| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pediatric patients 1 to 11 years old, inclusive, with endoscopically-proven GERD. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10017885 |
| E.1.2 | Term | Gastrooesophageal reflux disease |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study was to determine the area under the plasma concentration time curve (AUC) of esomeprazole after single oral doses of 5 mg, 10 mg, or 20 mg esomeprazole in pediatric patients 1 to 11 years old, inclusive, with endoscopically proven GERD. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives were as follows:
1. To determine the area under the plasma concentration time curve from time zero to the last quantifiable concentration (AUC(0 t)), maximum plasma concentration (Cmax), time to reach Cmax (tmax), terminal half life (t1/2λz), apparent oral clearance (CL/F), and apparent volume of distribution during terminal phase (Vλz/F) of esomeprazole after single oral doses of 5 mg, 10 mg, and 20 mg esomeprazole in pediatric patients 1 to 11 years old, inclusive, with endoscopically-proven GERD.
2. To determine AUC, AUC(0 t), Cmax, tmax, and t1/2λz of the 5-hydroxy and sulphone metabolites of esomeprazole after a single oral dose of 5 mg, 10 mg, and 20 mg esomeprazole in pediatric patients 1 to 11 years old, inclusive, with endoscopically proven GERD.
3. To assess the safety and tolerability of esomeprazole in pediatric patients 1 to 11 years old, inclusive, with endoscopically-proven GERD.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For inclusion in the study, patients had to fulfill all of the following criteria:
1. Provide signed, written informed consent from patient’s parent/guardian with assent from the patient, if appropriate
2. Patients were between the ages of 1 and 11, inclusive, and able to take solid or bland food (eg, applesauce)
3. Patients weighed at least 8 kg and, at the investigator’s discretion, were able to undergo extraction of an adequate volume of blood
4. The patient’s weight for height percentile should have been less than the 90th percentile or the body mass index (BMI) must have been between the 5th and 95th percentile for age.
5. Patients were diagnosed with endoscopically proven GERD by the investigator during the screening period (Visit 1). In addition, patients with a previous (within 42 days of Visit 1) endoscopic diagnosis of GERD induced esophagitis were not required to have another endoscopy to be enrolled into this study. Patients weighing <20 kg with a previous endoscopy performed within 90 days of Visit 1 were eligible for enrollment. The diagnosis of esophagitis could have been made by the Principal Investigator or referred from other endoscopy specialists or centers. Endoscopic evidence was accepted if there was adequate documentation (ie, complete endoscopic reports, pathology reports, or photo documentation). Patients with extra esophageal and/or atypical symptoms (ie, failure to thrive, reactive airway disease, etc.) who were candidates for endoscopy qualified for inclusion provided they had endoscopic signs of GERD.
6. Patients were not to take any prescription or over the counter (OTC) PPIs for 7 days and/or H2RA therapy for 3 days before the dose of the study drug through completion of study procedures on Day 1. Resumption of treatment with PPIs and H2RAs was at the discretion of the investigator.
7. Patients/parents/guardians must have been willing to communicate with the investigator and comply with all study procedures.
8. Post menarchal females must have had a negative urine pregnancy test at the time of randomization on Day 1.
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| E.4 | Principal exclusion criteria |
Any of the following was regarded as a criterion for exclusion from the study:
1. Use of any other investigational compound or participation in another clinical trial within 28 days before the screening visit.
2. History or presence of gastrointestinal (GI), hepatic, or renal disease, or other conditions that could interfere with absorption, distribution, metabolism, or excretion of esomeprazole.
3. Unstable diabetes mellitus or history of seizure disorder.
4. Any acute or chronic illness or a medical history, which in the opinion of the investigator and/or sponsor, could have compromised the patient’s safety or successful participation in the study.
5. Patients with the following diseases/conditions:active GI bleed, active peptic ulcer disease, eosinophilic gastroenteritis, allergic gastroenteropathies, inflammatory bowel disease, bleeding disorders, seizure disorders, acute pancreatitis, metabolic diseases, or meningitis. Patients with a past history (before study enrollment) of erosive esophagitis (EE), duodenal ulcers (DU), gastric ulcers (GU) and/or Helicobacter pylori (H. pylori) infection were eligible for this study if they satisfied other inclusion/exclusion criteria. Patients with active H. pylori infection may have been enrolled into the study provided anti Helicobacter antibiotic therapy was withheld until after the study was completed. This decision was made at the investigator’s discretion and with agreement from the patient’s parent/guardian.
6. Female patients who were taking hormonal contraceptives for medical reasons.
7. Patients who must have remained on any of the following concomitant medications during the course of the study: bismuth containing products, barbiturates, anti convulsants, anti coagulants, narcotics, anti neoplastic agents, H2RAs, sucralfate, anti emetics, systemic steroids (oral and intravenous), pro motility drugs (eg, cisapride, metoclopramide, domperidone) or macrolide antibiotics such as erythromycin. Use of topical erythromycin was permissible. Occasional doses of nonsteroidal anti inflammatory drugs or salicylates (3 days) to treat acute conditions were permissible.
8. The patient’s endoscopic findings must have had no evidence of advanced esophageal lesions due to GERD or other severe upper GI tract pathology (eg, Barrett’s, stricture, neoplasm).
9. Patients with a history or a current need for resectional or reconstructive surgery of the GI tract (eg, esophagus, stomach, duodenum, jejunum, or colon) were excluded except for those who required surgery for a diagnosis of esophageal atresia (any variant) or pyloric stenosis.
10. History of multiple drug allergies unless otherwise agreed by AstraZeneca and the investigator.
11. Hypersensitivity, allergy, or intolerance to esomeprazole, any ingredient in its formulation or any drug with a similar chemical structure to esomeprazole.
12. Current use of anti epileptic medications phenytoin, mephenytoin, antineoplastic agents, pro motility drugs (prokinetics), sucralfate, or warfarin.
13. Use of any drug known to affect the pharmacokinetic parameters of esomeprazole within 14 days before administration of study drug on Day 1. These drugs included, but were not limited to, enzyme inducers such as phenobarbital, carbamazepine, rifampin, and St. John’s Wort, or enzyme inhibitors such as clarithromycin, erythromycin, selective serotonin re uptake inhibitors, cimetidine, itraconazole, protease inhibitors, and ketaconazole.
14. Clinically significant abnormal values at screening from laboratory measurements, vital signs, or other physical examination findings other than those directly related to some concurrent and stable disease, which, in the investigator’s opinion, may have either put the patient at risk when participating in the study or were both unexplained and clinically significant.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Variables
- Pharmacokinetic
Blood samples were analyzed to determine the pharmacokinetics of esomeprazole (AUC, AUC(0 t), Cmax, tmax, t1/2λz, CL/F, Vλz/F) and its 5 hydroxy and sulphone metabolites (AUC, AUC(0 t), Cmax, tmax, t1/2λz).
- Safety
Safety and tolerability were evaluated from the incidence and severity of all adverse events and the assessment of laboratory parameters, vital signs measurements, and physical examination findings
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| During the course of the study. Treatment one day. Safety follow-up up to 2 weeks post dosing. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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