Clinical trial NCT02949011: Study of S-033188 (Baloxavir Marboxil) Compared With Placebo or Oseltamivir in Patients With Influenza at High Risk of Influenza Complications
Official title: A Phase 3, Multicenter, Randomized, Double-blind Study of a Single Dose of S-033188 Compared With Placebo or Oseltamivir 75 mg Twice Daily for 5 Days in Patients With Influenza at High Risk of Influenza Complications
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Influenza
Keywords: Tamiflu®
Influenza
Oseltamivir
Flu
S-033188
Lead sponsor: Shionogi Inc.
Sponsor class: INDUSTRY
First posted: 2016-10-31
Enrollment: 2184
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_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 improvement of influenza symptoms in patients with influenza presenting within 48 hours of symptom onset.


Eligibility criteria: Inclusion Criteria:

1. Patients or their legal guardians who provide written informed consent to participate in the study on a voluntary basis. For adolescent patients, informed consent/assent of voluntary participation should be obtained in accordance with local requirements.
2. Male or female patients ≥ 12 years at the time of signing the informed consent/assent form.
3. Patients with a diagnosis of influenza confirmed by all of the following:

   1. Fever ≥ 38ºC (axillary) during the predose examinations or within the 4 hours prior if antipyretics were taken
   2. A positive rapid influenza diagnostic test (RIDT) result OR A patient with a negative RIDT may be enrolled if the patient reports contact with a known case of influenza within the prior 7 days and all other inclusion criteria are met.
   3. At least 1 each of the following general and respiratory symptoms associated with influenza is present with a severity of moderate or greater:

   i. General symptoms (headache, feverishness or chills, muscle or joint pain, or fatigue) ii. Respiratory symptoms (cough, sore throat, or 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 1 new general or respiratory symptom
5. If a women of childbearing potential, agrees to use a highly effective method of contraception for 3 months after the first dose of study drug
6. Patients will be considered at high risk\* of influenza complications due to the presence of at least 1 of the following inclusion criteria:

   1. Asthma or chronic lung disease (such as chronic obstructive pulmonary disease or cystic fibrosis)
   2. Endocrine disorders (including diabetes mellitus)
   3. Residents of long-term care facilities (eg, nursing homes)
   4. Compromised immune system (including patients receiving corticosteroids not exceeding 20 mg of prednisolone or equivalent, and patients being treated for human immunodeficiency virus \[HIV\] infection with a CD4 count \> 350 cells/mm³ within the last 6 months)
   5. Neurological and neurodevelopmental disorders (including disorders of the brain, spinal cord, peripheral nerve, and muscle, eg, cerebral palsy, epilepsy \[seizure disorders\], stroke, muscular dystrophy, or spinal cord injury)
   6. Heart disease (such as congenital heart disease, congestive heart failure, or coronary artery disease), excluding hypertension without any other heart-related symptoms
   7. Adults aged ≥ 65 years
   8. American Indians and Alaskan Natives
   9. Blood disorders (such as sickle cell disease)
   10. Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders)
   11. Morbid obesity (body mass index ≥ 40 kg/m²)
   12. Women who are within 2 weeks postpartum and are not breastfeeding

Exclusion Criteria:

1. Patients with severe influenza virus infection requiring inpatient treatment.
2. Patients with known allergy to oseltamivir (Tamiflu®).
3. Patients unable to swallow tablets or capsules.
4. Patients who have previously received baloxavir marboxil.
5. Patients weighing ≤ 40 kg.
6. Patients who have been exposed to an investigational drug within 30 days prior to the predose examinations.
7. Women who are pregnant, breastfeeding, or have a positive pregnancy test at the predose examinations. The following female patients who have documentation of either a or b below do not need to undergo a pregnancy test at the predose examinations:

   1. Postmenopausal women (defined as cessation of regular menstrual periods for 2 years or more and confirmed by a follicle-stimulating hormone test)
   2. Women who are surgically sterile by hysterectomy, bilateral oophorectomy, or tubal ligation
8. Patients with concurrent infections at the predose examinations requiring systemic antimicrobial therapy.
9. Patients with liver disease associated with hepatic impairment.
10. Patients with cancer within the last 5 years (unless nonmelanoma skin cancer).
11. Patients with untreated HIV infection or treated HIV infection with a CD4 count below 350 cells/mm3 in the last 6 months.
12. Patients with immunosuppression following organ or bone marrow transplants.
13. Patients exceeding 20 mg of prednisolone or equivalent dose of chronic systemic corticosteroids.
14. Patients who have received peramivir, laninamivir, oseltamivir, zanamivir, rimantadine, umifenovir or amantadine within 30 days prior to the predose examinations.
15. Patients who have received an investigational monoclonal antibody for a viral disease in the last year.
16. Patients with known creatinine clearance ≤ 60 mL/min.
17. 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 Improvement of Influenza Symptoms
timeFrame: From Day 1 pretreatment up to Day 14
Secondary outcomes:
measure: Percentage of Participants With Positive Influenza Virus Titer at Each Time Point
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
timeFrame: Days 2, 3, 4 (optional), 5, 6 (optional), and 9.
measure: Change From Baseline in Virus Titer at Each Time Point
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
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
timeFrame: Day 1 to Day 9
measure: Area Under the Curve (AUC) Adjusted by Baseline in Viral RNA
timeFrame: Day 1 to Day 9
measure: Time to Cessation of Viral Shedding Determined by Virus Titer
timeFrame: Day 1 to Day 9
measure: Time to Cessation of Viral Shedding Determined by Virus RNA
timeFrame: Day 1 to Day 9
measure: Percentage of Participants Whose Symptoms Were Improved at Each Time Point
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 Symptoms
timeFrame: Initiation of study treatment up to Day 14
measure: Time to Improvement of the Four Systemic Symptoms
timeFrame: Initiation of study treatment up to Day 14
measure: Time to Improvement of the Three Respiratory Symptoms
timeFrame: Initiation of study treatment up to Day 14
measure: Time to Resolution of Fever
timeFrame: Initiation of study treatment up to Day 14
measure: Percentage of Participants Reporting Normal Temperature at Each Time Point
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
timeFrame: 12, 24, 36, 48, 72, 96 and 120 hours after the initial dose of study treatment
measure: Time to Improvement of Individual Symptoms
timeFrame: Initiation of study treatment up to Day 14
measure: Time to Return to Preinfluenza Health Status
timeFrame: Baseline to Day 14
measure: Percentage of Participants Requiring Systemic Antibiotics for Infections Secondary to Influenza Infection
timeFrame: Day 2 to Day 22
measure: Percentage of Participants With Influenza-related Complications
timeFrame: Day 1 to Day 22
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: Shionogi Clinical Trials Administrator Clinical Support Help Line
role: STUDY_DIRECTOR
References:
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: Ison MG, Portsmouth S, Yoshida Y, Shishido T, Mitchener M, Tsuchiya K, Uehara T, Hayden FG. Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial. Lancet Infect Dis. 2020 Oct;20(10):1204-1214. doi: 10.1016/S1473-3099(20)30004-9. Epub 2020 Jun 8.