Clinical trial NCT03640312
Conditions: Hypertension
Keywords: Hypertension Blood Pressure
Sponsor: Washington University School of Medicine
Start date: 2019-08-30; Completion date: 2024-07-31
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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 as per current guidelines 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 as per contemporary clinical practice guideline recommendations.

Detailed description:
This trial will investigate whether initiating treatment with ultra-low-dose quadruple-combination therapy (LDQT; including candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg) will lower automated office blood pressure and 24-hour ambulatory blood pressure at 12 weeks more effectively, and with no increase in side effects, compared to initiating standard dose monotherapy (candesartan 8 mg) in adults with raised blood pressure (SBP\>130 mmHg or DBP\>80 mmHg) and without cardiovascular disease. Our preliminary data from a short-term (4-week) crossover trial of 18 participants suggest that LDQT lowers office blood pressure by 22/13 mmHg on average compared with placebo with no difference in serious adverse events. Effects on 24-hour ambulatory blood pressure were similar.

The investigators will perform this phase II, single site, randomized controlled trial in a network of federally qualified health centers in Chicago because this population bears a disproportionate burden of blood pressure related diseases, and the investigators have previously successfully conducted clinical studies in this population.

While the investigators hypothesize this intervention will be easily implemented and efficacious for all patients and clinicians, the investigators will explore variation in treatment effect by potential moderating variables, including age, sex, race/ethnicity, and health literacy level. Beyond examining efficacy, the investigators also plan to assess feasibility of implementing this intervention in a clinical setting by simultaneously evaluating implementation outcomes of acceptability, preferences, and lessons of LDQT among patients and clinicians.

Arms: arm 1: Patients randomized to the intervention arm will take a once daily ultra-low-dose quadruple combination therapy (QUARTET LDQT). The LDQT is an overencapsulated combination pill comprising four types of blood pressure lowering medications each at ¼ standard doses. QUARTET includes candesartan 2mg, amlodipine besylate 1.25mg, indapamide 0.625mg, and bisoprolol 2.5mg. The individual components are currently approved and marketed within the United States. arm 2: Patients randomized to the comparison arm will take a once daily 8mg candesartan.
Interventions: intervention 1: QUARTET LDQT intervention 2: Candesartan
Intervention descriptions: intervention 1: Ultra-low-dose combination therapy comprising four different blood pressure lowering drugs at 1/4 dosages. Taken once daily for 12 weeks. intervention 2: Standard monotherapy of 8mg candesartan. Taken once daily for 12 weeks.

Protocol documents:
ICF_000.pdf: 
Informed Consent Form: July 21, 2020 
INFORMED CONSENT FORM (ICF) 
QUARTET USA:  
A double blind randomized controlled trial to assess the efficacy and safety of a 
quadruple ultra-low-dose treatment for hypertension  
NCT03640312 
Version: July 21, 2020 
IRB Number: STU00205834 


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Title of Research Study: A double blind randomized controlled trial to assess the efficacy 
and safety of a quadruple ultra-low-dose treatment for hypertension (QUARTET). 
Protocol Number: 00205834
Investigator: Mark Huffman, MD, MPH
Supported By: This research is supported by the National Heart, Lung, and Blood Institute.
Key Information: 
The first few pages of this document include a summary of this study to help you 
decide whether or not to participate. Detailed information is provided after the 
summary.
Why am I being asked to take part in this research study?
We are asking you to take part in this research study because you are a patient at Access 
Community Health Network (ACCESS) with a history of high blood pressure. We are also 
asking you to take part in this study because you are either not currently taking medicine for 
your high blood pressure or are taking one medicine but have not achieved blood pressure 
control.
What should I know about a research study?

Someone will explain this research study to you.

Whether or not you take part is up to you.

You can choose not to take part.

You can agree to take part and later change your mind.

Your decision will not be held against you.

You can ask all the questions you want before you decide.
Why is this research being done?
ACCESS has partnered with researchers from Northwestern University to better understand if 
combining four different types of medicines for high blood pressure into one pill can help lower 
high blood pressure with fewer side effects. The medicines being used in this study - 
amlopdipine, bisoprolol, candesartan, and indapamide - are all approved by the Food and Drug 
Administration (FDA) and commonly prescribed by medical providers to help treat high blood 
pressure. In this study, they will be combined into one pill (a “4-in-1 pill”) at ultra-low doses. In 
this study, the 4-in-1 pill will be compared to Candesartan, an FDA-approved drug that is 
commonly used to treat high blood pressure.
While the (FDA) has not approved the 4-in-1 pill for general use, the FDA has approved the use 
of the pill as an investigational new drug for purposes of this study. Results from a smaller study 
suggest that the 4-in-1 pill is safe and effective to use but further testing is needed.
We cannot guarantee any direct benefits to you, but you will be receiving medication that is a 
known therapy prescribed to patients with high blood pressure. If this study is successful, then 
we will develop a larger study to try to discover how well the 4-in-1 pill can help prevent heart 
attacks, stroke, and heart failure.
From this point on, the 4-in-1 pill will be referred to as the “study drug”. 
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How long will the research last and what will I need to do?
We expect that you will be in this research study for about 12 weeks (3 months).
You will be given the study drug or candesartan and asked to complete up to 5 study visits in 
order to perform tests and procedures.
More detailed information about the study procedures can be found under the section What 
happens if I say “Yes, I want to be in this research”?
Is there any way being in this study could be bad for me?

You may be taking the study drug, which has not been approved by the FDA for 
treatment of high blood pressure even though the medicines in the pill are approved.

There is a chance that your blood pressure may go up while you are in this study. If this 
does happen, you will be given an additional 5mg amlodipine. Amlodipine is FDA-
approved and commonly used to help control blood pressure.

In addition, blood pressure lowering medicines can cause side effects in some people. 
Some of the more common side effects include irregular or slow heartbeat, headache, 
swelling of legs or ankles and feeling faint or lightheaded or falling. 
More detailed information about the risks of these medicines can be found under “Detailed 
Risks: Is there any way being in this study could be bad for me?”
Will being in this study help me any way?

We cannot promise any benefits to you or others from your taking part in this study. 

However, possible benefits include additional knowledge about the effects and safety of 
the study drug for high blood pressure. 

While you take part in this research study, you will receive blood pressure-lowering 
medication, which may help control your blood pressure.
What happens if I do not want to be in this research?
Participation in research is completely voluntary. You decide whether or not to participate. If you 
choose to not participate, there will be no penalty to you or loss of benefit to which you are 
entitled. Instead of being in this research study, you may continue normal care through your 
healthcare provider. 
Detailed Information:
The rest of this document includes detailed information about this study (in addition to the 
information listed above).
Whom can I talk to?
If you have questions, concerns, or complaints, or think the research has hurt you, you can talk 
to the research team. You can call or email us.

Hiba Abbas, Study nurse: hiba.abbas@achn.net | (872) 772-0389

Fallon Flowers, Study nurse: fallon.flowers@achn.net | (872) 772-0423

Abigail Baldridge, Project director: abigail.baldridge@northwestern.edu | (312) 503-3911
If you have any questions regarding your study medication, please contact Abigail Baldridge.
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This research has been reviewed and approved by an Institutional Review Board (IRB). You 
may talk to them at (312) 503-9338 or irb@northwestern.edu if:

Your questions, concerns, or complaints are not being answered by the research team.

You cannot reach the research team.

You want to talk to someone besides the research team.

You have questions about your rights as a research participant.

You want to get information or provide input about this research.
How many people will be studied?
We expect about 364 people in the Chicago area to participate in this study. There are also 
ongoing studies in other countries that include about 1000 other people.
What happens if I say “Yes, I want to be in this research”?
If you decide you would like to participate in this study, you will be asked to come to one of the 
following locations for study visits: 

Martin T. Russo Family Health Center, at 245 S Gary Ave., Bloomingdale IL, 60108

Ashland Family Health Center, at 5159 S. Ashland Ave., Chicago IL, 60609
From this point on, the Martin T. Russo and Ashland Family Health Centers will be referred to 
as the “study site”.
The study team may contact you over the phone, by text messaging, or by electronic 
communication through MyChart, a web-based portal used to access your health information.
If you qualify to take part in the study, you will be randomized at Visit 2, into one of the following
groups:
•
Study drug: Candesartan (2 mg), amlodipine (1.25 mg), indapamide (0.625 mg), 
bisoprolol (2.5 mg); or
•
Candesartan (8 mg)
Which of these 2 treatments you receive is chosen at random, which means that you will be
put into one treatment group by chance. A computer will randomly select your treatment. This
allows the treatments to be compared more fairly. The chance you will receive the study drug or 
candesartan is 1 in 2 (50%). Neither you nor the study doctor will know which treatment you 
receive. But the study doctor can find out if necessary, for example, if there is a problem.
During the study, you will be instructed to take the study drug or candesartan by mouth, once a 
day. Do not crush or chew the study drug.
Below is a list of study procedures that will take place at each visit during your participation in 
the study:
Screening Visit (Visit 1): 
To help the study doctor determine if you are eligible to participate in this study, you will be 
asked to come to the study site or contacted via telehealth for a screening visit. This may be 
done today if you decide to participate. The Screening Visit will last approximately 3 hours with 
approximately 1 hour in the clinic setting. The following activities will be performed:

You will be asked to read and sign this consent form. 
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
A review of your health and medical history and your demographics (such as your 
gender, income, and other background information), and any medications (prescription, 
nonprescription, and over-the-counter herbal and dietary) you have taken and are 
currently taking will be done.

You will be asked about your alcohol and smoking use.

You will have your vital signs (heart rate and blood pressure) taken as well as your 
height and weight.

An additional visit to the study site will be needed if the initial screening process 
is completed via telehealth.
If you have not had certain tests recently (within the last 3 months), we will:

Ask you to provide us with blood samples to run a series of lab tests (i.e. lipid panel, 
glucose, sodium). 

We will use a needle to take about two teaspoons (approximately 10 mL) of 
blood from your arm and collect it in two vials.

Ask you to provide a urine sample. 

We will ask you to pee into a cup to give us around 4 teaspoons (approximately 
10 mL) of urine.

Do an electrocardiogram test (ECG). An ECG is a test that give a measure of the heart’s 
electrical activity. 
You will be given the option to be fitted with a 24-hour blood pressure monitor.

You will be asked to take the blood pressure monitor home and wear it for 24 hours. 

You will be asked to log what activities you did while wearing the blood pressure 
monitor. The study staff will provide you with information about how to complete your 
activities log.
Selected procedures in visit 1 may instead be completed during visit 2.
Study Visit 2: 
1 day after after Visit 1, you will be asked to return to the study site for Study Visit 2. This visit 
will last approximately 1 hour. The following activities will be performed:

If you chose to complete the 24-hour blood pressure monitors, you will bring it back  
along with the activities log.

The study team will review results from your electrocardiogram, laboratory tests, and 
blood pressure readings and monitor if it was completed – these results will help us 
determine full eligibility.

If you are eligible, then we will randomize what type of treatment you get – which is like 
choosing by chance, like flipping a coin. Neither you nor the study team will choose what 
treatment you get.

You will receive 6 weeks worth of the study drug or candesartan, depending on what 
group you get randomized into.

You will receive an Omron 3 Series BP7100 upper arm blood pressure monitor that is 
yours to keep after the study.
Please be aware: you will be receiving a known therapy for your high blood pressure regardless 
of which of the two study medicines you receive.
Study Visit 3 (Week 6):
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6 weeks after Visit 2, you will be asked to return to the study site or complete a telehealth 
appointment for Study Visit 3. This visit will last approximately 1 ½  hours. The following 
activities will be performed:

You will bring back the bottle of study drug or candesartan, with any unused study 
medication. The study team will ask you about any times you missed taking the study 
drug or candesartan.

You will be asked how you are feeling and what medications you are taking and have 
taken since your last visit. This can be completed during the telehealth appointment. 

You will have your vital signs (heart rate and blood pressure) taken. 
o
If you complete your visit through telehealth, you will be asked to check your 
blood pressure with the Omron 3 Series BP7100 monitor. The study staff will 
train and guide you through this process.
o
If your blood pressure is greater than 130/80 mmHg, then we will give you an 
additional pill of amlodipine 5 mg to take each day in addition to your study drug 
or candesartan.  

We will ask you to provide us with blood samples to run a series of lab tests (i.e. lipid 
panel, glucose, sodium). 
o
You will need to come to the study site to complete this.
o
For this, we will use a needle to take about two teaspoons of blood from your arm 
and collect it in two vials.

We will ask you to provide a urine sample. 
o
We will ask you to pee into a cup to give us around 4 teaspoons (approximately 
10 mL) of urine.

After we obtain your lab results, you will be asked to come to the study site to receive 6 
more weeks worth of the study drug or candesartan, depending on what group are are 
randomized to.
Study Visit 4 (Week 12):
6 weeks after after Visit 3, you will be asked to return to the study site or complete a telehealth 
appointment for Study Visit 4. This visit will last approximately 1 ½  hours. The following 
activities will be performed:

You will be asked how you are feeling and what medications you are taking and have 
taken since your last visit.This can be completed during the telehealth appointment.

You will have your vital signs (heart rate and blood pressure) taken. 
o
If you complete your visit through telehealth, you will be asked to check your 
blood pressure with the Omron 3 Series BP7100 monitor. The study staff will 
guide you through this process.

We will ask you to provide us with blood samples to run a series of lab tests (i.e. lipid 
panel, glucose, sodium). 
o
You will need to come to the study site to complete this.
o
For this, we will use a needle to take about two teaspoons of blood from your arm 
and collect it in two vials.

We will ask you to provide a urine sample. 
o
We will ask you to pee into a cup to give us around 4 teaspoons (approximately 
10 mL) of urine.
Regardless of whether you completed the 24-hour blood pressure monitor during the baseline 
visit, you will be asked if you are willing to be fitted with a monitor at this visit.
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
You will be asked to take the blood pressure monitor home and wear it for 24 hours. 

You will be asked to log what activities you did while wearing the blood pressure 
monitor. The study staff will provide you with information about how to complete your 
activities log.
If you are not going to be fitted for the 24-hour blood pressure monitor, then you will bring back 
the bottle of study drug or candesartan, with any unused study medication. The study team will 
ask you about any times you missed taking the study drug or candesartan.

You will be asked how you are feeling and what medications you are taking and have 
taken since your last visit.

You will answer a series of questions about the study drug or candesartan and your 
opinion(s) about it.
Study Visit 5 (Week 12):
1 day after after Visit 4, you will be asked to return to the study site for Study Visit 5. This visit 
will last approximately 1 hour. The following activities will be performed:

You will bring back the blood pressure monitor and the activities log for the 24-hour 
blood pressure monitor.

You will bring back the bottle of study drug or candesartan, with any unused study 
medication. The study team will ask you about any times you missed taking the study 
drug or candesartan.

You will be asked how you are feeling and what medications you are taking and have 
taken since your last visit.

You will answer a series of questions regarding about the study drug or candesartan and 
your opinion(s) about it.

Schedule a visit with your primary care provider to transition you out of the study for 
continued care.
Study Activities
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Sign consent form
X1
Demographic questions
X*
X*
Take your blood pressure and heart rate
X
X1
X1
Electrocardiogram (ECG)
X
Take your measurements (i.e. weight, 
height)
X
Ask you questions about your medical and 
medicine use history
X*
X*
Additional questions about your medicine 
use
X*
X*
X1
X1
Questions about your general health 
X*
X*
X1
Blood and urine tests
X
X
X
Fit 24-Hour Blood Pressure Monitor
X2
X2
Return 24-Hour Blood Pressure Monitor 
X
X3
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Check for full eligibility
X
X
Dispense study medication
X
X
Collect any unused study medication
X
X
X
Ask questions about medication 
adherence
X
X
Ask questions about your health service 
utilization 
X1
X1
X1
Capture if you have been experiencing any 
side effects
X1
X1
X1
X1
X1
 “X*” means that these activities may be completed either at Visit 1 or Visit 2 and via a telehealth 
visit.
 “X1” means that these activites may be completed through a telehealth visit.
 “X2” means that these activites are optional. 
What are my responsibilities if I take part in this research?
If you take part in this research, then we will ask you to attend all 5 study visits to the study site 
or through a telehealth visit. We will ask you to take your study drug or candesartan as 
prescribed and to tell the research team accurate information on how often and how much you 
took.
What happens if I say “Yes”, but I change my mind later?
You can leave the research at any time; it will not be held against you. If you decide to leave the 
research, please let the study team know so we can work with you and your provider to 
schedule a close-out visit, which will include the assessments planned for the final visit.  
Choosing not to be in this study or to stop being in this study will not result in any penalty to you 
or loss of benefit to which you are entitled. Specifically, your choice not to be in this study will 
not negatively affect your right to any present or future medical treatment.
If you stop participating in the research, data that has been already collected may not be 
removed from the study database. You will be asked whether the investigator can collect data 
from your routine medical care. If you agree, then these data will be handled the same as 
research data. 
Detailed Risks: Is there any way being in this study could be bad for me?
Study Drug Risks
The known side effects of each of these medicines are shown below. These side effects 
typically go away after stopping the medication. If any of these side effects occur while you are 
in the trial, then they will be reported as adverse events.  
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
Reported Side Effects
Amlodipine
Bisoprolol
Candesartan
Indapamide
Allergic reactions like skin rash, 
Uncommon
Rare
Rare
Common
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Reported Side Effects
Amlodipine
Bisoprolol
Candesartan
Indapamide
itching or hives, or swelling of the 
face, lips, or tongue
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
-
-
-
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
“ – “ means that there have been no reported side effects
Blood Draw Risks
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The risks of taking blood include pain, a bruise at the point where the blood is taken, redness 
and swelling of the vein and infection, feeling lightheaded, and a rare risk of fainting.
Questionnaire Risks
Some of the questions asked may be upsetting, or you may feel uncomfortable answering them. 
If you do not wish to answer a question, then you may skip it and go to the next question.
Controlling Blood Pressure Risks
Depending on what treatment group you received, there is a chance that your blood pressure 
may go up while you are in this study. If this does happen you will be given extra medication to 
help control your blood pressure.
Unknown Risks 
In addition to these risks, this research may hurt you 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.  
Personal Health Information
This study involves the use of your identifiable, personal information and there is a chance that 
a loss of confidentiality could occur. The researchers have procedures in place to decrease the 
chance of this happening. See the section below titled: “What happens to the information 
collected for the research?”. 
What do I need to know about reproductive health and/or sexual activity if I am in this 
study? 
The study drug or candesartan 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. 
You should not be or become pregnant, breastfeed, father a baby, or donate eggs/sperm while 
on this research study. 
If you are sexually active, then both men and women should use at least one effective type of 
birth control while participating in this research study. According to the World Health 
Organization and the United States Centers for Disease Control and Prevention, the most 
effective forms of birth control include complete abstinence, surgical sterilization (both male and 
female), intrauterine devices (IUDs), and the contraceptive implant. The next most effective 
forms of birth control include injectables, oral contraceptive pills, the contraceptive ring, or the 
contraceptive patch. Acceptable but least effective methods of birth control include male 
condoms (with or without spermicide) and female condoms.
If you or your partner become pregnant while participating in this research study or for 1 month 
after you complete the study, then it is important that you tell the study doctor or other research 
team member immediately. You may be required to stop participation in this study; however, 
other treatment options will be discussed with you at that time if necessary.
If you or your partner are / is considered to be postmenopausal, then you are not required to 
use contraception while participating in this research study. Postmenopausal women rarely 
become pregnant. If you or your partner become pregnant while participating in this research 
study or for 1 month after you complete the study, then it is important that you tell the study 
doctor or other research team member immediately. You may be required to stop participation 
in this study; however, other treatment options will be discussed with you at that time, if 
necessary.
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Will it cost me anything to participate in this research study?
Taking part in this research study will not lead to any costs to you. 
You and your insurance company will be charged for the health care services that you would 
ordinarily be responsible to pay. In some cases, insurance will not pay for services ordinarily 
covered because these services were performed in a research study. You should check with 
your insurance to see which services will be covered by your insurance and which you will be 
responsible to pay.
Will being in this study help me in any way?
We cannot promise any benefits to others from your taking part in this research. Possible 
benefits include additional knowledge about the effects and safety of the study drug for high 
blood pressure. While you take part in this research study, you will receive blood pressure-
lowering medication, which may help control your blood pressure.
What happens to the information collected for the research?
Efforts will be made to limit the use and disclosure of your personal information, including 
research study and medical records, to people who have a need to review this information. We 
cannot promise complete secrecy. Organizations that may inspect and copy your information 
include the IRB and other representatives of this institution. 
Blood and urine samples collected for this study will only be used for this study and will be 
destroyed after testing. 
The study sponsor (National Heart, Lung, and Blood Institute), monitors, auditors, the IRB, the 
Northwestern University Office for Research Integrity, the US Office of Research Integrity (ORI), 
the US Office for the Protection of Human Research Protections (OHRP), and the US Food and 
Drug Administration (FDA) may be granted direct access to your medical records to conduct 
and oversee the research. By signing this document, you are allowing them to get that access. 
We may publish the results of this research. However, we will keep your name and other 
identifying information confidential.
A description of this clinical trial is available at www.ClinicalTrials.gov (Identifier: 
NCT03640312), as required by U.S. Law. This website will not include information that can 
identify you. After the trial is completed, then the website will include a summary of the results. 
You can search this website at any time.
Data Sharing 
De-identified data from this study may be shared with the research community at large to 
advance science and health. We will remove or change the code of any personal information 
that could identify you before files are shared with other researchers to ensure that, by current 
scientific standards and known methods, no one will be able to identify you from the information 
we share. Despite these measures, we cannot completely guarantee anonymity of your 
personal data.
Can I be removed from the research without my OK?
The person in charge of the research study or the sponsor can remove you from the research 
study without your approval. Possible reasons for removal include occurrence of an adverse 
event that your treating physician feels may be related to the study treatment. If you are 
removed, a member from the study team will reach out to you to notify you. S/he will also help 
IRB #: STU00205834-MOD0014 Approved by NU IRB for use on or after 8/13/2020 through 6/29/2021.


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you schedule an appointment with your primary care provider so they can continue with your 
medical care and treatment of high blood pressure.
What else do I need to know?
If you become ill or are injured as a result of this study (medications, devices or procedures), 
then you should seek medical treatment through your doctor or treatment center of choice. You 
should promptly tell the study staff about any illness or injury so we may be able to 
communicate your participation in the study with your primary care provider.  
The researchers and clinical staff will not pay for medical care required because of a bad 
outcome resulting from your participation in this research study. This does not keep you from 
seeking to be paid back for care required because of a bad outcome.
Compensation
If you agree to take part in this research study, we will compensate you for your time and effort 
based on the following schedule. If you require transportation assistance, please speak with a 
study team member as we may be able to provide you with transportation assistance in the form 
of PACE, CTA, or Lyft service (up to $5 per ride). The maximum amount to be paid by 
participating in this study is $115. 
Compensation
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Incentive (cash)
$15 if ineligble 
to continue
$30
$30
-
$30
PACE, CTA, Lyft or 
equivalent
$5
$5
$5
$5
$5
Home blood pressure 
monitor
1 monitor
Some participants may be ineligible after completing procedures during Visits 1 and 2. If you 
have attended a single visit and have been determined ineligible, you will be compensated $15. 
If you have attended two visits, you will be compensated $30 regardless of whether you are 
ineligible or eligible (able to participate in the study).  
Study Dissemination
After all participants have completed the research study:

You will receive a letter indicating if you received the study drug or candesartan while 
you participated in the study.

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 for you to call or email if you have questions about the 
results of the study. 

Research findings will be available at www.ClinicalTrials.gov (Identifier: NCT03640312) 
within 1 year.

The research findings will be published in the form of research articles and presentations 
at scientific meetings. 
The study sponsor, the National Heart, Lung, and Blood Institute of the National Institutes of 
Health, requires that all research papers from this study be made freely available to the public 
through PubMed Central (https://www.ncbi.nlm.nih.gov/pmc/) within 12 months of publication.
IRB #: STU00205834-MOD0014 Approved by NU IRB for use on or after 8/13/2020 through 6/29/2021.


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HIPAA Authorization
We are committed to respect your privacy and to keep your personal information confidential.  
When choosing to take part in this study, you are giving us the permission to use your personal 
health information that includes health information in your medical records and information that 
can identify you. For example, personal health information may include your name, address, 
phone number or social security number. Health information we may collect and use for this 
research includes: 

All information in your medical record 
You have the right to inspect and copy the mental health and developmental disabilities records 
that will be collected as part of this study.
This consent expires on December 31st, 2032. After this date, Northwestern University may not 
gather new information about you, use or disclose your personal health information collected in 
this study for any purpose other than the research study described in this consent unless 
Northwestern University obtains permission to do so from you. Illinois State Law permits use 
and disclosure of your mental health information only to the extent specified in this document.
Once we have the health information listed above, we may share some of this information with 
the following offices or entities outside of Northwestern University and its clinical partners (or 
affiliates): the Northwestern University Institutional Review Board Office and Office for Research 
Integrity; the US Office of Research Integrity; the US Office for Human Research Protections; 
the US Food and Drug Administration.  
Any research information shared with outside entities will not contain your name, address, 
telephone or social security number or any other personal identifier unless disclosure of the 
identifier is necessary for review by such parties or is required by law or University policy except 
that such information may be viewed by the study sponsor and its partners or contractors at the 
Principal Investigators’ offices.
The following entities may receive your health information: 

Authorized members of the Northwestern University workforce, who may need to see 
your information, such as administrative staff members from the Office for Research, 
Office for Research Integrity and members of the Institutional Review Board.

Other University research centers and University contractors who are also working 
on the study,

Study monitors and auditors who make sure that the study is being done properly, 

Government agencies and public health authorities, such as the Food and Drug 
Administration (FDA) and the Department of Health and Human Services (DHHS).

The following individuals or organizations may also access, receive, or use your 
personal health information: Access Community Health Network.
Those persons who receive your health information may not be required by Federal privacy 
laws (such as the Privacy Rule) to protect it. Some of those persons may be able to share your 
information with others without your separate permission. The results of this study may also be 
used for teaching, publications, or for presentation at scientific meetings.  
Also, Federal law/42 CFR Part 2 prohibits unauthorized disclosure of these records. 
IRB #: STU00205834-MOD0014 Approved by NU IRB for use on or after 8/13/2020 through 6/29/2021.


Permission to Take Part in a Human Research Study
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The results of this study may also be used for teaching, publications, or presentation at scientific 
meetings.
Unless you revoke your consent, it will expire on December 31st, 2032.
Although you may revoke consent to participation in this research at any time and in any format, 
you must revoke authorization for use or disclosure of your health information in writing. To 
revoke your authorization, write to:
Principal Investigator (PI) Name: Mark Huffman, MD, MPH
Institution: Northwestern University
Department: Preventive Medicine
Address: 680 N Lake Shore Drive Suite 1400, Chicago IL 60611
You do not have to authorize the use or disclosure of your health information; however, you will 
not be allowed to take part in this research study if you do not authorize it. If you do not 
authorize the use or disclosure of your health information, then it will not affect your treatment 
by health care providers, or the payment or enrollment in any health plans, nor will it affect your 
eligibility for benefits. 
Your signature documents your permission to take part in this research.  You will be provided a 
copy of this signed document.
_______________________________________________               __________________
Signature of Participant                                                                       Date
_______________________________________________
  
Printed Name of Participant
_______________________________________________              __________________
Signature of Person Obtaining Consent                                              Date
_______________________________________________
Printed Name of Person Obtaining Consent
My signature below documents that the information in the consent document and assent 
process and any other written and verbal information was accurately explained to, and 
apparently understood by, the participant, and that consent was freely given by the participant.
_________________________________________________      _________________
Signature of Witness to Consent/Assent Process      
Date
IRB #: STU00205834-MOD0014 Approved by NU IRB for use on or after 8/13/2020 through 6/29/2021.


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_________________________________________________   
Printed Name of Person Witnessing Consent/Assent Process
IRB #: STU00205834-MOD0014 Approved by NU IRB for use on or after 8/13/2020 through 6/29/2021.

SAP_002.pdf: 
 
 
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STATISTICAL ANALYSIS PLAN (SAP) 
 
QUARTET USA:  
A double blind randomized controlled trial to assess the efficacy and safety of a quadruple 
ultra-low-dose treatment for hypertension  
 
 
February 9, 2022 
 
Version 2.0 
 
IRB Number: STU00205834 
 
 


 
 
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List of Abbreviations 
ABPM 
Ambulatory blood pressure monitoring 
ACE-I 
Angiotensin-converting-enzyme inhibitor 
AE 
Adverse event 
ALP 
Alkaline phosphatase, a liver function test 
ALT 
Alanine transaminase, a liver function test 
ANCOVA Analysis of covariance  
API 
Application Programming Interface 
ARB 
Angiotensin II receptor blocker 
AST 
Aspartate Aminotransferase, a liver function test 
BB 
Beta blocker 
BMI 
Body mass index 
BP 
Blood pressure 
CABG 
Coronary artery bypass graft, 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 
DMP 
Data Management Plan 
DSMB 
Data and Safety Monitoring Board 
DSMP 
Data and Safety Monitoring Plan 
ECG  
Electrocardiogram 
ECT 
Electroconvulsive therapy, a medical treatment used in patients with severe, major 
depression 
eGFR 
Estimated glomerular filtration rate, which estimates kidney function 
HER 
Electronic health record 
GCP 
Good clinical practice 
GGT 
Gamma-glutamyl transferase, a liver function test 
HDL-c 
High density lipoprotein cholesterol 
IPD 
Individual participant data  
mITT 
(modified) Intention-to-treat 
LDQT 
(ultra-) Low-dose quadruple combination therapy 
LVH          Left ventricular hypertrophy, or muscle thickening of the heart’s left pumping chamber  
MI 
Myocardial infarction, also known as a heart attack 
MOP 
Manual of Operating Procedures 
PCI 
Percutaneous coronary intervention, a non-surgical procedure to open narrowings or 
blockages of the coronary arteries  
PROMIS 
Patient-Reported Outcome Measurement Information System 
QRS 
An ECG-derived interval that represents ventricular depolarization 
QTc 
An ECG-derived interval that represents the time from ventricular depolarization to 
repolarization 
REDCap 
Research Electronic Data Capture 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 


 
 
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SBP 
Systolic blood pressure 
TIA 
Transit ischemic attack, a stroke-like attack resolves within 24 hours  
UACR 
Urine albumin: creatinine ratio 


 
 
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STATISTICAL ANALYSIS PLAN (SAP) 
 
QUARTET USA:  
A double blind, randomized controlled trial to assess the efficacy and safety of a quadruple 
ultra-low-dose treatment for hypertension  
  
Co-Principal Investigator: Mark D. Huffman, MD, MPH 
Co-Principal Investigator: Jody D. Ciolino, PhD 
 
1. INTRODUCTION 
 
This document outlines the proposed analyses for the QUARTET USA phase II clinical trial, which 
aims to compare clinical and safety outcomes for adult participants with elevated blood pressure (BP) 
at baseline who receive treatment with ultra-low-dose quadruple-combination therapy (LDQT) to 
those outcomes in participants given standard dose monotherapy at 12 weeks. Thus, we plan to 
conduct a two-arm, double-blind randomized controlled trial with equal allocation (1:1) in adults with 
uncontrolled blood pressure who are eligible for monotherapy. The purpose of this document is to 
provide detail regarding the statistical analysis plan (SAP) for this study. 
 
Study Aims 
The overarching study aims are as follows: 
 
Aim 1: To investigate whether initiating treatment with ultra-low-dose quadruple-combination therapy 
(“LDQT”) including candesartan 2mg, amlodipine 1.25mg, indapamide 0.625mg, and bisoprolol 2.5mg 
will lower office blood pressure at 12 weeks more effectively, and with no increase in side effects, 
compared to initiating standard dose monotherapy (candesartan 8mg) in adults with elevated blood 
pressure who are eligible for monotherapy based on the 2017 AHA/ACC guideline.  
 
We hypothesize that initiating treatment with LDQT will lower office blood pressure at 12 weeks more 
effectively, and with no increase in side effects, compared to initiating standard dose monotherapy in 
adults with elevated blood pressure who are eligible for monotherapy. 
 
Aim 2: To investigate whether initiating treatment with LDQT will lower mean 24-hour ambulatory 
blood pressure at 12 weeks more effectively, and with no increase in side effects, compared to 
initiating standard dose monotherapy in adults with elevated blood pressure who are eligible for 
monotherapy. 
 
We hypothesize that initiating treatment with LDQT will lower mean 24-hour ambulatory blood 
pressure at 12 weeks more effectively, and with no increase in side effects, compared to initiating 
standard dose monotherapy in adults with elevated blood pressure who are eligible for monotherapy. 
 
Exploratory Aim 1: Assess heterogeneity of treatment effect by hypothesized moderators 
(age, sex, race/ethnicity, and health literacy level).  
We hypothesize that the treatment effect of LDQT will be greater in participants with limited health 
literacy than those with adequate health literacy. We also hypothesize that treatment effect of LDQT 
will differ by age, sex, and race/ethnicity subgroups.  
 
Exploratory Aim 2: To evaluate acceptability, preferences, and lessons for implementation of 
LDQT among patients and clinicians using mixed methods.  


 
 
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We hypothesize that patients and clinicians will prefer LDQT more than standard dose monotherapy 
for initial blood pressure lowering therapy; we further hypothesize that LDQT will be simpler and 
easier for both patients and clinicians than standard dose monotherapy for initial blood pressure 
lowering therapy, including patients with low health literacy. 
 
This SAP will focus on the details of analyses for Aims 1, 2, and part of exploratory Aim 1 (pertaining 
to age, sex, and race/ethnicity as potential moderators); we reserve details of the exploration of 
health literacy and implementation analyses (exploratory Aim 2) for a separate document.  
 
Study time points include baseline assessment (completed over approximately two days), a six-week 
follow-up time point, and a 12-week follow-up time point (also completed over approximately two 
days).  
 
2. STUDY OUTCOMES 
 
In the sections below, we include the relevant specific field names for variables within the study 
database as of the time of SAP creation. These are indicated by the [brackets]. 
 
Primary Outcome 
Primary efficacy outcome is mean change (from baseline) in automated office systolic blood 
pressure (SBP) at 12 weeks [sbpavg], and analyses will compare this change across arms for 
primary outcome analyses, adjusting for baseline. 
 
Secondary Outcomes 
Secondary efficacy outcomes include:  
1) Mean automated office SBP at 12 weeks, adjusted for baseline values [sbpavg]. 
2) Other BP measures that will be compared across arms, controlling for baseline values:  
a. Mean change (from baseline) in automated office SBP [sbpavg] at six weeks.  
b. Mean automated office SBP [sbpavg] at six weeks.  
c. Mean change (from baseline) in automated office DBP [dbpavg] at six and 12 
weeks.  
d. Mean automated office DBP [dbpavg] at six and12 weeks.  
e. Proportion of patients with hypertension control (SBP < 130 mmHg and DBP <80 
mmHg) at six and 12 weeks [sbpavg, dbpavg].  
f. Proportion of patients requiring step-up treatment [amlo_dispnd].  
g. Proportion of patients with adverse event-free hypertension control (SBP < 130 
mmHg and DBP < 80 mmHg [sbpavg, dbpavg]). For the purposes of this 
outcome, we will define adverse event-free as absence of any events that are 
documented as either possibly, probably, or definitely related to study medication 
([saerelate] = 3, 4, 5). 
3) Medication adherence: proportion of participants deemed adherent to study medication 
based on the 80% criterion (i.e., participant took at least 80% of assigned study medication). 
This information will be captured via: 
a. Objective pill counts [capsret6, lost6, capsret12, lost12], and  
b. Self-reported measures [forget, miss30, miss7] in addition to the objective pill 
counts. 
4) Health-related quality of life: Mean change from baseline in health-related quality of life 


 
 
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using PROMIS Global Health instrument [global01—global10]. There are two domains 
within this construct:  
a. Global Mental Health (assessed via a T-score) 
b. Global Physical Health (assessed via a T-score) 
 
Safety Outcomes 
We plan to evaluate the following safety outcomes: 
1) Proportion of participants with any SAE according to the Good Clinical Practice  (GCP) 
definition [sae_present, saedeath, saelifethrt, saehosp, saedisp, saecong, saeimpevnt].  
2) Proportion of participants with any potentially relevant side effect ([sae_term] refer to the 
adverse event case report form and the list of relevant side effects from the informed consent 
form).  
3) Rate of relevant side effects at the participant level (i.e., count per participant [sae_term]).  
4) Mean change (from baseline) in continuous serum potassium (mEq/L), controlling for baseline 
value [potassium].  
5) Mean change (from baseline) in continuous serum sodium (mEq/L), controlling for baseline 
value [sodium].  
6) Mean change (from baseline) in continuous blood urea nitrogen (mg/dl), controlling for 
baseline value [urea].  
7) Mean change (from baseline) in continuous serum creatinine (mg/dl), controlling for baseline 
value [creat].  
Exploratory Outcomes  
The following outcomes are relevant to the overall aims; however, they carry less weight, and we 
consider them exploratory in nature. This SAP will not focus in detail on analyses of these outcomes, 
but we anticipate the general analytic approach to apply. In the event of small numbers that would 
make modeling infeasible, these data may be reported as descriptive statistics.  
 
ABPM measures 
24-hour ambulatory blood pressure monitor (ABPM) measures at 12 weeks adjusted for 
baseline values:  
1) Mean 24-hour SBP and DBP [overall_abpsbp, overall_abpdpb].  
2) Mean daytime (0600 to 2200) [awake_abpsbp, awake_abpdbp] SBP and DBP. 
3) Mean nighttime (2200 to 0600) SBP and DBP [asleep_abpsbp, asleep_abpdbp].  
4) Proportion of dippers [sys_dip, dia_dip], defined as nighttime BP 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. 
5) Mean daytime SBP and DBP load. Load is defined as the percentage of abnormally elevated 
readings; daytime SBP / DBP elevated readings would be 130 / 80 mmHg or above.  
6) Mean nighttime SBP and DBP load. Abnormally elevated readings for nighttime SBP / DBP 
would be 120 / 70 mmHg or above.  
7) Percentage of participants with morning surge, calculated as the difference between the mean 
SBP during the morning hours and nighttime trough SBP. Trough SBP is defined as the mean 
of three SBP measurements: the lowest nighttime SBP and the measurements immediately 
preceding and following this measurement. 
8) 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.  


 
 
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9) Day-night variability (SDdn), which uses the standard deviation (SD) for daytime 
measurements and, separately for nighttime measurements, to calculate a weighted mean of 
these SDs. 
10) Average real variability (ARV), calculated as the average absolute difference between 
consecutive readings over the 24-hour ABPM period.  
 
We will assess additional exploratory outcomes as needed to inform individual participant data (IPD) 
meta-analysis with international QUARTET studies. The details of these IPD analyses are reserved 
for a separate analytic plan.  
 
3. DEMOGRAPHICS AND BASELINE ASSESSMENTS 
 
The following are specific demographic / baseline assessments of interest for analyses. Primary 
analyses will adjust for these covariates as we anticipate they will influence outcome. We plan to 
report both model-adjusted and simple unadjusted intervention effect estimates. In the cases of 
adjusted models, we will include the following variables as fixed effects, regardless of significance: 
1) Sex [sex]. 
2) Age [age]. 
3) Race/ethnicity [ethnic]. We plan to categorize participants into White (ethnic = 1), Hispanic 
(ethnic = 3, 4, 5, 6), African American (ethnic = 2), or other categories. In the event of low cell 
counts in any one category, we may consider collapsing categories, foregoing adjustment for 
race (if collapsing cannot be justified scientifically), or failing to adjust for race altogether. We 
may also consider another potential covariate that is heavily related to race and ethnicity or 
conduct sensitivity analyses under different parameterizations / assumptions.  
4) Literacy score according to the Newest Vital Sign (NVS, sum of [vs_totcal, vs_carb, vs_fat, 
vs_daily, vs_safe, vs_peanut]) as defined per scoring manual. The score ranges from 0-6, with 
0-1 indicating limited literacy, 2-3 indicating likely limited literacy, and 4-6 indicating adequate 
literacy.  
5) Indicator of monotherapy at baseline [inc04 = 3]. 
 
Additional demographics in general include: 
1) Country of birth [birth]. 
2) Insurance status [insurance]. 
3) Education [edu]. 
4) Employment status [emplst]. 
5) Income [income_usd]. 
6) Marital status [marst]. 
7) Number of people in household [pple]. 
 
Note that some additional exploratory analyses may examine these additional demographic variables 
as covariates and/or effect modifiers as well. We will label any exploratory analyses involving 
additional potential covariates as post hoc in any dissemination materials.  
 
4. DATA STORAGE 
 
Data will be collected and managed using Research Electronic Data Capture (REDCap) housed at 
Northwestern University’s Clinical and Translational Sciences Institute (CTSA), NUCATS [1].  
REDCap is a secure, web-based application designed for research studies that provides an intuitive 
interface for validated data entry, audit trails for tracking data manipulation and export procedures, 


 
 
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and automated export procedures for seamless data downloads to common statistical packages, and 
procedures for importing data from external sources. Refer to the study Data Management Plan 
(DMP) for details. 
 
5. RANDOMIZATION METHODS 
 
We plan for equal allocation (1:1) across study arms; the study statistician (Co-PI: Ciolino) generated 
a randomization list using random block assignments (i.e., randomly varying block sizes). The details 
of the block sizes and number of blocks will remain confidential until study completion. The study 
statistician uploaded a “Development” randomization list and a separate “Production” randomization 
list into REDCap. Each participant will be assigned a randomly-generated kit number that will 
correspond to either an active comparator (candesartan) or investigational product (LDQT) drug kit. 
The randomization lists are housed on Northwestern University’s “FSMResFiles” with restricted 
access such that only unblinded individuals can access. Neither the study coordinator / study nurse / 
individual assigning the study kit numbers nor the participants will have ability to determine which kit 
numbers correspond to each arm as they were generated via a random uniform distribution with the 
seed number, block sizes, and subsequently sorted randomization lists restricted to this set of folders 
on Northwestern University’s servers. Randomization does not involve any stratification factors; 
however, with the addition of a second study site, the randomization is de facto stratified by site (i.e., 
each site has its own randomization sequence).   
 
6. STATISTICAL METHODS   
 
Descriptive statistics will summarize participant demographics and baseline clinical outcomes overall 
and across arms: proportion (percentages) for categorical variables; mean (± standard deviation) for 
continuous variables; and median (interquartile range) for skewed or count variables. Analyses in 
general will employ normal theory methods and residual diagnostics will evaluate validity of 
assumptions; where appropriate (i.e., in the event of low cell counts for categorical data or questions 
of normality), transformation of variables, nonparametric methods, or exact tests may be employed. 
All primary efficacy and safety analyses will be pre-specified as outlined in this SAP, and deviations 
from planned analyses or post hoc analyses will be labeled as such in any reports or dissemination 
materials.   
 
Analyses will assume a two-sided 5% type I error rate unless otherwise specified; there will be some 
exploratory analyses that will involve a relaxed type I error rate (10%). There will be no corrections 
made for multiple hypothesis tests, as this is a phase II study evaluating preliminary efficacy.  
 
Planned Primary, Secondary, Safety Analyses 
The primary study analysis time point for all relevant outcomes is 12 weeks post randomization. The 
original analysis plan called for an analysis of covariance (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).  We deem these variables 
clinically relevant, important covariates; thus, all analyses will plan for adjustment for these covariates 
of interest (regardless of statistical significance in the current dataset) in evaluating efficacy of 
intervention 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 


 
 
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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):  
 
𝑌𝑌𝑖𝑖𝑖𝑖= 𝛽𝛽0 + 𝛽𝛽1𝑰𝑰(𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿) + 𝐵𝐵2(𝑌𝑌0𝑖𝑖) + 𝐵𝐵3𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣+ 𝐵𝐵4(𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑥𝑥 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑎𝑎𝑎𝑎𝑎𝑎) + 𝑏𝑏𝑖𝑖+ 𝑒𝑒𝑖𝑖𝑖𝑖 
 
Under the assumption that error terms 𝑒𝑒𝑖𝑖𝑖𝑖~𝑁𝑁(0, 𝜎𝜎2) is the random error term, 𝑏𝑏𝑖𝑖~𝑁𝑁(0, 𝜎𝜎𝑏𝑏
2) is the 
participant-level random effect. If visit-by-study arm (𝐵𝐵4) 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 (𝐵𝐵3). If insignificant, we will also remove that effect from the model and evaluate intervention 
effect via the primary hypothesis test of interest: 
𝐻𝐻0: 𝛽𝛽1 = 0 𝑣𝑣𝑣𝑣. 𝐻𝐻1: 𝛽𝛽1 ≠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.  
 
Secondary analyses (i.e., those for the secondary and exploratory outcomes of interest) 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 5% level of significance. If insignificant at the 5% 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 5% level.   
 
The table below summarizes the general modeling strategy for each outcome. In each case, we plan 
to conduct both adjusted and unadjusted analyses. Adjusted analyses will include the aforementioned 
covariates.  
 
 
 


 
 
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Table: Modeling Strategy by Outcome 
Outcome 
Variable Type 
Model Link 
Assumption 
Note on Covariates 
Primary, secondary / 
exploratory blood pressure 
measurements at 
individual study time points 
Continuous  
(assume normality) 
Identity 
Same as in primary outcome 
analyses 
Dipping at 12 weeks 
Binary / categorical 
Logit 
Indicator of dipping status at 
baseline in addition to other 
covariates as in primary 
analyses 
Hypertension control at 
individual study time points Binary / categorical 
Logit 
Same as in primary outcome 
analyses, including baseline 
SBP 
Requirement for 
amlodipine add-on therapy 
Binary / categorical 
Logit 
Same as in primary outcome 
analyses, including baseline 
SBP 
Adverse event-free 
hypertension control at 
each study time point 
Binary / categorical 
Logit 
Same as in primary outcome 
analyses, including baseline 
SBP 
Medication adherence  
(at least 80%) 
Binary / categorical 
Logit 
Same as in primary outcome 
analyses, including baseline 
SBP 
Change in PROMIS Global 
Health 
Continuous  
(assume normality) 
Identity 
Same as in primary outcome 
analyses 
Indicator for any SAE 
Binary / categorical 
Logit 
Same as in primary outcome 
analyses, including baseline 
SBP 
Indicator for any relevant 
side effect 
Binary / categorical 
Logit 
Same as in primary outcome 
analyses, including baseline 
SBP 
Rate of relevant side 
effects 
Count  
(Poisson 
assumption) 
Log 
Same as in primary outcome 
analyses, including baseline 
SBP 
Continuous laboratory 
measurements (potassium, 
sodium, urea, creatinine) 
Continuous  
(assume normality) 
Identity 
Same as in primary outcome 
analyses 
 
Subgroup Analyses and Heterogeneity of Intervention Effects 
An exploratory objective of this study is to assess heterogeneity of treatment effect by the following 
potential hypothesized moderators: age, sex, and race/ethnicity. To address this, we will analyze 
primary and secondary blood pressure (12-week SBP, DBP) outcomes via the aforementioned 


 
 
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LMMs; we will add an arm-by-<potential moderator> effect in the original model specified above for 
each potential moderator of interest. Moderation effects will be explored via model-adjusted type III 
Wald test for fixed effects at the relaxed 10% level of significance. If significant, then we will examine 
the intervention effect within each subgroup via a series LMMs: male/female, age category, 
racial/ethnic category.  
 
Agreement between Outcomes 
We will use simple sample Pearson correlation coefficients (and 95% confidence limits), Bland-
Altman plots, or both to examine agreement among continuous outcome measures (primarily focused 
on office SBP and 24-hour SBP measures). Though these analyses are not the primary focus of this 
trial and its results, we will use agreement analyses to make inference regarding quality of SBP 
measurement methods and variability.  
 
Analyses Contingent on Add-on Therapy Requirements 
If there is evidence of a difference in proportion of participants requiring amlodipine add-on therapy at 
six weeks across arms, then we will also explore dividing the sample into four strata: (1) those that 
required amlodipine add-on treatment + received active control, (2) those that required add-on + 
received LDQT, (3) those that did not require add-on + received active control, and (4) those that did 
not require add-on and received LDQT. Depending on cell counts, we will attempt a series of 
exploratory analyses for key outcomes (SBP, DBP) to evaluate an effect. Additional analyses of this 
nature will be indicated as exploratory.  
 
7. ANALYTIC DATASET 
 
Analyses will include the (modified) intention-to-treat (mITT) dataset, whereby all those participants 
with data at any follow-up time point and baseline to contribute to analyses will be included in 
analyses according to arm to which they were randomized, regardless of adherence to the study 
protocol. We will conduct a sensitivity analysis on the per protocol dataset (defined as 80% treatment 
regimen adherence) since precise estimates of intervention effect (if any) on outcomes are important 
in a phase II study. 
 
Power and sample size considerations allowed for some missing data (20%); however, in the event of 
large amounts of missing data (i.e., more than 10%), multiple imputation analyses will be explored. 
We will examine rates of missing data for all variables and determine whether the rates vary by 
participant characteristics, etc. These summarizations will inform potential biases resulting from 
missing data. Mixed effects models planned for longitudinal analysis are generally robust for 
unbalanced data across study time points. Additional sensitivity analyses will explore multiple 
imputation methods and the global sensitivity analysis to evaluate overall trial robustness [2]. These 
analyses will again serve as sensitivity analyses to the previously outlined analyses.  
   
8. POWER AND SAMPLE SIZE CONSIDERATIONS   
 
The initial sample size calculations called for a total of 365 participants to be randomized (1:1 
allocation). We anticipated an analytic sample size of 292 based on 365 participants at randomization 
and a 20% dropout rate by the 12-week follow-up time point. We originally based sample size and 
power calculations conservatively on an independent two-sample t-test. Based on results of interim 
analyses (refer to Section 10 for details), we updated our recruitment target to 87 participants (1:1 
allocation). The analytic sample size of 77 is anticipated based on 87 participants at randomization 


 
 
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and a conservatively estimated 12% dropout rate by the 12-week follow-up time point based on 8% 
dropout rate observed through September 2021.  
 
The initial, conservative plan for primary outcome analyses involving an independent two-sample t-
test provided an estimated 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. This estimate is based on a 2017 Cochrane systematic review update 
evaluating the effects of fixed-dose combination therapy and systematic review on quarter dose 
combination therapy, and a pilot trial of quarter-dose combination therapy [3]. We assumed baseline 
SBP has a moderate correlation with follow-up SBP (r≈0.50-0.6); under this assumption, sample size 
calculations based on ANCOVA has the potential to allow for over 90% power under the same 
assumptions for remaining parameters.  
 
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. 
  
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), we 
estimate over 95% power with the planned sample size 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. 
 
9. TECHNICAL DETAILS 
 
The SAP is subject to version control, and we anticipate modifications to analytic plans be 
documented herein. As in any study, the analytic plan may change due to assumption violations, 
logistical issues, unexpected empirical distributions of study outcomes, or a combination thereof. In 
these cases, the SAP will be updated accordingly. All analyses will be performed via SAS version 9.4 
or higher (The SAS Institute; Cary, NC) or R version 3.6.0 or higher (The R Foundation for Statistical 
Computing platform). Table and figure formatting and style may be dictated by mode of dissemination 
or specific target journal(s) for results dissemination. 
 
Summary of updates:  
Version 2.0:  
1) Removed reference to heterogeneity of treatment effects based on health literacy as these 
analyses will be outlined in a separate document.  
2) Moved ABPM to exploratory analyses.  
3) Updated target sample size based on interim analyses at request of the DSMB.  
4) Updated modeling strategy overall to involve mixed modelling techniques (previously planned 
for ANCOVA at Week 12, only) to use both Week 6 and Week 12 data in analysis models. All 
longitudinal models will first explore a time-by-arm interaction term at the 5% level of 
significance in evaluating treatment effect.   
5) Specified minor details on treatment of covariates in analyses. 


 
 
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6)  Added in plans to explore potential strata combining study arm and add-on therapy.  
 
10. TIMELINE FOR ANALYSES 
 
As this is a phase II clinical trial, the original analysis plan did not include any formal interim statistical 
analyses involving hypothesis testing or any pre-specified stopping criteria for efficacy or futility on 
primary or secondary outcomes. Interim reports to the study team and data and safety monitoring 
board (DSMB) will consist of process measures such as protocol departures, missing values, missing 
forms, treatment regimen adherence, etc. and simple descriptive statistics on primary and safety 
outcomes of interest. In addition, weekly meetings with the study team will utilize central statistical 
monitoring techniques as a method of quality control and quality assurance for trial data on an 
ongoing basis. We foresee the DSMB requiring specific data listings or summarizations, but these will 
be specified at the time of the relevant DSMB meeting(s). At the request of the DSMB, we conducted 
an interim conditional power analysis, taking into consideration from both the QUARTET USA trial 
data as of August 2021 and further the QUARTET (Australia) results. These interim analyses, 
incorporating information to date, resulted in an updated recruitment target (and thus overall sample 
size goal). These interim analyses also resulted in the ultimate updates to the analytic strategy from 
an ANCOVA to one involving a mixed modeling approach to make use of both the six- and 12-week 
follow-up data for all participants. These modifications to the analytic plan resulted in an updated SAP 
(to version 2.0).  
 
To preserve the integrity of the study, no formal final statistical analyses will occur until the REDCap 
database has been locked and all queries/discrepancies resolved; the date of database lock will be 
documented.  
 


 
 
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References:  
 
1. 
Harris, P.A., et al., Research electronic data capture (REDCap): a metadata-
driven methodology and workflow process for providing translational reserach 
informatics support. Journal of Biomedical Informatics, 2009. 42(4): p. 377-381. 
2. 
Scharfstein, D., et al., Global sensitivity analysis for repeated measures studies 
with informative dropout: A fully parametric approach. Statistics in 
Biopharmaceutical Research, 2014. 6(4): p. 338-348. 
3. 
Bahiru, E., et al., Fixed‐dose combination therapy for the prevention of 
atherosclerotic cardiovascular diseases. Cochrane Database of Systematic 
Reviews, 2017(3). 
 

Prot_001.pdf: 
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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 
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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-
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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 
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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: 
• 
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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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