Clinical Study to Investigate the Urinary Excretion of N-nitrosodimethylamine (NDMA) After Ranitidine Administration
Condition: Ranitidine Adverse Reaction; Pharmacokinetics; Food-drug Interaction
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Ranitidine; Placebo; Low nitrite/NDMA meals; High nitrite/NDMA meals
Intervention type(s): Drug; Drug; Other; Other
Intervention description(s): Ranitidine 300 mg; Oral placebo tablet; Meals containing low levels of nitrites and NDMA; Meals containing higher levels of nitrites and NDMA
Other intervention name(s): Noncured-meats diet; Cured-meats diet
Intervention MeSH terms: Ranitidine; Ranitidine bismuth citrate
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: This is a randomized, placebo-controlled, single-dose, 4-period crossover study with 18 healthy subjects
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Ranitidine; N-nitrosodimethylamine; NDMA; Urine excretion