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

Study Overview
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Brief Summary
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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.

Official Title
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Oral Viscous Budesonide Suspension (MB-7) in Subjects With Eosinophilic Esophagitis: A Randomized, Placebo-Controlled, Dose-Ranging Study in Children and Adolescents

Conditions
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Eosinophilic Esophagitis (EoE)

Intervention / Treatment
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* Drug: budesonide
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 1<br> | Drug: placebo<br>* oral suspension matching budesonide<br>|
| Experimental: 2<br>Low Dose Group | Drug: budesonide<br>* oral suspension<br>|
| Experimental: 3<br>Medium Dose Group | Drug: budesonide<br>* oral suspension<br>|
| Experimental: 4<br>High Dose Group | Drug: budesonide<br>* oral suspension<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants Who Responded to Therapy | 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. | 12 weeks after the start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With Histologic Response | 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. | 12 weeks after the start of treatment | 
| Percent of Participants With Histologic Remission | 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. | 12 weeks after the start of treatment | 
| Percent Change From Baseline in Peak Eosinophil Count | 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. | Baseline, 12 weeks after the start of treatment | 
| Change From Baseline in Endoscopy Score | 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. | Baseline, 12 weeks after the start of treatment | 
| Percent of Participants With Clinical Response | 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. | 12 weeks after the start of treatment | 
| Percent of Participants With Clinical Remission | 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. | 12 weeks after the start of treatment | 
| Percent Change From Baseline in 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. A negative change from baseline indicates that symptoms decreased. | Baseline, 12 weeks after the start of treatment | 
| Change From Baseline in Physician's Global Assessment Score of Disease Severity | 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. | Baseline, 12 weeks after the start of treatment | 
| Maximum Plasma Concentration (Cmax) of Budesonide | 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. | Week 2, 4, or 8, or at the Final Treatment Evaluation | 
| Time to Maximum (Tmax) And Half Maximum (T1/2) Plasma Concentration of Budesonide | 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. | Week 2, 4, or 8, or at the Final Treatment Evaluation | 
| Area Under The Plasma Concentration-Time Curve (AUC) of Budesonide From Time Zero to Time of The Last Measurable Concentration (AUC0-last) | 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. | Week 2, 4, or 8, or at the Final Treatment Evaluation | 
| Percent of Participants With Potential Corticosteroid-Related Treatment-Emergent Adverse Events (TEAEs) | 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. | 15 weeks after the start of treatment | 
| Mean Change in Blood Pressure (BP) at End of Treatment | BP was assessed for each treatment group at baseline and at each post-baseline visit including the final treatment evaluation. | Baseline, 12 weeks after the start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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eosinophilic esophagitis