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

• Sponsor: Adare Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Adare Pharmaceuticals, Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Eosinophilic Esophagitis	Drug: APT-1011; Drug: Placebo	Phase 2

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, 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double Blind
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: June 30, 2017
• Estimated Primary Completion Date: January 30, 2019
• Estimated Study Completion Date: August 30, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: APT-1011 1.5 mg HS; Placebo after breakfast, APT-1011 1.5 mg HS	Drug: APT-1011; APT-1011 is an orally disintegrating tablet formulation of fluticasone propionate; Other Name: Fluticasone propionate ODT; Drug: Placebo; Placebo tablets are identical in composition to APT-1011 except they exclude the active ingredient.; Other Name: Matching placebo dose
Experimental: APT-1011 1.5 mg BID; APT-1011 1.5 mg after breakfast, APT-1011 1.5 mg HS	Drug: APT-1011; APT-1011 is an orally disintegrating tablet formulation of fluticasone propionate; Other Name: Fluticasone propionate ODT
Experimental: APT-1011 3 mg HS; Placebo after breakfast, APT-1011 3 mg HS	Drug: APT-1011; APT-1011 is an orally disintegrating tablet formulation of fluticasone propionate; Other Name: Fluticasone propionate ODT; Drug: Placebo; Placebo tablets are identical in composition to APT-1011 except they exclude the active ingredient.; Other Name: Matching placebo dose
Experimental: APT-1011 3 mg BID; APT-1011 3 mg after breakfast, APT-1011 3 mg HS	Drug: APT-1011; APT-1011 is an orally disintegrating tablet formulation of fluticasone propionate; Other Name: Fluticasone propionate ODT
Placebo Comparator: Placebo BID; Placebo 30 minutes after breakfast and HS	Drug: Placebo; Placebo tablets are identical in composition to APT-1011 except they exclude the active ingredient.; Other Name: Matching placebo dose

Outcome Measures

Primary Outcome Measures :

1. Histological response [ Time Frame: Week 12 ]
   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).

Secondary Outcome Measures :

1. EoE sustained response [ Time Frame: Week 12, Week 26, and Week 52 ]
   Percentage of subjects who met the primary endpoint (histology) at Week 12 and maintained the primary endpoint at Week 26 and Week 52
2. Change from baseline EREFs at Week 12, 26, and 52 [ Time Frame: Week 12, Week 26, and Week 52 ]
   Endoscopic changes will be assessed as per the EREFs evaluation based on the following endoscopic features: edema, rings, exudates, furrows, stricture, and several miscellaneous features (crepe paper esophagus, narrow caliber esophagus, and esophageal erosions).
3. EoE histologic response [ Time Frame: Week 12, Week 26, and Week 52 ]
   Percentage of subjects with a peak eosinophils/HPF <1 and <15 at Week 12, 26 and 52.
4. Change from baseline Global EoE Symptom Score [ Time Frame: Week 52 ]
   Compared score prior to randomization to scores for 7-day recall at Week 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52 visits
5. Dysphagia [ Time Frame: Week 12, Week 26 and Week 52 ]
   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

Other Outcome Measures:

1. HPA axis suppression [ Time Frame: baseline to Week 52 ]
   Number of subjects discontinuing due to HPA axis suppression
2. Candidiasis [ Time Frame: baseline to Week 52 ]
   Frequency of oral and esophageal candidiasis
3. Oral clearance [ Time Frame: Week 12 ]
   Oral clearance (CL/F)
4. Volume of distribution [ Time Frame: Week 12 ]
   Volume of distribution (V/F)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

  Show 75 Study Locations

Sponsors and Collaborators

Adare Pharmaceuticals, Inc.

Investigators

• Study Director: Peter C Richardson; Adare Pharmaceuticals, Inc.

More Information

• Responsible Party: Adare Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03191864 History of Changes
• Other Study ID Numbers: SP-1011-002; 2016-004749-10 ( EudraCT Number )
• First Posted: June 19, 2017
• Last Update Posted: December 13, 2018
• Last Verified: December 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Adare Pharmaceuticals, Inc.:

Esophagitis; Eosinophilic Esophagitis; Fluticasone; Dysphagia; Safety; Efficacy; Pharmacokinetics; Esophageal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Glucocorticoids; Orally Disintegrating Tablet

Additional relevant MeSH terms:

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; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents; Dermatologic Agents; Anti-Allergic Agents