Efficacy, Safety, and Pharmacokinetics of APT-1011 in Subjects With Eosinophilic Esophagitis (EoE)

Study Overview
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Brief Summary
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Eosinophilic esophagitis (EoE) is an inflammatory disease of the esophagus, characterized by eosinophilic infiltration and gastrointestinal symptoms. Swallowed, topically acting corticosteroids, such as fluticasone, appear to be effective in resolving acute clinical and pathological features of EoE. APT-1011 is an orally disintegrating tablet (ODT) formulation of fluticasone propionate. This study is designed to compare the efficacy and safety of APT-1011 with placebo in adults with EoE for an initial 12-week treatment period, followed by an additional 40-week maintenance treatment phase. Histologic response, pharmacokinetics, and dysphagia will be assessed.

Detailed Description
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FLUTE is a phase 2b randomized, double-blind, placebo-controlled dose-ranging clinical trial of APT-1011 versus placebo in 100 adult subjects (≥18 years of age) diagnosed with EoE. Efficacy (including histologic, endoscopic, and symptomatic response), safety, and PK of APT-1011 will be examined. Participants will be given an electronic diary to record symptoms and medication intake daily. FLUTE will be conducted in several parts (Screening [4 weeks], followed by a 4-week Baseline Symptom Assessment, and 2 treatment parts [Part 1: 14-week Induction and Part 2: 38-week Maintenance]), with a follow-up visit to occur 2 weeks after the final dose of study drug. In Part 1 of the study, approximately 100 subjects will be randomized 1:1:1:1:1 to receive placebo or one of 4 active doses of APT-1011. All subjects will receive one tablet 30 minutes after breakfast and one tablet at bedtime (HS). The dosing groups include: 1.5 mg HS APT-1011, 1.5 mg twice daily (BID) (total daily dose of 3 mg) APT-1011, 3 mg HS APT-1011, and 3 mg BID (total daily dose of 6 mg) APT-1011, and placebo BID. In Part 2, all subjects classified as histologic responders at Week 12 will continue to be treated according to the dosing group to which they were randomized, and non-responders will receive single-blind 3 mg BID. All subjects who are histologic non-responders at Week 26 will stop treatment at Week 28 and enter the 2-week follow-up and exit the study. Histologic responders at Week 26 will continue on the same dose until end-of-study at Week 52. Subjects will complete a follow-up visit 2 weeks after the final dose of study drug. All subjects must have a final EGD within 3 weeks prior to completing the Follow-up Visit unless the subject withdraws consent or has a contraindication to EGD.

Official Title
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FLUTicasone in Eosinophilic Esophagitis (FLUTE): A Randomized, Double-blind, Placebo-controlled, Dose-ranging, and Maintenance Study of APT-1011 in Subjects With Eosinophilic Esophagitis

Conditions
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Eosinophilic Esophagitis

Intervention / Treatment
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* Drug: APT-1011
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female between ≥18 and ≤75 years of age at the time of informed consent Signed informed consent Evidence of EoE defined by ≥15 peak eosinophils per HPF as measured from proximal and distal biopsies Subject-reported history of ≥3 episodes of dysphagia in the 7 days prior to Screening 7-day Global EoE Symptom Score >3 at baseline and at screening Willing and able to adhere to study-related treatment regimens, procedures, and visit schedule Exclusion Criteria: Have known contraindication, hypersensitivity, or intolerance to corticosteroids; Have any physical, mental, or social condition or history of illness or laboratory abnormality that in the Investigator's judgment might interfere with study procedures or the ability of the subject to adhere to and complete the study; Presence of oral or esophageal mucosal infection of any type; Have any mouth or dental condition that prevents normal eating; Have any condition affecting the esophageal mucosa or altering esophageal motility other than EoE; Use of systemic corticosteroids within 60 days prior to Screening, use of inhaled/swallowed corticosteroids within 30 days prior to Screening, or extended use of high-potency dermal topical corticosteroids within 30 days prior to Screening; Initiation of an elimination diet or elemental diet within 30 days before Screening (diet must remain stable after signing ICF); Morning serum cortisol level ≤5 μg/dL (138 nmol/L); Use of biologic immunomodulators in the 24 weeks prior to Screening; Use of calcineurin inhibitors or purine analogues, or potent cytochrome P450 (CYP) 3A4 inhibitors in the 12 weeks prior to Screening; Have a contraindication to or factors that substantially increase the risk of EGD or esophageal biopsy or have narrowing of the esophagus that precludes EGD with a standard 9 mm endoscope; Have a history of an esophageal stricture requiring dilatation within the previous 12 weeks prior to Screening; Have initiated, discontinued or changed dosage regimen of PPIs, H2 antagonists, antacids or antihistamines for any condition such as GERD or allergic rhinitis within 4 weeks prior to qualifying endoscopy. These drugs must remain constant throughout the study. A serum cortisol level <18 μg/dL (497 nmol/L) at 60 minutes with adrenocorticotropic hormone (ACTH) stimulation test using 250 μg cosyntropin (i.e., a positive result on the ACTH stimulation test).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APT-1011 1.5 mg HS<br>Placebo after breakfast, APT-1011 1.5 mg HS | Drug: APT-1011<br>* APT-1011 is an orally disintegrating tablet formulation of fluticasone propionate<br>* Other names: Fluticasone propionate ODT;Drug: Placebo<br>* Placebo tablets are identical in composition to APT-1011 except they exclude the active ingredient.<br>* Other names: Matching placebo dose;|
| Experimental: APT-1011 1.5 mg BID<br>APT-1011 1.5 mg after breakfast, APT-1011 1.5 mg HS | Drug: APT-1011<br>* APT-1011 is an orally disintegrating tablet formulation of fluticasone propionate<br>* Other names: Fluticasone propionate ODT;|
| Experimental: APT-1011 3 mg HS<br>Placebo after breakfast, APT-1011 3 mg HS | Drug: APT-1011<br>* APT-1011 is an orally disintegrating tablet formulation of fluticasone propionate<br>* Other names: Fluticasone propionate ODT;Drug: Placebo<br>* Placebo tablets are identical in composition to APT-1011 except they exclude the active ingredient.<br>* Other names: Matching placebo dose;|
| Experimental: APT-1011 3 mg BID<br>APT-1011 3 mg after breakfast, APT-1011 3 mg HS | Drug: APT-1011<br>* APT-1011 is an orally disintegrating tablet formulation of fluticasone propionate<br>* Other names: Fluticasone propionate ODT;|
| Placebo Comparator: Placebo BID<br>Placebo 30 minutes after breakfast and HS | Drug: Placebo<br>* Placebo tablets are identical in composition to APT-1011 except they exclude the active ingredient.<br>* Other names: Matching placebo dose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With ≤6 Peak Eosinophils/High-power Field (HPF) | Histology (eosinophils per high power field [HPF]): percentage of subjects with ≤6 PEAK eosinophils/HPF after assessing at least 5-6 biopsies from the proximal and distal esophagus ( 3 each) where the HPF area is 235 square microns (40 magnification lens with a 22 mm ocular). | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Who Met the Primary Endpoint at Week 12 and Maintained the Primary Endpoint at Weeks 26 and 52 | Percentage of subjects who entered Part 2 - Maintenance and met the primary endpoint (histology) at Week 12 and maintained the primary endpoint at Week 26 and Week 52. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect percentage of subjects who met the primary endpoint following 12 or 38 weeks of treatment. | Week 26, and Week 52 | 
| Change From Baseline Eosinophilic Esophagitis Endoscopic Reference Score (EREFs) at Week 12, 26, and 52 | Endoscopic changes will be assessed as per the EREFs evaluation based on the following endoscopic features: edema [Grade {Gr} 0 (absent) or Gr 1 (present)], strictures [Gr 0 (absent) or Gr 1 (present)], rings [Gr 0 (none), Gr 1 (mild), Gr 2 (moderate), Gr 3 (severe)], exudates [Gr 0 (none), Gr 1 (mild), Gr (severe)], furrows [Gr 0 (none), Gr 1 (mild), Gr 2 (severe)], crepe paper esophagus [Gr 0 (absent) or Gr 1 (present)], narrow caliber esophagus [Gr 0 (absent) or Gr 1 (present)], and esophageal erosions [Normal (0), Gr A (1), Gr B (2), Gr C (3), or Gr D (4)]. EREFs: 0 (best) to 15 (worst) based on the sum of the subscores listed above. Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3 mg BID and results reflect EREF evaluation following 12 or 38 weeks of treatment. | Week 12, Week 26, and Week 52 | 
| Percentage of Subjects With a Peak Eosinophils/HPF Number <1 and <15 | Percentage of subjects with a peak eosinophils/HPF <1 and <15 at Week 12, 26 and 52. Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect peak eosinophils/HPF following 12 or 38 weeks of treatment. | Week 12, Week 26, and Week 52 | 
| Change From Baseline Global EoE Symptom Score | Change from baseline global EOE symptom score assessed prior to randomization to scores for 7-day recall at Week 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52 visits. Global Eosinophilic Esophagitis Symptom Score: On a scale from 0 (no symptoms) to 10 (most severe symptoms), how severe were your EoE symptoms over the past 7 days? Patients were asked to think of all their symptoms due to EoE and make an overall statement by selecting a number. Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline global EOE symptom score following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment. | Week 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52 | 
| Change in the Number of Dysphagia Episodes | Change in the number of dysphagia episodes at baseline (14-day period prior to randomization) compared with the 14-day period prior to the time point of interest. Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect the change in the number of dysphagia episodes following 12 or 38 weeks of treatment. | Week 12, Week 26 and Week 52 | 
| Change From Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Total Score | Change from Baseline 7-Day EEsAI total score assessed prior to randomization and those assessed at Weeks 12, 26 and 52 (Total score 100). Eosinophilic Esophagitis Activity Index Total Score: 0 (best) to 100 (worst) based on the sum of the categorized subscores for frequency of trouble swallowing [never (0), 1-3x (15) or 4-6x (27) per week]; duration of trouble swallowing [≤5 min (0), >5 min (6)]; pain when swallowing [no (0), yes (15)]; Visual Dysphagia Question score [0 (best),12,19, 21, or 23 (worst)]; avoidance modification and slow eating score [0 (best), 9, or 25 (worst)]. A higher score means a worse outcome. Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect the change from baseline 7-day EEs | Weeks 12, 26 and 52 | 
| Change From Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Subscores | The Avoidance, Modification and Slow Eating (AMS) Score and Visual Dysphagia Question (VDQ) Score are components of the EEsAI. AMS: Answers to three items determining the pattern of behavioral adaptation were scored for each food consistency consumed by the subject (avoidance, modification, and eating slowly). The AMS score ranges from 0 (best) to 25 (worst). VDG: The degree of perceived difficulty when eating 8 different food consistencies was assessed. The VDQ score ranges from 0 (best) to 23 (worst). A higher score for either subscore means a worse outcome. Negative change from baseline represents a worsening in quality of life for the total score or subscore. Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline. | Weeks 12, 26 and 52 | 
| Percentage of Subjects With Mean 7-day EEsAI Total Score <20 | Percentage of subjects with mean 7-day EEsAI total score <20 to those assessed at Weeks 12, 26 and 52. Eosinophilic Esophagitis Activity Index Total Score: 0 (best) to 100 (worst) based on the sum of the categorized subscores for frequency of trouble swallowing [never (0), 1-3x (15) or 4-6x (27) per week]; duration of trouble swallowing [<= 5 min (0), >5 min (6)]; pain when swallowing [no (0), yes (15)]; Visual Dysphagia Question score [0 (best),12,19,21, or 23 (worst)]; avoidance modification and slow eating score [0 (best), 9, or 25 (worst)]. Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline global EOE symptom score following 12 or 38 weeks of treatment | Weeks 12, 26, and 52 | 
| Change From Baseline Patient Global Impression of Severity (PGIS) for EoE Symptoms as Assessed Prior to Randomization Post-Baseline Visit | Change From Baseline PGIS for EoE Symptoms as Assessed Prior to Randomization at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52. Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline global EOE symptoms following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment. | Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52 | 
| Change From Baseline PGIS for Difficulty With Food or Pills Going Down as Assessed Prior to Randomization Post-Baseline Visit | Change From Baseline PGIS for Difficulty with Food or Pills Going Down as Assessed Prior to Randomization at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52. Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline PGIS for difficulty with food or pills going down following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment. | Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52 | 
| Change From Baseline Patient Global Impression of Change (PGIC) for EoE Symptoms as Assessed Prior to Randomization Post-Baseline Visit | Change From Baseline PGIC for EoE Symptoms as Assessed Prior to Randomization at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52. Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline PGIC for EoE symptoms following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment. | Weeks 4, 8, 12, 14, 18, 22, 26, 36, 44, and 52 | 
| Change From Baseline PGIC of Difficulty With Food or Pills as Assessed Prior to Randomization Post-Baseline Visit | Change From Baseline PGIC of Difficulty with Food or Pills as Assessed Prior to Randomization at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52. Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline PGIC of difficulty with food or pills following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment. | Weeks 4, 8, 12, 14, 18, 22, 26, 36, 44, and 52 | 
| Percentage of Histologic Non-responders by Dose at Weeks 12, 26, and 52 | Percentage of histologic non-responders by dose at Weeks 12, 26, and 52. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect non-response following 12 or 38 weeks of treatment. | Weeks 12, 26 and 52 | 
| Percentage of Subjects Requiring Emergency Endoscopic Food Dis-impaction | Percentage of subjects requiring emergency endoscopic food dis-impaction by dose before Week 14, between Week 14 and Week 28, and between Week 28 and Week 52. Note: There were no patients in the placebo group after Week 14. | before Week 14, between Week 14 and Week 28, between Week 28 and Week 52 | 
| Percentage of Subjects Requiring Esophageal Dilation | Percentage of subjects requiring esophageal dilation by dosing group and part of the study. Note: There were no patients in the placebo group after Week 14. | baseline to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Esophagitis, Eosinophilic Esophagitis, Fluticasone, Dysphagia, Safety, Efficacy, Pharmacokinetics, Esophageal Diseases, Gastrointestinal Diseases, Digestive System Diseases, Glucocorticoids, Orally Disintegrating Tablet