Efficacy and Safety APT-1011 in Adult Subjects With Eosinophilic Esophagitis (EoE) (FLUTE-2)

Study Overview
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Brief Summary
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This is a 2-part randomized, double-blind, placebo-controlled study followed by an open-label extension (OLE) of APT-1011 in adults with EoE. Part A will evaluate the efficacy and safety of APT-1011 3 mg administered hora somni (HS; at bedtime) for the induction of response to treatment (histologic and symptomatic) over 12 weeks. Part B will evaluate histological relapse-free status in patients re-randomized to continue APT-1011 or placebo (active treatment withdrawal) until Week 52. Part C, the OLE, will continue until regulatory approval of APT-1011 or Sponsor termination of the study.

Detailed Description
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This is a 2-part randomized, double-blind, placebo-controlled study followed by an OLE of APT-1011 in adults with EoE. Part A will evaluate the efficacy and safety of APT-1011 3 mg administered HS for the induction of response to treatment (histologic and symptomatic) over 12 weeks. At Week 14, subjects will move into Part B. Subjects with histological response to APT-1011, defined as ≤6 peak eos/HPF, will be re-randomized to continue APT-1011 or receive placebo (active treatment withdrawal). APT-1011 histological non-responders will continue APT-1011, and placebo histological non-responders will receive APT-1011 3 mg HS. Placebo histological responders will continue placebo. The double-blind will be sustained throughout Part B. Histological responder status will be determined at the time of esophagogastroduodenoscopy (EGD) in Part B (at or prior to Week 52, depending on unscheduled EGDs performed when the Investigator deems the subject's symptoms necessitate EGD) and is defined as ≤6 peak eos/HPF. At Week 52, subjects may enter Part C, an open-label single-arm extension phase, and continue study drug uninterrupted. Part C will terminate upon regulatory approval of APT-1011 or Sponsor termination of the study.

Official Title
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Fluticasone Propionate Oral Dispersible Tablet Formulation in Eosinophilic Esophagitis: A Two-Part, Randomized, Double-blind, Placebo-Controlled Study of APT-1011 With an Open-label Extension, in Adult Subjects With Eosinophilic Esophagitis

Conditions
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Eosinophilic Esophagitis

Intervention / Treatment
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* Drug: APT-1011
* Drug: Placebo oral tablet
* Procedure: Esophagogastroduodenoscopy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥18 years of age at the time of informed consent or assent Each subject must read, understand, and provide consent on the ICF for this study and be willing and able to adhere to study-related treatment regimens, procedures, and visit schedule Diagnosis or presumptive diagnosis of EoE that is confirmed during the Screening period by histology that demonstrates ≥15 peak eos/HPF. In order to ensure that a diagnosis can be made, at least 6 biopsies should be taken including both proximal and distal specimens (at least 3 each). Mid-esophageal biopsies are not required (optional). HPF will be defined as a standard area of 235 square microns in a microscope with 40x lens (0.3 mm^2) and 22 mm ocular. Esophagogastroduodenoscopies and biopsies are to be obtained during the Screening period Biopsies will be read by a central pathologist Esophagogastroduodenoscopies and biopsies performed outside the study will not be accepted to meet eligibility criteria Optional biopsies may be taken and processed locally for local use, if specified in the local ICF. If serious pathology is unexpectedly encountered biopsies of such lesions must be processed locally Have a subject-reported history of ≥6 episodes of dysphagia in the 14 days prior to baseline Completion of the daily diary on at least 11 out of the 14 days during the 2-week Baseline Symptom Assessment Exclusion Criteria: Have known contraindication, hypersensitivity, or intolerance to corticosteroids Have a contraindication to, or factors that substantially increase the risk of, EGD procedure or esophageal biopsy or have narrowing of the esophagus that precludes EGD with a standard 9 mm endoscope Have history of an esophageal stricture requiring dilatation within the 12 weeks prior to Screening 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 or increase the safety risk to the subject such as uncontrolled diabetes or hypertension History or presence of oral or esophageal mucosal infection whilst using inhaled or nasal corticosteroids Have any mouth or dental condition that prevents normal eating (excluding braces) Have any condition affecting the esophageal mucosa or altering esophageal motility other than EoE, including erosive esophagitis (grade B or higher as per the Los Angeles Classification of Gastroesophageal Reflux Disease; hiatus hernia longer than 3 cm, Barrett's esophagus, and achalasia) Use of systemic (oral or parenteral) corticosteroids within 60 days before Screening, use of swallowed corticosteroids within 30 days before Screening Initiation of either inhaled or nasal corticosteroids or high-potency dermal topical corticosteroids within 30 days before Screening Use of calcineurin inhibitors or purine analogues (azathioprine, 6-mercaptopurine) in the 12 weeks before Screening Use of potent cytochrome P450 (CYP) 3A4 inhibitors (eg, ritonavir and ketoconazole) in the 12 weeks before Screening Initiation of an elimination diet or elemental diet within 30 days before Screening (diet must remain stable after signing ICF) Morning (07:00 to 09:00, or as close to that window as possible) serum cortisol level ≤5 μg/dL (138 nmol/L) that is not responsive to adrenocorticotropic hormone (ACTH) stimulation: defined as a serum cortisol level <16 μg/dL (440 nmol/L) at 60 minutes with ACTH stimulation test using 250 μg cosyntropin (i.e., an abnormal result on the ACTH stimulation test) Use of biologic immunomodulators in the 24 weeks before Screening (allergy desensitization injection or oral therapy is allowed as long as the course of therapy is not altered during the study period) Subjects who have initiated, discontinued, or changed dosage regimen of histamine H2 receptor antagonists, antacids or antihistamines for any condition such as gastro-esophageal reflux disease within 4 weeks before qualifying endoscopy during Screening. If already receiving these drugs, the dosage must remain constant throughout the study Subjects who have changed dosage regimen of PPIs within 8 weeks before qualifying endoscopy. If already receiving PPIs, the dosage must remain constant throughout the study Infection with hepatitis B, hepatitis C, or human immunodeficiency virus Have gastrointestinal bleeding or documented active peptic ulcer within 4 weeks prior to Screening or entering a new study period Have chronic infection such as prior or active tuberculosis, active chicken pox or measles or absence of prior measles, mumps and rubella vaccine. Subjects with tuberculosis exposure or who live in, or travel to, high endemic areas should be assessed locally for tuberculosis before consideration for the study Immunosuppression or immunodeficiency disorder Have a history or presence of Crohn's disease, celiac disease, or other inflammatory disease of the gastrointestinal tract, including eosinophilic gastroenteritis Have current drug abuse in the opinion of the Investigator. Have current alcohol abuse in the opinion of the Investigator. Female subjects who are pregnant, breastfeeding, or planning to become pregnant during the study Sexually active females of childbearing potential who do not agree to follow highly effective contraceptive methods through the End of Study visit Have received an investigational product, as part of a clinical trial within 30 days (or 5 half-lives, whichever is longest) of Screening. Subjects who are currently participating in observational studies or enrolled in patient registries are allowed in this study Have participated in a prior study with investigational product APT-1011

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APT-1011<br>APT-1011 3 mg HS | Drug: APT-1011<br>* APT-1011 is an orally disintegrating tablet that includes fluticasone propionate as its active ingredient.<br>* Other names: fluticasone propionate;Procedure: Esophagogastroduodenoscopy<br>* Esophagogastroduodenoscopy (EGD) is a test that involves an endoscope, a lighted camera on the end of a tube, that is passed down a subject's throat to visualize their esophagus.<br>|
| Placebo Comparator: Placebo<br>HS | Drug: Placebo oral tablet<br>* Placebo orally disintegrating tablet.<br>* Other names: PBO;Procedure: Esophagogastroduodenoscopy<br>* Esophagogastroduodenoscopy (EGD) is a test that involves an endoscope, a lighted camera on the end of a tube, that is passed down a subject's throat to visualize their esophagus.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Week 12 histologic responder rates | To compare the Week 12 histologic responder rates (≤ 6 peak eosinophils [eos]/high power field [HPF]) for APT-1011 3 mg HS with that for placebo. HPF will be defined as a standard area of 235 square microns in a microscope with 40x lens (0.3 mm^2) and 22 mm ocular | Week 12 | 
| Mean change in number of dysphagia episodes | To compare the mean change in number of dysphagia episodes from baseline to Week 12 for APT-1011 3 mg HS with that for placebo | Week 0 to Week 12 | 
| Histologic responder rates at the end of the Randomized Withdrawal Phase (RWS) | To compare the histologic responder rates (≤ 6 peak eos/HPF) for APT-1011 responders randomized to continuing APT-1011 3 mg HS (maintenance) with responders randomized to placebo (withdrawal of APT-1011 3 mg HS) at the end of the RWS | Week 12 to Week 52 | 
| Percentage subjects with complete symptomatic response at the end of the RWS | Percentage of subjects with complete symptomatic response (i.e., no dysphagia episodes for the 14 consecutive days prior to the end of the randomized withdrawal phase) at the end of the randomized withdrawal phase, in the RWS APT-1011 3 mg HS arm versus placebo arm | Week 0 to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in EREFs from Week 0 to Week 12 | To compare endoscopic appearance evaluated by the mean change from baseline to Week 12 in Eosinophilic Esophagitis Endoscopic Reference Score (EREFs) for APT-1011 3 mg HS with that for placebo. | Week 0 to Week 12 | 
| Percentage of subjects with <1 peak eos/HPF at Week 12 | To compare the percentage of subjects with <1 peak eos/HPF at Week 12 for APT-1011 3 mg HS with that for placebo. | Week 12 | 
| Mean change in PROSE Symptom Burden Score | To compare the mean change from baseline to Week 12 in the day-level symptom burden utilizing the Patient Reported Outcomes Symptoms of EoE (PROSE) for APT-1011 3 mg HS with that for placebo. | Week 0 to Week 12 | 
| Mean Change in PROSE Day-Level Difficulty Swallowing | To compare the mean change from baseline to Week 12 in day-level difficulty swallowing using the Patient Reported Outcomes Symptoms of EoE (PROSE) for APT-1011 3 mg HS with that for placebo. Each symptom is rated on a numeric rating scale (NRS) with values ranging from 0 (not at all) to 10 (as bad as I can imagine). | Week 0 to Week 12 | 
| Mean Histologic Change from Baseline to Week 12 | To compare mean histologic change from baseline to Week 12 for APT-1011 3 mg HS with that for placebo. | Week 0 to Week 12 | 
| Percentage of Subjects with <15 peak eos/HPF | To compare the percentage of subjects with <15 peak eos/HPF for APT-1011 3 mg HS with that for placebo. | Week 12 | 
| Mean Number of Dysphagia-free Days | To compare the mean number of dysphagia-free days from baseline to Week 12 for APT-1011 3 mg HS with that for placebo | Week 0 to Week 12 | 
| Mean Change in Dysphagia Episodes | To compare mean change in number of dysphagia episodes from baseline to the end of RWS for APT-1011 responders randomized to continue APT-1011 3 mg HS with responders randomized to placebo (withdrawal of APT-1011 3 mg HS) | Week 0 to Week 52 | 
| Mean Change in EREFs from Week 0 to Week 52 | To compare endoscopic appearance evaluated by the mean change from baseline to the end of RWS, in Eosinophilic Esophagitis Endoscopic Reference Score (EREFs) for APT-1011 responders randomized to continue APT-1011 3 mg HS with responders randomized to placebo (withdrawal of APT-1011 3 mg HS). The EREF score has a range from 0-9, with 9 being worst result. | Week 0 to Week 52 | 
| Mean Histologic Change | To compare the mean change from baseline to the end of the RWS in peak eosinophil counts for APT-1011 responders randomized to APT-1011 3 mg HS with those randomized to placebo in the RWS. | Week 0 to Week 52 | 
| Mean Change in PROSE Day-Level Symptom Burden | To compare the mean change in day-level symptom burden using the Patient Reported Outcomes Symptoms of EoE (PROSE) from baseline to the end of RWS, for APT-1011 responders randomized to continue APT-1011 3 mg HS with responders randomized to placebo (withdrawal of APT-1011 3 mg HS). Day-level symptom burden has values ranging from 0 (no symptoms) to 10 (symptoms are as bad as I can imagine). | Week 0 to Week 52 | 
| Mean Change in PROSE Day-Level Difficulty Swallowing | To compare the mean change in day-level difficulty swallowing using the Patient Reported Outcomes Symptoms of EoE (PROSE) from baseline to the end of randomized withdrawal phase, for APT-1011 responders randomized to continue APT-1011 3 mg HS with responders randomized to placebo (withdrawal of APT-1011 3 mg HS). Each symptom is rated on a numeric rating scale (NRS) with values ranging from 0 (not at all) to 10 (as bad as I can imagine). | Week 0 to Week 52 | 
| Mean Change in Dysphagia-Free Days | To compare the mean number of dysphagia-free days from baseline to the end of RWS, for APT-1011 responders randomized to continue APT-1011 3 mg HS with responders randomized to placebo (withdrawal of APT-1011 3 mg HS) | Week 0 to Week 52 | 
| Mean Change in Number of Dysphagia Episodes | To compare mean change in number of dysphagia episodes from baseline at or prior to Week 52 (based on timing of > 6 peak eos/HPF) for APT-1011 responders randomized to continue APT-1011 3 mg HS with those randomized to placebo (withdrawal of APT-1011 3 mg HS) | Week 0 to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematologic Diseases, Hypersensitivity, Immediate, Hypersensitivity, Immune System Diseases, APT-1011, Esophagitis, Eosinophilic Esophagitis, Esophageal Diseases, Gastrointestinal Diseases, Digestive System Diseases, Gastroenteritis, Eosinophilia, Leukocyte Disorders, Fluticasone, Anti-Inflammatory Agents, Bronchodilator Agents, Autonomic Agents, Peripheral Nervous System Agents, Anti-Asthmatic Agents, Respiratory System Agents, Anti-Allergic Agents