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A Study in Adolescents and Adults With Eosinophilic Esophagitis (EoE) Measuring Histologic Response and Determine if Reduction in Dysphagia is Achieved

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ClinicalTrials.gov Identifier: NCT02605837
Recruitment Status : Active, not recruiting
First Posted : November 16, 2015
Last Update Posted : September 20, 2018
Sponsor:
Information provided by (Responsible Party):
Shire

Brief Summary:
A study in adolescents and adults with eosinophilic esophagitis (EoE) to measure the histologic response and determine if any reduction in dysphagia is achieved.

Condition or disease Intervention/treatment Phase
Eosinophilic Esophagitis (EoE) Drug: Oral Budesonide Suspension (OBS) Drug: Placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 420 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Oral Budesonide Suspension (OBS) in Adolescent and Adult Subjects (11 to 55 Years of Age, Inclusive) With Eosinophilic Esophagitis: A Phase 3 Randomized, Double-blind, Placebo-controlled Study
Actual Study Start Date : October 1, 2015
Estimated Primary Completion Date : January 21, 2019
Estimated Study Completion Date : January 21, 2019


Arm Intervention/treatment
Experimental: Oral Budesonide Suspension (OBS)
Participants will receive Oral Budesonide Suspension (OBS) 10 milliliter (ml) of 0.2 milligram per milliliter (mg/ml) twice daily up to 16 weeks.
Drug: Oral Budesonide Suspension (OBS)
Oral Budesonide Suspension (OBS) 10 milliliter (ml) of 0.2 milligram per milliliter (mg/ml) twice daily up to 16 weeks.

Placebo Comparator: Placebo
Participants will receive oral dose of 10 ml of placebo matched with the experimental drug twice daily up to 16 weeks.
Drug: Placebo
Oral dose of 10 ml of placebo matched with the experimental drug.




Primary Outcome Measures :
  1. Number of Participants With Histologic Response [ Time Frame: Baseline to Week 16 (end of the treatment) ]
    Histologic response is defined as a peak eosinophil count of less than or equal to (<=) 6/ high-powered field (HPF) across all available esophageal levels. Number of participants with histologic response will be assessed.

  2. Number of Participants With Dysphagia Symptom Response [ Time Frame: Baseline to Week 16 (end of the treatment) ]
    Dysphagia symptom response is defined as greater than or equal to (>=) 30 percent (%) reduction in the Dysphagia Symptom Questionnaire (DSQ) combined score (questions 2+3). The DSQ contains 4 questions related to consumption of solid food, the presence of dysphagia and its severity, as well as pain. It is calculated by following formula. DSQ score= [(Sum of points from questions 2+3 in the daily DSQ)×14]/ Number of diaries reported with non-missing data.


Secondary Outcome Measures :
  1. Change From Baseline in Dysphagia Symptom Questionnaire (DSQ) Combined Score [ Time Frame: Baseline, Week 16 (end of the treatment) ]
    The DSQ contains 4 questions related to consumption of solid food, the presence of dysphagia and its severity, as well as pain.The DSQ contains 4 questions related to consumption of solid food, the presence of dysphagia and its severity, as well as pain. It is calculated by following formula. DSQ score= [(Sum of points from questions 2+3 in the daily DSQ) × 14]/ Number of diaries reported with non-missing data. Questions 1 and 4 will be excluded from the DSQ score.

  2. Change From Baseline in Total Endoscopy Score [ Time Frame: Baseline, Week 16 (end of the treatment) ]
    Endoscopic findings with separate evaluations of the proximal and distal esophagus will be recorded with respect to 5 categories: 1) exudates or plaques (grade 0-2); 2) fixed esophageal rings (grade 0-3); 3) edema (grade 0-2); 4) furrows (grade 0-2); and 5) strictures (grade 0-1) where grade 0= None/absent and grade 2/3 = Severe. An endoscopy score for each category will be calculated and summed for each anatomic location (proximal and distal). The maximum endoscopy score is 10 points for each location, and a Total Endoscopy Score is the sum of the scores for the proximal and distal locations.

  3. Number of Participants With Peak Eosinophil Count [ Time Frame: Baseline, Week 16 (end of the treatment) ]
    Number of participants with peak eosinophil count less than (<)15/high-powered field (HPF) and less than or equal to (<=)1/HPF across all available esophagus levels will be assessed.

  4. Change From Baseline in the Peak Eosinophil Count [ Time Frame: Baseline, Week 16 (end of the treatment) ]
    Change from baseline in the peak eosinophil count to the final treatment period evaluation for each available esophageal level (proximal, mid-, and distal) will be assessed.

  5. Change From Baseline in the Histopathologic Epithelial Features [ Time Frame: Baseline, Week 16 (end of the treatment) ]
    Change from baseline in the histopathologic epithelial features combined total score (grade and stage) to the final treatment period evaluation will be assessed by measuring eight histopathologic epithelial features (basal layer hyperplasia, eosinophil density, eosinophil micro-abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, lamina propria fibrosis) will be scored on a 4-point scale (0=normal, 3=worst) for both the severity of the abnormality (that is, grade) and the amount of tissue affected by the abnormality (that is, stage).

  6. Change From Baseline in Dysphagia Symptom Response (Binary Response) [ Time Frame: Baseline, Week 16 (end of the treatment) ]
    Dysphagia symptom response (binary response) is defined as a >=50% reduction in the DSQ combined score (questions 2+3). The DSQ contains 4 questions related to consumption of solid food, the presence of dysphagia and its severity, as well as pain. It is calculated by following formula. DSQ score= [(Sum of points from questions 2+3 in the daily DSQ) × 14]/ Number of diaries reported with non-missing data. Questions 1 and 4 will be excluded from the DSQ score.

  7. Change From Baseline in the Dysphagia Symptom Questionnaire (DSQ) Combined Score (Questions 2+3) Over Time [ Time Frame: Baseline to end of study (32 months) ]
    Change from baseline in the DSQ combined score (questions 2+3) over time will be assessed. The DSQ contains 4 questions related to consumption of solid food, the presence of dysphagia and its severity, as well as pain. It is calculated by following formula. DSQ score= [(Sum of points from questions 2+3 in the daily DSQ) × 14]/ Number of diaries reported with non-missing data. Questions 1 and 4 will be excluded from the DSQ score.

  8. Change From Baseline in Cumulative Distribution Function [ Time Frame: Baseline, Week 16 (end of the treatment) ]
    Change from baseline cumulative distribution function curves will be measured to assess the the change and the percent change in the DSQ score from baseline to the final treatment period evaluation. The DSQ contains 4 questions related to consumption of solid food, the presence of dysphagia and its severity, as well as pain. It is calculated by following formula. DSQ score= [(Sum of points from questions 2+3 in the daily DSQ) × 14]/ Number of diaries reported with non-missing data. Questions 1 and 4 will be excluded from the DSQ score. .

  9. Number of Participants With Overall Binary Response I [ Time Frame: Baseline to Week 16 (end of the treatment) ]
    Overall binary response I is defined as a reduction in the DSQ score of >=30% from baseline to the final treatment period evaluation and a peak eosinophil count of <=6/HPF across all esophageal levels at the final treatment period evaluation. The DSQ contains 4 questions related to consumption of solid food, the presence of dysphagia and its severity, as well as pain. It is calculated by following formula. DSQ score= [(Sum of points from questions 2+3 in the daily DSQ) × 14]/ Number of diaries reported with non-missing data. Questions 1 and 4 will be excluded from the DSQ score.

  10. Number of Participants With Overall Binary Response II [ Time Frame: Baseline to Week 16 (end of the treatment) ]
    Overall binary response II is defined as a reduction in the DSQ score of >=50% from baseline to the final treatment period evaluation and a peak eosinophil count of <=6/HPF across all esophageal levels at the final treatment period evaluation. The DSQ contains 4 questions related to consumption of solid food, the presence of dysphagia and its severity, as well as pain. It is calculated by following formula. DSQ score= [(Sum of points from questions 2+3 in the daily DSQ) × 14]/ Number of diaries reported with non-missing data. Questions 1 and 4 will be excluded from the DSQ score.

  11. Change From Baseline in the Dysphagia Symptom Questionnaire (DSQ) + Pain Score (Questions 2 +3+4) [ Time Frame: Baseline, Week 16 (end of the treatment) ]
    Change from baseline in the DSQ + pain score (questions 2+3+4) will be assessed. The DSQ contains 4 questions related to consumption of solid food, the presence of dysphagia and its severity, as well as pain. The DSQ + pain score will be calculated by summing the scores of responses to questions 2, 3, and 4 by using following formula: DSQ + pain score= [(Sum of points from questions 2+3+4 in the daily DSQ) ×14]/ Number of diaries reported with non-missing data. Question 1 will be excluded from the DSQ + pain score.

  12. Change From Baseline in the Dysphagia Symptom Questionnaire (DSQ) Pain Score (Question 4) [ Time Frame: Baseline, Week 16 (end of the treatment) ]
    Change from baseline in the DSQ pain score (question 4) will be assessed. The DSQ contains 4 questions related to consumption of solid food, the presence of dysphagia and its severity, as well as pain. The DSQ pain score will be calculated by summing the scores of responses to Question 4 only by using following formula: DSQ pain score= [(Sum of points from question 4 in the daily DSQ)×14]/ Number of diaries reported with non-missing data.

  13. Number of Participants With Adverse Events (AE) [ Time Frame: Baseline to Week 20. ]
    An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment.

  14. Area Under the Curve (AUCtau) of Budesonide [ Time Frame: Pre-dose, 0.5 hours (h) and 1h, 2h, 3h, 4h, 6h, 8h, and 12h post-dose on Week 8, 12 and 16 (or early termination) ]
    The AUCtau of budesonide will be assessed.

  15. Maximum Concentration (Cmax) of Budesonide [ Time Frame: Pre-dose, 0.5 hours (h) and 1h, 2h, 3h, 4h, 6h, 8h, and 12h post-dose on Week 8, 12 and 16 (or early termination) ]
    The Cmax of budesonide will be assessed.

  16. Time to Maximum Concentration (Tmax) of Budesonide [ Time Frame: Pre-dose, 0.5 hours (h) and 1h, 2h, 3h, 4h, 6h, 8h, and 12h post-dose on Week 8, 12 and 16 (or early termination) ]
    The Tmax of budesonide will be assessed.



Information from the National Library of Medicine

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Ages Eligible for Study:   11 Years to 55 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Participants is able to provide written informed consent (participant, parent or legal guardian, and, as appropriate, participant assent) to participate in the study before completing any study-related procedures.
  • Participant is male or female aged 11-55 years, inclusive, at time of consent.
  • Participant has histologic evidence of eosinophilic esophagitis (EoE) with a peak eosinophil count of greater than or equal to (>=) 15/ high-powered field (HPF), from 2 of 3 (proximal, mid-, and/or distal) levels of the esophagus at the screening endoscopy.
  • Participant has a history of clinical symptoms of esophageal dysfunction (for example, eating problems, abdominal pain, heartburn, dysphagia, vomiting, food impaction, weight loss) intermittently or continuously at screening (Visit -1).
  • Participants must have experienced dysphagia (response of "yes" to question 2 on Dysphagia Symptom Questionnaire [DSQ]) on a minimum of 4 days and completed the DSQ on >= 70 percent (%) of days in any 2 consecutive weeks of the screening period and in the last 2 weeks prior to the baseline visit (Visit 1).
  • Participant must not have PPI-responsive EoE based on esophageal biopsies performed after the patient has been on at least 8 weeks of high-dose PPI therapy (high-dose therapy refers to the total daily dose, which may have been administered as a once or twice daily dosing regimen). This may occur at the time of the qualifying esophagogastroduodenoscopy (EGD) (in which case the same proton pump inhibitor (PPI) regimen must be continued), or this may have been done previously (in which case PPI therapy may have been stopped if there was no response to therapy based on esophageal biopsy results). If PPI responsiveness was excluded by a previous EGD and biopsy, the historical EGD and biopsy must have been performed after the patient had been on a minimum of 6 weeks of high-dose PPI therapy.
  • Participant will be on a stable (no changes) diet >=3 months prior to the screening visit (Visit -1).
  • Participant is willing and able to continue any dietary therapy, environmental therapy, and/or medical regimens (including gastric acid suppression) in effect at the screening visit (Visit -1). There should be no change to these regimens during study participation.
  • All female participants must have a negative serum pregnancy test (beta-human chorionic gonadotropin [β-hCG]) prior to enrollment into the study. Females of childbearing potential must agree to continue acceptable birth control measures (for example, abstinence, stable oral contraceptives, or double-barrier methods) throughout study participation.
  • Participant is willing and has an understanding and ability to fully comply with study procedures and restrictions defined in this protocol.

Exclusion Criteria

  • Participant has any condition or abnormality (including laboratory abnormalities), current or past, that, in the opinion of the principal investigator or medical monitor, would compromise the safety of the participant or interfere with or complicate the assessment of signs or symptoms of EoE. Such conditions may include psychiatric problems; neurologic deficits or disease; developmental delay; cardiovascular, metabolic, or pulmonary disease; or previous gastroesophageal surgery. These should be discussed with the medical monitor.
  • Participant has used immunomodulatory therapy within 8 weeks prior to the qualifying EGD or between the qualifying EGD and baseline visit (Visit 1) or anticipates using immunomodulatory therapy during the treatment period (except for any ongoing regimen of allergy shots). Use of long-acting immunomodulatory therapy (for example, Rituxan) within 3 months of the qualifying EGD should be reviewed with the medical monitor.
  • Participant has been using swallowed topical corticosteroid for EoE or systemic corticosteroid for any condition within the 4 weeks prior to the qualifying EGD, between the qualifying EGD and baseline visit (Visit 1), or anticipates use during the treatment period; any temporary use (less than or equal to [<=]7 days) or initiation of new steroid treatment during the study should be documented and discussed with the medical monitor prospectively but cannot occur within 4 weeks of the final EGD.
  • Participant has been on inhaled steroids and has not been on stable treatment for >=3 months prior to screening visit (Visit -1). Participants on inhaled steroids need to stay on a stable treatment during study participation. Participant has been on intranasal steroids and has not been on stable treatment for a minimum of 4 weeks prior to the qualifying EGD. After the qualifying EGD, participants with seasonal allergic rhinitis may resume (or discontinue) intranasal corticosteroids based on the participant's usual treatment regimen for allergy season.
  • Participant has initiated, discontinued, or changed dosage regimen of PPIs, H2 antagonists, antacids, or leukotriene inhibitors for any condition (such as gastroesophageal reflux disease, asthma or allergic rhinitis) within the 4 weeks prior to the qualifying EGD, between the qualifying EGD and baseline visit (Visit 1), or anticipates changes in the use of such medications during the treatment period.
  • Participant has been using cytochrome P450 3A4 (CYP450 3A4) inhibitors (for example, ketoconazole, grapefruit juice) within the 2 weeks prior to the baseline visit (Visit 1) or within 5 half-lives (whichever is greater) or anticipates using such medications during the treatment period.
  • Participant has an appearance on qualifying EGD of an esophageal stricture (high-grade), as defined by the presence of a lesion that does not allow passage of a diagnostic adult upper endoscope (for example, with an insertion tube diameter of greater than [>]9 millimeter [mm]).
  • Participant is on a pure liquid diet or the 6-food elimination diet.
  • Participant has had an esophageal dilation within the 3 months prior to screening (Visit -1).
  • Participant has presence of esophageal varices at the screening endoscopy.
  • Participant has any current disease of the gastrointestinal tract, aside from EoE, including eosinophilic gastritis, enteritis, colitis, or proctitis; inflammatory bowel disease; or celiac disease.
  • Participant has other diseases causing or associated with EoE, including hypereosinophilic syndrome, collagen vascular disease, vasculitis, achalasia, or parasitic infection.
  • Participant has current evidence of oropharyngeal or esophageal candidiasis.
  • Participant has a potentially serious acute or chronic viral infection or immunodeficiency condition, including tuberculosis, fungal, bacterial, viral/parasite infection, ocular herpes simplex, herpes esophagitis, or chicken pox/measles.
  • Participant has upper gastrointestinal bleeding within 4 weeks prior to the screening visit (Visit - 1) or between the screening visit and baseline visit (Visit 1).
  • Participant has evidence of active infection with Helicobacter pylori.
  • Participant has evidence of unstable asthma within 4 weeks prior to the screening visit (Visit -1) and between the screening visit and baseline visit (Visit 1).
  • Participant is female and pregnant or nursing.
  • Participant has a history of intolerance, hypersensitivity, or idiosyncratic reaction to budesonide (or any other corticosteroids) or to any other ingredients of the investigational product.
  • Participant has taken part and received intervention in an interventional study related to EoE (except for an interventional study for a topical swallowed steroid) within 6 months prior to the screening visit (Visit -1), or any investigational study within 30 days prior to the screening visit (Visit -1). An investigational topical swallowed steroid must have been discontinued at least 30 days prior to the screening visit (Visit -1).
  • Participant has a history or high risk of noncompliance with treatment or regular clinic visits.
  • Participant has previously completed, discontinued, or withdrawn from this study.
  • Participant has participated in a previous clinical study involving oral budesonide suspension (OBS) (SHP621).
  • Participant anticipates using sucralfate during the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02605837


  Show 77 Study Locations
Sponsors and Collaborators
Shire
Investigators
Study Director: Study Director Shire

Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT02605837     History of Changes
Other Study ID Numbers: SHP621-301
First Posted: November 16, 2015    Key Record Dates
Last Update Posted: September 20, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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