Phase I Clinical Trial of 13C-Urea Breath Test (C-13UBT)

Helicobacter pylori (HP) has recently attracted attention for its involvement in the occurrence and progression of gastritis, as well as in the occurrence, worsening to intractable stage, and relapse of gastric or duodenal ulcer. However, there is no safe and simple method to accurately diagnose the presence and degree of HP infection, to evaluate the reduction in bacterial count after attempted eradication of HP, and to evaluate the success or failure of the eradication without subjecting the patient to considerable discomfort on pain. Taking advantage of the urease activity of HP to produce carbon dioxide from urea, we developed a new 13C-urea breath test (C-13UBT) that uses urea labeled with carbon 13, a stable, naturally occurring non-radioactive isotope, to detect the presence of HP infection. The present phase I study was designed to determine the safety and efficacy of the C-13UBT. Healthy volunteers ingested 100, 200, and 300 mg of 13C-urea dissolved in 100 ml of water. The subjects were placed in the sitting position in order to bring the 13C-urea into close contact with the gastric mucosa, and their expired breath was collected at designated time intervals. The subjects were divided into two groups, HP antibody titer-positive group and HP antibody titer-negative group ; the relationship between HP infection and the amount of 13C-carbon dioxide detected in the expired breath was examined. The results showed a definite difference in the amount of 13C-carbon dioxide between the HP antibody titer-positive group and the HP antibody titer-negative group at all test doses. Although a dose of 100 mg was considered to be optimal in detecting HP positive subjects in the present study, further investigation is needed to accurately determine the optimal dose and the timing for assessment. Blood biochemistry, urinalysis, observations and examinations of subjective symptoms and objective signs, and safety assessment revealed no abnormalities related to the ingestion of 13C-urea. The serum pharmacokinetic parameters of the 13C-urea were obtained by subtracting endogenous 13C-urea from the measured values. As a result, the Cmax and AUC increased dose-dependently, with the AUC0-lim (AUC until the time of final detection) and Cmax for 100, 200, and 300 mg being 22.7μg·hr/ml and 2.7μg/ml, 63.6 μg·hr/ml and 5.5μg/ml, and 83.9μg·hr/ml and 9.0μg/ml, respectively. The mean total urinary excretion of 13C-urea during the 24 hours post-ingestion was 412 mg at 100 mg, 550 mg at 200 mg, and 504 mg at 300 mg, showing an increase over the theoretical range of 150 to 300 mg which was obtained by computing the total daily urea excretion (normal laboratory test value) from the percentage of endogenous 13C-urea in the urine (about 1%). Serum levels of ammonia and blood urea nitrogen (BUN) and urinary levels of urea showed no changes dependent on the dose of 13C-urea. These results suggest that C-13UBT is a highly safe, simple, and useful test that accurately reflects the status of HP infection.