AD17002 Treating Poorly Controlled, Moderate to Severe Eosinophilic Asthma

Study Overview
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Brief Summary
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This clinical trial aims to investigate patients with poorly controlled, moderate to severe eosinophilic asthma. The main questions it aims to answer are Could the LTh(αK) intranasal treatment improve the clinical condition of these patients? Could patients self-administrate LTh(αK) via the intranasal route? Is the LTh(αK) at multiple doses safe for asthmatic patients? Participants will be asked to self-administrate two doses per week for a total of 6 weeks (11 doses). A diary on LTh(αK) usage, adverse events, and reliever medication will be recorded.

Detailed Description
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Eosinophilic asthma is recognized as a sub-phenotype of asthma based on the pattern of inflammatory cellular infiltration in the airway. Eosinophilic asthma can be associated with increased asthma severity, atopy, late-onset disease, and steroid refractoriness. Induced sputum cell count is the standard for identifying eosinophilic inflammation in asthma and fractional exhaled nitric oxide (FeNO) and serum periostin are emerging as potential surrogates. The Type I and III interferons (IFNs) can negatively regulate the allergic reaction, and their production from mucosal epithelium is reported to be lower in patients with asthma. The investigational intranasal pharmaceutical product named AD17002 contains a detoxified Escherichia coli heat-labile enterotoxin, LTh(αK). Studies have shown that AD17002 enhanced the production of Type I and III IFNs from mucosal epithelial cells. Studies also supported that AD17002 attenuates allergic reactions. The safety and tolerability of LTh(αK) have been demonstrated in several clinical trials as an intranasal adjuvant for influenza vaccine (NCT03293732 and NCT03784885) or an intranasal immunomodulator for respiratory hypersensitivity (NCT04088721) and viral infection (NCT05069610 and NCT05541510). This study is conducted to determine the potential efficacy and mechanism of LTh(αK) as an immunomodulator in attenuating the severity of clinical manifestations in patients with unstable, moderate to severe eosinophilic asthma. Patients with clinical history and ongoing eosinophilic asthma will be randomly assigned to either AD17002 (10 μg or 20 μg) or placebo, per 3-4 days, in a 1:1 ratio, in a single-blinded (patient-blinded) fashion. The nasal administration will be self-administrated by participants. Progression and improvement in asthmatic symptoms will be recorded. All study subjects will sign ethics committee-approved informed consent forms before participating in any trial-related activities. Subjects who participate in this trial of AD17002 will provide information about the dosing, efficacy, and safety of the new indication that will guide its future clinical use.

Official Title
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A Single-blind (Patient-blind), Randomized, Placebo-controlled, Intranasal Administration Study on Mechanisms and Potential Efficacy of AD17002 in Subjects With Poorly Controlled, Moderate to Severe Eosinophilic Asthma

Conditions
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Eosinophilic Asthma

Intervention / Treatment
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* Drug: AD17002
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject 20-80 years of age on the day of signing informed consent Subject who is not a current smoker with poorly controlled, moderate to severe eosinophilic asthma based on GINA 2022 criteria. The subject is diagnosed with asthma. Subjects who have the post-bronchodilator reversibility of Forced expiratory volume 1 (FEV1) of ≥ 12% and ≥ 200 mL in response to a SABA at the screening visit or documented in the medical chart within 3 months of the screening visit. Subjects who have ≥3% eosinophil counts in the induced sputum within 7 days of Visit 1. Subjects with ACT scores ≤ 19 under regular low to moderate-dose inhaled corticosteroids (ICS) and/or a combination with inhaled long-acting beta 2 agonists for at least 3 months before the Screening Visit. Have a negative serum pregnancy test at the screening, and randomization visits (female subjects of childbearing potential). A female subject who is of reproductive potential agrees to remain abstinent or use (or have their partner use) an acceptable method of birth control within the projected duration of the trial. Acceptable birth control methods are intrauterine devices, hormonal contraception, diaphragm with spermicide, contraceptive sponge, condoms, and vasectomy, as per local regulations or guidelines. A female subject who is not of reproductive potential is eligible without requiring the use of contraception. A female subject who is not of reproductive potential is defined as one who has either Reached natural menopause (defined as 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone levels in the postmenopausal range as determined by the laboratory, or 12 months of spontaneous amenorrhea), Six weeks postsurgical documented total hysterectomy and/or bilateral salpingo-oophorectomy, or Bilateral tubal ligation. Subject or the subject's legal representative understands the trial procedures, alternative treatments available, and risks involved with the trial, and voluntarily agrees to participate by giving written informed consent. Provide written informed consent for the trial and be willing to adhere to dose and visit schedules. Exclusion Criteria: Subjects with serious underlying chronic illness or severe systemic disease, including SLE, malignant diseases, uremia and heart failure, or abnormal liver function. Subjects without a recent respiratory tract infection within 3 weeks before the study. Subjects without a recent COVID-19 infection within 1 month before study. Subjects with clinically important lung disease, including but not limited to COPD (Chronic Obstructive Pulmonary Disease), chronic respiratory infection, lung cancer, etc. Arrhythmia, myocardial infarction, or stroke in the last 3 months. Active COVID-19 disease (SARS-CoV-2 Lateral flow tests (LFA)-positive) at Screening. A clinical history of persistent allergic asthma or rhinitis caused by an allergen to which the subject is regularly exposed and sensitized. A clinical history of active chronic sinusitis (> 3 months). Any clinically relevant chronic disease (>=3 months duration) (e.g. cystic fibrosis, malignancy, renal or hepatic insufficiency). Subject with a documented history of Bell's palsy. The subject has any nasal condition that could confound the efficacy or safety assessments. Immunosuppressive treatment (ATC code L04 or L01) within 3 months before the screening visit (except the specified concomitant medications for allergy and asthma symptoms). Has unstable or severe asthma, as judged by the clinical Investigator, or a subject who has experienced a life-threatening asthma attack or an occurrence of any clinical deterioration of asthma that resulted in emergency treatment, hospitalization due to asthma, or treatment with systemic corticosteroids (but allowing SABA) at any time within the last 3 months before Screening Visit. Has asthma requiring high-dose oral corticosteroid (OCS) within the last 3 months before Screening Visit. Has a history of anaphylaxis with cardiorespiratory symptoms with prior immunotherapy, unknown cause, or inhalant allergen. Is pregnant or expecting to conceive within the projected duration of the trial. Is nursing at randomization and within the projected duration of the trial? Has had previous exposure to the study drug or Flu Vaccine AD07030. The subject is receiving ongoing treatment with any specific immunotherapy at the time of the Screening Visit. Has a known history of allergy, hypersensitivity, or intolerance to investigational medicinal products, rescue medications, or self-injectable epinephrine.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Cohort 1 Placebo<br>Formulation buffer | Drug: Placebo<br>* Formulation buffer. Dosing days: 1, 4, 8, 11, 15, 18, 22, 25, 29, 32.<br>* Other names: Formulation buffer;|
| Experimental: Cohort 1 Low dose<br>Formulation buffer + 10 μg LTh(αK) | Drug: AD17002<br>* The investigational intranasal pharmaceutical product named AD17002 contains a detoxified Escherichia coli heat-labile enterotoxin, LTh(αK). Dosing days: 1, 4, 8, 11, 15, 18, 22, 25, 29, 32.<br>* Other names: LTh(αK);|
| Placebo Comparator: Cohort 2 Placebo<br>Formulation buffer | Drug: Placebo<br>* Formulation buffer. Dosing days: 1, 4, 8, 11, 15, 18, 22, 25, 29, 32.<br>* Other names: Formulation buffer;|
| Experimental: Cohort 2 High dose<br>Formulation buffer + 20 μg LTh(αK) | Drug: AD17002<br>* The investigational intranasal pharmaceutical product named AD17002 contains a detoxified Escherichia coli heat-labile enterotoxin, LTh(αK). Dosing days: 1, 4, 8, 11, 15, 18, 22, 25, 29, 32.<br>* Other names: LTh(αK);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 improvement | Lung function tests with spirometry | Day 1 to Day 78 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change to the use of Short-Acting Beta Agonists (SABA) | The number of use of rescue Short-Acting Beta Agonists | Day 1 to Day 78 | 
| Fractional exhaled nitric oxide (FeNO) change | Change to the FeNO levels | Day 1 to Day 78 | 
| Sputum eosinophil change | Change to the induced sputum eosinophils' count | Day 1 to Day 78 | 
| Asthma Control Test (ACT) scores improvement | Change to the ACT scores. A maximum score of 25 points indicates complete asthma control. A score between 20 and 25 represents well controlled asthma, while a score of 19 or below represents not well controlled asthma, and a score less than 16 indicates very poorly controlled asthma. | Day 1 to Day 78 | 
| Corticosteroid used to control asthma | Numbers of corticosteroid used, inhaled or oral | Day 1 to Day 78 | 
| Immunological biomarkers of sputum | Changes in the concentration of sputum IL-4, -5, -13, IFN-α, eosinophil peroxidase (EPO), eosinophil cationic protein (ECP) from the baseline | Day 1 to Day 78 | 
| Immunological biomarkers of serum | Change of concentration from baseline of induced serum IL-4, -5, -13 | Day 1 to Day 78 | 
| Peripheral eosinophil count | Change of cell numbers from baseline of peripheral eosinophil count | Day 1 to Day 78 | 
| Adverse events_clinical visit | Clinical visit and check up by physicians | Day 1 to Day 36 and Day 78 | 
| Adverse events-Diary | Patient self report adverse events via diary | Day 1 to Day 78 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LTh(αK), Type I/III Interferon, Immunomodulator, epithelial