A Double Blind Randomized Controlled Trial to Assess the Efficacy and Safety of a Quadruple Ultra-low-dose Treatment for Hypertension (QUARTET USA)
Phase: PHASE2
Conditions: Hypertension
Sponsor: Washington University School of Medicine

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PROTOCOL TITLE: A double blind randomized controlled trial to assess the efficacy and safety 
of a quadruple ultra-low-dose treatment for hypertension (QUARTET USA). 
 
 
CO-PRINCIPAL INVESTIGATORS: 
Mark Huffman, MD, MPH (contact PI) 
Professor of Medicine 
Division of Cardiology 
Washington University School of Medicine  
660 S. Euclid Ave., MSC 8086-43-13 
St. Louis, MO  63110 
(314) 747-9487   
Email: m.huffman@wustl.edu  
 
Jody Ciolino, PhD 
Assistant Professor in Preventive Medicine and Medicine 
Northwestern University Feinberg School of Medicine 
680 N. Lake Shore Drive, Suite 1400 
Chicago, IL 60611 
Tel: +1-312-503-3980 
Fax: +1-312-908-9588           
Email: jody.ciolino@northwestern.edu 
 
 
VERSION NUMBER: 6.1 
 
VERSION DATE: April 20, 2022 
 
 
 

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STUDY SUMMARY: 
Investigational Agent(s)  
(Drugs or Devices) 
Active Treatment: Low Dose Quadruple Combination 
Therapy (LDQT) comprising candesartan 2 mg, 
amlodipine 1.25 mg, indapamide 0.625 mg, and 
bisoprolol 2.5 mg 
Comparator: Candesartan 8 mg 
IND / IDE / HDE #  133846 
Indicate 
Special Population(s) 
 Children  
 Children who are wards of the state  
 Adults Unable to Consent   
 Cognitively Impaired Adults  
 Neonates of Uncertain Viability  
 Pregnant Women  
 Prisoners (or other detained/paroled individuals)  
 Students/Employees  
Sample Size 87 
Funding Source National Heart, Lung, and Blood Institute 
Indicate the type of consent 
to be obtained 
Written  
Verbal/Waiver of Documentation of Informed Consent 
Waiver of HIPAA Authorization  
Waiver/Alteration of Consent Process   
Site 
 Lead Site (For A Multiple Site Research Study) 
 Data Coordinating Center (DCC) 
Research Related 
Radiation Exposure 
Yes  
 No  
DSMB / DMC / IDMC 
Yes  
No 
 
 
 

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ABBREVIATIONS: 
ABPM 
Ambulatory Blood Pressure Monitoring 
ACE-I 
Angiotensin-converting-enzyme inhibitor 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase, a kind of enzyme 
ALT 
Alanine Transaminase, a kind of enzyme  
ARB 
Angiotensin II receptor blocker 
AST 
Aspartate Aminotransferase, a kind of enzyme 
BB 
Beta Blocker 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CABG 
Coronary Artery Bypass, a type of surgery that improves blood flow to the heart 
CAD  
Coronary Artery Disease 
CCB 
Calcium Channel Blocker 
CRF 
Case Report Form 
DBP 
Diastolic Blood Pressure 
DSMB 
Data and Safety Monitoring Board 
DSMP 
Data and Safety Monitoring Plan 
ECG/EKG  Electrocardiogram 
eConsent 
Electronic consent 
ECT 
Electroconvulsive Therapy, a medical treatment used in patients with severe major 
depression 
eGFR 
Estimated Glomerular Filtration rate, a number based on the creatinine level in the blood 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase, a kind of enzyme found in many organs throughout the 
body 
HDL 
High Density Lipoprotein, a group of lipoproteins that transport all fat molecules around 
the body in the extracellular water 
IPD 
Individual Participant Data  
LVH            Left Ventricular Hypertrophy, a term for a heart’s left pumping chamber that has 
thickened and may not be pumping efficiently 
MI 
Myocardial Infarction, a kind of heart attack 
PCI 
Percutaneous Coronary Intervention, a non-surgical procedure to treat narrowing of the 
coronary arteries  
PROMIS 
Patient-reported Outcome Measurement Information System 
QRS 
The main spike seen on an ECG line 
QTc 
The interval that represents the total time from ventricular depolarization to complete 
repolarization 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
TIA 
Transit Ischemic Attack, a brief stroke-like attack that can be resolved within minutes to 
hours  
UACR 
Urine Albumin: Creatinine Ratio 

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1. OBJECTIVES 
To investigate, in a double-blind randomized controlled trial, whether initiating treatment with 
ultra-low-dose quadruple-combination therapy (“LDQT”) will lower office blood pressure more 
effectively, and with fewer side effects, compared to initiating standard dose monotherapy in 
patients with hypertension. 
Primary hypothesis: A combination pill comprising four types of blood pressure lowering 
medications, each at one-quarter standard doses, will lower office blood pressure more 
effectively than initiating patients with standard dose monotherapy in patients with hypertension. 
 
2. BACKGROUND 
2.1. Burden of raised blood pressure and treatment gaps  
Elevated blood pressure, also known as hypertension when >130/>80 mmHg, is a leading 
cause of preventable morbidity and mortality globally.1 In the United States, approximately 
45.6% of adults, or 103.3 million individuals have hypertension, and prevalence rates are rising, 
particularly among non-Hispanic black men and women in whom prevalence rates exceed 
50%.2 Among Americans with elevated blood pressure, 81.9 million are eligible for 
pharmacotherapy based on the 2017 AHA/ACC blood pressure guideline, an absolute increase 
of 4.2 million Americans compared with previous thresholds for initiation of pharmacotherapy 
(>140/>90 mmHg). The benefits of blood pressure lowering in reducing cardiovascular events 
are unequivocal. Blood pressure lowering therapy leads to an estimated 11% reduction in all-
cause mortality (relative risk [RR] = 0.89 [95% CI 0.85, 0.95]), 16% reduction in coronary heart 
disease events (RR = 0.84 [95% CI 0.79, 0.90]), and 36% reduction in stroke (RR = 0.64 [95% 
CI 0.56, 0.73]). The typical estimated blood pressure lowering effect from a standard dose of a 
single drug ranges from 6-9/3-6mmHg.3 Therefore, improving blood pressure control is a 
strategic priority for reducing the burden of cardiovascular disease in the United States2 and 
around the world.1  
While most Americans are aware of their hypertension and while most of those who are aware 
receive treatment (75%), less than half (47%) are controlled using a goal blood pressure of 
<130/<80 mmHg when using nationally representative data (compared with 52% based on the 
previous target of <140/<90 mmHg).2 These recommendations were based on high-quality data 
from the Systolic Blood Pressure Intervention Trial (SPRINT),3,4 yet the method of implementing 
this strategy, which includes repeated clinic visits with repeated dose titrations of individuals 
drugs, is challenging. This strategy is also limited because maximizing doses of individual drugs 
leads to a greater risk of side effects without a similar benefit to blood pressure reduction.  
This proposal aims to substantially simplify and improve the efficacy and safety of blood 
pressure-lowering treatment by changing the initial treatment paradigm for patients with 
essential hypertension who are eligible for pharmacotherapy without prevalent cardiovascular 
disease. We hope to change the treatment paradigm from moderate dose, single-drug therapy 
with repeated dose titration to ultra-low dose, quadruple combination therapy (LDQT). 
Combination therapy improves adherence in many chronic conditions, including elevated blood 
pressure5 and cardiovascular diseases,6 but it has been typically reserved for individuals with 
very high (systolic blood pressure [SBP] >150 mmHg in the 2017 guideline compared with >160 

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mmHg in previous guidelines) or difficult to control blood pressures.3 The proposed treatment 
regimen has the potential to make it easier for typical patients and clinicians to achieve blood 
pressure goals with fewer pills and fewer clinic visits to prevent fatal and non-fatal 
cardiovascular disease events and to improve cardiovascular health with a focus on vulnerable 
groups who bear a disproportionate burden of hypertension and hypertension-related diseases. 
 
2.2. Barriers to hypertension control 
There are multiple barriers to hypertension control, including patient-and physician-related 
factors. Patient adherence is a major factor in hypertension control and is worsened by 
increased number of medications, complexity of dosing regimens, and medication side effects.8 
“Therapeutic inertia”, which is the reluctance of clinicians to treat “mild” hypertension (SBP <160 
mmHg) despite demonstrated benefits7 or to up-titrate medications, remains an important barrier 
to hypertension control. Current guidelines typically recommend initiating monotherapy, up-
titration, switching drugs if not tolerated, and adding other agents if needed.3 This strategy often 
takes multiple visits to achieve blood pressure goals, which results in most patients remaining 
on monotherapy with inadequate blood pressure control. SPRINT participants randomized to a 
SBP goal <120 mmHg took, on average, three pills at standard dose for blood pressure control 
compared with two pills at standard dose among individuals randomized to the SBP goal <140 
mmHg.4 Translating these important research findings into routine clinical practice, particularly 
among vulnerable populations, will be difficult using the current paradigm of blood pressure 
management. 
 
2.3. Combination therapy for blood pressure lowering 
Because 50% to 75% of patients require multi-drug treatment for blood pressure control, there 
has been increasing interest in the initial use of combination therapy. A 2013 survey of 31 
international hypertension guidelines demonstrated that 27 (87%) of guidelines recommend use 
of combination for initial treatment but typically only as an option for patients at >20/10 mmHg 
from goal,8 which is concordant with the 2017 AHA/ACC blood pressure guideline. 
Nevertheless, there is evidence of improved adherence for combination-based therapy (albeit 
typically two drug combinations) compared to monotherapy for treatment of elevated blood 
pressure, cardiovascular diseases, and other chronic conditions with estimates ranging from 
25% to 50%.6 Most recently, the TRIple pill vs. Usual care Management for Patients with mild-
to-moderate Hypertension (TRIUMPH) trial evaluating half-dose, triple drug combination 
(telmisartan 20 mg, amlodipine 2.5 mg, chlorthalidone 12.5 mg) demonstrated hypertension 
control rates of 70% in the intervention compared with 55% in the usual care arm at six months 
among 700 adults in Sri Lanka.9  
While these data are promising for the use of low-dose combination therapy for the treatment of 
mild and moderate hypertension, they need further study with an active comparator arm to 
reduce the risk of performance bias and within a broader, more diverse population. 
Combinations with more drugs but at lower doses (four drugs at quarter doses) than what was 
used in TRIUMPH (three drugs at half doses) may be even more effective and with a better side 
effect profile. Therefore, there is a clear need for improved strategies to: 1) make treatment of 
hypertension more effective and easier to implement for patients and clinicians, 2) quickly and 

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safely bring elevated blood pressure to lower goals than those recommended in the past, and 3) 
increase long-term adherence with therapy.  
In August 2021, the QUARTET (Australia) trial compared the effect of irbesartan at 37.5 mg, 
amlodipine at 1.25 mg, indapamide at 0.625 mg, and bisoprolol at 2.5 mg with irbesartan 150 
mg daily among 591 patients with mild to moderate hypertension who had a baseline mean 
(SD) systolic blood pressure of 142 (13) mmHg in the intervention group and 140 (13) mmHg in 
the control group.10 Compared with the irbesartan control group, patients randomized to the 
quadpill had a 6.9 mmHg (95% CI: 4.9-8.9) greater systolic blood pressure lowering at 12 
weeks. These results were sustained up to 12 months in a sample of 417 patients who were 
followed for 12 months when the difference was 7.7 mmHg (95% CI: 5.2-10.3) of systolic blood 
pressure. Dizziness was reported among 93 (31.0%) patients in the intervention group 
compared with 74 (25.4%) patients in the control group (RR 1.27 [95% CI: 0.98-1.64]). There 
were no serious adverse events due to syncope, falls, or acute kidney injury. The study 
participants were largely White (82%) and Asian (12%) race/ethnicity. Thus, there is promising 
evidence of an ultra-low-dose combination approach, but additional data are needed in more 
diverse populations. 
 
3. STUDY ENDPOINTS 
3.1. Primary 
Mean change (from baseline) in automated office SBP at 12 weeks adjusted for baseline 
values. 
3.2. Secondary 
1. Mean automated office SBP at 12 weeks adjusted for baseline values.  
2. Other blood pressure measures in active vs. control groups (adjusted for baseline values 
in each case):  
a. Mean change (from baseline) in automated office SBP at six weeks. 
b. Mean automated office SBP at six weeks.  
c. Mean change (from baseline) in automated office DBP at six and 12 weeks. 
d. Mean automated office DBP at six and12 weeks.  
e. Proportion of patients with hypertension control (percent with SBP < 130 mmHg 
and DBP <80 mmHg) at six and 12 weeks. 
f. Proportion of patients requiring step-up treatment (ever, and at each study time 
point). 
g. Proportion of patients with adverse event-free hypertension control (percent with 
SBP < 130 mmHg and DBP < 80 mmHg). 
 
3. Medical adherence:  
a. Medication adherence defined by objective pill counts. 
 
4. Health-related quality of life: 
a. Mean change (from baseline) in health-related quality of life using PROMIS 
Global Health instrument. 

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3.3. Tolerability & Safety 
a. Percentage of participants with any SAE according to GCP definition. 
b. Percentage of participants with any potentially relevant side effect (refer to the 
adverse event case report form and the list of relevant side effects from the 
informed consent form, included as an Appendix). 
c. Rate of relevant side effects at the participant level. 
d. Mean change (from baseline) in continuous serum potassium (mEq/L). 
e. Mean change (from baseline) in continuous serum sodium (mEq/L). 
f. Mean change (from baseline) in continuous blood urea nitrogen (mg/dl). 
g. Mean change (from baseline) in continuous serum creatinine (mg/dl). 
 
3.4. Exploratory 
1. 24-hour ambulatory blood pressure measures 
a. 
Mean 24-hour SBP and DBP assessed through 24-hour ambulatory blood 
pressure monitoring. 
b. 
Mean daytime (0600 to 2200) SBP and DBP assessed through 24-hour 
ambulatory blood pressure. 
c. 
Mean nighttime (2200 to 0600) SBP and DBP assessed through 24-hour 
ambulatory blood pressure. 
d. 
Proportion of dippers* assessed through 24-hour ambulatory blood pressure.  
e. 
Mean daytime SBP and DBP load assessed through 24-hour ambulatory blood 
pressure. Load is defined as the percentage of abnormally elevated readings; 
daytime SBP / DBP elevated readings would be 130 / 80 mmHg or above.  
f. 
Mean nighttime SBP and DBP load assessed through 24-hour ambulatory blood 
pressure. Abnormally elevated readings for nighttime SBP / DBP would be 120 / 
70 mmHg or above. 
g. 
Percentage of participants with morning surge, calculated as the difference 
between the mean SBP during the morning hours and nighttime trough SBP. 
Trough SBP was defined as the mean of three SBP measurements: the lowest 
nighttime SBP and the measurements immediately preceding and following this 
measurement.11  
h. 
Coefficient of variation of SBP and DBP assessed through 24-hour ambulatory 
blood pressure as defined as the ratio of the 24-hour standard deviation of BP / 
mean 24-hour value.  
i. 
Day-night variability (SDdn), which uses the SD for daytime measurements and, 
separately for nighttime measurements, to calculate a weighted mean of these 
SDs.12 
j. 
Average real variability (ARV), which is calculated as the average absolute 
difference between consecutive readings over the 24-hour ABPM period.12 
k. 
Additional exploratory outcomes will be assessed as needed to inform individual 
participant data (IPD) meta-analysis with international QUARTET studies. 
*Dipping is defined as nighttime blood pressure falling more than 10% from the daytime values OR night / day blood 
pressure ratio less than 0.9 and greater than 0.8 with normal diurnal blood pressure pattern.11 
 

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4. STUDY INTERVENTION 
Patients who are eligible to participate in the trial will be randomized (1:1 allocation) to one of 
two study arms, and they will take daily:  
1. Low Dose Quadruple Therapy (LDQT) comprising candesartan 2 mg, amlodipine 1.25 
mg, indapamide 0.625 mg, and bisoprolol 2.5 mg 
OR 
2. Candesartan 8 mg  
The LDQT includes quarter standard doses of four blood pressure lowering medications, which 
are currently approved by the US Food and Drug Administrations for the treatment of 
hypertension. The active comparator follows current clinical practice guidelines for the majority 
of Americans, initiating treatment with an angiotensin II receptor blockers (ARB), which has the 
best side effect profile of any blood pressure lowering therapy. In both arms, if blood pressure is 
not controlled (SBP > 130 mmHg or DBP > 80 mmHg) at the six-week follow-up assessment, 
then study staff will provide participants with an open label pill of amlodipine 5 mg to supplement 
their study drug, which may be relevant to participants from some race/ethnic groups, including 
African-Americans. The combination of a calcium channel blocker with an ACE-inhibitor has 
been demonstrated to be more effective in reducing cardiovascular events than the combination 
of a thiazide-like diuretic with an ACE-inhibitor based on the ACCOMPLISH trial.13  
All study drugs, including LDQT, active comparator, and amlodipine add-on will be stored, 
controlled, and administered centrally. Control of drugs is described in full in the detailed Manual 
of Procedures. Drug product used in this study is subject to regulatory review and approval 
through an investigator-initiated investigational new drug (IND) process. Prior to use in human 
subjects, IND approval will be required.  
 
5. PROCEDURES INVOLVED 
QUARTET USA is a phase II, two-arm, randomized (1:1 allocation), double-blind clinical trial. 
Study participation involves the following study visits: (1) a two-day screening and baseline visit 
(including 24-hour ABPM and randomization if eligible), (2) six-week follow-up visit, and (3) 12-
week follow-up visit. We do not plan for any long-term follow-up data at this time. After 
participants complete all procedures in their 12-week visit and return their ABPM, they will exit 
the study, and we plan to stop data collection for them at that time. 
To monitor safety, we will document all adverse events in case report forms (CRFs) with 
expedited reporting for adverse events meeting criteria as defined by regulatory authorities 
(e.g., MedWatch form for SAEs that are probably or definitely related to the study drug and 
unexpected). We plan to perform centralized monitoring of all essential study data with targeted 
on-site visits as appropriate (refer to the DSMP and Adverse Event Reporting Plan for details). 
An external DSMB will also review all essential outcome and safety data every six months at 
minimum.   
The following study visit matrix explains the research procedures and assessments / data 
collected at each visit. Full description of procedures and assessments is included within the 
Manual of Procedures. 

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REDCap Event 
 
 
 
Study Timeline 
Screening and  
Randomization 
6-Week Follow-up 
Visit 
12-Week Follow-up 
Visit 
Visit Window from Previous Visit 
-12 weeks 
+/- 7 days 
+/- 7 days 
Location 
Clinic with 
telehealth 
screening and 
eConsent option 
Clinic 
Clinic 
Study Activities 
  
  
 
Informed consent 
X1 
 
 
Demographics2 
X1 
 
 
Automated office (clinic) blood 
pressure measured in the 
previous 12 weeks 
X1 
 
 
Blood pressure and heart rate 
measurements, by research 
team 
X 
X 
X 
ECG 
X3 
 
 
Anthropometrics and Medical 
history 
X1 
 
 
Concomitant medications 
X1 
X 
X 
Lifestyle questions 
X1 
 
 
PROMIS global health 
X1 
 
X 
Laboratory assessments4 
X3 
X 
X 
24-hour ABPM 
X 
 
X 
Inclusion and exclusion criteria 
X1 
 
 
Randomization 
X 
 
 
Study Drug dispense 
X 
X 
 
Study Drug return 
 
X 
X 
Medication adherence 
 
X 
X 
Participant status 
 
X 
X 
Health service utilization 
 
X 
X 
AEs and SAEs 
X 
X 
X 
1This form may be completed electronically via a telehealth visit up to 90 days before the date of randomization (12 
weeks in the case of previous automated office blood pressure measurement).  
2Such as date of birth, sex, and ethnicity. 
3If these tests completed within 3 months of the screening visit, and the results are available, then these tests will not 
be required at this visit.  
 
4Urine test and blood tests. Blood tests include sodium, potassium, chloride, bicarbonate, urea, serum creatinine, 
estimated glomerular filtration rate, AST, ALT, glucose, low density lipoprotein cholesterol, high density lipoprotein 

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cholesterol, total cholesterol, and triglycerides. Urinary analysis include hCG (for women only) and urinary albumin 
and creatinine for both men and women. For women, urine test is required to rule out pregnancy. 
Laboratory assessments, concomitant medications, and medical history will be obtained from 
the electronic health record (EHR), which will be considered source for these assessments.  
If a telehealth visit is conducted prior to randomization, then all information collected during 
these visits will be documented electronically, including the consent as outlined in the Consent 
Process section of the protocol. During the in-person screening and randomization visits, the 
electronic information will be verified and documented on paper CRFs. Any updates to 
previously reported information will be made at that point in time both electronically and if 
necessary, on paper versions of CRFs in accordance with Good Clinical Practice guidelines. 
Other study-related data indicated in the visit schedule above will be collected via paper CRFs, 
which will serve as source documents. The data from the paper CRFs and EHR will be entered 
electronically into REDCap, housed at Northwestern University. See the appendix for current 
CRFs. We plan to use a “first / second pass” workflow, whereby one study team member will 
enter study data into the eCRFs and leave the data as “unverified”. Then, a second study team 
member will review the data entered for accuracy and consistency in comparison to the EHR 
and paper CRFs. If there are any queries, then he / she will use the Data Resolution Workflow 
module in REDCap to resolve these issues. If there are no queries or data issues noted, then 
the second pass study team member will mark the form(s) as “complete”. All study data must be 
entered into the electronic database within two business days after collection on paper CRFs. 
AEs may be deemed an exception to this rule as they have separate reporting requirements as 
outlined in the AE Reporting Plan and Data and Safety Monitoring Plan.  
 
6. DATA AND SPECIMEN BANKING 
Data will be collected on paper CRFs and entered into a REDCap database housed at 
Northwestern University within two business days of collection. The exception is the capture of 
AEs, which is specified in the AE Reporting Plan. Only study staff with Northwestern NetIDs will 
have access to the electronic database. We will restrict export rights to the study statistician 
only. All exports will be housed in secure Northwestern fsmresfiles folder directories with 
restricted access. These files are routinely backed up through Northwestern’s Information 
Technology services. Refer to the DSMP and DMP for details on data and safety monitoring and 
quality checks. Blood and urine samples collected for this study will only be used for this study 
and will be destroyed after testing. 
The results of this trial are not intended to support a New Drug Application (NDA) to bring the 
LDQT to market in the US. The study team will retain all study records required by applicable 
regulatory bodies in a secure and safe facility for a minimum period of seven years. Access to 
study records will be limited to study team members, unless through written application to and 
approval by the study Steering Committee. 
 
 

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7. SHARING RESULTS WITH PARTICIPANTS 
When the study is over, research findings will be available at www.ClinicalTrials.gov (Identifier: 
NCT03640312), as required by US law. After all participants have completed the research 
study, each participant will receive a letter indicating which study drug he/she received when at 
randomization. The study staff will host an open forum at the Access Center for Discovery and 
Learning to share the study results. The study staff will be available to participants if they have 
questions regarding the results of the study. The research findings will also be published in the 
form of research articles or presented at scientific meetings. The sponsor, the National Heart, 
Lung, and Blood Institute of the NIH, requires that these research papers be made freely 
available to the public through PubMed Central (https://www.ncbi.nlm.nih.gov/pmc/) within 12 
months of publication with data available thereafter in accordance with NHLBI policy through 
BioLINCC. 
 
8. STUDY TIMELINES 
An individual consenting participant will spend a maximum of 12 weeks (three months) 
participating in the QUARTET USA study. Refer to the study schedule above for details. We 
anticipate enrollment taking 30 months, assuming an average of 15 participants per month after 
an initial “ramp up” period. Thus, primary analyses will begin February 2022 with an estimated 
completion date of November 2022.  
 
9. INCLUSION AND EXCLUSION CRITERIA 
9.1. Inclusion Criteria:  
• 
Adults (≥18 years). 
• 
Spanish or English speaker. 
• 
Previous documentation within the past 24 months of hypertension or high blood 
pressure (SBP 130-179 mmHg or DBP 80-109 mmHg) from general practitioner, 
pharmacist or health care professional (e.g., medical assistant, physician or nurse). 
 
And either: 
 
1) Untreated (automated) clinic SBP 140-179 or DBP 90-109 mmHg in the last 12 
weeks.  
 
Or  
 
2) Monotherapy with clinic SBP 130-159 or DBP 85-99 mmHg in the last 12 weeks. 
 
A SBP or DBP level higher than these thresholds would lead to ineligibility. However, if 
an individual were eligible based on an in-range SBP or DBP level (i.e., isolated systolic 

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hypertension or isolated diastolic hypertension), then a lower corresponding DBP or SBP 
would not lead to exclusion. 
And 1 of the following: 
• 
Treatment naïve 
• 
Currently not on treatment (not take in last 4 weeks) 
• 
Currently taking 1 BP lowering drug (ACE, ARB, CCB, thiazide- or thiazide-like diuretic, 
BB, MRA, alpha blocker) at any dose 
 
The blood pressure inclusion criteria align more closely with the QUARTET trial. The table 
shows the range of automated office (clinic) blood pressures for inclusion, as well as a 
comparison with the QUARTET study in Australia. Safety data from QUARTET (Australia) were 
published in August 2021.10 Among 591 participants followed for 12 weeks, there were 7 (3%) 
SAEs in the intervention group (one each of positional vertigo, shortness of breath, non-cardiac 
chest pain, tonic clonic seizure, fracture of ankle, cholecystitis, and migraine) and 3 (1%) SAEs 
in the control group (one each of non-cardiac chest pain, pneumonia, and myocardial infarction). 
There were 12 (4.0%) treatment withdrawals for any event in the intervention group, versus 
seven (2.4%) in the control group. 
 
 
A SBP or DBP level higher than these thresholds would lead to ineligibility. However, if 
an individual were eligible based on an in-range SBP or DBP level (i.e., isolated systolic 
hypertension or isolated diastolic hypertension), then a lower DBP or SBP would not 
lead to exclusion. 
 
If either or both mean research grade blood pressures were lower than the listed SBP 
and DBP thresholds, then the participant would not be eligible. 
 
 
 
SBP lower 
limit, mmHg 
SBP upper 
limit, mmHg 
DBP lower 
limit, mmHg 
DBP upper 
limit, mmHg 
Automated office (clinic) 
measurement within the last 12 
weeks, untreated 
140 
179 
90 
109 
Automated office (clinic) 
measurement within the last 12 
weeks, on monotherapy 
130 
159 
85 
99 
Research grade blood pressure 
measurement in QUARTET 
Australia 
No limit 
No limit 
No limit 
No limit 
Research grade blood pressure 
measurement (baseline mean) 
115 
None 
60 
None 

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9.2. Exclusion criteria:  
• 
Known contraindication to candesartan, amlodipine, indapamide or bisoprolol.  
• 
Previous diagnosis of coronary artery disease, stroke, or heart failure.  
• 
Presence of significant proteinuria (based on 3+ proteinuria via spot urinalysis or >300 
mg/dL of proteinuria based on random urinary albumin-to-creatinine ratio testing of 300 
mg/g) 
• 
Evidence of secondary cause of hypertension e.g., renal artery stenosis; significant renal 
impairment (eGFR <50 ml/min/1.73 m2), raised serum potassium (above lab normal limit 
of 5.5 mEq/L).  
• 
Women who are pregnant, breast feeding or of childbearing potential and are not using 
and do not plan to continue using medically acceptable form of contraception throughout 
the study (pharmacological or barrier methods).  
• 
Concomitant illness, physical impairment or mental condition which in the opinion of the 
study team / primary care physician could interfere with the conduct of the study 
including outcome assessments.  
• 
Participation in a concurrent interventional medical investigation or pharmacologic 
clinical trial. Patients in observational, natural history or epidemiological studies not 
involving an intervention are eligible.  
• 
Participant’s responsible primary care or other responsible physician believes it is not 
appropriate for participant to switch current monotherapy.  
• 
Inability or unwillingness to provide written informed consent. 
• 
Unable to complete study procedures.  
This study will not include any of the following special populations: a) adults unable to consent; 
b) individuals who are not yet adults (minors): i.e. infants, children, or teenagers; c) pregnant 
women; or d) prisoners or other detained individuals.  
 
We will identify a list of potentially eligible participants at the participating site(s) through the 
Epic-based health information technology system at Access Community Health Network. After 
obtaining a list of potential participants, the study staff will review these potential participants’ 
charts in the EHR, ensure permission from the patients’ treating physicians to contact for 
potential participation in the QUARTET USA study, and call or electronically message these 
potential participants to determine interest in an initial telephone screen. Electronic messages 
will be sent through MyChart. If patients express interest, then the study coordinator will 
schedule a two-day screening visit. During the screening visit, the coordinator will obtain 
informed consent and conduct baseline assessments with the study nurse to determine 
eligibility status. Potentially eligible participants will be fitted for an ABPM and asked to wear it 
for 24 hours and return to clinic. The study coordinator and nurse will conduct a final 
assessment on eligibility based on the 24-hour ABPM and any other outstanding assessments / 
results upon the participant’s return to clinic. Eligible participants will then be randomized via the 
randomization module in REDCap. The randomization module will return a study drug kit 
number. This will preserve the blinding of treatment allocation, since only the study statistician 
(or representative as a backup) will have access to the master list of drug kit numbers and 
corresponding treatment codes.  

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10. PARTICIPANT POPULATION(S) 
Accrual 
Number: 
Category/Group: 
(Adults/Children 
Special/Vulnerable 
Populations) 
Consented: 
Maximum Number to be 
Consented or 
Reviewed/Collected/Screened 
Enrolled: 
Number to Complete 
the Study or Needed 
to Address the 
Research Question 
Local 
Adults 
No Limit 
87 
Study-wide 
Adults 
No Limit 
87 
Total: 
Adults 
No Limit 
87 
 
11. RECRUITMENT METHODS 
Participants will be recruited from two of the community clinics within Access Community Health 
Network using its Epic-based health information technology system. This system allows for 
rapid electronic identification of eligible participants based on routinely collected clinical data as 
well as direct communication with their clinicians to seek their permission to contact potential 
participants. This methodology has been used in numerous studies between Northwestern 
investigators and ACCESS for successful recruitment. Participants may be contacted for 
screening either by phone or through electronic messaging, through MyChart. After initial 
contact by phone or electronic messaging, participants may also be contacted via text for 
appointment scheduling and reminders and retention.  
In the event of lagging recruitment or lack of diversity in study population to reach our targets, 
we plan to open up recruitment and enrollment efforts to additional Access Community Health 
Network site(s). If this occurs, then we will submit a protocol amendment and seek IRB approval 
prior to initiating study procedures at any additional sites.  
 
12. COMPENSATION FOR PARTICIPATION IN RESEARCH ACTIVITIES 
Study participants will be paid according to the following schedule via cash ($30 per study visit 
and reimbursement for transportation costs with CTA or PACE cards ($5 per round trip). The 
maximal amount to be paid for participating in this study is $115.  
 
Screening and 
Randomization 
6-Week 
Follow-up Visit 
12-week Follow-up 
Visit 
Payment Schedule 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Incentive (cash) 
$15 if 
ineligible to 
continue 
$30 
$30 
- 
$30 

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PACE, CTA, Lyft or 
equivalent 
$5 
$5 
$5 
$5 
$5 
Automated home blood 
pressure monitor 
 
X 
 
 
 
 
Some participants may be ineligible after completing components of the screening and 
randomization visits. If the participant has attended a single visit and has been determined 
ineligible, they will be compensated $15. If the participant has attended two visits and has been 
determined ineligible or eligible, they will be compensated $30.   
 
13. WITHDRAWAL OF PARTICIPANTS 
If a participant is withdrawn or decides to withdraw from the study, then attempts will be made to 
conduct a close-out visit, which will include the assessments planned for the 12-week visit. Data 
that have been already collected will not be removed from the study database unless explicitly 
requested by the participant.  
If the study physician / medical monitor / DSMB deems it unsafe for any participant to continue 
study drug or any study procedures, then he / she may withdraw the study participant without 
his / her consent. If a study participant experiences an AE requiring discontinuation of study 
drug, then we will collect any remaining study drug and refrain from any additional dispensation 
for that participant. We will continue to follow the participant and collect all required follow-up 
data per the study visit schedule. If a participant is incarcerated, becomes terminally ill, or 
experiences any other circumstance that would make continued involvement in the study 
unfeasible or unethical, then the study team may withdraw the participant without his / her 
consent. In all cases, any data already collected will not be removed from the study database 
and may still be used in analyses unless explicitly requested by the participant.  
 
14. RISKS TO PARTICIPANTS 
• 
The risks of taking a blood sample include pain, a bruise at the point where the blood is 
taken, redness and swelling of the vein, infection, and a rare risk of fainting.  
• 
The ECG procedure may cause some redness or itching on the skin where the leads are 
placed. 
• 
If participants are randomized to the control arm, then they will be taking candesartan, 
an FDA-approved drug for the treatment of hypertension (high blood pressure).  
• 
If participants are randomized to the active intervention arm, then they will be taking the 
four-drug combination pill, which includes ultra-low doses of candesartan, amlodipine, 
indapamide, and bisoprolol. These drugs are each approved by the FDA for treatment of 
hypertension, but a combination pill of these medications at these lower doses has not 
been approved to date. The known side effects of each of these medicines are shown 

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below. These side effects typically go away after stopping the medication. If any of these 
side effects occur while a participant is in the trial, then they will be reported as AEs.   
 
Very common: 
More than 1 out of 10 people have reported this side effect 
Common:    
From 1 to 10 out of 100 people reported this side effect 
Uncommon: 
From 1 to 10 out of 1,000 people have reported this side effect 
Rare: 
 
From 1 to 10 out of 10,000 people have reported this side effect 
Very rare:  
Less than 1 in 10,000 people have reported this side effect 
The frequency of side effects in based on standard doses, and an important hypothesis of 
this study is that quarter doses, even in combination, will be better tolerated than a standard 
dose. 
 
Reported Side Effects 
Amlodipine 
Bisoprolol 
Candesartan 
Indapamide 
Allergic reactions like skin rash, itching 
or hives, or swelling of the face, lips, or 
tongue 
Uncommon 
Rare 
Rare 
Common 
Anxiety 
 
Uncommon 
 
Uncommon 
Blurred vision or changes in vision or 
hearing 
Uncommon 
 
 
Common 
Breathing problems 
Uncommon 
Uncommon 
Uncommon 
 
Change in sex drive or performance 
 
Uncommon 
Uncommon 
 
Chest pain 
Rare 
Common 
Common 
 
Cold, tingling or numb hands or feet 
 
Common 
 
 
Confusion 
 
Uncommon 
 
 
Cough 
 
 
Uncommon 
 
Depression 
 
Uncommon 
 
 
Diarrhea 
 
Common 
 
Common 
Dry mouth 
Uncommon 
 
 
Rare 
Dry or burning eyes 
 
Uncommon 
 
 
Facial flushing 
Uncommon 
 
 
 

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Feeling faint or lightheaded or falling 
 
 
Very common 
 
Headache 
 
Common 
Common 
Common 
Infection or flu-like symptoms 
 
 
 
Common 
Irregular or fast heartbeat 
Uncommon 
 
Uncommon 
Common 
Irregular or slow heartbeat 
 
Very common 
 
Common 
Loss of appetite 
 
 
 
Common 
Muscle aches and pains 
 
Common 
 
Common 
Muscle cramps or spasms 
 
 
 
Common 
Nausea, vomiting 
Uncommon 
Common 
Common 
Uncommon 
Passing less urine 
 
 
Common 
 
Redness, blistering, peeling or 
loosening of the skin, including inside 
the mouth 
 
 
 
Very rare 
Stomach gas, pain 
Common 
 
Common 
 
Sweating 
 
Uncommon 
 
 
Swelling of hands or feet 
 
 
Uncommon 
 
Swelling of legs or ankles 
Very 
common 
Uncommon 
 
 
Tremors 
 
Uncommon 
 
 
Trouble sleeping 
Uncommon 
 
 
 
Unusually weak or tired 
Uncommon 
 
 
Common 
 
• 
In addition to these risks, this research may harm participants in ways that are unknown. 
These may be a minor inconvenience or may be so severe as to cause death but this is 
not expected.   
• 
This study involves the use of participants’ identifiable, personal health information and 
there is a chance that a loss of confidentiality could occur. The researchers have 
procedures in place to lessen the possibility of this happening.  
• 
The study drug may also hurt a pregnancy or fetus in ways that are unknown. These 
may be a minor inconvenience or may be so severe as to cause death. Participants 
currently pregnant or nursing will be excluded from this study, and eligibility is contingent 
on participants’ willingness to use acceptable forms for birth control. If participants 
become pregnant during the course of the study, then they are asked to notify the study 
team, and the study team will halt study drug administration. The study team will 

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continue to follow these participants and collect any AE and study-related data through 
the final study time point.  
 
15. POTENTIAL BENEFITS TO PARTICIPANTS 
During this research study, participants will receive blood pressure lowering medication, which 
may help control their blood pressure during this period.  
 
16. DATA MANAGEMENT AND CONFIDENTIALITY 
Paper CRFs will be housed at the study site in a locked, secure location. Only authorized study 
staff, monitors or auditors will have access to these files. Electronic data will be stored in the 
eCRFs maintained using the Northwestern University REDCap platform. Thus, only those with 
an appropriate Northwestern NetID and password will have ability to enter and view study data. 
Export rights will be restricted to the study statistician only, and data will only be exported when 
necessary for reporting and quality control purposes to a restricted ‘fsmresfiles’ location at 
Northwestern. The randomization list and any blinded material will also only be restricted to the 
study statistician, with files located on fsmresfiles with restricted access.  
To ensure data quality, we will build in field validation(s) and branching logic within the forms, 
use a first / second pass data entry workflow, and we will use the field comment logs and data 
resolution workflow module within REDCap. Before obtaining data entry rights in production, 
study team members must complete a training and pilot test entry of hypothetical data. We will 
document these training sessions and successful completion of any study data entry 
practicums. 
Further, we will perform centralized monitoring through Data and Status Quality Reports 
(DSQRs) and REDCap reporting features. The DSQRs will use the REDCap application 
programming interface (API) functionality to export the study data, and then restructure and 
summarize the data using statistical software such as R or SAS. The output for these DSQRs 
will be housed on Northwestern University’s secure servers with restricted access to study team 
members only. The reports will be reviewed and discussed weekly, on average, but once the 
systems are in place and code generated, the reports may be updated in real-time.  
The contents of these reports may continually evolve throughout the course of the study, but 
they will focus on the following essential study data: 
• 
Baseline information – screening and consent, enrollment, demographics 
• 
Adherence to intervention (pill counts) and protocol adherence 
• 
Primary and secondary response variables 
• 
AEs / SAEs 
• 
Concomitant medications 
• 
Other pre-specified response variables and/or covariates (laboratory data, exploratory 
outcomes) 

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For the purposes of these reports, we will only present data in aggregate form (i.e., we will not 
summarize results by study arm) overall. In addition to these general data summarizations, we 
plan to employ statistical methods for monitoring clinical trial data.14 The general strategies 
include: 
• 
Exploration of:  
o Descriptive statistic summaries overall and by site for essential study data as 
indicated above. 
o Frequency of outlying values overall and by site. 
o Process measures overall and by site: 
§ 
Screen failure rate 
§ 
Outlier and inlier rates 
§ 
Correlation coefficients of key covariates 
§ 
Deviations and AEs by site 
§ 
Timeliness of data entry 
§ 
Proportion of dropouts / losses to follow-up 
• 
Evaluating important response and safety data univariately and also longitudinal 
trajectories over time (within the same person). 
• 
Multivariate techniques involving principal components (PC1 vs. PC2) and examining 
multivariate outliers. For example, we may examine mean for individual center vs. that of 
all other centers. Plot PCs for p-values for all variables and identify outliers (those 
outside of the central cloud). 
• 
Tests on randomness – Benford’s law on the distribution of digits. 
 
16.1. Sample Size  
A target of 87 participants will be randomized (1:1 allocation). The analytic sample size of 77 is 
anticipated based on 87 participants at randomization and a conservatively estimated 12% 
dropout rate by the 12-week follow-up time point based on 8% dropout rate observed through 
September 2021. This sample size is conservatively based on an independent two-sample t-
test. The analysis methods, linear mixed models including a fixed baseline value term, will 
increase precision on intervention effect when controlling for relevant baseline covariates, 
thereby providing additional power of detecting intervention effect.   
The initial, conservative sample size and power calculations based on an independent two-
sample t-test suggested 80% power to detect a 5 mmHg difference in SBP between the 
intervention and comparator arms assuming a two-sided 5% level of significance and a 15 
mmHg standard deviation in outcome. At the request of the DSMB, we conducted an interim 
conditional power analysis, taking into consideration information from both the QUARTET USA 
trial data as of August 2021 and further the QUARTET (Australia) results.10 These interim 
analyses, incorporating information to date, suggested that a recruited sample size of at least 
77, and a 12% dropout rate, would provide over 90% conditional power based on a sample of 
87 randomized participants.  

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Previously, the protocol required the 24-hour ambulatory blood pressure assessments, and we 
thus conducted initial power calculations based on several a priori assumptions for this endpoint 
as follows: Since expected mean 24-hour ambulatory blood pressure may be more precise than 
office blood pressure (with a standard deviation of 12 mmHg vs. 15 mmHg for office blood 
pressure), over 95% power was anticipated with the original sample size (N=364) to detect a 5 
mmHg difference across arms in this important secondary outcome under the same 
assumptions as outlined for our primary outcome (office blood pressure). However, subsequent 
protocol modifications allowed for optional 24-hour ambulatory blood pressure, and this 
outcome has been modified to become an exploratory outcome.  
 
16.2. Statistical Analysis 
The primary study analysis time point for all relevant outcomes is 12 weeks post randomization. 
The original analysis plan called for ANCOVA, controlling for baseline value of each relevant 
outcome in addition to the following baseline covariates: sex, age at baseline, race/ethnicity, 
health literacy level (indicator of limited literacy as defined by the Newest Vital Sign instrument), 
and an indicator of monotherapy at baseline (vs. untreated; this variable will serve as a 
stratification factor for randomization).  These variables are deemed clinically relevant and 
important covariates; thus, all analyses will plan for adjustment for these covariates of interest 
(regardless of statistical significance in the current dataset) in predicting outcome in the present 
study. However, to better align with the analytic strategies of the QUARTET Australia study, and 
to make most efficient use of all follow-up data (both six-week and 12-week data), primary 
analyses will involve a linear mixed model with fixed study arm and baseline outcome value 
effects and a random participant effect to account for within-participant correlation. We plan to 
conduct both unadjusted (for potential covariates mentioned above) and adjusted analyses. The 
updated details of these analyses are reserved for the statistical analysis plan. The basic 
analytic model will be as follows for each outcome (Y) for participant i (i=1…N) at visit j (j=1,2; 
corresponding to Week 6 and Week 12):  
 
𝑌!" = 𝛽# + 𝛽$𝑰(𝐿𝐷𝑄𝑇) + 𝐵%(𝑌#!) + 𝐵&𝑣𝑖𝑠𝑖𝑡+ 𝐵'(𝑣𝑖𝑠𝑖𝑡 𝑥 𝑠𝑡𝑢𝑑𝑦 𝑎𝑟𝑚) + 𝑏! + 𝑒!" 
 
Under the assumption that error terms 𝑒!"~𝑁(0, 𝜎%) is the random error term, 𝑏!~𝑁(0, 𝜎(
%) is the 
participant-level random effect. If visit-by-study arm (𝐵') is insignificant at the 5% level, we will 
remove that term from the model, and subsequently, we will further examine for an overall main 
effect for visit (𝐵&). If insignificant, we will also remove that effect from the model and evaluate 
intervention effect via the primary hypothesis test of interest: 
𝐻#: 𝛽$ = 0 𝑣𝑠. 𝐻$: 𝛽$ ≠0 
for each outcome. However, if the visit-by-study arm interaction term or the visit term alone is 
significant, we will plan to evaluate the 12-week contrast via model-estimated least squared 
means as our primary analyses. All between-arm differences at both six- and 12-week time 
points will be reported as model-based estimates, corresponding 95% confidence limits, and p-
value of the corresponding hypothesis test.  
 

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Secondary analyses will utilize data from all time points via (generalized) linear mixed modeling 
(GLMM) methods with the following specifications: identity, logit, or log link for continuous, 
binary, or count outcomes, respectively; fixed arm, visit, visit-by-arm interaction, and 
aforementioned covariates; and random participant effect. For secondary analyses, the model 
adjusted Wald type III tests for fixed effects will first evaluate significance of a visit-by-arm 
interaction at the relaxed 10% level of significance. If insignificant at the 10% level, then this 
interaction term will be removed and the model Wald type III test for fixed arm effect will 
evaluate the overall intervention effect in this longitudinal model at the 10% level (since these 
analyses are exploratory and secondary).   
 
Safety outcomes will be treated similarly: adverse event rates and relevant outcomes previous 
listed will be tabulated overall and by arm. Chi-squared tests or exact methods will evaluate the 
differences across arms in event rates at the participant level.  For outcomes such as relevant 
side effects that may occur more than once in any participant, descriptive statistics or GLMMs 
as specified above will be examined, and continuous laboratory safety assessments will also be 
analyzed as specified above (GLMMs, as appropriate).       
 
Procedures for control and handling of specimens are described within the Laboratory 
Procedures document.  
 
17. PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF PARTICIPANTS 
The DSMP documents the provisions to monitor the data and ensure safety of all study 
participants. Briefly, (1) we have convened an independent DSMB consisting of five members 
with diverse backgrounds and fields of expertise, including an expert in research methodology 
and ABPM, a biostatistician, a clinician-scientist with expertise in hypertension combination 
treatment trials and prevention of heart and kidney disease, an ethicist, and a patient 
representative; (2) the DSMB will meet at minimum every six months to review safety and 
essential study data; (3) we will employ centralized monitoring approaches as mentioned above 
to monitor data quality and safety; (4) we will program an email alert to study staff in the event of 
an SAE; (5) we plan for targeted on-site monitoring by an external clinical research associate; 
(6) and we will adhere to regulatory requirements for expedited AE / SAE reporting.  
  
18. PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF PARTICIPANTS 
Information regarding patient privacy relevant to data and specimens is described within this 
protocol in section Data and Specimen Banking. All study related procedures and visits will 
occur at Access Community Health Network clinics which complies with federal regulations for 
patient privacy. All study-related visits will be completed in a designated enclosed study-room 
whereby only the study participant and study team (e.g. research coordinator and/or research 
nurse) will be present. The study room is in the back end of the health center far removed from 
clinical rooms, nurse stations, and reception/waiting room area whereby study participants may 
feel at ease to discuss matters as it relates to their participation in the research study. 

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19. COMPENSATION FOR RESEARCH-RELATED INJURY 
This study is investigator-initiated. If participants become ill or are injured as a result of this 
study (medications, devices or procedures), they are directed to seek medical treatment through 
their doctor or treatment center of choice and to promptly tell the study doctor about any illness 
or injury. The researchers and clinical staff will not pay for medical care required because of a 
bad outcome resulting from participation in this research study. This does not keep participants 
from seeking to be paid back for care required because of a bad outcome. 
 
20. ECONOMIC BURDEN TO PARTICIPANTS 
We do not anticipate that patients will experience economic burdens related to participation in 
this study. Evaluation of hypertension will be performed according to clinical practice guidelines. 
Twelve-week treatment will be provided at no cost to participants. Participants will be 
reimbursed for their time and travel costs for study related visits.  
 
21. CONSENT PROCESS 
Participation will require informed consent from all participants. The study coordinator will 
consent participants at Access Community Health Network clinics or through a telehealth visit. 
Consent will be taken by the study coordinator and the research nurse will be available to 
consult during the consent process. Ample time will be devoted to the consent process 
according to participant request. Participants will be allowed time to consider the trial and ask 
questions and will be reminded they are free to leave the trial at any time. Prior to 
randomization, we will confirm participant consent and understanding of the trial. At each study 
follow-up visit, the consent will be confirmed.  
• 
If conducted in person, both the participant and witness will sign and date two copies of 
the consent form if the participant agrees to the study procedures. A hard copy will be 
kept in the participant’s file, housed at the health center where the study is being 
conducted (in a locked file cabinet in a locked closet). The participant will be provided 
with the other copy to take home. 
• 
If conducted via a telehealth visit, the participant will have two options on how to 
complete consent form: 
o A. The participant will receive an electronic version of consent form (eConsent) 
as an automated survey sent from a 21 CFR, Part 11 compliant instance of 
REDCap. The participant will electronically sign and date the consent form, which 
will be stored in REDCap. The witness will electronically sign and date the 
consent form after the participant has completed the REDCap eConsent survey. 
A hard copy will be kept in the participant’s file, housed at the health center 
where the study is being conducted (in a locked file cabinet in a locked closet). 
The participant will be sent a link to the executed electronic consent form.  

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o B. The participant will receive a hard copy of the consent form sent via regular 
mail or will print out a copy that is emailed to them through the patient’s ACCESS 
MyChart account within Epic. The participant will provide a wet signature, will 
date the consent form, and will upload an image of the last page with their 
signature to their ACCESS MyChart account. A copy of the signed signature 
page of the consent will be saved in the patient’s electronic health record. The 
witness will be able to print the signed form and provide a wet signature and 
date. A hard copy will be kept in the participant’s file, housed at the health center 
where the study is being conducted (in a locked file cabinet in a locked closet).  
 
22. PROTECTED HEALTH INFORMATION (PHI AND HIPAA) 
This study involves collection and use of Protected Health Information. All participants will be 
identified by a unique study ID. Access to the full study database with identifying information 
(names, medical record numbers, dates, ages, email and telephone) will be restricted to 
authorized study personnel. Data collection will be secure, and these data will not be used for 
any other purpose than to contact the study participant during their participation in the trial and 
to disseminate results. Data shared from this study will be completely de-identified.  
The informed consent form for this study includes HIPAA authorization. 
 
23. NON-ENGLISH-SPEAKING PARTICIPANTS 
We anticipate enrolling Spanish speaking participants in this study. Prior enrollment of any 
primarily Spanish speaking participants, all participant-facing study documents will be translated 
and back-translated for quality assurance, reviewed and approved by the IRB. All study drug will 
include labelling in both English and Spanish. Informed consent will be completed in either 
English or Spanish, according to participant preference.  
 
24. QUALIFICATIONS TO CONDUCT RESEARCH AND RESOURCES AVAILABLE 
For 25 years, Access Community Health Network (ACCESS) has been on the frontlines of 
community-based health care. ACCESS is the largest provider of primary care for Medicaid 
beneficiaries in Illinois and provides more primary care annually than the Cook County Health 
System. ACCESS provides a continuum of care model that connects patients to health care 
resources both within and beyond the walls of its 36 federally-qualified health centers (FQHCs). 
ACCESS's mission is to partner with patients at all points of care, providing high quality, patient 
centered health services accessible to all in their own communities. ACCESS is Joint 
Commission Accredited, and 35 of its health centers are Level III National Committee for Quality 
Assurance Patient Centered Medical Home Certified.  
This study will enroll participants through the following centers: 
• 
Martin T. Russo Family Health Center, at 245 S Gary Ave., Bloomingdale IL, 60108 

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• 
Ashland Family Health Center, at 5159 S. Ashland Ave., Chicago IL, 60609 
ACCESS's patient demographics reflect the communities served: across all clinics, 40% are 
children age 17 years and under, 51% are Hispanic, 29% are African-American, 74% were at or 
below the 200% of the 2015 Federal Poverty Level ($23,540 annually), which is a common 
measure of economic stability. 
The Russo and Ashland clinics serve over 2000 patients per month. Additional centers will be 
contacted via email, text message, or phone call using a MyChart-based communication system 
(Epic campaigns). Additional sites can also brought on based on the patient enrollment. At 
minimum, hall-time research nurses and project coordinators will support QUARTET USA at 
each location for the duration of the trial. All study-related visits will occur with the research 
nurse and coordinator. Co-investigator Dr. Jairo Mejia serves as the Chief Medical Officer for 
ACCESS and is based at the Russo clinic as the site principal investigator. Dr. Daneen 
Woodard is based at the Ashland clinic as the site principal investigator. 
The QUARTET USA team holds routine meetings on a weekly basis with all operations staff. All 
members of the QUARTET USA team have previous experience in clinical trials and have 
current certification in Protection of Human Subjects and Good Clinical Practice.  
 
25. MULTI-SITE OR COLLABORATIVE RESEARCH: 
Northwestern investigators will collaborate with the research team at Washington University in 
St. Louis and Access Community Health Network. Study procedures will occur at the Access 
Community Health Network, where informed consent will be sought and study procedures will 
be conducted. The Northwestern IRB will serve as the IRB of record, and no activities will occur 
at Washington University in St. Louis until the SMART IRB LOA reliance agreement has been 
fully executed and appropriate local regulatory processes are followed and completed. The 
project is federally funded. The IRB approved the initial protocol before the Cooperative 
Research Requirement effective date. A single IRB is not required but is permissible. 
Northwestern University has served as the prime institution since the study start in 2018. As of 
January 2022, the prime institution will be Washington University in St. Louis based on the 
institutional change by the contact mPI, Dr. Mark Huffman. Enrollment will be completed in May 
2022. The Access Community Health Network has agreed for Northwestern to serve as the IRB 
of record in accordance with their local policies. 
 

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1. 
GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national 
age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–
2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 
2015;385:117–171.  
2. 
Muntner P, Carey RM, Gidding S, Jones DW, Taler SJ, Wright JT Jr, Whelton PK. 
Potential U.S. population impact of the 2017 ACC/AHA High Blood Pressure Guideline. J 
Am Coll Cardiol. 2018 Jan 16;71(2):109-118. 
3. 
Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison-Himmelfarb C, 
DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, 
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