Baloxavir in Combination With Oseltamivir in Allogenic Bone Marrow Transplant Recipients With Influenza
Primary Purpose
Influenza
Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Baloxavir Marboxil
Placebo
Oseltamivir
Sponsored by
About this trial
This is an interventional treatment trial for Influenza focused on measuring Influenza, Bone marrow transplant, Flu, Baloxavir Marboxil, Xofluza, Oseltamivir
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
Sites / Locations
- Weill Cornell MedicineRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Active and standard of care
Placebo and standard of care
Arm Description
Active Baloxavir Marboxil and standard of care Oseltamivir
Placebo-matched Baloxavir Marboxil and standard of care Oseltamivir
Outcomes
Primary Outcome Measures
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.
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.
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.
Secondary Outcome Measures
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.
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.
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).
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).
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).
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.
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]).
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.
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.
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.
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.
Full Information
NCT ID
NCT05170009
First Posted
December 9, 2021
Last Updated
August 22, 2023
Sponsor
Weill Medical College of Cornell University
Collaborators
Genentech, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT05170009
Brief Title
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
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 22, 2022 (Actual)
Primary Completion Date
July 2026 (Anticipated)
Study Completion Date
September 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Weill Medical College of Cornell University
Collaborators
Genentech, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Influenza
Keywords
Influenza, Bone marrow transplant, Flu, Baloxavir Marboxil, Xofluza, Oseltamivir
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
30 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Active and standard of care
Arm Type
Active Comparator
Arm Description
Active Baloxavir Marboxil and standard of care Oseltamivir
Arm Title
Placebo and standard of care
Arm Type
Placebo Comparator
Arm Description
Placebo-matched Baloxavir Marboxil and standard of care Oseltamivir
Intervention Type
Drug
Intervention Name(s)
Baloxavir Marboxil
Other Intervention Name(s)
Xofluza
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo at baseline, day 4, and day 7.
Intervention Type
Drug
Intervention Name(s)
Oseltamivir
Other Intervention Name(s)
Tamiflu
Intervention Description
Oseltamivir 75 mg twice daily for 10 days.
Primary Outcome Measure Information:
Title
Change of influenza viral RNA loads from baseline at the end of treatment as measured by quantitative real time polymerase chain reaction.
Description
Influenza viral RNA loads will be measured by quantitative real time polymerase chain reaction.
Time Frame
Baseline; Day 10
Title
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.
Description
Influenza viral load will be measured by the quantitative real time polymerase chain reaction.
Time Frame
Baseline; Day 10
Title
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).
Description
Influenza viral load will be measured by the influenza plaque assay.
Time Frame
Baseline; Day 10
Secondary Outcome Measure Information:
Title
Change of influenza viral RNA load from baseline at day 4 and day 7 and 10 in each treatment arm
Description
Influenza viral RNA load will be measured by quantitative real time polymerase chain reaction.
Time Frame
Baseline; Day 4; Day 7; Day 10
Title
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
Description
Influenza viral RNA load will be measured by quantitative real time polymerase chain reaction.
Time Frame
Baseline; Day 4; Day 7; Day 10
Title
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
Description
Influenza viral load will be measured by the influenza plaque assay (replicating virus).
Time Frame
Baseline; Day 4; Day 7; Day 10
Title
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)
Description
Influenza viral load will be measured by the influenza plaque assay (replicating virus).
Time Frame
Baseline; Day 4; Day 7; Day 10
Title
Time to improvement of individual influenza symptoms as assessed by patient-reported outcome measures on a single scale
Description
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).
Time Frame
Baseline to Day 30
Title
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
Description
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.
Time Frame
Day 1 to Day 30
Title
Time to return to preinfluenza health status
Description
Preinfluenza health status will be measured on a score from 0 (worst possible health) to 10 (normal health [for someone your age and condition]).
Time Frame
Day 1 to Day 30
Title
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)
Description
Time to viral clearance will be assessed by percentage of participants positive by influenza plaque assay at each time-point.
Time Frame
Baseline to Day 30
Title
Time to viral clearance, as assessed by difference in Percentage of Participants Positive by quantitative real time polymerase chain reaction
Description
Time to viral clearance will be assessed by percentage of participants positive by qPCR at each time-point.
Time Frame
Baseline to Day 30
Title
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
Description
Treatment-emergent variants will be identified using direct next-generation sequencing of a comprehensive panel of genes.
Time Frame
Baseline to Day 30
Title
Percentage of participants with adverse events (AEs)
Description
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.
Time Frame
Day 1 to Day 15
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mirella Salvatore, MD
Phone
646-318-8506
Email
mis2053@med.cornell.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Anna Gwak, BA
Phone
212-746-4089
Email
ang4021@med.cornell.edu'
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mirella Salvatore, MD
Organizational Affiliation
Weill Medical College of Cornell University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Weill Cornell Medicine
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anna Gwak, BA
Phone
202-746-4089
Email
ang4021@med.cornell.edu
First Name & Middle Initial & Last Name & Degree
Elizabeth L Salsgiver, MPH
Phone
212-746-4089
Email
els7021@med.cornell.edu
First Name & Middle Initial & Last Name & Degree
Mirella Salvatore, MD
12. IPD Sharing Statement
Plan to Share IPD
No
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Links:
URL
http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm
Description
Influenza Antiviral Medications: Summary for Clinicians
Learn more about this trial
Baloxavir in Combination With Oseltamivir in Allogenic Bone Marrow Transplant Recipients With Influenza
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