Study to Assess the Safety, Pharmacokinetics, and Efficacy of Baloxavir Marboxil in Healthy Pediatric Participants With Influenza-Like Symptoms

A Multicenter, Randomized, Double-Blind, Active (Oseltamivir)-Controlled Study to Assess the Safety, Pharmacokinetics, and Efficacy of Baloxavir Marboxil in Otherwise Healthy Pediatric Patients 1 to <12 Years of Age With Influenza-Like Symptoms

This study will evaluate the safety, pharmacokinetics, and efficacy of baloxavir marboxil compared with oseltamivir in a single influenza episode in otherwise healthy pediatric participants (i.e., 1 to <12 years of age) with influenza-like symptoms.

Study Overview

• Status: Completed
• Conditions: Influenza
• Intervention / Treatment: Drug: Baloxavir Marboxil; Drug: Oseltamivir

• Study Type: Interventional
• Enrollment (Actual): 173
• Phase: Phase 3

Contacts and Locations

Study Locations

• Costa Rica
  • San Jose, Costa Rica, 10108
    • ICIMED Instituto de Investigación en Ciencias Médicas
• Israel
  • Petach Tikva, Israel, 4931807
    • Clalit Health Services- Pediatric Ambulatory Clinic; Pediatric Ambulatory Clinic
• Mexico
  • Monterrey, N.L, Mexico, 64710
    • Hospital San Jose; Centro de investigacion y transferencia en salud del Tec de Monterrey
• Poland
  • Bydgoszcz, Poland, 85-079
    • NZOZ Vitamed
  • Bydgoszcz, Poland, 85-030
    • Wojewodzki Szpital Obserwacyjno-Zakazny; Oddział Pediatrii, Chorób Infekcyjnych i Hepatologii
  • Debica, Poland, 39-200
    • Prywatny Gabinet Lekarski
  • Siemianowice Śląskie, Poland, 41-103
    • NZLA Michalkowice Jarosz i partnerzy Spolka Lekarska
• Russian Federation
  • Samara, Russian Federation, 443100
    • MC Gepatolog
• Spain
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre; Servicio de Pediatria
  • LA Coruña
    • Santiago de Compostela, LA Coruña, Spain, 15706
      • Complejo Hospitalario Universitario de Santiago (CHUS); Area Asistencial Integrada de Pediatría
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Central Alabama Research; Pediatrics
  • Arkansas
    • Harrisburg, Arkansas, United States, 72432
      • Harrisburg Family Medical Center
    • Jonesboro, Arkansas, United States, 72401
      • The Children's Clinic of Jonesboro, P.A.
  • California
    • Los Angeles, California, United States, 90004
      • The Probe Medical Research
    • Ontario, California, United States, 91762
      • Orange County Research Institute
    • San Diego, California, United States, 92102
      • Khruz Biotechnology Research Institute
  • Florida
    • Pensacola, Florida, United States, 32503
      • Avanza Medical Research Center
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Clinical Research Prime
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Cotton O'Neil Clinic; Stormont-Vail Hlth Care
  • Kentucky
    • Bardstown, Kentucky, United States, 40004
      • Kentucky Pediatric Research Center
  • Missouri
    • Bridgeton, Missouri, United States, 63044
      • Spiegel, Craig
  • Nebraska
    • Omaha, Nebraska, United States, 68134
      • Meridian Clinical Research, LLC
  • Nevada
    • Las Vegas, Nevada, United States, 89104
      • Machuca Family Medicine
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • OnSite Clinical Solutions LLC
    • Smithfield, North Carolina, United States, 15478
      • Montgomery Medical Research /Frontier Clinical Research
  • Ohio
    • Dayton, Ohio, United States, 45414
      • Ohio Pediatric Research Association
  • South Carolina
    • Charleston, South Carolina, United States, 29414
      • Coastal Pediatric Research
  • Tennessee
    • Cleveland, Tennessee, United States, 37312
      • AFC Urgent Care- Cleveland
    • Kingsport, Tennessee, United States, 37660
      • Holston Medical Group
  • Texas
    • Dallas, Texas, United States, 75243
      • Oak Cliff Research Company, LLC
    • Houston, Texas, United States, 77004
      • HD Research Corp
    • Houston, Texas, United States, 77036-3316
      • Mercury Clinical Research
    • San Antonio, Texas, United States, 78240
      • Tekton Research
    • Tomball, Texas, United States, 77375
      • DM Clinical Research
    • Waxahachie, Texas, United States, 75165
      • ClinPoint Trials
  • Utah
    • Salt Lake City, Utah, United States, 84123
      • Advanced Clinical Research - Jordan Ridge Family Medicine
    • Salt Lake City, Utah, United States, 84121
      • FirstMed East (J Lewis Research)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 11 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Aged 1 to < 12 years at randomization (Day 1).
• Written informed consent/assent for study participation obtained from participant's parents or legal guardian, with assent as appropriate by the participant, depending on the patient's level of understanding
• Participant able to comply with study requirements, depending on the patient's level of understanding
• Participant with a diagnosis of influenza virus infection confirmed by the presence of all of the following:
• Fever ≥ 38 degree celsius (tympanic temperature) at screening
• At least one respiratory symptom (either cough or nasal congestion)
• The time interval between the onset of symptoms and screening is ≤ 48 hours

Exclusion Criteria:

• Severe symptoms of influenza virus infection requiring inpatient treatment
• Concurrent infections requiring systemic antiviral therapy at screening
• Require, in the opinion of the investigator, any of the prohibited medication during the study
• Previous treatment with peramivir, laninamivir, oseltamivir, zanamivir, or amantadine within 2 weeks prior to screening
• Immunization with a live/attenuated influenza vaccine in the 2 weeks prior to randomization
• Concomitant treatment with steroids or other immuno-suppressant therapy
• Known HIV infection or other immunosuppressive disorder
• Uncontrolled renal, vascular, neurologic, or metabolic disease (e.g., diabetes, thyroid disorders, adrenal disease), hepatitis, cirrhosis, or pulmonary disease or participants with known chronic renal failure.
• Active cancer at any site
• History of organ transplantation
• Known allergy to either study drug (i.e., baloxavir marboxil and oseltamivir) or to acetaminophen
• Females with child-bearing potential
• Participation in a clinical trial within 4 weeks or five half-lives of exposure to an investigational drug prior to screening, whichever is longer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Baloxavir Marboxil; Participants will receive a single oral dose of baloxavir marboxil on Day 1 (based on body weight). Oseltamivir matching placebo will also be administered orally twice daily (BID) for 5 days.	Drug: Baloxavir Marboxil; Baloxavir marboxil will be administered as oral suspension in a single dose on Day 1. Oseltamivir matching placebo will also be administered as oral suspension twice daily (BID) for 5 days.
ACTIVE_COMPARATOR: Oseltamivir; Participants will receive oseltamivir orally BID for 5 days (based on body weight). Baloxavir marboxil matching placebo will also be administered orally on Day 1	Drug: Oseltamivir; Oseltamivir will be administered as oral suspension BID for 5 days. Participants receiving oseltamivir will also receive baloxavir marboxil matching placebo as oral suspension, single dose on Day 1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. A serious adverse event (SAE) is any significant hazard, contraindication, side effect that is fatal or life-threatening, requires hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability/ incapacity, is a congenital anomaly/ birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above.	Up to Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Alleviation of Influenza Signs and Symptoms	Time to alleviation of influenza signs and symptoms is defined as the length of time taken from the start of treatment to the point at which all of the following criteria are met and remain so for at least 21.5 hours: A score of 0 (no problem) or 1 (minor problem) for cough and nasal symptoms (items 14 and 15 of the Canadian Acute Respiratory Illness and Flu Scale [CARIFS]); A "yes" response to the following question on the CARIFS: "Since the last assessment has the subject been able to return to day care/school, or resume his or her normal daily activity in the same way as performed prior to developing the flu?"; First return to afebrile state (tympanic temperature ≤37.2 degree Celsius [°C])	Up to Day 15
Duration of Fever	Length of time taken by participants to return to afebrile state [tympanic temperature ≤ 37.2°C] and remaining so for at least 21.5 hours.	Up to Day 15
Percentage of Participants Requiring Antibiotics		Up to Day 29
Plasma Concentrations of Baloxavir Marboxil - Sparse PK Population	Results provided by body-weight groups for participants in the Baloxavir Marboxil arm. Values below lower limit of quantification (0.5 ng/mL) are set to zero.	Days 1 (Post-Dose), 2, 4, 6 and 10
Plasma Concentrations of S-033447 - Sparse PK Population	Results provided by body-weight groups for participants in the Baloxavir Marboxil arm.	Days 1 (Post-Dose), 2, 4, 6 and 10
Plasma Concentrations of Baloxavir Marboxil - Extensive PK Population	Results provided by body-weight groups for participants in the Baloxavir Marboxil arm. Values below lower limit of quantification (0.5 ng/mL) are set to zero.	Days 1 (Post-Dose), 2, 4, 6 and 10
Plasma Concentrations of S-033447 - Extensive PK Population	Results provided by body-weight groups for participants in the Baloxavir Marboxil arm. Values below lower limit of quantification (0.5 ng/mL) are set to zero.	Days 1 (Post-Dose), 2, 4, 6 and 10
Duration of Symptoms	The clinical efficacy of baloxavir marboxil is evaluated by duration of symptoms i.e., alleviation of all symptoms as defined by a score of 0 [no problem] or 1 [minor problem] and remaining so for at least 21.5 hours, for all 18 symptoms specified in the CARIFS questionnaire.	Up to Day 15
Time to Return to Normal Health and Activity	Time to Return to Normal health and activity' is identified by a 'Yes' response to the following question on the CARIFS: "Since the last assessment has the patient been able to return to day care/school, or resume his or her normal daily activity in the same way as performed prior to developing the flu?"	Up to Day 15
Frequency of Influenza-Related Complications	Influenza related complications include death, hospitalization, radiologically confirmed pneumonia, bronchitis, sinusitis, otitis media, encephalitis/encephalopathy, febrile seizures, myositis.	Up to Day 29
Percentage of Participants With Influenza-Related Complications	Influenza related complications include death, hospitalization, radiologically confirmed pneumonia, bronchitis, sinusitis, otitis media, encephalitis/encephalopathy, febrile seizures, myositis.	Up to Day 29
Time to Cessation of Viral Shedding by Virus Titer	Time to cessation of viral shedding by virus titer is defined as the time, in hours, between the initiation of any study treatment and first time when the influenza virus titer is below the limit of detection.	Day 1 - Day 29
Time to Cessation of Viral Shedding by RT-PCR	Time to cessation of viral shedding by RT-PCR, in hours, is defined as the time between the initiation of any study treatment and first time when the virus RNA by RT-PCR is below the limit of detection.	Day 1 - Day 29
Change From Baseline in Influenza Virus Titer at Day 2, 4, 6, 10, 15, 29	Influenza virus titer (log10TCID50/ML) is the quantity of influenza virus in a given volume within the samples obtained from nasal swabs. If influenza virus titer was less than the lower limit of quantification, the virus titer was imputed as 0.749 (log10TCID50/mL). A lower value indicates lower viral titer.	Baseline, Day 2, 3 (optional), 4, 6, 10, 15 (optional), 29
Change From Baseline in the Amount of Virus RNA (RT-PCR) at Day 2, 4, 6, 10, 15, 29	If the amount of virus RNA was less than the lower limit of quantification, the amount of virus RNA was imputed as 2.18 for flu A and 2.93 for flu B (log10 virus particles/mL)	Baseline, Day 2, 3 (optional), 4, 6, 10, 15 (optional), 29
Percentage of Participants With Positive Influenza Virus Titer at Day 2, 4, 6, 10		Baseline, Day 2, 3 (optional), 4, 6, 10
Percentage of Participants Positive by RT-PCR at Day 2, 4, 6, 10, 15, 29		Day 2, 3 (optional), 4, 6, 10, 15 (optional), 29
Area Under the Curve in Virus Titer	Area under the curve (AUC) in virus titer was calculated using the trapezoidal method.	Day 1 - Day 29
Area Under the Curve in the Amount of Virus RNA (RT-PCR)	AUC in virus RNA (RT-PCR) is defined as AUC of change from baseline in the amount of virus RNA (RT-PCR) from Day 1 to Day 10. AUC is calculated using the trapezoidal method similar to AUC in virus titer.	Day 1 - Day 10
Area Under the Concentration to Time Curve From Time 0 to Infinity (AUC0-inf) of Baloxavir Marboxil	Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs.	Up to Day 10
Area Under the Concentration to Time Curve From Time 0 to Infinity (AUC0-inf) of S-033447.	Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs.	Up to Day 10
Maximum Plasma Concentration (Cmax) of Baloxavir Marboxil	Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs.	Up to Day 10
Maximum Plasma Concentration (Cmax) of S-033447	Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs.	Up to Day 10
Time to Maximum Plasma Concentration (Tmax) of Baloxavir Marboxil	Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs.	Up to Day 10
Time to Maximum Plasma Concentration (Tmax) of S-033447	Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs.	Up to Day 10
Plasma Concentrations of Baloxavir Marboxil by Dosage	Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs.	24, 72, 96 and 240 hours post-dose
Plasma Concentrations of S-033447 by Dosage	Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs.	24, 72, 96 and 240 hours post-dose

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Baker J, Block SL, Matharu B, Burleigh Macutkiewicz L, Wildum S, Dimonaco S, Collinson N, Clinch B, Piedra PA. Baloxavir Marboxil Single-dose Treatment in Influenza-infected Children: A Randomized, Double-blind, Active Controlled Phase 3 Safety and Efficacy Trial (miniSTONE-2). Pediatr Infect Dis J. 2020 Aug;39(8):700-705. doi: 10.1097/INF.0000000000002747.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 20, 2018
• Primary Completion (ACTUAL): April 3, 2019
• Study Completion (ACTUAL): April 3, 2019

Study Registration Dates

• First Submitted: August 10, 2018
• First Submitted That Met QC Criteria: August 10, 2018
• First Posted (ACTUAL): August 14, 2018

Study Record Updates

• Last Update Posted (ACTUAL): April 29, 2020
• Last Update Submitted That Met QC Criteria: April 28, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Oseltamivir; Baloxavir
• Other Study ID Numbers: CP40563; 2018-002169-21 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No