Conditions: Hypertension Hyperlipidemia
Keywords: combination pill polypill primary prevention
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 303
Healthy volunteers: no

Brief summary:
In this study the investigators will examine the effect of the polypill on medication adherence, systolic blood pressure, and LDL cholesterol over a 12 month span.

Detailed description:
The purpose of this study is to assess if a polypill-based approach to primary CVD prevention is feasible in a low socioeconomic status population. The study will assess whether a polypill approach is associated with better cardiovascular risk factor control compared with usual care.

The polypill will be supplied as a compounded pill containing atorvastatin 10 mg, amlodipine 2.5 mg, losartan 25 mg, and hydrochlorothiazide 12.5 mg. The medications in the polypill have been extensively evaluated individually and in combination. Each of the medications in the polypill is approved by the United States Food and Drug Administration (FDA) and widely administered in the US for the treatment of and prevention of cardiovascular disease. The doses of each component medication included in the polypill are low, which should minimize the chance of any potential side-effects.

In this study we assess medication adherence, systolic blood pressure, and LDL cholesterol over a 12 month span, in subjects taking the polypill versus subjects under usual care.

Arms:
arm 1: Subjects in this arm will not receive any investigational medications. They will remain on the same care that they are use to receiving. arm 2: The study medication will be a fixed-dose combination pill (polypill) containing: Atorvastatin 10 mg, amlodipine 2.5 mg, losartan 25 mg, and hydrochlorothiazide 12.5 mg.

Polypill will be taken once daily.

Interventions: intervention 1: Polypill (atorvastatin, amlodipine, losartan, and hydrochlorothiazide)
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
The SCCS Polypill Pilot Trial 
NCT02278471 
 
 
 
Redacted Study Protocol 
Version Date: 12/28/2016 
 


Protocol Version # 7 
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PI: Wang, Thomas 
Protocol Date: 12/28/2016 
 
Center Director: Harrison, David 
 
 
 
 
 
 
 
The SCCS Polypill Pilot Trial 
 
 
 
Thomas Wang, M.D., Professor 
Cardiovascular Medicine 
Vanderbilt University 
2220 Pierce Avenue Suite 383 
Nashville, TN 37232 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Center Director: Harrison, David 
 
Table of Contents 
 
Study Schema 
1 
Background and Significance 
1.1 
The public Health Burden of cardiovascular disease 
1.2 
Poor control of cardiovascular risk factors contributes to the 
problem 
1.3 
The challenge of primary prevention in low SES populations 
1.4 
The “polypill” approach and underserved populations 
2 
Previous Work 
2.1 
Establishment of the Southern Community Cohort Study 
2.2 
Blood pressure and hypertension in the Southern Community Cohort 
Study 
2.3 
Dyslipidemia, statin use, and mortality in the SCCS 
2.4 
Cardiovascular mortality in the SCCS 
3 
Research design and methods 
3.1 
Overview and study hypothesis 
3.2 
Study Sample 
3.3 
Study medication (polypill) 
3.4 
Participant Recruitment 
4 
Participant selection and withdrawal criteria 
4.1 
Overview 
4.2 
Inclusion criteria 
4.3 
Exclusion criteria 
4.4 
Study withdrawal and early termination 
4.5 
Preliminary eligibility data from Franklin SCCS participants   
5 
Study Treatments 
5.1 
Polypill 
 
5.2 
Treatment assignment 
5.3 
Blinding 
5.4 
Product accountability 
5.5 
Concomitant medications 
6 
Study assessments and procedures 
6.1 
Baseline visit 
 
6.2 
Follow up visits 
6.3 
Remuneration 
7 
Outcome measures and statistical analysis 
7.1 
Primary and secondary outcome measures 
7.2 
Statistical analyses and power 
8 
Study risks and discomforts 
8.1 
Fasting 
8.2 
Phlebotomy 
8.3 
Overview of study medication risks 
8.3.1 Atorvastatin risks 
8.3.2 Amlodipine risks 


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8.3.3 Losartan risks 
8.3.4 Hydrochlorothiazide risks 
8.4 
Adverse Events 
8.4.1 Definition of an Adverse Event (AE) 
8.4.2 Definition of a Serious Adverse Event (SAE) 
9 
Monitoring and quality assurance 
9.1 
Data and Safety Monitoring and Quality Assurance 
9.2 
Privacy and Confidentiality 
9.3 
Records Retention 
10 
Literature cited 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. BACKGROUND AND SIGNIFICANCE 
 
1.1 The public health burden of cardiovascular disease 
 
Heart disease represents a significant public health burden around the globe and remains 
the leading cause of death for both men and women in the United States. Coronary Heart 
Disease (CHD), the most common form of heart disease, kills nearly 400,000 Americans 
annually.1 Each year, approximately 720,000 Americans suffer a heart attack, resulting in 
significant morbidity and lost quality of life.2 Taking into account the cost of health care 
services, medications, and lost productivity, CHD alone costs the U.S. nearly $110 billion 
per year.3  
 
1.2 Poor control of cardiovascular risk factors contributes to the problem 
 
The disease-producing and disease-perpetuating roles of certain CHD risk factors, such 
as hypertension and dyslipidemia, have been well established. Effective management of 
these risk factors remains a key strategy in both the primary and secondary prevention of 
CHD.4,5    
 
1.3  The challenge of primary prevention in low SES populations 
 
Individuals of low socioeconomic status (SES) experience a disproportionately high risk 
of cardiovascular disease and cancer.   
 
 
 
 
 
 
 
Pharmacologic measures are frequently needed, but there is no consensus on how to 
optimally implement such measures.  Two competing approaches have been advocated 
for cardiovascular risk reduction: the “high-risk strategy” and the “population-based 
strategy.”6,7 In the high-risk strategy, preventive measures are targeted specifically at 
high-risk individuals, with medication therapy tailored to each patient’s risk factor profile 
(i.e. a personalized approach).  The identification of high-risk patients typically relies on 
clinical and laboratory-based prediction algorithms, such as the Framingham Risk Score.  
This has been the traditional approach endorsed in major guidelines, such as JNC 8 and 
ATP 3.  In contrast, the population-based strategy focuses on shifting the entire risk 
distribution, with measures implemented at the population level.  This approach 
emphasizes low-cost interventions generally associated with a low incidence of side 
effects. 
 
The relative merits of these competing approaches have stimulated active debate in 
cardiovascular prevention.  The attractiveness of the high-risk strategy lies in its 
concentrated efforts on individuals who are most likely to develop a cardiovascular event.  


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On the other hand, it is estimated that two-thirds or more of cardiovascular events occur 
in individuals who are at low or intermediate risk by current prediction algorithms.  
Furthermore, the cost/benefit equation may differ in low SES populations.  
 
 
 
 
 
 
 
 
The most recent cholesterol guidelines from the ACC/AHA (an update to ATP 3) endorse 
a hybrid of the high-risk and population-based approaches.  The guidelines recommend 
statin pharmacotherapy for individuals with a predicted 10-year cardiovascular risk of 
7.5% or higher.9  Targeting individuals based on individual risk estimates embodies a 
high-risk approach.  On the other hand, by moving the risk threshold from 20% over 10 
years (in ATP 3) to 7.5% over 10 years, the guidelines seek to apply pharmacotherapy to 
a much broader population that is closer to that seen in population-based approaches.  
Furthermore, the guidelines no longer advocate specific LDL targets and recommend a 
standard dose of statin therapy for the majority of individuals, a shift toward a less 
personalized strategy.  
 
 
 
 
 
  
 
 
 
 
 
 
1.4  The “polypill” approach and underserved populations 
 
A relatively recent iteration of the population strategy is the “polypill” concept.  The polypill 
refers to a fixed dose combination of medications with proven benefits for cardiovascular 
prevention, 
  
 
  
 
The polypill offers several potential advantages to usual pharmacotherapies.  The 
simplicity of a single daily pill is likely to improve adherence.  For blood pressure control, 
the combination of multiple medications at low doses rather than 1 or 2 medications at 
higher doses may be better tolerated, as side effects are typically dose-dependent.  
Furthermore, components of the polypill could have offsetting side effects; for instance, 
adding an ACE inhibitor or ARB to a thiazide is likely to reduce the risk of hypokalemia.  


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Lastly, eliminating the need for dose titration may insulate against physician “inertia,” and 
may be rational in settings where frequent follow-up visits are impractical. 
 
The feasibility of the polypill approach has been evaluated in several randomized trials 
outside the United States.  In the Indian Polycap Study (TIPS), approximately 2,000 
individuals in India were assigned to one of 9 arms, including 412 individuals to the 
Polycap (aspirin 100 mg, simvastatin 20 mg, atenolol 25 mg, HCTZ 12.5 mg, and ramipril 
20 mg).12  The other arms comprised various combinations of the individual component 
medications in the polypill.  The polypill was well-tolerated and effectively reduced blood 
pressure and LDL cholesterol.  Several smaller trials have been performed with similar 
findings (e.g. the PILL Study, TIPS-2, UMPIRE), with sample sizes ranging from 50 to 
500 individuals.13-15  Only 13 individuals from the U.S. have been enrolled in all of these 
studies combined, and none of the studies focused specifically on low SES individuals.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
we propose to test the feasibility and effectiveness of daily administration of 
a “polypill” in a medically-underserved population.  The proposed study should establish 
whether larger outcomes trials are warranted to assess the effectiveness of the polypill in 
reducing the incidence of cardiovascular events. 
 
 
 
 
 
 
 
 
 
 
 


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3. RESEARCH DESIGN AND METHODS 
 
3.1 Overview and study hypothesis 
 
The proposed study is a two-group, randomized, open-label comparison of polypill 
versus usual care in 300 individuals (150 per arm) without prior cardiovascular disease.  
The duration of treatment is 1 year, and outcomes will include medication adherence, 
blood pressure, and LDL cholesterol.  We hypothesize that use of a polypill is 
feasible in a low SES, primary prevention setting, and will be associated with 
better cardiovascular risk factor control compared with usual care. 


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3.2 Study sample 
 
 We will leverage an existing epidemiologic resource, the NCI-funded Southern 
Community Cohort Study (SCCS).  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.3 Study medication (polypill) 
 
The study medication will be a fixed-dose combination pill (polypill) containing: 
atorvastatin 10 mg, amlodipine 2.5 mg, losartan 25 mg, and hydrochlorothiazide 12.5 mg.  
As this is an open-label trial, there will be no placebo provided in the “usual care” arm. 
The polypill is formulated to be taken once daily, to maximize compliance. The lowest 
standard doses (or half-doses) of the component medications are used to minimize side 
effects that might lead to discontinuation of the entire combination.  Fixed dosing is 
intended to obviate the need for titration and frequent follow-up visits.  Nonetheless, 
physicians treating subjects in the polypill arm are free to prescribe add-on therapy at 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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their discretion.  Individuals in the polypill arm on existing statin or anti-hypertensive 
monotherapy will be converted to the polypill at study initiation.  Individuals taking more 
than 2 anti-hypertensive medications at baseline will not be included in the trial. 
 
 
 
 
 
 
Atorvastatin.  Evidence from 14 primary prevention trials randomizing nearly 50,000 
individuals indicates that statins reduce coronary events by approximately 25%, and all-
cause mortality by 14%.18  Though myalgias and asymptomatic liver function test 
abnormalities may occur, they are often dose-dependent (i.e. more common at doses 
higher than the dose chosen for the polypill) and cease with drug discontinuation.  In fact, 
rates of myalgia and liver function test abnormalities do not differ between statin and 
placebo groups enrolled in randomized trials.  The same is true for rates of adverse events 
or drug discontinuation.  Clinically overt liver failure and rhabdoymyolysis with statins are 
exceedingly rare, particularly in the absence of interacting drugs, which will be excluded 
by protocol.19  Recent trials suggest a small excess risk of incident diabetes among 
patients randomized to statins, though this risk appears to be substantially outweighed by 
the reduction in cardiovascular risk.20,21 
 
 
 
 
 
 
 
 
 
 
Anti-hypertensive therapy.  The proposed anti-hypertensive combination (amlodipine, 
HCTZ, and losartan at half doses) is identical to that used in the trial by Wald and 
colleagues.22 In that randomized, cross-over study, the pill was effective and well 
tolerated, with no side effects requiring discontinuation. 
 
 
 
   
 
  
 
 
 
 
 
 


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. 
 
3.4 Participant recruitment  
 
We will send an introductory letter and pre-screening questionnaire to participants at the 
Franklin Primary site who are age-eligible and not known to meet any of the exclusion 
criteria listed above.  The letter will describe the nature of the study, its goals, and the 
risks and benefits of participating, and invite the participant to call the study team if 
questions arise and to complete the questionnaire and mail it back in the provided prepaid 
mailer.  The questionnaire will seek updated information on medication use, health status, 
and other characteristics to assess potential eligibility into the trial.  Participants not 
returning the questionnaire after a three-week lapse will be sent a second packet.  Phone 
calls will then be made to non-responders to seek their involvement and, if desired by the 
person being called, to complete the questionnaire over the phone and schedule a clinic 
visit.  Calls will also be made to those who returned the questionnaires and remain 
potentially eligible to arrange a study screening visit at the clinic.  We estimate that we 
will attempt contact with up to 1,050 Franklin-SCCS participants over a 15-month period 
to enroll 300 participants into the feasibility study trial (see 3.2). 
 
 
 
 
Eligible participants, who are not enrolled in the SCCS, may also be identified and 
approached about participation by the site investigator (or a trained member of his staff) 
at one of their regularly scheduled visits to Franklin Primary Health Center. 
 
 
   


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4. Participant selection and withdrawal criteria 
 
4.1 Overview  
 
We will recruit individuals at risk for cardiovascular disease, but without prevalent disease, 
who have no contraindications to any of the components of the polypill.  The inclusion 
and exclusion criteria are similar to those of previous primary prevention studies involving 
the polypill that have been performed outside the U.S.12-15 
 
4.2 Inclusion criteria  
 
Participants eligible for enrollment in the study must meet all of the following criteria:  
• Enrolled at the SCCS site in Mobile, Alabama, obtain care at Franklin Primary 
Health Center, or live in the surrounding area.  
• Aged 45 to 75 years 
• Baseline systolic blood pressure ≥120 mm Hg. In this open-label trial, the study 
physicians are permitted to prescribe any additional medication deemed 
appropriate to achieve blood pressure control.  
 
4.3 Exclusion criteria  
 
Participants meeting any of the following criteria will not be enrolled in the study: 
• History of coronary heart disease or stroke 
• History of cancer, except for basal cell skin cancer 
• History of advanced liver disease, not including chronic, clinically-stable hepatitis  
• Laboratory evidence of hepatic dysfunction (an alanine aminotransferase level 
more than three times the upper limit of the normal range) 
• Known renal disease, estimated creatinine clearance < 60, 
• Current use of more than 2 anti-hypertensive medications 
• LDL cholesterol ≥190 mg/dl 
• Insulin-dependent diabetes 
• Known intolerance to any of the components of the polypill 
• Potassium <3.4 or >5.5 mEq/L 
• Use of medications that interact with statins, including those affecting the 
cytochrome P450 system 
• Current use of diuretics for indications other than hypertension 
• Comorbidities that might be expected to limit lifespan during the 12-month follow-
up period 
• Inability to provide informed consent. 
 
4.4 Study withdrawal and early termination 
 
Participants have the right to withdraw their consent for further participation in the study 
(i.e., precluding continued data collection). A participant may also be asked to stop study 


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participation at the investigator’s discretion. In participants withdrawing their consent to 
provide any additional information, no further study visits or study-related telephone 
contacts can be conducted. 
 
4.5 Preliminary eligibility data from Franklin SCCS participants   
 
We applied the inclusion and exclusion criteria to the Franklin SCCS sample based on 
data collected at entry and during routine follow up of the cohort.  Even restricting the 
Franklin population to SCCS participants who participated in the routine follow-up 
contacts (and thus have demonstrated recent continuing active interest in participating in 
SCCS follow up activities), we estimate that nearly 1,000 individuals would be eligible for 
entry into the trial, with greater numbers available should participants who did not 
complete a follow-up survey be considered.  One of the study’s aims will be to estimate 
and measure recruitment rates,
 
 
 
5. Study treatments 
 
5.1 Polypill 
 
The polypill will be produced and dispensed by the Vanderbilt Investigational Drug 
Service (IDS). 
 
 
 
 
 
  Participants will be instructed to 
take one pill per day for the duration of the study. 
 
All polypill medication, including unopened or partially-used containers, must be 
maintained at the study site for eventual return to the Vanderbilt IDS. 
 
5.2 Treatment assignment 
 
Participants who meet eligibility criteria after the initial Franklin visit will be invited to 
participate in the study, and randomized to polypill versus usual care.  Block 
randomization will be performed according to baseline hypertension status.  The 
randomization key will be maintained at the International Epidemiology Institute (IEI).  
Physicians at the Franklin Primary site will prescribe the polypill to those in the active arm.  
 
5.3 Blinding 
 
This is an open-label study and thus will not be blinded. Please see Section 8.1. 
 
 


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5.4 Product accountability 
 
In accordance with local regulatory requirements, the investigator or designated site staff 
must document the quantity of polypill dispensed and/or administered to study 
participants, the amount returned by study participants, and the amount received from 
and returned to the Vanderbilt IDS when applicable. Product accountability records must 
be maintained throughout the course of the study. 
 
5.5 Concomitant medications 
 
Medications and non-drug therapies not specifically prohibited by the study are allowed. 
All concomitant medications taken during the study will be recorded by study staff. 
 
Prohibited medications include all medications that interact with statins, including those 
affecting the cytochrome P450 system, and diuretics used for indications other than 
hypertension.   
 
6. Study assessments and procedures 
Procedures 
Screening/Baseline 
Visit 1 
2 month follow-up 
Visit 2 
12 month follow-up 
Visit 3 
Introductory letter 
(sent prior to visit) 
X 
 
 
Pre-screening 
questionnaire (sent 
prior to visit) 
X 
 
 
Written informed 
consent 
X 
 
 
Medical history 
X 
 
 
Inclusion exclusion 
criteria 
X 
 
 
Vital Signs (blood 
pressure/heart rate) 
X 
X 
X 
Weight 
X 
X 
X 
Height 
X 
X 
X 
Social History 
X 
 
 
Follow-up 
questionnaire (sent 
prior to visit) 
 
X 
X 
Self-reported 
adherence 
 
X 
X 
Moriskey 
questionnaire 
 
X 
X 
Medication packaging 
return 
 
X 
X 
Adverse events 
 
X 
X 
Fasting blood draw 
(20 mL) 
X 
X 
X 
Urine Pregnancy Test 
Xa 
 
 
a. 
Urine pregnancy test will be performed for pre-menopausal women. 
 
 


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6.1 Baseline visit 
 
Individuals will be asked to fast for at least 8 hours prior to the clinic visit.  At the visit, 
responses to the baseline questionnaire will be reviewed by a study coordinator as a final 
check on inclusion and exclusion criteria and current medication use.  Blood pressure will 
be measured twice in the left-arm of the seated subject, and results will be averaged.  
Following the informed consent process, a 5mL blood sample will be obtained for eligibility 
screening laboratories: comprehensive metabolic panel, lipid panel.   Any pre-
menopausal women will also undergo a rapid urine pregnancy test. 
 
 
 
 
 
 
 
 Subjects will be randomized at this visit to either the polypill or usual care 
arm.  When the baseline lab results are received, they will be reviewed for any values 
meeting exclusion criteria. 
 
 
 
 if any exclusion criteria are found to be met at this time the 
subject will be contacted and removed from the study.  
 
6.2 Follow-up visits   
 
At 2 and 12 months post-randomization, participants will be sent follow-up questionnaires 
and scheduled for a follow-up visit at the health center.  At these follow-up visits, the study 
coordinators will review questionnaires for completeness, measure blood pressure, and 
collect a fasting blood sample for repeat laboratories. Procedures for blood collection, 
analysis, shipment, and storage will be identical to those of the baseline visit. Information 
on tolerability and side effects will be collected.  Additional clinic visits as desired by the 
participants’ physicians will be allowed at their discretion. 
 
Pill vials will be collected for pill counts. Self-reported adherence will also be ascertained 
for all medications, recorded as the number of days the medication was taken in the week 
prior to the study visit.  
 
  
 
6.3 Remuneration  
 
Subjects will receive $50 per study visit. In addition, subjects in the polypill arm will receive 
$10 every three months when they return to the Franklin Primary Health Center to pick 
up their next three month supply of medication and return the previous months used pill 
vials.    
 


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7.  Outcome measures and statistical analysis 
 
7.1 Primary and secondary outcome measures 
 
Primary outcomes 
The co-primary outcomes will be medication adherence (based on pill count and self-
report), systolic blood pressure, and LDL cholesterol, at 12 months.  
 
Secondary outcomes 
Medication adherence, systolic blood pressure, and LDL cholesterol at 2 months.  The 
primary endpoint variables will also be measured at the interim, 2-month visit. 
 
Drug metabolite profile.  Medication adherence will be further assessed using a novel 
drug screening panel
 
 
 
 
 
 
 
 
 
 
Insulin resistance.  At baseline and 12 months, we will measure HOMA-IR using fasting 
glucose and insulin as previously described.34 
 
Inflammatory profile.  The measures of inflammation will include plasma levels of IL-17, 
IFN-g, IL-6, IL-10 and high-sensitivity C-reactive protein. 
 
 
 
 
 
 
   
 
Recruitment response rates. Recruitment response rates will be tracked
 
 
 
 7.2 Statistical analyses and power 
 
 In our primary analyses, we will evaluate systolic blood pressure (SBP) and low-density 
lipoprotein cholesterol (LDL) using multivariable regression models with treatment group 
as the primary covariate, and age, gender, racial/ethnic group as additional covariates.  


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The baseline measurement of each outcome will be included in the respective model.  
Note that even though systolic blood pressure is used in stratified randomization, we will 
include it in the SBP model following the recommendations by Senn and Raab.35,36 To 
allow for the treatment effect estimates to differ between subgroups, in exploratory 
additional analyses interaction terms will be considered between treatment and each of 
age, gender, and racial/ethnic group.  Secondary outcomes will be analyzed in the same 
fashion.  A two-sided p-value of 0.05 will be considered statistically significant.  Because 
this is a pilot study, we will not divide the p-value for these 2 co-primary outcomes. 
 
 
Detectable treatment effects for SBP and LDL depend on the true correlation between 
the baseline and 12 month data.  The Table above summarizes the detectable difference 
with sample size of 150 in each group at 80% power for plausible correlations between 
two time points.  We expect a high correlation between the time points, suggesting that 
the scenarios shown for r=0.7 or r=0.8 are most likely.  Estimates of baseline variability 
(SD) are based on existing SCCS data, and closely approximate those obtained in other 
cohorts with large minority representation, such as the Jackson Heart Study.16,17 
 
We also incorporated the possibility of 10% and 20% dropout (n=135 and n=120 in each 
arm, respectively).  Type I error rate was controlled at 5%.  As shown, we have excellent 
power to detect clinically meaningful differences.  Indeed, the detectable differences for 
SBP and LDL are far lower than those found using a similar polypill in the Wald study, 
though that study used a placebo comparison rather than usual care, which likely 
overestimates the differences.22 Further, these power analyses are based on simple 
univariate tests; our proposed multivariable regression models should be more powerful 
because they take into account covariates. 
 
For recruitment, with 1,050 contacts to potential enrollees, we can estimate recruitment 
response rates to within ±3%.  For adherence, our sample size is large enough to estimate 
a simplified adherence measure (Yes/No) with a precision of ±8%.  In additional 
regression models, pill count will be square-root transformed if necessary to satisfy the 
regression assumption (normality of the residuals). 
 
 
 
 
 
 
 
Sample size in 
each arm 
Correlation between baseline and 
12-month measures 
r=0.5 
r=0.6 
r=0.7 
r=0.8 
Detectable Difference for SBP, mmHg 
N = 150 
6.8 
6.1 
5.3 
4.3 
N = 135 
7.2 
6.4 
5.6 
4.5 
N = 120 
7.6 
6.8 
5.9 
4.8 
Detectable Difference for LDL, mg/dl 
N = 150 
12.7 
11.3 
9.8 
8.0 
N = 135 
13.3 
11.9 
10.3 
8.4 
N = 120 
14.2 
12.7 
11.0 
9.0 


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8.  Study risks and discomforts 
 
8.1 Fasting 
Participants will be required to fast prior to each study visit. Risks related to overnight 
fasting include hypovolemia. Study participants will be instructed to drink plenty of fluids 
on the day prior to their visit. 
 
8.2 Phlebotomy 
Risks related to phlebotomy are rare and include syncope, hematoma formation, and 
phlebitis. A total of approximately 45 mL (equivalent to a few tablespoons) will be drawn 
from study participants, with no more than 15 mL drawn at any study visit. The risk 
associated with this amount of phlebotomy should be minimal. 
 
8.3.  Overview of study medication risks  
The medications in the polypill have been extensively evaluated individually and in 
combination.  Each of the medications in the polypill is approved by the United States 
Food and Drug Administration (FDA) and widely administered in the US for the treatment 
of cardiovascular disease. The doses of each medication included in the polypill are low, 
which should minimize the change of any potential side-effects. Prior studies using a 
polypill with the identical medications have confirmed high tolerability.  
 
Patients in the usual care arm will be informed of the risks of the medications they are 
prescribed. The risks associated with each drug contained in the polypill are detailed in 
subsequent sections. 
 
The first study visit on medication will take place at 2 months, with additional visits at the 
discretion of the participants’ physicians.  During the trial, all adverse events will be 
reported to the study IRB in a timeframe consistent with IRB policies.  The trial will also 
be monitored by an independent Data Safety and Monitoring Committee and by the FDA 
under an approved IND (#124626). 
 
8.3.1 Atorvastatin risks 
The most common side effects of atorvastatin are myalgias and liver function test 
abnormalities without symptoms. The risk of these side effects is very low at the dose 
delivered by the polypill.  Discontinuation of atorvastatin eliminates these side effects of 
the drug. The most serious side effects of atorvastatin are liver failure and myositis, which 
occur, if at all, in less than 1% of patients receiving a statin. 
 
8.3.2 Amlodipine risks 
Potential side effects of amlodipine are swelling, rapid heart rate, dizziness, fatigue, and 
flushing. These side effects are rare (likely to be less than 5%) and are likely to cease as 
soon as the medication is discontinued.  
 
8.3.3 Losartan risks 


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Potential side effects of losartan are dizziness, cough, diarrhea, weakness/fatigue, 
hypoglycemia, anemia, and hyperkalemia. These side effects are rare (likely to be less 
than 5%) and are likely to cease as soon as the medication is discontinued. Furthermore, 
the theoretical risk of hyperkalemia is offset by the concomitant administration of 
hydrochlorothiazide.  
 
8.3.4 Hydrochlorothiazide risks 
Uncommon side effects of hydrochlorothiazide are weakness, jaundice, diarrhea, 
vomiting, imbalances and abnormalities in blood electrolyte levels (e.g., hypokalemia), 
rash, photophobia, and impotence. Serious side effects of hydrochlorothiazide include 
kidney disease or kidney failure. However, these serious side effects generally occur at 
high medication doses (≥25mg). For the 12.5 mg dose contained in the polypill, the 
chance of serious side effects is likely to be less than 1%.  Furthermore, the theoretical 
risk of hypokalemia is offset by the concomitant administration of Losartan.  
 
 
8.4 Adverse events 
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.  All AEs and SAEs will be collected from 
the time of the first dose of study medication through the final study visit.  All SAEs will be 
reported to the DSMB and to the IRB within 24 hours. 
 
8.4.1 Definition of an Adverse Event (AE) 
Any untoward medical occurrence in a participant, temporally associated with the use of 
the polypill or any usual care medications.  Note: An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
(new or exacerbated) temporally associated with the use of the polypill.  
 
Events meeting the definition of an AE include: 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after medication administration even 
though it may have been present prior to the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of study 
medication or a concomitant medication (overdose per se will not be reported as 
an AE/SAE). 
 
Events that do not meet the definition of an AE include: 
• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE. 
• Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 


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• The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
 
8.4.2 Definition of a Serious Adverse Event (SAE) 
 
A SAE is any untoward medical occurrence that, results in: 
a. death 
 
b. a life-threatening experience 
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the participant was at risk of death at the time of the event.  It does not refer 
to an event, which hypothetically might have caused death, if it were more severe. 
 
c. inpatient hospitalization 
NOTE: In general, hospitalization signifies that the participant has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or out-patient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious.  
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
 
d. persistent or significant disability or incapacity, or 
NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which 
may interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
 
 
e. requires, based on reasonable medical judgment, a medical or surgical 
 
intervention to prevent an outcome described in list a – d.   
 
NOTE: Medical judgment should be exercised in deciding whether reporting is 
 
appropriate in situations, such as important medical events that may not be 
 
immediately life-threatening or result in death or hospitalization but may 
 
jeopardize the participant or may require medical or surgical intervention to 
 
prevent one of the other outcomes listed in the above definition.  These should 
 
also be considered serious.  Examples of such events are invasive or malignant 
 
cancers, intensive treatment in an emergency room or at home for allergic 
 
bronchospasm, blood dyscrasias or convulsions that do not result in 
 
hospitalization, or development of drug dependency or drug abuse. 
 
 


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9.  Monitoring and quality assurance 
 
9.1 Data and Safety Monitoring and Quality Assurance 
Informed consents, case report forms and data will be reviewed by the principal 
investigators and a DSMB every 3 months to ensure the safety of study participants.  The 
DSMB will consist of a group of three individuals; Harvey J. Murff, M.D, M.P.H, Associate 
professor of Medicine, Vanderbilt University, Chang Yu, Ph.D; Associate Professor, 
Department of Biostatistics, Vanderbilt University, and Michael Blaha, M.D., M.P.H; 
Assistant Professor, Division of Cardiology, Johns Hopkins Hospital.  The safety data that 
will be reviewed includes: all reported AEs, any participants with early study termination 
or withdrawal of consent and any protocol deviations.  Other data to be reviewed includes 
appropriate handling and processing of blood samples and laboratory data and 
maintenance of patient confidentiality. 
 
The review and decision regarding altering or stopping the protocol will be performed by 
the principal investigators and an independent data and safety monitor.  Reasons to stop 
the study include an unexpected incidence of AEs attributed to the polypill.  
 
The principal investigator will review any AEs immediately following their occurrence and 
report them to the IRB in accordance with their guidelines.  All SAEs will be reported by 
phone, fax or email within 24 hours to both the IRB and the data safety monitor, followed 
by a full written report within 10 business/14 calendar days. 
 
9.2 Privacy and Confidentiality 
All participant data, including case report forms, blood samples, and written study 
questionnaires will be coded by an identification number to maintain participant 
confidentiality.  The master key to the identification numbers will be kept in a locked 
storage at each site accessible only by the principal investigator. 
 
9.3 Records Retention 
Following closure of the study the investigators must maintain and store complete study 
records for a period of 5 years in a safe and secure location.  
 
 
 
 
 
 
 
 
 
 
 


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