Dose-Ranging Study of Oral Viscous Budesonide in Pediatrics With Eosinophilic Esophagitis

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00762073
• Collaborator: (none)
• Enrollment: 82
• Locations: 20
• Arms: 4
• Actual Duration (Months): 14.8
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is a randomized, placebo-controlled, parallel-arm, dose-ranging study in subjects with eosinophilic esophagitis, 2-18 years of age. Eligible subjects will be randomized into one of four treatment groups. The Treatment Period will be 12 weeks during which subjects will visit the clinic at study weeks 0 (Baseline Visit), 2, 4, 8 and 12 (Final Treatment Evaluation) for clinical symptom assessment and safety evaluation (including adverse events and vital signs). All study treatments (active drug and placebo) will be administered orally twice daily during the Treatment Period, once in the morning after breakfast and once in the evening at bedtime.

Condition or Disease	Intervention/Treatment	Phase
Eosinophilic Esophagitis (EoE)	Drug: budesonide; Drug: placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 82 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Oral Viscous Budesonide Suspension (MB-7) in Subjects With Eosinophilic Esophagitis: A Randomized, Placebo-Controlled, Dose-Ranging Study in Children and Adolescents
• Actual Study Start Date: Jan 8, 2009
• Actual Primary Completion Date: Apr 2, 2010
• Actual Study Completion Date: Apr 2, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 1	Drug: placebo; oral suspension matching budesonide
Experimental: 2 Low Dose Group	Drug: budesonide; oral suspension
Experimental: 3 Medium Dose Group	Drug: budesonide; oral suspension
Experimental: 4 High Dose Group	Drug: budesonide; oral suspension

Outcome Measures

Primary Outcome Measures

1. Percent of Participants Who Responded to Therapy [12 weeks after the start of treatment]

   Response was defined as a ≥50% reduction from baseline in the eosinophilic esophagitis (EoE) clinical symptom score (CSS) and a reduction in peak eosinophil count to ≤6/high power field (light microscopy) from esophageal biopsies collected at the final evaluation. The EoE CSS, scored from 0 to 18 by a doctor, assessed 6 categories: 1) heartburn, 2) abdominal pain, 3) nocturnal awakening with symptoms, 4) nausea, regurgitation, or vomiting, 5) anorexia or early satiety, and 6) dysphagia, odynophagia, or food impaction (a severe symptom). Each domain was scored as follows, based on symptoms in the 2 weeks prior to the assessment: 0 = No symptoms and no coping behaviors required; 1 = Mild: Symptoms limited to 1-3 days or no symptoms because coping behaviors were required to avoid symptoms; 2 = Moderate: Symptoms on >3 days, with or without minor coping behaviors; 3 = Severe: Symptoms interfered with activities of daily living or symptoms persisted and required major coping behaviors.

Secondary Outcome Measures

1. Percent of Participants With Histologic Response [12 weeks after the start of treatment]

   Histologic response was defined as a maximum peak eosinophil count at the final treatment evaluation of ≤6 eosinophils/high power field (light microscopy). The maximum peak was identified by examining the peak eosinophil counts obtained from the proximal, mid, and distal esophageal biopsies and selecting the maximum value.

2. Percent of Participants With Histologic Remission [12 weeks after the start of treatment]

   Histologic remission was defined as a maximum peak eosinophil count at the final treatment evaluation of ≤1 eosinophils/high power field (light microscopy). The maximum peak was identified by examining the peak eosinophil counts obtained from the proximal, mid, and distal esophageal biopsies and selecting the maximum value.

3. Percent Change From Baseline in Peak Eosinophil Count [Baseline, 12 weeks after the start of treatment]

   The maximum peak number of eosinophils at baseline and at the final treatment evaluation was identified by examining the peak eosinophil counts obtained from the proximal, mid, and distal esophageal biopsies and selecting the maximum value. A negative change from baseline indicates that eosinophil count has decreased.

4. Change From Baseline in Endoscopy Score [Baseline, 12 weeks after the start of treatment]

   Esophageal endoscopy was used to assess the level of inflammation and eosinophilia. Four categories of endoscopic findings were evaluated and scored for this study: (1) pallor and diminished vascular markings; (2) furrowing with thickened mucosa; (3) presence of white mucosal plaques; and (4) concentric rings or strictures. For each category, 0 points were allocated if no esophageal sites were involved, 1 point if 1 or 2 esophageal sites were involved, and 2 points for pan-esophageal involvement (see Aceves et al., 2007). The maximum possible endoscopy score was 8 points. A negative change from baseline indicates that esophageal inflammation decreased.

5. Percent of Participants With Clinical Response [12 weeks after the start of treatment]

   Response was defined as a ≥50% reduction from baseline in the eosinophilic esophagitis (EoE) clinical symptom score (CSS). The EoE CSS, scored from 0 to 18 by a doctor, assessed 6 categories: 1) heartburn, 2) abdominal pain, 3) nocturnal awakening with symptoms, 4) nausea, regurgitation, or vomiting, 5) anorexia or early satiety, and 6) dysphagia, odynophagia, or food impaction (a severe symptom). Each domain was scored as follows, based on symptoms in the 2 weeks prior to the assessment: 0 = No symptoms and no coping behaviors required; 1 = Mild: Symptoms limited to 1-3 days or no symptoms because coping behaviors were required to avoid symptoms; 2 = Moderate: Symptoms on >3 days, with or without minor coping behaviors; 3 = Severe: Symptoms interfered with activities of daily living or symptoms persisted and required major coping behaviors.

6. Percent of Participants With Clinical Remission [12 weeks after the start of treatment]

   Clinical remission was defined as an eosinophilic esophagitis (EoE) clinical symptom score (CSS) of zero. EoE CSS, scored from 0 to 18 by a doctor, assessed 6 categories: 1) heartburn, 2) abdominal pain, 3) nocturnal awakening with symptoms, 4) nausea, regurgitation, or vomiting, 5) anorexia or early satiety, and 6) dysphagia, odynophagia, or food impaction (a severe symptom). Each domain was scored as follows, based on symptoms in the 2 weeks prior to the assessment: 0 = No symptoms and no coping behaviors required; 1 = Mild: Symptoms limited to 1-3 days or no symptoms because coping behaviors were required to avoid symptoms; 2 = Moderate: Symptoms on >3 days, with or without minor coping behaviors; 3 = Severe: Symptoms interfered with activities of daily living or symptoms persisted and required major coping behaviors.

7. Percent Change From Baseline in Eosinophilic Esophagitis (EoE) Clinical Symptom Score (CSS) [Baseline, 12 weeks after the start of treatment]

   The EoE CSS, scored from 0 to 18 by a doctor, assessed 6 categories: 1) heartburn, 2) abdominal pain, 3) nocturnal awakening with symptoms, 4) nausea, regurgitation, or vomiting, 5) anorexia or early satiety, and 6) dysphagia, odynophagia, or food impaction (a severe symptom). Each domain was scored as follows, based on symptoms in the 2 weeks prior to the assessment: 0 = No symptoms and no coping behaviors required; 1= Mild: Symptoms limited to 1-3 days or no symptoms because coping behaviors were required to avoid symptoms; 2= Moderate: Symptoms on >3 days, with or without minor coping behaviors; 3= Severe: Symptoms interfered with activities of daily living or symptoms persisted and required major coping behaviors. A negative change from baseline indicates that symptoms decreased.

8. Change From Baseline in Physician's Global Assessment Score of Disease Severity [Baseline, 12 weeks after the start of treatment]

   Physician investigators were asked to complete a visual analog scale (VAS) to provide a global assessment of eosinophilic esophagitis (EoE) activity in each participant. The VAS was a 100-mm horizontal line on which the right extreme (100) was labeled "worst possible disease activity" and the left (0) was labeled "no disease activity." Investigators were instructed to consider the line for the VAS as a continuum with their own opinion of extremes on either end. Investigators drew a vertical line at a point that best approximated the participant's current level of EoE disease activity. The investigator was to take into consideration how esophageal disease was impacting the participant's daily activities. The following instruction was given to the investigators: "Using the visual analog scale below, please mark a vertical line on the scale to indicate your assessment of EoE activity in this participant at this time." A negative change from baseline indicates that symptoms decreased.

9. Maximum Plasma Concentration (Cmax) of Budesonide [Week 2, 4, or 8, or at the Final Treatment Evaluation]

   On the day that pharmacokinetic (PK) blood samples were obtained, each participant delayed the morning dose of study medication until instructed to dose in the clinic. The sampling timepoints included pre-dose (0), and 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose. The lower limit of quantitation (LLOQ) for the analytical method was approximately 20 pg/mL in plasma using 0.2 mL of the sample. Because the PK analyses for the medium and high dose oral budesonide suspension (OBS) groups were based on plasma samples collected following administration of identical single doses of OBS, the data for the medium-dose group (OBS once-daily) and high-dose group (OBS twice-daily) were summarized together.

10. Time to Maximum (Tmax) And Half Maximum (T1/2) Plasma Concentration of Budesonide [Week 2, 4, or 8, or at the Final Treatment Evaluation]

    On the day that pharmacokinetic (PK) blood samples were obtained, each participant delayed the morning dose of study medication until instructed to dose in the clinic. The sampling timepoints included pre-dose (0), and 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose. The lower limit of quantitation (LLOQ) for the analytical method was approximately 20 pg/mL in plasma using 0.2 mL of the sample. Because the PK analyses for the medium and high dose oral budesonide suspension (OBS) groups were based on plasma samples collected following administration of identical single doses of OBS, the data for the medium-dose group (OBS once-daily) and high-dose group (OBS twice-daily) were summarized together. T1/2 is the time to terminal elimination half-life.

11. Area Under The Plasma Concentration-Time Curve (AUC) of Budesonide From Time Zero to Time of The Last Measurable Concentration (AUC0-last) [Week 2, 4, or 8, or at the Final Treatment Evaluation]

    On the day that pharmacokinetic (PK) blood samples were obtained, each participant delayed the morning dose of study medication until instructed to dose in the clinic. The sampling timepoints included pre-dose (0), and 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose. The lower limit of quantitation (LLOQ) for the analytical method was approximately 20 pg/mL in plasma using 0.2 mL of the sample. Because the PK analyses for the medium and high dose oral budesonide suspension (OBS) groups were based on plasma samples collected following administration of identical single doses of OBS, the data for the medium-dose group (OBS once-daily) and high-dose group (OBS twice-daily) were summarized together.

12. Percent of Participants With Potential Corticosteroid-Related Treatment-Emergent Adverse Events (TEAEs) [15 weeks after the start of treatment]

    Corticosteroid-Related TEAEs included candidiasis, oesophageal candidiasis, crying, psychomotor hyperactivity, aggression, anger, anxiety, conduct disorder, emotional disorder, insomnia, or mood altered mood. Corticosteroid-Related TEAEs were assessed systematically during the treatment and taper periods.

13. Mean Change in Blood Pressure (BP) at End of Treatment [Baseline, 12 weeks after the start of treatment]

    BP was assessed for each treatment group at baseline and at each post-baseline visit including the final treatment evaluation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female subjects between the ages of 2-18 years, inclusive

• History of clinical symptoms of esophageal dysfunction intermittently or continuously

• Histologic evidence of EoE with a peak eosinophil count of greater than or equal to 20 eosinophils per HPF, from two or more levels of the esophagus, within six weeks prior to the Baseline Visit

• At the Baseline Visit, subjects must have symptoms with a total EoE Clinical Symptom Score of greater than or equal to 3

• Willingness and ability to continue the dietary therapy, environmental therapy, and/or medical regimens (including gastric acid suppression, if any) in effect at the Screening Visit

• Females of childbearing potential must have a negative serum pregnancy test (beta human chorionic gonadotropin) prior to randomization into the study and sexually active subjects must agree to continue acceptable birth control measures throughout the duration of the study

• Written informed consent (parent or legal guardian) and, as appropriate, subject assent

Exclusion Criteria:

• Current use of immunomodulatory therapy (or anticipated use within 12 weeks following the Baseline Visit)

• Diagnosis of inflammatory bowel disease

• Chronic viral infection or immunodeficiency condition (current)

• Use of swallowed topical corticosteroids for EoE in the 1 month prior to the biopsy required for entrance to this study or at any time between the biopsy and the Baseline Visit

• Use of systemic (oral or parenteral) corticosteroid within 1 month prior to the biopsy required for entrance to this study or at any time between the biopsy and the Baseline Visit

• Morning plasma cortisol level below the lower limit of normal (per Central Laboratory reference range) at the Screening Visit

• Upper gastrointestinal bleeding within 1 month prior to the Screening Visit or between the Screening Visit and Baseline Visit

• Current use of anticoagulants

• Current disease of the gastrointestinal tract aside from the current EoE diagnosis

• Evidence of concurrent eosinophilic gastritis, enteritis, colitis, or proctitis

• Evidence of active infection with Helicobacter pylori

• Evidence of unstable asthma or changes in asthma or allergic rhinitis therapy within 1 month prior to the biopsy required for entrance to this study

• Any female who is pregnant, who is planning to become pregnant, or who is breast-feeding

• Current evidence or history of hypersensitivity or idiosyncratic reaction to budesonide or any other ingredients of the study medication

• Current evidence of oropharyngeal or esophageal candidiasis

• Receipt of an investigational drug within 30 days prior to the biopsy required for entrance to this study

• Any condition or abnormality that, in the opinion of the Principal Investigator, would compromise the safety of the subject or successful conduct of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Children's Hospital	Phoenix	Arizona	United States	85006
2	Children's Hospital of Orange County	Orange	California	United States	92868
3	Stanford University Medical Center	Palo Alto	California	United States	94305
4	Rady Children's Hospital	San Diego	California	United States	92123
5	The Children's Hospital	Aurora	Colorado	United States	80045
6	Emory University-Emory Children's Center	Atlanta	Georgia	United States	30322
7	Children's Center for Digestive Healthcare	Atlanta	Georgia	United States	30342
8	Children's Memorial Hospital	Chicago	Illinois	United States	60614
9	Center for Children's Digestive Health	Park Ridge	Illinois	United States	60068
10	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
11	Tufts Medical Center	Boston	Massachusetts	United States	02111
12	Children's Hospital Boston	Boston	Massachusetts	United States	02115
13	The Center for Human Nutrition	Omaha	Nebraska	United States	68105
14	Pediatric Gastroenterology and Nutrition Associates	Las Vegas	Nevada	United States	89109
15	South Jersey Pediatric Gastroenterology	Mays Landing	New Jersey	United States	08330
16	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
17	Children's Center for Digestive Health	Greenville	South Carolina	United States	29615
18	Children's Hospital of the King's Daughters	Norfolk	Virginia	United States	23507
19	Virginia Commonwealth University, Medical College of Virginia	Richmond	Virginia	United States	23219
20	Carilion Pediatric Gastroenterology	Roanoke	Virginia	United States	24013

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT00762073
• Other Study ID Numbers: MPI-101-01
• First Posted: Sep 30, 2008
• Last Update Posted: Jun 11, 2021
• Last Verified: Jun 1, 2021

• Keywords provided by Shire: eosinophilic esophagitis
• Additional relevant MeSH terms: Esophagitis; Eosinophilic Esophagitis; Budesonide

Study Results

Participant Flow

Arm/Group Title	Placebo	Low Dose	Medium Dose	High Dose
Arm/Group Description	Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks with a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 0.35 mg (2 to 9 years) or 0.50 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 1.4 mg (2 to 9 years) or 2.0 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 2.8 mg (2 to 9 years) or 4.0 mg (10 to 18 years), followed by a 3 week taper period.
Period Title: Overall Study
STARTED	21	21	20	20
COMPLETED	17	17	18	17
NOT COMPLETED	4	4	2	3

Baseline Characteristics

Arm/Group Title	Placebo	Low Dose	Medium Dose	High Dose	Total
Arm/Group Description	Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks with a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 0.35 mg (2 to 9 years) or 0.50 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 1.4 mg (2 to 9 years) or 2.0 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 2.8 mg (2 to 9 years) or 4.0 mg (10 to 18 years), followed by a 3 week taper period.	Total of all reporting groups
Overall Participants	21	21	19	20	81
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.2 (4.36)	9.0 (5.88)	10.2 (4.89)	8.1 (4.58)	9.1 (4.93)
Age, Customized (Count of Participants)
2 to 9 years	12 57.1%	12 57.1%	10 52.6%	12 60%	46 56.8%
10 to 18 years	9 42.9%	9 42.9%	9 47.4%	8 40%	35 43.2%
Sex: Female, Male (Count of Participants)
Female	5 23.8%	4 19%	2 10.5%	4 20%	15 18.5%
Male	16 76.2%	17 81%	17 89.5%	16 80%	66 81.5%

Outcome Measures

1. Primary Outcome

Title	Percent of Participants Who Responded to Therapy
Description	Response was defined as a ≥50% reduction from baseline in the eosinophilic esophagitis (EoE) clinical symptom score (CSS) and a reduction in peak eosinophil count to ≤6/high power field (light microscopy) from esophageal biopsies collected at the final evaluation. The EoE CSS, scored from 0 to 18 by a doctor, assessed 6 categories: 1) heartburn, 2) abdominal pain, 3) nocturnal awakening with symptoms, 4) nausea, regurgitation, or vomiting, 5) anorexia or early satiety, and 6) dysphagia, odynophagia, or food impaction (a severe symptom). Each domain was scored as follows, based on symptoms in the 2 weeks prior to the assessment: 0 = No symptoms and no coping behaviors required; 1 = Mild: Symptoms limited to 1-3 days or no symptoms because coping behaviors were required to avoid symptoms; 2 = Moderate: Symptoms on >3 days, with or without minor coping behaviors; 3 = Severe: Symptoms interfered with activities of daily living or symptoms persisted and required major coping behaviors.
Time Frame	12 weeks after the start of treatment

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), defined as participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.

Arm/Group Title	Placebo	Low Dose	Medium Dose	High Dose
Arm/Group Description	Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 0.35 mg (2 to 9 years) or 0.50 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 1.4 mg (2 to 9 years) or 2.0 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 2.8 mg (2 to 9 years) or 4.0 mg (10 to 18 years), followed by a 3 week taper period.
Measure Participants	18	17	19	17
Number [percentage of participants]	5.6 26.7%	11.8 56.2%	52.6 276.8%	47.1 235.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.5282
	Comments	p-values comparing each active treatment group to placebo were determined by a logistic regression analysis with treatment (all four groups) and age as main effects.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.239
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Medium Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0092
	Comments	p-values comparing each active treatment group to placebo were determined by a logistic regression analysis with treatment (all four groups) and age as main effects.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	18.860
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, High Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0174
	Comments	p-values comparing each active treatment group to placebo were determined by a logistic regression analysis with treatment (all four groups) and age as main effects.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	15.009
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percent of Participants With Histologic Response
Description	Histologic response was defined as a maximum peak eosinophil count at the final treatment evaluation of ≤6 eosinophils/high power field (light microscopy). The maximum peak was identified by examining the peak eosinophil counts obtained from the proximal, mid, and distal esophageal biopsies and selecting the maximum value.
Time Frame	12 weeks after the start of treatment

Outcome Measure Data

Analysis Population Description

The FAS, defined as participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.

Arm/Group Title	Placebo	Low Dose	Medium Dose	High Dose
Arm/Group Description	Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 0.35 mg (2 to 9 years) or 0.50 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 1.4 mg (2 to 9 years) or 2.0 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 2.8 mg (2 to 9 years) or 4.0 mg (10 to 18 years), followed by a 3 week taper period.
Measure Participants	18	17	19	17
Number [percentage of participants]	5.6 26.7%	23.5 111.9%	52.6 276.8%	94.1 470.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1786
	Comments	p-values were determined by a logistic regression analysis with treatment (all four groups) and age group as main effects.
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Medium Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0090
	Comments	p-values were determined by a logistic regression analysis with treatment (all four groups) and age group as main effects.
	Method	Regression, Logistic
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, High Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	p-values were determined by a logistic regression analysis with treatment (all four groups) and age group as main effects.
	Method	Regression, Logistic
	Comments

3. Secondary Outcome

Title	Percent of Participants With Histologic Remission
Description	Histologic remission was defined as a maximum peak eosinophil count at the final treatment evaluation of ≤1 eosinophils/high power field (light microscopy). The maximum peak was identified by examining the peak eosinophil counts obtained from the proximal, mid, and distal esophageal biopsies and selecting the maximum value.
Time Frame	12 weeks after the start of treatment

Outcome Measure Data

Analysis Population Description

The FAS, defined as participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.

Arm/Group Title	Placebo	Low Dose	Medium Dose	High Dose
Arm/Group Description	Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 0.35 mg (2 to 9 years) or 0.50 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 1.4 mg (2 to 9 years) or 2.0 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 2.8 mg (2 to 9 years) or 4.0 mg (10 to 18 years), followed by a 3 week taper period.
Measure Participants	18	17	19	17
Number [percentage of participants]	0.0 0%	11.8 56.2%	42.1 221.6%	76.5 382.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.4959
	Comments	p-values were determined by a logistic regression analysis with treatment (all four groups) and age group as main effects.
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Medium Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0040
	Comments	p-values were determined by a logistic regression analysis with treatment (all four groups) and age group as main effects.
	Method	Regression, Logistic
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, High Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-values were determined by a logistic regression analysis with treatment (all four groups) and age group as main effects.
	Method	Regression, Logistic
	Comments

4. Secondary Outcome

Title	Percent Change From Baseline in Peak Eosinophil Count
Description	The maximum peak number of eosinophils at baseline and at the final treatment evaluation was identified by examining the peak eosinophil counts obtained from the proximal, mid, and distal esophageal biopsies and selecting the maximum value. A negative change from baseline indicates that eosinophil count has decreased.
Time Frame	Baseline, 12 weeks after the start of treatment

Outcome Measure Data

Analysis Population Description

The FAS, defined as all participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.

Arm/Group Title	Placebo	Low Dose	Medium Dose	High Dose
Arm/Group Description	Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 0.35 mg (2 to 9 years) or 0.50 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 1.4 mg (2 to 9 years) or 2.0 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 2.8 mg (2 to 9 years) or 4.0 mg (10 to 18 years), followed by a 3 week taper period.
Measure Participants	18	17	19	17
Mean (Standard Deviation) [percent change]	7.93 (84.162)	-52.62 (51.22)	-44.02 (89.106)	-94.75 (19.615)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0108
	Comments	p-values comparing percent change from baseline for each active treatment group to placebo were determined by an ANCOVA model with treatment and age strata as main effects and baseline as a covariate.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Medium Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0208
	Comments	p-values comparing percent change from baseline for each active treatment group to placebo were determined by an ANCOVA model with treatment and age strata as main effects and baseline as a covariate.
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, High Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-values comparing percent change from baseline for each active treatment group to placebo were determined by an ANCOVA model with treatment and age strata as main effects and baseline as a covariate.
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Change From Baseline in Endoscopy Score
Description	Esophageal endoscopy was used to assess the level of inflammation and eosinophilia. Four categories of endoscopic findings were evaluated and scored for this study: (1) pallor and diminished vascular markings; (2) furrowing with thickened mucosa; (3) presence of white mucosal plaques; and (4) concentric rings or strictures. For each category, 0 points were allocated if no esophageal sites were involved, 1 point if 1 or 2 esophageal sites were involved, and 2 points for pan-esophageal involvement (see Aceves et al., 2007). The maximum possible endoscopy score was 8 points. A negative change from baseline indicates that esophageal inflammation decreased.
Time Frame	Baseline, 12 weeks after the start of treatment

Outcome Measure Data

Analysis Population Description

The FAS, defined as all participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.

Arm/Group Title	Placebo	Low Dose	Medium Dose	High Dose
Arm/Group Description	Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 0.35 mg (2 to 9 years) or 0.50 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 1.4 mg (2 to 9 years) or 2.0 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 2.8 mg (2 to 9 years) or 4.0 mg (10 to 18 years), followed by a 3 week taper period.
Measure Participants	18	17	19	17
Mean (Standard Deviation) [scores on a scale]	-0.6 (2.28)	-0.9 (1.90)	-1.3 (2.23)	-2.2 (1.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1095
	Comments	p-values comparing each active treatment group to placebo were determined by an ANCOVA model with treatment and age strata as main effects and baseline as a covariate
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Medium Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0264
	Comments	p-values comparing each active treatment group to placebo were determined by an ANCOVA model with treatment and age strata as main effects and baseline as a covariate
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, High Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments	p-values comparing each active treatment group to placebo were determined by an ANCOVA model with treatment and age strata as main effects and baseline as a covariate
	Method	ANCOVA
	Comments

6. Secondary Outcome

Title	Percent of Participants With Clinical Response
Description	Response was defined as a ≥50% reduction from baseline in the eosinophilic esophagitis (EoE) clinical symptom score (CSS). The EoE CSS, scored from 0 to 18 by a doctor, assessed 6 categories: 1) heartburn, 2) abdominal pain, 3) nocturnal awakening with symptoms, 4) nausea, regurgitation, or vomiting, 5) anorexia or early satiety, and 6) dysphagia, odynophagia, or food impaction (a severe symptom). Each domain was scored as follows, based on symptoms in the 2 weeks prior to the assessment: 0 = No symptoms and no coping behaviors required; 1 = Mild: Symptoms limited to 1-3 days or no symptoms because coping behaviors were required to avoid symptoms; 2 = Moderate: Symptoms on >3 days, with or without minor coping behaviors; 3 = Severe: Symptoms interfered with activities of daily living or symptoms persisted and required major coping behaviors.
Time Frame	12 weeks after the start of treatment

Outcome Measure Data

Analysis Population Description

The FAS, defined as participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.

Arm/Group Title	Placebo	Low Dose	Medium Dose	High Dose
Arm/Group Description	Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 0.35 mg (2 to 9 years) or 0.50 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 1.4 mg (2 to 9 years) or 2.0 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 2.8 mg (2 to 9 years) or 4.0 mg (10 to 18 years), followed by a 3 week taper period.
Measure Participants	18	17	19	17
Number [percentage of participants]	77.8 370.5%	64.7 308.1%	78.9 415.3%	52.9 264.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3769
	Comments	p-values comparing each active treatment group to placebo were determined by a logistic regression analysis with treatment (all four groups) and age as main effects.
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Medium Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.9363
	Comments	p-values comparing each active treatment group to placebo were determined by a logistic regression analysis with treatment (all four groups) and age as main effects.
	Method	Regression, Logistic
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, High Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1235
	Comments	p-values comparing each active treatment group to placebo were determined by a logistic regression analysis with treatment (all four groups) and age as main effects.
	Method	Regression, Logistic
	Comments

7. Secondary Outcome

Title	Percent of Participants With Clinical Remission
Description	Clinical remission was defined as an eosinophilic esophagitis (EoE) clinical symptom score (CSS) of zero. EoE CSS, scored from 0 to 18 by a doctor, assessed 6 categories: 1) heartburn, 2) abdominal pain, 3) nocturnal awakening with symptoms, 4) nausea, regurgitation, or vomiting, 5) anorexia or early satiety, and 6) dysphagia, odynophagia, or food impaction (a severe symptom). Each domain was scored as follows, based on symptoms in the 2 weeks prior to the assessment: 0 = No symptoms and no coping behaviors required; 1 = Mild: Symptoms limited to 1-3 days or no symptoms because coping behaviors were required to avoid symptoms; 2 = Moderate: Symptoms on >3 days, with or without minor coping behaviors; 3 = Severe: Symptoms interfered with activities of daily living or symptoms persisted and required major coping behaviors.
Time Frame	12 weeks after the start of treatment

Outcome Measure Data

Analysis Population Description

The FAS, defined as all participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.

Arm/Group Title	Placebo	Low Dose	Medium Dose	High Dose
Arm/Group Description	Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 0.35 mg (2 to 9 years) or 0.50 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 1.4 mg (2 to 9 years) or 2.0 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 2.8 mg (2 to 9 years) or 4.0 mg (10 to 18 years), followed by a 3 week taper period.
Measure Participants	18	17	19	17
Number [percentage of participants]	33.3 158.6%	17.6 83.8%	31.6 166.3%	17.6 88%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3444
	Comments	p-values comparing each active treatment group to placebo were determined by a logistic regression analysis with treatment (all four groups) and age as main effects.
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Medium Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.9258
	Comments	p-values comparing each active treatment group to placebo were determined by a logistic regression analysis with treatment (all four groups) and age as main effects.
	Method	Regression, Logistic
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, High Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3215
	Comments	p-values comparing each active treatment group to placebo were determined by a logistic regression analysis with treatment (all four groups) and age as main effects.
	Method	Regression, Logistic
	Comments

8. Secondary Outcome

Title	Percent Change From Baseline in Eosinophilic Esophagitis (EoE) Clinical Symptom Score (CSS)
Description	The EoE CSS, scored from 0 to 18 by a doctor, assessed 6 categories: 1) heartburn, 2) abdominal pain, 3) nocturnal awakening with symptoms, 4) nausea, regurgitation, or vomiting, 5) anorexia or early satiety, and 6) dysphagia, odynophagia, or food impaction (a severe symptom). Each domain was scored as follows, based on symptoms in the 2 weeks prior to the assessment: 0 = No symptoms and no coping behaviors required; 1= Mild: Symptoms limited to 1-3 days or no symptoms because coping behaviors were required to avoid symptoms; 2= Moderate: Symptoms on >3 days, with or without minor coping behaviors; 3= Severe: Symptoms interfered with activities of daily living or symptoms persisted and required major coping behaviors. A negative change from baseline indicates that symptoms decreased.
Time Frame	Baseline, 12 weeks after the start of treatment

Outcome Measure Data

Analysis Population Description

The FAS, defined as all participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.

Arm/Group Title	Placebo	Low Dose	Medium Dose	High Dose
Arm/Group Description	Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 0.35 mg (2 to 9 years) or 0.50 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 1.4 mg (2 to 9 years) or 2.0 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 2.8 mg (2 to 9 years) or 4.0 mg (10 to 18 years), followed by a 3 week taper period.
Measure Participants	18	17	19	17
Mean (Standard Deviation) [percent change]	-64.46 (45.759)	-60.83 (30.347)	-65.89 (32.382)	-47.21 (40.790)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.6729
	Comments	p-values comparing percent change from Baseline for each active treatment group to placebo were determined by an ANCOVA model with treatment and age strata as main effects and baseline as a covariate.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Medium Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.8894
	Comments	p-values comparing percent change from Baseline for each active treatment group to placebo were determined by an ANCOVA model with treatment and age strata as main effects and baseline as a covariate.
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, High Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1532
	Comments	p-values comparing percent change from Baseline for each active treatment group to placebo were determined by an ANCOVA model with treatment and age strata as main effects and baseline as a covariate.
	Method	ANCOVA
	Comments

9. Secondary Outcome

Title	Change From Baseline in Physician's Global Assessment Score of Disease Severity
Description	Physician investigators were asked to complete a visual analog scale (VAS) to provide a global assessment of eosinophilic esophagitis (EoE) activity in each participant. The VAS was a 100-mm horizontal line on which the right extreme (100) was labeled "worst possible disease activity" and the left (0) was labeled "no disease activity." Investigators were instructed to consider the line for the VAS as a continuum with their own opinion of extremes on either end. Investigators drew a vertical line at a point that best approximated the participant's current level of EoE disease activity. The investigator was to take into consideration how esophageal disease was impacting the participant's daily activities. The following instruction was given to the investigators: "Using the visual analog scale below, please mark a vertical line on the scale to indicate your assessment of EoE activity in this participant at this time." A negative change from baseline indicates that symptoms decreased.
Time Frame	Baseline, 12 weeks after the start of treatment

Outcome Measure Data

Analysis Population Description

The FAS, defined as all participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.

Arm/Group Title	Placebo	Low Dose	Medium Dose	High Dose
Arm/Group Description	Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 0.35 mg (2 to 9 years) or 0.50 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 1.4 mg (2 to 9 years) or 2.0 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 2.8 mg (2 to 9 years) or 4.0 mg (10 to 18 years), followed by a 3 week taper period.
Measure Participants	18	17	19	16
Mean (Standard Deviation) [scores on a scale]	-38.9 (28.02)	-30.2 (27.11)	-39.3 (22.89)	-35.7 (28.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.4197
	Comments	p-values comparing each active treatment group to placebo were determined by an ANCOVA model with treatment and age strata as main effects and baseline as a covariate.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Medium Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.9787
	Comments	p-values comparing each active treatment group to placebo were determined by an ANCOVA model with treatment and age strata as main effects and baseline as a covariate.
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, High Dose
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.8987
	Comments	p-values comparing each active treatment group to placebo were determined by an ANCOVA model with treatment and age strata as main effects and baseline as a covariate.
	Method	ANCOVA
	Comments

10. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Budesonide
Description	On the day that pharmacokinetic (PK) blood samples were obtained, each participant delayed the morning dose of study medication until instructed to dose in the clinic. The sampling timepoints included pre-dose (0), and 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose. The lower limit of quantitation (LLOQ) for the analytical method was approximately 20 pg/mL in plasma using 0.2 mL of the sample. Because the PK analyses for the medium and high dose oral budesonide suspension (OBS) groups were based on plasma samples collected following administration of identical single doses of OBS, the data for the medium-dose group (OBS once-daily) and high-dose group (OBS twice-daily) were summarized together.
Time Frame	Week 2, 4, or 8, or at the Final Treatment Evaluation

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) Set, defined as all participants in the safety analysis set who received oral budesonide suspension (OBS) and had sufficient PK samples to calculate PK parameters.

Arm/Group Title	0.35 mg Dose	0.50 mg Dose	1.4 mg Dose	2.0 mg Dose
Arm/Group Description	Participants 2 to 9 years old received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc), with a total daily dose of 0.35 mg.	Participants 10 to 18 years old received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc), with a total daily dose of 0.50 mg.	Participants 2 to 9 years old received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and either placebo or OBS 0.2 mg/ml after breakfast (qAM, pc), with a total daily dose of 1.4 mg (medium dose group) or 2.8 mg (high dose group).	Participants 10 to 18 years old received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and either placebo or OBS 0.2 mg/ml after breakfast (qAM, pc), with a total daily dose of 2.0 mg (medium dose group) or 4.0 mg (high dose group).
Measure Participants	4	5	15	13
Mean (Standard Deviation) [pg/mL]	492.0 (417.81)	195.0 (64.37)	1019.5 (670.18)	958.4 (527.64)

11. Secondary Outcome

Title	Time to Maximum (Tmax) And Half Maximum (T1/2) Plasma Concentration of Budesonide
Description	On the day that pharmacokinetic (PK) blood samples were obtained, each participant delayed the morning dose of study medication until instructed to dose in the clinic. The sampling timepoints included pre-dose (0), and 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose. The lower limit of quantitation (LLOQ) for the analytical method was approximately 20 pg/mL in plasma using 0.2 mL of the sample. Because the PK analyses for the medium and high dose oral budesonide suspension (OBS) groups were based on plasma samples collected following administration of identical single doses of OBS, the data for the medium-dose group (OBS once-daily) and high-dose group (OBS twice-daily) were summarized together. T1/2 is the time to terminal elimination half-life.
Time Frame	Week 2, 4, or 8, or at the Final Treatment Evaluation

Outcome Measure Data

Analysis Population Description

The PK Set, defined as all participants in the safety analysis set who received oral budesonide suspension (OBS) and had sufficient PK samples to calculate PK parameters.

Arm/Group Title	0.35 mg Dose	0.50 mg Dose	1.4 mg Dose	2.0 mg Dose
Arm/Group Description	Participants 2 to 9 years old received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc), with a total daily dose of 0.35 mg.	Participants 10 to 18 years old received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc), with a total daily dose of 0.50 mg.	Participants 2 to 9 years old received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and either placebo or OBS 0.2 mg/ml after breakfast (qAM, pc), with a total daily dose of 1.4 mg (medium dose group) or 2.8 mg (high dose group).	Participants 10 to 18 years old received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and either placebo or OBS 0.2 mg/ml after breakfast (qAM, pc), with a total daily dose of 2.0 mg (medium dose group) or 4.0 mg (high dose group).
Measure Participants	4	5	15	13
T1/2	3.288 (0.8265)	3.398 (0.7841)	3.472 (2.6753)	3.528 (1.0223)
Tmax	0.68 (0.360)	1.20 (0.447)	0.93 (0.372)	1.12 (0.546)

12. Secondary Outcome

Title	Area Under The Plasma Concentration-Time Curve (AUC) of Budesonide From Time Zero to Time of The Last Measurable Concentration (AUC0-last)
Description	On the day that pharmacokinetic (PK) blood samples were obtained, each participant delayed the morning dose of study medication until instructed to dose in the clinic. The sampling timepoints included pre-dose (0), and 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose. The lower limit of quantitation (LLOQ) for the analytical method was approximately 20 pg/mL in plasma using 0.2 mL of the sample. Because the PK analyses for the medium and high dose oral budesonide suspension (OBS) groups were based on plasma samples collected following administration of identical single doses of OBS, the data for the medium-dose group (OBS once-daily) and high-dose group (OBS twice-daily) were summarized together.
Time Frame	Week 2, 4, or 8, or at the Final Treatment Evaluation

Outcome Measure Data

Analysis Population Description

The PK Set, defined as all participants in the safety analysis set who received oral budesonide suspension (OBS) and had sufficient PK samples to calculate PK parameters.

Arm/Group Title	0.35 mg Dose	0.50 mg Dose	1.4 mg Dose	2.0 mg Dose
Arm/Group Description	Participants 2 to 9 years received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc), with a total daily dose of 0.35 mg.	Participants 10 to 18 years received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc), with a total daily dose of 0.50 mg.	Participants 2 to 9 years old received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and either placebo or OBS 0.2 mg/ml after breakfast (qAM, pc), with a total daily dose of 1.4 mg (medium dose group) or 2.8 mg (high dose group).	Participants 10 to 18 years received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and either placebo or OBS 0.2 mg/ml after breakfast (qAM, pc), with a total daily dose of 2.0 mg (medium dose group) or 4.0 mg (high dose group).
Measure Participants	4	5	15	13
Mean (Standard Deviation) [hr*pg/mL]	1139.5 (800.84)	743.8 (425.26)	3259.3 (2109.37)	3636.9 (1769.88)

13. Secondary Outcome

Title	Percent of Participants With Potential Corticosteroid-Related Treatment-Emergent Adverse Events (TEAEs)
Description	Corticosteroid-Related TEAEs included candidiasis, oesophageal candidiasis, crying, psychomotor hyperactivity, aggression, anger, anxiety, conduct disorder, emotional disorder, insomnia, or mood altered mood. Corticosteroid-Related TEAEs were assessed systematically during the treatment and taper periods.
Time Frame	15 weeks after the start of treatment

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set, defined as all randomized participants who received at least one dose of double-blind study drug.

Arm/Group Title	Placebo	Low Dose	Medium Dose	High Dose
Arm/Group Description	Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 0.35 mg (2 to 9 years) or 0.50 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 1.4 mg (2 to 9 years) or 2.0 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 2.8 mg (2 to 9 years) or 4.0 mg (10 to 18 years), followed by a 3 week taper period.
Measure Participants	21	21	19	20
Number [percentage of participants]	9.5 45.2%	9.5 45.2%	21.0 110.5%	15.0 75%

14. Secondary Outcome

Title	Mean Change in Blood Pressure (BP) at End of Treatment
Description	BP was assessed for each treatment group at baseline and at each post-baseline visit including the final treatment evaluation.
Time Frame	Baseline, 12 weeks after the start of treatment

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set, defined as all randomized participants who received at least one dose of double-blind study drug.

Arm/Group Title	Placebo	Low Dose	Medium Dose	High Dose
Arm/Group Description	Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 0.35 mg (2 to 9 years) or 0.50 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 1.4 mg (2 to 9 years) or 2.0 mg (10 to 18 years), followed by a 3 week taper period.	Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 2.8 mg (2 to 9 years) or 4.0 mg (10 to 18 years), followed by a 3 week taper period.
Measure Participants	21	21	19	20
Systolic BP	-1.5 (14.74)	1.8 (11.13)	3.5 (8.20)	8.0 (13.58)
Diastolic BP	-3.1 (10.31)	0.5 (8.89)	3.1 (9.18)	5.1 (8.83)

Adverse Events

Adverse Event Reporting Description	Adverse events are presented for the Safety Analysis Set, defined as all randomized participants who received at least one dose of double-blind study drug. Treatment group assignment was the treatment actually received. One participant in the medium dose group was enrolled and randomized then withdrew consent and did not receive study drug.
Arm/Group Title	Placebo		Low Dose		Medium Dose		High Dose
Arm/Group Description	Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks with a 3 week taper period.		Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks with a 3 week taper period.		Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks with a 3 week taper period.		Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks with a 3 week taper period.
All Cause Mortality
	Placebo		Low Dose		Medium Dose		High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Low Dose		Medium Dose		High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/21 (0%)		0/19 (0%)		1/20 (5%)
Metabolism and nutrition disorders
Diet refusal	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Low Dose		Medium Dose		High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/21 (47.6%)		13/21 (61.9%)		16/19 (84.2%)		17/20 (85%)
Eye disorders
Conjunctivitis	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Gastrointestinal disorders
Diarrhoea	0/21 (0%)	0	3/21 (14.3%)	5	1/19 (5.3%)	1	3/20 (15%)	4
Constipation	0/21 (0%)	0	1/21 (4.8%)	1	0/19 (0%)	0	3/20 (15%)	3
Vomiting	2/21 (9.5%)	2	0/21 (0%)	0	2/19 (10.5%)	2	2/20 (10%)	2
Abdominal pain	1/21 (4.8%)	1	1/21 (4.8%)	1	1/19 (5.3%)	1	1/20 (5%)	1
Nausea	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	1/20 (5%)	2
Abdominal pain upper	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	2/20 (10%)	3
Aphthous stomatitis	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Flatulence	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Oral pain	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Teething	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
General disorders
Pyrexia	3/21 (14.3%)	3	3/21 (14.3%)	3	2/19 (10.5%)	2	4/20 (20%)	5
Early Satiety	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Feeling jittery	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Pain	0/21 (0%)	0	1/21 (4.8%)	1	1/19 (5.3%)	1	0/20 (0%)	0
Thirst	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Immune system disorders
Milk allergy	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Infections and infestations
Sinusitis	1/21 (4.8%)	1	2/21 (9.5%)	3	2/19 (10.5%)	2	3/20 (15%)	4
Nasopharyngitis	1/21 (4.8%)	1	2/21 (9.5%)	2	3/19 (15.8%)	5	1/20 (5%)	1
Influenza	0/21 (0%)	0	1/21 (4.8%)	1	2/19 (10.5%)	3	1/20 (5%)	1
Ear infection	0/21 (0%)	0	1/21 (4.8%)	1	1/19 (5.3%)	1	0/20 (0%)	0
Upper respiratory tract infection	0/21 (0%)	0	1/21 (4.8%)	1	0/19 (0%)	0	2/20 (10%)	2
Candidiasis	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Oesophageal candidiasis	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Pharyngitis	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Respiratory tract infection viral	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Viral infection	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Bronchitis	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Injury, poisoning and procedural complications
Animal bite	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Arthropod sting	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Meniscus lesion	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Upper limb fracture	1/21 (4.8%)	1	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Investigations
Blood alkaline phosphatase increased	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Blood pressure increased	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Weight decreased	0/21 (0%)	0	1/21 (4.8%)	1	0/19 (0%)	0	1/20 (5%)	1
Metabolism and nutrition disorders
Dehydration	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Failure to thrive	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Musculoskeletal and connective tissue disorders
Limb discomfort	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Musculoskeletal stiffness	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Muscle spasms	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Nervous system disorders
Headache	1/21 (4.8%)	2	1/21 (4.8%)	1	3/19 (15.8%)	4	2/20 (10%)	2
Dizziness	1/21 (4.8%)	1	0/21 (0%)	0	2/19 (10.5%)	2	0/20 (0%)	0
Crying	0/21 (0%)	0	1/21 (4.8%)	1	0/19 (0%)	0	1/20 (5%)	1
Psychomotor hyperactivity	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	1/20 (5%)	1
Psychiatric disorders
Insomnia	1/21 (4.8%)	1	1/21 (4.8%)	1	1/19 (5.3%)	1	0/20 (0%)	0
Anxiety	0/21 (0%)	0	2/21 (9.5%)	2	0/19 (0%)	0	0/20 (0%)	0
Emotional Disorder	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Renal and urinary disorders
Pollakiuria	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/21 (4.8%)	1	4/21 (19%)	5	4/19 (21.1%)	4	0/20 (0%)	0
Oropharyngeal pain	1/21 (4.8%)	1	3/21 (14.3%)	3	2/19 (10.5%)	2	2/20 (10%)	3
Nasal congestion	1/21 (4.8%)	1	1/21 (4.8%)	1	0/19 (0%)	0	3/20 (15%)	3
Asthma	1/21 (4.8%)	2	0/21 (0%)	0	1/19 (5.3%)	3	0/20 (0%)	0
Bronchial hyperreactivity	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Epistaxis	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Rhinorrhoea	1/21 (4.8%)	1	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Skin and subcutaneous tissue disorders
Rash	0/21 (0%)	0	3/21 (14.3%)	5	3/19 (15.8%)	4	1/20 (5%)	1
Cellulitis	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Eczema	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0
Ingrowing nail	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Pruritus	0/21 (0%)	0	0/21 (0%)	0	0/19 (0%)	0	1/20 (5%)	1
Vascular disorders
Hot flush	0/21 (0%)	0	0/21 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.