24-Week Induction Study of APT-1011 in Adult Subjects With Eosinophilic Esophagitis (EoE) (FLUTE 3)

Study Overview
=================
Brief Summary
-----------------
This is a 24-week randomized, double-blind, placebo-controlled induction study of APT-1011 in adults (≥18 years old) with eosinophilic esophagitis (EoE) followed by a single-arm, open-label extension. This study will evaluate the efficacy and safety of APT-1011 3 mg administered HS (hora somni, at bedtime) for the induction of response to treatment (symptomatic and histologic) over 24 weeks. The open-label extension will continue to evaluate long-term safety in subjects who consent to continue on open-label treatment with APT-1011.

Detailed Description
-----------------
The efficacy and safety of APT-1011 3 mg administered at bedtime will be evaluated for the induction of response (histologic and symptomatic) after 24 weeks of treatment. After completing 24 weeks of double-blind study treatment, subjects may consent to participate in the open-label extension, otherwise they will complete study drug treatment and enter a 2-week off treatment safety follow-up. The duration of the double-blind portion of the study, screening through follow-up visit for subjects completing study drug at Week 24, will be up to 32 weeks long, i.e., 6-week screening period (the includes a 4-week run-in phase) followed by 24 weeks induction phase and 2 weeks off-treatment follow-up. For subjects consenting to participate in the open-label extension, the duration of the study will be determined by the Sponsor.

Official Title
-----------------
Fluticasone Propionate Oral Disintegrating Tablet Formulation in Eosinophilic Esophagitis: A Randomized, Double-blind, Placebo-Controlled 24-Week Induction Study of APT-1011, Followed by a Single-arm Open-label Extension, in Adult Subjects With Eosinophilic Esophagitis

Conditions
-----------------
Eosinophilic Esophagitis

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult male or female ≥18 years of age at the time of informed consent 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 in total from both proximal and distal esophageal mucosal areas (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, only where 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 to a maximum of 30 episodes of dysphagia in a 14-consecutive-day period within 18 days prior to baseline Completion of the evening eDiary on at least 11 out of the 14-consecutive-day observation period during the 4-week run-in period (Baseline Symptom Assessment).The minimum requirement of 11 days need not be consecutive. 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 (8-10 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 of recurrent or current oral or esophageal mucosal infection due to 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 30 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 (e.g., ritonavir and ketoconazole) in the 4 weeks before Screening Initiation of an elimination diet or elemental diet within 30 days before Screening (diet must remain stable after signing ICF) Abnormal 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 Use of biologic immunomodulators, including dupilumab for EoE, with dose last administered within 6 months before Screening (allergy desensitization injection or oral therapies 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, leukotriene inhibitors, or sodium cromolyn within 4 weeks before qualifying endoscopy during Screening. If already receiving these drugs, the dosage must remain constant throughout the study Subjects who have initiated PPIs within 8 weeks before qualifying endoscopy. If already receiving PPIs, the dosage regimen must remain constant throughout the study 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 Current malignancy or malignancy within 3 years of Screening, with the exception of skin cancers other than melanoma. Subjects in remission for at least 3 years post-treatment may be enrolled. Have a history or presence of Crohn's disease, celiac disease, or other inflammatory disease of the gastrointestinal tract, including non-EoE eosinophilic gastrointestinal disorders (EGIDs) 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
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel 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. Other Names: fluticasone propionate<br>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>Placebo HS | Drug: Placebo oral tablet<br>* Placebo orally disintegrating tablet. Other Names: PBO<br>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?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histological Remission (Co-Primary Outcome Measure) | To evaluate the percentage of subjects with histological remission (defined ≤ 6 peak eosinophils [eos]/high power field [HPF] on esophageal mucosal biopsies at Week 24). 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 24 | 
| Complete Symptomatic Response (Co-Primary Outcome Measure) | To evaluate the percentage of subjects with complete symptomatic response at Week 24 (defined as zero dysphagia episodes in the 14 consecutive days prior to Week 24) | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinicopathologic Responder Rate | To compare the percentage of clinicopathologic responders, defined as having complete symptomatic AND histological response at Week 24 (defined as zero dysphagia episodes in the 14 consecutive days prior to Week 24 AND ≤ 6 peak eos/HPF on esophageal mucosal biopsies) | Week 24 | 
| Percentage of Subjects with ≥70% Reduction in Dysphagia Frequency | To evaluate the percentage of subjects with ≥70% reduction in dysphagia frequency at Week 24 as compared to baseline (as measured over the 14 consecutive days prior to each visit) | Week 24 | 
| Mean Change in Dysphagia Frequency | To compare the mean change from baseline to Week 24 in dysphagia frequency (as measured over the 14 consecutive days prior to each visit) | Week 24 | 
| Mean Change in PROSE Difficulty Swallowing | To compare the mean change from baseline to Week 24 in difficulty swallowing using the Patient Reported Outcomes Symptoms of Eosinophilic Esophagitis (PROSE) | Week 24 | 
| Mean Change in PROSE Pain with Swallowing | To compare the mean change from baseline to Week 24 in pain with swallowing using the PROSE | Week 24 | 
| Mean Number of Dysphagia-Free Days | To compare the mean number of dysphagia-free days from baseline to Week 24 | Week 24 | 
| Percentage of Responders (Strictures and ≥Grade 2 rings) | To compare the percentage of responders, defined as no longer having strictures and/or ≥Grade 2 rings which were present at baseline, at Week 24 | Week 24 | 
| Percentage of Responders (Strictures) | To compare the percentage of responders, defined as no longer having strictures which were present at baseline, at Week 24 | Week 24 | 
| Percentage of Responders (≥Grade 2 rings) | To compare the percentage of responders, defined as no longer having ≥Grade 2 rings which were present at baseline, at Week 24 | Week 24 | 
| Mean Change in EREFs | To compare endoscopic appearance evaluated by the mean change from baseline to Week 24 in Eosinophilic Esophagitis Endoscopic Reference Score (EREFs) | Week 24 | 
| Time to First Complete Symptom Response | Time to first complete symptom response (defined as zero dysphagia episodes in a 14-consecutive-day period) | Week 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
APT-1011, Esophagitis, Eosinophilic Esophagitis, Esophageal Diseases, Gastrointestinal Diseases, Digestive System Diseases, Gastroenteritis, Eosinophilia, Leukocyte Disorders, Hematologic Diseases, Hypersensitivity, Immediate, Hypersensitivity, Immune System Diseases, Fluticasone, Anti-Inflammatory Agents, Bronchodilator Agents, Autonomic Agents, Peripheral Nervous System Agents, Anti-Asthmatic Agents, Respiratory System Agents, Anti-Allergic Agents, FLUTE 3, FLUTE III, Flute