This study will evaluate the efficacy, safety, and pharmacokinetics of baloxavir marboxil in combination with a standard-of-care (SOC) neuraminidase inhibitor (NAI) (i.e., oseltamivir, zanamivir, or peramivir) compared with a matching placebo in…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
TTCI defined as:
** Time to hospital discharge OR
** Time to NEWS2 of * 2 maintained for 24 hours
Secondary outcome
Key Secondary Endpoint:
** Response rates of the 6-point ordinal scale at Day 7
** Time to clinical response based on temperature ranges, oxygen saturation,
respiratory status, heart rate, and hospitalization status.
Other Secondary Endpoints:
** Incidence of mechanical ventilation
** Duration of mechanical ventilation
** Incidence of ICU stay
** Duration of ICU stay
** Time to clinical failure, defined as the time to death, mechanical
ventilation, or ICU admission, corresponding to ordinal scale categories 6, 5,
and 4, respectively, from baseline
** Time to hospital discharge
** Incidence of post-treatment influenza-related complications a
** Mortality rate at Day 7
** Mortality rate at Day 28
** Time to NEWS2 of * 2 maintained for 24 hours
Exploratory Endpoints:
** Time to clinical response based on temperature ranges, oxygen saturation,
respiratory status, heart rate, and hospitalization status
Virology Endpoints
**Time to cessation of viral shedding by virus titer
**Time to cessation of viral shedding by RT-PCR
**Change from baseline in influenza virus titer and in the amount of virus RNA
(RT-PCR) at each timepoint
**Proportion of patients with positive influenza virus titer and proportion of
patients positive by RT-PCR at each timepoint
** AUC in virus titer and in the amount of virus RNA (RT-PCR)
** Polymorphic and treatment-emergent amino acid substitutions in the PA, PB1,
PB2, and NA genes
** Drug susceptibility in patients with evaluable virus
Safety Endpoints
*** Compare the incidence and severity of AEs and SAEs
*** Incidence of AEs leading to discontinuation
*** Proportion of patients with any post-treatment ALT and AST above baseline
and *3 * ULN, *5 * ULN,*10 * ULN
Pharmacokinetic Endpoints
***Plasma concentrations of baloxavir (active metabolite) at specified
timepoints
***After each dose, concentration at predose and 24 hours postdose will be
summarized
*** Non-compartmental PK parameters such as AUC, Cmax and t1/2 (only for
patients undergoing sequential PK sampling)
Exploratory Palatability and Acceptability Endpoint
***Number and proportion of patients reporting each palatability and
acceptability response at each timepoint
Background summary
Influenza virus infection can lead to severe outcomes in patients with
underlying medical
comorbidities or in other vulnerable groups at risk of complications. For
example,
influenza predisposes individuals to secondary bacterial infection, which may
progress in
severity leading to poor prognosis. Other serious
complications can also develop, including cardiac and neurological
complications.
There are no approved drugs licensed for the treatment of patients hospitalized
with
influenza; however, treatment guidelines endorse the use of NAIs, such as
oseltamivir,
in the hospitalized population. Baloxavir marboxil
appears to have significant virological efficacy, offering the potential to
treat influenza in
the hospitalized population more effectively than currently available
treatments.
Preclinical studies of baloxavir marboxil used in combination with NAIs have
shown
synergistic effects on inhibition of viral replication. Baloxavir
marboxil in combination with a NAI is expected to produce a greater reduction
in viral
load than either baloxavir marboxil or a NAI alone.
Therefore, an active-controlled study to assess the efficacy and safety of
baloxavir
marboxil in hospitalized patients with influenza is justified to address the
high unmet
need and burden of disease in hospitalized patients. See rationale in protocol.
Study objective
This study will evaluate the efficacy, safety, and pharmacokinetics of
baloxavir marboxil in combination with a standard-of-care (SOC) neuraminidase
inhibitor (NAI) (i.e., oseltamivir, zanamivir, or peramivir) compared with a
matching placebo in combination with a SOC NAI in
hospitalized patients with influenza. Specific objectives and corresponding
endpoints for the study are outlined below. In this protocol, "study treatment"
refers to baloxavir marboxil or its matching placebo. Study treatment is given
in combination with a SOC NAI.
Primary Objective Corresponding Endpoint
* * To evaluate the clinical efficacy of baloxavir marboxil plus a SOC NAI
compared with matching placebo plus a SOC NAI, Endpoint: Time to clinical
improvement (defined as time to hospital discharge OR time to NEWS2 of less
than or equal to 2 maintained for 24 hours.
Efficacy Objectives
* * To evaluate the clinical efficacy of baloxavir marboxil plus a SOC NA
compared with matching placebo plus a SOC NAI
Virology Objectives
* *To evaluate the virological activity of baloxavir marboxil plus a SOC NAI
compared with matching placebo plus a SOC NAI
* To evaluate the polymorphic and treatment-emergent amino acid
substitutions in the PA, PB1, PB2, and NA genes and drug susceptibility in
patients with evaluable virus
Safety Objective (cont.)
** To evaluate the safety of baloxavir marboxil plus a SOC NAI compared
with matching placebo plus a SOC NAI in hospitalized patients
with influenza
Pharmacokinetic Objective
** To evaluate the single- and multiple-dose pharmacokinetics of baloxavir
Exploratory Palatability and Acceptability Objective
**To describe the palatability and acceptability of the oral suspension in
hospitalized patients with influenza
Study design
Description of Study
This is a Phase III, randomized, double-blind, placebo-controlled, multicenter
study to assess the efficacy, safety, and pharmacokinetics of baloxavir
marboxil in combination with a SOC NAI(i.e., oseltamivir, zanamivir, or
peramivir), compared with a matching placebo in combination
with a SOC NAI in approximately 240 hospitalized adults and adolescent patients
(aged 12 years) with influenza.
Intervention
Patients will be randomized as soon as possible after screening, providing they
are within 96 hours of symptom onset and hospitalized (includes assessment in
emergency centers pending admission to a hospital ward). Patients will be
assigned in a 2:1 ratio to receive baloxavir marboxil or matching placebo.
Study treatment must be given in combination with a SOC NAI according to
investigator preference (i.e., oseltamivir, zanamivir, or peramivir).
Re-screening of patients who fail to meet the inclusion and exclusion criteria
will be permitted only once, providing the time from symptom onset to
randomization is still within 96 hours. Baloxavir marboxil will be administered
as a weight-based dose (40 mg for patients weighing 40 to * 80 kg, 80 mg for
patients weighing * 80 kg) on Days 1 and 4, and also on Day 7 if clinical
improvement has not occurred at Day 5, per protocol defined criteria. Treatment
with a SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) should be
administered in accordance with local clinical practice. To fully explore the
utility of the combination with baloxavir marboxil, or matching placebo, the
dosing regimen of the SOC NAI should aim to ensure that anti-viral activity is
maintained from Day 1 to Day 5. The SOC NAI treatment may be extended to Day 10
or beyond at the discretion of the investigator and in accordance with local
clinical practice. The study consists of two periods: a 10-day treatment period
and a 25-day follow-up period. Therefore, the maximum study duration for each
patient will be 35 days.
The study assessments to be conducted include the following: physical
examination, vital signs, assessment of consciousness, presence, or absence of
respiratory support, adverse events, concomitant therapies, clinical laboratory
tests, and nasopharyngeal swabs. An external independent Data Monitoring
Committee (iDMC) will evaluate safety according to policies and procedures
detailed in an iDMC Charter.
Study burden and risks
Procedure
* Nasopharyngeal swab
* Screening (possibly twice)
* Days 2, 3, 4, 5, 7, 10
* Further swabs after Day 10 taken only if the study doctor thinks it*s
necessary based on flu recovery
Potential Risks
* The nasal swab may be uncomfortable
Procedure
* Tracheal (windpipe) aspirates
* Same time points as Nasopharyngeal swab but only if the
patient is intubated
Potential Risks
* Potential risk of scratching or bruising and may cause discomfort.
Other less common side effects may include irregular heartbeat,
tracheal mucosal damage, and possible chance of infection
Procedure
* Blood sample (about 1 tablespoon on Screening/Day 1, and about * tablespoon
or less on each day(s) listed after Screening/Day 1)
* Screening/Day 1 (4-5 blood draws)
* Day 2 (1 blood draws)
* Day 4 (1*2 blood draws)
* Day 5 (1 blood draws)
* Day 7 (1*2 blood draws)
* Day 10 (1 blood draw)
* Days 11 to 30 (1 blood draw during this period). If you remain in
hospital during this period additional draws only if it*s necessary
* Any unscheduled visits (if the study doctor thinks it is necessary)
* Day 35 (1 blood draw)
Potential Risks
* Drawing blood can cause pain, bruising, or infection where the needle
is inserted. Some people experience dizziness, fainting, or upset
stomach when their blood is drawn.
Screening/Day 1 * On the first day, some procedures will be done to see if the
patient meets the criteria to be in the study (Screening). Also, some
procedures will be done after the patients receives the first dose of study
treatment (Day 1).
Non-Invasive Procedures with Minimal Risks
* Review of medical history, including medications at screening
* Recording of demographic information, such as age, sex, race/ethnicity at
screening
* Vital signs: temperature, pulse rate, blood pressure, breathing rate, oxygen
level in circulating blood
* Screening
* Every day while in the hospital on a regular basis to monitor the patient;
for example, four times a day
* Every visit after leaving the hospital (if the study doctor thinks it is
necessary)
* Complete physical examination (including height and weight) at screening/ day
1
* Limited physical examination (may include height or weight)
* Every day while in the hospital (if the study doctor thinks it is
necessary)
* Every visit after leaving the hospital (if the study doctor thinks it is
necessary)
* Review changes in your health or medications
* Every day while in the hospital
* Every visit after leaving the hospital
* Electrocardiogram (ECG) at screening at day 2
* Chest X ray or CT scan at screening/ day 1
* Urine sample for pregnancy test (females of chilbearing potential only)
* Any unscheduled visits (if the study doctor thinks it is necessary)
* Day 35
* Serum sample for pregnancy test (females of chilbearing potential only)
* Screening
Grenzacherstrasse 124
Basel 4070
CH
Grenzacherstrasse 124
Basel 4070
CH
Listed location countries
Age
Inclusion criteria
- Adult patients: signed Informed Consent Form
- Adolescent patients not able to legally consent: written informed
consent/assent for study
participation obtained from patient*s parents or legal guardian, with assent as
appropriate
by the patient, depending on the patient*s level of understanding
- Age * 12 years at the time of signing the Informed Consent Form/Assent Form
- Ability to comply with the study protocol, in the investigator*s judgment
- Patients who require hospitalization for severe influenza or acquire
influenza during
hospitalization, the severity of which requires an extension of hospitalization
- Diagnosis of influenza A and/or B by a positive Rapid Influenza Diagnostic
Test (RIDT) or
reverse transcriptase polymerase chain reaction (RT-PCR)
Positive results from local tests are acceptable if results are documented
within the
previous 24 hours.
- The time interval between the onset of symptoms and randomization is within 5
days
The onset of symptoms is defined as the time when the patient experiences at
least
one new general symptom (headache, feverishness or chills, muscle or joint pain,
fatigue), respiratory symptom (cough, sore throat, nasal congestion), or fever.
- A score of * 4 based on the National Early Warning Score 2 (NEWS2)
- Patients will require objective criteria of seriousness defined by at least
one of the following
criteria:
* Requires ventilation or supplemental oxygen to support respiration
* Has a complication related to influenza that requires hospitalization (e.g.,
pneumonia,
CNS involvement, myositis, rhabdomyolysis, acute exacerbation of chronic kidney
disease, asthma or chronic obstructive pulmonary disease [COPD], severe
dehydration,
myocarditis, pericarditis, ischemic heart disease)
- 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 less than 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 (*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
influenza at the
time of screening
- Patients who have received baloxavir marboxil for the current influenza
infection
- Known contraindications to the SOC NAI, unless an alternative NAI is
available for use in
the study
- Known hypersensitivity to baloxavir marboxil or the drug product
excipients
- Patients hospitalized for social reasons (e.g., lack of carers at home)
- Patients expected to die or be discharged within 48 hours, according to the
investigator*s
judgement
- Patients weighing < 40 kg
- Patients with 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 of
screening (according to local laboratory reference ranges if using local
laboratory data:
- 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
- Patients who have received treatment within 5 half-lives or 30 days
(whichever is longer) of
exposure to an investigational drug
- 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-001416-30-NL |
| ClinicalTrials.gov | NCT03684044 |
| CCMO | NL67116.029.19 |