Clinical trial NCT02954354: A Study of S-033188 (Baloxavir Marboxil) Compared With Placebo or Oseltamivir in Otherwise Healthy Patients With Influenza
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Influenza
Keywords: Flu
Baloxavir Marboxil
Oseltamivir
Tamiflu®
Lead sponsor: Shionogi Inc.
Sponsor class: INDUSTRY
First posted: 2016-11-03
Enrollment: 1436
Sex: ALL
Minimum age (years): 12
Maximum age (years): 64
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: Inclusion Criteria:

1. 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
2. Male or female patients aged ≥ 12 to ≤ 64 years at the time of signing the informed consent/assent form.
3. Patients with a diagnosis of influenza virus infection confirmed by all of the following:

   1. Fever ≥ 38ºC (axillary) in the predose examinations or \> 4 hours after dosing of antipyretics if they were taken
   2. At least one of the following general systemic symptoms associated with influenza are present with a severity of moderate or greater

      * Headache
      * Feverishness or chills
      * Muscle or joint pain
      * Fatigue
   3. 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
4. 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:

   1. Time of the first increase in body temperature (an increase of at least 1ºC from normal body temperature)
   2. Time when the patient experiences at least one general or respiratory symptom
5. Women of childbearing potential who agree to use a highly effective method of contraception for 3 months after the first dose of study drug

Exclusion Criteria:

1. Patients with severe influenza virus infection requiring inpatient treatment.
2. Patients aged ≥ 20 years with known allergy to oseltamivir (Tamiflu®).
3. Patients with any of the following risk factors

   1. Women who are pregnant or within 2 weeks post-partum
   2. Residents of long-term care facilities (eg, welfare facilities for the elderly, nursing homes)
   3. Chronic respiratory diseases including bronchial asthma
   4. 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)
   5. Heart disease (such as congenital heart disease, congestive heart failure, or coronary artery disease), excluding hypertension without any other heart-related symptoms)
   6. American Indians and Alaskan natives
   7. Blood disorders (such as sickle cell disease)
   8. Endocrine disorders (including diabetes mellitus)
   9. Kidney disorders
   10. Liver disorders
   11. Metabolic disorders
   12. Compromised immune system (including patients receiving immunosuppressant therapy, or those with cancer or human immunodeficiency virus \[HIV\] infection)
   13. Morbid obesity (body mass index \[BMI\] ≥ 40)
4. Patients unable to swallow tablets or capsules.
5. Patients who have previously received Baloxavir Marboxil.
6. Patients weighing \< 40 kg
7. Patients who have been exposed to an investigational drug within 30 days prior to the predose examinations.
8. 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:

   1. Postmenopausal (defined as cessation of regular menstrual periods for 2 years or more and confirmed by a follicle-stimulating hormone test) women
   2. Women who are surgically sterile by hysterectomy, bilateral oophorectomy, or tubal ligation
9. Patients with concurrent infections requiring systemic antimicrobial and/or antiviral therapy at the predose examinations.
10. Patients who have received peramivir, laninamivir, oseltamivir, zanamivir, rimantadine, umifenovir, or amantadine within 30 days prior to the predose examinations.
11. Patients who have received an investigational monoclonal antibody for a viral disease in the last year.
12. Patients with severe underlying diseases.
13. Patients with known creatinine clearance ≤ 60 mL/min.
14. Patients who, in the opinion of the investigator, would be unlikely to comply with required study visits, self-assessments, and interventions

Primary outcomes:
measure: Time to Alleviation of Symptoms in Participants Randomized to Baloxavir or Placebo
timeFrame: Initiation of study treatment up to Day 14
measure: Time to Alleviation of Symptoms in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Initiation of study treatment up to Day 14
Secondary outcomes:
measure: Percentage of Participants With Positive Influenza Virus Titer at Each Time Point in Participants Randomized to Baloxavir or Placebo
timeFrame: Days 2, 3, 4 (optional), 5, 6 (optional), and 9
measure: Percentage of Participants With Positive Influenza Virus Titer at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Days 2, 3, 4 (optional), 5, 6 (optional), and 9
measure: Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point in Participants Randomized to Baloxavir or Placebo
timeFrame: Days 2, 3, 4 (optional), 5, 6 (optional), and 9
measure: Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Days 2, 3, 4 (optional), 5, 6 (optional), and 9
measure: Change From Baseline in Virus Titer at Each Time Point in Participants Randomized to Baloxavir or Placebo
timeFrame: Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9
measure: Change From Baseline in Virus Titer at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9
measure: Change From Baseline in Virus RNA (RT-PCR) at Each Time Point in Participants Randomized to Baloxavir or Placebo
timeFrame: Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9
measure: Change From Baseline in Virus RNA (RT-PCR) at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9
measure: Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer in Participants Randomized to Baloxavir or Placebo
timeFrame: Day 1 to Day 9
measure: Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Day 1 to Day 9
measure: Area Under the Curve (AUC) Adjusted by Baseline of Influenza Virus RNA in Participants Randomized to Baloxavir or Placebo
timeFrame: Day 1 to Day 9
measure: Area Under the Curve (AUC) Adjusted by Baseline of Influenza Virus RNA in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Day 1 to Day 9
measure: Time to Cessation of Viral Shedding Determined by Virus Titer in Participants Randomized to Baloxavir or Placebo
timeFrame: Day 1 to Day 9
measure: Time to Cessation of Viral Shedding Determined by Virus Titer in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Day 1 to Day 9
measure: Time to Cessation of Viral Shedding Determined by Virus RNA in Participants Randomized to Baloxavir or Placebo
timeFrame: Day 1 to Day 9
measure: Time to Cessation of Viral Shedding Determined by Virus RNA in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Day 1 to Day 9
measure: Percentage of Participants Whose Symptoms Were Alleviated at Each Time Point in Participants Randomized to Baloxavir or Placebo
timeFrame: 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours after the initial dose of study treatment
measure: Percentage of Participants Whose Symptoms Were Alleviated at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours after the initial dose of study treatment
measure: Time to Alleviation of the Four Systemic Symptoms in Participants Randomized to Baloxavir or Placebo
timeFrame: Initiation of study treatment up to Day 14
measure: Time to Alleviation of the Four Systemic Symptoms in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Initiation of study treatment up to Day 14
measure: Time to Alleviation of the Three Respiratory Symptoms in Participants Randomized to Baloxavir or Placebo
timeFrame: Initiation of study treatment up to Day 14
measure: Time to Alleviation of the Three Respiratory Symptoms in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Initiation of study treatment up to Day 14
measure: Change From Baseline in Composite Symptom Score at Each Time Point in Participants Randomized to Baloxavir or Placebo
timeFrame: 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.
measure: Change From Baseline in Composite Symptom Score at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: 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.
measure: Time to Resolution of Fever in Participants Randomized to Baloxavir or Placebo
timeFrame: Initiation of study treatment up to Day 14
measure: Time to Resolution of Fever in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Initiation of study treatment up to Day 14
measure: Percentage of Participants Reporting Normal Temperature at Each Time Point in Participants Randomized to Baloxavir or Placebo
timeFrame: 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours after the initial dose of study treatment
measure: Percentage of Participants Reporting Normal Temperature at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours after the initial dose of study treatment
measure: Body Temperature at Each Time Point in Participants Randomized to Baloxavir or Placebo
timeFrame: 12, 24, 36, 48, 72, 96 and 120 hours after the initial dose of study treatment
measure: Body Temperature at Each Time Point in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: 12, 24, 36, 48, 72, 96 and 120 hours after the initial dose of study treatment
measure: Time to Alleviation of Individual Symptoms in Participants Randomized to Baloxavir or Placebo
timeFrame: Initiation of study treatment up to Day 14
measure: Time to Alleviation of Individual Symptoms in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Initiation of study treatment up to Day 14
measure: Time to Return to Preinfluenza Health Status in Participants Randomized to Baloxavir or Placebo
timeFrame: Initiation of study treatment up to Day 14
measure: Time to Return to Preinfluenza Health Status in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Initiation of study treatment up to Day 14
measure: Percentage of Participants With Influenza-related Complications in Participants Randomized to Baloxavir or Placebo
timeFrame: Initiation of study treatment up to Day 14
measure: Percentage of Participants With Influenza-related Complications in Adults Randomized to Baloxavir or Oseltamivir
timeFrame: Initiation of study treatment up to Day 14
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: From first dose of study drug to Day 22
Other outcomes:
Locations:
Study officials:
affiliation: Shionogi
name: Clinical Support Help Line Shionogi Clinical Trials Administrator
role: STUDY_DIRECTOR
References:
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.
citation: Retout 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.
citation: Uehara 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.