Viral Inhibition in Children for Treatment of RSV

Study Overview
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Brief Summary
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VICTOR is a randomized, double-blind, placebo-controlled, multicenter, 2-part study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and antiviral effect of single and multiple dosing of AK0529 in infants hospitalized with RSV infection.

Detailed Description
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Globally, Respiratory Syncytial Virus (RSV) is recognized as the leading cause of respiratory tract infections in infants and young children and a major cause of hospitalization due to severe respiratory infection. Despite four decades of effort, there are still no effective methods to control RSV infection. Treatment of RSV has been limited to supportive measures. There is an urgent need for safe and effective drugs to treat and prevent RSV disease. AK0529 is an investigational antiviral agent that targets the RSV fusion protein on the surface of the viral envelope and exerts antiviral activity against RSV by inhibiting viral entry into host cells and preventing fusion protein induced cell-cell fusion. AK0529 was generally well tolerated in healthy volunteers. This study is designed as a randomized, double-blind, placebo-controlled, multicenter, phase 2 study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and antiviral effect of single and multiple dosing of AK0529 in infants hospitalized with RSV infection. It will consist of two parts, Part 1 and Part 2. Each part will consist of three phases, a pre-treatment phase, a treatment phase and post-treatment follow-up phase.

Official Title
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A Randomized, Double-blind, Placebo-controlled, 2-Part Study of Orally Administered AK0529 to Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Effect of Single and Multiple Dosing in Hospitalized Infants With Respiratory Syncytial Virus Infection

Conditions
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RESPIRATORY SYNCYTIAL VIRUS INFECTIONS

Intervention / Treatment
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* Drug: AK0529
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients of any race or ethnicity with an age adjusted for any prematurity of ≥1 month and ≤24 months. Diagnosis of RSV infection by virological means, which may include rapid diagnostic point-of-care testing, within 96 hours preceding screening for Part 1 and 72 hours for Part 2. Patient must weigh >3 kg at screening and be within the 10th and 90th percentiles (inclusive) for the patient's age, based on the local child growth standards, i.e. the Australian Paediatric Endocrine Group Growth Charts. The parent / legal guardian of the patient must have provided written informed consent for the patient to participate. For patients aged <12 months, an occipito-frontal head circumference within the normal range for age and gender. Exclusion Criteria: The patient has taken, is currently taking or requires any restricted medications. Patient is known to be HIV-positive (or the mother, if the potential patient is a child aged <6 months). Participation in an investigational drug or device study within 30 days prior to the date of screening. Requires vasopressors or inotropic support at the time of enrolment. Concurrent gastrointestinal conditions that could, in the opinion of the investigator, prejudice absorption of the Investigational Medicinal Product (e.g. protracted vomiting, malabsorption syndrome, a history of necrotising enterocolitis with consequent short gut syndrome). Bronchopulmonary dysplasia or chronic lung disease requiring assisted ventilation at the time of enrolment. Diminished ventilatory reserve at risk for hypercapnia (e.g. pulmonary hypoplasia, sequestration syndromes, cystadenomatoid malformation, a history of surgery for diaphragmatic hernia). Left to right shunt meriting corrective therapy. Renal failure including renal anomalies likely to be associated with renal insufficiency (e.g. clinical conditions of renal dysplasia, polycystic renal disease, renal agenesis). Clinical evidence of hepatic decompensation (e.g. hepatic disorder with associated coagulopathy or associated encephalopathy). Cerebral palsy with microcephaly, chronic or persistent feeding difficulties or seizures. Symptomatic because of inborn errors of metabolism (e.g. mitochondrial disorders, disorders of carbohydrate metabolism, glycogen storage disorders). Congenital or acquired immunodeficiency (e.g. congenital agammaglobulinaemia, common variable immunodeficiency, immunosuppressive therapy other than glucocorticoid or montelukast therapy forming part of care directed by the treating physician). For Part 2 of this study, children with a history of having received palivizumab or any other monoclonal agent directed against RSV in the preceding 120 days. This exclusion criterion does not apply to Part 1. Evidence of active or uncontrolled respiratory, cardiac, hepatic, central nervous system or renal disease unrelated to RSV infection at baseline or any other medical condition that in the opinion of the investigator renders the patient unsuitable for enrolment. A history of epilepsy or seizures including febrile seizures. Allergy to test medication or constituents. Weight less than 10th percentile or greater than 90th percentile for age and gender adjusted for any prematurity. The patient's parent or legally acceptable representative is an employee of the investigator or the study center, with direct involvement in the proposed study or other studies under the direction of that investigator of the study center, or any family members of the employees or the investigator. Failure to satisfy the investigator of fitness to participate for any other reason.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 24 Months

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AK0529<br>Subjects will receive single or multiple doses of AK0529 at different dose levels within different cohorts. | Drug: AK0529<br>* AK0529 is a novel compound being developed for the treatment of RSV infection. The enteric coated drug pellets with sugar core can be administered orally with apple sauce/purée or yoghurt, or by flushing with 10% dextrose water via a nasogastric or other feeding tube, or upon a glucose wafer.<br>|
| Placebo Comparator: Placebo<br>Patients who are randomized to the control arm within each cohort will receive the corresponding placebo to AK0529. | Drug: Placebo<br>* The placebo was made with the same smell and appearance as AK0529 but without the active ingredients. The placebo supplements are composed primarily of microcrystaline cellulose pellet.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events during the study |  | Day -4 to single dose Day 7 (Part 1) and Day -3 to multiple dose Day 14 (Part 2) | 
| Subject withdrawals due to Adverse Events |  | Day -4 to single dose Day 7 (Part 1) and Day -3 to multiple dose Day 14 (Part 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve from time 0 to infinity (AUC) | For patients without intravenous cannulation, samples will be collected at pre-dose, 2, 6 and 12 hours post-dose on Day 1. | Pharmacokinetic samples will be taken predose, 2, 4, 6, 12, 18, 24 hours postdose on Day 1, 48 hours postdose (Part 1 and Part 2) and Day 5 (Part 2 ) | 
| Maximum plasma concentration of AK0529 (Cmax) | For patients without intravenous cannulation, samples will be collected at pre-dose, 2, 6 and 12 hours post-dose on Day 1. | Pharmacokinetic samples will be taken predose, 2, 4, 6, 12, 18, 24 hours postdose on Day 1, 48 hours postdose (Part 1 and Part 2) and Day 5 (Part 2 ) | 
| Plasma concentration of AK0529 at 12 hours postdose (C12) | For patients without intravenous cannulation, samples will be collected at pre-dose, 2, 6 and 12 hours post-dose on Day 1. | Pharmacokinetic samples will be taken predose, 2, 4, 6, 12, 18, 24 hours postdose on Day 1, 48 hours postdose (Part 1 and Part 2) and Day 5 (Part 2 ) | 
| Apparent total body clearance (CL/F) | For patients without intravenous cannulation, samples will be collected at pre-dose, 2, 6 and 12 hours post-dose on Day 1. | Pharmacokinetic samples will be taken predose, 2, 4, 6, 12, 18, 24 hours postdose on Day 1, 48 hours postdose (Part 1 and Part 2) and Day 5 (Part 2 ) | 
| Apparent central compartment volume of distribution (Vc/F) | For patients without intravenous cannulation, samples will be collected at pre-dose, 2, 6 and 12 hours post-dose on Day 1. | Pharmacokinetic samples will be taken predose, 2, 4, 6, 12, 18, 24 hours postdose on Day 1, 48 hours postdose (Part 1 and Part 2) and Day 5 (Part 2 ) | 
| Area under curve change of viral load | The antiviral effects in infants hospitalized with RSV are to be determined by measuring the RSV viral load area under the curve in nasal, pharyngeal and tracheal washes / aspirates from baseline to last administration of study medication (Day 5). | From baseline to Day 5 | 
| Incidence of F-protein genotypes | The incidence of F-protein genotypes associated with reduced sensitivity to IMP will be evaluated. | Specimen will be collected predose and 24 hours postdose on Day 1 (Part 1) and on Day 1-5 (Part 2). | 
| Change of symptom score | To evaluate the change of RSV related symptom score in AK0529 arms compared with the change in placebo arm after treatment. The total score is reported with a range from 0 to 12. A decreasing value of total score represents clinical improvement. Subscales are not applicable in this symptom score. | From baseline to Day 1 (Part 1) and up to Day 5 after multiple drug administration (Part 2). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RSV, AK0529