Study to Assess the Efficacy of Baloxavir Marboxil Versus Placebo to Reduce Onward Transmission of Influenza A or B in Households

Study Overview
=================
Brief Summary
-----------------
Otherwise healthy index patients (IP) are randomized to either baloxavir marboxil or placebo if their influenza symptoms onset was within 48 hours of screening. Their households are enrolled within 24 hours of randomization if at least 1 household contacts (HHC) have not received influenza vaccine within 6 months of screening and if all HHC screen negative for influenza infection. The main endpoints are assessed based on multiple respiratory swabs, obtained from both IP and HHC up to 9 (+/-1) days post IP randomization, and through the assessment of symptoms.

Official Title
-----------------
A Phase IIIB, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Clinical Efficacy Study of Baloxavir Marboxil for the Reduction of Direct Transmission of Influenza From Otherwise Healthy Patients to Household Contacts

Conditions
-----------------
Influenza

Intervention / Treatment
-----------------
* Drug: Baloxavir Marboxil
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: Index Patients (IPs): Able to comply with the study protocol per investigator judgment. Diagnosed with acute influenza infection by investigator. Polymerase chain reaction [PCR] (+) or Rapid Influenza Diagnostic Test [RIDT] (+) for influenza A/B based on cobas® SARS-CoV-2 and influenza A/B or other point-of-care / local laboratory results. PCR (-) or antigen test (-) for SARS-CoV-2 based on cobas® SARS-CoV-2 and Influenza A/B test or other point-of-care / local laboratory result Presence of (a) fever (>=38.0 °C per tympanic or rectal thermometer; >=37.5 °C per axillary, oral or forehead/temporal thermometer) or (b) any influenza symptoms (cough, sore throat, nasal congestion, headache, feverishness or chills, muscle or joint pain, fatigue). The time interval between the onset of fever or influenza symptoms and the pre-dose examinations is 48 hours or less. IP lives in a household where: (1) No HHC is known to have been diagnosed with influenza or SARS-CoV-2 infection by a healthcare professional (HCP) in the past 4 weeks; (2) All HHCs are expected to meet the key HHC inclusion criteria; (3) >=1 HHCs are expected to participate in the full study who have not received the influenza vaccine within 6 months prior to screening. Women of childbearing potential: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures specified in the protocol All HHCs (Part 1): PCR (-) or RIDT (-) based on cobas® SARS-CoV-2 and influenza A/B or other local point-of-care / local laboratory result. PCR (-) or antigen test (-) for SARS-CoV-2 based on cobas® SARS-CoV-2 and Influenza A/B or other POC / local laboratory result. HHC lives with no HHC who will be present in the home at any time during the study and who meets any HHC exclusion criteria. HHC lives with no HHC who does not meet HHC inclusion criteria (part 1). HHC lives in a household where ≥1 HHCs meet all of the following: Start screening within 24 hours after IP randomization; Have NOT received the influenza vaccine within 6 months prior to screening; and Fulfill full study HHC inclusion criteria part 2. Full study HHCs (part 2) intended for full study must meet the following additional criteria for study entry: Agree to participate in the full study. Able to comply with the study protocol per investigator judgment No influenza symptoms within 7 days prior to screening. Alternatively, mild symptoms are permissible if determined by the investigator to be due to a preexisting condition. Temperature <38.0 °C (tympanic). Will reside in the index patient's house for at least 7 of the next 9 days and will be present for scheduled study visits. Willing and able to measure and record temperature, or have another household member perform the task on his or her behalf. Furthermore, a responsible adult will assume responsibility to oversee or perform this task on behalf of minors. In the 6 months prior to screening: a) Has not been diagnosed with influenza by a healthcare professional b) Has not received BXM, peramivir, laninamivir, oseltamivir, zanamivir, rimantadine, umifenovir, favipiravir or amantadine. Does not have a moderate or worse active infections OR infections requiring systemic (e.g., oral or intravenous) or otherwise internally administered (e.g., inhaled, intrathecal) antibiotic/antiviral/antifungal therapy, (topical therapies for mild external infections allowed). EXCLUSION CRITERIA: IPs: IPs with severe influenza virus infection requiring inpatient treatment. IPs judged by the investigator to be at high risk for complications of influenza. IP is ≥12 years old and unable to swallow tablets (not applicable to IPs 5 to 11 year olds who will receive oral suspension). Women who are breastfeeding or have a positive pregnancy test in the pre-dose examinations. IPs with concurrent (non-influenza) infections requiring systemic antimicrobial and/or antiviral therapy at the pre-dose examinations. IPs who have received baloxavir marboxil, peramivir, laninamivir, oseltamivir, zanamivir, rimantadine, umifenovir, favipiravir or amantadine, or an investigational drug, within 30 days or 5 drug-elimination half-lives, whichever is longer, prior to screening. IPs who have received an investigational monoclonal antibody for a viral disease in the last year. Known hypersensitivity to baloxavir marboxil or the drug product excipients. IP previously included in the study IP lives with an HHC who, based on available information, meets the HHC exclusion criteria HHC: Pregnant or within 2 weeks post-partum at screening. Immunocompromised. Less than 2 years old. Who have received an investigational therapy within the 30 days or 5 drug elimination half-lives, whichever is longer, prior to screening. Diagnosed with influenza or SARS-CoV-2 infection by a healthcare professional in the past 4 weeks. HHC who plans to arrive home after 24 hours post IP randomization to Day 9 and is not willing to be consented as soon as possible upon arrival. HHC previously included in the study.

Ages Eligible for Study
-----------------
Minimum Age: 5 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Baloxavir Marboxil<br>Participants who are IPs will receive a single oral dose of baloxavir marboxil. HHCs of the IPs will not receive study medication. | Drug: Baloxavir Marboxil<br>* IPs less than 12 years old will receive either 2 mg/kg (if weight less than 20 kg) or 40 mg (if weight more than or equal to 20 kg) of Baloxavir Marboxil as oral suspension. IPs more than or equal to 12 years old will receive either 40 mg (if weight less than 80 kg) or 80 mg (if weight more than or equal to 80 kg) of Baloxavir Marboxil as tablets. HHCs of IPs will not receive study medication.<br>* Other names: Xofluza;|
| Placebo Comparator: Placebo<br>Participants who are IPs will receive a single oral dose of placebo. HHCs of the IPs will not receive study medication. | Drug: Placebo<br>* IPs less than 12 years old will receive placebo oral suspension and those above 12 years will receive placebo tablets. HHCs of IPs will not receive study medication.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virological Transmission by Day 5 | Defined as the percentage of Household Contacts (HHCs) who become Polymerase Chain Reaction Positive (PCR+) for Influenza by Day 5 post IP randomization. HHCs may be symptomatic or asymptomatic and their virus subtype must match that of the index patient (IP) in their household. The primary efficacy analysis population will consist of all enrolled unvaccinated HHCs of the randomized IPs. | Baseline to Day 5 (5 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic Transmission by Day 5 | Defined as the percentage of HHCs who become PCR+ for Influenza by Day 5 post IP randomization and develop Influenza symptoms at any time during the study. HHCs ≥12 years old were defined symptomatic if (1) Presence of temperature ≥38.0 Celsius and one respiratory symptom (cough, sore throat, nasal congestion) or (2) Presence of one respiratory symptom and one general systemic symptom (headache, feverishness or chills, muscle or joint pain, fatigue), with or without fever. HHCs ≥2 and <12 years old were defined symptomatic if presence of temperature ≥38.0 Celsius and cough, nasal congestion, or rhinorrhea. Note: For HHCs of any age, respiratory or general systemic symptoms had to be either (1) new, or (2) worsened versus baseline with baseline symptoms due to a pre-existing comorbidity. HHCs must have their virus subtype match that of the IP. | Baseline to Day 5 (5 days) | 
| Virological Transmission at the Household Level by Day 5 | Defined as the percentage of households with at least one HHC who meets the primary endpoint. | Baseline to Day 5 (5 days) | 
| Symptomatic Transmission at the Household Level by Day 5 | Defined as the percentage of households with at least one HHC who meets the Symptomatic transmission by Day 5 endpoint. | Baseline to Day 5 (5 days) | 
| Virological Transmission by Day 9 | Defined as the percentage of HHCs who become PCR+ for Influenza by Day 9 post IP randomization. HHCs must have their virus subtype match that of the IP, and include: (1) all HHC meeting primary endpoint, AND (2) all HHC cases detected after Day 5 Visit meeting the following criteria: (2a) included HHC case is in a household where another HHC has already met the primary endpoint, OR (2b) included HHC case is PCR (+) for influenza bearing an amino acid substitution of isoleucine for another amino acid at position 38 (I38X) in the polymerase acidic (PA) protein, that have been associated with reduced susceptibility to baloxavir marboxil. | Baseline to Day 9 (9 days) | 
| Symptomatic Transmission by Day 9 | Defined as the percentage of HHCs who meet the Virological transmission by Day 9 endpoint AND are symptomatic per the definition for symptoms in the Symptomatic transmission by Day 5 endpoint. | Baseline to Day 9 (9 Days) | 
| Any Virological Infection by Day 9 | Defined as the percentage of HHCs who become PCR (+) for influenza (confirmed at central laboratory) by Day 9. | Baseline to Day 9 (9 Days) | 
| Any Virological Infection at the Household Level by Day 9 | Defined as the percentage of households with at least one HHC who meets the Any virological infection by Day 9 endpoint. | Baseline to Day 9 (9 Days) | 
| Any Symptomatic Infection by Day 9 | Defined as the percentage of HHCs who meet the Any virological infection by Day 9 endpoint AND are symptomatic per the definition for symptoms in the Symptomatic transmission by Day 5 endpoint. | Baseline to Day 9 (9 Days) | 
| Any Symptomatic Infection at the Household Level by Day 9 | Defined as the percentage of households with at least one HHC who meets the Any symptomatic infection by Day 9 endpoint. | Baseline to Day 9 (9 Days) | 
| Percentage of IPs With Adverse Events (AEs) |  | Baseline to Day 9 (for IPs ≥12 years old) and Day 21 (for IPs <12 years old) | 
| Percentage of IPs (<= 12 years old) Reporting each Palatability and Acceptability Response | The Palatability and Acceptability questionnaire consists of 2 questions: 1) How was the taste of this medicine; 2) Would you be happy to take this medicine again. Response for question (1) will be captured on a Likert scale (1-5) and for question (2) will be either Yes, No, or Not Sure/No Answer. | Baseline |