Clinical trial NCT04281108: Efficacy and Safety APT-1011 in Adult Subjects With Eosinophilic Esophagitis (EoE) (FLUTE-2)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Eosinophilic Esophagitis
Keywords: 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
Lead sponsor: Ellodi Pharmaceuticals, LP
Sponsor class: INDUSTRY
First posted: 2020-02-24
Enrollment: 143
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Male or female ≥18 years of age at the time of informed consent or assent
2. 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
3. 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.

   1. Esophagogastroduodenoscopies and biopsies are to be obtained during the Screening period
   2. Biopsies will be read by a central pathologist
   3. Esophagogastroduodenoscopies and biopsies performed outside the study will not be accepted to meet eligibility criteria
   4. 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
4. Have a subject-reported history of ≥6 episodes of dysphagia in the 14 days prior to baseline
5. Completion of the daily diary on at least 11 out of the 14 days during the 2-week Baseline Symptom Assessment

Exclusion Criteria:

1. Have known contraindication, hypersensitivity, or intolerance to corticosteroids
2. 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
3. Have history of an esophageal stricture requiring dilatation within the 12 weeks prior to Screening
4. 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
5. History or presence of oral or esophageal mucosal infection whilst using inhaled or nasal corticosteroids
6. Have any mouth or dental condition that prevents normal eating (excluding braces)
7. 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)
8. Use of systemic (oral or parenteral) corticosteroids within 60 days before Screening, use of swallowed corticosteroids within 30 days before Screening
9. Initiation of either inhaled or nasal corticosteroids or high-potency dermal topical corticosteroids within 30 days before Screening
10. Use of calcineurin inhibitors or purine analogues (azathioprine, 6-mercaptopurine) in the 12 weeks before Screening
11. Use of potent cytochrome P450 (CYP) 3A4 inhibitors (eg, ritonavir and ketoconazole) in the 12 weeks before Screening
12. Initiation of an elimination diet or elemental diet within 30 days before Screening (diet must remain stable after signing ICF)
13. 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)
14. 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)
15. 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
16. 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
17. Infection with hepatitis B, hepatitis C, or human immunodeficiency virus
18. Have gastrointestinal bleeding or documented active peptic ulcer within 4 weeks prior to Screening or entering a new study period
19. 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
20. Immunosuppression or immunodeficiency disorder
21. Have a history or presence of Crohn's disease, celiac disease, or other inflammatory disease of the gastrointestinal tract, including eosinophilic gastroenteritis
22. Have current drug abuse in the opinion of the Investigator.
23. Have current alcohol abuse in the opinion of the Investigator.
24. Female subjects who are pregnant, breastfeeding, or planning to become pregnant during the study
25. Sexually active females of childbearing potential who do not agree to follow highly effective contraceptive methods through the End of Study visit
26. 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
27. Have participated in a prior study with investigational product APT-1011

Primary outcomes:
measure: Week 12 histologic responder rates
timeFrame: Week 12
measure: Mean change in number of dysphagia episodes
timeFrame: Week 0 to Week 12
measure: Histologic responder rates at the end of the Randomized Withdrawal Phase (RWS)
timeFrame: Week 12 to Week 52
measure: Percentage subjects with complete symptomatic response at the end of the RWS
timeFrame: Week 0 to Week 52
Secondary outcomes:
measure: Change in EREFs from Week 0 to Week 12
timeFrame: Week 0 to Week 12
measure: Percentage of subjects with <1 peak eos/HPF at Week 12
timeFrame: Week 12
measure: Mean change in PROSE Symptom Burden Score
timeFrame: Week 0 to Week 12
measure: Mean Change in PROSE Day-Level Difficulty Swallowing
timeFrame: Week 0 to Week 12
measure: Mean Histologic Change from Baseline to Week 12
timeFrame: Week 0 to Week 12
measure: Percentage of Subjects with <15 peak eos/HPF
timeFrame: Week 12
measure: Mean Number of Dysphagia-free Days
timeFrame: Week 0 to Week 12
measure: Mean Change in Dysphagia Episodes
timeFrame: Week 0 to Week 52
measure: Mean Change in EREFs from Week 0 to Week 52
timeFrame: Week 0 to Week 52
measure: Mean Histologic Change
timeFrame: Week 0 to Week 52
measure: Mean Change in PROSE Day-Level Symptom Burden
timeFrame: Week 0 to Week 52
measure: Mean Change in PROSE Day-Level Difficulty Swallowing
timeFrame: Week 0 to Week 52
measure: Mean Change in Dysphagia-Free Days
timeFrame: Week 0 to Week 52
measure: Mean Change in Number of Dysphagia Episodes
timeFrame: Week 0 to Week 52
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Pinnacle Research Group, LLC
state: Alabama
city: Dothan
country: United States
facility: Gut P.C., dba; Digestive Health Specialists of the Southeast
state: Alabama
city: Mobile
country: United States
facility: East View Medical Research, LLC
state: Alabama
city: Tucson
country: United States
facility: Del Sol Research Management, LLC
state: Arizona
city: Little Rock
country: United States
facility: Preferred Research Partners Inc.
state: Arkansas
city: North Little Rock
country: United States
facility: Arkansas Gastroenterology
state: Arkansas
city: Camarillo
country: United States
facility: Camarillo Endoscopy Center
state: California
city: Canoga Park
country: United States
facility: Hope Clinical Research
state: California
city: Mission Hills
country: United States
facility: Facey Medical Foundation
state: California
city: Murrieta
country: United States
facility: United Medical Doctors
state: California
city: San Diego
country: United States
facility: Medical Associates Research Group
state: California
city: Colorado Springs
country: United States
facility: Asthma and Allergy Associates, PC
state: Colorado
city: Colorado Springs
country: United States
facility: Peak Gastroenterology Associates
state: Colorado
city: Wheat Ridge
country: United States
facility: Western States Clinical Research Inc.
state: Colorado
city: Danbury
country: United States
facility: Western Connecticut Medical Group - Gastroenterology
state: Connecticut
city: Hamden
country: United States
facility: Medical Research Center of Connecticut, LLC
state: Connecticut
city: Fleming Island
country: United States
facility: Fleming Island Center for Clinical Research
state: Florida
city: Inverness
country: United States
facility: Nature Coast Clinical Research
state: Florida
city: Jacksonville
country: United States
facility: Encore Borland Groover Clinical Research
state: Florida
city: Orlando
country: United States
facility: Endoscopic Research, Inc.
state: Florida
city: Pembroke Pines
country: United States
facility: DBC Research USA
state: Florida
city: Athens
country: United States
facility: Summit Clinical Research
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Chevy Chase
country: United States
facility: MGG Group Co., Inc., Chevy Chase Clinical Research
state: Maryland
city: Columbia
country: United States
facility: Gastro Center of Maryland
state: Maryland
city: Ann Arbor
country: United States
facility: Michigan Medicine, University of Michigan
state: Michigan
city: Chesterfield
country: United States
facility: Clinical Research Institute of Michigan LLC
state: Michigan
city: Novi
country: United States
facility: Henry Ford Health System
state: Michigan
city: Wyoming
country: United States
facility: West Michigan Clinical Research Center
state: Michigan
city: Plymouth
country: United States
facility: Minnesota Gastroenterology, P.A.
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Chesterfield
country: United States
facility: Clinical Research Professionals
state: Missouri
city: Bozeman
country: United States
facility: Bozeman Health GI Clinic
state: Montana
city: Great Neck
country: United States
facility: Long Island Gastrointestinal Research Group LLP
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Health Systems (UNC Hospital)
state: North Carolina
city: Greenville
country: United States
facility: Carolina Research
state: North Carolina
city: Cincinnati
country: United States
facility: Consultants for Clinical Research
state: Ohio
city: Cincinnati
country: United States
facility: Bernstein Clinical Research Center, LLC
state: Ohio
city: Mentor
country: United States
facility: Great Lakes Gastroenterology Research, LLC
state: Ohio
city: Westlake
country: United States
facility: Northshore Gastroenterology Research, LLC
state: Ohio
city: Tulsa
country: United States
facility: Vital Prospects Clinical Research Institute, P.C.
state: Oklahoma
city: Philadelphia
country: United States
facility: Perelman Center for Advanced Medicine
state: Pennsylvania
city: Wyomissing
country: United States
facility: Digestive Disease Associates LTD
state: Pennsylvania
city: Rapid City
country: United States
facility: Rapid City Medical Center LLP
state: South Dakota
city: Garland
country: United States
facility: DHAT Research Institute
state: Texas
city: Ogden
country: United States
facility: Advanced Research Institute
state: Utah
city: Fairfax
country: United States
facility: Verity Research, Inc.
state: Virginia
city: Lynchburg
country: United States
facility: Blue Ridge Medical Research
state: Virginia
city: Darlinghurst
country: Australia
facility: St. Vincent's Hospital Sydney
state: New South Wales
city: Kogarah
country: Australia
facility: Swallow Clinic, St George Hospital
state: New South Wales
city: New Lambton
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Elizabeth Vale
country: Australia
facility: Lyell McEwin Hospital
state: South Australia
city: Fitzroy
country: Australia
facility: St. Vincent's Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Tomelloso
country: Spain
facility: Hosital General de Tomelloso
state: Ciudad Real
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal (Madrid)
Study officials:
affiliation: UNC Center for Eosphageal Diseases and Swallowing
name: Evan Dellon, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: