Efficacy and Safety APT-1011 in Adult Subjects With Eosinophilic Esophagitis (EoE) (FLUTE-2)

Eosinophilic Esophagitis Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04281108
• Other study ID #: SP-1011-003
• Status: Completed
• Phase: Phase 3
• Start date: January 30, 2020
• Est. completion date: October 24, 2022

Study information

• Verified date: June 2023
• Source: Ellodi Pharmaceuticals, LP
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 143
• Est. completion date: October 24, 2022
• Est. primary completion date: May 5, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Eosinophilic Esophagitis
• Esophagitis

Intervention

Drug:
• APT-1011
APT-1011 is an orally disintegrating tablet that includes fluticasone propionate as its active ingredient.
• Placebo oral tablet
Placebo orally disintegrating tablet.

Procedure:
• Esophagogastroduodenoscopy
Esophagogastroduodenoscopy (EGD) is a test that involves an endoscope, a lighted camera on the end of a tube, that is passed down a subject's throat to visualize their esophagus.

Locations

Country	Name	City	State
Australia	St. Vincent's Hospital Sydney	Darlinghurst	New South Wales
Australia	Lyell McEwin Hospital	Elizabeth Vale	South Australia
Australia	St. Vincent's Hospital	Fitzroy	Victoria
Australia	Swallow Clinic, St George Hospital	Kogarah	New South Wales
Australia	Alfred Hospital	Melbourne	Victoria
Australia	John Hunter Hospital	New Lambton	New South Wales
Spain	Hospital Universitario Ramón y Cajal (Madrid)	Madrid
Spain	Hosital General de Tomelloso	Tomelloso	Ciudad Real
United States	Michigan Medicine, University of Michigan	Ann Arbor	Michigan
United States	Pinnacle Research Group, LLC	Anniston	Alabama
United States	Summit Clinical Research	Athens	Georgia
United States	Bozeman Health GI Clinic	Bozeman	Montana
United States	Camarillo Endoscopy Center	Camarillo	California
United States	Hope Clinical Research	Canoga Park	California
United States	University of North Carolina Health Systems (UNC Hospital)	Chapel Hill	North Carolina
United States	Clinical Research Institute of Michigan LLC	Chesterfield	Michigan
United States	Clinical Research Professionals	Chesterfield	Missouri
United States	MGG Group Co., Inc., Chevy Chase Clinical Research	Chevy Chase	Maryland
United States	Bernstein Clinical Research Center, LLC	Cincinnati	Ohio
United States	Consultants for Clinical Research	Cincinnati	Ohio
United States	Asthma and Allergy Associates, PC	Colorado Springs	Colorado
United States	Peak Gastroenterology Associates	Colorado Springs	Colorado
United States	Gastro Center of Maryland	Columbia	Maryland
United States	Western Connecticut Medical Group - Gastroenterology	Danbury	Connecticut
United States	Gut P.C., dba; Digestive Health Specialists of the Southeast	Dothan	Alabama
United States	Verity Research, Inc.	Fairfax	Virginia
United States	Fleming Island Center for Clinical Research	Fleming Island	Florida
United States	DHAT Research Institute	Garland	Texas
United States	Long Island Gastrointestinal Research Group LLP	Great Neck	New York
United States	Carolina Research	Greenville	North Carolina
United States	Medical Research Center of Connecticut, LLC	Hamden	Connecticut
United States	Nature Coast Clinical Research	Inverness	Florida
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Encore Borland Groover Clinical Research	Jacksonville	Florida
United States	Preferred Research Partners Inc.	Little Rock	Arkansas
United States	Blue Ridge Medical Research	Lynchburg	Virginia
United States	Great Lakes Gastroenterology Research, LLC	Mentor	Ohio
United States	Facey Medical Foundation	Mission Hills	California
United States	East View Medical Research, LLC	Mobile	Alabama
United States	United Medical Doctors	Murrieta	California
United States	Arkansas Gastroenterology	North Little Rock	Arkansas
United States	Henry Ford Health System	Novi	Michigan
United States	Advanced Research Institute	Ogden	Utah
United States	Endoscopic Research, Inc.	Orlando	Florida
United States	DBC Research USA	Pembroke Pines	Florida
United States	Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania
United States	Minnesota Gastroenterology, P.A.	Plymouth	Minnesota
United States	Rapid City Medical Center LLP	Rapid City	South Dakota
United States	Mayo Clinic	Rochester	Minnesota
United States	Medical Associates Research Group	San Diego	California
United States	Del Sol Research Management, LLC	Tucson	Arizona
United States	Vital Prospects Clinical Research Institute, P.C.	Tulsa	Oklahoma
United States	Northshore Gastroenterology Research, LLC	Westlake	Ohio
United States	Western States Clinical Research Inc.	Wheat Ridge	Colorado
United States	West Michigan Clinical Research Center	Wyoming	Michigan
United States	Digestive Disease Associates LTD	Wyomissing	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Ellodi Pharmaceuticals, LP

Countries where clinical trial is conducted

United States,  Australia,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Week 12 histologic responder rates	To compare the Week 12 histologic responder rates (= 6 peak eosinophils [eos]/high power field [HPF]) for APT-1011 3 mg 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
Primary	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
Primary	Histologic responder rates at the end of the Randomized Withdrawal Phase (RWS)	To compare the histologic responder rates (= 6 peak eos/HPF) for APT-1011 responders randomized to continuing APT-1011 3 mg HS (maintenance) with responders randomized to placebo (withdrawal of APT-1011 3 mg HS) at the end of the RWS	Week 12 to Week 52
Primary	Percentage subjects with complete symptomatic response at the end of the RWS	Percentage of subjects with complete symptomatic response (i.e., no dysphagia episodes for the 14 consecutive days prior to the end of the randomized withdrawal phase) at the end of the randomized withdrawal phase, in the RWS APT-1011 3 mg HS arm versus placebo arm	Week 0 to Week 52
Secondary	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.	Week 0 to Week 12
Secondary	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
Secondary	Mean change in PROSE Symptom Burden Score	To compare the mean change from baseline to Week 12 in the day-level symptom burden utilizing the Patient Reported Outcomes Symptoms of EoE (PROSE) for APT-1011 3 mg HS with that for placebo.	Week 0 to Week 12
Secondary	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 Patient Reported Outcomes Symptoms of EoE (PROSE) for APT-1011 3 mg HS with that for placebo. Each symptom is rated on a numeric rating scale (NRS) with values ranging from 0 (not at all) to 10 (as bad as I can imagine).	Week 0 to Week 12
Secondary	Mean 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
Secondary	Percentage of Subjects with <15 peak eos/HPF	To compare the percentage of subjects with <15 peak eos/HPF for APT-1011 3 mg HS with that for placebo.	Week 12
Secondary	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
Secondary	Mean Change in Dysphagia Episodes	To compare mean change in number of dysphagia episodes from baseline to the end of RWS for APT-1011 responders randomized to continue APT-1011 3 mg HS with responders randomized to placebo (withdrawal of APT-1011 3 mg HS)	Week 0 to Week 52
Secondary	Mean Change in EREFs from Week 0 to Week 52	To compare endoscopic appearance evaluated by the mean change from baseline to the end of RWS, in Eosinophilic Esophagitis Endoscopic Reference Score (EREFs) for APT-1011 responders randomized to continue APT-1011 3 mg HS with responders randomized to placebo (withdrawal of APT-1011 3 mg HS). The EREF score has a range from 0-9, with 9 being worst result.	Week 0 to Week 52
Secondary	Mean Histologic Change	To compare the mean change from baseline to the end of the RWS in peak eosinophil counts for APT-1011 responders randomized to APT-1011 3 mg HS with those randomized to placebo in the RWS.	Week 0 to Week 52
Secondary	Mean Change in PROSE Day-Level Symptom Burden	To compare the mean change in day-level symptom burden using the Patient Reported Outcomes Symptoms of EoE (PROSE) from baseline to the end of RWS, for APT-1011 responders randomized to continue APT-1011 3 mg HS with responders randomized to placebo (withdrawal of APT-1011 3 mg HS). Day-level symptom burden has values ranging from 0 (no symptoms) to 10 (symptoms are as bad as I can imagine).	Week 0 to Week 52
Secondary	Mean Change in PROSE Day-Level Difficulty Swallowing	To compare the mean change in day-level difficulty swallowing using the Patient Reported Outcomes Symptoms of EoE (PROSE) from baseline to the end of randomized withdrawal phase, for APT-1011 responders randomized to continue APT-1011 3 mg HS with responders randomized to placebo (withdrawal of APT-1011 3 mg HS). Each symptom is rated on a numeric rating scale (NRS) with values ranging from 0 (not at all) to 10 (as bad as I can imagine).	Week 0 to Week 52
Secondary	Mean Change in Dysphagia-Free Days	To compare the mean number of dysphagia-free days from baseline to the end of RWS, for APT-1011 responders randomized to continue APT-1011 3 mg HS with responders randomized to placebo (withdrawal of APT-1011 3 mg HS)	Week 0 to Week 52
Secondary	Mean Change in Number of Dysphagia Episodes	To compare mean change in number of dysphagia episodes from baseline at or prior to Week 52 (based on timing of > 6 peak eos/HPF) for APT-1011 responders randomized to continue APT-1011 3 mg HS with those randomized to placebo (withdrawal of APT-1011 3 mg HS)	Week 0 to Week 52