OBS in Adolescent and Adults With EOE: A Phase II, Randomized, Double-Blind, Placebo Controlled, Study With an Open Label Extension

Oral Budesonide Suspension (OBS) in Adolescent and Adult Subjects (11-40 Years of Age)With Eosinophilic Esophagitis: A Phase II, Randomized, Double-Blind, Placebo-Controlled Study With an Open Label Extension

This is a clinical trial to test an experimental drug for the treatment of Eosinophilic Esophagitis (EoE)

Study Overview

• Status: Completed
• Conditions: Eosinophilic Esophagitis (EoE)
• Intervention / Treatment: Drug: Placebo; Drug: Oral Budesonide Suspension (MB-9)

Detailed Description

Eosinophilic Esophagitis (EoE) is an inflammatory disorder of the esophagus and is a recognized clinical entity. Symptoms include feeding problems, heartburn, regurgitation, vomiting, abdominal pain and food impaction. The symptoms of EoE may be similar to gastroesophageal reflux disease (GERD) but do not resolve with gastric acid suppression. EoE is defined histologically as the presence of > 15 intraepithelial eosinophils per high power fields on one or more esophageal biopsy specimens.

This Phase II study is comparing oral budesonide (OBS) to placebo to demonstrate that OBS induces a histologic response and a symptom response using a Dysphagia Symptom Questionnaire over a 16 week course of therapy.

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Diego, California, United States, 92123
      • UCSD Rady Children's Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Children's Center for Digestive Healthcare
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital
    • Chicago, Illinois, United States, 60611
      • Northwestern Scool of Medicine
    • Park Ridge, Illinois, United States, 60068
      • Center for Children's Digestive Health
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health University Hospital
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • The Mayo Clinic
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina At Chapel Hill
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • The Cincinnati Center for Eosinophilic Disorders
    • Mentor, Ohio, United States, 44060
      • Great Lakes Gastroenterology
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Greenville, South Carolina, United States, 29615
      • Children's Center For Digestive Health
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Healthcare
  • Virginia
    • Roanoke, Virginia, United States, 24013
      • Carilion Pediatric Gastroenterology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 11 years to 40 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males and Females, age 11-40
• Histologic evidence of EoE
• History of clinical symptoms of EoE including dysphagia
• Willing to continue with dietary, environmental or medical therapy
• Ability to read and understand english
• Written Consent

Exclusion Criteria:

• Any Medical condition that may compromise the safety of the subjects or interfere with the signs and symptoms of EoE
• Use of immunomodulatory therapy
• Current use of swallowed corticosteroids
• Esophageal strictures,varices or upper GI bleed
• Other current diseases of the GI tract
• Current viral infection or immunodeficiency condition
• Pregnancy
• Hypersensitivity to budesonide
• History of non compliance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Oral Budesonide Suspension; Taken once or twice daily for up to 40 weeks	Drug: Oral Budesonide Suspension (MB-9); OBS suspension to be taken bid over a 16 week course of double blind therapy and OBS suspension to be taken qd to bid during a 24 week optional open label extension period
PLACEBO_COMPARATOR: Matching Placebo; Taken once or twice daily for 20 weeks	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of Participants Who Were Histologic Responders	Histologic response was defined as a peak eosinophil count </= 6/high power field (light microscopy) (HPF) across all esophageal levels at the final treatment evaluation (Week 16). An independent, central pathologist determined the peak eosinophil count from the proximal, mid-, and distal levels and selected the maximum peak value. Histopathology data were collected in a blinded fashion.	Week 16
Change From Baseline in The Dysphagia Symptom Questionnaire (DSQ) Score at The Final Treatment Period Evaluation	Participants' dysphagia symptoms were evaluated using the 4-item DSQ. The questionnaire was developed by the Sponsor, as an ePRO measure, according to the principles of the Final Guidance for Industry for Patient Reported Outcome Measures (PRO Guidance December 2009). All participants used a diary, and responded to Questions 1 (did you eat solid food) and 2 (did food pass slowly or get stuck). If the participant's answer to Question 2 was 'No', the diary ended for that day. If a participant answered 'Yes', he/she advanced to Questions 3 (did you have to do anything to make the food go down or get relief) and 4 (extent to which the participant experienced pain while swallowing).The DSQ score was calculated based on responses to Questions 2 and 3 [14 x (sum of points from Questions 2 and 3 in the daily DSQ)/number of diaries with non-missing data]. Baseline was the DSQ score of the 14-day period before randomization. A negative change from baseline indicates that symptoms decreased.	Baseline, Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in The DSQ Score Over Time	Participants' dysphagia symptoms were evaluated using the 4-item DSQ. The questionnaire was developed by the Sponsor, as an ePRO measure, according to the principles of the Final Guidance for Industry for Patient Reported Outcome Measures (PRO Guidance December 2009). All participants used a diary, and responded to Questions 1 (did you eat solid food) and 2 (did food pass slowly or get stuck). If the participant's answer to Question 2 was 'No', the diary ended for that day. If a participant answered 'Yes', he/she advanced to Questions 3 (did you have to do anything to make the food go down or get relief) and 4 (extent to which the participant experienced pain while swallowing).The DSQ score was calculated based on responses to Questions 2 and 3 [14 x (sum of points from Questions 2 and 3 in the daily DSQ)/number of diaries with non-missing data]. Baseline was the DSQ score of the 14-day period before randomization. A negative change from baseline indicates that symptoms decreased.	Baseline, Weeks 8 and 12
Change From Baseline in The DSQ Score For The 50th Percentile of Participants at The Final Treatment Period Evaluation	A cumulative distribution function curve was constructed to illustrate the cumulative proportion of participants (x-axis) vs. the change in the DSQ score from baseline to the final treatment evaluation (y-axis). The 50th percentile is participants with a DSQ score that is in the middle of the distribution of all scores. A negative change from baseline indicates that symptoms decreased.	Baseline, Week 16
Percent of Participants With a Peak Eosinophil Count </= 15/High Power Field (Light Microscopy) (HPF) And </= 1/HPF at The Final Treatment Period Evaluation	An independent, central pathologist determined the peak eosinophil count from the proximal, mid-, and distal levels and selected the maximum peak value across all available esophagus levels. Histopathology data were collected in a blinded fashion. The values reported are for participants with histologic response.	Week 16
Percent of Participants With a >/= 30% And >/= 50% Reduction In The DSQ Score From Baseline to The Final Treatment Period Evaluation	Participants' dysphagia symptoms were evaluated using the 4-item DSQ. The questionnaire was developed by the Sponsor, as an ePRO measure, according to the principles of the Final Guidance for Industry for Patient Reported Outcome Measures (PRO Guidance December 2009). All participants used a diary, and responded to Questions 1 (did you eat solid food) and 2 (did food pass slowly or get stuck). If the participant's answer to Question 2 was 'No', the diary ended for that day. If a participant answered 'Yes', he/she advanced to Questions 3 (did you have to do anything to make the food go down or get relief) and 4 (extent to which the participant experienced pain while swallowing).The DSQ score was calculated based on responses to Questions 2 and 3 [14 x (sum of points from Questions 2 and 3 in the daily DSQ)/number of diaries with non-missing data]. Baseline was the DSQ score of the 14-day period before randomization.	Baseline, Week 16
Percent of Participants Who Were Overall Responders at The Final Treatment Period Evaluation	Overall response was defined as a reduction in the 2-week DSQ score of >/= 30% and >/= 50% from baseline to the final treatment period evaluation and a peak eosinophil count of </= 6/high power field (light microscopy) (HPF) across all available esophageal levels at the final treatment period evaluation. An independent, central pathologist determined the peak eosinophil count from the proximal, mid-, and distal levels and selected the maximum peak value. Histopathology data were collected in a blinded fashion.	Week 16
Change From Baseline in The Histopathologic Epithelial Features Combined Total Score at The Final Treatment Period Evaluation	Each esophageal biopsy specimen was evaluated microscopically by an independent, central pathologist for signs of epithelial inflammation and lamina propria fibrosis. Histopathologic epithelial features of each available esophageal level biopsy consisting of basal layer hyperplasia, eosinophil peak, dilated intercellular spaces, eosinophil microabcesses, surface layering, surface alteration, and apoptotic epithelial cells were scored and summed. Histopathology data were collected in a blinded fashion. Histopathology epithelial features were scored for both grade and stage. Each feature had a possible score of 0-3 for grade as well as stage. Thus each of the 3 levels had a possible score of 21, and a possible total grade or stage score of 63 for a maximum combined score of 126. The grade and stage score of the lamina propria was not included because the biopsy material was not available. A negative change from baseline indicates that epithelial inflammation decreased.	Baseline, Week 16
Change From Baseline in The Total Endoscopy Score at The Final Treatment Period Evaluation	The gross endoscopic appearance of the esophageal surface was evaluated by a blinded study center physician. Endoscopic findings with separate evaluations of the proximal and distal esophagus were recorded with respect to 5 major categories, including exudates or plaques, fixed esophageal rings, edema, furrows, and strictures. The endoscopy score was the sum of the scores for the 5 major categories - grade 0-1 for strictures; grade 0-2 for exudates or plaques, edema, and furrows; and grade 0-3 for fixed esophageal rings for the proximal and distal locations. The maximum endoscopy score was 10 points for each location (proximal and distal), and the total endoscopy score was the sum of the scores for the proximal and distal locations (maximum total score of 20 points). Baseline was defined as the endoscopy score at screening. A negative change from baseline indicates that appearance improved.	Baseline, Week 16
Change From Baseline in The Peak Eosinophil Count at Each Available Esophageal Level at The Final Treatment Period Evaluation	An independent, central pathologist determined the peak eosinophil count from the proximal, mid-, and distal levels and selected the maximum peak value across all available esophagus levels. Histopathology data were collected in a blinded fashion. Baseline was defined as the score at screening. A negative change from baseline indicates that eosinophil count decreased.	Baseline, Week 16
Change From Baseline in The Physician's Global Assessment (PGA) of Disease Activity at The Final Treatment Period Evaluation	The physician Investigator (or qualified physician's assistant or nurse practitioner) completed the PGA to provide the global assessment of eosinophilic esophagitis (EoE) disease activity using a 0 to 100 mm visual analog scale (VAS) scale. The VAS is a 100 mm horizontal line on which the right extreme (100) is labeled "worst possible disease activity" and the left extreme (0) is labeled "no disease activity". The PGA raters were instructed to consider the line for the VAS a continuum with their own medical opinion or judgment of extremes on either end and to draw a vertical line at a point that best approximates the participant's current level of EoE disease activity. A negative change from baseline indicates that disease activity decreased.	Baseline, Week 16
Distribution of Responses For The Patient Global Impression of Change (PGIC) Survey at The Final Treatment Evaluation	Participants evaluated the change in their dysphasia (food passing slowly/difficulty swallowing) since the start of the study (screening) by choosing 1 of 7 responses on the PGIC survey: much worse (-3), worse (-2), a little worse (-1), no change (0), a little better (1), better (2), or much better (3). The values reported are the percent of participants who chose that response.	Week 16
Percent of Participants With Improved Symptoms on The Eosinophilic Esophagitis (EoE) Symptom Survey at The Final Treatment Period Evaluation	The EoE survey assessed the following symptoms: heartburn, chest pain, regurgitation, abdominal pain, nausea, and vomiting. Participants indicated, by checking a box, if they had a change in symptoms (excluding dysphasia or food impaction) within the past 2 weeks. Baseline was defined as the assessment before randomization. Responses were as follows regarding symptoms at the final treatment evaluation: Improved - participant reported a specific symptom at baseline, but changed to no specific symptom ('Yes' to 'No'); No change - participant reported or did not report a specific symptom at both baseline and the final treatment evaluation; Worsened -participant did not report a specific symptom at baseline, but changed to report that specific symptom ('No' to 'Yes').	Week 16
Percent of Participants With No Change in Symptoms on The EoE Symptom Survey at The Final Treatment Period Evaluation	The EoE survey assessed the following symptoms: heartburn, chest pain, regurgitation, abdominal pain, nausea, and vomiting. Participants indicated, by checking a box, if they had a change in symptoms (excluding dysphasia or food impaction) within the past 2 weeks. Baseline was defined as the assessment before randomization. Responses were as follows regarding symptoms at the final treatment evaluation: Improved - participant reported a specific symptom at baseline, but changed to no specific symptom ('Yes' to 'No'); No change - participant reported or did not report a specific symptom at both baseline and the final treatment evaluation; Worsened -participant did not report a specific symptom at baseline, but changed to report that specific symptom ('No' to 'Yes').	Week 16
Percent of Participants With Worsened Symptoms on The EoE Symptom Survey at The Final Treatment Period Evaluation	The EoE survey assessed the following symptoms: heartburn, chest pain, regurgitation, abdominal pain, nausea, and vomiting. Participants indicated, by checking a box, if they had a change in symptoms (excluding dysphasia or food impaction) within the past 2 weeks. Baseline was defined as the assessment before randomization. Responses were as follows regarding symptoms at the final treatment evaluation: Improved - participant reported a specific symptom at baseline, but changed to no specific symptom ('Yes' to 'No'); No change - participant reported or did not report a specific symptom at both baseline and the final treatment evaluation; Worsened -participant did not report a specific symptom at baseline, but changed to report that specific symptom ('No' to 'Yes').	Week 16
Percent of Participants Without Symptoms on The EoE Symptom Survey at The Final Treatment Period Evaluation	This outcome assessed the symptoms of participants who were symptom-free at baseline. The EoE survey assessed the following symptoms: heartburn, chest pain, regurgitation, abdominal pain, nausea, and vomiting. Participants indicated, by checking a box, if they had a change in symptoms (excluding dysphasia or food impaction) within the past 2 weeks. Baseline was defined as the assessment before randomization. Responses were as follows regarding symptoms at the final treatment evaluation: No change - participant did not report a specific symptom at both baseline and the final treatment evaluation; Worsened -participant did not report any symptom at baseline, but changed to report at least 1 symptom at the final treatment evaluation.	Week 16
Percent of Participants With New Symptoms on The EoE Symptom Survey at The Final Treatment Period Evaluation	This outcome assessed the symptoms of participants who were symptom-free at baseline. The EoE survey assessed the following symptoms: heartburn, chest pain, regurgitation, abdominal pain, nausea, and vomiting. Participants indicated, by checking a box, if they had a change in symptoms (excluding dysphasia or food impaction) within the past 2 weeks. Baseline was defined as the assessment before randomization. Responses were as follows regarding symptoms at the final treatment evaluation: No change - participant reported or did not report a specific symptom at both baseline and the final treatment evaluation; Worsened -participant did not report any symptom at baseline, but changed to report at least 1 symptom at the final treatment evaluation.	Week 16
Percent of Participants Who Were Symptom Responders on The DSQ+Pain Scale at The Final Treatment Period Evaluation	Participants' dysphagia symptoms were evaluated using the 4-item DSQ. The questionnaire was developed by the Sponsor, as an ePRO measure, according to the principles of the Final Guidance for Industry for Patient Reported Outcome Measures (PRO Guidance December 2009). All participants used a diary, and responded to Question 1 (did you eat solid food) and Question 2 (did food pass slowly or get stuck). If the answer to Question 2 was 'No', the diary ended for that day. If a participant answered 'Yes', he/she advanced to Question 3 (did you have to do anything to make the food go down or get relief) and Question 4 (extent to which the participant experienced pain while swallowing).The DSQ+pain response was defined as a >/= 30% and >/= 50% reduction from baseline in the combined score from Questions 2, 3, and 4. The 2-week DSQ+pain score was calculated by adding points from Questions 2, 3, and 4 and then taking the average of the available scores over each 2-week interval.	Week 16
Percent of Days That Participants Reported That They Avoided Solid Food During The Baseline And Treatment Periods	Participants' dysphagia symptoms were evaluated using the 4-item DSQ. The questionnaire was developed by the Sponsor, as an ePRO measure, according to the principles of the Final Guidance for Industry for Patient Reported Outcome Measures (PRO Guidance December 2009). All participants used a diary, and responded to Questions 1 (did you eat solid food) and 2 (did food pass slowly or get stuck). If the participant's answer to Question 2 was 'No', the diary ended for that day. If a participant answered 'Yes', he/she advanced to Questions 3 (did you have to do anything to make the food go down or get relief) and 4 (extent to which the participant experienced pain while swallowing). Values were calculated for all the days that Question 1 was answered from 14 days prior to baseline visit up to the final treatment period evaluation.	From 14 days prior to the baseline visit to the final treatment period evaluation
Change From Baseline in The Scores of DSQ Question 1 During The Treatment Period	Participants' dysphagia symptoms were evaluated using the 4-item DSQ. The questionnaire was developed by the Sponsor, as an ePRO measure, according to the principles of the Final Guidance for Industry for Patient Reported Outcome Measures (PRO Guidance December 2009). All participants used a diary, and responded to Questions 1 (did you eat solid food) and 2 (did food pass slowly or get stuck). If the participant's answer to Question 2 was 'No', the diary ended for that day. If a participant answered 'Yes', he/she advanced to Questions 3 (did you have to do anything to make the food go down or get relief) and 4 (extent to which the participant experienced pain while swallowing). Question 1 is rated as Yes (score=0) or No (score=1); higher values indicate a worse outcome. Baseline was the DSQ score of the 14-day period before randomization. A negative change from baseline indicates that symptoms decreased.	Baseline, Weeks 8, 12, and 16
Change From Baseline in The Scores of DSQ Question 4 During The Treatment Period	Participants' dysphagia symptoms were evaluated using the 4-item DSQ. The questionnaire was developed by the Sponsor, as an ePRO measure, according to the principles of the Final Guidance for Industry for Patient Reported Outcome Measures (PRO Guidance December 2009). All participants used a diary, and responded to Questions 1 (did you eat solid food) and 2 (did food pass slowly or get stuck). If the participant's answer to Question 2 was 'No', the diary ended for that day. If a participant answered 'Yes', he/she advanced to Questions 3 (did you have to do anything to make the food go down or get relief) and 4 (extent to which the participant experienced pain while swallowing). Question 4 is rated as None, I had no pain (score=0), mild pain (score=1), moderate pain (score=2), severe pain (score=3), or very severe pain (score=4); 4 is the worst pain. Baseline was the DSQ score of the 14-day period before randomization. A negative change from baseline indicates that symptoms decreased.	Baseline, Weeks 8, 12, and 16

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General Publications

• Dellon ES, Collins MH, Katzka DA, Hudgens S, Lan L, Williams J, Vera-Llonch M, Hirano I. Improvements in Dysphagia and Pain With Swallowing in Patients With Eosinophilic Esophagitis Receiving Budesonide Oral Suspension. Clin Gastroenterol Hepatol. 2021 Apr;19(4):699-706.e4. doi: 10.1016/j.cgh.2020.03.060. Epub 2020 Apr 6.
• Hirano I, Dellon ES, Collins MH, Williams J, Lan L, Katzka DA. Clinical Features at Baseline Cannot Predict Symptom Response to Placebo in Patients With Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2019 Sep;17(10):2126-2128.e1. doi: 10.1016/j.cgh.2018.11.045. Epub 2018 Nov 28.
• Dellon ES, Katzka DA, Collins MH, Gupta SK, Lan L, Williams J, Hirano I. Safety and Efficacy of Budesonide Oral Suspension Maintenance Therapy in Patients With Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2019 Mar;17(4):666-673.e8. doi: 10.1016/j.cgh.2018.05.051. Epub 2018 Jun 12.
• Dellon ES, Katzka DA, Collins MH, Hamdani M, Gupta SK, Hirano I; MP-101-06 Investigators. Budesonide Oral Suspension Improves Symptomatic, Endoscopic, and Histologic Parameters Compared With Placebo in Patients With Eosinophilic Esophagitis. Gastroenterology. 2017 Mar;152(4):776-786.e5. doi: 10.1053/j.gastro.2016.11.021. Epub 2016 Nov 23.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 23, 2012
• Primary Completion (ACTUAL): October 30, 2014
• Study Completion (ACTUAL): October 30, 2014

Study Registration Dates

• First Submitted: July 13, 2012
• First Submitted That Met QC Criteria: July 16, 2012
• First Posted (ESTIMATE): July 17, 2012

Study Record Updates

• Last Update Posted (ACTUAL): June 8, 2021
• Last Update Submitted That Met QC Criteria: May 19, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: EoE
• Additional Relevant MeSH Terms: Digestive System Diseases; Immune System Diseases; Hypersensitivity, Immediate; Hematologic Diseases; Gastrointestinal Diseases; Gastroenteritis; Hypersensitivity; Esophageal Diseases; Leukocyte Disorders; Eosinophilia; Eosinophilic Esophagitis; Esophagitis; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Budesonide
• Other Study ID Numbers: MPI-101-06

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR