Evaluate the Efficacy and Safety of FB825 in Adult With Allergic Asthma

Study Overview
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Brief Summary
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This is a randomized, placebo-controlled and double-blind study to evaluate the efficacy and safety of FB825 in adult patients with moderate-to-severe allergic asthma.

Detailed Description
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The study comprises of a 4-week (±2 weeks) screening period, a 24-week treatment period and a 12-week follow-up period. Approximately 100 subjects who meet the criteria for study entry are planned to be enrolled to the study. Eligible subjects will be randomized to receive placebo or FB825 in a 1:1 ratio with 50 subjects in each arm. Eligibility will be checked in patients with allergic asthma during the 4-week (±2 weeks) screening period. Potential candidates should provide signed informed consent forms before starting any screening activities. The subjects will receive one dose of 8 mg/kg FB825 or placebo, and five doses of 4 mg/kg FB825 or placebo every 4 weeks subsequently. The study drug will be administered as a 1-hour IV infusion. Patients may administer albuterol (or equivalents) as rescue medications as needed throughout the study. Prior to screening, patients must be on a stable dose of any of formulations of inhaled corticosteroids (ICS)/long-acting beta-agonist (LABA) combination therapy for at least 1 month, including Fluticasone/salmeterol, Budesonide/formoterol, or Mometasone/formoterol. Patients who have been on budesonide/formoterol or mometasone/formoterol will be switched to an equivalent dose of fluticasone/salmeterol at randomization (Day 1), and patients who have been on fluticasone/salmeterol will remain on their current treatment as background therapy. ICS/LABA (fluticasone/salmeterol) combination therapy during background therapy stable phase (Day 1 to Day 28) followed by ICS only (fluticasone) during ICS tapering phase (Day 29 to Day 140), and than followed by the FB825 monotherapy phase (Day 141 to Day 168). Upon completing 24 weeks of treatment with the investigational product, patients will be placed on their original dose of fluticasone/salmeterol combination therapy (dose at study entry) and albuterol (or equivalents) (as needed) to control their symptoms. Occurrence of an exacerbation of asthma will be evaluated as the primary endpoint at week 24. Mean change in morning PEF and the occurrence of an exacerbation of asthma at other time points will also be evaluated as the secondary endpoint in the study. Exacerbation of asthma as defined by any of the following: A 30% or greater reduction from baseline in morning peak expiratory flow (PEF) on 2 consecutive days, or ≥6 additional reliever puffs of albuterol (or equivalents)in a 24 hour period (compared to baseline) on 2 consecutive days or, Deterioration of asthma, as determined by the investigator, requiring: Systemic (oral and/or parenteral) steroid treatment, or An increase of ICS usage by ≥4 times of the protocol-defined dose (refer to 5.1.3 background therapy table) at each phase throughout the study period, or Hospitalization, or ER (emergency room visit) due to asthma attack Subjects will have site visits after receiving study drug for efficacy, safety, and biomarker evaluation (see Study Flow Chart). Subjects who prematurely withdraw from the study will have an end of study (EOS) visit within 7 days. The daily status of subject, such as peak flow, will be recorded in the e-diary every day during the study. PI can ask the subject for an unscheduled visit any time if any abnormal status reported on the e-diary. The e-diary system will send a notification to the PI automatically once the subject meets the protocol defined exacerbation of asthma. Relative change in pre-bronchodilator FEV1 , post-bronchodilator FEV1, and asthma symptoms will be evaluated during the study. Immunologic biomarkers including changes from baseline in total IgE, allergen-specific IgE, blood eosinophils, exhaled NO, mIgE B cell counts, Immunoglobulin G (IgG)2, Immunoglobulin G (IgG)4, and cytokines such as serum thymus and activation-regulated chemokine (TARC), periostin and eotaxin-3, will be measured and evaluated. Adverse events will be checked and recorded at every visit. Laboratory tests, vital signs and physical examinations will be performed as scheduled and will also be used in safety evaluation. Serum levels of FB825 for pharmacokinetic assessments will be measured via intensive and sparse PK. For intensive PK, 24 subjects (12 subjects of each Arm) participate in the intensive PK sub-study, serum samples will be collected at 0.5 hour pre-dose and at 0.5, 1, 1.25, 2, and 4 hours after the start of infusion on dosing days at Visits 2 and 9, and a single collection at any time on Visit 3 and Visit 10. For sparse PK, all other subjects will participate in the sparse pharmacokinetic (PK) assessments, serum samples will be collected at 0.5 hour pre-dose and at 1.25 hour after the start of infusion at Visits 2 and 9. Serum samples will be collected at 0.5 hour pre-dose and at 1.25 hour after the start of infusion at Visits 5, 6, 7 and 8, and a single collection will be conducted at Visits 4 as well as at follow-up Visits 11, 12, 13 and 14 for intensive and sparse PK. IgE (total IgE and allergen-specific IgE) will be analyzed and serum samples will be collected at all visits during treatment and follow-up periods. IgG2, IgG4, and biomarkers (e.g. TARC, eotaxin-3, and periostin), will be measured and collected at all Visits except visit 1. Peripheral Blood Mononuclear Cells (PBMC) analysis (assessing the mIgE B cell counts) will be measured at Visits 2, 4, 5, 7, 9, 11, 13 and 14. Serum anti-drug antibodies (ADAs) will be assessed in samples before infusion at Visits 2, 7, and 9, and at any time at Visits 11, 13 and 14. For risk management of the sponsor, independent Data Safety Monitoring Board (DSMB) meetings will be conducted to evaluate participant safety data during the study. The DSMB will be conducted in one month after the visit 2 of 10th, 30th, and 80th randomized patient. Unscheduled meetings may be recommended and initiated by the DSMB Chairperson, the sponsor, or the principal investigator.

Official Title
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A Phase II Study to Evaluate the Efficacy and Safety of FB825 in Adult Patients With Moderate-to-severe Allergic Asthma

Conditions
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Allergic Asthma

Intervention / Treatment
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* Biological: FB825
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or females 18-75 years old. Subjects diagnosed with moderate-to-severe allergic asthma [Global Initiative for Asthma [GINA]; GINA, 2021) at least 12 months prior to Visit 1. Documented reversibility from historical data within 3 years of Visit 1 of at least 12% and 200 mL in FEV1 after the administration of 200 to 400 mcg albuterol/salbutamol (or other standard office practice) OR documented airway hyperresponsiveness (methacholine PC20 < 8 mg/mL [or PC20 < 16 mg/mL on ICS]) within 3 years of Visit 1. If documented reversibility data is not available, the bronchodilator test should be finished before randomization. Subjects must have a pre-bronchodilator FEV1 value of ≥ 40% and ≤ 80% predicted within 2 months from randomization . Subjects must have received a physician-prescribed asthma regimen with medium- or high-dose ICS plus LABA for at least 3 month prior to Visit 1 and the dose of ICS must be stable for at least 30 days prior to Visit 1 and throughout the screening period. High-dose ICS is defined as total daily dose of >500 mcg fluticasone propionate or equivalent Medium-dose ICS is defined as a total daily dose of 250 to 500 mcg fluticasone propionate or equivalent. Equivalence ICS doses will be based upon the GINA guidelines (GINA, 2019), shown in Appendix 12.1 According to the medical history, subject have no more than a maximum of 2000 mcg/day equipotent ICS daily dosage of fluticasone propionate or equivalent in 3 months before entry of study. Prior to screening, subjects must be on a stable dose of any of the following doses and formulations of ICS/LABA combination therapy for at least 1 month: Fluticasone/salmeterol combination therapy Advair® Diskus - dry powder inhaler (DPI): 250/50 μg BID or 500/50 μg BID, or Advair® HFA - metered dose inhaler (MDI): 230/42 μg BID or 460/42 μg BID, or Budesonide/formoterol combination therapy (Symbicort® -160/9 μg BID or 320/9 μg BID), or Mometasone/formoterol combination therapy (Dulera® -200/10 μg BID or 400/10 μg BID). Subjects must have a documented history of protocol-defined severe asthma exacerbation at least 1 or more times within the 12 months. A total serum IgE ≥ 360 IU/mL. Subjects must have at least one positive in skin prick test or at least one environmental allergen-specific IgE greater than normal range. Uncontrolled asthma demonstrated both during the screening period and at the time of randomization defined as ACQ-5 (5-item Asthma Control Questionnaire) ≥ 1.5 If recently treated for respiratory tract infection, the treatment must have been completed at least 4 weeks prior to screening. Subjects who have an upper respiratory tract infection during screening are allowed to be rescreened 4 weeks after resolution. Female subjects of childbearing potential must use at least two forms of birth control. One must be barrier protection (i.e., condom or female condom) and the other is one of acceptable method of birth control (ie, diaphragm, intrauterine device, hormonal contraceptives, or abstinence) throughout the study. Subjects who are surgically sterile (ie, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or postmenopausal (defined as amenorrhea for 12 consecutive months and documented serum follicle stimulating hormone level >40 mU/mL) will be considered as no childbearing potential. All female subjects of child-bearing potential must have a negative serum pregnancy test at screening. Note: The subject must use the methods of contraception mentioned above during study period and at least 120 days after the last dosing of FB825. The subject has a body weight ≥ 40 kg at screening. The subject has a normal, as determined by the investigator, 12-lead electrocardiogram (ECG). The subject is able to provide written informed consent. The subject agrees to comply with all protocol requirements. Exclusion Criteria: Asthma exacerbation or any other reason requiring systemic steroids in the 30 days prior to randomization. Subjects are allowed to be rescreened 30 days after completion of treatment. >20% relative change in FEV1 between screening and randomization. Female subjects who are pregnant or lactating. A positive human immunodeficiency virus (HIV) test (e.g., HIV Ag/Ab combo test) at screening or subject taking antiretroviral medications, as determined by medical history. Patients with positive HBeAg or HCV RNA results should be excluded as they are indications of active Hepatitis B virus and Hepatitis C virus replication. Active lung diseases (e.g., bronchitis, chronic obstructive pulmonary disease) other than allergic asthma. Use of any experimental drug within 30 days or 5 half-lives, whichever is longer, prior to or during the screening period. Current or history of treatment with a monoclonal antibody, for example, interleukin (IL)-4, IL-5, IL-13 or IL-15 antibody treatment within 6 months prior to the screening. Current or history of treatment with anti-IgE antibody treatment within 6 months or 5 half-lives, whichever is longer. The subject has a history of alcohol or drug abuse that would impair or risk the patients' full participation in the study, in the opinion of the investigator. The subject has any condition that, in the opinion of the investigator, would compromise the study or the well-being of the subject or prevent the subject from meeting or performing study requirements. The subject has indication of severe liver disease, defined by serum levels of either alanine aminotransferase (ALT), aspartate transaminase (AST) above 3x upper limits of normal (ULN) or elevated total bilirubin >2x ULN as determined at screening. The subject has severe kidney disease, defined as estimated glomerular filtration rate (GFR)<30ml/min/1.73m2 or creatinine > 3x ULN. The subject has known or suspected history of immunosuppression or immunodeficiency. Known history of active tuberculosis (TB) or evidence of tuberculosis infection as defined by a positive purified protein derivative (PPD) skin test and/or interferon-gamma release assay. The interferon-gamma release assay should be repeated in case of an indeterminate result. The subject has history of malignancy within 5 years before the screening period. Patients with non-invasive carcinoma in-situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin may be eligible if they have undergone curative resection at least 12 months prior to screening. Current smoker with > 10 packs year prior to screening. A smoker is defined as a subject who has taken inhaled nicotine containing products (e.g. cigarette, cigar, pipe), including e-cigarettes prior to screening. High risk of parasite infection • Risk factors for parasitic disease (living in an endemic area, travel within the last 6 months to regions where geohelminthic infections are endemic, and/or chronic immunosuppression). AND • Evidence of parasitic colonization or infection on stool evaluation for ova and parasites. Note: stool ova and parasite evaluation will only be conducted in patients with risk factors and an eosinophil count more than twice the upper limit of normal. The subject has received live vaccine within 12 weeks prior to dosing or planned live attenuated vaccinations during the study. The subject has a history of any clinically relevant arrhythmias as determined by the investigator. The subject has a history of respiratory failure or near fatal asthma events which resulted in intensive care unit admission or intubation within five years before the screening period. History of anaphylaxis to any biologic therapy. The subject has major surgery, for example organ replacement, joint replacement, full hysterectomy, heart surgeries, within 8 weeks before the screening. The subject who has major surgery prior to 8 weeks of screening should have fully recovered from any surgical procedures. The subject has comorbid disease that might interfere with the evaluation of IMP (investigational medicinal product) or conduct of study procedures (eg, bronchodilator test). The subject requiring non-selective beta-adrenergic receptor blockers for any reason and initiation or dose change of a selective beta-1 adrenergic receptor blocker within 3 months prior to Visit 1. The subject who received bronchial thermoplasty within 3 years of Visit 1 OR patients who plan to begin therapy during the Screening Period or the Randomized Treatment Period. The subject with active autoimmune disease (excluding atopic dermatitis) or patients using immunosuppressive therapy for autoimmune disease (excluding atopic dermatitis) (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc.) or patients with high titer autoantibodies at screening who are suspected of having high risk for developing autoimmune disease at the discretion of the Investigator or the Sponsor. Use of Traditional Chinese Medications in the treatment of asthma within 3 months prior to screening. (To be listed in Prohibited Medications) Aggravating factors that are inadequately controlled e.g., medication uncontrolled gastroesophageal reflux disease. The subject has adrenal insufficiency (ACTH-resistant) by rapid ACTH stimulation test due to known history of adrenal insufficiency or being suspected of adrenal insufficiency or long-term use of systemic corticosteroids (annual average more than 6 months in the past two years). Adrenal insufficiency: after 30 minutes of ACTH injection, the cortisol level ≦20 mg/ml in rapid ACTH stimulation test.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FB825<br>FB825 will be administered at 8 mg/kg for the first dose and 4 mg/kg for the other five doses. FB825 will be administered as 1-hour IV- infusions every 4 weeks. | Biological: FB825<br>* A humanized monoclonal immunoglobulin G1 (IgG1) targeting the CεmX domain on human B lymphocytic cells expressing membrane-bound IgE (mIgE).<br>|
| Placebo Comparator: Placebo<br>Placebo will be administered at 8 mg/kg for the first dose and 4 mg/kg for the other five doses. Placebo will be administered as 1-hour IV- infusions every 4 weeks. | Other: Placebo<br>* Formulation buffer<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of an exacerbation of asthma at week 24. | Exacerbation of asthma as defined by any of the following: A 30% or greater reduction from baseline in morning peak expiratory flow (PEF) on 2 consecutive days, or ≥6 additional reliever puffs of albuterol (or equivalents) in a 24 hour period (compared to baseline) on 2 consecutive days or Deterioration of asthma, as determined by the investigator, requiring: Systemic (oral and/or parenteral) steroid treatment, or An increase of ICS usage by ≥4 times of the protocol-defined dose (refer to 5.1.3 background therapy table) at each phase throughout the study period, or Hospitalization, or ER (emergency room visit) due to asthma attack. | week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in morning peak expiratory flow (PEF) from baseline | peak expiratory flow (PEF) | week 12, 16, and 24 | 
| Change in ACQ 5 from baseline | 5-item Asthma Control Questionnaire (ACQ-5) will be applied to evaluate the condition of asthma control. All items are scored on a 7-point scale, which ranges from 0 (indicating good control) to 6 (poor control). The overall score is the mean of all questions, with a high score indicating poor control. | week 12, 16, and 24 | 
| Percentage of patients achieving decrease in score by greater than or equal to 0.5 points on the ACQ (with a minimal importance difference improvement) | ACQ | week 12, 16, and 24 | 
| Change in FEV1 from baseline | Forced expiratory volume in 1 second (FEV1) is the volume exhaled during the first second of a forced expiratory maneuver started from the level of total lung capacity. Spirometry testing must be performed in the morning between 6 11 am according to the schedule of study procedures. | week 12, 16, and 24 | 
| Occurrence of an exacerbation of asthma | Exacerbation of asthma as defined by any of the following: A 30% or greater reduction from baseline in morning peak expiratory flow (PEF) on 2 consecutive days, or ≥6 additional reliever puffs of albuterol (or equivalents) in a 24 hour period (compared to baseline) on 2 consecutive days or Deterioration of asthma, as determined by the investigator, requiring: Systemic (oral and/or parenteral) steroid treatment, or An increase of ICS usage by ≥4 times of the protocol-defined dose (refer to 5.1.3 background therapy table) at each phase throughout the study period, or Hospitalization, or ER (emergency room visit) due to asthma attack. | week 12 and 16 | 
| The incidence of treatment emergent adverse events throughout the study |  | Week 24 |