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Completed

NCT Number: NCT03191864

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

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.

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Key information

Conditions

Eosinophilic Esophagitis Deglutition Disorders Digestive System Diseases Eosinophilia Esophageal Diseases Esophagitis Gastroenteritis Gastrointestinal Diseases Hematologic Diseases Hemic and Lymphatic Diseases Hypersensitivity Hypersensitivity, Immediate Immune System Diseases Leukocyte Disorders Otorhinolaryngologic Diseases Pharyngeal Diseases

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

AZ Sint-Lucas, Bruges, Belgium

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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).

Treatment and study plan

APT-1011

Drug

APT-1011 is an orally disintegrating tablet formulation of fluticasone propionate

Other names: Fluticasone propionate ODT

Placebo

Drug

Placebo tablets are identical in composition to APT-1011 except they exclude the active ingredient.

Other names: Matching placebo dose

Primary outcomes

  1. Percentage of Subjects With ≤6 Peak Eosinophils/High-power Field (HPF)

    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 outcomes

  1. Percentage of Subjects Who Met the Primary Endpoint at Week 12 and Maintained the Primary Endpoint at Weeks 26 and 52

    Time frame: Week 26, and Week 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.

  2. Change From Baseline Eosinophilic Esophagitis Endoscopic Reference Score (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 [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.

  3. Percentage of Subjects With a Peak Eosinophils/HPF Number <1 and <15

    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.

    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.

  4. Change From Baseline Global EoE Symptom Score

    Time frame: Week 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52

    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.

  5. Change in the Number of Dysphagia Episodes

    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.

    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.

  6. Change From Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Total Score

    Time frame: Weeks 12, 26 and 52

    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

  7. Change From Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Subscores

    Time frame: Weeks 12, 26 and 52

    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.

  8. Percentage of Subjects With Mean 7-day EEsAI Total Score <20

    Time frame: Weeks 12, 26, and 52

    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

  9. Change From Baseline Patient Global Impression of Severity (PGIS) for EoE Symptoms as Assessed Prior to Randomization Post-Baseline Visit

    Time frame: Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52

    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.

  10. Change From Baseline PGIS for Difficulty With Food or Pills Going Down as Assessed Prior to Randomization Post-Baseline Visit

    Time frame: Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52

    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.

  11. Change From Baseline Patient Global Impression of Change (PGIC) for EoE Symptoms as Assessed Prior to Randomization Post-Baseline Visit

    Time frame: Weeks 4, 8, 12, 14, 18, 22, 26, 36, 44, and 52

    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.

  12. Change From Baseline PGIC of Difficulty With Food or Pills as Assessed Prior to Randomization Post-Baseline Visit

    Time frame: Weeks 4, 8, 12, 14, 18, 22, 26, 36, 44, and 52

    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.

  13. Percentage of Histologic Non-responders by Dose at Weeks 12, 26, and 52

    Time frame: 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.

  14. Percentage of Subjects Requiring Emergency Endoscopic Food Dis-impaction

    Time frame: before Week 14, between Week 14 and Week 28, between Week 28 and Week 52

    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.

  15. Percentage of Subjects Requiring Esophageal Dilation

    Time frame: baseline to Week 52

    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.

Other outcomes

  1. Number of Subjects Discontinuing Due to HPA Axis Suppression

    Time frame: baseline to Week 52

    Number of subjects discontinuing due to HPA axis suppression.

    Note: There were no patients in the placebo group after Week 14.

  2. Number of Subjects With Oral and Esophageal Candidiasis

    Time frame: baseline to Week 52

    Frequency of oral and esophageal candidiasis.

    Note: There were no patients in the placebo group after Week 14.

  3. Number of Subjects With Treatment-Emergent Adverse Events Leading to Study Discontinuation in Part 1

    Time frame: baseline to Week 12

    Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Study Discontinuation in Part 1.

  4. Number of Subjects With Treatment-Emergent Adverse Events Leading to Study Discontinuation in Part 2

    Time frame: Week 12 to 52

    Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Study Discontinuation in Part 2.

  5. Percentage of Subjects With Serum Cortisol Level ≤5 μg/dL or Abnormal Adrenocorticotropic Hormone (ACTH) Stimulation Test

    Time frame: Week 12 to 52

    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.

Sponsors and collaborators

Lead sponsor

Adare Pharmaceuticals, Inc.

Industry

Registry information

Official study 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

Acronym: FLUTE

Important dates

Study start
2017
Primary completion
2019
Study completion
2019
First posted
Jun 19, 2017
Registry last updated
Apr 26, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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