Study to Investigate the Efficacy and Safety of Apomivir®

Study Overview
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Brief Summary
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Apomivir® is extracted from a proprietary spirulina strain, FEM-101, a kind of blue cyanobacterium with patented freeze-thaw lysis and extraction method. According to the preclinical studies, Apomivir® have been proven to have excellent broad-spectrum anti-viral ability, especially for seasonal influenza viruses (Influenza virus A and B) that may cause illness, paralysis and even death, especially in children and elderly people. This phase II study is designed to evaluate the efficacy and safety of Apomivir® (120 mg b.i.d.) in subjects with seasonal influenza.

Detailed Description
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This is a prospective, randomized, double-blind, parallel, placebo-controlled, multi-center study. Approximately 196 subjects with fever defined as body temperature >= 38˚C, with at least one respiratory symptom and one other constitutional symptom will be invited into this study to target 156 evaluable subjects. A nasopharyngeal/throat swabs rapid test for influenza A and B will be conducted and only subjects with positive results could be recruited. All eligible subjects will be randomized to one of the following treatment group in a 1:1 ratio. Study Group: Apomivir® 1 capsule (120 mg/cap) twice daily for 5 days Control Group: Placebo 1 capsule twice daily for 5 days A pack of acetaminophen (500 mg) will be provided at enrollment. All flu symptom relief agents could be used only for rescue use of persistent fever or flu symptoms (>= 24 hours). A digital thermometer and diary card will be dispensed at baseline (Day 1). Subjects will be instructed to complete the body temperature record, and daily record regarding the severity of their influenza symptoms and the level of interference on daily activity. The monitoring frequency will be twice daily (after drug administration) from Day 1 to Day 5, and cut down to once daily until Day 29 or completed cure (defined as remission of all flu symptoms and interferences). Treatment failure is defined as secondary illnesses, antibiotic use and hospitalization due to disease progression. For safety and efficacy assessments, all subjects should return on Day 3, 6 and 15. For subjects who are not completely cured before Day 15 (Visit 4), further therapy will be conducted and they should return on Day 29; for those who are completely cured, only a telephone follow-up will be conducted on Day 29. The severity of fever will be scored using a 4-point scale: 0 = < 37.2°C = >= 37.2 to < 38.0°C = >= 38.0 to < 39.0°C = >= 39.0 °C Other influenza symptoms (such as cough, nasal obstruction, sore throat, fatigue, headache and myalgias) will also be assessed using a 4-point scale: 0 = none, = mild, = moderate, = severe The level of interference on daily activities (including running, lifting heavy objects, participating in strenuous sports, moderate activities), such as moving a table, pushing a vacuum cleaner, bowling, or playing golf, lifting or carrying groceries, climbing several flights of stairs, climbing one flight of stairs, bending, kneeling, or stooping, walking more than a mile, walking several blocks, walking one blocks, and bathing or dressing yourself, will be assessed according to a 3-point scale 0 = no, no limited = yes, limited a little = yes, limited a lot Confirmatory tests for infective virus strain, real-time RT-PCR and viral culture will be conducted at baseline. In the following study visits, real-time RT-PCR will be performed to measure the influenza viral load/titer in nasopharyngeal/throat swabs specimen. For those who have been completely cured prior to Day 15, the real-time RT-PCR assessment could be omitted on Day 29. All subjects enrolled will be followed until the end of study, but only subjects with influenza PCR or viral culture positive could be evaluable population.

Official Title
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A Prospective, Randomized, Double-blind, Parallel, Placebo-controlled, Multi-center Study to Investigate the Efficacy and Safety of Apomivir® in Relieving Influenza Symptoms

Conditions
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Influenza

Intervention / Treatment
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* Drug: Apomivir®
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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1. Main inclusion criteria: Females and males aged between 20 and 65 Presumptive diagnosis of influenza based on the following clinical characteristics: Present at least one respiratory symptom (e.g. cough, nasal obstruction, sore throat) and at least one constitutional symptom other than fever (e.g. fatigue, headache, myalgias) of less than 48-hour duration Positive for influenza A or B (nasopharyngeal/throat swab - rapid test) Able and willing to comply with the study procedure and give written informed consent 2. Main exclusion criteria: Female who is pregnant/lactating or planning to be pregnant, or female of childbearing potential* who is not using medically recognized method of contraception * Other than those who have been surgically sterilized (defined as having undergone hysterectomy or bilateral oophorectomy or bilateral salpingectomy; tubal ligation alone is not considered sufficient) or one year post-menopausal Subject with chronic pulmonary diseases or critical condition or already developed severe respiratory distress with hypoxaemia on presentation Subject with a history of non-febrile convulsions, neuromuscular disorders or cognitive dysfunction that may compromise respiratory secretions, or who are currently receiving anticonvulsive agents Subject with clinically important illness, malignancies, systemic infection, other medical or psychiatric condition which places the subject at unacceptable risk to participate in the study or confounds the ability to interpret data from the study Subject with significant abnormal laboratory findings (hemoglobin level < 9.0 g/dL, WBC < 4000/mm3, platelet count < 100,000/mm3, ALT or AST > 2.5 x upper limit of normal (ULN), or estimated creatinine clearance < 30 mL/min within 4 weeks prior to baseline) Subject who are currently receiving immunosuppressive therapy, Subject has taken daily supplement(s) containing blue agar within 1 month prior to screening, or any other medication that may affect the study results Known hypersensitivity to any ingredients in Apomivir® or other blue agar Use of any investigational product within 1 month prior to screening

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 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 |
| --- | --- |
| Placebo Comparator: Control Group<br>Placebo 1 capsule twice daily. All subjects will be treated for 5 days, and all drugs should be taken orally after meal | Drug: Placebo<br>* Control Group: Placebo 1 capsule twice daily. All subjects will be treated for 5 days, and all drugs should be taken orally after meal.<br>|
| Experimental: Study Group<br>Apomivir® 1 capsule twice daily. All subjects will be treated for 5 days, and all drugs should be taken orally after meal. | Drug: Apomivir®<br>* Study Group: Apomivir® 1 capsule twice daily. All subjects will be treated for 5 days, and all drugs should be taken orally after meal.<br>* Other names: FE-L-APO(drug substance);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety profile of Apomivir® treatment (120 mg b.i.d.). | Safety endpoints: Change in laboratory data Adverse events Serious adverse events (SAE) | from day1 to day 29, the entire treatment period and follow-up period. | 
| To evaluate the time to resolution of influenza symptoms defined as all flu symptom scores ≤ 1 after initiation of study treatment. | The time to resolution of influenza symptom is defined as the duration from the study drug initiation to all flu symptom scores ≤ 1. Subject who is withdrawn prior to the resolution of influenza symptom is censored at the last known time point. | from day 1 to day 29, depends on the time to sympton resolution of individual subjects. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in virus titer. | To evaluate the change in virus titer assessed by real-time RT-PCR15. | Day 3, 6 compared to baseline (Day 1) | 
| Time to achieve afebrile | Time to bring down a fever (oral temperature < 37.2˚C) | after initiation of study treatment | 
| Severity of influenza symptom score during study period | All subjects should complete the diary card twice daily from Day 1 to Day 6 and cut down to once daily until Day 29 or completely cured. | twice daily from Day 1 to Day 6 and once daily until Day 29 or completely cured | 
| Level of interference on daily activity and time to alleviation of the interference during study period | All subjects should complete the diary card twice daily from Day 1 to Day 6 and cut down to once daily until Day 29 or completely cured. | twice daily from Day 1 to Day 6 and once daily until Day 29 or completely cured | 
| Proportion of rescue medication used for fever or influenza symptoms during study period | All subjects should complete the diary card twice daily from Day 1 to Day 6 and cut down to once daily until Day 29 or completely cured. | twice daily from Day 1 to Day 6 and once daily until Day 29 or completely cured | 
| Proportion and time to treatment failure during study period | Proportion and time to treatment failure (including secondary illnesses, antibiotic use and hospitalization due to disease progression) during study period | from day 1 to day 29, including treatment period and follow-up period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oral temperature, respiratory symptom, cough, nasal obstruction, sore throat, fever