Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Clinical Study to Investigate the Urinary Excretion of N-nitrosodimethylamine (NDMA) After Ranitidine Administration

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04397445
Recruitment Status : Active, not recruiting
First Posted : May 21, 2020
Last Update Posted : July 1, 2020
Sponsor:
Collaborator:
Spaulding Clinical Research LLC
Information provided by (Responsible Party):
Food and Drug Administration (FDA)

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.


Condition or disease Intervention/treatment Phase
Ranitidine Adverse Reaction Pharmacokinetics Food-drug Interaction Drug: Ranitidine Other: Low nitrite/NDMA meals Drug: Placebo Other: High nitrite/NDMA meals Phase 1

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
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.
Primary Purpose: Basic Science
Official Title: Clinical Study to Investigate the Urinary Excretion of N-nitrosodimethylamine (NDMA) After Ranitidine Administration
Actual Study Start Date : June 22, 2020
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Ranitidine and Low Nitrite/NDMA Meals
Single dose of ranitidine (300 mg) plus low nitrite/NDMA meals
Drug: Ranitidine
Ranitidine 300 mg

Other: Low nitrite/NDMA meals
Meals containing low levels of nitrites and NDMA

Placebo Comparator: Placebo and Low Nitrite/NDMA Meals
Single dose of placebo plus low nitrite/NDMA meals
Other: Low nitrite/NDMA meals
Meals containing low levels of nitrites and NDMA

Drug: Placebo
Oral placebo tablet

Experimental: Ranitidine and High Nitrite/NDMA Meals
Single dose of ranitidine (300 mg) plus high nitrite/NDMA meals
Drug: Ranitidine
Ranitidine 300 mg

Other: High nitrite/NDMA meals
Meals containing higher levels of nitrites and NDMA

Placebo Comparator: Placebo and High Nitrite/NDMA Meals
Single dose of placebo plus high nitrite/NDMA meals
Drug: Placebo
Oral placebo tablet

Other: High nitrite/NDMA meals
Meals containing higher levels of nitrites and NDMA




Primary Outcome Measures :
  1. 24-hour Urinary NDMA Excretion [ Time Frame: 24 hours ]
    Determined by calculating cumulative amount excreted during specified intervals, and summarizing totals over a 24-h period.


Other Outcome Measures:
  1. Area under the curve from time zero to infinity (AUC(0-inf)) of plasma ranitidine [ Time Frame: 24 hours ]
    Determined for each subject using non-compartmental methods. All parameters will be reported with standard descriptive statistics including the geometric mean and coefficient of variation. Calculation of pharmacokinetic parameters will be performed using actual sampling times over a 24-h period.

  2. AUC(0-inf) of plasma NDMA [ Time Frame: 24 hours ]
    Determined for each subject using non-compartmental methods. All parameters will be reported with standard descriptive statistics including the geometric mean and coefficient of variation. Calculation of pharmacokinetic parameters will be performed using actual sampling times over a 24-h period.

  3. AUC(0-inf) of plasma dimethylamine (DMA) [ Time Frame: 24 hours ]
    Determined for each subject using non-compartmental methods. All parameters will be reported with standard descriptive statistics including the geometric mean and coefficient of variation. Calculation of pharmacokinetic parameters will be performed using actual sampling times over a 24-h period.

  4. Cumulative ranitidine amount excreted in urine over 24 hours after drug administration [ Time Frame: 24 hours ]
    Determined by calculating cumulative amount excreted during specified intervals, and summarizing totals over a 24-h period.

  5. Cumulative DMA amount excreted in urine over 24 hours after drug administration [ Time Frame: 24 hours ]
    Determined by calculating cumulative amount excreted during specified intervals, and summarizing totals over a 24-h period.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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 1month 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04397445


Locations
Layout table for location information
United States, Wisconsin
Spaulding Clinical Research
West Bend, Wisconsin, United States, 53095
Sponsors and Collaborators
Food and Drug Administration (FDA)
Spaulding Clinical Research LLC
Investigators
Layout table for investigator information
Principal Investigator: Colleen Nalepinski, MPAS, PA-C Spaulding Clinical Research LLC
Additional Information:
Publications:
Layout table for additonal information
Responsible Party: Food and Drug Administration (FDA)
ClinicalTrials.gov Identifier: NCT04397445    
Other Study ID Numbers: SCR-010
First Posted: May 21, 2020    Key Record Dates
Last Update Posted: July 1, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Plan is to make data from the study publicly available as part of a manuscript publication. In addition, the protocol and statistical analysis plan will be made available online at this site as well as with any eventual publications.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Food and Drug Administration (FDA):
Ranitidine
N-nitrosodimethylamine
NDMA
Urine excretion
Additional relevant MeSH terms:
Layout table for MeSH terms
Ranitidine
Ranitidine bismuth citrate
Anti-Ulcer Agents
Gastrointestinal Agents
Histamine H2 Antagonists
Histamine Antagonists
Histamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs