Efficacy, Safety, and Pharmacokinetics of APT-1011 in Subjects With Eosinophilic Esophagitis (EoE)

Eosinophilic Esophagitis Clinical Trial

— FLUTE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03191864
• Other study ID #: SP-1011-002
• Secondary ID: 2016-004749-10
• Status: Completed
• Phase: Phase 2
• Start date: June 22, 2017
• Est. completion date: October 23, 2019

Study information

• Verified date: April 2023
• Source: Adare Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 106
• Est. completion date: October 23, 2019
• Est. primary completion date: January 3, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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).

Related Conditions & MeSH terms

• Eosinophilic Esophagitis
• Esophagitis

Intervention

Drug:
• APT-1011
APT-1011 is an orally disintegrating tablet formulation of fluticasone propionate
• Placebo
Placebo tablets are identical in composition to APT-1011 except they exclude the active ingredient.

Locations

Country	Name	City	State
Belgium	AZ Sint-Lucas	Brugge
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	AZ Groeninge - Kennedylaan	Kortrijk
Belgium	UZ Leuven	Leuven
Canada	Viable Clinical Research	Bridgewater	Nova Scotia
Canada	Viable Clinical Research	Lindsay	Ontario
Canada	London Health Science Centre	London	Ontario
Canada	Taunton Surgical Centre	Oshawa	Ontario
Canada	(G.I.R.I.) GI Research Institute	Vancouver	British Columbia
Germany	Staedisches Klinikum Brandenburg	Brandenburg an der Havel	Brandenburg
Germany	Universitaetsklinikum Schleswig-Holstein	Kiel	Schleswig Holstein
Germany	Universitaetsklinikum Leipzig AoeR	Leipzig	Sachsen
Germany	Klinikum rechts der Isar der TU Muenchen	Muenchen	Bayern
Germany	Praxis am Germania	Muenster	Nordrhein Westfalen
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario de La Princesa	Madrid
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital General de Tomelloso	Tomelloso	Ciudad Real
Spain	Hospital Clinico Universitario de Valencia	Valencia
Spain	Hospital Clinico Universitario Lozano Blesa	Zaragoza
Spain	Hospital Universitario Miguel Servet	Zaragoza
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne
United States	Avant Research Associates, LLC - Austin	Austin	Texas
United States	Avant Research Associates, LLC	Beaumont	Texas
United States	Hope Clinical Research	Canoga Park	California
United States	Del Sol Research Management, LLC	Chandler	Arizona
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Northwestern Medical Faculty Foundation	Chicago	Illinois
United States	Bernstein Clinical Research Center, LLC	Cincinnati	Ohio
United States	Aventiv Research Inc.	Columbus	Ohio
United States	Western Connecticut Health Network	Danbury	Connecticut
United States	TriWest Research Associates, LLC	El Cajon	California
United States	MediSphere Medical Research Center, an AMR affiliate	Evansville	Indiana
United States	Verity Research Inc	Fairfax	Virginia
United States	SC Clinical Research, Inc.	Garden Grove	California
United States	Long Island Gastrointestinal Research Group, LLP	Great Neck	New York
United States	Medical Research Center of Connecticut, LLC	Hamden	Connecticut
United States	Gastroenterology Associates	Hazard	Kentucky
United States	Eastern Research, Inc.	Hialeah	Florida
United States	Nature Coast Clinical Research, LLC	Inverness	Florida
United States	Sunrise Medical Research	Lauderdale Lakes	Florida
United States	Beverly Hills Center for Digestive Health	Los Angeles	California
United States	Allergy and Asthma Center of South Oregon	Medford	Oregon
United States	Research Institute of the Carolinas, PLC	Mooresville	North Carolina
United States	Weill Cornell Medical College	New York	New York
United States	Henry Ford Medical Center	Novi	Michigan
United States	Southwest Gastroenterology	Oak Lawn	Illinois
United States	Advanced Research Institute	Ogden	Utah
United States	Unity Clinical Research	Oklahoma City	Oklahoma
United States	Focilmed	Oxnard	California
United States	DBC Research, Corp	Pembroke Pines	Florida
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Carolina's GI Research, LLC	Raleigh	North Carolina
United States	Wake Research Associates, LLC	Raleigh	North Carolina
United States	Rapid City Medical Center, LLP	Rapid City	South Dakota
United States	DHAT Research Institute	Richardson	Texas
United States	Rockford Gastroenterology Associates, Ltd.	Rockford	Illinois
United States	St. Louis Center for Clinical Research	Saint Louis	Missouri
United States	PMG Research of Salisbury, LLC	Salisbury	North Carolina
United States	Care Access Research LLC	Salt Lake City	Utah
United States	University of Utah	Salt Lake City	Utah
United States	Medical Associates Research Group, Inc.	San Diego	California
United States	Precision Research Institute, LLC	San Diego	California
United States	Care Access Research LLC	San Pablo	California
United States	Arkansas Gastroenterology, P.A.	Sherwood	Arkansas
United States	Stanford University School of Medicine	Stanford	California
United States	Cotton-O'Neil Clinical Research Center, Digestive Health	Topeka	Kansas
United States	Del Sol Research Management, LLC	Tucson	Arizona
United States	Advanced Gastroenterology	Union City	Tennessee
United States	Clinical Trials of America, Inc.	West Monroe	Louisiana
United States	Metro Health	Wyoming	Michigan
United States	Digestive Disease Associates, Ltd.	Wyomissing	Pennsylvania
United States	St. Jude Healthcare	Yorba Linda	California

Sponsors (1)

Lead Sponsor	Collaborator
Adare Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Germany,  Spain,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Subjects Discontinuing Due to HPA Axis Suppression	Number of subjects discontinuing due to HPA axis suppression.; Note: There were no patients in the placebo group after Week 14.	baseline to Week 52
Other	Number of Subjects With Oral and Esophageal Candidiasis	Frequency of oral and esophageal candidiasis.; Note: There were no patients in the placebo group after Week 14.	baseline to Week 52
Other	Number of Subjects With Treatment-Emergent Adverse Events Leading to Study Discontinuation in Part 1	Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Study Discontinuation in Part 1.	baseline to Week 12
Other	Number of Subjects With Treatment-Emergent Adverse Events Leading to Study Discontinuation in Part 2	Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Study Discontinuation in Part 2.	Week 12 to 52
Other	Percentage of Subjects With Serum Cortisol Level =5 µg/dL or Abnormal Adrenocorticotropic Hormone (ACTH) Stimulation Test	Percentage of subjects with serum cortisol level =5 µg/dL (=138 nmol/L) or abnormal adrenocorticotropic hormone (ACTH) stimulation test (serum cortisol <16 µg/dL [=440 nmol/L] at 60 minutes).; Population used are those who entered Part 2 - Maintenance. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint.	Week 12 to 52
Primary	Percentage of Subjects With =6 Peak Eosinophils/High-power Field (HPF)	Histology (eosinophils per high power field [HPF]): percentage of subjects with =6 PEAK eosinophils/HPF after assessing at least 5-6 biopsies from the proximal and distal esophagus (~3 each) where the HPF area is 235 square microns (40 magnification lens with a 22 mm ocular).	Week 12
Secondary	Percentage of Subjects Who Met the Primary Endpoint at Week 12 and Maintained the Primary Endpoint at Weeks 26 and 52	Percentage of subjects who entered Part 2 - Maintenance and met the primary endpoint (histology) at Week 12 and maintained the primary endpoint at Week 26 and Week 52.; Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect percentage of subjects who met the primary endpoint following 12 or 38 weeks of treatment.	Week 26, and Week 52
Secondary	Change From Baseline Eosinophilic Esophagitis Endoscopic Reference Score (EREFs) at Week 12, 26, and 52	Endoscopic changes will be assessed as per the EREFs evaluation based on the following endoscopic features: edema [Grade {Gr} 0 (absent) or Gr 1 (present)], strictures [Gr 0 (absent) or Gr 1 (present)], rings [Gr 0 (none), Gr 1 (mild), Gr 2 (moderate), Gr 3 (severe)], exudates [Gr 0 (none), Gr 1 (mild), Gr (severe)], furrows [Gr 0 (none), Gr 1 (mild), Gr 2 (severe)], crepe paper esophagus [Gr 0 (absent) or Gr 1 (present)], narrow caliber esophagus [Gr 0 (absent) or Gr 1 (present)], and esophageal erosions [Normal (0), Gr A (1), Gr B (2), Gr C (3), or Gr D (4)].; EREFs: 0 (best) to 15 (worst) based on the sum of the subscores listed above.; Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3 mg BID and results reflect EREF evaluation following 12 or 38 weeks of treatment.	Week 12, Week 26, and Week 52
Secondary	Percentage of Subjects With a Peak Eosinophils/HPF Number <1 and <15	Percentage of subjects with a peak eosinophils/HPF <1 and <15 at Week 12, 26 and 52.; Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect peak eosinophils/HPF following 12 or 38 weeks of treatment.	Week 12, Week 26, and Week 52
Secondary	Change From Baseline Global EoE Symptom Score	Change from baseline global EOE symptom score assessed prior to randomization to scores for 7-day recall at Week 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52 visits.; Global Eosinophilic Esophagitis Symptom Score: On a scale from 0 (no symptoms) to 10 (most severe symptoms), how severe were your EoE symptoms over the past 7 days? Patients were asked to think of all their symptoms due to EoE and make an overall statement by selecting a number.; Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline global EOE symptom score following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment.	Week 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52
Secondary	Change in the Number of Dysphagia Episodes	Change in the number of dysphagia episodes at baseline (14-day period prior to randomization) compared with the 14-day period prior to the time point of interest.; Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect the change in the number of dysphagia episodes following 12 or 38 weeks of treatment.	Week 12, Week 26 and Week 52
Secondary	Change From Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Total Score	Change from Baseline 7-Day EEsAI total score assessed prior to randomization and those assessed at Weeks 12, 26 and 52 (Total score 100).; Eosinophilic Esophagitis Activity Index Total Score: 0 (best) to 100 (worst) based on the sum of the categorized subscores for frequency of trouble swallowing [never (0), 1-3x (15) or 4-6x (27) per week]; duration of trouble swallowing [=5 min (0), >5 min (6)]; pain when swallowing [no (0), yes (15)]; Visual Dysphagia Question score [0 (best),12,19, 21, or 23 (worst)]; avoidance modification and slow eating score [0 (best), 9, or 25 (worst)].; A higher score means a worse outcome.; Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect the change from baseline 7-day EEs	Weeks 12, 26 and 52
Secondary	Change From Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Subscores	The Avoidance, Modification and Slow Eating (AMS) Score and Visual Dysphagia Question (VDQ) Score are components of the EEsAI.; AMS: Answers to three items determining the pattern of behavioral adaptation were scored for each food consistency consumed by the subject (avoidance, modification, and eating slowly). The AMS score ranges from 0 (best) to 25 (worst).; VDG: The degree of perceived difficulty when eating 8 different food consistencies was assessed. The VDQ score ranges from 0 (best) to 23 (worst).; A higher score for either subscore means a worse outcome. Negative change from baseline represents a worsening in quality of life for the total score or subscore.; Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline.	Weeks 12, 26 and 52
Secondary	Percentage of Subjects With Mean 7-day EEsAI Total Score <20	Percentage of subjects with mean 7-day EEsAI total score <20 to those assessed at Weeks 12, 26 and 52.; Eosinophilic Esophagitis Activity Index Total Score: 0 (best) to 100 (worst) based on the sum of the categorized subscores for frequency of trouble swallowing [never (0), 1-3x (15) or 4-6x (27) per week]; duration of trouble swallowing [<= 5 min (0), >5 min (6)]; pain when swallowing [no (0), yes (15)]; Visual Dysphagia Question score [0 (best),12,19,21, or 23 (worst)]; avoidance modification and slow eating score [0 (best), 9, or 25 (worst)].; Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline global EOE symptom score following 12 or 38 weeks of treatment	Weeks 12, 26, and 52
Secondary	Change From Baseline Patient Global Impression of Severity (PGIS) for EoE Symptoms as Assessed Prior to Randomization Post-Baseline Visit	Change From Baseline PGIS for EoE Symptoms as Assessed Prior to Randomization at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52.; Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline global EOE symptoms following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment.	Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52
Secondary	Change From Baseline PGIS for Difficulty With Food or Pills Going Down as Assessed Prior to Randomization Post-Baseline Visit	Change From Baseline PGIS for Difficulty with Food or Pills Going Down as Assessed Prior to Randomization at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52.; Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline PGIS for difficulty with food or pills going down following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment.	Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52
Secondary	Change From Baseline Patient Global Impression of Change (PGIC) for EoE Symptoms as Assessed Prior to Randomization Post-Baseline Visit	Change From Baseline PGIC for EoE Symptoms as Assessed Prior to Randomization at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52.; Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline PGIC for EoE symptoms following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment.	Weeks 4, 8, 12, 14, 18, 22, 26, 36, 44, and 52
Secondary	Change From Baseline PGIC of Difficulty With Food or Pills as Assessed Prior to Randomization Post-Baseline Visit	Change From Baseline PGIC of Difficulty with Food or Pills as Assessed Prior to Randomization at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52.; Population used are those who entered Part 1 - Induction. The number of participants analyzed for each timepoint reflect the actual number of participants with data at that timepoint. Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline PGIC of difficulty with food or pills following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment.	Weeks 4, 8, 12, 14, 18, 22, 26, 36, 44, and 52
Secondary	Percentage of Histologic Non-responders by Dose at Weeks 12, 26, and 52	Percentage of histologic non-responders by dose at Weeks 12, 26, and 52.; Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect non-response following 12 or 38 weeks of treatment.	Weeks 12, 26 and 52
Secondary	Percentage of Subjects Requiring Emergency Endoscopic Food Dis-impaction	Percentage of subjects requiring emergency endoscopic food dis-impaction by dose before Week 14, between Week 14 and Week 28, and between Week 28 and Week 52.; Note: There were no patients in the placebo group after Week 14.	before Week 14, between Week 14 and Week 28, between Week 28 and Week 52
Secondary	Percentage of Subjects Requiring Esophageal Dilation	Percentage of subjects requiring esophageal dilation by dosing group and part of the study.; Note: There were no patients in the placebo group after Week 14.	baseline to Week 52