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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Shire
ClinicalTrials.gov Identifier:
NCT00762073
First received: September 29, 2008
Last updated: September 2, 2015
Last verified: March 2014
  Purpose
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 Intervention Phase
Eosinophilic Esophagitis (EoE)
Drug: budesonide
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by Shire:

Primary Outcome Measures:
  • Percent of Participants Who Responded to Therapy [ Time Frame: 12 weeks after the start of treatment ] [ Designated as safety issue: No ]

    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:
  • Percent of Participants With Histologic Response [ Time Frame: 12 weeks after the start of treatment ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Histologic Remission [ Time Frame: 12 weeks after the start of treatment ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Peak Eosinophil Count [ Time Frame: Baseline, 12 weeks after the start of treatment ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Endoscopy Score [ Time Frame: Baseline, 12 weeks after the start of treatment ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Clinical Response [ Time Frame: 12 weeks after the start of treatment ] [ Designated as safety issue: No ]

    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.


  • Percent of Participants With Clinical Remission [ Time Frame: 12 weeks after the start of treatment ] [ Designated as safety issue: No ]

    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.


  • Percent Change From Baseline in Eosinophilic Esophagitis (EoE) Clinical Symptom Score (CSS) [ Time Frame: Baseline, 12 weeks after the start of treatment ] [ Designated as safety issue: No ]

    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.


  • Change From Baseline in Physician's Global Assessment Score of Disease Severity [ Time Frame: Baseline, 12 weeks after the start of treatment ] [ Designated as safety issue: No ]
    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.

  • Maximum Plasma Concentration (Cmax) of Budesonide [ Time Frame: Week 2, 4, or 8, or at the Final Treatment Evaluation ] [ Designated as safety issue: No ]
    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 to Maximum (Tmax) And Half Maximum (T1/2) Plasma Concentration of Budesonide [ Time Frame: Week 2, 4, or 8, or at the Final Treatment Evaluation ] [ Designated as safety issue: No ]
    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.

  • Area Under The Plasma Concentration-Time Curve (AUC) of Budesonide From Time Zero to Time of The Last Measurable Concentration (AUC0-last) [ Time Frame: Week 2, 4, or 8, or at the Final Treatment Evaluation ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Potential Corticosteroid-Related Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: 15 weeks after the start of treatment ] [ Designated as safety issue: No ]
    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.

  • Mean Change in Blood Pressure (BP) at End of Treatment [ Time Frame: Baseline, 12 weeks after the start of treatment ] [ Designated as safety issue: No ]
    BP was assessed for each treatment group at baseline and at each post-baseline visit including the final treatment evaluation.


Enrollment: 82
Study Start Date: November 2008
Study Completion Date: April 2010
Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   2 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00762073

Locations
United States, Arizona
Phoenix Children's Hospital
Phoenix, Arizona, United States, 85006
United States, California
Children's Hospital of Orange County
Orange, California, United States, 92868
Stanford University Medical Center
Palo Alto, California, United States, 94305
Rady Children's Hospital
San Diego, California, United States, 92123
United States, Colorado
The Children's Hospital
Aurora, Colorado, United States, 80045
United States, Georgia
Children's Center for Digestive Healthcare
Atlanta, Georgia, United States, 30342
Emory University-Emory Children's Center
Atlanta, Georgia, United States, 30322
United States, Illinois
Children's Memorial Hospital
Chicago, Illinois, United States, 60614
Center for Children's Digestive Health
Park Ridge, Illinois, United States, 60068
United States, Indiana
Riley Hospital for Children
Indianapolis, Indiana, United States, 46202
United States, Massachusetts
Tufts Medical Center
Boston, Massachusetts, United States, 02111
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
United States, Nebraska
The Center for Human Nutrition
Omaha, Nebraska, United States, 68105
United States, Nevada
Pediatric Gastroenterology and Nutrition Associates
Las Vegas, Nevada, United States, 89109
United States, New Jersey
South Jersey Pediatric Gastroenterology
Mays Landing, New Jersey, United States, 08330
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, South Carolina
Children's Center for Digestive Health
Greenville, South Carolina, United States, 29615
United States, Virginia
Children's Hospital of the King's Daughters
Norfolk, Virginia, United States, 23507
Virginia Commonwealth University, Medical College of Virginia
Richmond, Virginia, United States, 23219
Carilion Pediatric Gastroenterology
Roanoke, Virginia, United States, 24013
Sponsors and Collaborators
Shire
  More Information

No publications provided by Shire

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT00762073     History of Changes
Other Study ID Numbers: MPI-101-01 
Study First Received: September 29, 2008
Results First Received: August 3, 2015
Last Updated: September 2, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Shire:
eosinophilic esophagitis

Additional relevant MeSH terms:
Eosinophilic Esophagitis
Esophagitis
Digestive System Diseases
Eosinophilia
Esophageal Diseases
Gastroenteritis
Gastrointestinal Diseases
Hematologic Diseases
Hypersensitivity
Hypersensitivity, Immediate
Immune System Diseases
Leukocyte Disorders
Budesonide
Anti-Asthmatic Agents
Anti-Inflammatory Agents
Autonomic Agents
Bronchodilator Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Respiratory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on February 04, 2016