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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 : Completed
First Posted : May 21, 2020
Results First Posted : July 19, 2021
Last Update Posted : August 9, 2021
Sponsor:
Collaborator:
Spaulding Clinical Research LLC
Information provided by (Responsible Party):
Food and Drug Administration (FDA)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Basic Science
Conditions Ranitidine Adverse Reaction
Pharmacokinetics
Food-drug Interaction
Interventions Drug: Ranitidine
Drug: Placebo
Other: Low nitrite/NDMA meals
Other: High nitrite/NDMA meals
Enrollment 18
Recruitment Details  
Pre-assignment Details  
Arm/Group Title ABCD BACD ABDC BADC
Hide Arm/Group Description

Participants first received a single dose of ranitidine, 300 mg, with a noncured meats diet designed to contain lower amounts of nitrites, nitrates (nitrate-reducing bacteria can convert nitrates to nitrites), and NDMA (Treatment A), then crossed over to the sequential treatments with one day of washout in between treatments.

Treatment B: Single dose of oral placebo with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA

Treatment C: Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA

Treatment D: Single dose of oral placebo with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA

Participants first received a single dose of oral placebo with a noncured meats diet designed to contain lower amounts of nitrites, nitrates (nitrate-reducing bacteria can convert nitrates to nitrites), and NDMA (Treatment B), then crossed over to the sequential treatments with one day of washout in between treatments.

Treatment A: Single dose of oral ranitidine, 300 mg, with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA

Treatment C: Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA

Treatment D: Single dose of oral placebo with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA

Participants first received a single dose of ranitidine, 300 mg, with a noncured meats diet designed to contain lower amounts of nitrites, nitrates (nitrate-reducing bacteria can convert nitrates to nitrites), and NDMA (Treatment A), then crossed over to the sequential treatments with one day of washout in between treatments.

Treatment B: Single dose of oral placebo with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA

Treatment D: Single dose of oral placebo with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA

Treatment C: Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA

Participants first received a single dose of oral placebo with a noncured meats diet designed to contain lower amounts of nitrites, nitrates (nitrate-reducing bacteria can convert nitrates to nitrites), and NDMA (Treatment B), then crossed over to the sequential treatments with one day of washout in between treatments.

Treatment A: Single dose of oral ranitidine, 300 mg, with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA

Treatment D: Single dose of oral placebo with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA

Treatment C: Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA

Period Title: Overall Study
Started 5 5 4 4
Completed 4 5 4 4
Not Completed 1 0 0 0
Reason Not Completed
Withdrawal by Subject             1             0             0             0
Arm/Group Title All Participants
Hide Arm/Group Description Participants were randomized to 1 of 4 treatment sequences (i.e., ABCD, BACD, ABDC, and BADC) and over 4 periods received ranitidine (300 mg) and placebo (randomized order) with a noncured-meats diet and then a cured-meats diet.
Overall Number of Baseline Participants 18
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 18 participants
33.0
(28.3 to 42.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants
Female
9
  50.0%
Male
9
  50.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants
Hispanic or Latino
3
  16.7%
Not Hispanic or Latino
15
  83.3%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants
American Indian or Alaska Native
0
   0.0%
Asian
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
11
  61.1%
White
7
  38.9%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 18 participants
18
Body Weight  
Median (Inter-Quartile Range)
Unit of measure:  Kg
Number Analyzed 18 participants
76.9
(62.6 to 83.7)
1.Primary Outcome
Title Cumulative NDMA Amount Excreted in Urine Over 24 Hours After Drug Administration (Comparison Between Ranitidine and Placebo)
Hide Description 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.
Time Frame 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.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who completed two paired treatment periods (i.e., ranitidine and placebo with the same diet)
Arm/Group Title Ranitidine and Noncured Meats Diet Placebo and Noncured Meats Diet Ranitidine and Cured Meats Diet Placebo and Cured Meats Diet
Hide Arm/Group Description:
Single dose of ranitidine, 300 mg with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA
Single dose of oral placebo with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA
Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Single dose of oral placebo with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Overall Number of Participants Analyzed 17 17 17 17
Median (Inter-Quartile Range)
Unit of Measure: nanograms
0.6
(0 to 29.7)
10.5
(0 to 17.8)
11.9
(5.6 to 48.6)
23.4
(8.6 to 36.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranitidine and Noncured Meats Diet, Placebo and Noncured Meats Diet
Comments A Wilcoxon signed-rank test was used for analyses, per the statistical analysis plan, as NDMA urine data were not normally distributed
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.54
Comments A 1-sided lower P value <.05 was considered significant for ranitidine vs. placebo as the aim was to evaluate if ranitidine increased NDMA exposure. Comparisons were performed separately with each diet without adjustment for multiplicity.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Other Statistical Analysis The median of the paired differences (interquartile range) between ranitidine and placebo is 0 (-6.9 to 0) ng. The median of the paired differences is calculated by first determining the difference between the two treatments for each individual participant and then determining the median of those values. The Wilcoxon signed-rank test that was used for NDMA analyses is also based on first determining the difference between the treatment groups for each individual participant.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranitidine and Cured Meats Diet, Placebo and Cured Meats Diet
Comments A Wilcoxon signed-rank test was used for analyses, per the statistical analysis plan, as NDMA urine data were not normally distributed
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.71
Comments A 1-sided lower P value <.05 was considered significant for ranitidine vs. placebo as the aim was to evaluate if ranitidine increased NDMA exposure. Comparisons were performed separately with each diet without adjustment for multiplicity.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Other Statistical Analysis The median of the paired differences (interquartile range) between ranitidine and placebo is -1.1 (-9.1 to 11.5) ng. The median of the paired differences is calculated by first determining the difference between the two treatments for each individual participant and then determining the median of those values. The Wilcoxon signed-rank test that was used for NDMA analyses is also based on first determining the difference between the treatment groups for each individual participant.
2.Other Pre-specified Outcome
Title Cumulative NDMA Amount Excreted in Urine Over 24 Hours After Drug Administration (Comparison Between Diets)
Hide Description 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.
Time Frame 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.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who completed two paired treatment periods (i.e., ranitidine and placebo with the same diet)
Arm/Group Title Ranitidine and Cured Meats Diet Ranitidine and Noncured Meats Diet Placebo and Cured Meats Diet Placebo and Noncured Meats Diet
Hide Arm/Group Description:
Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Single dose of ranitidine, 300 mg with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA
Single dose of oral placebo with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Single dose of oral placebo with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA
Overall Number of Participants Analyzed 17 17 17 17
Median (Inter-Quartile Range)
Unit of Measure: nanograms
11.9
(5.6 to 48.6)
0.6
(0 to 29.7)
23.4
(8.6 to 36.7)
10.5
(0 to 17.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranitidine and Cured Meats Diet, Ranitidine and Noncured Meats Diet
Comments A Wilcoxon signed-rank test was used for analyses, per the statistical analysis plan, as NDMA urine data were not normally distributed
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005
Comments Exploratory analyses on the effect of diet used a 1-sided lower P value <.05 for NDMA as the cured-meats diet was designed to have higher NDMA.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Other Statistical Analysis The median of the paired differences (interquartile range) between the cured-meats diet and noncured-meats diet is 9.3 (3.8 to 25.0) ng. The median of the paired differences is calculated by first determining the difference between the two treatments for each individual participant and then determining the median of those values. The Wilcoxon signed-rank test that was used for NDMA analyses is also based on first determining the difference between the treatment groups for each individual participant.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo and Cured Meats Diet, Placebo and Noncured Meats Diet
Comments A Wilcoxon signed-rank test was used for analyses, per the statistical analysis plan, as NDMA urine data were not normally distributed
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.007
Comments Exploratory analyses on the effect of diet used a 1-sided lower P value <.05 for NDMA as the cured-meats diet was designed to have higher NDMA
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Other Statistical Analysis The median of the paired differences (interquartile range) between the cured-meats diet and noncured-meats diet is 6.4 (0 to 23.4) ng. The median of the paired differences is calculated by first determining the difference between the two treatments for each individual participant and then determining the median of those values. The Wilcoxon signed-rank test that was used for NDMA analyses is also based on first determining the difference between the treatment groups for each individual participant.
3.Other Pre-specified Outcome
Title Cumulative Dimethylamine (DMA) Amount Excreted in Urine Over 24 Hours After Drug Administration
Hide Description The cumulative amount of DMA 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.
Time Frame 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.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who completed two paired treatment periods (i.e., ranitidine and placebo with the same diet)
Arm/Group Title Ranitidine and Noncured Meats Diet Placebo and Noncured Meats Diet Ranitidine and Cured Meats Diet Placebo and Cured Meats Diet
Hide Arm/Group Description:
Single dose of ranitidine, 300 mg with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA
Single dose of oral placebo with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA
Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Single dose of oral placebo with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Overall Number of Participants Analyzed 17 17 17 17
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: milligrams
38.8
(38%)
41.1
(33%)
40.7
(52%)
43.1
(34%)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranitidine and Noncured Meats Diet, Placebo and Noncured Meats Diet
Comments As DMA data were log-normally distributed, analyses were based on a mixed-effect analysis of geometric means with terms for treatment, period, and sequence
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.92
Comments A 1-sided lower P value <.05 was considered significant for the exploratory analyses of ranitidine vs. placebo because the study aim was to evaluate if ranitidine increased DMA exposure.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 0.94
Confidence Interval (2-Sided) 90%
0.87 to 1.01
Estimation Comments This compares the results from ranitidine (numerator) with placebo (denominator).
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranitidine and Cured Meats Diet, Placebo and Cured Meats Diet
Comments As DMA data were log-normally distributed, analyses were based on a mixed-effect analysis of geometric means with terms for treatment, period, and sequence
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.74
Comments A 1-sided lower P value <.05 was considered significant for the exploratory analyses of ranitidine vs. placebo because the study aim was to evaluate if ranitidine increased DMA exposure.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 0.95
Confidence Interval (2-Sided) 90%
0.81 to 1.10
Estimation Comments This compares the results from ranitidine (numerator) with placebo (denominator).
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ranitidine and Noncured Meats Diet, Ranitidine and Cured Meats Diet
Comments As DMA data were log-normally distributed, analyses were based on a mixed-effect analysis of geometric means with terms for treatment, period, and sequence.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.52
Comments A 2-sided P value <.05 was used for DMA as the diet was not expected to affect these outcomes
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.05
Confidence Interval (2-Sided) 95%
0.90 to 1.23
Estimation Comments This compares the results from the cured-meats diet (numerator) with the noncured-meats diet (denominator)
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo and Noncured Meats Diet, Placebo and Cured Meats Diet
Comments As DMA data were log-normally distributed, analyses were based on a mixed-effect analysis of geometric means with terms for treatment, period, and sequence.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.42
Comments A 2-sided P value <.05 was used for DMA as the diet was not expected to affect these outcomes
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.05
Confidence Interval (2-Sided) 95%
0.93 to 1.19
Estimation Comments This compares the results from the cured-meats diet (numerator) with the noncured-meats diet (denominator)
4.Other Pre-specified Outcome
Title Cumulative Ranitidine Amount Excreted in Urine Over 24 Hours After Drug Administration
Hide Description The cumulative amount of ranitidine 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.
Time Frame 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.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who completed two paired treatment periods (i.e., ranitidine and placebo with the same diet)
Arm/Group Title Ranitidine and Cured Meats Diet Ranitidine and Noncured Meats Diet
Hide Arm/Group Description:
Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Single dose of ranitidine, 300 mg with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA
Overall Number of Participants Analyzed 17 17
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: milligrams
91.7
(29%)
74.1
(39%)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranitidine and Cured Meats Diet, Ranitidine and Noncured Meats Diet
Comments As ranitidine data were log-normally distributed, analyses were based on a mixed-effect analysis of geometric means with terms for treatment, period, and sequence
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments Exploratory analyses on the effect of diet used a 2-sided P value <.05 for ranitidine as the diet was not expected to affect these outcomes
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 0.81
Confidence Interval (2-Sided) 95%
0.72 to 0.91
Estimation Comments [Not Specified]
Other Statistical Analysis This compares the results from the cured-meats diet (numerator) with the noncured-meats diet (denominator)
5.Other Pre-specified Outcome
Title Area Under the Curve From Time Zero to the Last Sample Time (AUC(0-t)) of Plasma NDMA
Hide Description 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.
Time Frame 24-hours post-dose with planned samples at 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 11, 14, and 24 h post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who completed two paired treatment periods (i.e., ranitidine and placebo with the same diet) and with sufficient data for calculating pharmacokinetic parameters. Note: AUC could not be calculated for NDMA for any participant during any period. The majority of samples (87-91% of plasma samples by period) were below the lower limit of quantification. The NDMA plasma profiles did not show sustained quantifiable amounts of NDMA and thus did not support calculation of an AUC.
Arm/Group Title Ranitidine and Noncured Meats Diet Placebo and Noncured Meats Diet Ranitidine and Cured Meats Diet Placebo and Cured Meats Diet
Hide Arm/Group Description:
Single dose of ranitidine, 300 mg with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA
Single dose of oral placebo with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA
Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Single dose of oral placebo with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
6.Other Pre-specified Outcome
Title AUC(0-t) of Plasma DMA
Hide Description 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.
Time Frame 24-hours post-dose with planned samples at 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 11, 14, and 24 h post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who completed two paired treatment periods (i.e., ranitidine and placebo with the same diet) and with sufficient data for calculating pharmacokinetic parameters.
Arm/Group Title Ranitidine and Noncured Meats Diet Placebo and Noncured Meats Diet Ranitidine and Cured Meats Diet Placebo and Cured Meats Diet
Hide Arm/Group Description:
Single dose of ranitidine, 300 mg with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA
Single dose of oral placebo with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA
Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Single dose of oral placebo with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Overall Number of Participants Analyzed 17 17 17 17
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: micrograms*hour/milliliter
26.3
(34%)
26.2
(35%)
20.9
(53%)
20.9
(46%)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranitidine and Noncured Meats Diet, Placebo and Noncured Meats Diet
Comments As DMA data were log-normally distributed, analyses were based on a mixed-effect analysis of geometric means with terms for treatment, period, and sequence
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.46
Comments A 1-sided lower P value <.05 was considered significant for the exploratory analyses of ranitidine vs. placebo because the study aim was to evaluate if ranitidine increased DMA exposure.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.00
Confidence Interval (2-Sided) 90%
0.91 to 1.11
Estimation Comments This compares the results from ranitidine (numerator) with placebo (denominator)
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranitidine and Cured Meats Diet, Placebo and Cured Meats Diet
Comments As DMA data were log-normally distributed, analyses were based on a mixed-effect analysis of geometric means with terms for treatment, period, and sequence
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.49
Comments A 1-sided lower P value <.05 was considered significant for the exploratory analyses of ranitidine vs. placebo because the study aim was to evaluate if ranitidine increased DMA exposure.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.00
Confidence Interval (2-Sided) 90%
0.80 to 1.25
Estimation Comments [Not Specified]
Other Statistical Analysis This compares the results from ranitidine (numerator) with placebo (denominator)
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ranitidine and Noncured Meats Diet, Ranitidine and Cured Meats Diet
Comments As DMA data were log-normally distributed, analyses were based on a mixed-effect analysis of geometric means with terms for treatment, period, and sequence.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02
Comments A 2-sided P value <.05 was used for DMA as the diet was not expected to affect these outcomes
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.67 to 0.95
Estimation Comments This compares the results from the cured-meats diet (numerator) with the noncured-meats diet (denominator)
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo and Noncured Meats Diet, Placebo and Cured Meats Diet
Comments As DMA data were log-normally distributed, analyses were based on a mixed-effect analysis of geometric means with terms for treatment, period, and sequence
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.03
Comments A 2-sided P value <.05 was used for DMA as the diet was not expected to affect these outcomes
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.65 to 0.98
Estimation Comments [Not Specified]
Other Statistical Analysis This compares the results from the cured-meats diet (numerator) with the noncured-meats diet (denominator)
7.Other Pre-specified Outcome
Title AUC(0-t) of Plasma Ranitidine
Hide Description 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.
Time Frame 24-hours post-dose with planned samples at 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 11, 14, and 24 h post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who completed two paired treatment periods (i.e., ranitidine and placebo with the same diet) and with sufficient data for calculating pharmacokinetic parameters.
Arm/Group Title Ranitidine and Cured Meats Diet Ranitidine and Noncured Meats Diet
Hide Arm/Group Description:
Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Single dose of ranitidine, 300 mg with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA
Overall Number of Participants Analyzed 17 17
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanograms*hour/milliliter
3736
(29%)
4857
(21%)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranitidine and Cured Meats Diet, Ranitidine and Noncured Meats Diet
Comments As ranitidine data were log-normally distributed, analyses were based on a mixed-effect analysis of geometric means with terms for treatment, period, and sequence
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments Exploratory analyses on the effect of diet used a 2-sided P value <.05 for ranitidine as the diet was not expected to affect these outcomes
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 0.77
Confidence Interval (2-Sided) 95%
0.66 to 0.89
Estimation Comments This compares the results from the cured-meats diet (numerator) with the noncured-meats diet (denominator).
Time Frame 10 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Lead-in (No Treatment) Ranitidine and Noncured Meats Diet Placebo and Noncured Meats Diet Ranitidine and Cured Meats Diet Placebo and Cured Meats Diet
Hide Arm/Group Description Participants checked in one day early in order to standardize meals given the day prior to treatment start.

Single dose of ranitidine (300 mg) plus low nitrite/NDMA meals

Ranitidine: Ranitidine 300 mg

Low nitrite/NDMA meals: Meals containing low levels of nitrites and NDMA (noncured meats diet)

Single dose of placebo plus low nitrite/NDMA meals

Placebo: Oral placebo tablet

Low nitrite/NDMA meals: Meals containing low levels of nitrites and NDMA (noncured meats diet)

Single dose of ranitidine (300 mg) plus high nitrite/NDMA meals

Ranitidine: Ranitidine 300 mg

High nitrite/NDMA meals: Meals containing higher levels of nitrites and NDMA (cured meats diet)

Single dose of placebo plus high nitrite/NDMA meals

Placebo: Oral placebo tablet

High nitrite/NDMA meals: Meals containing higher levels of nitrites and NDMA (cured meats diet)

All-Cause Mortality
Lead-in (No Treatment) Ranitidine and Noncured Meats Diet Placebo and Noncured Meats Diet Ranitidine and Cured Meats Diet Placebo and Cured Meats Diet
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/18 (0.00%)      0/18 (0.00%)      0/18 (0.00%)      0/17 (0.00%)      0/17 (0.00%)    
Hide Serious Adverse Events
Lead-in (No Treatment) Ranitidine and Noncured Meats Diet Placebo and Noncured Meats Diet Ranitidine and Cured Meats Diet Placebo and Cured Meats Diet
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/18 (0.00%)      0/18 (0.00%)      0/18 (0.00%)      0/17 (0.00%)      0/17 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Lead-in (No Treatment) Ranitidine and Noncured Meats Diet Placebo and Noncured Meats Diet Ranitidine and Cured Meats Diet Placebo and Cured Meats Diet
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/18 (11.11%)      3/18 (16.67%)      1/18 (5.56%)      1/17 (5.88%)      2/17 (11.76%)    
Gastrointestinal disorders           
Abdominal Pain  1  0/18 (0.00%)  0 1/18 (5.56%)  1 0/18 (0.00%)  0 0/17 (0.00%)  0 0/17 (0.00%)  0
Diarrhoea  1  0/18 (0.00%)  0 1/18 (5.56%)  1 0/18 (0.00%)  0 0/17 (0.00%)  0 0/17 (0.00%)  0
General disorders           
Vessel Puncture Site Inflammation  1  0/18 (0.00%)  0 0/18 (0.00%)  0 0/18 (0.00%)  0 0/17 (0.00%)  0 1/17 (5.88%)  1
Vessel Puncture Site Pain  1  0/18 (0.00%)  0 1/18 (5.56%)  1 1/18 (5.56%)  1 1/17 (5.88%)  1 1/17 (5.88%)  1
Reproductive system and breast disorders           
Vaginal gardnerella  1  1/18 (5.56%)  1 0/18 (0.00%)  0 0/18 (0.00%)  0 0/17 (0.00%)  0 0/17 (0.00%)  0
Vaginal Discharge  1  1/18 (5.56%)  1 0/18 (0.00%)  0 0/18 (0.00%)  0 0/17 (0.00%)  0 0/17 (0.00%)  0
1
Term from vocabulary, MedDRA (23.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: David Strauss, MD, PhD
Organization: U.S. Food and Drug Administration
Phone: 301-796-6323
EMail: David.Strauss@fda.hhs.gov
Layout table for additonal information
Responsible Party: Food and Drug Administration (FDA)
ClinicalTrials.gov Identifier: NCT04397445    
Other Study ID Numbers: SCR-010
First Submitted: May 15, 2020
First Posted: May 21, 2020
Results First Submitted: June 28, 2021
Results First Posted: July 19, 2021
Last Update Posted: August 9, 2021