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

Eosinophilic Esophagitis (EoE) Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00762073
• Other study ID #: MPI-101-01
• Status: Completed
• Phase: Phase 2
• Start date: January 8, 2009
• Est. completion date: April 2, 2010

Study information

• Verified date: June 2021
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 82
• Est. completion date: April 2, 2010
• Est. primary completion date: April 2, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Eosinophilic Esophagitis
• Eosinophilic Esophagitis (EoE)
• Esophagitis

Intervention

Drug:
• budesonide
oral suspension
• placebo
oral suspension matching budesonide

Locations

Country	Name	City	State
United States	Children's Center for Digestive Healthcare	Atlanta	Georgia
United States	Emory University-Emory Children's Center	Atlanta	Georgia
United States	The Children's Hospital	Aurora	Colorado
United States	Children's Hospital Boston	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Children's Memorial Hospital	Chicago	Illinois
United States	Children's Center for Digestive Health	Greenville	South Carolina
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	Pediatric Gastroenterology and Nutrition Associates	Las Vegas	Nevada
United States	South Jersey Pediatric Gastroenterology	Mays Landing	New Jersey
United States	Children's Hospital of the King's Daughters	Norfolk	Virginia
United States	The Center for Human Nutrition	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	Stanford University Medical Center	Palo Alto	California
United States	Center for Children's Digestive Health	Park Ridge	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Virginia Commonwealth University, Medical College of Virginia	Richmond	Virginia
United States	Carilion Pediatric Gastroenterology	Roanoke	Virginia
United States	Rady Children's Hospital	San Diego	California

Sponsors (1)

Lead Sponsor	Collaborator
Shire

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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