Trial Outcomes & Findings for Clinical Study to Investigate the Urinary Excretion of N-nitrosodimethylamine (NDMA) After Ranitidine Administration (NCT NCT04397445)

Last Updated: 2021-08-09

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

18 participants

Primary outcome timeframe

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.

Results posted on

2021-08-09

Participant Flow

Participant milestones

Participant milestones
Measure	ABCD 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	BACD 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	ABDC 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	BADC 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
Overall Study STARTED	5	5	4	4
Overall Study COMPLETED	4	5	4	4
Overall Study NOT COMPLETED	1	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	ABCD 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	BACD 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	ABDC 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	BADC 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
Overall Study Withdrawal by Subject	1	0	0	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=18 Participants 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.
Age, Continuous	33.0 years n=99 Participants
Sex: Female, Male Female	9 Participants n=99 Participants
Sex: Female, Male Male	9 Participants n=99 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=99 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	15 Participants n=99 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants
Race (NIH/OMB) Black or African American	11 Participants n=99 Participants
Race (NIH/OMB) White	7 Participants n=99 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants
Region of Enrollment United States	18 participants n=99 Participants
Body Weight	76.9 kg n=99 Participants

PRIMARY outcome

Timeframe: 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.

Population: All participants who completed two paired treatment periods (i.e., ranitidine and placebo with the same diet)

Outcome measures

Outcome measures
Measure	Ranitidine and Noncured Meats Diet n=17 Participants Single dose of ranitidine, 300 mg with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA	Placebo and Noncured Meats Diet n=17 Participants Single dose of oral placebo with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA	Ranitidine and Cured Meats Diet n=17 Participants Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA	Placebo and Cured Meats Diet n=17 Participants Single dose of oral placebo with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Cumulative NDMA Amount Excreted in Urine Over 24 Hours After Drug Administration (Comparison Between Ranitidine and Placebo)	0.6 nanograms Interval 0.0 to 29.7	10.5 nanograms Interval 0.0 to 17.8	11.9 nanograms Interval 5.6 to 48.6	23.4 nanograms Interval 8.6 to 36.7

OTHER_PRE_SPECIFIED outcome

Population: All participants who completed two paired treatment periods (i.e., ranitidine and placebo with the same diet)

Outcome measures

Outcome measures
Measure	Ranitidine and Noncured Meats Diet n=17 Participants Single dose of ranitidine, 300 mg with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA	Placebo and Noncured Meats Diet n=17 Participants Single dose of oral placebo with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA	Ranitidine and Cured Meats Diet n=17 Participants Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA	Placebo and Cured Meats Diet n=17 Participants Single dose of oral placebo with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Cumulative NDMA Amount Excreted in Urine Over 24 Hours After Drug Administration (Comparison Between Diets)	11.9 nanograms Interval 5.6 to 48.6	0.6 nanograms Interval 0.0 to 29.7	23.4 nanograms Interval 8.6 to 36.7	10.5 nanograms Interval 0.0 to 17.8

OTHER_PRE_SPECIFIED outcome

Population: All participants who completed two paired treatment periods (i.e., ranitidine and placebo with the same diet)

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.

Outcome measures

Outcome measures
Measure	Ranitidine and Noncured Meats Diet n=17 Participants Single dose of ranitidine, 300 mg with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA	Placebo and Noncured Meats Diet n=17 Participants Single dose of oral placebo with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA	Ranitidine and Cured Meats Diet n=17 Participants Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA	Placebo and Cured Meats Diet n=17 Participants Single dose of oral placebo with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Cumulative Dimethylamine (DMA) Amount Excreted in Urine Over 24 Hours After Drug Administration	38.8 milligrams Geometric Coefficient of Variation 38	41.1 milligrams Geometric Coefficient of Variation 33	40.7 milligrams Geometric Coefficient of Variation 52	43.1 milligrams Geometric Coefficient of Variation 34

OTHER_PRE_SPECIFIED outcome

Population: All participants who completed two paired treatment periods (i.e., ranitidine and placebo with the same diet)

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.

Outcome measures

Outcome measures
Measure	Ranitidine and Noncured Meats Diet n=17 Participants Single dose of ranitidine, 300 mg with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA	Placebo and Noncured Meats Diet n=17 Participants Single dose of oral placebo with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA	Ranitidine and Cured Meats Diet Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA	Placebo and Cured Meats Diet Single dose of oral placebo with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
Cumulative Ranitidine Amount Excreted in Urine Over 24 Hours After Drug Administration	91.7 milligrams Geometric Coefficient of Variation 29	74.1 milligrams Geometric Coefficient of Variation 39	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

Population: 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.

Outcome measures

Outcome measures
Measure	Ranitidine and Noncured Meats Diet n=17 Participants Single dose of ranitidine, 300 mg with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA	Placebo and Noncured Meats Diet n=17 Participants Single dose of oral placebo with a noncured meats diet designed to contain lower amounts of nitrites, nitrates, and NDMA	Ranitidine and Cured Meats Diet n=17 Participants Single dose of ranitidine, 300 mg with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA	Placebo and Cured Meats Diet n=17 Participants Single dose of oral placebo with a cured meats diet designed to contain higher amounts of nitrites, nitrates, and NDMA
AUC(0-t) of Plasma DMA	26.3 micrograms*hour/milliliter Geometric Coefficient of Variation 34	26.2 micrograms*hour/milliliter Geometric Coefficient of Variation 35	20.9 micrograms*hour/milliliter Geometric Coefficient of Variation 53	20.9 micrograms*hour/milliliter Geometric Coefficient of Variation 46

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

Population: 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.