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

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.

Time frame: Baseline, Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Week 16

Population: The modified Intent-to-Treat (MITT) Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Baseline, Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Baseline, Weeks 8 and 12

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Baseline, Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Baseline, Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Baseline, Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Baseline, Weeks 8, 12, and 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Baseline, Weeks 8, 12, and 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Baseline, Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: From 14 days prior to the baseline visit to the final treatment period evaluation

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Baseline, Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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').

Time frame: Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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').

Time frame: Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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.

Time frame: Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.

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').

Time frame: Week 16

Population: The MITT Analysis Set: all randomized participants who received at least 1 dose of double-blind study drug and had both an evaluable post-baseline biopsy during the treatment period and a post-baseline DSQ score. Participants were analyzed based on the randomization schedule, regardless of the treatment actually received.