headedness (syncope). The risk of local infection is less than 
1 in 1,000. 
 
iii) There is a possibility that subjects may suffer from an allergic reaction to Atorvastatin and / or 
Omeprazole or even suffer from adverse effects to Atorvastatin. The risk of elevated serum 
transaminases with Atorvastatin 40mg is 0.6%. The risk of rhabdomyolysis, a severe form of muscle 
injury, resulting from Atorvastatin therapy is about 0.5 – 1.0% over 5 years. 
 
a. 
End Points - Efficacy 
Results from the metabolic panel and biomarkers obtained from blood sample. 
b. 
End Points - Safety 
Although both drugs are approved by regulatory authorities such as Singapore Health Sciences 
Authority (HSA) as well as the United States (US) Food and Drug Administration (FDA) and 
are also widely prescribed, there is still a possibility that you may experience an allergic reaction 
to Atorvastatin and / or Omeprazole or even suffer from the side effects of Atorvastatin. There 

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is a possibility that Atorvastatin may result in liver injury or muscle-related side-effects. The risk 
of getting a severe form of muscle injury is about 0.5 – 1.0% over 5 years.  
 
3. 
STUDY POPULATION 
 
3.1. 
List the number of subjects to be enrolled.  
 
We aim to assess the effect size of a minimum clinically significant difference in Atorvastatin 
lactone concentration of 1.68μg/L for the Atorvastatin + Omeprazole group compared to the 
Atorvastatin monotherapy group. Goh et al. 2023 reported a 1.4 times higher ATVlac in 
patients who were on ATV + OMP and literature on the pharmacokinetics of ATV reported 
the Cmax of ATVlac to be  4.2 ± 2.4 μg/L following oral administration of ATV 40mg. By 
inference, we expect a ATVlac concentration of 4.2 x 1.4 = 5.88μg/L in the ATV + OMP arm 
and this equates to a difference of 1.68μg/L in ATVlac concentration compared to the ATV 
monotherapy arm. Using a 2-sample t-test at a power (1-beta) of 85% and one-sided 
significance level (ɑ) of 95%, we will need 30 subjects per treatment arm. To account for 30% 
drop-out after randomization, we will need to recruit at least 39 subjects per treatment arm and 
a total of 78 subjects for the study. 
 
3.2. 
Criteria for Recruitment 
 
3.3. 
Inclusion Criteria 
 
1) Males between 21 and 75 years old or females between 50 and 75 years old. 
2) No contraindications to the use of Atorvastatin amp; Omeprazole. 
3) Ability to comply with study requirements eg administer Atorvastatin and Omeprazole once 
daily and return for follow-up 1 month later. 
4) Capable of understanding the study requirements and provide informed written consent to 
participate. 
5) Have not taken any statins or proton pump inhibitors in the past 30 days. 
 
3.4. 
Exclusion Criteria 
 
1) Women of child-bearing age (<50 years old) 
2) Pregnancy / Planning to conceive or breast-feeding 
3) Current or recent history of liver disease / renal impairment / myopathy / rhabdomyolysis 
4) Recent history of alcohol or drug abuse 
5) Concurrent use of other drugs that may interact with Atorvastatin, Omeprazole eg clopidogrel 
6) Acute infection or illness 
7) Allergy to any statins or proton pump inhibitors 
8) Medical condition(s) that might compromise safety or successful completion of study 
 
3.5. 
Withdrawal Criteria  
 
Participation in the study is fully voluntary. Study participants can withdraw from the study at 
any time without comment or penalty. The decision to participate will in no way impact upon 
their present or future care. In addition, study participants may be withdrawn from the study 

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solely at the discretion of the Investigator or nominee. The investigator can withdraw a subject 
from the study for (1) they decide that it is in the patient's best interests due to urgent medical 
reasons or (2) if a protocol violation occurs or (3) if the patient requests withdrawal. Withdrawn 
patients will not be replaced in this study. 
 
The reasons for discontinuation/withdrawal will be recorded in the study participant’s Case 
Report Form (CRF). Any study participant(s) withdrawn from the study prior to their 
completion for any reason will have data compiled to the point of discontinuation to be used 
for analysis. 
 
3.6. 
Subject Replacement 
There is no need for subject replacement. 
 
4. 
TRIAL SCHEDULE 
 
Table 1 shows the trial plan and procedures to be conducted on each study visit. 
 
5. 
STUDY DESIGN 
 
5.1. 
Summary of Study Design 
This is a 2-arm, prospective, randomized, parallel-group, open-label, longitudinal study that lasts 30 days 
for each study participant. Assessment of primary and secondary outcomes have been planned in an 
exploratory setting. 
Fig. 1 shows the study protocol. 
Table 1 shows trial plan and procedure to be conducted on each study visit. 
 
2. Description of study visits: 
a) Pre-screening, consenting process, and screening procedures 
Potential subjects will be identified through (i) direct advertisement such as posters to be put up around 
NUS / NUH, (ii) indirect – through word or mouth or snowballing. Participants who are interested will 
be interviewed over the phone by the study’s Clinical Research Coordinator (CRC). During the 
telephone interview, participants will be given a brief description of the study design and procedures to 
be followed. If the participant is eligible, with their verbal agreement, arrangement will be made for 
them to visit NUHS IMU (located in NUS MD6, level 7) for a screening and enrolment visit. 
 
b) Informed consent 
Informed consent will be taken by the PI. The study will be explained to the participant in detail. This 
will be performed in the privacy of a closed-door room. During the consenting process, the study will 
first be explained to the participants and ample time will be provided for patients to read through the 
informed consent form. They will also be (i) given opportunity to clarify any doubts before 
acknowledging the consent form; (ii) allowed to return home to discuss their participation with their 
family prior to consenting. Non-English speakers will have the English informed consent form with a 
short consent form in their language, so that they can understand the purpose of this study and what is 
required of them. If the participant agrees to participate, the informed consent form will be signed by 

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the PI and the participant, in the presence of a prescribed witness. In the event that the participant is 
illiterate, or a short consent form will be used, an impartial witness will be present instead. A copy of 
the informed consent will be kept by both the PI and the participant. Enrolled subjects will be updated 
in the Screening and Enrolment Log. Unselected subjects will be documented in the Pre-screening Log. 
 
(c) Screening and baseline data collection 
Participants who have signed the informed consent form will be assessed for eligibility to participate, 
based on the following assessments: (i) Demographic data; (ii) Medical and medication history; (iii) 
history of adverse drug reactions (if any). Patients will be interviewed directly to provide the above 
health information; medical records will not be assessed. Based on the collected data, approval for 
participation will be finalised by either the PI or Co-PI. Participants who are eligible for the study will 
be informed by the CRC and enrolled as a subject for the study. 
 
(d) Blood draw 
Post-fasting (8 hours) whole blood will be drawn twice. 18mL will be collected by ventipuncture each 
time, once at the time of recruitment (before intervention) and a second time on the second visit (T2) 
30 days after the start of the intervention period. This amounts to a total of 36mL of blood collected 
throughout the study period. Blood will be drawn into EDTA vacutainers. All samples will be 
transferred from NUHS IMU to the PI's research laboratory (located in CDrum lab, NUS MD6, level 
8). All the blood will be spun down to plasma. With an estimated plasma extraction efficiency of 45% 
via centrifugation, we expect to obtain about 8.1mL of plasma from 18mL of blood. The plasma will be 
aliquoted and stored in a -80 degrees Celsius freezer until analysis. For atorvastatin lactone metabolite 
profiling, a 1mL aliquot will be subjected to protein precipitation and used for analysis. Another 1mL 
aliquot will be used for high sensitivity c-reactive protein (hs-CRP) assays using the cobas c-111 
machine. Another 3mL of plasma will be used for lipid panel profiling using cobas c-111 machine. The 
remaining plasma samples will be stored at -80 degrees Celsius for repeated analysis, if necessary. 
 
3. Randomization and treatment allocation 
The study will be open-label since our primary endpoint is an objective pharmacokinetic parameter. 
 
Treatment allocation between the Atorvastatin + Omeprazole and Atorvastatin only arms will be 
generated by a random allocation sequence using real-time web-based randomization system (IVRS) in a 
1:1 ratio. Our desired allocation ratio (1:1) can be achieved using permuted block randomization. Block 
randomization ensures balance between the 2 groups, in which the order of allocation is chosen at 
random at the beginning of the block. Block size will be determined by the study team member. 
Intervention group 1: Atorvastatin 40mg/day + Omeprazole 20mg/day 
Control group: Atorvastatin 40mg/day 
We target to recruit 78 patients, of whom 39 patients will be assigned to each of the 2 treatment arms. 
The pharmacist will dispense the IP to the study participants. Each participant will be supplied 30 
tablets of Atorvastatin and those in the intervention arm will receive an additional 30 capsules of 
Omeprazole during the trial. A total of 60 tablets / capsules will be dispensed to each participant in the 
intervention arm and 30 tablets to each participant in the control arm. An additional 5 surplus tablets / 
capsules of each drug will also be supplied to replace any damaged or missing tablets / capsules. 
Atorvastatin and Omeprazole will all be packaged and coded by the manufacturer. The pharmacist will 
be provided with the code list and will dispense the IP to each participant based on the unique subject 
ID for that participant. A CRC will provide a prescription on the day of the study visit and ensure that 
it is kept at the appropriate storage condition prior to administration. 
 
Possible IFs: 

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a) Adverse events following co-administration of atorvastatin and omeprazole in healthy participants. 
b) Participant found to have an elevated C-reactive protein (CRP) level (>10mg/L), which may indicate 
that the participant has an underlying inflammation or infectious condition. 
c) Participant found to have elevated low-density lipoprotein (LDL) and/or triglycerides (TG) (LDL 
?4.9 mmol/L, TG ?4.5 mmol/L), which may indicate that the participant may have hyperlipidemia 
and/or hypertriglyceridemia. 
 
4. Incidental Finding (IF) management plan: 
(a) In the event that the researchers believe that the IF may affect the health or well-being of the study 
participant, the researchers will base their determination of the IF on criterias including how accurate 
the test that identified the IF was, and the researchers will have the test repeated and validated in a 
clinical laboratory, should a valid test be available to confirm the IF. Otherwise, justification will be 
submitted to the IRB as to why clinical verification is not ethically appropriate or practicably possible, 
and therefore, the results will not be returned to the participant. The PI is responsible for reporting IFs, 
in accordance with evidence-based best practice's guideline for managing IFs. The PI, who is a qualified 
medical professional, is responsible for assessing the clinical significance of the IF, and managing the IF 
to ensure the safety of all the study participants. When an IF has an "immediate clinical relevance", in 
the absence of clear evidence or when faced with unanticipated IFs of potential concern, researchers 
will (i) consult qualified clinical experts to assess the clinical significance of the finding and plan a 
response; (ii) consult with colleagues to determine the standards within the discipline, and combine with 
the practical wisdom of a consultant medical specialist; or (iii) consult DSRB ethics board about 
possible disclosure and be ethically responsible or required to disclose such findings to study 
participants. Prior to disclosure, the results will be verified by an accredited diagnostic laboratory / 
expert, whether it is practicably possible. Please refer to IF Management Plan on the types of IFs that 
may arise from this study. Considering (i) the preferences of participants in the decision-making 
regarding IF disclosure; (ii) the potential benefits vs harms of disclosure, the study PI or another 
qualified member of the research team will communicate the IF to the participant, either directly or 
indirectly by the participant's primary treating physician. The IFs will be communicated verbally, in a 
timely mannger, and documented in writing, and the process of communicating IFs should be 
completely transparent. The informed consent process will include IFs (including information about 
follow-up and the cost of managing the finding). During the consent process, research participants 
should be informed of these practices. 
 
(b) The decision of whether to return IFs will typically be the responsibility of the study team members, 
i.e., Co-I, who is a GCP qualified and registered medical practitioner under the Singapore Medical 
Council (SMC) respectively. This is because IFs are typically more of a clinical issue rather than a 
research issue. For medical reasons, it is desirable that the information concerning the IFs be returned 
by a person who has a clinical relationship with the participant. If the researcher is not a physician or 
does not have a clinical relationship with the participant, someone else, such as a medical counsellor, 
may be more suitable for returning the IF to the participant. Only verified results will be returned and 
the primary treating physician responsible for the participant's care should always be notified. Physicians 
who can judge the potential health implications of a finding will advise the research participant, and 
fully inform the participant of the likelihood of IFs and the threat the IFs might pose. 
 
(c) The mode of communication to be used and the limits of effort of re-contacting in case an IF is 
identified during the course of study: physician will notify the participant if they choose to be notified as 
indicated in their consent form. In such an event, the study PI or delegated study team member will 
attempt to contact the participant by (i) mailing a general letter; (ii) by email and (iii) phone call at the 
requested time using their preferred number. Extended efforts with follow-up and phone call strategies 

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(varying calling times, calling multiple times) until contact is successfully made with the study 
participant. The researcher will communicate the IF to the participant in a way that is sensitive to the 
issues raised. If it is anticipated that there will be a high likelihood of finding grave IFs in the study, 
researchers may ask the participant during the consent process if they consent to disclosure of medically 
significant IFs to their primary care physician, with whom they already have a relationship. Researchers 
disclosing an IF to the participant may consider communicating the IF directly to the participant's 
attending physician, so that the attending physician can discuss and address the IF promptly with the 
participant. If the participant has no physician, the researchers should offer to suggest one. Depending 
on the specific IFs revealed, the participant may ask the researchers to suggest a specialist, such as a 
cardiologist. The researchers should respond to such requests with recommendations or referral. The 
study team may provide a reasonable standard of care and give feedback on health information that is 
likely to result in avoidance of significant harm to the participant, whichever appropriate. 
 
6. 
METHODS AND ASSESSMENTS 
 
6.1. 
Randomisation and Blinding 
 
The study will be open-label since our primary endpoint is an objective pharmacokinetic 
parameter. 
 
Treatment allocation between the Atorvastatin + Omeprazole and Atorvastatin only arms will 
be generated by a random allocation sequence using real-time web-based randomization system 
(IVRS) in a 1:1 ratio. Our desired allocation ratio (1:1) can be achieved using permuted block 
randomization. Block randomization ensures balance between the 2 groups, in which the order 
of allocation is chosen at random at the beginning of the block. Block size will be determined by 
the study team member. 
Intervention group 1: Atorvastatin 40mg/day + Omeprazole 20mg/day 
Control group: Atorvastatin 40mg/day 
We target to recruit 78 patients, of whom 39 patients will be assigned to each of the 2 treatment 
arms. The pharmacist will dispense the IP to the study participants. Each participant will be 
supplied 30 tablets of Atorvastatin and those in the intervention arm will receive an additional 
30 capsules of Omeprazole during the trial. A total of 60 tablets / capsules will be dispensed to 
each participant in the intervention arm and 30 tablets to each participant in the control arm. 
An additional 5 surplus tablets / capsules of each drug will also be supplied to replace any 
damaged or missing tablets / capsules. Atorvastatin and Omeprazole will all be packaged and 
coded by the manufacturer. The pharmacist will be provided with the code list and will dispense 
the IP to each participant based on the unique subject ID for that participant. A CRC will 
provide a prescription on the day of the study visit and ensure that it is kept at the appropriate 
storage condition prior to administration.  
 
 
 

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6.2. 
Study Visits and Procedures 
 
The total study duration is 31 days and consists of 2 study visits (Fig. 1). Blood samples will be 
collected at each timepoint (T1 and T2) for metabolic panel and biomarker measurements. All 
blood sampling (B) are study activities and not routine medical care. 
 
Study Visit T1 (Day 0) 
This will be the screening and enrolment visit. Estimated duration is 90 mins. The following 
procedures will be performed during this visit: 
i) Confirming eligibility and Informed consent taking (30 minutes)  
ii) Completion of demographic + medical + medication history survey (10 minutes) 
iii) Blood sample collection (10 minutes) 
iv) Post-collection health monitoring (20 minutes) 
v) Randomization, distribution of drugs and explain how to take the assigned medications (20 
minutes) 
 
Study Visit T2 (Day 30) 
T2 will be follow-up visit 30 days after intervention. Estimated duration is 60 mins. The 
following procedures will be performed during this visit: 
i) Self-reported compliance questionnaire and return of unused drugs if any (20 minutes) 
ii) Blood sample collection (10 minutes) 
iii) Post-collection health monitoring (20 minutes) 
iv) Reimbursement (10 minutes)  
 
 
 
a. Post Study Follow up and Procedures 
 
There will not be post study follow-up or procedures. 
 

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b. Discontinuation Visit and Procedures 
 
The last study visit (T2) should be done if withdrawal occurs. Participants may withdraw 
voluntarily from the study at any time and for any reason without penalty. This will not affect 
their routine medical care. If voluntary withdrawal occurs, the participant should be asked to 
continue scheduled evaluations, complete an end of study evaluation and be given appropriate 
care under medical supervision until the symptoms of any adverse event resolve or until the 
participant’s condition stabilizes. The PI may also withdraw the patient’s participation in the 
study at any time if they decide that it is in the patient’s best interests or if they have other 
medical problems. 
 
The reasons for withdrawal or discontinuation will be documented in the participant’s Case 
Report Form. In the case of any premature withdrawal from the study, blood samples and study 
data that have been collected up to the time of withdrawal or discontinuation will be kept and 
analysed as intention-to-treat analysis. 
 
c. Measurements 
 
1) Demographic + medical + medication history survey on the first visit. Information to be 
collected include: age, gender, race, history of liver or kidney disease, whether a statin or proton 
pump inhibitor has been taken in the past 30 days, any diagnosed medical condition and regular 
medications, as well as whether the participant is taking any supplements, traditional or herbal 
products. 
2) Blood sample collection (18mL each time x 2 times, on enrolment and after 30 days of 
intervention). 
3) Consumption of investigational drugs (Atorvastatin or Atorvastatin + Omeprazole) 
4) Self-reported compliance questionnaire at the second visit timepoint. Questions include: (i) 
Have you missed taking the medications on any day(s) during the 30 days study period? (Yes / 
No. If yes, please state how many days: ___); (ii) How many tablets / capsules have you been 
taking each day? (___) 
5) LC-MS measurement: Blood samples will be processed to extract plasma. Plasma samples, 
calibrators and quality control samples will be transferred into a deep well 96-well plate and 
standard curve will be used for quantification of Atorvastatin lactone levels in the plasma 
samples. 
6) hs-CRP and lipid panel assays on participant’s plasma samples using cobas c-111 machine 
 
7. 
TRIAL MATERIALS 
 
7.1. 
Trial Product (s) 
 
Both drugs are US FDA and Singapore HSA approved drugs.  
 
(i) Atorvastatin is a synthetic lipid-lowering agent, which is an inhibitor of HMG-CoA 
reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and 
rate-limiting step in cholesterol biosynthesis.Atorvastatin is indicated as an adjunct to diet for 
reduction of elevated total-cholesterol (total-C), low density lipoprotein cholesterol (LDL-C), 
apolipoprotein B (apo B) and triglycerides (TG) in adults, adolescents and children aged 10 
years or older with primary hypercholesterolemia, heterozygous familial hypercholesterolemia or 

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combined (mixed) hyperlipidaemia (Fredrickson Types IIa and IIb), elevated serum triglyceride 
(TG) levels (Fredrickson Type IV), and for patients with dysbetalipoproteinemia (Fredrickson 
Type III) when response to diet and other non-pharmacological measures is inadequate. 
Atorvastatin is also indicated to reduce total-C and LDL-C in adults with homozygous familial  
hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if 
such treatments are unavailable. Atorvastatin is also indicated to reduce the risk of myocardial 
infarction (MI) in adult hypertensive patients without clinically evident coronary heart disease 
(CHD), but with at least three additional risk factors for CHD such as age ? 55 years, male sex, 
smoking, left ventricular hypertrophy, other specified abnormalities on electrocardiogram 
(ECG), microalbuminuria or proteinuria, ratio of plasma total cholesterol (total-C) to HDL-
cholesterol ? 6, or premature family history of CHD. Atorvastatin is indicated in adults with 
type 2 diabetes and without clinically evident CHD, but with multiple risk factors for CHD such 
as retinopathy, albuminuria, smoking or hypertension, as well as in adults with clinically evident 
CHD. 
 
(ii) Omeprazole is a proton pump inhibitor which suppresses gastric basal and stimulated acid 
secretion by inhibiting the parietal cell H+/K+ ATP pump. Omeprazole is indicated for the 
treatment of gastroesophageal reflux disease (acute, healing or symptomatic), heartburn, 
helicobacter pylori eradication, peptic ulcer disease, duodenal or gastric ulcers and zollinger-
ellison syndrome. 
 
There is a possibility that subjects may suffer from an allergic reaction to Atorvastatin and / or 
Omeprazole or even suffer from adverse effects to Atorvastatin. The risk of elevated serum 
transaminases with Atorvastatin 40mg is 0.6%. The risk of rhabdomyolysis, a severe form of 
muscle injury, resulting from Atorvastatin therapy is about 0.5 – 1.0% over 5 years.  
 
7.2. 
Storage and Drug Accountability 
 
Both drugs have similar storage requirements, with reference to their individual product 
information leaflet. The drugs need to be store in a cool and dry place, away from direct 
sunlight, at or below 30°C. Specifically for Atorvastatin, it should also be stored in its original 
aluminium blister to protect from moisture. Hence, if we are packaging Atorvastatin tablets in 
bottles for the subjects, a moisture absorber should be included in the bottle, such as a packet 
of silica gel, and subjects should be reminded not to remove that moisture absorber as well as to 
minimize exposure of the medication to moisture. 
 
8. 
TREATMENT 
8.1. 
Rationale for Selection of Dose 
The proposed dosing used is 40mg/day for Atorvastatin and 20mg/day for Omeprazole, which 
are within approved therapeutic ranges (Atorvastatin 10 - 80mg, Omeprazole 20 - 360mg). The 
chosen doses are also the commonly prescribed doses for each drug based on clinical 
experience, with well-documented safety and efficacy profile.  
 
8.2. 
Study Drug Formulations 
Atorvastatin is formulated as oral tablets while Omeprazole is formulated as oral capsules. 
 

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8.3. 
Study Drug Administration 
Since Atorvastatin is dosed once daily while Omeprazole can be dosed once or twice a day, for 
convenience and to improve compliance, we decided to schedule both drugs for once a day 
administration. Omeprazole should preferably be taken on an empty stomach, such as 30 - 60 
mins before breakfast, while Atorvastatin can be administered without regard to food, hence, to 
standardize administration across all treatment arms, we will advise patients to take their 
assigned drugs 30 mins before breakfast. 
 
8.4. 
Specific Restrictions / Requirements  
The risk of myopathy during treatment with Atorvastatin (HMG-CoA reductase inhibitor) is 
increased with concurrent administration of cyclosporine, fibric acid derivatives, lipid-modifying 
doses of niacin or CYP 3A4/transporter inhibitors (e.g., erythromycin and azole antifungals). 
These medications should be avoided during the study period or spaced at least 2 – 4 hours 
apart from Atorvastatin if not possible to omit. 
 
The Omeprazole and Clopidogrel combination is a well-known drug interaction whereby 
Omeprazole may diminish the antiplatelet effects of Clopidogrel due to Omeprazole-mediated 
inhibition of CYP2C19, an enzyme responsible for clopidogrel metabolism to its active 
metabolite. Nonetheless, clinical evidence has suggested limited impact on clinical efficacy for 
using this drug combination and it is still a popularly prescribed pair of drugs, but for the 
purpose of this study, we will advise against initiating Clopidogrel during the study period. 
 
8.5. 
Blinding 
The study will be open-label. 
 
 
8.6. 
Concomitant therapy 
 
All medications (prescription and over the counter), vitamin and mineral supplements, and / or 
traditional or herbal products taken by the participant should be documented. 
 
 
9. 
SAFETY MEASUREMENTS 
 
9.1 
Collecting, Recording and Reporting of “Unanticipated Problems Involving Risk 
to Subjects or Others” – UPIRTSO events to the NHG Domain Specific Review 
Boards (DSRB) 
 
 
UPIRTSO events refers to problems, in general, to include any incident, experience, or 
outcome (including adverse events) that meets ALL of the following criteria: 
1. Unexpected 
In terms of nature, severity or frequency of the problem as described in the study 
documentation (eg: Protocol, Consent documents etc). 
 
2. Related or possibly related to participation in the research 
Possibly related means there is a reasonable possibility that the problem may have been 

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caused by the procedures involved in the research; and  
 
3. Risk of harm 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
Reporting Timeline for UPIRTSO Events to the NHG DSRB. 
1. Urgent Reporting: All problems involving local deaths, whether related or not, should be 
reported immediately – within 24 hours after first knowledge by the NHG investigator. 
 
2. Expedited Reporting: All other problems must be reported as soon as possible but not later 
than 7 calendar days after first knowledge by the NHG investigator. 
 
9.2 
Collecting, Recording and Reporting of Serious Adverse Events (SAEs) to the 
Health Science Authority (HSA) 
 
1. For Principal Investigator initiated Trials  
All SAEs that are unexpected and related to the study drug must be reported to HSA. 
 
“A serious adverse event or serious adverse drug reaction is any untoward medical occurrence at 
any dose that:  
• Results in death.  
• Is life-threatening (immediate risk of death).  
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
• Results in persistent or significant disability/incapacity.  
• Results in congenital anomaly/birth defect.  
• Is a Medically important event. 
 
Medical and scientific judgment should be exercised in determining whether an event is an 
important medical event. An important medical event may not be immediately life threatening 
and/or result in death or hospitalization. However, if it is determined that the event may jeopardize 
the subject and/or may require intervention to prevent one of the other adverse event outcomes, 
the important medical event should be reported as serious.”  
 
All SAEs that are unexpected and related to the study drug will be reported. The investigator is 
responsible for informing HSA no later than 15 calendar days after first knowledge that the case 
qualifies for expedited reporting. Follow-information will be actively sought and submitted as it 
becomes available. For fatal or life-threatening cases, HSA will be notified as soon as possible but 
no later than 7 calendar days after first knowledge that a case qualifies, followed by a complete 
report within 8 additional calendar days. 
 
 
9.3 
Safety Monitoring Plan 
Safety assessments during the study include monitoring the wellbeing of each study participant 
regarding any adverse events he/she may experience. All study participants receiving treatment 
will be attended by the site PI if any medical issues arise. 
 

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Regular reports on conduct and progress of the project will be provided by the study team to 
the Domain Specific Review Board (DSRB) ethics committees and to the team of investigators. 
The team of investigators will conduct random inspections of the research procedures, data and 
consent documentation, which includes the checking of the completeness of the Investigator 
File and verifying data collection forms. In addition, the Investigators will ensure the integrity of 
the data through the following strategies: 
- 
Regular project meetings (monthly) with project progress (written and verbal) and 
dedicated time for discussion and intellectual exchange (monthly) 
- 
Rotation of meetings among different sites to enable easy attendance 
- 
Use of secured shared IT procedures to allow investigators and collaborators from 
the different organizations and sites to access shared databases. 
 
9.4 
Complaint Handling – 
All complains or feedback about this research study will either be dealt with by the Principal 
Investigator and/or the NHG Domain Specific Review Board Secretariat. Participants will be 
notified in the patient information consent form to contact the PI if they have any questions, 
complaints or concerns. In addition, they can also contact the NHG Domain Specific Review 
Board Secretariat at 6471-3266 if they want an independent opinion to discuss problems and 
questions, obtain information and offer inputs on their rights as a research subject. 
 
 
10 DATA ANALYSIS 
10.1 Data Quality Assurance 
 
LC-MS metabolite quantification as well as hs-CRP and lipid panel assays will be done in 
duplicates or triplicates to ensure accurate and reproducible results.  
 
10.2 Data Entry and Storage 
 
Data collected and entered in the Case Report Forms (CRF) and questionnaires will be stored in 
a secure location at the main study site (NUS CVRI). A patient coded electronic database 
containing data extracted from the Case Report Forms will also be securely stored. Only the 
research team will have access to the Case Report CRF or any medical data. In the event of any 
publication regarding this study, the data will be de-identified so that the identity of the patient 
remains confidential. 
 
 
11 SAMPLE SIZE AND STATISTICAL METHODS 
 
11.1 Determination of Sample Size  
We aim to assess the effect size of a minimum clinically significant difference in Atorvastatin 
lactone concentration of 1.68μg/L for the Atorvastatin + Omeprazole group compared to the 
Atorvastatin monotherapy group. Goh et al. 2023 reported a 1.4 times higher ATVlac in 
patients who were on ATV + OMP and literature on the pharmacokinetics of ATV reported 
the Cmax of ATVlac to be  4.2 ± 2.4 μg/L following oral administration of ATV 40mg. By 
inference, we expect a ATVlac concentration of 4.2 x 1.4 = 5.88μg/L in the ATV + OMP arm 

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and this equates to a difference of 1.68μg/L in ATVlac concentration compared to the ATV 
monotherapy arm. Using a 2-sample t-test at a power (1-beta) of 85% and one-sided 
significance level (ɑ) of 95%, we will need 30 subjects per treatment arm. To account for 30% 
drop-out after randomization, we will need to recruit at least 39 subjects per treatment arm and 
a total of 78 subjects for the study. 
 
11.2 Statistical and Analytical Plans 
To avoid potential bias due to exclusion of patients (type 1 error), the effect of intervention 
will be assessed according to the Intention-to-Treat (ITT) principle, such that every patient 
randomized in the study will enter the primary analysis. Since we expect dropout of some 
patients on follow-up assessments, all randomized patients will be included in the intention-
to-treat analysis, where missing data will be imputed by a multiple imputation method. 
 
We will compare the atorvastatin lactone level between the 2 treatment arms at the second 
visit timepoint. A one-sided t-test will be performed using R 4.3.1 software. 
 
No interim analyses will be carried out since the study has a short study duration. 
 
 
12 ETHICAL CONSIDERATIONS 
12.1 Informed Consent 
 
Informed consent will be obtained by the PI who is a qualified practitioner. Co-I or CRC will 
only assist with the informed consent process. The study will be explained to patients in detail. 
This will be performed in the privacy of a closed-door room within NUHS IMU. During the 
consenting process, the study will first be explained to participants, and they will be given ample 
time to read through the informed consent form. Participants will be (1) given opportunity to 
clarify any doubts before acknowledging the consent form and (2) allowed to return home to 
discuss their participation with their family prior to consenting. Non-English speaking 
participants will have the English informed consent form with a short consent form translated 
in their preferred language. Hence, the informed consent process gives participants sufficient 
time to consider their participation in the study by having all their questions answered and 
allowing them to consult others, such as their physician, as well as give them the option of 
further discussing with their family members before making a decision. Participants would not 
be approached in a situation where they may feel compromised, thus preventing coercion and 
undue influence. If the participant agrees to participate, the informed consent form will be 
signed by the PI and the patient, in the presence of a prescribed witness. If a short consent form 
is used or if the participant is illiterate, an impartial witness will be present instead. A copy of 
the informed consent will be kept by both the PI and the participant.  
 
12.2 IRB review 
Each participating institution must provide for the review and approval of this protocol and the 
associated informed consent documents by the NHG DSRB.  
 

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12.3 Confidentiality of Data and Patient Records 
 
The study team would store all research data within the institution. For hardcopy data, they will 
be stored in designated locked cabinet(s) or room(s) that are accessible to authorized study 
personnel only. For electronic data, they will be stored in a secured computer that is password 
protected. The databases will not contain subject identifiers and the data linking subject 
identifiers and the subject identification codes will be stored separately. When portable media 
(e.g. CD, USB drives etc.) are used to store the data, subject identifiers are stored separately. 
Records for all participants, including all source documentations (containing evidence to study 
eligibility, history, billing information and physical findings, laboratory data, etc.) as well as IRB 
records and other regulatory documentation will be retained by the PI in a secure storage facility 
at the institution. All information will be coded, stored in a secure area and treated 
confidentially. Only the PI, co-I, study administrators and research coordinators will have access 
to the research data. All data files will be password protected and the study team will have 
access to the research data. All research data and biological materials (blood samples) will be 
collected prospectively and kept at the PI’s lab at NUS-MD6 Centre for Translational Medicine 
for up to 6 years, for future research. Collected data and blood samples will be de-identified / 
coded. The PI and / or delegated CRCs will maintain the source code. 
 
 
13 PUBLICATIONS 
 
In the event of any publication regarding this study, the data will be de-identified so that the 
identity of the patient remains confidential. In addition, no identifying information or names 
will be included in any transcripts, conference presentations, research / industry reports or 
publications. 
 
 
14 RETENTION OF TRIAL DOCUMENTS 
 
Records for all participants, including CRFs, all source documentation (containing evidence to 
study eligibility, history and physical findings, laboratory data, results of consultations, etc.) as 
well as IRB records and other regulatory documentation should be retained by the PI as original 
hard copy in a secure storage facility and data stored in computer databases will be kept in 
secure network drives during and after the project, for up to 6 years. The records should be 
accessible for inspection and copying by authorized authorities.  
 

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List of Attachments 
 
Appendix 1 
Study Schedule 
 
Procedure 
Screening & 
enrolment 
(visit T1) 
30-days 
follow-up 
(visit T2) 
Subject information & Informed consent signature 
X 
 
Verification of inclusion and exclusion criteria 
X 
 
Demographics, medical & medication history survey (D) 
X 
 
Randomisation 
X 
 
Peripheral intravenous blood collection (B) 
X 
X 
Self-reported compliance questionnaire (Q) 
 
X 
Oral administration of drugs 
Atorvastatin or Atorvastatin + Omeprazole 
<=======================➔ 
Serious/Adverse events (AE/SAE) 
<=======================➔ 
X = experimental procedure; ==> = Intervention.  
Timepoint: T1 = Screening & enrolment; T2 = Follow-up after 30 days of 
intervention 
 
 
Appendix 2 
Study design flow chart 
 

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Appendix 3 
Demographic + Medical + Medication history survey 
 
Subject ID: 
Date & Time: 
 
 
 
1) Age (as of January 2024): _______________ 
 
2) Gender:      
 Male               
 Female 
 
 
3) Race:         
 Chinese          
 Malay          
 Tamil           

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 Others (Please specify: 
______________________________)   
 
4) Have you ever been diagnosed with the following? (please tick if applicable) 
 Liver disease 
 Kidney disease 
 
5) Do you have any other diagnosed medication conditions? (E.g., High blood 
pressure, high cholesterol, diabetes, heart conditions etc.) 
 
Please specify: 
_________________________________________________ 
 
6) Have you taken any of the following medications in the past 30 days? 
(please tick if applicable) 
 

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 Statin (E.g., Atorvastatin, Rosuvastatin, Simvastatin, Pravastatin) 
 Omeprazole / Esomeprazole / Pantoprazole 
 
7) Are you taking any medications on a regular basis e.g., every day? 
Please specify the name of the medication + dose (e.g., 5mg) + how often 
you are taking it (e.g., two times a day):  
 
 
____________________________________________________________ 
____________________________________________________________ 
____________________________________________________________ 
 
8) Are you taking any supplements, herbal or traditional products? 
Please specify: _____________________ 
 
 
Appendix 4  
 
 
Self-reported compliance questionnaire 
 
Subject ID: 
Date & Time: 
Study intervention period (e.g., DD/MM/YY to DD/MM/YY): 
 
 
1) Have you missed taking your assigned medication(s) on any day(s)?  
     
 Yes 

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 No 
 
 
2) If your answer to Question 1 above is ‘Yes’, please state how many day(s) 
you have missed:  
 
           ____________________ 
 
You may also circle the dates you have missed taking medication(s) on the 
calendar below if you remember the dates: 
(A monthly calendar will be attached here based on the subject’s study 
intervention period, example shown below) 
 
 
3) How many tablet(s) / capsule(s) of each of these medications have you 
been taking each day? (Indicate ‘NA’ for the medication you did not receive) 
 
       
          ____________________ 
 

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      ____________________ 
 
 
 
References 
Studies on Atorvastatin + Omeprazole on Atorvastatin lactone: 
1) Goh, E., Wu, L. H., Pakkiri, L., Ng, M. L., George, M., Aminkeng, F., … Drum, C. (2023). Statin 
Lactone Metabolism Is a Determinant of 5-Year Cardiovascular Outcomes. doi:10.2139/ssrn.4548670 
2) Turner, R. M., Fontana, V., FitzGerald, R., Morris, A. P., & Pirmohamed, M. (2020). Investigating the 
clinical factors and comedications associated with circulating levels of atorvastatin and its major 
metabolites in secondary prevention. British Journal of Clinical Pharmacology, 86(1), 62–74. 
doi:10.1111/bcp.14133 
 
Studies related to giving Atorvastatin to healthy volunteers: 
1) Cilla, D. D., Whitfield, L. R., Gibson, D. M., Sedman, A. J., & Posvar, E. L. (1996). Multiple-dose 
pharmacokinetics, pharmacodynamics, and safety of Atorvastatin, an inhibitor of HMG-COA reductase, in 
healthy subjects. Clinical Pharmacology &amp; Therapeutics, 60(6), 687–695. doi:10.1016/s0009-
9236(96)90218-0 
2) Abdelkawy, K. S., Abdelaziz, R. M., Abdelmageed, A. M., Donia, A. M., & El-Khodary, N. M. (2020). 
Effects of green tea extract on atorvastatin pharmacokinetics in healthy volunteers. European Journal of 
Drug Metabolism and Pharmacokinetics, 45(3), 351–360. doi:10.1007/s13318-020-00608-6 
 
Studies related to giving Omeprazole to healthy volunteers: 
1) Baldwin, R. M., Ohlsson, S., Pedersen, R. S., Mwinyi, J., Ingelman-Sundberg, M., Eliasson, E., & 
Bertilsson, L. (2008). Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a 
pharmacokinetic study in healthy volunteers. British Journal of Clinical Pharmacology, 65(5), 767–774. 
doi:10.1111/j.1365-2125.2008.03104.x 
 
For sample size calculation: 
1) Lennernäs, H. (2003a). Clinical pharmacokinetics of atorvastatin. Clinical Pharmacokinetics, 42(13), 
1141–1160. doi:10.2165/00003088-200342130-00005