Nizatidine for the treatment of pediatric gastroesophageal reflux symptoms: an open-label, multiple-dose, randomized, multicenter clinical trial in 210 children.

Background: Gastroesophageal reflux disease (GERD), which is reflux that produces damage or troubling symptoms, afflicts approximately 7% of infants and children to the extent that administration of physician-directed pharmacotherapy is warranted.

Objective: This study was designed in conjunction with the US Food and Drug Administration (FDA) to assess the tolerability and effectiveness of nizatidine, in different doses and formulations, including a newly formulated premade oral solution, for pediatric GERD.

Methods: Children aged 5 days through 18 years were recruited to this 8-week, open-label, multiple-dose, randomized, parallel-group, multicenter study. The original study design specified that patients aged 5 days through 12 years at study start be given a nizatidine capsule dissolved in infant formula or apple juice depending on patient age ("extemporaneous solution"). Children 13 through 18 years old were to be given the "adult dose" of nizatidine capsules 150 mg BID regardless of body weight. All patients aged < 13 years were randomized in blocks of 4 between 2 dose levels (2.5 and 5 mg/kg per dose BID). A protocol amendment during the study added a newly formulated, more pediatric-appropriate, premade oral solution that was developed at the request of the FDA. This premade formulation ("oral solution") was to replace the extemporaneous solution mixed in infant formula or apple juice. Subsequently, an additional 44 children aged < 13 years old were enrolled in the study and randomized to receive the new nizatidine oral solution for 8 weeks at the same 2 dose levels as used for the extemporaneous solution. Outcome data at 4 and 8 weeks included adverse events (AEs) (severity, relation to study drug, and any relationship to study withdrawal) and effectiveness (investigators' assessment of changes in reflux symptoms and overall physical well-being, and parent/child assessment of change in antacid use). Formal statistical analyses were not planned, but post hoc chi-square analyses were performed.

Results: Of 214 children enrolled, 210 (98%) intent-to-treat (ITT) patients received > or = 1 dose; of these, 173 (82%) completed 8 weeks of study. At least 77% were compliant (ie, medicated on > or = 75% of days). Of the ITT patients, 37 did not complete 8 weeks due to insufficient response, AEs (regardless of relationship to study drug), or other reasons. Although 292 AEs occurred in 115 patients, 277 (95%) were mild to moderate and 15 (5%) were severe. Most of the AEs in these children studied during the winter were related to infectious illnesses. Only 4 serious AEs occurred; 3 were unrelated to study drug. The fourth AE--considered possibly related--was worsening sickle cell anemia 18 days after medication discontinuation. Approximately 30% of patients became asymptomatic after 8 weeks of treatment, regardless of dosing or formulation, and despite reduction of antacid use in half of the patients. No clear superiority of any dose or formulation was demonstrated.

Conclusions: This large study, although limited by its open-label design and post hoc analyses, supports the tolerability and effectiveness of 8 weeks of treatment with nizatidine in children aged 5 days through 18 years. AE incidence and severity were as expected for children during the winter season. There was an overall improvement in symptoms and a decrease in antacid use. Formulation did not appear to alter tolerability or effectiveness assessments: the premade solution, extemporaneous solution, and capsule provided comparable symptomatic relief with no disproportionate adverse reactions.