Clinical Trial Results:
A Single-Blind, Randomised, Parallel-Group, Single-Centre
Pharmacokinetic and pH-Monitoring Study of Esomeprazole in Infants up
to 24 Months of Age
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Summary
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EudraCT number |
2012-001159-37 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
15 Feb 2006
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Feb 2017
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First version publication date |
12 Aug 2015
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
SH-NEC-0001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
AstraZeneca R&D Mölndal
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Sponsor organisation address |
Pepparedsleden 1, Mölndal, Sweden, 43183
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Public contact |
AstraZeneca Clinical Trial Transparency group, AstraZeneca R&D, ClinicalTrialTransparency@astrazeneca.com
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Scientific contact |
Per Lundborg, MD PhD, AstraZeneca R&D Mölndal, 46 317761000,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000331-PIP01-08 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
15 Feb 2006
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
15 Feb 2006
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Global end of trial reached? |
Yes
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Global end of trial date |
15 Feb 2006
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the pharmacokinetics of esomeprazole and its efficacy in controlling intragastric pH in infants.
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Protection of trial subjects |
The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with ICH/Good Clinical Practice and applicable regulatory requirements and the AstraZeneca policy on Bioethics. Considerations were taken to the ICH guideline “Clinical investigation of medicinal products in the paediatric population” when developing the CSP.The study was approved by the Independent Research Ethics Committee (IEC) of the Women’s and Children’s Hospital, 72 King William Road, North Adelaide, South Australia 5006
Since all subjects in this study were infants aged 24 months or younger, informed consent could not be obtained from the subjects themselves. Therefore, the principal investigator ensured that the parent/guardian was given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study before enrolment. The parent/guardian was also notified that his/her child’s participation in the study, as well the identity, was to be treated confidentially and that he/she was free to withdraw the child from participation in the study at any time. The parent/guardian was given time for consideration and the opportunity to ask questions. The parent’s/guardian’s signed informed consent was obtained before any study specific procedure was conducted.
Subjects could be withdrawn from study treatment and assessments at any time at the discretion of the investigator.
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Background therapy |
The subject population comprised outpatient infants up to 24 months of age with symptoms of GERD and diagnosis confirmed by 24-hour pH-monitoring. Medication considered necessary for the subject’s safety and well-being was to be given at the discretion of the investigator.Use of any pharmacological antireflux therapy within 24 hours prior to the first dose of investigational product, or use of any proton pump inhibitor within 72 hours of the first dose of investigational product were exclusion criteria.Mylanta or equivalent could be used for treatment of gastrointestinal symptoms, except within +/- 1 hour of the administration of investigational product . | ||
Evidence for comparator |
No comparator group | ||
Actual start date of recruitment |
06 Jun 2002
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 50
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Worldwide total number of subjects |
50
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
50
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
First subject enrolled 6 June 2002 Last subject completed 23 March 2005 | ||||||||||||||||||
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Pre-assignment
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Screening details |
107 subjects attended pre-entry visit <7 days before first study day. At pre-visit informed consent was obtained, routine lab, physical examination and 24-hour pH monitoring was performed. Out of these, 50 eligible subjects were randomised to 1 of the parallel treatment arms and given a subject number 2 days prior to first dose administered. | ||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
50 | ||||||||||||||||||
Number of subjects completed |
50 | ||||||||||||||||||
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Period 1
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Period 1 title |
Treatment period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Single blind | ||||||||||||||||||
Roles blinded |
Carer [1] | ||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Esomeprazole 0.25 mg/kg | ||||||||||||||||||
Arm description |
Esomeprazole 0.25 mg/kg | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Esomeprazole
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Investigational medicinal product code |
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Other name |
NEXIUM
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
0.25 mg/kg orally od for 1 week
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Arm title
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Esomeprazole 1.0 mg/kg | ||||||||||||||||||
Arm description |
Esomeprazole 1.0 mg/kg | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Esomeprazole
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Investigational medicinal product code |
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Other name |
NEXIUM
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
1.0 mg/kg orally od for 1 week
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| Notes [1] - The roles blinded appear inconsistent with a simple blinded trial. Justification: Individual NSAE occurring in > 1 subject in the trial (>5%) is included |
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Baseline characteristics reporting groups
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Reporting group title |
Esomeprazole 0.25 mg/kg
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Reporting group description |
Esomeprazole 0.25 mg/kg | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Esomeprazole 1.0 mg/kg
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Reporting group description |
Esomeprazole 1.0 mg/kg | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
ITT population
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All randomised subjects who took at least 1 dose of study medication and for whom pharmacokinetic, pharmacodynamic or symptom data post-dose are available were included in the ITT population
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End points reporting groups
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Reporting group title |
Esomeprazole 0.25 mg/kg
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Reporting group description |
Esomeprazole 0.25 mg/kg | ||
Reporting group title |
Esomeprazole 1.0 mg/kg
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Reporting group description |
Esomeprazole 1.0 mg/kg | ||
Subject analysis set title |
ITT population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All randomised subjects who took at least 1 dose of study medication and for whom pharmacokinetic, pharmacodynamic or symptom data post-dose are available were included in the ITT population
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End point title |
Pharmacokinetic variables AUCτ [1] | ||||||||||||||||
End point description |
AUCτ
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End point type |
Primary
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End point timeframe |
1 week (7 or 8 days)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: For the pharmacokinetic endpoints only disscriptive statistics were used. |
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| Notes [2] - PK total 40 subjects, in 5 of these no PK value due to too few post-dose samples or below LLQ [3] - PK total 40 subjects, in 5 of these no PK value due to too few post-dose samples or below LLQ [4] - Ratios for the Geometric means (Eso 1.0 mg/kg/Eso 0.25 mg/kg) and confidence intervals presented |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Pharmacokinetics Cmax steady state [5] | ||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
at 1 week (day 7/8)
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: For the pharmacokinetic endpoints only disscriptive statistics were used. |
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| Notes [6] - PK total 40 subjects, in 5 of these no PK value due to too few post-dose samples or below LLQ [7] - PK total 40 subjects, in 5 of these no PK value due to too few post-dose samples or below LLQ [8] - Ratios for the Geometric means (Eso 1.0 mg/kg/Eso 0.25 mg/kg) and confidence intervals presented |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
PharmacodynamicThe percentage of time with intragastric pH above 4 during the 24-hour period | ||||||||||||||||
End point description |
The percentage of time with intragastric pH above 4 during the 24-hour period
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End point type |
Primary
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End point timeframe |
pre-entry visit and on Day 7/8
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| Notes [9] - Subjects who had intragastric pH measurement [10] - Subjects who had intragastric pH measurement [11] - Difference between treatment groups |
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Statistical analysis title |
Intragastric pH>4 after one week of treatment | ||||||||||||||||
Comparison groups |
Esomeprazole 0.25 mg/kg v Esomeprazole 1.0 mg/kg v ITT population
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
> 0.0009 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
21.34
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
9.23 | ||||||||||||||||
upper limit |
33.45 | ||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
6
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Adverse events information
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Timeframe for reporting adverse events |
During enrollment and randomised treatment (1 week)
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
Not known
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Reporting groups
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Reporting group title |
Esomeprazole 1.0 mg/kg
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Reporting group description |
Esomeprazole 1.0 mg/kg | |||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Esomeprazole 0.25 mg/kg
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Reporting group description |
Esomeprazole 0.25 mg/kg | |||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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10 Dec 2001 |
Addition of exclusion criteria no 2; “Current or previous evidence of liver disease and necrotising enterocolitis”. |
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14 Feb 2002 |
information that “At least 24 of the 40 evaluable subjects should be less than 12 months of age” was added. |
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27 Feb 2002 |
Clarification around antacids as rescue medication |
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05 Feb 2003 |
The study was changed from being double-blind to become single-blind, and prolongation of recruitment time. |
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02 Apr 2003 |
Change of exclusion criteria no 5a; Reflux index for subjects ≤12 months of age was change from ≥10%” to ≥5% |
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14 Sep 2003 |
The CSP was changed to also include infants 1 to 3 months of age in order to comply with an FDA request. |
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20 Jan 2004 |
The methods of drug administration for subjects ≥1 month but <3 months of age was changed (through funnel pan) |
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07 Apr 2004 |
The number of pharmacokinetically evaluable subjects needed in the study was changed from 40 to 30 subjects, |
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09 Sep 2004 |
date for last subject out was postponed until first/second quarter of 2005 |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
