Trial Outcomes & Findings for Phase 3/Safety & Efficacy of Esomeprazole in Infants (NCT NCT00468559)

NCT ID: NCT00468559

Last Updated: 2014-06-02

Results Overview

Number of participants discontinuing during the 4-week of randomized double-blind withdrawal phase that met the pre-set definition of symptom worsening criteria.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 98 participants
• Primary outcome timeframe: Treatment-withdrawal phase (up to 4 weeks following randomization, or until earlier discontinuation from the study)
• Results posted on: 2014-06-02

Participant Flow

Participants aged 1 to 11 months inclusive with a clinical diagnosis of suspected Gastroesophageal Reflux Disease (GERD), symptomatic GERD, or endoscopically proven GERD were enrolled across the USA France Germany and Poland. All patients were symptomatic at study entry.

All participants received 2-weeks open label esomeprazole (Open-label phase) according to baseline weight (3 to 5kg: 2.5mg; >5 to 7.5kg:5mg; >7.5-12kg:10mg). Following the open-label phase, those with symptom improvement of at least one category in the physician global assessment were eligible to be randomized into the withdrawal phase.

Participant milestones

Measure	Open Label Esomeprazole Open-label daily esomeprazole (2.5mg, 5mg or 10mg daily during open-label phase of the study, according to baseline weight). Eligible participants from the Open Label phase were randomized to the the double blind withdrawal phase.	Double Blind Esomeprazole	Double Blind Placebo
Open-label Treatment Phase STARTED	98	0	0
Open-label Treatment Phase COMPLETED	80	0	0
Open-label Treatment Phase NOT COMPLETED	18	0	0
Double-blind, Treatment-withdrawal Phase STARTED	0	39	41
Double-blind, Treatment-withdrawal Phase COMPLETED	0	29	24
Double-blind, Treatment-withdrawal Phase NOT COMPLETED	0	10	17

Reasons for withdrawal

Measure	Open Label Esomeprazole Open-label daily esomeprazole (2.5mg, 5mg or 10mg daily during open-label phase of the study, according to baseline weight). Eligible participants from the Open Label phase were randomized to the the double blind withdrawal phase.	Double Blind Esomeprazole	Double Blind Placebo
Open-label Treatment Phase Adverse Event	5	0	0
Open-label Treatment Phase Lack of Efficacy	9	0	0
Open-label Treatment Phase Withdrawal by Subject	4	0	0
Double-blind, Treatment-withdrawal Phase Lack of Efficacy	0	8	17
Double-blind, Treatment-withdrawal Phase Adverse Event	0	2	0

Baseline Characteristics

Phase 3/Safety & Efficacy of Esomeprazole in Infants

Baseline characteristics by cohort

Measure	Double Blind Esomeprazole n=39 Participants	Double Blind Placebo n=41 Participants	Total n=80 Participants Total of all reporting groups
Age, Continuous	4.9 Months STANDARD_DEVIATION 2.6 • n=5 Participants	4.9 Months STANDARD_DEVIATION 3.2 • n=7 Participants	4.9 Months STANDARD_DEVIATION 2.9 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	14 Participants n=7 Participants	23 Participants n=5 Participants
Sex: Female, Male Male	30 Participants n=5 Participants	27 Participants n=7 Participants	57 Participants n=5 Participants

PRIMARY outcome

Timeframe: Treatment-withdrawal phase (up to 4 weeks following randomization, or until earlier discontinuation from the study)

Population: reporting cumulative discontinuations

Number of participants discontinuing during the 4-week of randomized double-blind withdrawal phase that met the pre-set definition of symptom worsening criteria.

Outcome measures

Measure	Double Blind Esomeprazole n=39 Participants In the double-blind treatment-withdrawal phase of the study, participants in this group received double-blind esomeprazole at the same dose they received in the preceeding open-label phase of the study.	Double Blind Placebo n=41 Participants Participants in this group received placebo during the double-blind treatment withdrawal phase.
Number of Participants Discontinuing Due to Symptom Worsening in the Randomized Treatment Withdrawal Phase (Treatment Withdrawal Phase Endpoint) Week 1	1 Participants	6 Participants
Number of Participants Discontinuing Due to Symptom Worsening in the Randomized Treatment Withdrawal Phase (Treatment Withdrawal Phase Endpoint) Week 2	8 Participants	12 Participants
Number of Participants Discontinuing Due to Symptom Worsening in the Randomized Treatment Withdrawal Phase (Treatment Withdrawal Phase Endpoint) Week 3	9 Participants	13 Participants
Number of Participants Discontinuing Due to Symptom Worsening in the Randomized Treatment Withdrawal Phase (Treatment Withdrawal Phase Endpoint) Week 4	15 Participants	20 Participants

SECONDARY outcome

Timeframe: Treatment withdrawal phase (up to 4 weeks following randomization, or until earlier discontinuation from the study)

Population: Reporting cumulative discontinuations. Results for the analysis of the secondary variable, time to discontinuation due to any cause, were identical to that found for the primary variable, time to discontinuation due to symptom.

Number of participants discontinuing due to any reason was identical to the number of participants discontinuing due to symptom worsening (the primary assessment) when no participants discontinued due to reason other than symptom worsening.

Outcome measures

Measure	Double Blind Esomeprazole n=39 Participants In the double-blind treatment-withdrawal phase of the study, participants in this group received double-blind esomeprazole at the same dose they received in the preceeding open-label phase of the study.	Double Blind Placebo n=41 Participants Participants in this group received placebo during the double-blind treatment withdrawal phase.
Number of Participants Discontinuing Due to Any Reason, Including Symptom Worsening, in the Randomized Treatment Withdrawal Phase (Treatment Withdrawal Phase Endpoint) Week 1	1 Participants	6 Participants
Number of Participants Discontinuing Due to Any Reason, Including Symptom Worsening, in the Randomized Treatment Withdrawal Phase (Treatment Withdrawal Phase Endpoint) Week 2	8 Participants	12 Participants
Number of Participants Discontinuing Due to Any Reason, Including Symptom Worsening, in the Randomized Treatment Withdrawal Phase (Treatment Withdrawal Phase Endpoint) Week 3	9 Participants	13 Participants
Number of Participants Discontinuing Due to Any Reason, Including Symptom Worsening, in the Randomized Treatment Withdrawal Phase (Treatment Withdrawal Phase Endpoint) Week 4	15 Participants	20 Participants

SECONDARY outcome

Timeframe: Treatment withdrawal phase (up to 4 weeks following randomization, or until earlier discontinuation from the study)

The number of participants reaching the end of the treatment withdrawal phase without discontinuing from the study (for any reason) or showing symptom worsening in the physician global assessment of Gastroesophageal Reflux Disease (GERD) symptoms. Based on the severity of symptoms reported by the parent/guardian in IVRS, the investigator provided the overall clinical impression of the patient's GERD-related symptoms over the last 7 days as:

None Mild Moderate Severe

Outcome measures

Measure	Double Blind Esomeprazole n=39 Participants In the double-blind treatment-withdrawal phase of the study, participants in this group received double-blind esomeprazole at the same dose they received in the preceeding open-label phase of the study.	Double Blind Placebo n=41 Participants Participants in this group received placebo during the double-blind treatment withdrawal phase.
Treatment Successes at the End of the 4-week Double-blind Treatment Withdrawal Phase (Treatment Withdrawal Phase Endpoint).	24 Participants	21 Participants

SECONDARY outcome

Timeframe: Treatment withdrawal phase (up to 4 weeks following randomization, or until earlier discontinuation from the study)

Percentage of participants with Physician's Global Assessment (PGA) score at the final treatment withdrawal assessment in following categories: None (no symptoms), Mild, Moderate or Severe. The worst post-randomization Physician's Global Assessment (PGA) assessment during double blind phase is taken into account.

Outcome measures

Measure	Double Blind Esomeprazole n=39 Participants In the double-blind treatment-withdrawal phase of the study, participants in this group received double-blind esomeprazole at the same dose they received in the preceeding open-label phase of the study.	Double Blind Placebo n=41 Participants Participants in this group received placebo during the double-blind treatment withdrawal phase.
Physician's Global Assessment (PGA) of Gastroesophageal Reflux Disease (GERD) Symptoms (Treatment Withdrawal Phase Endpoint) None	10.3 Percentage of participants	4.9 Percentage of participants
Physician's Global Assessment (PGA) of Gastroesophageal Reflux Disease (GERD) Symptoms (Treatment Withdrawal Phase Endpoint) Mild	51.3 Percentage of participants	48.8 Percentage of participants
Physician's Global Assessment (PGA) of Gastroesophageal Reflux Disease (GERD) Symptoms (Treatment Withdrawal Phase Endpoint) Moderate	25.6 Percentage of participants	31.7 Percentage of participants
Physician's Global Assessment (PGA) of Gastroesophageal Reflux Disease (GERD) Symptoms (Treatment Withdrawal Phase Endpoint) Severe	12.8 Percentage of participants	14.6 Percentage of participants

SECONDARY outcome

Timeframe: Treatment withdrawal phase (up to 4 weeks following randomization, or until earlier discontinuation from the study) Change was calculated from baseline to last measure obtained

Change from baseline in symptom severity (Severity is scored as 0-4 [none, mild moderate, severe]). For each participant, final severity score is the mean severity in the final 7-days, while baseline is the mean severity in the 7-day period up to and including randomization. Changes less than zero indicate improved severity versus baseline. Participants needed baseline measure and one additional post baseline measure to be included in analysis.

Outcome measures

Measure	Double Blind Esomeprazole n=37 Participants In the double-blind treatment-withdrawal phase of the study, participants in this group received double-blind esomeprazole at the same dose they received in the preceeding open-label phase of the study.	Double Blind Placebo n=40 Participants Participants in this group received placebo during the double-blind treatment withdrawal phase.
Severity of Vomiting/Regurgitation Symptoms as Reported by the Parent/Guardian (Treatment Withdrawal Phase Endpoint)	0.040 Units on a scale Standard Deviation 0.560	0.090 Units on a scale Standard Deviation 0.610

SECONDARY outcome

Timeframe: Treatment withdrawal phase (up to 4 weeks following randomization, or until earlier discontinuation from the study) Change was calculated from baseline to last measure obtained

Change from baseline in symptom severity (Severity is scored as 0-4 [none, mild moderate, severe]). For each participant, final severity score is the mean severity in the final 7-days, while baseline is the mean severity in the 7-day period up to and including randomization. Changes less than zero indicate improved severity versus baseline. Participants needed baseline measure and one additional post baseline measure to be included in analysis.

Outcome measures

Measure	Double Blind Esomeprazole n=37 Participants In the double-blind treatment-withdrawal phase of the study, participants in this group received double-blind esomeprazole at the same dose they received in the preceeding open-label phase of the study.	Double Blind Placebo n=40 Participants Participants in this group received placebo during the double-blind treatment withdrawal phase.
Severity of Irritability Crying/Fussing Symptoms as Reported by the Parent/Guardian (Treatment Withdrawal Phase Endpoint)	0.060 Units on a scale Standard Deviation 0.580	0.190 Units on a scale Standard Deviation 0.590

SECONDARY outcome

Timeframe: Treatment withdrawal phase (up to 4 weeks following randomization, or until earlier discontinuation from the study) Change was calculated from baseline to last measure obtained

Change from baseline in symptom severity (Severity is scored as 0-4 [none, mild moderate, severe]). For each participant, final severity score is the mean severity in the final 7-days, while baseline is the mean severity in the 7-day period up to and including randomization. Changes less than zero indicate improved severity versus baseline. Participants needed baseline measure and one additional post baseline measure to be included in analysis.

Outcome measures

Measure	Double Blind Esomeprazole n=37 Participants In the double-blind treatment-withdrawal phase of the study, participants in this group received double-blind esomeprazole at the same dose they received in the preceeding open-label phase of the study.	Double Blind Placebo n=40 Participants Participants in this group received placebo during the double-blind treatment withdrawal phase.
Severity of Supraesophageal/Respiratory Disturbances (Coughing/Wheezing,Labored Breathing) as Reported by Parent/Guardian (Treatment Withdrawal Phase Endpoint)	0.120 Units on a scale Standard Deviation 0.480	0.030 Units on a scale Standard Deviation 0.580

SECONDARY outcome

Timeframe: Treatment withdrawal phase (up to 4 weeks following randomization, or until earlier discontinuation from the study) Change was calculated from baseline to last measure obtained

Change from baseline in symptom severity (Severity is scored as 0-4 [none, mild moderate, severe]). For each participant, final severity score is the mean severity in the final 7-days, while baseline is the mean severity in the 7-day period up to and including randomization. Changes less than zero indicate improved severity versus baseline. Participants needed baseline measure and one additional post baseline measure to be included in analysis.

Outcome measures

Measure	Double Blind Esomeprazole n=37 Participants In the double-blind treatment-withdrawal phase of the study, participants in this group received double-blind esomeprazole at the same dose they received in the preceeding open-label phase of the study.	Double Blind Placebo n=40 Participants Participants in this group received placebo during the double-blind treatment withdrawal phase.
Severity of Feeding Difficulties Reported by Parent/Guardian (Treatment Withdrawal Phase Endpoint)	0.090 Units on a scale Standard Deviation 0.480	0.100 Units on a scale Standard Deviation 0.610

SECONDARY outcome

Timeframe: Open-label treatment period (2 weeks)

Population: 95 patients received open-label esomeprazole during the open-label phase.

Number of patients who had an improvement of at least one category in the PGA at the end of open-label treatment with esomeprazole compared to baseline. Improvement in PGA was a pre-requisite for randomization into the randomized treatment withdrawal phase. Only patients with PGA at baseline and end of open-label are analyzed here.

Outcome measures

Measure	Double Blind Esomeprazole n=95 Participants In the double-blind treatment-withdrawal phase of the study, participants in this group received double-blind esomeprazole at the same dose they received in the preceeding open-label phase of the study.	Double Blind Placebo Participants in this group received placebo during the double-blind treatment withdrawal phase.
Improvement in Physician's Global Assessment (PGA) Following Open-label Esomeprazole (Open-label Phase Endpoint)	81 Participants	—

SECONDARY outcome

Timeframe: Open Label phase (Screening plus two weeks)

Population: 84 patients were analyzed at the screening timepoint, 84 patients were analyzed at week 1 and 79 patients were analyzed at Week 2 due to discontinuations.

Symptom severity (Severity is scored as 0-4 [none, mild moderate, severe]). For each participant, The score is the mean severity in each 7-day period.

Outcome measures

Measure	Double Blind Esomeprazole n=84 Participants In the double-blind treatment-withdrawal phase of the study, participants in this group received double-blind esomeprazole at the same dose they received in the preceeding open-label phase of the study.	Double Blind Placebo Participants in this group received placebo during the double-blind treatment withdrawal phase.
Severity of Vomiting/Regurgitation Symptoms as Reported by the Parent/Guardian (Open-label Phase) Screening	1.42 Units on a scale Standard Deviation 0.76	—
Severity of Vomiting/Regurgitation Symptoms as Reported by the Parent/Guardian (Open-label Phase) Week 1	1.14 Units on a scale Standard Deviation 0.67	—
Severity of Vomiting/Regurgitation Symptoms as Reported by the Parent/Guardian (Open-label Phase) Week 2	1.00 Units on a scale Standard Deviation 0.72	—

SECONDARY outcome

Timeframe: Open Label Phase (Screening plus two weeks)

Population: 84 patients were analyzed at the screening timepoint, 84 patients were analyzed at week 1 and 79 patients were analyzed at Week 2 due to discontinuations.

Symptom severity (Severity is scored as 0-4 [none, mild moderate, severe]). For each participant, The score is the mean severity in each 7-day period.

Outcome measures

Measure	Double Blind Esomeprazole n=84 Participants In the double-blind treatment-withdrawal phase of the study, participants in this group received double-blind esomeprazole at the same dose they received in the preceeding open-label phase of the study.	Double Blind Placebo Participants in this group received placebo during the double-blind treatment withdrawal phase.
Severity of Irritability Crying/Fussing Symptoms as Reported by the Parent/Guardian (Open-label Phase Endpoint) Screening	1.50 Units on a scale Standard Deviation 0.67	—
Severity of Irritability Crying/Fussing Symptoms as Reported by the Parent/Guardian (Open-label Phase Endpoint) Week 1	1.22 Units on a scale Standard Deviation 0.68	—
Severity of Irritability Crying/Fussing Symptoms as Reported by the Parent/Guardian (Open-label Phase Endpoint) Week 2	1.02 Units on a scale Standard Deviation 0.74	—

SECONDARY outcome

Timeframe: Open Label Phase (Screening plus two weeks)

Population: 84 patients were analyzed at the screening timepoint, 84 patients were analyzed at week 1 and 79 patients were analyzed at Week 2 due to discontinuations.

Symptom severity (Severity is scored as 0-4 [none, mild moderate, severe]). For each participant, The score is the mean severity in each 7-day period.

Outcome measures

Measure	Double Blind Esomeprazole n=84 Participants In the double-blind treatment-withdrawal phase of the study, participants in this group received double-blind esomeprazole at the same dose they received in the preceeding open-label phase of the study.	Double Blind Placebo Participants in this group received placebo during the double-blind treatment withdrawal phase.
Severity of Supraesophageal/Respiratory Disturbances (Coughing/Wheezing,Labored Breathing) as Reported by Parent/Guardian (Open-label Phase Endpoint) Screening	0.54 Units on a scale Standard Deviation 0.69	—
Severity of Supraesophageal/Respiratory Disturbances (Coughing/Wheezing,Labored Breathing) as Reported by Parent/Guardian (Open-label Phase Endpoint) Week 1	0.48 Units on a scale Standard Deviation 0.61	—
Severity of Supraesophageal/Respiratory Disturbances (Coughing/Wheezing,Labored Breathing) as Reported by Parent/Guardian (Open-label Phase Endpoint) Week 2	0.44 Units on a scale Standard Deviation 0.69	—

SECONDARY outcome

Timeframe: Open Label Phase (Screening plus two weeks)

Population: 83 patients were analyzed at the screening timepoint, 83 patients were analyzed at week 1 and 78 patients were analyzed at Week 2 due to discontinuations.

Symptom severity (Severity is scored as 0-4 [none, mild moderate, severe]). For each participant, The score is the mean severity in each 7-day period.

Outcome measures

Measure	Double Blind Esomeprazole n=83 Participants In the double-blind treatment-withdrawal phase of the study, participants in this group received double-blind esomeprazole at the same dose they received in the preceeding open-label phase of the study.	Double Blind Placebo Participants in this group received placebo during the double-blind treatment withdrawal phase.
Severity of Feeding Difficulties as Reported by Parent/Guardian (Open-label Phase Endpoint) Screening	1.16 Units on a scale Standard Deviation 0.76	—
Severity of Feeding Difficulties as Reported by Parent/Guardian (Open-label Phase Endpoint) Week 1	0.94 Units on a scale Standard Deviation 0.71	—
Severity of Feeding Difficulties as Reported by Parent/Guardian (Open-label Phase Endpoint) Week 2	0.83 Units on a scale Standard Deviation 0.76	—

Adverse Events

Open-label Phase

Serious events: 4 serious events

Other events: 26 other events

Deaths: 0 deaths

Double Blind Esomeprazole

Serious events: 3 serious events

Other events: 19 other events

Deaths: 0 deaths

Double Blind Placebo

Serious events: 0 serious events

Other events: 20 other events

Deaths: 0 deaths

Serious adverse events

Measure	Open-label Phase n=98 participants at risk Open-label daily esomeprazole (2.5mg, 5mg or 10mg daily during open-label phase of the study, according to baseline weight).	Double Blind Esomeprazole n=39 participants at risk Eligible participants from the Open Label phase were randomized to the the double blind withdrawal phase.	Double Blind Placebo n=41 participants at risk Eligible participants from the Open Label phase were randomized to the the double blind withdrawal phase.
Respiratory, thoracic and mediastinal disorders Apnoea	0.00% 0/98	2.6% 1/39 • Number of events 1	0.00% 0/41
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.00% 0/98	2.6% 1/39 • Number of events 1	0.00% 0/41
Infections and infestations Chlamydial Infection	1.0% 1/98 • Number of events 1	2.6% 1/39 • Number of events 1	0.00% 0/41
Metabolism and nutrition disorders Failure To Thrive	1.0% 1/98 • Number of events 1	0.00% 0/39	0.00% 0/41
Vascular disorders Poor Peripheral Circulation	0.00% 0/98	2.6% 1/39 • Number of events 1	0.00% 0/41
Infections and infestations Respiratory Syncytial Virus Bronchiolitis	0.00% 0/98	2.6% 1/39 • Number of events 1	0.00% 0/41
Infections and infestations Rotavirus Infection	1.0% 1/98 • Number of events 1	0.00% 0/39	0.00% 0/41
Infections and infestations Urinary Tract Infection	1.0% 1/98 • Number of events 1	0.00% 0/39	0.00% 0/41

Other adverse events

Measure	Open-label Phase n=98 participants at risk Open-label daily esomeprazole (2.5mg, 5mg or 10mg daily during open-label phase of the study, according to baseline weight).	Double Blind Esomeprazole n=39 participants at risk Eligible participants from the Open Label phase were randomized to the the double blind withdrawal phase.	Double Blind Placebo n=41 participants at risk Eligible participants from the Open Label phase were randomized to the the double blind withdrawal phase.
Infections and infestations Bronchitis	4.1% 4/98	7.7% 3/39	4.9% 2/41
Gastrointestinal disorders Constipation	1.0% 1/98	2.6% 1/39	9.8% 4/41
Respiratory, thoracic and mediastinal disorders Cough	3.1% 3/98	7.7% 3/39	9.8% 4/41
Gastrointestinal disorders Diarrhoea	3.1% 3/98	10.3% 4/39	4.9% 2/41
Gastrointestinal disorders Flatulence	1.0% 1/98	5.1% 2/39	2.4% 1/41
Infections and infestations Nasopharyngitis	2.0% 2/98	10.3% 4/39	7.3% 3/41
Infections and infestations Otitis Media	2.0% 2/98	5.1% 2/39	2.4% 1/41
General disorders Pyrexia	4.1% 4/98	12.8% 5/39	7.3% 3/41
Skin and subcutaneous tissue disorders Rash	1.0% 1/98	5.1% 2/39	2.4% 1/41
Infections and infestations Rhinitis	3.1% 3/98	10.3% 4/39	7.3% 3/41
Gastrointestinal disorders Teething	4.1% 4/98	7.7% 3/39	4.9% 2/41
Infections and infestations Upper Respiratory Tract Infection	5.1% 5/98	15.4% 6/39	9.8% 4/41
Gastrointestinal disorders Vomiting	2.0% 2/98	5.1% 2/39	4.9% 2/41
Infections and infestations Ear Infection	0.00% 0/98	5.1% 2/39	2.4% 1/41
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal Pain	0.00% 0/98	5.1% 2/39	0.00% 0/41

Additional Information

Gerard Lynch

AstraZeneca

Email: AZTrial_Results_Posting@astrazeneca.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: LTE60