Clinical trial NCT03191864: Efficacy, Safety, and Pharmacokinetics of APT-1011 in Subjects With Eosinophilic Esophagitis (EoE)
Official title: FLUTicasone in Eosinophilic Esophagitis (FLUTE): A Randomized, Double-blind, Placebo-controlled, Dose-ranging, and Maintenance Study of APT-1011 in Subjects With Eosinophilic Esophagitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Eosinophilic Esophagitis
Keywords: Esophagitis
Eosinophilic Esophagitis
Fluticasone
Dysphagia
Safety
Efficacy
Pharmacokinetics
Esophageal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Glucocorticoids
Orally Disintegrating Tablet
Lead sponsor: Adare Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2017-06-19
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Percentage of Subjects With ≤6 Peak Eosinophils/High-power Field (HPF)
timeFrame: Week 12
Secondary outcomes:
measure: Percentage of Subjects Who Met the Primary Endpoint at Week 12 and Maintained the Primary Endpoint at Weeks 26 and 52
timeFrame: Week 26, and Week 52
measure: Change From Baseline Eosinophilic Esophagitis Endoscopic Reference Score (EREFs) at Week 12, 26, and 52
timeFrame: Week 12, Week 26, and Week 52
measure: Percentage of Subjects With a Peak Eosinophils/HPF Number <1 and <15
timeFrame: Week 12, Week 26, and Week 52
measure: Change From Baseline Global EoE Symptom Score
timeFrame: Week 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52
measure: Change in the Number of Dysphagia Episodes
timeFrame: Week 12, Week 26 and Week 52
measure: Change From Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Total Score
timeFrame: Weeks 12, 26 and 52
measure: Change From Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Subscores
timeFrame: Weeks 12, 26 and 52
measure: Percentage of Subjects With Mean 7-day EEsAI Total Score <20
timeFrame: Weeks 12, 26, and 52
measure: Change From Baseline Patient Global Impression of Severity (PGIS) for EoE Symptoms as Assessed Prior to Randomization Post-Baseline Visit
timeFrame: Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52
measure: Change From Baseline PGIS for Difficulty With Food or Pills Going Down as Assessed Prior to Randomization Post-Baseline Visit
timeFrame: Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52
measure: Change From Baseline Patient Global Impression of Change (PGIC) for EoE Symptoms as Assessed Prior to Randomization Post-Baseline Visit
timeFrame: Weeks 4, 8, 12, 14, 18, 22, 26, 36, 44, and 52
measure: Change From Baseline PGIC of Difficulty With Food or Pills as Assessed Prior to Randomization Post-Baseline Visit
timeFrame: Weeks 4, 8, 12, 14, 18, 22, 26, 36, 44, and 52
measure: Percentage of Histologic Non-responders by Dose at Weeks 12, 26, and 52
timeFrame: Weeks 12, 26 and 52
measure: Percentage of Subjects Requiring Emergency Endoscopic Food Dis-impaction
timeFrame: before Week 14, between Week 14 and Week 28, between Week 28 and Week 52
measure: Percentage of Subjects Requiring Esophageal Dilation
timeFrame: baseline to Week 52
Other outcomes:
measure: Number of Subjects Discontinuing Due to HPA Axis Suppression
timeFrame: baseline to Week 52
measure: Number of Subjects With Oral and Esophageal Candidiasis
timeFrame: baseline to Week 52
measure: Number of Subjects With Treatment-Emergent Adverse Events Leading to Study Discontinuation in Part 1
timeFrame: baseline to Week 12
measure: Number of Subjects With Treatment-Emergent Adverse Events Leading to Study Discontinuation in Part 2
timeFrame: Week 12 to 52
measure: Percentage of Subjects With Serum Cortisol Level ≤5 μg/dL or Abnormal Adrenocorticotropic Hormone (ACTH) Stimulation Test
timeFrame: Week 12 to 52
Locations:
city: Chandler
country: United States
facility: Del Sol Research Management, LLC
state: Arizona
city: Tucson
country: United States
facility: Del Sol Research Management, LLC
state: Arizona
city: Sherwood
country: United States
facility: Arkansas Gastroenterology, P.A.
state: Arkansas
city: Canoga Park
country: United States
facility: Hope Clinical Research
state: California
city: El Cajon
country: United States
facility: TriWest Research Associates, LLC
state: California
city: Garden Grove
country: United States
facility: SC Clinical Research, Inc.
state: California
city: Los Angeles
country: United States
facility: Beverly Hills Center for Digestive Health
state: California
city: Oxnard
country: United States
facility: Focilmed
state: California
city: San Diego
country: United States
facility: Precision Research Institute, LLC
state: California
city: San Diego
country: United States
facility: Medical Associates Research Group, Inc.
state: California
city: San Pablo
country: United States
facility: Care Access Research LLC
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Yorba Linda
country: United States
facility: St. Jude Healthcare
state: California
city: Danbury
country: United States
facility: Western Connecticut Health Network
state: Connecticut
city: Hamden
country: United States
facility: Medical Research Center of Connecticut, LLC
state: Connecticut
city: Hialeah
country: United States
facility: Eastern Research, Inc.
state: Florida
city: Inverness
country: United States
facility: Nature Coast Clinical Research, LLC
state: Florida
city: Lauderdale Lakes
country: United States
facility: Sunrise Medical Research
state: Florida
city: Pembroke Pines
country: United States
facility: DBC Research, Corp
state: Florida
city: Chicago
country: United States
facility: Northwestern Medical Faculty Foundation
state: Illinois
city: Oak Lawn
country: United States
facility: Southwest Gastroenterology
state: Illinois
city: Rockford
country: United States
facility: Rockford Gastroenterology Associates, Ltd.
state: Illinois
city: Evansville
country: United States
facility: MediSphere Medical Research Center, an AMR affiliate
state: Indiana
city: Topeka
country: United States
facility: Cotton-O'Neil Clinical Research Center, Digestive Health
state: Kansas
city: Hazard
country: United States
facility: Gastroenterology Associates
state: Kentucky
city: West Monroe
country: United States
facility: Clinical Trials of America, Inc.
state: Louisiana
city: Novi
country: United States
facility: Henry Ford Medical Center
state: Michigan
city: Wyoming
country: United States
facility: Metro Health
state: Michigan
city: Saint Louis
country: United States
facility: St. Louis Center for Clinical Research
state: Missouri
city: Great Neck
country: United States
facility: Long Island Gastrointestinal Research Group, LLP
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Mooresville
country: United States
facility: Research Institute of the Carolinas, PLC
state: North Carolina
city: Raleigh
country: United States
facility: Carolina's GI Research, LLC
state: North Carolina
city: Raleigh
country: United States
facility: Wake Research Associates, LLC
state: North Carolina
city: Salisbury
country: United States
facility: PMG Research of Salisbury, LLC
state: North Carolina
city: Cincinnati
country: United States
facility: Bernstein Clinical Research Center, LLC
state: Ohio
city: Columbus
country: United States
facility: Aventiv Research Inc.
state: Ohio
city: Oklahoma City
country: United States
facility: Unity Clinical Research
state: Oklahoma
city: Medford
country: United States
facility: Allergy and Asthma Center of South Oregon
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
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: Union City
country: United States
facility: Advanced Gastroenterology
state: Tennessee
city: Austin
country: United States
facility: Avant Research Associates, LLC - Austin
state: Texas
city: Beaumont
country: United States
facility: Avant Research Associates, LLC
state: Texas
city: Richardson
country: United States
facility: DHAT Research Institute
state: Texas
city: Ogden
country: United States
facility: Advanced Research Institute
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Salt Lake City
country: United States
facility: Care Access Research LLC
state: Utah
city: Fairfax
country: United States
facility: Verity Research Inc
state: Virginia
city: Brugge
country: Belgium
facility: AZ Sint-Lucas
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Kortrijk
country: Belgium
facility: AZ Groeninge - Kennedylaan
city: Leuven
country: Belgium
facility: UZ Leuven
city: Vancouver
country: Canada
facility: (G.I.R.I.) GI Research Institute
state: British Columbia
city: Bridgewater
country: Canada
facility: Viable Clinical Research
state: Nova Scotia
city: Lindsay
country: Canada
facility: Viable Clinical Research
state: Ontario
city: London
country: Canada
facility: London Health Science Centre
state: Ontario
city: Oshawa
country: Canada
facility: Taunton Surgical Centre
state: Ontario
city: Muenchen
country: Germany
facility: Klinikum rechts der Isar der TU Muenchen
state: Bayern
city: Brandenburg an der Havel
country: Germany
facility: Staedisches Klinikum Brandenburg
state: Brandenburg
city: Muenster
country: Germany
facility: Praxis am Germania
state: Nordrhein Westfalen
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig AoeR
state: Sachsen
city: Kiel
country: Germany
facility: Universitaetsklinikum Schleswig-Holstein
state: Schleswig Holstein
city: Tomelloso
country: Spain
facility: Hospital General de Tomelloso
state: Ciudad Real
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Zaragoza
country: Spain
facility: Hospital Clinico Universitario Lozano Blesa
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
Study officials:
affiliation: Adare Pharmaceuticals, Inc.
name: Peter C Richardson
role: STUDY_DIRECTOR
References:
citation: Dellon ES, Lucendo AJ, Schlag C, Schoepfer AM, Falk GW, Eagle G, Nezamis J, Comer GM, Knoop K, Hirano I. Fluticasone Propionate Orally Disintegrating Tablet (APT-1011) for Eosinophilic Esophagitis: Randomized Controlled Trial. Clin Gastroenterol Hepatol. 2022 Nov;20(11):2485-2494.e15. doi: 10.1016/j.cgh.2022.02.013. Epub 2022 Feb 16.