| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064220 |
| E.1.2 | Term | Eosinophilic esophagitis |
| E.1.2 | System Organ Class | 100000004856 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to evaluate the efficacy (histological response) of APT-1011 in adults with eosinophilic esophagitis (EoE). |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are as follows:
• To define the dose-response of APT-1011;
• To select a dose(s) of APT-1011 for Phase 3;
• To evaluate the effect of APT-1011 on histology and endoscopic appearance;
• To evaluate maintenance of efficacy and long-term safety of APT-1011;
• To evaluate the population pharmacokinetics (PopPK) of APT-1011;
• To evaluate the effect of APT-1011 on dysphagia episodes.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must satisfy all of the following criteria:
Before entering 4-week Baseline Symptom Assessment
1. Male or female between ≥18 and ≤75 years of age at the time of
informed consent;
2. Signed the informed consent form (ICF) and willing and able to
adhere to all study procedures;
3. Diagnosis or presumptive diagnosis of EoE;
Diagnosis of EoE must be confirmed by symptoms, histology, and historical documentation of failed treatment on ≥8 weeks of high-dose proton pump inhibitors (PPI), as determined by the Investigator. High-dose PPI is defined as
20 to 40 mg BID of any marketed PPI, or alternatively this total dose administered once daily; maintenance doses of PPIs are not acceptable.
Note: Documentation of PPI failure prior to initial diagnosis or by documentation of PPI failure at the time of Screening is required. The subjects may be pre-screened but should not be consented, sign an ICF, or be offered participation in FLUTE if they have not met the diagnostic criteria for EoE that requires that they fail an 8-week trial of high-dose PPIs except those who have taken PPIs for 8 weeks will use the EGD within the study for this documentation. The Investigator and potential subject must make the decision to complete a PPI trial independent of any considerations of the study. There is insufficient time to do the 8-week trial within the current study. Should a subject be consented in
error and screen fails due to this point, they may be re-screened as described in the protocol.
4. Have a subject-reported history of ≥3 episodes of dysphagia (difficulty with food going down or an awareness of the sensation of food going down the esophagus) in the 7 days prior to Screening;
5. Have a 7-day Global EoE Symptom Score >3 at baseline (EoE score must remain >3 at each of Visits 1, 2 and 3 before randomization). This will be performed on paper during the Screening visit.
6. Willing and able to adhere to study-related treatment regimens, procedures, and visit schedule.
Before randomization
7. To be determined prior to randomization: have evidence of EoE, as defined by ≥15 PEAK eosinophils/HPF. In order to ensure that a diagnosis can be made, at least 5-6 biopsies should be taken including both proximal and distal specimens (~3 each);
-No EGDs and biopsies performed outside FLUTE are acceptable for meeting eligibility criteria.
-Optional biopsies may be taken and processed locally for local use, if specified in the local ICF.
-Biopsies are to be obtained PRIOR to the 4-week Baseline Symptom Assessment. Eligibility from a histological perspective will be based solely on the central pathologist’s assessment.
8. To be determined prior to randomization: in the daily diary, report at least 3 episodes of dysphagia (difficulty with food going down or an awareness of the sensation of food going down the esophagus) for each of the last 7 days during the last 14 days of the 4-week Baseline Symptom Assessment
9. To be determined prior to randomization: completion of the daily diary on at least 5 out of each 7 days during the last 14 days of the 4-week Baseline Symptom Assessment. |
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| E.4 | Principal exclusion criteria |
1. Have known contraindication, hypersensitivity, or intolerance to corticosteroids
2. 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
3. Presence of oral or esophageal mucosal infection of any type
4. Have any mouth or dental condition that prevents normal eating
5. 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
6. Use of systemic (oral or parenteral) 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
7. Initiation of an elimination diet or elemental diet within 30 days before Screening (diet must remain stable after signing ICF)
8. Morning serum cortisol level ≤5 μg/dL (138 nmol/L) that is not responsive to ACTH stimulation
9. Use of biologic immunomodulators in the 24 weeks prior to Screening (allergy desensitization injection or oral therapy is allowed as long as the course of therapy is not altered during the study period)
10. Use of calcineurin inhibitors or purine analogues (azathioprine, 6-mercaptopurine) in the 12 weeks prior to Screening
11. Use of potent cytochrome P450 (CYP) 3A4 inhibitors (e.g., ritonavir and ketoconazole) in the 12 weeks prior to Screening
12. 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
13. Have history of an esophageal stricture requiring dilatation within
the previous 12 weeks prior to Screening
14. Subjects who have initiated, discontinued, or changed dosage regimen of PPIs, H2 antagonists, antacids or antihistamines for any condition such as GERD or alergic rhinitis within 4 weeks prior to qualifying endoscopy. If already on these drugs, the dosage must remain constant throughout the study.
15. Subjects who are on a regimen of leukotrienes inhibitors (e.g., montelukast) or oral cromolyn sodium for allergic rhinitis/asthma after ICF signature.
16. Infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV);
The following parameters will be utilized to determine hepatitis B and hepatitis C infection: positive for hepatitis B surface antigen [HBsAg], total hepatitis B core antibody [anti-HBc] positive alone if also hepatitis B virus (HBV) deoxyribonucleic
acid (DNA) positive, or hepatitis C virus (HCV) antibody if also HCV ribonucleic acid (RNA) positive. Subjects who are positive for hepatitis B surface antibody, but negative for HBsAg and anti-HBc, will be eligible.
HIV 1 and HIV 2 will be tested by polymerase chain reaction (PCR).
17. Have gastrointestinal (GI) bleeding or documented active peptic ulcer within 4 weeks prior to Screening or between the Screening Visit and the Randomization Visit;
18. Have current (>30 days) chronic infection such as prior or active tuberculosis (TB), active chicken pox or measles or absence of prior measles, mumps and rubella (MMR) vaccine, immunosuppression, immunodeficiency, malignancy except treated non-melanoma skin cancer, or known severe bleeding disorder.
Subjects with TB exposure or who live in high endemic areas should be assessed locally for TB before consideration for the study;
19. Have history or presence of Crohn’s disease, celiac disease, or other inflammatory disease of the GI tract, including eosinophilic gastroenteritis;
20. Have current alcohol or drug abuse in the opinion of the Investigator. Chronic consumption of 3 or more standard drinks (≥42 g/L) per day is prohibited;
21. Female subjects who are pregnant, breastfeeding, or planning to
become pregnant during the study;Serum pregnancy test at Screening and urine pregnancy test during 4-week Baseline Symptom Assessment in women of
childbearing potential must be negative
22. Sexually active females of childbearing potential who do not agree
to follow highly effective contraceptive methods through the Follow-up Visit; For systemic contraceptives, use must be stable for ≥28 days prior to Screening.
23. Have received an investigational product, as part of a clinical trial within 30 days (or 5 half-lives) of Screening. Subjects who are currently on observational studies or enrolled in patient registries are allowed in this study
24. A serum cortisol level <16 μg/dL (440 nmol/L) at 60 minutes with adrenocorticotropic hormone (ACTH) stimulation test using 250 μg
cosyntropin administered intramuscularly |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The following primary efficacy endpoint will be evaluated at Week 12 to assess
EoE response:
• Histology: percentage of subjects with a with ≤6 PEAK eosinophils/HPF after assessing at least 5-6 biopsies from the proximal and distal esophagus where the HPF area is 235 square microns (40 magnification lens with a 20 mm ocular). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
The following secondary efficacy endpoints will be evaluated:
• EoE sustained response: percentage of subjects who met the primary endpoint at Week 12 and maintained the primary endpoint at Week 26 and Week 52;
• Change from baseline EREFs at Week 12, Week 26, and Week 52;
• Endoscopic changes will 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).
• Percentage of subjects with a peak eosinophils/HPF number <1 and <15 at Week 12, Week 26, and Week 52;
• Change from baseline Global EoE Symptom Score assessed prior to randomization, which will be assessed for the 7 day period prior to the following study visits: Week 4, Week 8, Week 12, Week 14, Week 18, Week 22, Week 26, Week 28, Week 36, Week 44, and Week 52;
• Dysphagia: 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 (Week 12, Week 26 and Week 52);
• Change from baseline 7-day EEsAI total score assessed prior to randomization to those assessed at Week 12, Week 26, and Week 52;
• Change from baseline 7-day EEsAI subscores to those assessed at Week 12, Week 26, and Week 52;
• Percentage of subjects with mean 7-day EEsAI total score <20 to those assessed at Week 12, Week 26, and Week 52;
• Change from baseline PGIS assessed prior to randomization to those assessed at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44 and 52;
• PGIC at weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52.
• Assessment of treatment failure and relapse, including:
• Percentage of histologic non-responders by dose at Week 12, Week 26, and Week 52;
• Percentage of subjects requiring emergency endoscopic food disimpaction by dose before Week 14, between Week 14 and Week 28, and between Week 28 and Week 52;
• Percentage of subjects requiring esophageal dilation by dosing group and part of the study
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 12, Week 26, Week 52 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| Germany |
| Spain |
| Switzerland |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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