Eosinophilic Esophagitis (EoE)
Conditions
Keywords
eosinophilic esophagitis
Brief 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.
Interventions
DRUGbudesonide
oral suspension
DRUGplacebo
oral suspension matching budesonide
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants Who Responded to Therapy | 12 weeks after the start of treatment | 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
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Histologic Remission | 12 weeks after the start of treatment | 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 | Baseline, 12 weeks after the start of treatment | 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 | Baseline, 12 weeks after the start of treatment | 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 | 12 weeks after the start of treatment | 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 | 12 weeks after the start of treatment | 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) | Baseline, 12 weeks after the start of treatment | 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. |
| Percent of Participants With Histologic Response | 12 weeks after the start of treatment | 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. |
| Change From Baseline in Physician's Global Assessment Score of Disease Severity | Baseline, 12 weeks after the start of treatment | 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 | Week 2, 4, or 8, or at the Final Treatment Evaluation | 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 | Week 2, 4, or 8, or at the Final Treatment Evaluation | 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) | Week 2, 4, or 8, or at the Final Treatment Evaluation | 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) | 15 weeks after the start of treatment | 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 | Baseline, 12 weeks after the start of treatment | BP was assessed for each treatment group at baseline and at each post-baseline visit including the final treatment evaluation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo twice daily at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks with a 3 week taper period. | 21 |
| Low Dose Participants received oral budesonide suspension (OBS) 0.05 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 0.35 mg (2 to 9 years) or 0.50 mg (10 to 18 years), followed by a 3 week taper period. | 21 |
| Medium Dose Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and placebo after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 1.4 mg (2 to 9 years) or 2.0 mg (10 to 18 years), followed by a 3 week taper period. | 19 |
| High Dose Participants received oral budesonide suspension (OBS) 0.2 mg/mL at bedtime (hs) and after breakfast (qAM, pc) for 12 weeks, with a total daily dose of 2.8 mg (2 to 9 years) or 4.0 mg (10 to 18 years), followed by a 3 week taper period. | 20 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 1 | 1 |
| Overall Study | Lack of Efficacy | 1 | 1 | 0 | 0 |
| Overall Study | Not on treatment for >/= 77 days | 1 | 0 | 0 | 0 |
| Overall Study | Significant Subject Noncompliance | 0 | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Low Dose | Medium Dose | High Dose | Total |
|---|---|---|---|---|---|
| Age, Continuous | 9.2 years STANDARD_DEVIATION 4.36 | 9.0 years STANDARD_DEVIATION 5.88 | 10.2 years STANDARD_DEVIATION 4.89 | 8.1 years STANDARD_DEVIATION 4.58 | 9.1 years STANDARD_DEVIATION 4.93 |
| Age, Customized 10 to 18 years | 9 Participants | 9 Participants | 9 Participants | 8 Participants | 35 Participants |
| Age, Customized 2 to 9 years | 12 Participants | 12 Participants | 10 Participants | 12 Participants | 46 Participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 2 Participants | 4 Participants | 15 Participants |
| Sex: Female, Male Male | 16 Participants | 17 Participants | 17 Participants | 16 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 21 | 13 / 21 | 16 / 19 | 17 / 20 |
| serious Total, serious adverse events | 0 / 21 | 0 / 21 | 0 / 19 | 1 / 20 |
Outcome results
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.
Time frame: 12 weeks after the start of treatment
Population: The Full Analysis Set (FAS), defined as participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percent of Participants Who Responded to Therapy | 5.6 percentage of participants |
| Low Dose | Percent of Participants Who Responded to Therapy | 11.8 percentage of participants |
| Medium Dose | Percent of Participants Who Responded to Therapy | 52.6 percentage of participants |
| High Dose | Percent of Participants Who Responded to Therapy | 47.1 percentage of participants |
p-value: 0.5282Regression, Logistic
p-value: 0.0092Regression, Logistic
p-value: 0.0174Regression, Logistic
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.
Time frame: Week 2, 4, or 8, or at the Final Treatment Evaluation
Population: The PK Set, defined as all participants in the safety analysis set who received oral budesonide suspension (OBS) and had sufficient PK samples to calculate PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under The Plasma Concentration-Time Curve (AUC) of Budesonide From Time Zero to Time of The Last Measurable Concentration (AUC0-last) | 1139.5 hr*pg/mL | Standard Deviation 800.84 |
| Low Dose | Area Under The Plasma Concentration-Time Curve (AUC) of Budesonide From Time Zero to Time of The Last Measurable Concentration (AUC0-last) | 743.8 hr*pg/mL | Standard Deviation 425.26 |
| Medium Dose | Area Under The Plasma Concentration-Time Curve (AUC) of Budesonide From Time Zero to Time of The Last Measurable Concentration (AUC0-last) | 3259.3 hr*pg/mL | Standard Deviation 2109.37 |
| High Dose | Area Under The Plasma Concentration-Time Curve (AUC) of Budesonide From Time Zero to Time of The Last Measurable Concentration (AUC0-last) | 3636.9 hr*pg/mL | Standard Deviation 1769.88 |
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.
Time frame: Baseline, 12 weeks after the start of treatment
Population: The FAS, defined as all participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Endoscopy Score | -0.6 scores on a scale | Standard Deviation 2.28 |
| Low Dose | Change From Baseline in Endoscopy Score | -0.9 scores on a scale | Standard Deviation 1.9 |
| Medium Dose | Change From Baseline in Endoscopy Score | -1.3 scores on a scale | Standard Deviation 2.23 |
| High Dose | Change From Baseline in Endoscopy Score | -2.2 scores on a scale | Standard Deviation 1.81 |
p-value: 0.1095ANCOVA
p-value: 0.0264ANCOVA
p-value: 0.001ANCOVA
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.
Time frame: Baseline, 12 weeks after the start of treatment
Population: The FAS, defined as all participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Physician's Global Assessment Score of Disease Severity | -38.9 scores on a scale | Standard Deviation 28.02 |
| Low Dose | Change From Baseline in Physician's Global Assessment Score of Disease Severity | -30.2 scores on a scale | Standard Deviation 27.11 |
| Medium Dose | Change From Baseline in Physician's Global Assessment Score of Disease Severity | -39.3 scores on a scale | Standard Deviation 22.89 |
| High Dose | Change From Baseline in Physician's Global Assessment Score of Disease Severity | -35.7 scores on a scale | Standard Deviation 28.49 |
p-value: 0.4197ANCOVA
p-value: 0.9787ANCOVA
p-value: 0.8987ANCOVA
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.
Time frame: Week 2, 4, or 8, or at the Final Treatment Evaluation
Population: The Pharmacokinetic (PK) Set, defined as all participants in the safety analysis set who received oral budesonide suspension (OBS) and had sufficient PK samples to calculate PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Plasma Concentration (Cmax) of Budesonide | 492.0 pg/mL | Standard Deviation 417.81 |
| Low Dose | Maximum Plasma Concentration (Cmax) of Budesonide | 195.0 pg/mL | Standard Deviation 64.37 |
| Medium Dose | Maximum Plasma Concentration (Cmax) of Budesonide | 1019.5 pg/mL | Standard Deviation 670.18 |
| High Dose | Maximum Plasma Concentration (Cmax) of Budesonide | 958.4 pg/mL | Standard Deviation 527.64 |
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.
Time frame: Baseline, 12 weeks after the start of treatment
Population: The Safety Analysis Set, defined as all randomized participants who received at least one dose of double-blind study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change in Blood Pressure (BP) at End of Treatment | Diastolic BP | -3.1 mmHg | Standard Deviation 10.31 |
| Placebo | Mean Change in Blood Pressure (BP) at End of Treatment | Systolic BP | -1.5 mmHg | Standard Deviation 14.74 |
| Low Dose | Mean Change in Blood Pressure (BP) at End of Treatment | Diastolic BP | 0.5 mmHg | Standard Deviation 8.89 |
| Low Dose | Mean Change in Blood Pressure (BP) at End of Treatment | Systolic BP | 1.8 mmHg | Standard Deviation 11.13 |
| Medium Dose | Mean Change in Blood Pressure (BP) at End of Treatment | Systolic BP | 3.5 mmHg | Standard Deviation 8.2 |
| Medium Dose | Mean Change in Blood Pressure (BP) at End of Treatment | Diastolic BP | 3.1 mmHg | Standard Deviation 9.18 |
| High Dose | Mean Change in Blood Pressure (BP) at End of Treatment | Systolic BP | 8.0 mmHg | Standard Deviation 13.58 |
| High Dose | Mean Change in Blood Pressure (BP) at End of Treatment | Diastolic BP | 5.1 mmHg | Standard Deviation 8.83 |
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.
Time frame: Baseline, 12 weeks after the start of treatment
Population: The FAS, defined as all participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Eosinophilic Esophagitis (EoE) Clinical Symptom Score (CSS) | -64.46 percent change | Standard Deviation 45.759 |
| Low Dose | Percent Change From Baseline in Eosinophilic Esophagitis (EoE) Clinical Symptom Score (CSS) | -60.83 percent change | Standard Deviation 30.347 |
| Medium Dose | Percent Change From Baseline in Eosinophilic Esophagitis (EoE) Clinical Symptom Score (CSS) | -65.89 percent change | Standard Deviation 32.382 |
| High Dose | Percent Change From Baseline in Eosinophilic Esophagitis (EoE) Clinical Symptom Score (CSS) | -47.21 percent change | Standard Deviation 40.79 |
p-value: 0.6729ANCOVA
p-value: 0.8894ANCOVA
p-value: 0.1532ANCOVA
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.
Time frame: Baseline, 12 weeks after the start of treatment
Population: The FAS, defined as all participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Peak Eosinophil Count | 7.93 percent change | Standard Deviation 84.162 |
| Low Dose | Percent Change From Baseline in Peak Eosinophil Count | -52.62 percent change | Standard Deviation 51.22 |
| Medium Dose | Percent Change From Baseline in Peak Eosinophil Count | -44.02 percent change | Standard Deviation 89.106 |
| High Dose | Percent Change From Baseline in Peak Eosinophil Count | -94.75 percent change | Standard Deviation 19.615 |
p-value: 0.0108ANCOVA
p-value: 0.0208ANCOVA
p-value: <0.0001ANCOVA
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.
Time frame: 12 weeks after the start of treatment
Population: The FAS, defined as all participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percent of Participants With Clinical Remission | 33.3 percentage of participants |
| Low Dose | Percent of Participants With Clinical Remission | 17.6 percentage of participants |
| Medium Dose | Percent of Participants With Clinical Remission | 31.6 percentage of participants |
| High Dose | Percent of Participants With Clinical Remission | 17.6 percentage of participants |
p-value: 0.3444Regression, Logistic
p-value: 0.9258Regression, Logistic
p-value: 0.3215Regression, Logistic
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.
Time frame: 12 weeks after the start of treatment
Population: The FAS, defined as participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percent of Participants With Clinical Response | 77.8 percentage of participants |
| Low Dose | Percent of Participants With Clinical Response | 64.7 percentage of participants |
| Medium Dose | Percent of Participants With Clinical Response | 78.9 percentage of participants |
| High Dose | Percent of Participants With Clinical Response | 52.9 percentage of participants |
p-value: 0.3769Regression, Logistic
p-value: 0.9363Regression, Logistic
p-value: 0.1235Regression, Logistic
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.
Time frame: 12 weeks after the start of treatment
Population: The FAS, defined as participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percent of Participants With Histologic Remission | 0.0 percentage of participants |
| Low Dose | Percent of Participants With Histologic Remission | 11.8 percentage of participants |
| Medium Dose | Percent of Participants With Histologic Remission | 42.1 percentage of participants |
| High Dose | Percent of Participants With Histologic Remission | 76.5 percentage of participants |
p-value: 0.4959Regression, Logistic
p-value: 0.004Regression, Logistic
p-value: <0.0001Regression, Logistic
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.
Time frame: 12 weeks after the start of treatment
Population: The FAS, defined as participants who received at least one dose of study drug and had evaluable post-baseline esophageal biopsy and clinical symptom data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percent of Participants With Histologic Response | 5.6 percentage of participants |
| Low Dose | Percent of Participants With Histologic Response | 23.5 percentage of participants |
| Medium Dose | Percent of Participants With Histologic Response | 52.6 percentage of participants |
| High Dose | Percent of Participants With Histologic Response | 94.1 percentage of participants |
p-value: 0.1786Regression, Logistic
p-value: 0.009Regression, Logistic
p-value: 0.0001Regression, Logistic
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.
Time frame: 15 weeks after the start of treatment
Population: The Safety Analysis Set, defined as all randomized participants who received at least one dose of double-blind study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percent of Participants With Potential Corticosteroid-Related Treatment-Emergent Adverse Events (TEAEs) | 9.5 percentage of participants |
| Low Dose | Percent of Participants With Potential Corticosteroid-Related Treatment-Emergent Adverse Events (TEAEs) | 9.5 percentage of participants |
| Medium Dose | Percent of Participants With Potential Corticosteroid-Related Treatment-Emergent Adverse Events (TEAEs) | 21.0 percentage of participants |
| High Dose | Percent of Participants With Potential Corticosteroid-Related Treatment-Emergent Adverse Events (TEAEs) | 15.0 percentage of participants |
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.
Time frame: Week 2, 4, or 8, or at the Final Treatment Evaluation
Population: The PK Set, defined as all participants in the safety analysis set who received oral budesonide suspension (OBS) and had sufficient PK samples to calculate PK parameters.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Time to Maximum (Tmax) And Half Maximum (T1/2) Plasma Concentration of Budesonide | Tmax | 0.68 hours | Standard Deviation 0.36 |
| Placebo | Time to Maximum (Tmax) And Half Maximum (T1/2) Plasma Concentration of Budesonide | T1/2 | 3.288 hours | Standard Deviation 0.8265 |
| Low Dose | Time to Maximum (Tmax) And Half Maximum (T1/2) Plasma Concentration of Budesonide | Tmax | 1.20 hours | Standard Deviation 0.447 |
| Low Dose | Time to Maximum (Tmax) And Half Maximum (T1/2) Plasma Concentration of Budesonide | T1/2 | 3.398 hours | Standard Deviation 0.7841 |
| Medium Dose | Time to Maximum (Tmax) And Half Maximum (T1/2) Plasma Concentration of Budesonide | T1/2 | 3.472 hours | Standard Deviation 2.6753 |
| Medium Dose | Time to Maximum (Tmax) And Half Maximum (T1/2) Plasma Concentration of Budesonide | Tmax | 0.93 hours | Standard Deviation 0.372 |
| High Dose | Time to Maximum (Tmax) And Half Maximum (T1/2) Plasma Concentration of Budesonide | T1/2 | 3.528 hours | Standard Deviation 1.0223 |
| High Dose | Time to Maximum (Tmax) And Half Maximum (T1/2) Plasma Concentration of Budesonide | Tmax | 1.12 hours | Standard Deviation 0.546 |