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

NCT04397445 | Completed Phase 1 Results FDA Drug

• 1 other identifier: SCR-010
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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.

Conditions

Ranitidine Adverse Reaction; Pharmacokinetics; Food-drug Interaction

Keywords

Ranitidine; N-nitrosodimethylamine; NDMA; Urine excretion

Outcome Measures

Primary Outcomes (1)

• Cumulative NDMA Amount Excreted in Urine Over 24 Hours After Drug Administration (Comparison Between Ranitidine and Placebo)

  The cumulative amount of NDMA excreted over 24 hours is determined by calculating the amount excreted during specified intervals (includes all planned collections and unscheduled voids) and summarizing totals over a 24-h period.

  24-hours post-dose including planned collections (at 3, 6, 9, 12, 15, and 24 hours post-dose) and unscheduled voids. All subjects voided at approximately 0 hours (pre-dose), which was not included in the assessment.

Other Outcomes (6)

• Cumulative NDMA Amount Excreted in Urine Over 24 Hours After Drug Administration (Comparison Between Diets)

  24-hours post-dose including planned collections (at 3, 6, 9, 12, 15, and 24 hours post-dose) and unscheduled voids. All subjects voided at approximately 0 hours (pre-dose), which was not included in the assessment.

• Cumulative Dimethylamine (DMA) Amount Excreted in Urine Over 24 Hours After Drug Administration

  24-hours post-dose including planned collections (at 3, 6, 9, 12, 15, and 24 hours post-dose) and unscheduled voids. All subjects voided at approximately 0 hours (pre-dose), which was not included in the assessment.

• Cumulative Ranitidine Amount Excreted in Urine Over 24 Hours After Drug Administration

  24-hours post-dose including planned collections (at 3, 6, 9, 12, 15, and 24 hours post-dose) and unscheduled voids. All subjects voided at approximately 0 hours (pre-dose), which was not included in the assessment.

Study Arms (4)

Ranitidine and Low Nitrite/NDMA Meals (Noncured-Meats Diet)

EXPERIMENTAL

Single dose of ranitidine (300 mg) plus low nitrite/NDMA meals (noncured-meats diet)

Drug: Ranitidine; Other: Low nitrite/NDMA meals

Placebo and Low Nitrite/NDMA Meals (Noncured-Meats Diet)

PLACEBO COMPARATOR

Single dose of placebo plus low nitrite/NDMA meals (noncured-meats diet)

Drug: Placebo; Other: Low nitrite/NDMA meals

Ranitidine and High Nitrite/NDMA Meals (Cured-Meats Diet)

EXPERIMENTAL

Single dose of ranitidine (300 mg) plus high nitrite/NDMA meals (cured-meats diet)

Drug: Ranitidine; Other: High nitrite/NDMA meals

Placebo and High Nitrite/NDMA Meals (Cured-Meats Diet)

PLACEBO COMPARATOR

Single dose of placebo plus high nitrite/NDMA meals (cured-meats diet)

Drug: Placebo; Other: High nitrite/NDMA meals

Interventions

Ranitidine DRUG

Ranitidine 300 mg

Ranitidine and High Nitrite/NDMA Meals (Cured-Meats Diet); Ranitidine and Low Nitrite/NDMA Meals (Noncured-Meats Diet)

Placebo DRUG

Oral placebo tablet

Placebo and High Nitrite/NDMA Meals (Cured-Meats Diet); Placebo and Low Nitrite/NDMA Meals (Noncured-Meats Diet)

Low nitrite/NDMA meals OTHER

Meals containing low levels of nitrites and NDMA

Also known as: Noncured-meats diet

Placebo and Low Nitrite/NDMA Meals (Noncured-Meats Diet); Ranitidine and Low Nitrite/NDMA Meals (Noncured-Meats Diet)

High nitrite/NDMA meals OTHER

Meals containing higher levels of nitrites and NDMA

Also known as: Cured-meats diet

Placebo and High Nitrite/NDMA Meals (Cured-Meats Diet); Ranitidine and High Nitrite/NDMA Meals (Cured-Meats Diet)

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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.
• 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).
• Subject must have a negative test result for alcohol and drugs of abuse at screening and Check-in (Day -2).
• 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.
• Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.

You may not qualify if:

• Subject has used antacids or proton pump inhibitors within 14 days of screening (interferes with H. pylori testing).
• 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.
• 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.
• Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 6 weeks of Screening.
• 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.
• 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
• 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.

Sponsors & Collaborators

• Food and Drug Administration (FDA): lead
• Spaulding Clinical Research LLC: collaborator

Study Sites (1)

Spaulding Clinical Research

West Bend, Wisconsin, 53095, United States

Location

Related Publications (1)

• Florian J, Matta MK, DePalma R, Gershuny V, Patel V, Hsiao CH, Zusterzeel R, Rouse R, Prentice K, Nalepinski CG, Kim I, Yi S, Zhao L, Yoon M, Selaya S, Keire D, Korvick J, Strauss DG. Effect of Oral Ranitidine on Urinary Excretion of N-Nitrosodimethylamine (NDMA): A Randomized Clinical Trial. JAMA. 2021 Jul 20;326(3):240-249. doi: 10.1001/jama.2021.9199.

  PMID: 34180947 RESULT

Related Links

• FDA Updates and Press Announcements on NDMA in Zantac (ranitidine).
• Ranitidine Package Insert updated December 7, 2018.
• Zeng T, Mitch WA. Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine. Carcinogenesis. 2016 Jun;37(6):625-634. doi: 10.1093/carcin/bgw034. Epub 2016 Mar 18.

MeSH Terms

Interventions

Ranitidine

Intervention Hierarchy (Ancestors)

Furans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: David Strauss, MD, PhD
• Organization: U.S. Food and Drug Administration

David.Strauss@fda.hhs.gov

301-796-6323

Study Officials

• Colleen Nalepinski, MPAS, PA-C

  Spaulding Clinical Research LLC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: This is a randomized, placebo-controlled, single-dose, 4-period crossover study with 18 healthy subjects

Study Record Dates

• First Submitted: May 15, 2020
• First Posted: May 21, 2020
• Study Start: June 8, 2020
• Primary Completion: July 1, 2020
• Study Completion: July 1, 2020
• Last Updated: August 9, 2021
• Results First Posted: July 19, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP

Locations

US (1)