Clinical Study to Investigate the Urinary Excretion of N-nitrosodimethylamine (NDMA) After Ranitidine Administration
Condition: Ranitidine Adverse Reaction; Pharmacokinetics; Food-drug Interaction
Intervention: Ranitidine; Placebo; Low nitrite/NDMA meals; High nitrite/NDMA meals
Intervention description: Ranitidine 300 mg; Oral placebo tablet; Meals containing low levels of nitrites and NDMA; Meals containing higher levels of nitrites and NDMA
Intervention MeSH terms: Ranitidine; Ranitidine bismuth citrate
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
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)
Masking description: The pharmacist (and designated staff member responsible for confirmation of study drug dose) will be unblinded to subject treatment assignment; however, the pharmacist will not perform any study procedures other than study drug preparation and dispensing. Subjects and staff will be blinded to treatment assignment. The blind will be maintained through a randomization schedule held by the dispensing pharmacist. Subjects will be blindfolded during oral study drug administration. 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.
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Ranitidine; N-nitrosodimethylamine; NDMA; Urine excretion

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subject is willing and able to sign an institutional review board (IRB) approved
             written informed consent and privacy language as per national regulations (e.g.,
             Health Insurance Portability and Accountability Act authorization) before any study
             related procedures are performed.

          2. Subject is a healthy, non-smoking man or woman, 18 to 50 years of age, inclusive, who
             has a body mass index (BMI) of 18.5 to 32 kg/m2, inclusive, at Screening.

          3. Subject has normal medical history findings, clinical laboratory results, vital sign
             measurements, 12 lead electrocardiogram (ECG) results, and physical examination
             findings at screening or, if abnormal, the abnormality is not considered clinically
             significant (as determined and documented by the investigator or designee).

          4. Subject must have a negative test result for alcohol and drugs of abuse at screening
             and Check-in (Day -2).

          5. Female subjects must be of non-childbearing potential or, if they are of childbearing
             potential, they must: 1) have been strictly abstinent for 1 month before Check in (Day
             -2) and agree to remain strictly abstinent for the duration of the study and for at
             least 1 month after the last application of study drug; OR 2) be practicing 2 highly
             effective methods of birth control (as determined by the investigator or designee; one
             of the methods must be a barrier technique) from at least 1 month before Check in (Day
             -2) until at least 1 month after the end of the study.

          6. Subject is highly likely (as determined by the investigator) to comply with the
             protocol defined procedures and to complete the study.

        Exclusion Criteria:

          1. Subject has used antacids or proton pump inhibitors within 14 days of screening
             (interferes with H. pylori testing).

          2. Subject has used any prescription or nonprescription drugs (including antacids, proton
             pump inhibitors, aspirin or non-steroidal anti-inflammatory drugs [NSAIDs] and
             excluding oral contraceptives and acetaminophen) within 14 days or 5 half-lives
             (whichever is longer) or complementary and alternative medicines within 28 days before
             the first dose of study drug.

          3. Subject is currently participating in another clinical study of an investigational
             drug or has been treated with any investigational drug within 30 days or 5 half-lives
             (whichever is longer) of the compound.

          4. Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing
             tobacco, snuff) within 6 weeks of Screening.

          5. Subject has consumed alcohol, xanthine containing products (e.g., tea, coffee, cola),
             caffeine, grapefruit, or grapefruit juice within 24 h of check-in. Subjects must
             refrain from ingesting these throughout the study. Subjects must also refrain from
             using mouthwash from check-in until check-out.

          6. Subject has a history or evidence of a clinically significant disorder, condition, or
             disease (e.g., cancer, human immunodeficiency virus [HIV], hepatic or renal
             impairment) that, in the opinion of the investigator would pose a risk to subject
             safety or interfere with the study evaluation, procedures, or completion. This
             includes subjects with any underlying medical conditions that put subjects at higher
             risk for coronavirus disease of 2019 (COVID-19) complications; per current Center for
             Disease Control and Prevention (CDC) recommendations this includes:

               -  People with chronic lung disease or moderate to severe asthma

               -  People who have serious heart conditions

               -  People who are immunocompromised

               -  Many conditions can cause a person to be immunocompromised, including cancer
                  treatment, smoking, bone marrow or organ transplantation, immune deficiencies,
                  poorly controlled HIV, and prolonged use of corticosteroids and other immune
                  weakening medications

               -  People with severe obesity (BMI of 40 kg/m2 or higher)

               -  People with diabetes

               -  People with chronic kidney disease undergoing dialysis

               -  People with liver disease

          7. Subject has any signs or symptoms that are consistent with COVID-19. Per current CDC
             recommendations this includes subjects with the symptoms cough or shortness of breath
             or difficulty breathing, or at least two of the following symptoms: fever, chills,
             repeated shaking with chills, muscle pain, headache, sore throat or new loss of
             taste/smell. In addition, the subject has any other findings suggestive of COVID-19
             risk in the opinion of the investigator.

          8. Subject tests positive for severe acute respiratory syndrome coronavirus 2
             (SARS-CoV-2) by a molecular diagnostic test performed prior to admission.

          9. Subject has known or suspected allergies or sensitivities to the study drug.

         10. Subject has clinical laboratory test results (hematology, serum chemistry and
             urinalysis) at Screening or Check-In that are outside the reference ranges provided by
             the clinical laboratory and considered clinically significant by the investigator.

         11. Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C
             virus antibodies, or hepatitis B surface antigen.

         12. Subject has a history of H. pylori infection or ulcer disease or has a positive breath
             test for H. pylori at screening.

         13. Subject is unable or unwilling to undergo multiple venipunctures for blood sample
             collection because of poor tolerability or poor venous access.

         14. Female subjects are pregnant or lactating before enrollment in the study.

         15. Subject is not willing to eat all of every meal that will be served during the study.