Efficacy and Safety APT-1011 in Adolescent Subjects With Eosinophilic Esophagitis (EoE) - A Sub-Study of the FLUTE-2 Trial

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled study of APT-1011, followed by an open-label extension (OLE) in adolescents (≥12 to <18 years) with EoE.

Detailed Description
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This is a randomized, double-blind, placebo-controlled study of APT-1011, followed by an open-label extension (OLE) in adolescents (≥12 to <18 years) with EoE that 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 12, subjects may move into the open-label single arm study of APT-1011 3 mg hora somni (HS; at bedtime). All subjects who do not move into the open-label study will return at Week 14 for a 2-week off-treatment follow-up.

Official Title
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An Adolescent Sub-study Within FLUTE-2: A Randomized, Double-blind, Placebo-Controlled Study of APT-1011 (Fluticasone Propionate Oral Dispersible Tablet Formulation), With an Open-label Extension, in Adolescent Subjects With Eosinophilic Esophagitis

Conditions
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Eosinophilic Esophagitis

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥12 and <18 years of age Each subject and their parents or legal guardian, must read, understand and provide consent or assent 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 from 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, 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 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 at screening Have history of an esophageal stricture requiring dilatation within the 12 weeks prior to Screening Bone mineral density >2 SD below height-adjusted for age 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 or may increase risk of corticosteroid toxicity (e.g., abnormal bone mineral density) History of recurrent (persistent) 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 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 CYP 3A4 inhibitors (e.g., 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 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 (environmental allergen desensitization injection or oral therapy (excluding food allergen desensitization) 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, 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 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 Current malignancy or malignancy within 3 years of Screening. Subjects in remission for at least 3 years post-treatment may be enrolled. Known severe bleeding 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: 12 Years
Maximum Age: 17 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<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;|
| Placebo Comparator: Placebo<br>HS | Drug: Placebo oral tablet<br>* Placebo orally disintegrating tablet<br>* Other names: PBO;|

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 / high power field [eos/HPF]) for APT-1011 3 mg hora somni (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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean 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. The EREF score has a range from 0-9, with 9 being worst result. | 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 using 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 PROSE for APT-1011 3 mg HS with that for placebo | Week 0 to Week 12 | 
| 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 at Week 12 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 | 

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