Baloxavir in Combination With Oseltamivir in Allogenic Bone Marrow Transplant Recipients With Influenza

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled pilot study of the efficacy and safety of baloxavir in combination with oseltamivir (standard of care) for the treatment of influenza in allogeneic stem cell transplant patients. Although there are no data about this treatment option currently available, the investigator hypothesizes that combination therapy may be more effective in clearing influenza virus infection and decreasing the rate of emergence of resistant influenza in immunocompromised human hosts.

Detailed Description
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This is a randomized double-blind placebo-controlled pilot study of the efficacy and safety of baloxavir in combination with oseltamivir (standard of care) for the treatment of influenza in allogeneic stem cell transplant patients. 30 SCT recipients will take part in the study. Participants with be randomly assigned (1:1) to either baloxavir + oseltamivir or baloxavir-matched placebo +oseltamivir. Before randomization, patients will be stratified by hospitalization status and influenza type A (yes/no). Patients in the baloxavir combination arm will receive weight-adjusted baloxavir (40 mg for patients weighing <80 kg and 80 mg for those weighing ≥80 kg) at baseline and at day 4 and day 7. They will also receive oseltamivir 75 mg twice daily for 10 days. Patients in the baloxavir-matched placebo + oseltamivir arm will receive baloxavir-matched placebo at baseline and at day 3 and day 7and oseltamivir 75 mg twice daily for 10 days.

Official Title
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Randomized Double-blind, Placebo-controlled Single Center Pilot Study to Evaluate the Efficacy and Safety of Baloxavir in Combination With Oseltamivir in Adult Allogeneic Bone Marrow Transplant Recipients With Influenza

Conditions
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Influenza

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients: Signed informed consent by any patient capable of giving consent, or, where the patient is not capable of giving consent, by his or her legal/authorized representative Age greater than or equal to 18 years at the time of signing the Informed Consent Form/Assent Form Ability to comply with the study protocol, in the investigator's judgment Have received allogeneic bone marrow transplant Tested positive for influenza infection after the onset of symptoms using a polymerase chain reaction (PCR)-based diagnostic assay. 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 diagnosis of influenza and the pre-dose examinations is 48 hours or less. For women of childbearing potential: Agreement to remain abstinent (refrain from heterosexual intercourse): Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 28 days after the last dose of study treatment. Hormonal contraceptive methods must be supplemented by a barrier method. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state greater than or equal to 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Exclusion Criteria: Patients who have received more than 48 hours of antiviral treatment for the current influenza infection prior to screening Patients who have received Baloxavir for the current influenza infection Known contraindication to neuraminidase inhibitors Patients weighing < 40 kg Patients unable to swallow tablets Patients with known severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2) or receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis Patients with any of the following laboratory abnormalities detected within 24 hours prior to or during screening (according to local laboratory reference ranges: ALT or AST level > 5 times the upper limit of normal (ULN) OR ALT or AST > 3 times the ULN and total bilirubin level > 2 times the ULN Pregnant or breastfeeding, or positive pregnancy test in a predose examination, or intending to become pregnant during the study or within 28 days after the last dose of study treatment Exposure to an investigational drug within 5 half-lives or 30 days (whichever is longer) of randomization Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study Known hypersensitivity to baloxavir marboxil or the drug product excipients Known COVID-19 coinfection Unwilling to undergo nasopharyngeal (NP) swabs as per study schedule

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Active Comparator: Active and standard of care<br>Active Baloxavir Marboxil and standard of care Oseltamivir | Drug: Baloxavir Marboxil<br>* Weight-adjusted Baloxavir Marboxil (40 mg for patients weighing <80 kg and 80 mg for those weighing ≥80 kg) at baseline, day 4, and day 7.<br>* Other names: Xofluza;Drug: Oseltamivir<br>* Oseltamivir 75 mg twice daily for 10 days.<br>* Other names: Tamiflu;|
| Placebo Comparator: Placebo and standard of care<br>Placebo-matched Baloxavir Marboxil and standard of care Oseltamivir | Drug: Placebo<br>* Placebo at baseline, day 4, and day 7.<br>Drug: Oseltamivir<br>* Oseltamivir 75 mg twice daily for 10 days.<br>* Other names: Tamiflu;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of influenza viral RNA loads from baseline at the end of treatment as measured by quantitative real time polymerase chain reaction. | Influenza viral RNA loads will be measured by quantitative real time polymerase chain reaction. | Baseline; Day 10 | 
| Between-treatment-arm difference in the change of influenza viral RNA loads from baseline at the end of treatment as measured by quantitative real time polymerase chain reaction. | Influenza viral load will be measured by the quantitative real time polymerase chain reaction. | Baseline; Day 10 | 
| Between-treatment-arm difference in the change of influenza viral RNA loads from baseline at the end of treatment as measured by influenza plaque assay (replicating virus). | Influenza viral load will be measured by the influenza plaque assay. | Baseline; Day 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of influenza viral RNA load from baseline at day 4 and day 7 and 10 in each treatment arm | Influenza viral RNA load will be measured by quantitative real time polymerase chain reaction. | Baseline; Day 4; Day 7; Day 10 | 
| Difference in change of influenza viral loads from baseline at day 4, 7 and 10 between the two treatment arms as measured by quantitative real time polymerase chain reaction | Influenza viral RNA load will be measured by quantitative real time polymerase chain reaction. | Baseline; Day 4; Day 7; Day 10 | 
| Change of influenza viral loads from baseline at day 4, 7 and 10 as measured by influenza plaque assay (replicating virus) in each treatment arm | Influenza viral load will be measured by the influenza plaque assay (replicating virus). | Baseline; Day 4; Day 7; Day 10 | 
| Difference in change of influenza viral loads from baseline at day 4, 7 and 10 between the two treatment arms as measured by influenza plaque assay (replicating virus) | Influenza viral load will be measured by the influenza plaque assay (replicating virus). | Baseline; Day 4; Day 7; Day 10 | 
| Time to improvement of individual influenza symptoms as assessed by patient-reported outcome measures on a single scale | Patients will self-assess the severity of 7 influenza-associated symptoms on a 4-point single scale with 0 indicating no symptoms and higher scores indicating mild, moderate, and severe symptoms. Time to improvement of individual influenza symptoms are defined as the time from the start of treatment to the time when each of the influenza symptoms are alleviated, maintained, or improved for a duration of at least 21.5 hours. These are defined as: pre-existing symptoms (cough, fatigue, or muscle/join pain that existed prior to influenza) that were worse at baseline and had improved at least 1 point from baseline; pre-existing symptoms not worse at baseline that maintained baseline severity; and new symptoms that were alleviated, defined as a symptom score of non (0) or mild (1). | Baseline to Day 30 | 
| Percentage of patients who experience each influenza-related complications: hospitalization, death, sinusitis, otitis media, bronchitis, and radiologically-confirmed pneumonia as an adverse event after the initiation of study treatment | A composite score of multiple measures will be used and calculated by count of patients who experience each influenza-related complications. Adverse events will only include those that are determined to be related to the study drug. | Day 1 to Day 30 | 
| Time to return to preinfluenza health status | Preinfluenza health status will be measured on a score from 0 (worst possible health) to 10 (normal health [for someone your age and condition]). | Day 1 to Day 30 | 
| Time to viral clearance, as assessed by difference in Percentage of Participants Positive by influenza plaque assay at each time-point (in each treatment group) | Time to viral clearance will be assessed by percentage of participants positive by influenza plaque assay at each time-point. | Baseline to Day 30 | 
| Time to viral clearance, as assessed by difference in Percentage of Participants Positive by quantitative real time polymerase chain reaction | Time to viral clearance will be assessed by percentage of participants positive by qPCR at each time-point. | Baseline to Day 30 | 
| Change of treatment-emergent variants of neuraminidase and polymerase known to confer antiviral resistance to oseltamivir in each arm by direct next-generation sequencing symptoms | Treatment-emergent variants will be identified using direct next-generation sequencing of a comprehensive panel of genes. | Baseline to Day 30 | 
| Percentage of participants with adverse events (AEs) | Adverse events will only include those that are determined to be related to the study drug and will assess the safety and tolerability of Baloxavir in Combination with SOC treatment. | Day 1 to Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Influenza, Bone marrow transplant, Flu, Baloxavir Marboxil, Xofluza, Oseltamivir