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

Influenza Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05170009
• Other study ID #: 20-12023076
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: April 22, 2022
• Est. completion date: September 2026

Study information

• Verified date: August 2023
• Source: Weill Medical College of Cornell University
• Contact: Mirella Salvatore, MD
• Phone: 646-318-8506
• Email: mis2053[@]med.cornell.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: September 2026
• Est. primary completion date: July 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Influenza
• Influenza, Human

Intervention

Drug:
• Baloxavir Marboxil
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.
• Placebo
Placebo at baseline, day 4, and day 7.
• Oseltamivir
Oseltamivir 75 mg twice daily for 10 days.

Locations

Country	Name	City	State
United States	Weill Cornell Medicine	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Weill Medical College of Cornell University	Genentech, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (18)

Burnham P, Khush K, De Vlaminck I. Myriad Applications of Circulating Cell-Free DNA in Precision Organ Transplant Monitoring. Ann Am Thorac Soc. 2017 Sep;14(Supplement_3):S237-S241. doi: 10.1513/AnnalsATS.201608-634MG. — View Citation

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De Vlaminck I, Martin L, Kertesz M, Patel K, Kowarsky M, Strehl C, Cohen G, Luikart H, Neff NF, Okamoto J, Nicolls MR, Cornfield D, Weill D, Valantine H, Khush KK, Quake SR. Noninvasive monitoring of infection and rejection after lung transplantation. Proc Natl Acad Sci U S A. 2015 Oct 27;112(43):13336-41. doi: 10.1073/pnas.1517494112. Epub 2015 Oct 12. — View Citation

De Vlaminck I, Valantine HA, Snyder TM, Strehl C, Cohen G, Luikart H, Neff NF, Okamoto J, Bernstein D, Weisshaar D, Quake SR, Khush KK. Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection. Sci Transl Med. 2014 Jun 18;6(241):241ra77. doi: 10.1126/scitranslmed.3007803. — View Citation

Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM; Centers for Disease Control and Prevention (CDC). Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011 Jan 21;60(1):1-24. — View Citation

Fukao K, Ando Y, Noshi T, Kitano M, Noda T, Kawai M, Yoshida R, Sato A, Shishido T, Naito A. Baloxavir marboxil, a novel cap-dependent endonuclease inhibitor potently suppresses influenza virus replication and represents therapeutic effects in both immunocompetent and immunocompromised mouse models. PLoS One. 2019 May 20;14(5):e0217307. doi: 10.1371/journal.pone.0217307. eCollection 2019. — View Citation

Fukao K, Noshi T, Yamamoto A, Kitano M, Ando Y, Noda T, Baba K, Matsumoto K, Higuchi N, Ikeda M, Shishido T, Naito A. Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection. J Antimicrob Chemother. 2019 Mar 1;74(3):654-662. doi: 10.1093/jac/dky462. — View Citation

Harper SA, Bradley JS, Englund JA, File TM, Gravenstein S, Hayden FG, McGeer AJ, Neuzil KM, Pavia AT, Tapper ML, Uyeki TM, Zimmerman RK; Expert Panel of the Infectious Diseases Society of America. Seasonal influenza in adults and children--diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009 Apr 15;48(8):1003-32. doi: 10.1086/598513. — View Citation

Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, Ishida T, Sekino H, Yamada K, Portsmouth S, Kawaguchi K, Shishido T, Arai M, Tsuchiya K, Uehara T, Watanabe A; Baloxavir Marboxil Investigators Group. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018 Sep 6;379(10):913-923. doi: 10.1056/NEJMoa1716197. — View Citation

Hu Y, Lu S, Song Z, Wang W, Hao P, Li J, Zhang X, Yen HL, Shi B, Li T, Guan W, Xu L, Liu Y, Wang S, Zhang X, Tian D, Zhu Z, He J, Huang K, Chen H, Zheng L, Li X, Ping J, Kang B, Xi X, Zha L, Li Y, Zhang Z, Peiris M, Yuan Z. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet. 2013 Jun 29;381(9885):2273-9. doi: 10.1016/S0140-6736(13)61125-3. Epub 2013 May 29. — View Citation

Lee N, Chan PK, Hui DS, Rainer TH, Wong E, Choi KW, Lui GC, Wong BC, Wong RY, Lam WY, Chu IM, Lai RW, Cockram CS, Sung JJ. Viral loads and duration of viral shedding in adult patients hospitalized with influenza. J Infect Dis. 2009 Aug 15;200(4):492-500. doi: 10.1086/600383. — View Citation

Lee N, Ison MG. Diagnosis, management and outcomes of adults hospitalized with influenza. Antivir Ther. 2012;17(1 Pt B):143-57. doi: 10.3851/IMP2059. Epub 2012 Feb 3. — View Citation

Marty FM, Vidal-Puigserver J, Clark C, Gupta SK, Merino E, Garot D, Chapman MJ, Jacobs F, Rodriguez-Noriega E, Husa P, Shortino D, Watson HA, Yates PJ, Peppercorn AF. Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial. Lancet Respir Med. 2017 Feb;5(2):135-146. doi: 10.1016/S2213-2600(16)30435-0. Epub 2017 Jan 14. — View Citation

Muthuri SG, Venkatesan S, Myles PR, Leonardi-Bee J, Al Khuwaitir TS, Al Mamun A, Anovadiya AP, Azziz-Baumgartner E, Baez C, Bassetti M, Beovic B, Bertisch B, Bonmarin I, Booy R, Borja-Aburto VH, Burgmann H, Cao B, Carratala J, Denholm JT, Dominguez SR, Duarte PA, Dubnov-Raz G, Echavarria M, Fanella S, Gao Z, Gerardin P, Giannella M, Gubbels S, Herberg J, Iglesias AL, Hoger PH, Hu X, Islam QT, Jimenez MF, Kandeel A, Keijzers G, Khalili H, Knight M, Kudo K, Kusznierz G, Kuzman I, Kwan AM, Amine IL, Langenegger E, Lankarani KB, Leo YS, Linko R, Liu P, Madanat F, Mayo-Montero E, McGeer A, Memish Z, Metan G, Mickiene A, Mikic D, Mohn KG, Moradi A, Nymadawa P, Oliva ME, Ozkan M, Parekh D, Paul M, Polack FP, Rath BA, Rodriguez AH, Sarrouf EB, Seale AC, Sertogullarindan B, Siqueira MM, Skret-Magierlo J, Stephan F, Talarek E, Tang JW, To KK, Torres A, Torun SH, Tran D, Uyeki TM, Van Zwol A, Vaudry W, Vidmar T, Yokota RT, Zarogoulidis P; PRIDE Consortium Investigators; Nguyen-Van-Tam JS. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med. 2014 May;2(5):395-404. doi: 10.1016/S2213-2600(14)70041-4. Epub 2014 Mar 19. — View Citation

Paules C, Subbarao K. Influenza. Lancet. 2017 Aug 12;390(10095):697-708. doi: 10.1016/S0140-6736(17)30129-0. Epub 2017 Mar 13. — View Citation

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Salvatore M, Laplante JM, Soave R, Orfali N, Plate M, van Besien K, St George K. Baloxavir for the treatment of Influenza in allogeneic hematopoietic stem cell transplant recipients previously treated with oseltamivir. Transpl Infect Dis. 2020 Aug;22(4):e13336. doi: 10.1111/tid.13336. Epub 2020 Jun 10. — View Citation

Taniguchi K, Ando Y, Nobori H, Toba S, Noshi T, Kobayashi M, Kawai M, Yoshida R, Sato A, Shishido T, Naito A, Matsuno K, Okamatsu M, Sakoda Y, Kida H. Inhibition of avian-origin influenza A(H7N9) virus by the novel cap-dependent endonuclease inhibitor baloxavir marboxil. Sci Rep. 2019 Mar 5;9(1):3466. doi: 10.1038/s41598-019-39683-4. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Influenza Antiviral Medications: Summary for Clinicians