InfluenzaPhase 3CAPSTONE 1NCT02954354
A Study of S-033188 (Baloxavir Marboxil) Compared With Placebo or Oseltamivir in Otherwise Healthy Patients With Influenza
A Phase 3 study testing Baloxavir Marboxil and Oseltamivir in people with Influenza, run by Shionogi.
Trial summary
The primary objective of this study is to evaluate the efficacy of a single, oral dose of baloxavir marboxil compared with placebo by measuring the time to alleviation of symptoms in patients with uncomplicated influenza virus infection. Read more about this study
- Who is it for?
- Ages 12 to 64 years
- Conditions the study is for
- Influenza
- What is being tested?
- Baloxavir Marboxil and Oseltamivir
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,436 participants
- Where
- No sites listed yet
- Study dates
- 8 Dec 2016to 24 Apr 2017
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 64 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Patients who are able to understand the study and comply with all study procedures, and willing to provide written informed consent/assent prior to the predose examinations appropriately. As for adolescent patients, informed consent/assent of voluntary participation should be obtained in accordance with local requirements
- Male or female patients aged ≥ 12 to ≤ 64 years at the time of signing the informed consent/assent form.
- Patients with a diagnosis of influenza virus infection confirmed by all of the following:
- Fever ≥ 38ºC (axillary) in the predose examinations or > 4 hours after dosing of antipyretics if they were taken
- At least one of the following general systemic symptoms associated with influenza are present with a severity of moderate or greater
- Headache
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- Feverishness or chills
- Muscle or joint pain
- Fatigue
- At least one of the following respiratory symptoms associated with influenza are present with a severity of moderate or greater
- Cough
- Sore throat
- Nasal congestion
- The time interval between the onset of symptoms and the predose examinations is 48 hours or less. The onset of symptoms is defined as either:
- Time of the first increase in body temperature (an increase of at least 1ºC from normal body temperature)
- Time when the patient experiences at least one general or respiratory symptom
- Women of childbearing potential who agree to use a highly effective method of contraception for 3 months after the first dose of study drug
Who cannot join
- Patients with severe influenza virus infection requiring inpatient treatment.
- Patients aged ≥ 20 years with known allergy to oseltamivir (Tamiflu®).
- Patients with any of the following risk factors
- Women who are pregnant or within 2 weeks post-partum
- Residents of long-term care facilities (eg, welfare facilities for the elderly, nursing homes)
- Chronic respiratory diseases including bronchial asthma
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- Neurological and neurodevelopmental disorders including disorders of the brain, spinal cord, peripheral nerve, and muscle (eg, cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability, moderate to severe developmental delay, muscular dystrophy, or spinal cord injury)
- Heart disease (such as congenital heart disease, congestive heart failure, or coronary artery disease), excluding hypertension without any other heart-related symptoms)
- American Indians and Alaskan natives
- Blood disorders (such as sickle cell disease)
- Endocrine disorders (including diabetes mellitus)
- Kidney disorders
- Liver disorders
- Metabolic disorders
- Compromised immune system (including patients receiving immunosuppressant therapy, or those with cancer or human immunodeficiency virus [HIV] infection)
- Morbid obesity (body mass index [BMI] ≥ 40)
- Patients unable to swallow tablets or capsules.
- Patients who have previously received Baloxavir Marboxil.
- Patients weighing < 40 kg
- Patients who have been exposed to an investigational drug within 30 days prior to the predose examinations.
- Women who are breastfeeding or have a positive pregnancy test in the predose examinations. The following female patients who have documentation of either a or b below do not need to undergo a pregnancy test in the predose examinations:
- Postmenopausal (defined as cessation of regular menstrual periods for 2 years or more and confirmed by a follicle-stimulating hormone test) women
- Women who are surgically sterile by hysterectomy, bilateral oophorectomy, or tubal ligation
- Patients with concurrent infections requiring systemic antimicrobial and/or antiviral therapy at the predose examinations.
- Patients who have received peramivir, laninamivir, oseltamivir, zanamivir, rimantadine, umifenovir, or amantadine within 30 days prior to the predose examinations.
- Patients who have received an investigational monoclonal antibody for a viral disease in the last year.
- Patients with severe underlying diseases.
- Patients with known creatinine clearance ≤ 60 mL/min.
- Patients who, in the opinion of the investigator, would be unlikely to comply with required study visits, self-assessments, and interventions
About this study
Official title: A Phase 3, Multicenter, Randomized, Double-blind Study of a Single Dose of S-033188 (Baloxavir Marboxil) Compared With Placebo or Oseltamivir 75 mg Twice Daily for 5 Days in Otherwise Healthy Patients With Influenza
The primary objective of this study is to evaluate the efficacy of a single, oral dose of baloxavir marboxil compared with placebo by measuring the time to alleviation of symptoms in patients with uncomplicated influenza virus infection.
- Conditions
- Influenza
- Being tested
- Baloxavir Marboxil, Placebo to Baloxavir Marboxil, Oseltamivir, Placebo to Oseltamivir
- Keywords
- Flu, Baloxavir Marboxil, Oseltamivir, Tamiflu®
- Medical subject headings
- Influenza, Human
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Baloxavir MarboxilDrug
Also called S-033188
2 to4 X 20-mg tablets taken orally
Placebo to Baloxavir MarboxilDrug
2 to4 X 20-mg tablets taken orally
OseltamivirDrug
Also called Tamiflu®
75 mg capsules taken orally
Placebo to OseltamivirDrug
Placebo capsules matching oseltamivir 75 mg capsules
| Study group | Role | What they receive |
|---|---|---|
| Adults: Baloxavir Marboxil | Experimental | Participants aged 20 to 64 years will receive two or four 20 mg baloxavir marboxil tablets orally on Day 1 and one oseltamivir placebo capsule orally twice a day (BID) on Days 1 to 5. Receives: Drug: Baloxavir Marboxil; Drug: Placebo to Oseltamivir |
| Adults: Oseltamivir | Active comparator | Participants aged 20 to 64 years will receive 75 mg oseltamivir twice a day on Days 1 to 5 and two or four baloxavir marboxil placebo tablets on Day 1. Receives: Drug: Placebo to Baloxavir Marboxil; Drug: Oseltamivir |
| Adults: Placebo | Placebo comparator | Participants aged 20 to 64 years will receive two or four baloxavir marboxil placebo tablets on Day 1 and one oseltamivir placebo capsule orally twice a day on Days 1 to 5. Receives: Drug: Placebo to Baloxavir Marboxil; Drug: Placebo to Oseltamivir |
| Adolescents: Baloxavir Marboxil | Experimental | Participants aged 12 to 19 years will receive two or four baloxavir marboxil 20 mg tablets on Day 1. Receives: Drug: Baloxavir Marboxil |
| Adolescents: Placebo | Placebo comparator | Participants aged 12 to 19 years will receive two or four baloxavir marboxil placebo tablets on Day 1. Receives: Drug: Placebo to Baloxavir Marboxil |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to Alleviation of Symptoms in Participants Randomized to Baloxavir or Placebo
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms).
Time to alleviation of symptoms was defined as the time from the start of the study treatment to the time when all seven influenza-related symptoms were assessed by the participant as absent (0) or mild (1) for at least 21.5 hours.
Time to alleviation of symptoms was analyzed using the Kaplan-Meier (KM) method; participants who did not experience alleviation of symptoms were censored at the last observation time point.
Measured: Initiation of study treatment up to Day 14
Time to Alleviation of Symptoms in Adults Randomized to Baloxavir or Oseltamivir
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms).
Time to alleviation of symptoms was defined as the time from the start of the study treatment to the time when all seven influenza-related symptoms were assessed by the participant as absent (0) or mild (1) for at least 21.5 hours.
Time to alleviation of symptoms was analyzed using the Kaplan-Meier(KM) method; participants who did not experience alleviation of symptoms were censored at the last observation time point.
Measured: Initiation of study treatment up to Day 14
Secondary outcomes (37)
Percentage of Participants With Positive Influenza Virus Titer at Each Time Point in Participants Randomized to Baloxavir or Placebo
Virus titer was quantified from nasopharyngeal swabs (or throat swabs if nasopharyngeal swabbing was not feasible) by tissue culture methods. Positive influenza virus titer was defined as virus titer not less than the lower limit of quantification (0.7 log₁₀ of the 50% tissue culture infective dose (TCID₅₀/mL) among those assessed for virus titer on Days 2, 3, 4, 5, 6 and 9.
Measured: Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Percentage of Participants With Positive Influenza Virus Titer at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Virus titer was quantified from nasopharyngeal swabs (or throat swabs if nasopharyngeal swabbing was not feasible) by tissue culture methods. Positive influenza virus titer was defined as virus titer not less than the lower limit of quantification (0.7 log₁₀ of the 50% tissue culture infective dose (TCID₅₀/mL) among those assessed for virus titer on Days 2, 3, 4, 5, 6 and 9.
Measured: Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point in Participants Randomized to Baloxavir or Placebo
Influenza virus ribonucleic acid (RNA) was quantified from nasopharyngeal swabs (or throat swabs, if nasopharyngeal swabbing was not feasible). The percentage of participants with detectable virus RNA (2.05 for flu A and 2.83 for flu B log₁₀ virus particles/mL) among those assessed measured by reverse transcription polymerase chain reaction (RT-PCR) on Days 2, 3, 4, 5, 6 and 9.
Measured: Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Influenza virus RNA was quantified from nasopharyngeal swabs (or throat swabs, if nasopharyngeal swabbing was not feasible). The percentage of participants with detectable virus RNA (2.05 for flu A and 2.83 for flu B log₁₀ virus particles/mL) among those assessed measured by reverse transcription polymerase chain reaction (RT-PCR) on Days 2, 3, 4, 5, 6 and 9.
Measured: Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Change From Baseline in Virus Titer at Each Time Point in Participants Randomized to Baloxavir or Placebo
Virus titer was quantified from nasopharyngeal swabs (or throat swabs if nasopharyngeal swabbing was not feasible) by tissue culture methods.
If virus titer was less than the lower limit of quantification, the virus titer was imputed 0.7 (TCID₅₀/mL).
Measured: Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Change From Baseline in Virus Titer at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Virus titer was quantified from nasopharyngeal swabs (or throat swabs if nasopharyngeal swabbing was not feasible) by tissue culture methods.
If virus titer was less than the lower limit of quantification, the virus titer was imputed 0.7 (TCID₅₀/mL).
Measured: Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Change From Baseline in Virus RNA (RT-PCR) at Each Time Point in Participants Randomized to Baloxavir or Placebo
Nasopharyngeal swabs (or throat swabs, if nasopharyngeal swabbing was not feasible) were obtained for viral quantitation. Virus RNA is measured by reverse transcription polymerase chain reaction (RT-PCR).
Measured: Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Change From Baseline in Virus RNA (RT-PCR) at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Nasopharyngeal swabs (or throat swabs, if nasopharyngeal swabbing was not feasible) were obtained for viral quantitation. Virus RNA was measured by reverse transcription polymerase chain reaction (RT-PCR).
Measured: Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer in Participants Randomized to Baloxavir or Placebo
This endpoint was defined as AUC of change from Baseline in virus titer from Day 1 to Day 9. AUC was calculated using the trapezoidal method.
Measured: Day 1 to Day 9
Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer in Adults Randomized to Baloxavir or Oseltamivir
This endpoint was defined as AUC of change from Baseline in virus titer from Day 1 to Day 9. AUC was calculated using the trapezoidal method.
Measured: Day 1 to Day 9
Area Under the Curve (AUC) Adjusted by Baseline of Influenza Virus RNA in Participants Randomized to Baloxavir or Placebo
This endpoint was defined as AUC of change from baseline in the amount of virus RNA (RT-PCR) from Day 1 to Day 9. The AUC was calculated using the trapezoidal method.
Measured: Day 1 to Day 9
Area Under the Curve (AUC) Adjusted by Baseline of Influenza Virus RNA in Adults Randomized to Baloxavir or Oseltamivir
This endpoint was defined as AUC of change from baseline in the amount of virus RNA (RT-PCR) from Day 1 to Day 9. The AUC was calculated using the trapezoidal method.
Measured: Day 1 to Day 9
Time to Cessation of Viral Shedding Determined by Virus Titer in Participants Randomized to Baloxavir or Placebo
Time to cessation of viral shedding by virus titer was defined as the time between the initiation of the study treatment and first time when the virus titer was below the limit of detection (0.7 log₁₀[TCID₅₀/mL]). The median and 95% confidence interval (CI) for time to cessation of viral shedding determined by virus titer was analyzed using the Kaplan-Meier (KM) method; participants whose virus titer had not reached cessation by the last observation time point were treated as censored at that time point.
Measured: Day 1 to Day 9
Time to Cessation of Viral Shedding Determined by Virus Titer in Adults Randomized to Baloxavir or Oseltamivir
Time to cessation of viral shedding by virus titer was defined as the time between the initiation of the study treatment and first time when the virus titer was below the limit of detection (0.7 log₁₀[TCID₅₀/mL]). The time to cessation of viral shedding determined by virus titer was analyzed using the Kaplan-Meier (KM) method; participants whose virus titer had not reached cessation by the last observation time point were treated as censored at that time point.
Measured: Day 1 to Day 9
Time to Cessation of Viral Shedding Determined by Virus RNA in Participants Randomized to Baloxavir or Placebo
Time to cessation of viral shedding by RT-PCR was defined as the time between the initiation of the study treatment and first time when the virus RNA was below the limit of detection measured by RT-PCR.
Time to cessation of viral shedding by RT-PCR was analyzed using the KM method; participants whose virus RNA had not reached cessation by the last observation time point were treated as censored at that time point.
Measured: Day 1 to Day 9
Time to Cessation of Viral Shedding Determined by Virus RNA in Adults Randomized to Baloxavir or Oseltamivir
Time to cessation of viral shedding by RT-PCR was defined as the time between the initiation of the study treatment and first time when the virus RNA was below the limit of detection measured by RT-PCR.
Time to cessation of viral shedding by RT-PCR was analyzed using the KM method; participants whose virus RNA had not reached cessation by the last observation time point were treated as censored at that time point.
Measured: Day 1 to Day 9
Percentage of Participants Whose Symptoms Were Alleviated at Each Time Point in Participants Randomized to Baloxavir or Placebo
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms). Alleviation of symptoms was defined as all seven influenza-related symptoms assessed by the participant as absent (0) or mild (1) .
Measured: 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours after the initial dose of study treatment
Percentage of Participants Whose Symptoms Were Alleviated at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms). Alleviation of symptoms was defined as all seven influenza-related symptoms assessed by the participant as absent (0) or mild (1) .
Measured: 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours after the initial dose of study treatment
Time to Alleviation of the Four Systemic Symptoms in Participants Randomized to Baloxavir or Placebo
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms).
Time to alleviation of the 4 systemic symptoms was defined as the time between the initiation of the study treatment to the time when all 4 systemic symptoms (headache, feverishness or chills, muscle or joint pain, and fatigue) were assessed by the participant as 0 (None) or 1 (Mild) for a duration of at least 21.5 hours.
Time to alleviation of the 4 systemic symptoms was analyzed using KM methods; participants who did not experience alleviation of symptoms were censored at the last observation time point.
Measured: Initiation of study treatment up to Day 14
Time to Alleviation of the Four Systemic Symptoms in Adults Randomized to Baloxavir or Oseltamivir
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms).
Time to alleviation of the 4 systemic symptoms was defined as the time between the initiation of the study treatment to the time when all 4 systemic symptoms (headache, feverishness or chills, muscle or joint pain, and fatigue) were assessed by the participant as 0 (None) or 1 (Mild) for a duration of at least 21.5 hours.
Time to alleviation of the 4 systemic symptoms was analyzed using KM methods; participants who did not experience alleviation of symptoms were censored at the last observation time point.
Measured: Initiation of study treatment up to Day 14
Time to Alleviation of the Three Respiratory Symptoms in Participants Randomized to Baloxavir or Placebo
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms). Time to alleviation of the 3 respiratory symptoms was defined as the time from the start of study treatment to the time when all 3 respiratory symptoms (cough, sore throat and nasal congestion) were assessed by the participant as absent (0) or mild (1) for at least 21.5 hours.
Time to alleviation of the 3 respiratory symptoms was analyzed using the KM method; participants who did not experience alleviation of symptoms were censored at the last observation time point.
Measured: Initiation of study treatment up to Day 14
Time to Alleviation of the Three Respiratory Symptoms in Adults Randomized to Baloxavir or Oseltamivir
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms). Time to alleviation of the 3 respiratory symptoms was defined as the time from the start of study treatment to the time when all 3 respiratory symptoms (cough, sore throat and nasal congestion) were assessed by the participant as absent (0) or mild (1) for at least 21.5 hours.
Time to alleviation of the 3 respiratory symptoms was analyzed using the KM method; participants who did not experience alleviation of symptoms were censored at the last observation time point.
Measured: Initiation of study treatment up to Day 14
Change From Baseline in Composite Symptom Score at Each Time Point in Participants Randomized to Baloxavir or Placebo
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms).
The composite symptom score is the total score of the 7 influenza symptoms as assessed by the participant, and ranges from 0 to 21.
Measured: Day 1 pretreatment (Baseline) and 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 216 hours after the initial dose of study treatment.
Change From Baseline in Composite Symptom Score at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms).
The composite symptom score is the total score of the 7 influenza symptoms as assessed by the participant, and ranges from 0 to 21.
Measured: Day 1 pretreatment (Baseline) and 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 216 hours after the initial dose of study treatment.
Time to Resolution of Fever in Participants Randomized to Baloxavir or Placebo
Time to resolution of fever was defined as the time between the initiation of the study treatment and the resolution of fever. The resolution of fever was defined as the time when the participant's self-measured axillary temperature became less than 37ºC and was maintained at less than 37ºC for a duration of at least 12 hours.
Time to resolution of fever was analyzed using KM methods; participants who did not experience resolution of fever by the last observation time point were censored at that time point.
Measured: Initiation of study treatment up to Day 14
Time to Resolution of Fever in Adults Randomized to Baloxavir or Oseltamivir
Time to resolution of fever was defined as the time between the initiation of the study treatment and the resolution of fever. The resolution of fever was defined as the time when the participant's self-measured axillary temperature became less than 37ºC and was maintained at less than 37ºC for a duration of at least 12 hours.
Time to resolution of fever was analyzed using KM methods; participants who did not experience resolution of fever by the last observation time point were censored at that time point.
Measured: Initiation of study treatment up to Day 14
Percentage of Participants Reporting Normal Temperature at Each Time Point in Participants Randomized to Baloxavir or Placebo
Defined as the percentage of patients whose axillary temperature dropped to less than 37ºC after the initiation of study treatment.
Measured: 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours after the initial dose of study treatment
Percentage of Participants Reporting Normal Temperature at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Defined as the percentage of patients whose axillary temperature dropped to less than 37ºC after the initiation of study treatment.
Measured: 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours after the initial dose of study treatment
Body Temperature at Each Time Point in Participants Randomized to Baloxavir or Placebo
Participant's self-measured axillary temperature using an electronic thermometer.
Measured: 12, 24, 36, 48, 72, 96 and 120 hours after the initial dose of study treatment
Body Temperature at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Participant's self-measured axillary temperature using an electronic thermometer.
Measured: 12, 24, 36, 48, 72, 96 and 120 hours after the initial dose of study treatment
Time to Alleviation of Individual Symptoms in Participants Randomized to Baloxavir or Placebo
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms).
Time to alleviation of each symptom was defined as the time from the start of treatment to the start of the time period when the individual symptom was assessed by the participant as 0 (None) or 1 (Mild) for a duration of at least 21.5 hours.
Measured: Initiation of study treatment up to Day 14
Time to Alleviation of Individual Symptoms in Adults Randomized to Baloxavir or Oseltamivir
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms).
Time to alleviation of each symptom was defined as the time from the start of treatment to the start of the time period when the individual symptom was assessed by the participant as 0 (None) or 1 (Mild) for a duration of at least 21.5 hours.
Measured: Initiation of study treatment up to Day 14
Time to Return to Preinfluenza Health Status in Participants Randomized to Baloxavir or Placebo
Participants were asked to record their preinfluenza health status on a scale from 0 (worst possible health) to 10 (normal health [for someone your age and your health condition]), and their health status every day after initiation of study treatment on the same scale. Return to preinfluenza health status was defined as time from the initiation of the study treatment to the first time when the health status score was equal to or higher than the preinfluenza health status score.
Time to return to preinfluenza health status was analyzed using KM methods; participants with a smaller number on the scale for health status by the last observation time point were censored at that time point.
Measured: Initiation of study treatment up to Day 14
Time to Return to Preinfluenza Health Status in Adults Randomized to Baloxavir or Oseltamivir
Participants were asked to record their preinfluenza health status on a scale from 0 (worst possible health) to 10 (normal health [for someone your age and your health condition]), and their health status every day after initiation of study treatment on the same scale. Return to preinfluenza health status was defined as time from the initiation of the study treatment to the first time when the health status score was equal to or higher than the preinfluenza health status score.
Time to return to preinfluenza health status was analyzed using KM methods; participants with a smaller number on the scale for health status by the last observation time point were censored at that time point.
Measured: Initiation of study treatment up to Day 14
Percentage of Participants With Influenza-related Complications in Participants Randomized to Baloxavir or Placebo
The percentage of participants who experienced each influenza-related complication (hospitalization, death, sinusitis, otitis media, bronchitis, and radiologically confirmed pneumonia) as an adverse event after the initiation of the study treatment.
Measured: Initiation of study treatment up to Day 14
Percentage of Participants With Influenza-related Complications in Adults Randomized to Baloxavir or Oseltamivir
The percentage of participants who experienced each influenza-related complication (hospitalization, death, sinusitis, otitis media, bronchitis, and radiologically confirmed pneumonia) as an adverse event after the initiation of the study treatment.
Measured: Initiation of study treatment up to Day 14
Percentage of Participants With Adverse Events (AEs)
Measured: From first dose of study drug to Day 22
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Nov 2016 (estimated)
- Study start8 Dec 2016
- Primary completion4 Apr 2017
- Study completion24 Apr 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for InfluenzaStudies of the same condition, open and under way.
- More trials run by ShionogiThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 1,436 participants (actual)
Sponsor and investigators
- Lead sponsor
- Shionogi
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Clinical Support Help Line Shionogi Clinical Trials Administrator, Study director, Shionogi
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02954354
- Sponsor's protocol ID
- 1601T0831
- Acronym
- CAPSTONE 1
- Status last verified
- Apr 2019
- First submitted
- 27 Oct 2016
- Last updated
- 8 May 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
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.
PubMed 30184455Retout S, De Buck S, Jolivet S, Duval V, Cosson V. A Pharmacokinetics-Time to Alleviation of Symptoms Model to Support Extrapolation of Baloxavir Marboxil Clinical Efficacy in Different Ethnic Groups with Influenza A or B. Clin Pharmacol Ther. 2022 Aug;112(2):372-381. doi: 10.1002/cpt.2648. Epub 2022 Jun 10.
PubMed 35585696Uehara T, Hayden FG, Kawaguchi K, Omoto S, Hurt AC, De Jong MD, Hirotsu N, Sugaya N, Lee N, Baba K, Shishido T, Tsuchiya K, Portsmouth S, Kida H. Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza. J Infect Dis. 2020 Jan 14;221(3):346-355. doi: 10.1093/infdis/jiz244.
PubMed 31309975
Study at a glance
From the registry record, last updated by the sponsor on 8 May 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 3, Multicenter, Randomized, Double-blind Study of a Single Dose of S-033188 (Baloxavir Marboxil) Compared With Placebo or Oseltamivir 75 mg Twice Daily for 5 Days in Otherwise Healthy Patients With Influenza
- ClinicalTrials.gov ID
- NCT02954354
- Acronym / sponsor ID
- CAPSTONE 1 / 1601T0831
- Conditions
- Influenza
- Keywords
- Flu, Baloxavir Marboxil, Oseltamivir, Tamiflu®
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,436 participants (actual)
- Lead sponsor
- ShionogiIndustry (pharma, biotech, devices)
- Study start
- 8 Dec 2016 (actual)
- Primary completion
- 4 Apr 2017 (actual)
- Study completion
- 24 Apr 2017 (actual)
- First posted
- 3 Nov 2016 (estimated)
- Results
- Posted 14 Dec 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary objective of this study is to evaluate the efficacy of a single, oral dose of baloxavir marboxil compared with placebo by measuring the time to alleviation of symptoms in patients with uncomplicated influenza virus infection.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Adults: Baloxavir Marboxil | Experimental | Drug: Baloxavir Marboxil, Drug: Placebo to OseltamivirParticipants aged 20 to 64 years will receive two or four 20 mg baloxavir marboxil tablets orally on Day 1 and one oseltamivir placebo capsule orally twice a day (BID) on Days 1 to 5. |
| Adults: Oseltamivir | Active comparator | Drug: Placebo to Baloxavir Marboxil, Drug: OseltamivirParticipants aged 20 to 64 years will receive 75 mg oseltamivir twice a day on Days 1 to 5 and two or four baloxavir marboxil placebo tablets on Day 1. |
| Adults: Placebo | Placebo comparator | Drug: Placebo to Baloxavir Marboxil, Drug: Placebo to OseltamivirParticipants aged 20 to 64 years will receive two or four baloxavir marboxil placebo tablets on Day 1 and one oseltamivir placebo capsule orally twice a day on Days 1 to 5. |
| Adolescents: Baloxavir Marboxil | Experimental | Drug: Baloxavir MarboxilParticipants aged 12 to 19 years will receive two or four baloxavir marboxil 20 mg tablets on Day 1. |
| Adolescents: Placebo | Placebo comparator | Drug: Placebo to Baloxavir MarboxilParticipants aged 12 to 19 years will receive two or four baloxavir marboxil placebo tablets on Day 1. |
Who may qualify
- Ages
- 12 to 64 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (17 listed)
- Patients who are able to understand the study and comply with all study procedures, and willing to provide written informed consent/assent prior to the predose examinations appropriately. As for adolescent patients, informed consent/assent of voluntary participation should be obtained in accordance with local requirements
- Male or female patients aged ≥ 12 to ≤ 64 years at the time of signing the informed consent/assent form.
- Patients with a diagnosis of influenza virus infection confirmed by all of the following:
- The time interval between the onset of symptoms and the predose examinations is 48 hours or less. The onset of symptoms is defined as either:
- Women of childbearing potential who agree to use a highly effective method of contraception for 3 months after the first dose of study drug
Key exclusion criteria (29 listed)
- Patients with severe influenza virus infection requiring inpatient treatment.
- Patients aged ≥ 20 years with known allergy to oseltamivir (Tamiflu®).
- Patients with any of the following risk factors
- Patients unable to swallow tablets or capsules.
- Patients who have previously received Baloxavir Marboxil.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Baloxavir MarboxilAlso: S-0331882 to4 X 20-mg tablets taken orally | Drug | Adolescents: Baloxavir Marboxil, Adults: Baloxavir Marboxil |
| Placebo to Baloxavir Marboxil2 to4 X 20-mg tablets taken orally | Drug | Adolescents: Placebo, Adults: Oseltamivir, Adults: Placebo |
| OseltamivirAlso: Tamiflu®75 mg capsules taken orally | Drug | Adults: Oseltamivir |
| Placebo to OseltamivirPlacebo capsules matching oseltamivir 75 mg capsules | Drug | Adults: Baloxavir Marboxil, Adults: Placebo |
Primary outcome
Time to Alleviation of Symptoms in Participants Randomized to Baloxavir or Placebo
Time frame: Initiation of study treatment up to Day 14
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms). Time to alleviation of symptoms was defined as the time from the start of the study treatment to the time when all seven influenza-related symptoms were assessed by the participant as absent (0) or mild (1) for at least 21.5 hours. Time to alleviation of symptoms was analyzed using the Kaplan-Meier (KM) method; participants who did not experience alleviation of symptoms were censored at the last observation time point.
Time to Alleviation of Symptoms in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Initiation of study treatment up to Day 14
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms). Time to alleviation of symptoms was defined as the time from the start of the study treatment to the time when all seven influenza-related symptoms were assessed by the participant as absent (0) or mild (1) for at least 21.5 hours. Time to alleviation of symptoms was analyzed using the Kaplan-Meier(KM) method; participants who did not experience alleviation of symptoms were censored at the last observation time point.
37 secondary outcomes
Percentage of Participants With Positive Influenza Virus Titer at Each Time Point in Participants Randomized to Baloxavir or Placebo
Time frame: Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Percentage of Participants With Positive Influenza Virus Titer at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point in Participants Randomized to Baloxavir or Placebo
Time frame: Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Change From Baseline in Virus Titer at Each Time Point in Participants Randomized to Baloxavir or Placebo
Time frame: Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Change From Baseline in Virus Titer at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Change From Baseline in Virus RNA (RT-PCR) at Each Time Point in Participants Randomized to Baloxavir or Placebo
Time frame: Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Change From Baseline in Virus RNA (RT-PCR) at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer in Participants Randomized to Baloxavir or Placebo
Time frame: Day 1 to Day 9
Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Day 1 to Day 9
Area Under the Curve (AUC) Adjusted by Baseline of Influenza Virus RNA in Participants Randomized to Baloxavir or Placebo
Time frame: Day 1 to Day 9
Area Under the Curve (AUC) Adjusted by Baseline of Influenza Virus RNA in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Day 1 to Day 9
Time to Cessation of Viral Shedding Determined by Virus Titer in Participants Randomized to Baloxavir or Placebo
Time frame: Day 1 to Day 9
Time to Cessation of Viral Shedding Determined by Virus Titer in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Day 1 to Day 9
Time to Cessation of Viral Shedding Determined by Virus RNA in Participants Randomized to Baloxavir or Placebo
Time frame: Day 1 to Day 9
Time to Cessation of Viral Shedding Determined by Virus RNA in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Day 1 to Day 9
Percentage of Participants Whose Symptoms Were Alleviated at Each Time Point in Participants Randomized to Baloxavir or Placebo
Time frame: 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours after the initial dose of study treatment
Percentage of Participants Whose Symptoms Were Alleviated at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Time frame: 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours after the initial dose of study treatment
Time to Alleviation of the Four Systemic Symptoms in Participants Randomized to Baloxavir or Placebo
Time frame: Initiation of study treatment up to Day 14
Time to Alleviation of the Four Systemic Symptoms in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Initiation of study treatment up to Day 14
Time to Alleviation of the Three Respiratory Symptoms in Participants Randomized to Baloxavir or Placebo
Time frame: Initiation of study treatment up to Day 14
Time to Alleviation of the Three Respiratory Symptoms in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Initiation of study treatment up to Day 14
Change From Baseline in Composite Symptom Score at Each Time Point in Participants Randomized to Baloxavir or Placebo
Time frame: Day 1 pretreatment (Baseline) and 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 216 hours after the initial dose of study treatment.
Change From Baseline in Composite Symptom Score at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Day 1 pretreatment (Baseline) and 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 216 hours after the initial dose of study treatment.
Time to Resolution of Fever in Participants Randomized to Baloxavir or Placebo
Time frame: Initiation of study treatment up to Day 14
Time to Resolution of Fever in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Initiation of study treatment up to Day 14
Percentage of Participants Reporting Normal Temperature at Each Time Point in Participants Randomized to Baloxavir or Placebo
Time frame: 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours after the initial dose of study treatment
Percentage of Participants Reporting Normal Temperature at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Time frame: 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours after the initial dose of study treatment
Body Temperature at Each Time Point in Participants Randomized to Baloxavir or Placebo
Time frame: 12, 24, 36, 48, 72, 96 and 120 hours after the initial dose of study treatment
Body Temperature at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
Time frame: 12, 24, 36, 48, 72, 96 and 120 hours after the initial dose of study treatment
Time to Alleviation of Individual Symptoms in Participants Randomized to Baloxavir or Placebo
Time frame: Initiation of study treatment up to Day 14
Time to Alleviation of Individual Symptoms in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Initiation of study treatment up to Day 14
Time to Return to Preinfluenza Health Status in Participants Randomized to Baloxavir or Placebo
Time frame: Initiation of study treatment up to Day 14
Time to Return to Preinfluenza Health Status in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Initiation of study treatment up to Day 14
Percentage of Participants With Influenza-related Complications in Participants Randomized to Baloxavir or Placebo
Time frame: Initiation of study treatment up to Day 14
Percentage of Participants With Influenza-related Complications in Adults Randomized to Baloxavir or Oseltamivir
Time frame: Initiation of study treatment up to Day 14
Percentage of Participants With Adverse Events (AEs)
Time frame: From first dose of study drug to Day 22
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 May 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 30184455Hayden 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.
- Derived from this study: PubMed 35585696Retout S, De Buck S, Jolivet S, Duval V, Cosson V. A Pharmacokinetics-Time to Alleviation of Symptoms Model to Support Extrapolation of Baloxavir Marboxil Clinical Efficacy in Different Ethnic Groups with Influenza A or B. Clin Pharmacol Ther. 2022 Aug;112(2):372-381. doi: 10.1002/cpt.2648. Epub 2022 Jun 10.
- Derived from this study: PubMed 31309975Uehara T, Hayden FG, Kawaguchi K, Omoto S, Hurt AC, De Jong MD, Hirotsu N, Sugaya N, Lee N, Baba K, Shishido T, Tsuchiya K, Portsmouth S, Kida H. Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza. J Infect Dis. 2020 Jan 14;221(3):346-355. doi: 10.1093/infdis/jiz244.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Clinical Support Help Line Shionogi Clinical Trials Administrator study director
Shionogi
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Baloxavir Marboxil and Oseltamivir in people with Influenza, run by Shionogi.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 May 2019. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 Dec 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to Alleviation of Symptoms in Participants Randomized to Baloxavir or Placebo (time frame: Initiation of study treatment up to Day 14). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02954354, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 May 2019.