Clinical trial NCT05170009: Baloxavir in Combination With Oseltamivir in Allogenic Bone Marrow Transplant Recipients With Influenza
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Influenza
Keywords: Influenza
Bone marrow transplant
Flu
Baloxavir Marboxil
Xofluza
Oseltamivir
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2021-12-27
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change of Influenza Viral RNA Loads From Baseline at the End of Treatment as Measured by Quantitative Real Time Polymerase Chain Reaction.
timeFrame: Baseline; Day 10
measure: 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.
timeFrame: Baseline; Day 10
measure: 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).
timeFrame: Baseline; Day 10
Secondary outcomes:
measure: Change of Influenza Viral RNA Load From Baseline at Day 4 and Day 7 and 10 in Each Treatment Arm
timeFrame: Baseline; Day 4; Day 7; Day 10
measure: 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
timeFrame: Baseline; Day 4; Day 7; Day 10
measure: 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
timeFrame: Baseline; Day 4; Day 7; Day 10
measure: 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)
timeFrame: Baseline; Day 4; Day 7; Day 10
measure: Time to Improvement of Individual Influenza Symptoms as Assessed by Patient-reported Outcome Measures on a Single Scale
timeFrame: Baseline to Day 30
measure: 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
timeFrame: Day 1 to Day 30
measure: Time to Return to Preinfluenza Health Status
timeFrame: Day 1 to Day 30
measure: 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)
timeFrame: Baseline to Day 30
measure: Time to Viral Clearance, as Assessed by Difference in Percentage of Participants Positive by Quantitative Real Time Polymerase Chain Reaction
timeFrame: Baseline to Day 30
measure: 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
timeFrame: Baseline to Day 30
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: Day 1 to Day 15
Other outcomes:
Locations:
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
Study officials:
affiliation: Weill Medical College of Cornell University
name: Mirella Salvatore, MD
role: PRINCIPAL_INVESTIGATOR
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