Clinical trial NCT02961946
Conditions: Coronary Artery Disease
Sponsor: Massachusetts General Hospital
Start date: 2017-03-15; Completion date: 2018-08-02
Enrollment: 198 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate image quality of coronary CT angiography (cCTA) after sublingual and transdermal administration of Nitroglycerin. Aim of this prospective research study is to investigate equivalence on image quality after sublingual or transdermal Nitroglycerin administration (H0).

Furthermore, the feasibility of transdermal Nitroglycerin administration will be evaluated.

Detailed description:

Arms: arm 1: Sublingual Nitroglycerin spray of 0.8 mg arm 2: Sublingual Nitroglycerin tablet of 0.8 mg arm 3: Nitroglycerin skin patch of 0.8 mg/h
Interventions: intervention 1: Nitroglycerin
Intervention descriptions: intervention 1: Patients grouped in sublingual administration (group 1 and 2) will receive Nitroglycerin during the cCTA scan by the MD after the Calcium scoring scan and 5 minutes before the actual cCTA scan. Patients categorized to transdermal administration will receive Nitroglycerin 1 hour before the CT examination. The patch will be placed on the chest or the upper arm.

Protocol documents:
Prot_SAP_000.pdf: 
Effects of Sublingual and Transdermal Administration of 
Nitroglycerin for Coronary CT Angiography on Image Quality 
 
NCT#: NCT02961946 
 
 
 
Study protocol and statistical analysis plan 
October 14, 2018 
 


Methods  
This study had a prospective, randomized controlled design conducted at a single, 
academic hospital and was approved by our institution’s review board, which required 
signed consent. The study was HIPAA compliant and registered at the Clinical Trials 
Registry (#NCT02961946) with the title “Effects of Sublingual and Transdermal 
Administration of Nitroglycerin for Coronary CT Angiography on Image Quality”. 
Based on prior literature, we hypothesized that mean coronary artery diameter before and 
after nitroglycerin application would be 2.86 mm and 3.26 mm, respectively, with 13.8% 
vasodilation (13). We assumed an equivalence range of 3% and determined a type-I error 
of (0.05/3=0.017) for a 3-group comparison with 80% power. In total, 198 individuals and 
66 individuals per arm were necessary for a 3-group comparison.  
Coronary artery vasodilation was the primary outcome. Secondary outcomes included 
changes in vital signs and frequency of side effects after nitroglycerin application. The 
dependent variable was the method of nitroglycerin delivery which could be lingual, 
sublingual, or transdermal. 
Patient Selection 
We identified potential subjects from our clinical cardiac CT schedule and included those 
whose study required an ECG-gated non-contrast CT followed by CCTA acquisitions. 
Subjects with a history of coronary revascularization were included. Exclusion criteria 
were age under 18 years, known hypersensitivity to nitroglycerin, closed-angle glaucoma, 
use of phosphodiesterase type 5 inhibitors within 72 hours prior to the study, conditions 
associated with elevated intracranial pressure, hemodynamic instability, critical aortic 


stenosis, systolic blood pressure below 90 mmHg, pregnancy or lactating female, women 
with a positive urine pregnancy test, and subjects unwilling or unable to consent to 
participation.  
Study Workflow 
The physician enrolling the subject to the study was blinded to the method of nitroglycerin 
administration. After obtaining informed consent, subjects were randomized (block 
randomization, block size=198) to one of three nitroglycerin delivery methods: (1) 
sublingual as a tablet (2x0.4 mg, Nitrostat, Pfizer Inc., NY), (2) lingual as a spray (2x0.4 
mg, Nitrolingual, Pohl-Boskamp, Hohenlockstedt, Germany), or (3) transdermal as a 
patch (2x0.4 mg/h, Nitro-Dur, Merck&Co Inc., NJ). After assessing initial vital signs (heart 
rate, rhythm, and blood pressure), non-contrast CT was acquired. Subsequently, 
nitroglycerin was administered. Patches were placed on the upper chest, taking care to 
avoid body hair. The transdermal delivery method required an application time of at least 
45 minutes, while lingual and sublingual nitroglycerin required 5 minutes application time 
before CCTA acquisition (Figure 1). After CCTA, the patches were removed, and the 
location was inspected for skin reaction, while spray and tablets did not require further 
interaction. Next, we remeasured vital signs and asked for symptoms of allergic-type 
reactions and if sublingual tablets had completely dissolved. Systolic blood pressure >180 
mmHg or a drop of >10 mmHg compared to initial values required observation and follow-
up until normalization. Finally, patients filled out a query asking about side effects during 
the exam. 


Image Acquisition 
All individuals were scanned on a 128-slice dual-source CT (Somatom Definition Flash, 
Siemens Healthineers, Forchheim, Germany). Scan length was from carina to diaphragm 
and was extended if necessary. Scan parameters were as follows: non-contrast CT 
(prospectively-ECG-triggered at 350ms after the R wave, fixed 120kV, mA adjusted to 
body size, with a reference of 80 mAs [CareDose4D, Siemens Healthineers], 64x0.6mm 
collimation), CCTA (prospectively-ECG-triggered for heart rates <85 bpm, ≥85 bpm 
retrospectively-ECG-gated, with an acquisition window in late systole to early diastole 
(220-400 msec after the R-wave), 80-120kV with optimal kV [CarekV, Siemens 
Healthineers] and automatic mA selection based on the scout scan, reference 280 mAs, 
64x0.6mm collimation). No beta-blocker was administered, as per our standard site 
practice.  
Images were reconstructed using iterative reconstruction algorithm (strength level 3/5, 
Admire, Siemens Healthineers) with 0.6 mm slice thickness at 350ms for non-contrast 
images and 220-440ms (20ms intervals) for CCTA images. All studies were blinded as to 
the nitroglycerin delivery method. Coronary calcium scores (Agatston method) and 
severity of any coronary artery disease were assessed from the radiology reports. 
Quantitative Analysis 
A 
cardiovascular 
imaging-trained 
radiologist 
with 
six 
years 
of 
experience 
(X.X.)(anonymized) measured coronary diameters at seven locations (Figure 2) using a 
3D-workstation (Aquarius v.4.4.12, Terarecon Inc., Foster City, CA). These locations 
were predetermined as: (1) proximal right coronary artery (RCA) 1.5 cm distal from the 
ostium; (2) mid RCA 1.0 cm proximal of the acute marginal branch; (3) distal RCA 1.0 cm 


proximal of the bifurcation into posterior descending artery and right postero-lateral 
branch; (4) middle of the left main (LM); (5) proximal left anterior descending artery (LAD) 
1.0 cm after LM bifurcation or, if less distance to the 1st diagonal branch, in the middle of 
the proximal LAD; (6) mid LAD 2.0 cm distal of 1st diagonal branch or if less distance to 
the 2nd diagonal branch, in the middle of mid LAD; and (7) left circumflex coronary artery 
2.0 cm distal of the LM bifurcation. Positions were located in the non-contrast images and 
reaffirmed on CCTA images using a corresponding phase of the cardiac cycle. Locations 
with non-calcified or calcified plaques or unclear depiction of the coronary artery due to 
adjacent structures such as veins were avoided, and in those segments, the location of 
measurement was moved distally up to 1.0 cm from the original position while staying in 
the same coronary segment and avoiding bifurcations. If coronary diameters could not be 
measured at any of these positions, the location was excluded. We excluded stented or 
bypassed locations from measurements. All coronary diameters were measured twice at 
each location using short-axis views in an enlarged field-of-view and averaged using 
window width and level of 350 HU and 50 HU for non-contrast and 800 HU and 200 HU 
for CCTA images (Figure 2). Window settings were set based on preliminary 
measurements in 20 patients who underwent CCTA without nitroglycerin and therefore 
no diameter differences in non-contrast and CCTA images. Locations #1, #4, and #5 were 
defined as proximal-, locations #2 #6, and #7 as mid-, and location #3 as distal coronary 
segments.  


Safety 
By query, side effects were evaluated, including headache, dizziness, and nausea during 
the exam. The severity of headache was quantified on a 10-point scale ranging from 1 
minimal- to 10 maximal-intensity.  
 
Statistical Analysis 
Demographic and scan parameter summaries were calculated for the entire subject 
cohort and by nitroglycerin administration method. Categorical variables were 
summarized using frequencies and percentages, while continuous variables were 
summarized as means and standard deviations, or as median and interquartile range 
(25th and 75th percentiles) if the distribution of the variables were skewed. Differences in 
continuous variables by treatment were assessed using the Kruskal-Wallis test, and 
differences in categorical variables were assessed using either the Pearson χ2 test, or 
Fisher’s exact test.  Changes of vital parameters pre- and posttreatment were compared 
using paired t-test.   
A linear quantile (median) mixed-effects model was constructed to quantify the 
unadjusted association between treatment and vasodilation (contrast diameter/non-
contrast diameter x 100) while accounting for dependencies within the data set due to 
multiple observations per subject. This modeling approach permitted the estimation of the 
median vasodilation as a function of covariates while avoiding the parametric modeling 
assumptions that are typically associated with linear mixed models. Estimates of fixed-
effects, and their 95% Wald-type confidence intervals, were computed for all model 


parameters. Linear combinations of these parameters were used to estimate overall 
effects, and effects by treatment.  
Two additional models were constructed where we hierarchically accounted for patient 
demographics (i.e., age, gender, BMI and height) and then by patient demographics and 
disease severity measure (i.e., CA score). A subgroup analysis was performed where 
model parameters were estimated by proximal, mid and distal regions. Due to the 
explorative nature of this subgroup analysis, p-values were not adjusted for multiple 
comparisons. 
All analyses were performed using R 3.4.3 (R-Core Team, 2017, Vienna, Austria)  (20) 
and the lqmm R library (21).  
 

ICF_001.pdf: 
Effects of Sublingual and Transdermal Administration of 
Nitroglycerin for Coronary CT Angiography on Image Quality 
 
NCT#: NCT02961946 
 
 
 
Consent Form 
February 23, 2017 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
Page 1 of 8 
 
Subject Identification 
Protocol Title: Effects of sublingual and transdermal administration of 
Nitroglycerin for Coronary CT-Angiography on image quality 
 
Principal Investigator:       
 
Site Principal Investigator:       
 
Description of Subject Population: Adults who are scheduled for coronary CT 
Angiography 
 
 
About this consent form 
 
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form. 
 
Partners HealthCare System is made up of Partners hospitals, health care providers, and 
researchers.  In the rest of this consent form, we refer to the Partners system simply as 
“Partners.” 
 
If you have any questions about the research or about this form, please ask us.  Taking part in 
this research study is up to you.  If you decide to take part in this research study, you must sign 
this form to show that you want to take part.  We will give you a signed copy of this form to 
keep. 
 
 
Why is this research study being done? 
 
The purpose of this research study is to evaluate the image quality of the CT examination of your 
heart. We will give you a medication (Nitroglycerin) that will widen the vessels of your heart. 
There are different ways of giving you this medication. This medication is routinely given for the 
CT examination of your heart. It is a safe drug with few contraindications. If you don’t have a 
contraindication to this medication, you will be randomly placed in one of three groups. You will 
receive this medication as either a spray, a tablet under your tongue, or a patch on your skin. This 
study does not affect the medical decisions made by the doctor who has been treating you. We 
plan to investigate 210 patients in this study.  


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 2 of 8 
 
Subject Identification 
How long will I take part in this research study? 
 
You are scheduled for a CT examination of your heart. There is no additional visit to MGH 
necessary for this research study. The complete CT examination of your heart will take around 
1.5 hours. 
 
What will happen in this research study? 
 
When you decide you want to take part in this study and we verify that you have no 
contraindications to Nitroglycerin, we will ask you to sign this consent form. After signing the 
form, you will be placed in one of 3 groups which decides how we give you the medication. You 
will receive this medication as either a spray, a tablet under your tongue, or a patch on your skin. 
 
An electrocardiogram (ECG) will monitor your heart during the procedure. Blood pressure and 
heart rate will be measured before and after the CT examination. 
After the scan is finished, we make sure that you do not have any reactions to the drugs we gave 
you. After finishing the CT examination we will remove the skin patch if you have received it 
before. No treatment is necessary if you have received the spray or tablet.  
 
After the CT examination we would like to ask you to fill out a survey. This includes questions 
about discomfort during the study. 
 
What are the risks and possible discomforts from being in this research 
study? 
 
The medication is routinely given to improve the image quality. It has a few contra-indications 
which we go check with you before the examination. There is a small risk of allergic reaction 
and low blood pressure.  
 
What are the possible benefits from being in this research study? 
 
The results of this study does not influence your further treatment. Our aim is to optimize the 
process of the CT examination of the heart.  
 
What other treatments or procedures are available for my condition? 
 
Nitroglycerin is routinely given before the CT examination of the heart. We will give you a 
standard Nitroglycerin tablet under the tongue if you do not want to take part in this research 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 3 of 8 
 
Subject Identification 
study. The only time we wouldn’t give patient like you a Nitroglycerin tablet before a CT of your 
heart is if you have a medical condition that makes it unsafe. 
 
Taking part is totally voluntary. You can withdraw your consent and stop taking part in the study 
at any time without affecting your present or future care at the Massachusetts General Hospital.  
 
 
Can I still get medical care within Partners if I don’t take part in this 
research study, or if I stop taking part?  
 
Yes.  Your decision won’t change the medical care you get within Partners now or in the future.  
There will be no penalty, and you won’t lose any benefits you receive now or have a right to 
receive. 
 
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  We will tell you if we learn new 
information that could make you change your mind about taking part in this research study. 
 
 
What should I do if I want to stop taking part in the study? 
 
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed. 
 
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed. 
 
 
Will I be paid to take part in this research study? 
No. 
 
What will I have to pay for if I take part in this research study? 
 
There will be no cost to you for taking part in this research study.   
Costs for your regular, ongoing medical care, which is not a part of this study, will be billed to 
you or to your health insurance company in the usual way. 
 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
Page 4 of 8 
 
Subject Identification 
What happens if I am injured as a result of taking part in this research 
study?
 
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study.  We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury.  We will try to have these costs paid for, but you 
may be responsible for some of them.  For example, if the care is billed to your insurer, you will 
be responsible for payment of any deductibles and co-payments required by your insurer. 
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for an injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form. 
 
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher's name and phone number are listed in the next section of this consent form. 
 
 
If I have questions or concerns about this research study, whom can I 
call? 
 
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want.  
 
XXX is the person in charge of this research study.  You can call his office at XXX M-F 9 am - 5 
pm.  
 
If you have questions about the scheduling of appointments or study visits, call XXX.
 
If you want to speak with someone not directly involved in this research study, please contact 
the Partners Human Research Committee office.  You can call them at 857-282-1900. 
 
You can talk to them about: 
§ Your rights as a research subject 
§ Your concerns about the research 
§ A complaint about the research 
 
Also, if you feel pressured to take part in this research study, or to continue with it, they want to 
know and can help. 
 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 5 of 8 
 
Subject Identification 
If I take part in this research study, how will you protect my privacy? 
 
During this research, identifiable information about your health will be collected.  In the rest of 
this section, we refer to this information simply as “health information.”  In general, under 
federal law, health information is private.  However, there are exceptions to this rule, and you 
should know who may be able to see, use, and share your health information for research and 
why they may need to do so.    
 
In this study, we may collect health information about you from: 
• Past, present, and future medical records 
• Research procedures, including research office visits, tests, interviews, and 
questionnaires 
 
Who may see, use, and share your identifiable health information and why they may 
need to do so: 
• Partners research staff involved in this study 
• The sponsor(s) of this study, and the people or groups it hires to help perform this 
research 
• Other researchers and medical centers that are part of this study and their ethics boards 
• A group that oversees the data (study information) and safety of this research 
• Non-research staff within Partners who need this information to do their jobs (such as for 
treatment, payment (billing), or health care operations) 
• The Partners ethics board that oversees the research and the Partners research quality 
improvement programs. 
• People from organizations that provide independent accreditation and oversight of 
hospitals and research 
• People or groups that we hire to do work for us, such as data storage companies, insurers, 
and lawyers 
• Federal and state agencies (such as the Food and Drug Administration, the Department of 
Health and Human Services, the National Institutes of Health, and other US or foreign 
government bodies that oversee or review research)  
• Public health and safety authorities (for example, if we learn information that could mean 
harm to you or others, we may need to report this, as required by law) 
• Other:        
 
Some people or groups who get your health information might not have to follow the same 
privacy rules that we follow and might use or share your health information without your 
permission in ways that are not described in this form.  For example, we understand that the 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 6 of 8 
 
Subject Identification 
sponsor of this study may use your health information to perform additional research on various 
products or conditions, to obtain regulatory approval of its products, to propose new products, 
and to oversee and improve its products’ performance.  We share your health information only 
when we must, and we ask anyone who receives it from us to take measures to protect your 
privacy.  The sponsor has agreed that it will not contact you without your permission and will not 
use or share your information for any mailing or marketing list.  However, once your information 
is shared outside Partners, we cannot control all the ways that others use or share it and cannot 
promise that it will remain private. 
 
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your health information. 
 
The results of this research study may be published in a medical book or journal, or used to teach 
others.  However, your name or other identifying information will not be used for these purposes 
without your specific permission. 
 
Your Privacy Rights 
 
You have the right not to sign this form that allows us to use and share your health information 
for research; however, if you don’t sign it, you can’t take part in this research study.    
 
You have the right to withdraw your permission for us to use or share your health information 
for this research study.  If you want to withdraw your permission, you must notify the person in 
charge of this research study in writing.  Once permission is withdrawn, you cannot continue to 
take part in the study. 
 
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others. 
 
You have the right to see and get a copy of your health information that is used or shared for 
treatment or for payment.  To ask for this information, please contact the person in charge of this 
research study.  You may only get such information after the research is finished.  
 
 
Informed Consent and Authorization 
 
Statement of Person Giving Informed Consent and Authorization 
 
§ I have read this consent form. 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 7 of 8 
 
Subject Identification 
§ This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study. 
§ I have had the opportunity to ask questions. 
§ I understand the information given to me. 
 
 
Signature of Subject: 
 
I give my consent to take part in this research study and agree to allow my health information to 
be used and shared as described above. 
 
 
 
 
 
 
 
 
Subject 
Date 
Time (optional) 
 
 
Signature of Study Doctor or Person Obtaining Consent: 
 
Statement of Study Doctor or Person Obtaining Consent 
 
§ I have explained the research to the study subject. 
§ I have answered all questions about this research study to the best of my ability. 
 
 
 
 
 
 
 
 
Study Doctor or Person Obtaining Consent 
Date 
Time (optional) 
 
 
Consent of Non-English Speaking Subjects Using the “Short Form” in the 
Subject’s Spoken Language 
 
 
Statement of Hospital Medical Interpreter 
 
As someone who understands both English and the language spoken by the subject, I interpreted, 
in the subject's language, the researcher's presentation of the English consent form.  The subject 
was given the opportunity to ask questions. 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 8 of 8 
 
Subject Identification 
 
 
 
 
 
 
 
Hospital Medical Interpreter 
Date 
Time (optional) 
 
OR 
 
Statement of Other Individual (Non-Interpreter) 
 
As someone who understands both English and the language spoken by the subject, I represent 
that the English version of the consent form was presented orally to the subject in the subject’s 
own language, and that the subject was given the opportunity to ask questions. 
 
 
 
 
 
 
 
 
Name 
Date 
Time (optional) 
Consent Form Version:  02/23/2017