Conditions: Ranitidine Adverse Reaction Pharmacokinetics Food-drug Interaction
Keywords: Ranitidine N-nitrosodimethylamine NDMA Urine excretion
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 18
Healthy volunteers: yes

Brief summary:
Ranitidine is an over-the-counter and prescription drug, which decreases the amount of acid secreted by the stomach. Some ranitidine medicines contain an impurity called N-nitrosodimethylamine (NDMA) at low levels. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables.

The US Food and Drug Administration (FDA) has found levels of NDMA in some ranitidine products similar to the levels you would expect to be exposed to if you ate common foods like grilled or smoked meats. The ranitidine that will be used in this study has been tested twice (months apart) and shown to have stable NDMA levels well below the acceptable daily limit. Of note, the risk of NDMA with ranitidine is only relevant with prolonged chronic administration as at the acceptable limit, there is approximately a 1 in 100,000 chance of cancer after 70 years of exposure to that level.

FDA has also conducted tests that simulate the potential formation of NDMA from ranitidine after it has been exposed to acid in the stomach with a normal diet. Results of these tests indicate that NDMA is not formed in typical stomach conditions. Similarly, if ranitidine is exposed to a simulated small intestinal fluid, NDMA is not formed. Other laboratory experiments suggest a combination of nitrites, such as found in processed meats, and an acidic environment may increase NDMA formation, however the levels of nitrites tested were very high. Separately, a previous study in 10 healthy volunteers showed that volunteers who received ranitidine had an increase in urinary NDMA excreted over 24 h. The level of increase was greater than would be expected from laboratory testing.

This clinical study is being performed to determine if and how much NDMA is produced from ranitidine in the human body and whether nitrite-containing foods may increase formation of NDMA. The study will use a prescription dose of ranitidine (300 mg) to test whether there is increased urinary NDMA excretion levels over 24-hours after ranitidine administration in comparison to placebo when participants are administered low nitrite/NDMA meals and when subjects are administered high nitrite/NDMA meals. On 4 different days, each participant will receive ranitidine or placebo with high nitrite/NDMA meals and ranitidine or placebo with low nitrite/NDMA meals.

Detailed description:
The U.S. Food and Drug Administration (FDA) has learned that some ranitidine medicines, including some products commonly known as the brand-name drug Zantac, contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA) at low levels. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables.

The FDA has been investigating NDMA and other nitrosamine impurities in blood pressure and heart failure medicines called Angiotensin II Receptor Blockers (ARBs) since 2018. In the case of ARBs, the FDA has recommended numerous recalls as it discovered unacceptable levels of nitrosamines.

FDA has found levels of NDMA in ranitidine active pharmaceutical ingredient and finished drugs that are similar to the levels you would expect to be exposed to if you ate common foods like grilled or smoked meats. FDA has requested removal of all ranitidine products from the market because some ranitidine products have NDMA levels above the acceptable limits (96 nanograms per day or 0.32 parts per million for 300 mg per day of ranitidine) and that levels of NDMA in ranitidine may increase to unacceptable levels over time. However, FDA has not withdrawn approvals of ranitidine new drug applications and abbreviated new drug applications and if a company can show, through scientific data, that their ranitidine product is stable and the NDMA levels do not increase over time to unsafe levels, FDA may consider allowing that ranitidine product back on the U.S. market. The ranitidine that will be used in this study has been tested twice (months apart) and shown to have stable NDMA levels well below the acceptable daily limit. Of note, the risk of NDMA with ranitidine is only relevant with prolonged chronic administration as at the acceptable limit, there is approximately a 1 in 100,000 chance of cancer after 70 years of exposure to that level.

FDA has also conducted tests that simulate the potential formation of NDMA from ranitidine after it has been exposed to acid in the stomach with a normal diet. Results of these tests indicate that NDMA is not formed in typical stomach conditions. Similarly, if ranitidine is exposed to a simulated small intestinal fluid, NDMA is not formed. Other in vitro experiments suggest a combination of nitrites, such as found in processed meats, and an acidic environment potentiate formation of NDMA. For that reason, prior to requesting removal of ranitidine products from the market, the FDA had advised consumers who wished to continue taking these medications to consider limiting consumption of nitrite-containing foods.

Separately, a previous study in 10 healthy volunteers showed that single dose administration of ranitidine 150 mg was associated with \~400-fold increase in urinary NDMA excreted over 24 h. This level of increase is substantially greater than would be expected from laboratory testing. Further evaluation is necessary to determine if and how much NDMA is produced from ranitidine in the human body and whether nitrite-containing foods may potentiate formation of NDMA in vivo.

Ranitidine

Ranitidine is an over-the-counter (OTC) and prescription drug. Ranitidine is an histamine-2 (H2) blocker, which decreases the amount of acid secreted by the stomach. Over-the-counter ranitidine is approved to prevent and relieve heartburn associated with acid ingestion and sour stomach and the approved dosage regiment is up to 150 mg twice a day. Prescription ranitidine is approved for multiple indications, including treatment and prevention of ulcers of the stomach and intestines and treatment of gastroesophageal reflux disease and the approved dosage regimen is up to 150 mg twice a day or 300 mg once a day.

Study Primary Objective

1\. To evaluate 24-hour urinary excretion of NDMA after oral administration of ranitidine compared to placebo

Study Exploratory Objectives

1. To evaluate plasma ranitidine, NDMA, and dimethylamine (DMA) after oral administration of ranitidine compared to placebo
2. To evaluate urinary excretion amounts over 24-hours of ranitidine and DMA after oral administration of ranitidine compared to placebo
3. To evaluate 24-hour urinary excretion and plasma concentration of NDMA and DMA with administration of high nitrite/NDMA meals compared to low nitrite/NDMA meals

Study Design

This is a randomized, placebo-controlled, single-dose, 4-period crossover study with 18 healthy subjects. Subjects check-in on Day -2 and receive the following 4 treatments starting on Day 1, with one washout day between treatment days. The treatments consist of oral administration of either a single dose of ranitidine (300 mg) or placebo administered at time 0 hr. All subjects will be provided low nitrite/NDMA meals for the first two periods of the study and high nitrite/NDMA meals for the last two periods of the study. This ordering of meals will allow purchasing a single lot of perishable items for different meals and to simplify meal preparation and serving at the study site. The four treatments are:

A. Ranitidine + low nitrite/NDMA meal;

B. Placebo + low nitrite/NDMA meal;

C. Ranitidine + high nitrite/NDMA meal;

D. Placebo + high nitrite/NDMA meal.

Subjects will report to the study site for screening from Days -28 to -3 and then will return to the site on Day -2 for baseline assessments. Subjects will receive three standardized meals and an evening snack per day starting on Day -1. Subjects will be served meals from a pre-specified menu for check-in and for all washout and treatment days. Subjects will be instructed to finish all their meals within 25 minutes with no leftovers. Subjects will only consume foods served to them at planned meal and snack times.

Two different full day menus of low nitrite/NDMA and high nitrite/NDMA meals have been developed. Additional details regarding the meals will be specified in the Meal Preparation Plan. Meals will be identical for treatments A and B (low nitrite/NDMA meal) of the study and a separate set of identical low nitrite/NDMA meals will be served on the washout days prior to treatment. Likewise, meals will be identical for treatments C and D (high nitrite/NDMA meal) and a separate set of identical high nitrite/NDMA meals will be served on the washout days prior to treatment. The last meal on Day -1, Day 2, Day 4, and Day 6 should be administered at approximately 18:00 to permit at least 12-hour fasting prior to dosing. Outside of meal times, subjects will be provided with distilled water to drink throughout the study.

On study treatment days, the first meal will be provided at the time of dosing. Subjects will be instructed to swallow the medication with approximately 250 mL of room temperature distilled water and begin eating one minute after dosing. Subjects are required to eat each meal in its entirety during the study. If the meal is not finished, the reason should be recorded, along with what was not eaten, and a picture of the remaining food should be taken.

Prior to and following study drug or placebo administration on Day 1, subjects will undergo assessments as described in the Schedule of Events. There will be one day of washout between periods. Participants will be confined in the study clinic from Day -2 until the morning of Day 8.

During the screening visit, the inclusion and exclusion criteria will be reviewed to ensure the subject is eligible for the study. Subjects will be shown the low and high nitrite/NDMA menus and informed that each meal in the menu must be finished in its entirety. The subject must agree to consume all planned meals in order to be eligible to participate. The informed consent form will be reviewed with the subject by a member of the study team and the subject will be encouraged to ask questions to ensure he or she has a good understanding of the study. If the subject is eligible and agrees to participate, the subject will be asked to sign the informed consent form before any study specific procedure is performed, including randomization. Results of all screening tests will be evaluated by the study clinician/investigator against the inclusion/exclusion criteria to confirm subject eligibility. For subjects that are eligible, a molecular diagnostic test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will be performed just before or at check-in.

During the study, urine and blood samples for pharmacokinetic assessments will occur before or after drug or placebo administration at the following timepoints:

* Urine samples will be collected using separate collection containers over 24 h. Collection times will occur at 0 (pre-dose), 3, 6, 9, 12, 15, and 24 h. Subjects will be instructed to void their bladder at each collection time and total weight of the sample will be recorded. If a subject must void their bladder at an unscheduled time, the unscheduled voids will be collected, and total weight of the unscheduled voiding will be recorded. The unscheduled voiding sample will be treated, analytically analyzed, and reported as part of scheduled sample collection for determining cumulative amounts of NDMA, ranitidine, and DMA excreted over 24 h.
* Plasma samples will be collected at 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 11, 14, and 24 h post-dose.

Subjects will be discharged from the study after completion of all study procedures. If a subject discontinues from the study prematurely, all procedures scheduled for the end of the study will be performed. Meals (timing and components), activity levels, and general conditions in the study clinic will be standardized to the extent possible on the treatment days.

Arms:
arm 1: Single dose of ranitidine (300 mg) plus low nitrite/NDMA meals (noncured-meats diet) arm 2: Single dose of placebo plus low nitrite/NDMA meals (noncured-meats diet) arm 3: Single dose of ranitidine (300 mg) plus high nitrite/NDMA meals (cured-meats diet) arm 4: Single dose of placebo plus high nitrite/NDMA meals (cured-meats diet)

Interventions: intervention 1: Ranitidine intervention 2: Placebo intervention 3: Low nitrite/NDMA meals intervention 4: High nitrite/NDMA meals
Intervention descriptions: intervention 1: Ranitidine 300 mg intervention 2: Oral placebo tablet intervention 3: Meals containing low levels of nitrites and NDMA intervention 4: Meals containing higher levels of nitrites and NDMA

Protocol document:
ICF_002.pdf: 
Study Title: Clinical Study to Investigate the Urinary Excretion of N-
nitrosodimethylamine (NDMA) after Ranitidine Administration   
 
Document Title: Informed Consent Form - Study No. SCR-010  
 
Document Date : 14 May 2020 
 
NCT Number: NCT04397445 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 1 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
CONSENT TO TAKE PART IN A CLINICAL RESEARCH STUDY 
AND 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
 
 
Sponsor/Study Title: 
  
US Food and Drug Administration / “Clinical Study to Investigate the 
Urinary Excretion of N-nitrosodimethylamine (NDMA) after Ranitidine 
Administration.” 
 
Protocol Number: 
 
SCR-010 
Principal 
Investigator: 
  
Study Doctor: 
 
Colleen Nalepinski, MPAS, PA-C. 
 
Carlos Sanabria, MD. 
Telephone: 
 
800.597.4507 (Recruitment Department) 
855.622.8100 (24-hour urgent question/care) 
 
Additional Contact(s): 
Sarah K., Project Manager 
Jody H., Project Manager 
 
Address: 
 
 
Spaulding Clinical Research, LLC 
525 S Silverbrook Dr. 
West Bend, WI 53095 
 
SUBJECT SCREENING #_______ 
 
Please read this form carefully. Take time to ask the study doctor or study staff as many questions about 
the study as you would like. The study doctor or study staff can explain words or information that you do 
not understand. Reading this form and talking to the study doctor or study staff may help you decide 
whether to take part or not. If you decide to take part in this study, you must sign your name at the end of 
this form and date it. You cannot take part in this research study until you sign and date this form. 
 
WHAT IS A SUBJECT INFORMED CONSENT? 
 
You are being asked to take part in a research study of a drug called ranitidine in oral pill formulation. 
This drug is already approved by the U.S. Food and Drug Administration (FDA).  Over-the-counter 
(OTC) ranitidine is approved to prevent and relieve heartburn associated with acid ingestion and sour 
stomach and prescription ranitidine is approved for multiple indications including treatment and 
prevention of ulcers of the stomach and intestines and treatment of gastroesophageal reflux disease 
(GRDS) related conditions. This research study will look at what happens to ranitidine after you take it 
with different diets. Before you decide to take part, you should understand the possible benefits and risks 
associated with this study. This process is known as informed consent and means that you will: 
 
• 
Receive detailed information about this research study. 
• 
Have a chance to ask and receive answers to any questions you may have. 
• 
Be asked to read and sign and date this informed consent, once you understand the study and wish 
to take part. 
• 
Be given a signed and dated copy of this informed consent to keep. 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 2 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
 
Taking part in this study is entirely voluntary. 
 
WHY IS THIS DRUG BEING STUDIED? 
 
This is a clinical research study. This study is sponsored by The US Food and Drug Administration, based 
in Maryland, USA.  
The U.S. Food and Drug Administration has learned that some ranitidine products, including some 
products commonly known as the brand-name drug Zantac, contain low levels of an impurity called N-
nitrosodimethylamine (NDMA). NDMA is a substance that possibly causes cancer based on results from 
laboratory tests. NDMA is known to be in the environment and is found in water and foods, including 
meats, dairy products, and vegetables. 
The U.S. Food and Drug Administration has requested removal of all ranitidine products from the market 
because some ranitidine products have NDMA levels above the acceptable limits (96 nanograms per day 
or 0.32 ppm for 300 mg per day of ranitidine).  At the acceptable limit, there is approximately a 1 in 
100,000 chance of cancer after 70 years of exposure to that level.  The ranitidine you will take in this 
study has been tested and shown to have NDMA levels well below the acceptable limits and these levels 
are stable on repeated testing. 
It is unknown whether NDMA is formed in the body after ranitidine is given and whether administering 
ranitidine with certain foods affects this. The goal of this study is to use a single prescription dose of 
ranitidine (300 mg) to test whether there is increased level of NDMA in your urine in the 24 hours 
following dosing with ranitidine compared to when you are dosed with a placebo. This will be done when 
ranitidine is given once with meals low in NDMA and nitrites (common preservative in meats and found 
in other foods), and when given once with meals high in NDMA and nitrites.   
 
WHO IS BEING ASKED TO TAKE PART IN THIS STUDY? 
 
Approximately eighteen healthy male and female adult subjects, who meet the requirements following a 
screening visit, will be enrolled in the study.   
 
You have been asked to take part in this study because you are in general good health, are 18-50 years of 
age, have no history of heart or liver disease, no history of allergies, no symptoms consistent with 
coronavirus disease of 2019 (COVID-19), no underlying medical conditions that put you at higher risk for 
COVID-19 complications and have not participated in another research study for an experimental drug (or 
a medical device) within 30 days of the first dose of study drug.  
 
HOW MUCH TIME IS REQUIRED TO TAKE PART IN THE STUDY? 
 
If you decide to take part in the study, you will be asked to attend a screening visit. If you pass the 
screening visit, you will return to the clinic and remain there for four dosing periods.  You will check-in 
on day -2, have a “washout day” on day -1 and then receive study treatment on days 1, 3, 5 and 7. There 
will be additional “washout days” on days 2, 4, and 6. Altogether you will be in house from day -2 to day 
8, for a total of 10 days and 9 nights in house.  
 
The duration of your participation in the study from screening to final follow-up will be up to 38 days. 
 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 3 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
INFORMATION FOR FEMALE SUBJECTS 
 
You should not screen for this study if: 
 
• 
There is any possibility that you may become, or are pregnant, 
• 
You have given birth in the last 3 months, or 
• 
You are breast feeding. 
 
You may screen for this study if:  
 
• 
You have had a hysterectomy (uterus removed) or bilateral oophorectomy (ovaries removed), 
confirmed with documentation, or 
• 
You are of post-menopausal age and have not had a menstrual period for 2 years, confirmed with 
hormone level at screening, or 
• 
You have a vasectomized partner who has been documented to no longer produce sperm, or 
• 
You are using TWO highly reliable methods of contraception to avoid pregnancy throughout the 
study and for at least 1 month after last study drug administration. Highly reliable methods of 
birth control include: 
 
o Hormonal implants/patch,  
o Oral hormonal contraceptives,  
o Injectable hormones,  
o Intra-uterine device (IUD), 
o Approved cervical ring,  
o Diaphragm with spermicide or condom (female or male) with spermicide 
 
One of the methods of birth control used must be a barrier method. The use of spermicide alone and 
condom alone are not acceptable methods of contraception.  
 
Except for continuous abstinence (no sexual intercourse with a male partner), no method of birth control 
can be considered 100% reliable in preventing pregnancy. Although the risk of becoming pregnant is low 
with many methods, unplanned pregnancies may occur with all birth control methods. Most occur 
because of improper or irregular use of the birth control method. If you are usually not sexually active but 
become sexually active, you must follow the advice documented above regarding contraceptive methods. 
 
All females enrolled in the study will have a pregnancy test performed at screening and at check-in on 
Day -2.  
 
Please be aware that a pregnancy test may not be positive until 12 days after conception (fertilization of 
the egg by sperm). Therefore, if you do not follow the study birth control requirements and/or your birth 
control method has failed, you will not be able to count on a negative test to confirm that you are not 
pregnant. 
 
If you know that you have not followed the study birth control requirements outlined above, then you 
must immediately inform us. You must not take any dose of the study drug if you have not followed these 
requirements. If you become pregnant, your pregnancy will be followed to document the outcome.  All 
live births must be followed for a minimum of 30 days or until the first well-baby visit. 
 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 4 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
INFORMATION FOR MALE SUBJECTS   
 
The effect of the study drug on male sperm is unknown. In rare cases, drugs may damage sperm in ways 
that affect a child that is fathered. Affected sperm may be present in the semen for about 2 months. 
Therefore, it is recommended to avoid fathering a child for 90 days after the last dose of the study drug. 
 
Male subjects must ensure that TWO acceptable methods of contraception are used for the entire duration 
of the study, one of which must be a barrier method, up to the study follow-up visit, if applicable. 
 
Periodic abstinence and withdrawal are not acceptable methods of contraception. 
 
HOW WILL YOU KNOW IF YOU ARE ELIGIBLE TO TAKE PART? 
 
At the beginning of the Screening visit, Informed Consent will be obtained. You may need to visit the 
study site more than once to complete the screening tests. 
 
You will need to fast for at least 8 hours prior to your arrival at Spaulding Clinical Research, LLC. for the 
clinical laboratory tests and H-pylori breath test for screening, meaning you should not eat any food and 
should only have water to drink. 
 
Before starting the study, the following screening procedures will be performed:  
 
• 
A complete medical history and physical examination (including height and weight 
measurements for Body Mass Index (BMI, a way to tell if your weight is proportional to your 
height). 
• 
Assessment of blood pressure, respiratory rate, heart rate, and oral temperature. 
• 
A complete history of relevant allergies or drug sensitivities. 
• 
An electrocardiogram (ECG), (a painless recording of the electrical activity of your heart). 
• 
You will be asked if you have taken any medication recently. 
• 
You will be asked if you have been feeling ill recently. 
• 
Clinical laboratory tests (urine and blood samples), including screening for drugs, alcohol, and 
pregnancy tests (all female subjects), and testing for HIV, hepatitis B and C. Positive results of 
HIV or hepatitis tests will be reported to local health authorities as required by state law.   
• 
You will be given an H-pylori breath test to find out whether you have the H. pylori bacteria in 
your gut.  If you do you cannot be in this trial.  You will have to fast before the test then have a 
drink of water into which a granulated powder has been dissolved.  Once this solution is in your 
stomach, if it mixes with H. pylori bacteria it can be picked up in the breath you exhale through a 
breath test instrument.  The test is safe and painless.    
If you meet the “entry criteria” of the study, according to the study doctor, you will be tested again when 
you are admitted to Spaulding Clinical Research, LLC. You will have the entry criteria reviewed again to 
ensure that you still are eligible for the study.  
In addition, prior to admission you will have a diagnostic test performed to detect severe acute respiratory 
syndrome coronavirus 2 (called “coronavirus” from now on), which is the virus that causes COVID-19. 
Depending on the time required to return results, this may be performed ~2 days before check-in or may 
be performed on the check-in day. You will only be allowed to be admitted if your coronavirus test is 
negative. In addition, when entering the building for screening and check-in, triage for COVID-19 will 
take place. The exact details of what will occur at triage may change as additional information or testing 
is available, however as of now it is planned to include asking about any potential contacts with COVID-


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 5 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
19, signs and symptoms associated with COVID-19, temperature monitoring and potentially antibody 
screening for coronavirus. 
 
HOW WILL THE STUDY BE DONE? 
 
Eighteen healthy adult subjects, both male and female will be enrolled in this study. The study will 
consist of four study treatment periods of one day each.  There will be a washout period (a period of time 
to allow the study drug to leave your system) of one day after each dose day, but you will remain at 
Spaulding Clinical Research for the entire duration of the study. This will be 10 days and 9 nights in total. 
All subjects will receive the following four study treatments in a randomized (by chance) order over the 
four study treatment periods: 
 
A. Ranitidine + low nitrite/NDMA meals;  
B. Placebo + low nitrite/NDMA meals;  
C. Ranitidine + high nitrite/NDMA meals;  
D. Placebo + high nitrite/NDMA meals. 
 
Once the study doctor determines that you are eligible to participate, you will be enrolled and randomized 
to receive either study treatment A or study treatment B for the first and second periods and to receive 
either study treatment C or study treatment D for the third and fourth periods. You will not be allowed to 
choose your study group or the order in which you receive the dosing regimens. Because this is a double 
blinded study, neither you nor the study doctor or study staff will know which study treatment you are 
receiving. However, your study doctor can find out which group you are in if there is an emergency. 
When you receive the study drug you will be asked to wear a blindfold so that you are unable to see the 
study drug or placebo.  A placebo is a medically inactive substance, which looks like the study drug. 
 
You will have received all of the above regimens by the end of the study. There will be one day in 
between each regimen. You will go through the same tests and procedures described below for any of the 
study treatments you receive.  
 
WHAT TESTS AND PROCEDURES WILL BE USED IN THE STUDY? 
 
Day –2 Admission 
 
Upon admission to Spaulding Clinical Research, LLC., you will be given an identity band to wear 
throughout your entire stay in the unit. 
 
You will need to fast for at least 8 hours prior to your arrival meaning you should not eat any food and 
should only have water to drink.  
 
The following admission procedures will be performed:  
 
• 
Perform/review results from coronavirus test.  
• 
Medical history updates. 
• 
Physical examination.  
• 
Clinical laboratory tests (urine and blood samples), including screening for drugs, alcohol, and 
pregnancy tests (all female subjects).  
• 
An electrocardiogram (ECG), (a painless recording of the electrical activity of your heart). 
• 
You will be asked for details of any medication taken since the screening or previous visit. 
• 
You will be asked if you have been ill since the screening or previous visit. 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 6 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
• 
You will be asked if you complied with study restrictions. 
• 
Meals (lunch, dinner and a small snack). 
• 
Inclusion/Exclusion assessment and preparation for randomization. 
 
The results from these tests will help the study staff determine whether you are still eligible to enter the 
study. None of these tests are investigational and are commonly performed during routine medical care. 
 
Study Treatment (Days 1, 3, 5 and 7)  
 
• 
Adverse event assessment (check for side effects) and changes in concomitant medications 
(medicines you are currently taking). 
• 
Randomization (assignment to a dose group) Period 1 only. 
• 
Assessment of temperature, blood pressure and heart rate.  
• 
Administration of study drug or placebo.  
• 
Breakfast within 2 minutes of taking the study drug or placebo.  
• 
Meals (lunch, dinner, and a small snack). 
• 
Pharmacokinetic (PK) blood and urine sampling (blood and urine samples for determination of 
study drug levels, NDMA and other constituents). Pharmacokinetics looks at how your body:  
• Takes the study drug into your bloodstream. 
• Delivers the study drug through the blood. 
• Breaks down or processes the study drug. 
• Removes the study drug. 
• 
In order to assess the amount of NDMA in your urine you will have all your urine collected at 
multiple timepoints over 24 hours after you take ranitidine or placebo. You will be encouraged to 
pass urine only at the specific timepoints, however, all urine will be captured over the 24-hour 
period.   
 
Washout (Days 2, 4 and 6) 
 
• 
Adverse event assessment and changes in concomitant medications. 
• 
PK blood and urine collection in the morning only for determination of study drug levels, 
NDMA, and other constituents.  
• 
Meals (Breakfast, Lunch, Dinner and a small snack). 
• 
Assessment of blood pressure, heart rate, and oral temperature.  
 
Discharge (Day 8) 
 
• 
Adverse event assessment and changes in concomitant medications. 
• 
PK blood and urine collection in the morning only for determination of study drug levels, 
NDMA, and other constituents.  
• 
Breakfast. 
• 
Clinical laboratory tests (urine and blood samples) for safety and also for drugs and alcohol and 
pregnancy. 
• 
An electrocardiogram (ECG), (a painless recording of the electrical activity of your heart). 
• 
Physical examination.  
• 
Assessment of blood pressure, heart rate, and oral temperature.  
• 
Discharge from Spaulding Clinical. 
 
 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 7 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
INFORMATION OBTAINED DURING THE STUDY 
 
Blood Sampling 
 
Blood samples will be collected for measurement of levels of ranitidine, NDMA and other constituents in 
every study treatment period at the following times: 
 
• 
Days 1, 3, 5 and 7 at: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 11, 14, and 24 hrs post-dose for a 
total of approximately 52 blood collections for determining study drug and NDMA levels.  
• 
The total number of blood draws including screening and safety laboratory draws is 
approximately 55 blood collections.  
 
You will have numerous blood samples drawn during the entire study for study drug levels as shown 
above, and three safety laboratory draws throughout the study. The blood samples may be taken by 
individual needle sticks into one of your arm veins, or, if necessary, by an indwelling catheter (a thin 
plastic tube placed in a vein in your arm). The total amount of blood taken for the entire study will be 
approximately 464 mL (416 mL for the determination of ranitidine, NDMA and other constituent 
concentrations, and approximately 48 mL for clinical laboratory tests) or about 2 cups for the entire study. 
For comparison, a standard blood donation (once every 56 days) is 470 mL or about 2 cups taken at one 
time. 
 
Urine Sampling 
 
You will have urine samples collected at screening, check in on day -2 and at check out on day 8.  These 
will be used to screen for either alcohol or drugs, and for routine safety analysis. 
 
On days 1, 3, 5 and 7 all your urine will be collected for 24 hours for measurement of study drug, NDMA, 
and other constituents for assessment of your body’s response. Your urine will be collected at specific 
timepoints and you will be encouraged to pass urine only at these timepoints. 
 
ECG Measurements 
 
Safety ECG measurements will occur at your screening visit, check in on day -2 and at check out on day 
8.   
 
Some individuals may develop redness, irritation, or discoloration of the skin at the site of ECG 
electrodes placed on the chest/body. This may develop due to sensitivity to the electrodes or to our skin 
preparation procedure. In order to get the quality results we need, it is necessary for us lightly scrub the 
skin with an abrasive pad to remove any skin impedance such as oil, dead skin cells and lotions. We may 
trace each electrode site with a permanent marker to assure electrodes are placed in the same place on the 
body for each ECG event to maintain quality and consistent results. This tracing may occur as often as 
once a day during confinement. 
 
WHAT ARE YOUR RESTRICTIONS DURING THE STUDY? 
 
You will need to avoid the following while taking part in this study (including between screening and 
check in), and for some of the following you will need to confirm you have not taken certain medications 
within a certain time prior to screening:   
 
• 
Subjects should not use antacids or heart burn medications for 2 weeks before screening. 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 8 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
• 
Subjects should not use prescription or non-prescription drugs, including antacids, heart burn 
medications, aspirin or NSAIDs (like ibuprofen and naproxen) excluding oral contraceptives or 
acetaminophen (Tylenol) for 28 days prior to the first dose until they have completed study 
participation.  
• 
Subjects should not use mouthwash from day -2 until they have completed study participation. 
• 
Subjects should not consume alcohol, grapefruit or grapefruit juice, caffeine or other 
methylxanthines (for example, coffee, tea, cola or chocolate) for 24 hr prior to first dose until 
they have completed study participation.   
• 
Male and female subjects must adhere to contraception methods as previously stated. 
• 
All subjects will fast for a minimum of 12 hours overnight ahead of dosing on days 1,3, 5 and 7, 
and will fast for 8 hours before safety labs are drawn at screening, day -2 and day 8.   
You will receive a diet that does not contain any alcohol or caffeine. You must eat all of each meal, snack 
and drink that is served to you and eat at a reasonable pace (within 25 minutes) throughout the entire 
study from the morning of day -1 until the end of day 7. You will be shown the menu for this study in full 
during your screening visit.  If you think you may be unable to eat each meal in full throughout the entire 
study you should not agree to be part of this study.  While you are at Spaulding Clinical you will be 
provided only distilled water to drink, not water from a tap or water fountain.    
 
You may eat only meals and snacks that are provided to you during periods of your stay. 
 
Due to current precautions being taken for COVID-19, the following restrictions will be in place: 
 
• 
Subjects must always wear masks except when in a private room without anyone else present or 
for a limited time for a study procedure (for example, study drug administration or eating) when 
instructed by study staff.  
• 
Subjects must practice social distancing, which will include having 1 subject per room for 
overnight stays and having common areas closed. Food will be served at subjects’ rooms with 
subjects sitting at their doorway to eat. Subjects will spend most of their time in their rooms 
except for specified times for walking in the halls (with masks). 
• 
Subjects must practice regular handwashing with soap and water, scrubbing hands for at least 20 
seconds or with approved hand sanitizer as supplied by study staff.  
 
If new information becomes available, there could be other precautions that lead to additional restrictions. 
 
ARE THERE RISKS TO YOU IF YOU ARE IN THIS STUDY? 
 
Please be advised that non-pharmacological treatments (such as heating pack, stretches, hydration, etc.) 
are our first line of therapy for mild adverse events (side effect). Our study doctor will be notified if a 
concomitant medication may be needed to treat an adverse event. Following the protocol (study plan) 
guidelines, the study doctor will assess your adverse event and develop a treatment plan. 
 
Risks are possible side effects of the study drug, the positive control medicine (placebo), and those of 
taking blood and other medical procedures: 
 
For Ranitidine (study drug):   
 
Headache, sometimes severe, is the most common adverse effect. The following additional adverse events 
have been reported in patients taking ranitidine, but whether they were caused by ranitidine has been 
unclear in many cases:  


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 9 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
 
• 
Neurological effects: Rarely malaise (general discomfort), dizziness, somnolence (sleepiness), 
insomnia (difficulty sleeping), vertigo (dizziness). Rare cases of reversible mental confusion 
(confusion that goes away after stopping the study drug), agitation, depression, hallucinations 
mainly in severely ill elderly patients, reversible blurred vision, or reversible involuntary motor 
disturbances. 
• 
Heart effects: Rare reports of abnormal heart rhythms. 
• 
Abdominal effects: Constipation, diarrhea, nausea/vomiting and abdominal discomfort/pain. 
Occasional reports of hepatitis (liver inflammation). Rare cases of liver failure or pancreatitis 
(inflammation of pancreas). 
• 
Musculoskeletal effects: Rare reports of arthralgias (joint pain) and myalgias (muscle aches). 
• 
Blood/vessel effects: Leukopenia, granulocytopenia and thrombocytopenia (decreased blood cell 
counts) in a few patients. Rare cases of vasculitis (blood vessel inflammation), agranulocytosis or 
pancytopenia (more severe decreased blood counts), and exceedingly rare cases of acquired 
immune hemolytic anemia (low red blood cell count). 
• 
Sexual effects: Controlled studies have shown no hormone effects, however, occasional cases of 
impotence (erectile dysfunction), and loss of libido (sex drive) have been reported in males, but 
the rates did not differ from that in the general population. Rare cases of breast symptoms and 
conditions, including galactorrhea (milky nipple discharge) and gynecomastia (enlarged breast 
tissue). 
• 
Skin/hair effects: Rash, including rare cases of erythema multiforme (skin or mouth lesions). Rare 
cases of alopecia (hair loss). 
• 
Lung effects: Potential increased risk of pneumonia (lung infection). 
• 
Other: Rare cases of hypersensitivity reactions (exaggerated immune response that can cause 
trouble breathing, fever, rash or increased blood counts), anaphylaxis (severe allergic reaction), 
angioneurotic edema (swelling under the skin), acute interstitial nephritis (kidney inflammation), 
and small increases in serum creatinine (effect on kidneys). 
 
Problems or side effects that are not now known could also occur. You will be given any new information 
that may affect your willingness to start or continue in the study. 
 
The tests done at each visit are standard medical tests. The most unpleasant is often having blood samples 
taken. The risks of taking blood may include: 
• 
Fainting 
• 
Pain 
• 
Bruising 
• 
Rarely, there may be a small blood clot or infection at the site of the needle puncture 
 
The blood pressure cuff may also cause discomfort or bruising to the upper arm.  
 
You will be asked to fast during this study, and you will not be able to drink alcohol, use nicotine-
containing products, or drink beverages containing caffeine or alcohol.  This may cause you some 
discomfort. 
 
In rare instances where a nurse, a doctor, or a technician, sustains an exposure to your blood, tissue or 
body fluids by needle stick, cut or splash to mucosa or damaged skin, it may be necessary to test your 
blood, tissue, or body fluid sample for certain viral infections including Hepatitis B and C and HIV on the 
sample already available. This is to enable that person to receive appropriate counseling, monitoring and 
treatment if necessary. In this instance the study doctor or designee will offer you the information relevant 
to your health and advise you on the next steps. Confidentiality of your data will be respected at all times 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 10 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
according to the state law. The study doctor may be required by law to report the result of these tests to 
the local health authority. 
 
Unknown Risks 
 
As described in the earlier section on “Why is this drug being studied?” some ranitidine products have 
been found to contain NDMA, which is a substance that possibly causes cancer. However, the ranitidine 
being used in this study has been tested twice and shown to have NDMA levels well below the acceptable 
limits. It is possible that some NDMA is formed in the body after taking ranitidine. However, your risk 
remains very low as at the acceptable limit for NDMA, there is approximately a 1 in 100,000 chance of 
cancer after 70 years of exposure to that level. During this study, you will only receive two doses of 
ranitidine.  
 
As with any drug, it is possible that you could experience an allergic reaction to the study drug used in 
this study. Symptoms of any allergic reaction can include: 
• 
Rash  
• 
Hives  
• 
Itching 
• 
Difficulty breathing 
• 
Closing of the throat  
• 
Swelling of the lips, tongue or face 
• 
Rarely, death. 
 
If you think you are having a severe allergic reaction, while outside the study center call 9-1-1 and 
seek medical attention immediately. 
 
It is very important that you tell the study doctor and the study staff about any side effects that you might 
experience. 
 
You may experience side effects or discomforts that are not listed on this form. Tell your study doctor or 
study staff immediately if you have any problems. Your safety will be closely monitored during the 
course of the study. 
 
For ECG Monitoring 
 
It is possible to be sensitive to the adhesives used on the electrodes that are applied to your chest when 
having an ECG performed. If this is the case, you could develop a temporary redness, irritation, or 
discoloration of the skin where the electrodes were applied. 
 
HIV Testing 
 
The risks of HIV testing include psychological and social risks. A positive test can lead to restrictions in 
freedom of travel to some countries and possible prejudices in job employment, insurance eligibility, 
housing and other forms of discrimination.  Positive HIV test results must be reported to health authorities 
under state law. 
 
Reproductive Risks 
 
The effects of the study drug on human pregnancy and the unborn child (fetus) are unknown. Therefore, it 
is very important that you do everything within your power not to become pregnant, or father a child 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 11 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
during this study and for 30 days following the last dose. Please ensure that you follow the study birth 
control requirements outlined in the sections regarding information for male and female subjects above. 
 
If you become pregnant during the course of the study, you will be withdrawn from the study 
immediately. Neither Spaulding Clinical Research, LLC. nor the sponsor will be responsible for the cost 
of any obstetric or related care, or for your child's care. Female subjects are agreeing, by signing and 
dating this form, that information about your pregnancy and birth of your child may be collected. The 
information collected will include your health and the health of your unborn child during pregnancy, 
pregnancy outcome (miscarriage, termination, live birth, etc.), and the health of the baby after it is born 
(for a minimum of 30 days or until the first well baby visit). 
 
COVID-19 Risks 
 
Despite the extra precautions (for example COVID-19 triage at screening/check-in, coronavirus testing, 
mandatory masks for study subjects and staff, social distancing including single-occupancy rooms, extra 
hand washing) that will be in place, there is still a risk of developing COVID-19 just as there is when you 
are not at Spaulding Clinical. Tell your study doctor or study staff about any new symptoms you develop 
during the study.  
 
The U.S. Centers for Disease Control and Prevention (CDC) currently highlights that people with the 
following symptoms may have COVID-19: 
• 
Cough 
• 
Shortness of breath or difficulty breathing 
 
Or at least two of these symptoms: 
• 
Fever 
• 
Chills 
• 
Repeated shaking with chills 
• 
Muscle pain 
• 
Headache 
• 
Sore throat 
• 
New loss of taste or smell 
 
It is important to note that COVID-19 can also present with other symptoms and just because you develop 
any of the above symptoms does not mean that you have COVID-19. Your study doctor will evaluate if 
your symptoms warrant additional testing, further isolation from other study subjects/staff until testing 
results are obtained, and any treatment. 
 
NEW FINDINGS 
 
Your study doctor will tell you of any information learned during the course of the study that might cause 
you to change your mind about taking part in the study. You may contact the study doctor at any time 
after your participation ends to find out if any new information about this study has become available. 
 
WHAT IS THE ALTERNATIVE TO BEING IN THE STUDY? 
 
Since this is a study involving healthy subjects, your alternative is not to take part. 
 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 12 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
WILL YOU BENEFIT FROM TAKING PART IN THE STUDY? 
 
You will not receive direct medical benefit from receiving the study drug. You may benefit by having 
your medical history recorded, undergoing a physical examination, and having blood and urine tests as 
they apply to this research project.    
 
Just by taking part in this research study, you may be helping future patients by providing important 
information about the study drug and by contributing to medical knowledge. 
 
WHO IS PAYING FOR THIS STUDY? 
 
The United States Food and Drug Administration is the Sponsor of the study.  
 
The US Food and Drug Administration pays the study doctor to run this study. 
 
The study drug and all tests, procedures and visits required by the study are provided at no cost to you.  
The sponsor, The US Food and Drug Administration pays for them. 
 
Information about this study is confidential. This information belongs to The US Food and Drug 
Administration.  We ask that you keep it private. You can discuss this information in private with your 
doctor or family to talk about your healthcare or to decide about taking part in this study. 
 
WILL YOU BE PAID FOR BEING IN THIS STUDY? 
 
Compensation for screening is as follows: 
 
• 
$55.00 if you qualify for a study. $55.00 for your time and inconvenience if you do not qualify 
for a study.  
• 
If the results of the drug and alcohol tests are positive, or if you attempt to falsify your drug 
screen you will not receive any compensation. 
• 
If you screen for the study, qualify and are enrolled, your screening payment will be included in 
your first stipend payment. If you are not accepted into the study your screening payment will be 
processed and mailed within 7 calendar days of study enrollment. 
 
Compensation for this study is as follows: 
 
For subjects that complete the entire study (Day -2 to Day 8), you will receive up to $3,625.00. This 
payment will be made in two separate payments as follows: 
 
• 
$1000.00 will be paid after all check out procedures have been completed at the end of Day 8, 
• 
The remaining $2,625.00 will be paid after any additional follow up procedures are completed, 
and all results are reviewed. 
 
If you withdraw from the study early, you will only be paid for the visits you completed. You will receive 
$100.00 for each full day that you were in-house. 
 
NOTE:  You may be required to return to the clinic for repeat blood test or other assessment (ECG, 
physical, vital signs) in between periods or after the final check out. This is considered part of the study 
and no additional compensation is available. Your final payment will not be released until all follow up 
procedures have been completed and accepted by the study doctor. Once follow up procedures have been 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 13 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
completed and accepted by study doctor, your final payment will be processed and mailed within 14 
calendar days. 
 
NOTE: If you meet eligibility criteria you may be asked to be an alternate subject. Alternate subjects are 
eligible subjects that are in addition to the number of subjects in the event an enrolled subject drops out 
before their dose can take place or in the event it is not safe for a subject to move forward with dosing. If 
you are selected as an alternate subject and you agree to participate as an alternate subject, you may 
receive up to $250 if you are not needed to dose. If you are needed to replace a subject, you will be paid 
as stated for participating in and completing the study. If you agree to be an alternate subject, you will 
have all of the predose procedures as the enrolled subjects so that if you are needed, you will be ready to 
participate. If you are not needed you will be discharged shortly after completion of the dosing round. 
 
No deductions for any state or federal withholding or any other similar taxes will be made and you are 
solely responsible for reporting such payments on your state and federal income tax returns.   
 
If you need to stay at Spaulding Clinical Research, LLC. for a longer period of time for safety reasons, 
you will be compensated at a rate proportional to the entire compensation for the study. 
 
If you are dismissed from the study for medical reasons OR if the study is temporarily or permanently 
halted, your compensation will be proportional to the time you spend in the study. 
 
If you are dismissed from the study because you have not complied with the instructions of the study 
staff, no compensation is available. Non-compliance includes, but is not limited to, improper conduct, 
taking alcohol and/or any drugs (including recreational drugs), tampering with the study drug, or 
consuming any foods/beverages not allowed in the study. 
Subjects may be reimbursed for travels expenses depending on need and Sponsor approval. 
 
By signing and dating this consent, you expressly agree that you are an Independent Contractor for 
Spaulding Clinical Research, LLC. As an Independent Contractor, you will receive a 1099 form from 
Spaulding Clinical Research, LLC. The 1099 form shall document and report all payments and/or study 
stipends you received as an Independent Contractor for Spaulding Clinical Research, LLC.  In addition, 
because you are an Independent Contractor and will be receiving payments and/or study stipends, those 
earnings are subject to wage garnishment.  If Spaulding Clinical receives an Earnings Garnishment Notice 
(or similar) from a State or Federal legal entity, we will adhere to that garnishment.   
 
COMPENSATION FOR INJURY 
 
It is important that you follow carefully all the instructions given by the study doctor and his/her study 
staff regarding this study.   
 
If you become ill or are physically injured as a result of participation in this study, please contact the 
study doctor right away at the telephone number listed on page one of this consent form. He/she will treat 
you or refer you for treatment. 
 
Spaulding Clinical Research, LLC. and/or its affiliated institutions has not set aside funds to provide you 
with financial compensation or reimbursement for the cost of care provided to treat a research-related 
injury or for other expenses arising from a research-related injury. You or your insurer will be responsible 
for the payment of any medical treatments for research related injuries or illness. By signing and dating 
this consent form, you are not giving up any legal rights. If this research study is conducted in a negligent 
manner and you are injured as a direct result, you may be able to recover the costs of care and other 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 14 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
damages from the individuals or organizations responsible for your injury as you still have the right to 
seek compensation for injury related to malpractice, negligence, fault, guilt or blame of those involved in 
the research. 
 
PROTECTING THE PRIVACY OF YOUR HEALTH DATA 
 
Unless required by law, your name will not be disclosed outside the research clinic. Your name will be 
available only to the following people or agencies: the study doctor and study staff; and authorized 
representatives of the study doctor; institutional review board (IRB), health authority inspectors, such as 
the US Food & Drug Administration and the European Medicines Agency; the US Food and Drug 
Administration, study monitors and auditors; and authorized Clinical Research Organization 
representatives. The above mentioned individuals will use the personal information collected as part of 
this study, including your medical records (“Study Information”) to check that the study is conducted 
correctly and to ensure the accuracy of the study information. These people are all obligated to maintain 
confidentiality by the nature of their work, or are bound by confidentiality agreements. If required, the 
study doctor may contact your personal  doctor to collect additional medical information and your past 
medical history. 
 
The study doctor may only share your study information with people whom you have permitted to see it. 
However once your study information is shared as authorized, it may no longer be protected by Federal 
law and may be re-disclosed without your permission. 
 
While participating in this study, the study doctor will replace your name with a special code that 
identifies you. This code, along with your study information, will be used by the study sponsor, the US 
Food and Drug Administration and their representatives, for the study purposes mentioned above and to 
help establish whether the study drug is safe and effective. The US Food and Drug Administration may 
share your coded information, as necessary, with the US Food and Drug Administration affiliates who 
work within the scope of this consent; people and companies who work with the US Food and Drug 
Administration and who work within the scope of this consent; Ethics committees and Regulatory 
agencies such as the US Food & Drug Administration, the National Health Authorities, and the European 
Medicines Agency. 
 
You should be aware that some countries may not offer the same level of privacy protection as you are 
used to in the country where you live or where this study is conducted. However, the US Food and Drug 
Administration will keep any information it receives to the same standard of confidentiality as far as 
permitted by applicable local law. The US Food and Drug Administration has also entered into 
agreements with third parties working for the US Food and Drug Administration to secure adequate 
protection of your data and samples.  
 
The Study Information will be kept confidential within the limits of the law and used only for research 
purposes mentioned above. De-identified data (data not linked to you) from the study may be released to a 
data warehouse (location that will store the data) or as a part of a publication. Research may be performed 
by researchers outside of the U.S. Food and Drug Administration and Spaulding Clinical Research, LLC. 
If the results of this study are published or presented in a meeting, you will not be named and no one will 
be able to tell that you were in the study from the publication or presentation.  
 
Your participation in this study is voluntary and you may cancel this consent at any time and without any 
reason. If you do so, your participation in the study will end and the study staff will stop collecting 
information from you, however, you will be asked to come back to the site for an end of study visit. Your 
samples will then be destroyed. However, the US Food and Drug Administration will continue to retain 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 15 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
and use any research results that have already been collected to verify the scientific integrity of the study. 
If you wish to leave the study inform your study doctor. 
 
You have the right to review your Study Information and medical records and request changes to the 
Study Information if it is not correct. However, please note that during the study, access to Study 
Information may be limited if it weakens the integrity of the research. You may have access to the Study 
Information held by the study doctor at the end of the study. 
 
If you have any questions about the collection and use of information about you, or would like to exercise 
rights that you may have regarding this information, you should ask your study doctor.  
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a research-related injury, or have 
questions, concerns or complaints about the study, please contact the study doctor at the telephone 
number listed on the first page of this consent document. If you seek emergency care, or hospitalization is 
required, alert the treating physician that you are participating in this research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the rights of 
research subjects. If you have any questions about your rights as a research subject, and/or concerns or 
complaints regarding this research study, contact: 
 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• 
or call toll free:    877-992-4724 
• 
or by email:          adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00043877. 
 
IS YOUR PARTICIPATION VOLUNTARY? 
 
Yes, your participation in this study is strictly voluntary. You may refuse to take part in it, or you may 
stop participating at any time, even after signing and dating this informed consent. There will be no 
penalty or loss of benefits to which you are otherwise entitled. However, if you decide to leave the study 
before it ends, the study doctor will need to see you before you are released from the study. 
 
The study doctor, Sponsor, FDA or Advarra IRB may also decide to remove you from the study at any 
time without your consent. The study doctor may choose to take you out of the study because of 
unexpected or serious side effects, or for other scientific, technical, or safety considerations. 
 
Examples why you may be taken out of the study are: 
• 
Staying in the study would be harmful to you or others. 
• 
You need treatment not allowed in this study. 
• 
You failed to follow instructions. 
• 
You become pregnant. 
• 
The study is cancelled. 
• 
Your study treatment arm is stopped. 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 16 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
If your participation ends for any reason, you will return to the study for the following study procedures: 
• 
Physical examination. 
• 
Pregnancy test (if necessary). 
• 
Body weight and body temperature. 
• 
Blood pressure and pulse rate. 
• 
ECG. 
• 
Blood draws for hematology and chemistry. 
• 
Blood draws for PK. 
• 
Urine will be collected for urinalysis. 
• 
Adverse events and concomitant medications. 
If you should decide to leave the study you should tell the study doctor or study staff. They will make 
sure that proper procedures are followed and a final visit is made for your safety. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This Web site will 
not include information that can identify you. At most, the Web site will include a summary of the results. 
You can search this Web site at any time. 
 
STATEMENT OF CONSENT  
 
I have read this form and its contents were explained to me. I agree to be in this research study for the 
purposes listed above. All of my questions were answered to my satisfaction. I will receive a signed and 
dated copy of this form for my records.  I am not giving up any of my legal rights by signing and dating 
this form.   
 
___________________________________ 
 
____/____/____ 
Signature of Research Subject 
 
Date 
 
___________________________________ 
 
 
 
 
_______________ 
Printed Name of Research Subject 
 
 
 
 
 
Time (24hr) 
 
STATEMENT OF PERSON OBTAINING INFORMED CONSENT  
 
I have carefully explained to the subject the nature and purpose of the above study. There has been an 
opportunity for the subject to ask questions about this research study. I have been available to answer any 
questions that the subject has about this study. 
 
                                                                                
 
____/____/____ 
Initials of Person Obtaining Informed Consent 
 
Date 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 17 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
HIPAA Authorization Agreement 
Permission to Review, Use and Release Information about You 
 
If you decide to be in this study, the study doctor and research team will use and share health data about 
you to conduct the study. Health data may include: 
 
• 
Your name. 
• 
Address. 
• 
Phone number. 
• 
Date of birth. 
• 
Medical history. 
• 
Information from your study visits, including all test results.   
 
Health data may come from your study records or from existing records kept by your personal doctor or 
other health care workers.   
 
For this study, the research team may share health data about you with authorized users. Authorized users 
may include: 
 
• 
Representatives of Spaulding Clinical Research, LLC. 
• 
Representatives of Advarra IRB (an Institutional Review Board that reviews this study). 
• 
The Food and Drug Administration (FDA) and other US governmental agencies. 
• 
Government agencies to whom certain diseases (like HIV, hepatitis, and STIs) must be reported. 
• 
Governmental agencies of other countries. 
• 
Labs working with the sponsor on this study. 
• 
Other authorized users. 
 
The sponsor and those working for the sponsor may use the health data sent to them: 
 
• 
To see if the study drug works and is safe. 
• 
To compare the study drug to other drugs. 
• 
For other research activities related to the study drug. 
 
Once your health data has been shared with authorized users, it may no longer be protected by federal 
privacy laws.   
 
Your permission to use and share health data about you will not end unless required by state law. If state 
law applies, your permission to use and share health data about you will end on December 31, 2060.  
 
You may take back your permission to use and share health data about you at any time by writing to the 
study doctor. If you do this, you will not be able to stay in this study. No new health data that identifies 
you will be gathered after your written request is received. However, health data about you that has 
already been gathered may still be used and given to others as described in this form.   
 
Your right to access your health data in the study records will be suspended during the study to keep from 
changing the study results. When the study is over, you can access your study health data. 
 
If you decide not to sign and date this form, you will not be able to take part in the study. 
 


U.S. Food and Drug Administration / Protocol Number SCR-010 
Page 18 of 18 
 
Colleen Nalepinski, MPAS,PA-C 
Advarra IRB Approved Version 14 May 2020 
 
STATEMENT OF AUTHORIZATION 
 
I have read this form and its contents were explained. My questions have been answered. I voluntarily 
agree to allow study staff to collect, use and share my health data as specified in this form. I will receive a 
signed and dated copy of this form for my records. I am not giving up any of my legal rights by signing 
and dating this form.   
 
 
 
 
 
____/____/____ 
Signature of Research Subject 
 
 
Date 
 
___________________________________ 
 
 
 
 
Printed Name of Research Subject 
 
 
 
 
 
 
STATEMENT OF PERSON OBTAINING AUTHORIZATION 
 
I have carefully explained to the subject the nature and purpose of this form. I have been available to 
answer any questions that the subject has about this form. 
 
                                                                        
 
 
____/____/____ 
Initials of Person Obtaining Authorization 
 
 
Date 
 
 
 
 
 
 
 

Prot_000.pdf: 
Study Title: Clinical Study to Investigate the Urinary Excretion of N-
nitrosodimethylamine (NDMA) after Ranitidine Administration   
 
Document Title: Clinical Study Protocol No. SCR-010  
 
Document Date : 19 June 2020 
 
NCT Number: NCT04397445 




Digitally signed by David Strauss -S 
DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 
cn=David Strauss -S, 0.9.2342.19200300.100.1.1=2000507494 
Date: 2020.06.22 15:00:21 -04'00'

















































































































SAP_001.pdf: 
Study Title: Clinical Study to Investigate the Urinary Excretion of N-
nitrosodimethylamine (NDMA) after Ranitidine Administration. 
 
Document Title: Statistical Analysis Plan – Study No. SCR-010 
 
Document Date : 13 January 2021 
 
NCT Number: NCT04397445 


Statistical Analysis Plan  
SCR-010: Clinical Study to Investigate the Urinary Excretion of N-
nitrosodimethylamine (NDMA) after Ranitidine Administration 
 
 
Page 1 of 17 
 
 
Statistical Analysis Plan  
 
 
SCR-010: Clinical Study to Investigate the Urinary 
Excretion of N-nitrosodimethylamine (NDMA) after 
Ranitidine Administration 
 
 
Sponsor: 
U.S. Food and Drug Administration 
White Oak Building #64, Room 2072 
10903 New Hampshire Avenue 
Silver Spring, MD 20993 
 
Sponsor Study Lead: 
David Strauss, MD, PhD 
Director, Division of Applied Regulatory Science  
U.S. Food and Drug Administration 
Telephone: 301-796-6323 
Email: david.strauss@fda.hhs.gov 
 
Sponsor Medical Monitor: Joyce Korvick, MD 
U.S. Food and Drug Administration 
Telephone: 301-796-0936 
Email: joyce.korvick@fda.hhs.gov 
Project Manager: 
Jeffry Florian, PhD 
U.S. Food and Drug Administration 
Study Monitor: 
Jill Brown 
FDA IRB Project Manager 
U.S. Food and Drug Administration 
Version of SAP: 
2.0 
Date of SAP: 
13 Jan 2021 
 
 
CONFIDENTIAL 
 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed 
written consent of the U.S. Food and Drug Administration. 
 
 
 


Statistical Analysis Plan  
SCR-010: Clinical Study to Investigate the Urinary Excretion of N-
nitrosodimethylamine (NDMA) after Ranitidine Administration 
 
 
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Sponsor Signatures Page 
 
Prepared by 
 
 
 
 
Victoria Gershuny, PhD 
Biologist, Division of Applied Regulatory 
Science 
U.S. Food and Drug Administration 
 
Date 
Prepared by 
 
 
 
 
Jeffry Florian, PhD 
General Health Scientist, Division of Applied 
Regulatory Science 
U.S. Food and Drug Administration 
 
Date 
Reviewed by 
 
 
 
 
 
Robbert Zusterzeel, MD, PhD 
Contractor, Division of Applied Regulatory 
Science  
U.S. Food and Drug Administration  
 
Date 
Approved by 
 
 
 
 
David Strauss, MD, PhD 
Director, Division of Applied Regulatory 
Science  
U.S. Food and Drug Administration 
 
Date 
 
 
Victoria Gershuny -S 
(Affiliate)
Digitally signed by Victoria Gershuny -S (Affiliate) 
DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, 
ou=People, 0.9.2342.19200300.100.1.1=2002874999, 
cn=Victoria Gershuny -S (Affiliate) 
Date: 2021.01.13 15:20:04 -05'00'
Jeffry Florian -S
Digitally signed by Jeffry Florian -S 
DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 
cn=Jeffry Florian -S, 0.9.2342.19200300.100.1.1=2000498765 
Date: 2021.01.13 15:30:04 -05'00'
Robbert Zusterzeel -
S
Digitally signed by Robbert Zusterzeel -S 
DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, 
ou=People, 0.9.2342.19200300.100.1.1=2001114905, 
cn=Robbert Zusterzeel -S 
Date: 2021.01.13 15:53:18 -05'00'
David Strauss -S
Digitally signed by David Strauss -S 
DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, 
ou=People, cn=David Strauss -S, 
0.9.2342.19200300.100.1.1=2000507494 
Date: 2021.01.13 15:56:33 -05'00'


Statistical Analysis Plan  
SCR-010: Clinical Study to Investigate the Urinary Excretion of N-
nitrosodimethylamine (NDMA) after Ranitidine Administration 
 
 
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Contents 
Sponsor Signatures Page ................................................................................................................. 2 
Abbreviations and definitions ......................................................................................................... 5 
Change Log ..................................................................................................................................... 6 
1. 
Introduction ............................................................................................................................. 7 
2. 
Objectives ................................................................................................................................ 7 
2.1 
Primary Objective ............................................................................................................ 7 
2.2 
Exploratory Objectives ..................................................................................................... 7 
3. 
Study Overview ....................................................................................................................... 7 
3.1 
Study Design .................................................................................................................... 7 
3.2 
Sample Size ...................................................................................................................... 9 
4. 
Study Endpoints ....................................................................................................................... 9 
4.1 
Primary Endpoints ............................................................................................................ 9 
4.2 
Exploratory Endpoints...................................................................................................... 9 
5. 
Analysis Populations ............................................................................................................... 9 
6. 
Data Screening and Acceptance ............................................................................................ 10 
6.1 
Handling of Missing and Incomplete Data .................................................................... 10 
7. 
General Statistical Considerations ......................................................................................... 10 
7.1 
Subject Disposition ........................................................................................................ 10 
7.2 
Demographic and Baseline Characteristics .................................................................... 10 
7.3 
Pharmacokinetic Analyses ............................................................................................. 10 
7.3.1 
Urine Pharmacokinetics .............................................................................................. 10 
7.3.2 
Plasma Pharmacokinetics ........................................................................................... 12 
7.4 
Additional Exploratory Analyses ................................................................................... 13 
7.4.1 
Physiologically-Based Pharmacokinetic Modeling .................................................... 13 
7.4.2 
Urine and Plasma Metabolomics ................................................................................ 13 
7.4.3 
Assessment of Meals .................................................................................................. 13 
7.5 
Safety Analyses .............................................................................................................. 14 
7.5.1 
Adverse Events ........................................................................................................... 14 
7.5.2 
Clinical Laboratory Tests ........................................................................................... 14 


Statistical Analysis Plan  
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7.5.3 
Vital Sign Measurements............................................................................................ 14 
7.5.4 
Safety 12-lead Electrocardiograms ............................................................................. 14 
7.5.5 
Physical Examinations ................................................................................................ 14 
7.5.6 
Other Safety Data ....................................................................................................... 14 
8. 
Data Quality Assurance ......................................................................................................... 14 
9. 
Appendices ............................................................................................................................ 16 
9.1 
Randomization schedule ................................................................................................ 16 
10. 
References .......................................................................................................................... 17 
 
 
 


Statistical Analysis Plan  
SCR-010: Clinical Study to Investigate the Urinary Excretion of N-
nitrosodimethylamine (NDMA) after Ranitidine Administration 
 
 
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Abbreviations and definitions 
AE 
Adverse event 
ANOVA 
Analysis of variance 
AUC0-inf  
Area under the plasma concentration time curve from time 0 extrapolated 
to infinity 
Clast 
Last quantifiable concentration 
Cmax  
Maximum observed plasma concentration 
DMA 
Dimethylamine 
ECG 
Electrocardiogram 
eCFRs 
Electronic case report forms 
inf 
Infinity 
Kel 
Elimination rate constant 
NDMA 
N-nitrosodimethylamine 
PK  
Pharmacokinetic 
SAP  
Statistical analysis plan 
SD 
Standard deviation 
t1/2 
Terminal half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time of maximum concentration (Cmax) 
 
 
 


Statistical Analysis Plan  
SCR-010: Clinical Study to Investigate the Urinary Excretion of N-
nitrosodimethylamine (NDMA) after Ranitidine Administration 
 
 
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Change Log 
Version Section 
Changes 
2.0 
General 
(Rationale) 
NDMA analyses will be based on arithmetic means instead of geometric 
means. Blinded review of the bioanalytical data revealed that a large 
number of urine and plasma samples for NDMA were below the lower 
limit of quantification (LLOQ). For multiple subjects, all samples from 1 
or more study periods were below the LLOQ. As zero values cannot be 
log-transformed for geometric mean analyses, these periods would have 
been removed from analysis. Furthermore, as analyses are paired, these 
subjects would have been removed from analyses. Utilizing arithmetic 
mean will allow data from all subjects and all periods to be used in the 
planned analysis. Ranitidine and DMA analyses will remain the same (i.e. 
utilizing geometric means). 
 
7.3.1 
Analysis of urine concentrations 
Analysis of NDMA urine 24-hr excretion will be performed using 
arithmetic means instead of geometric means. 
 
7.3.2 
Plasma pharmacokinetics 
Descriptive statistics for plasma PK parameters of NDMA will be 
calculated using arithmetic means. 
 
 


Statistical Analysis Plan  
SCR-010: Clinical Study to Investigate the Urinary Excretion of N-
nitrosodimethylamine (NDMA) after Ranitidine Administration 
 
 
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1. Introduction 
This document outlines the proposed statistical methods for data analysis of data collected from 
Protocol ‘SCR-010 Clinical study to investigate the urinary excretion of N-nitrosodimethylamine 
(NDMA) after ranitidine administration’.  
2. Objectives 
The following analysis plan provides the framework for the summarization of the data from this 
study. The analysis plan may change due to unforeseen circumstances but will be finalized prior 
to database lock. Any changes made after the database lock will be documented and justified in 
the clinical study report. 
2.1 Primary Objective 
The primary objective is to evaluate 24-hour urinary excretion of N-nitrosodimethylamine 
(NDMA) after oral administration of ranitidine compared to placebo. 
2.2 Exploratory Objectives 
Exploratory objectives include the following: 
x 
To evaluate plasma ranitidine, NDMA, and dimethylamine (DMA) after oral administration 
of ranitidine compared to placebo. 
x 
To evaluate urinary excretion amounts over 24-hours of ranitidine and DMA after oral 
administration of ranitidine compared to placebo. 
x 
To evaluate 24-hour urinary excretion and plasma concentration of NDMA and DMA with 
administration of high nitrite/NDMA meals compared to low nitrite/NDMA meals. 
3. Study Overview 
3.1 Study Design 
This is a randomized, placebo-controlled, single-dose, 4-period crossover study with 18 healthy 
subjects.  Subjects will receive 4 treatments over the 4 study periods (see Table 1).  Each subject 
will be randomized to 1 of 4 treatment sequences (i.e., ABCD, ABDC, BACD, or BADC).  The 
treatment will consist of oral administration of either a single dose of ranitidine (300 mg) or 
placebo administered at time zero on each of 4 different treatment days.  All subjects will be 
provided low nitrite/NDMA meals for the first 2 periods of the study and high nitrite/NDMA 
meals for the last two periods of the study.  Subjects will check in on Day -2 for baseline 
assessments and will complete each 2-day period over the next 8 days, followed by checkout (see 
Table 2).     
 


Statistical Analysis Plan  
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Two different full day menus of low nitrite/NDMA and high nitrite/NDMA meals have been 
developed. Meals will be identical for treatment periods 1 and 2(low nitrite/NDMA meals) of the 
study and a separate set of identical low nitrite/NDMA meals will be served on the washout days 
prior to treatment. Likewise, meals will be identical for treatment periods 3 and 4(high 
nitrite/NDMA meals) and a separate set of identical high nitrite/NDMA meals will be served on 
the washout days prior to treatment days.  The last meal on Day -1, Day 2, Day 4, and Day 6 
should be administered at approximately 6 PM to permit at least 12-hour fasting prior to dosing. 
Subjects will be provided with distilled water to drink throughout the study. 
On study treatment days, the first meal will be provided at the time of dosing. Subjects will be 
instructed to swallow the medication with approximately 250 mL of room temperature distilled 
water and begin eating within two minutes after dosing. Subjects are required to eat each meal in 
its entirety during the study. If the meal is not finished, the reason should be recorded, along with 
what was not eaten, and a picture of the remaining food should be taken.  
Urine samples will be collected using separate collection containers over 24 h. Collection times 
will occur at 0 (pre-dose), 3, 6, 9, 12, 15, and 24 h on study dosing days. Subjects will be 
instructed to void their bladder at each collection time and total weight of the sample will be 
recorded. If a subject must void their bladder at an unscheduled time (highly discouraged), the 
unscheduled voids will be collected, and total weight of the unscheduled voiding will be 
recorded. The unscheduled voiding sample will be treated, analytically analyzed, and reported as 
part of scheduled sample collection for determining cumulative amounts of NDMA, ranitidine, 
and DMA excreted over 24 h.  Plasma samples for NDMA, DMA, and ranitidine analysis will be 
collected at 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 11, 14, and 24 h post-dose on study dosing 
days. 
The study will be conducted at one center in the United States (Spaulding Clinical Research unit 
in West Bend, Wisconsin). Each treatment group will attempt to include equal representation of 
male and female subjects. 
 
Table 1: Study Treatments  
Treatment  
Drug 
A 
Ranitidine (300 mg) + low nitrite/NDMA meals  
B 
Placebo + low nitrite/NDMA meals 
C 
Ranitidine (300 mg) + high nitrite/NDMA meals 
D 
Placebo + high nitrite/NDMA meals 
 
 
 
Table 2: Study Design 


Statistical Analysis Plan  
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Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Check-in Washout 
Period 1 Washout 
Period 2 Washout Period 3 Washout Period 4 Check-out 
 
3.2 Sample Size 
Eighteen healthy participants are planned for enrollment. It is estimated that a sample size of 14 
completing subjects will provide at least 90% power at a 0.05 significance level to demonstrate 
an increase in 24-h urinary excretion of NDMA with ranitidine compared to placebo for a 1-
sided log-transformed paired comparison.  This assumes that geometric mean ratio between 24-h 
urinary NDMA with ranitidine and placebo is 2 and that the coefficient of variability is 100%.  
Enrolling 18 subjects allows for up to 20% dropouts. 
Sample size calculations for the study are based on results from Zeng and Mitch (2016), which 
showed a 400-fold increase in NDMA for 150 mg ranitidine compared to placebo (47,600 ng 
versus 110 ng, respectively).  The observed 24-h urinary excretion of NDMA with placebo for 
this and other studies ranged between 11-380 ng.  It is not known if 24-h urinary excretion of 
NDMA with placebo is higher than what has been historically observed or if the fold-increase 
observed in Zeng and Mitch with ranitidine would be observed in a study controlling for meals 
with a randomized crossover design.  The study sample size reflects assumptions that the overall 
fold-increase may be substantially lower but is still powered to detect an increase with 
assumptions as stated above.  
4. Study Endpoints 
4.1 Primary Endpoints 
The primary endpoint of this study is 24-h urinary NDMA excretion. 
4.2 Exploratory Endpoints 
The exploratory endpoints of this study are: 
1. AUC from time 0 extrapolated to infinity (AUC0-inf) of plasma ranitidine, NDMA and DMA 
2. Cumulative ranitidine and DMA amount excreted in urine over 24 h after ranitidine 
administration 
5. Analysis Populations 
The PK population will include all subjects who receive study drug and have at least one on-
treatment sample. The safety population will include all subjects who receive at least 1 dose of 
any of the study drugs. The analysis population will include all subjects in the PK population 
with sufficient data to calculate PK parameters from at least two study periods of the same meal 


Statistical Analysis Plan  
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type (i.e., low nitrite/NDMA or high nitrite/NDMA).  Treatment in all analysis populations will 
be assigned based upon the treatment which the subjects actually received.   
6. Data Screening and Acceptance 
6.1 Handling of Missing and Incomplete Data 
The following imputation of missing values will be done: 
x PK measurements (urine or plasma) below the quantification limits will be considered 
equal to zero for all analyses.  
x Missing PK data (e.g., skipped plasma sample collected or uncollected urine voids) will 
not be imputed.   
7. General Statistical Considerations 
All data will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings, but not included in the calculation of summary 
statistics. 
7.1 Subject Disposition 
The number of subjects who enroll in the study and the number and percentage of subjects who 
complete each assessment will be presented. The frequency and percentage of subjects who 
withdraw or discontinue from the study and the reason for withdrawal or discontinuation will be 
summarized. 
7.2 Demographic and Baseline Characteristics 
Continuous demographic and baseline characteristic variables (age, height, weight, and body 
mass index) will be summarized overall and by treatment using descriptive statistics (number of 
subjects, mean, standard deviation [SD], median, minimum, and maximum). The number and 
percentage of subjects in each class of categorical demographic and baseline characteristic 
variables will also be summarized. 
7.3 Pharmacokinetic Analyses 
7.3.1 Urine Pharmacokinetics  
The primary endpoint is a comparison of 24-h urinary NDMA excretion for ranitidine versus 
placebo when administered with either low nitrite/NDMA meals (comparison between 
treatments A and B, respectively) or high nitrite/NDMA meals (comparison between treatments 
C and D, respectively). No adjustment for multiplicity is planned as these comparisons are 
considered two separate studies for purposes of our overall design.  As an exploratory analysis, 
24-h urinary DMA for ranitidine versus placebo will likewise be compared between treatments A 
and B (low nitrite/NDMA meals) and treatments C and D (high nitrite/NDMA meals).  24-hr 
urinary excretion of ranitidine (exploratory) will be calculated for treatments A and C, though no 


Statistical Analysis Plan  
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comparisons are planned.  Finally, as an exploratory measure, the two placebo-treated treatments 
(treatment D versus B) will be compared to determine if meals comprised of foods traditionally 
identified as being higher in nitrites/NDMA result in a higher 24-hr urinary excretion of NDMA 
or DMA compared to meals identified as being lower in nitrites/NDMA.   
The cumulative amount of NDMA (primary), DMA (exploratory), and ranitidine (exploratory) 
excreted in urine over 24-h for placebo and ranitidine administration will be calculated for each 
subject. All urine voids over a 24-h period will be collected.  Each separate void will be weighed 
in a tarred contained.  The volume of the void will be determined assuming a specific gravity of 
1.01. Concentration of each collected sample will be used to determine a cumulative amount 
excreted as follows: 
Ae0-24,compound = ∑time Urineweight,time * 1.01 * Concurine,time 
Cumulative amounts of DMA and ranitidine will be log-transformed. A mixed-effect analysis of 
variance (ANOVA) approach will be used for comparing arithmetic means (for NDMA) and 
geometric means (for DMA and ranitidine) looking at the effects of treatment, period, and 
sequence. For NDMA, testing will be one-sided at a 0.05 significance level, and a significant 
increase will be concluded if the lower bound of the one-sided 95% interval for the arithmetic 
mean difference excludes 0.  For DMA and ranitidine, testing will be one-sided at a 0.05 
significance level, and a significant increase will be concluded if the lower bound of the one-
sided 95% interval for the geometric mean ratio excludes 1.  The results will be transformed 
back to the original scale by exponentiation to provide treatment geometric means. 
Normality assumption of the ANOVA will be verified using the Shapiro-Wilke test for normality 
and homogeneity of variances will be verified using Levene’s test. If either assumption is not 
valid, a Wilcoxon signed-rank test will be used for the comparison rather than an ANOVA. 
Individual and mean time course plots of NDMA, DMA, and ranitidine excreted over 24-hr will 
be evaluated for each treatment.  All urine PK parameters will be summarized using descriptive 
statistics (number of subjects, mean, SD, coefficient of variation [CV], median, minimum, and 
maximum) for NDMA, DMA, and ranitidine.  Individual time course plots will use actual 
sampling times.  Treatment mean plots will use planned sampling times.  
All calculations and the hypothesis testing will be done using R software. 
Total fraction of the ranitidine dose excreted in urine (Fe0-24,ranitidine) will be determined for 
Treatments A and C based on the cumulative amount of ranitidine excreted in urine over 24-h 
(Ae0-24,ranitidine) divided by 300 mg.  This will be calculated for each individual, summarized using 
descriptive statistics (number of subjects, mean, SD, CV, median, minimum, and maximum), and 
visualized graphically using box-and-whisker plots.     
Renal clearance of ranitidine will be determined (only for Treatments A and C) by calculating 
the rate of excretion as the difference between the later and earlier compound level divided by 
the difference in times points (i.e., [amountt2-amountt1]/[t2-t1]). The log-transform of the renal 


Statistical Analysis Plan  
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excretion will be plotted against the midpoint of each time stop. This will be fit to a linear 
regression using least-squares fitting and the slope and intercept will be used to determine the 
overall renal clearance. This will be calculated for each individual and summarized using 
descriptive statistics (number of subjects, mean, SD, CI, median, minimum, and maximum). All 
calculations will be done using R software. 
 
7.3.2 Plasma Pharmacokinetics 
The following PK parameters will be determined for NDMA, DMA, and ranitidine (only 
Treatments A and C) for each subject based on all available concentration-time points: 
x AUC from time 0 to the sampling time corresponding to the last quantifiable 
concentration (Clast) (AUC0-t) 
AUC0-t will be calculated according to the linear trapezoidal rule from 0 h to the last 
quantifiable concentration after drug administration. 
x AUC from time 0 extrapolated to infinity (AUC0-inf) 
AUC0-t will be extrapolated to infinity from the AUC from time 0 to the sampling time 
corresponding to the last quantifiable concentration plus the last quantifiable 
concentration divided by Kel, as follows: 
AUC0-inf = AUC0-t + Clast/Kel 
x Maximum concentration (observed peak drug concentration) (Cmax) 
Cmax will be read directly from the observed concentrations. 
x Time at which Cmax occurs (Tmax) 
Tmax will be read directly from the observed concentrations as the blood sampling time 
corresponding to Cmax.  The earlier time will be reported in cases where the same Cmax 
value is observed for a subject at multiple timepoints  
x Terminal half-life (t1/2) 
The terminal half-life will then be calculated using the elimination rate constant as: 
t1/2=ln(2)/Kel 
x Kel 
The terminal elimination rate constant, which will be determined from the terminal slope 
of the log-concentration curve using linear regression  
The PK parameters will be analyzed using noncompartmental methods based on actual sampling 
times. Serum concentrations below the limits of quantification will be set to zero for the purpose 
of this analysis (see Section 6).  AUC0-inf, t1/2, and Kel for each analyte and subject will only be 


Statistical Analysis Plan  
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included if the subject has 3 or more concentration values on the terminal portion of the 
pharmacokinetic curve and with an adjusted coefficient of determination (R2) greater than 0.80.  
AUC0-inf  and Cmax will be compared with either low nitrite/NDMA meals (comparison between 
Treatments A and B, respectively) or high nitrite/NDMA meals (comparison between Treatments 
C and D, respectively) using a paired t-test. Normality assumption will be verified using the 
Shapiro-Wilke test for normality. If the assumption is not valid, the data will be log-transformed, 
and then tested for normality. Homogeneity of variances will be verified using Lavene’s test. If 
the data in its original or transformed form does not meet the t-test assumptions, a Wilcoxon 
signed-rank test will be used for the comparison rather than a paired t-test. 
These PK parameters will be summarized using descriptive statistics (number of subjects, mean 
[arithmetic for NDMA; geometric for DMA and ranitidine], SD, coefficient of variation [CV], 
median, minimum, and maximum) for NDMA, DMA, and ranitidine. 
All parameters will be calculated using R software. Mean and individual concentration-time 
profiles will be presented in graphs. 
7.4 Additional Exploratory Analyses 
7.4.1 Physiologically-Based Pharmacokinetic Modeling 
Plasma and urine NDMA, DMA, and ranitidine concentration data may be used to conduct 
physiologically-based pharmacokinetic modeling to better understand absorption, distribution, 
metabolism, and elimination of these compounds. These analyses will be described in more 
detail in a separate analysis plan. 
7.4.2 Urine and Plasma Metabolomics 
Profiling metabolites and other molecular constituents in biofluids may have utility for 
exploratory research. Portions of collected blood and urine samples from this study may be used 
for the generation of such profiles (e.g., metabolomics) as hypothesis-generating analyses. Other 
exploratory analyses may also be performed. Additional details regarding the statistical methods 
for the exploratory analyses will be described in a separate protocol. 
7.4.3 Assessment of Meals 
All meals prepared for subjects in this study will utilize foods shown in the literature to have low 
nitrite/NDMA or high nitrite/NDMA content. However, the actual content of nitrites/NDMA in 
the different meals will not be known at the time of the study.  Two servings of each low 
nitrite/NDMA meal and each high nitrate/NDMA meal from both a washout and treatment day 
will be frozen to enable potential analysis of nitrite, NDMA and nitrate content. These results 
would be summarized as listings (i.e., washout/treatment, high/low, 
breakfast/lunch/dinner/snack) to document the actual intake of nitrites, NDMA, and nitrates in 
the different meals. 


Statistical Analysis Plan  
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7.5 Safety Analyses 
7.5.1 Adverse Events 
All adverse events (AEs) will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA). The incidence of treatment-emergent adverse event (TEAEs), 
organized by system organ class and frequency, will be summarized by seriousness, severity, 
relationship to treatment, and by treatment at onset of the TEAE. A detailed listing of serious 
AEs and TEAEs leading to withdrawal will also be provided. 
7.5.2 Clinical Laboratory Tests 
Clinical laboratory results (hematology, serum chemistry, and urinalysis) will be summarized 
using descriptive statistics (number of subjects, mean, SD, minimum, median, and maximum). 
Clinical laboratory results will be classified as normal or abnormal, according to the reference 
ranges of the individual parameter. The number and percentage of subjects with abnormal 
laboratory results will be provided. No statistical testing will be performed on clinical laboratory 
data. 
7.5.3 Vital Sign Measurements 
Vital sign measurements and changes from baseline will be summarized using descriptive 
statistics (number of subjects, mean, SD, minimum, median, and maximum) by treatment and 
time point. 
7.5.4 Safety 12-lead Electrocardiograms 
Abnormal 12-lead ECG findings will be recorded as AEs (not planned for each treatment period) 
in a data listing.  
7.5.5 Physical Examinations 
Abnormal physical examination findings will be recorded as AEs (not planned for each treatment 
period). 
7.5.6 Other Safety Data 
All concomitant medication usage and medications that changed in daily dose, frequency, or 
both since the subject provided informed consent will be summarized for each subject. 
8. Data Quality Assurance 
Completed electronic case report forms (eCRFs) are required for each subject randomly assigned 
to treatment. Electronic data entry will be accomplished through the ClinSpark® remote 
electronic data capture system, which allows for on-site data entry and data management. This 
system provides immediate, direct data transfer to the database, as well as immediate detection of 
discrepancies, enabling site coordinators to resolve and manage discrepancies in a timely 


Statistical Analysis Plan  
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manner. Each person involved with the study will have an individual identification code and 
password that allows for record traceability. Thus, the system, and subsequently any 
investigative reviews, can identify coordinators, investigators, and individuals who have entered 
or modified records. 
Furthermore, the investigator retains full responsibility for the accuracy and authenticity of all 
data entered into the electronic data capture system. The completed dataset and their associated 
files are the sole property of the sponsor and should not be made available in any form to third 
parties, except for appropriate governmental health or regulatory authorities, without written 
permission of the sponsor. 
 
 


Statistical Analysis Plan  
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9. Appendices 
9.1 Randomization schedule 
This is a 4-period, double-blind, crossover study where approximately 18 subjects will be 
enrolled to receive either ranitidine or placebo administered with meals from a pre-specified 
menu with foods that are either low or high in nitrites and NDMA.  Subjects will be randomized 
to one of four treatment sequences (i.e., ABCD, ABDC, BACD, or BADC), where treatment 
codes are summarized in the table below.  The sequence randomization is set so that all subjects 
will be provided low nitrite/NDMA meals for the first two periods of the study and high 
nitrite/NDMA meals for the last two periods of the study.  The first 16 subjects to get enrolled 
will be randomized in blocks of 4. The remaining two subjects will be randomly placed in 2 of 
the 4 treatment sequences. The study plans for 1:1 enrollment of males and females, but the 
randomization will not account for sex and treatment sequence interactions.   
Table 3:  Treatment Codes and Treatment Names 
Treatment Code 
Treatment Name 
A 
Ranitidine (300 mg) + low nitrite/NDMA meals 
B 
Placebo + low nitrite/NDMA meals 
C 
Ranitidine (300 mg) + high nitrite/NDMA meals 
D 
Placebo + high nitrite/NDMA meals 
 
 
 


Statistical Analysis Plan  
SCR-010: Clinical Study to Investigate the Urinary Excretion of N-
nitrosodimethylamine (NDMA) after Ranitidine Administration 
 
 
Page 17 of 17 
 
 
10. References 
Zeng T and Mitch WA. ‘Oral intake of ranitidine increases urinary excretion of N-
nitrosodimethylamine’ Carcinogenesis 2016 Jun; 37(6): 625-34