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Study of S-033188 (Baloxavir Marboxil) Compared With Placebo or Oseltamivir in Patients With Influenza at High Risk of Influenza Complications (CAPSTONE 2)

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ClinicalTrials.gov Identifier: NCT02949011
Recruitment Status : Completed
First Posted : October 31, 2016
Last Update Posted : May 3, 2018
Sponsor:
Information provided by (Responsible Party):
Shionogi Inc. ( Shionogi )

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.

Condition or disease Intervention/treatment Phase
Influenza Drug: Baloxavir Marboxil Drug: Placebo to Baloxavir Marboxil Drug: Oseltamivir Drug: Placebo to Oseltamivir Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2157 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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 Patients With Influenza at High Risk of Influenza Complications
Actual Study Start Date : December 1, 2016
Actual Primary Completion Date : April 12, 2018
Actual Study Completion Date : April 20, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Flu Flu Shot
Drug Information available for: Oseltamivir
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Baloxavir Marboxil
Participants aged ≥ 12 years will receive two or four 20-mg S 033188 tablets orally on Day 1 and one oseltamivir placebo capsule orally twice a day (BID) on Days 1 to 5.
Drug: Baloxavir Marboxil
2-4 X 20-mg tablets taken orally
Other Name: S-033188
Drug: Placebo to Oseltamivir
Placebo capsules matching oseltamivir 75-mg capsules
Active Comparator: Oseltamivir
Participants aged ≥ 12 years will receive 75 mg oseltamivir twice a day on Days 1 to 5 and two or four S 033188 placebo tablets on Day 1.
Drug: Placebo to Baloxavir Marboxil
2-4 X 20-mg tablets taken orally
Drug: Oseltamivir
75-mg capsules taken orally
Other Name: Tamiflu®
Placebo Comparator: Placebo
Participants aged ≥ 12 years will receive two or four S 033188 placebo tablets on Day 1 and one oseltamivir placebo capsule orally twice a day on Days 1 to 5.
Drug: Placebo to Baloxavir Marboxil
2-4 X 20-mg tablets taken orally
Drug: Placebo to Oseltamivir
Placebo capsules matching oseltamivir 75-mg capsules



Primary Outcome Measures :
  1. Time to improvement of symptoms [ Time Frame: From Day 1 pretreatment up to Day 14 ]
    Time to improvement of symptoms is defined as the time from initiation of study treatment to improvement of influenza symptoms for at least 24 hours.


Secondary Outcome Measures :
  1. Percentage of participants positive for influenza virus titer and viral RNA at each time point [ Time Frame: Days 1, 2, 3, 5 and 9 ]
    Defined as the percentage of patients whose virus titer and ribonucleic acid (RNA) load are greater than the lower limit of quantification among those assessed for virus titer and RNA load. RNA load is measured by reverse transcription polymerase chain reaction (RT-PCR).

  2. Change from baseline in virus titer at each time point [ Time Frame: From Day 1 pretreatment to Days 2, 3, 5, and 9 ]
  3. Change from Baseline in viral RNA load at each time point [ Time Frame: From Day 1 pretreatment to Days 2, 3, 5, and 9 ]
  4. Area under the curve (AUC) adjusted by baseline in virus titer [ Time Frame: Day 1 to Day 9 ]
    Defined as AUC of change from baseline in virus titer. The AUC is calculated using the trapezoidal method.

  5. Area under the curve (AUC) adjusted by baseline in viral RNA load [ Time Frame: Day 1 to Day 9 ]
    Defined as AUC of change from baseline in viral RNA load. The AUC is calculated using the trapezoidal method.

  6. Time to cessation of viral shedding [ Time Frame: From Day 1 to Day 9 ]
    Defined as the time between the initiation of the study treatment and first time when the virus titer/RT-PCR is less than the lower limit of quantification

  7. Percentage of participants whose symptoms have been improved at each time point [ Time Frame: Days 2-9, morning and evening, and days 10-14, evenings ]
  8. Time to alleviation of symptoms [ Time Frame: Day 1 pretreatment up to Day 14 ]
    Time to alleviation of symptoms is defined as the time between the initiation of the study treatment and the alleviation of influenza symptoms. The alleviation of influenza symptoms is defined as the time when all of 7 influenza symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) have been assessed by the patient.

  9. Time to improvement in the 4 systemic symptoms [ Time Frame: Day 1 pretreatment up to Day 14 ]
    Defined as the time between the initiation of the study treatment and the improvement in the 4 systemic symptoms symptoms (headache, feverishness or chills, muscle or joint pain, and fatigue).

  10. Time to improvement in the 3 respiratory symptoms [ Time Frame: Day 1 pretreatment up to Day 14 ]
    Defined as the time between the initiation of the study treatment and the improvement in the 3 respiratory symptoms (cough, sore throat, and nasal congestion).

  11. Time to resolution of fever [ Time Frame: Day 1 pretreatment up to Day 14 ]
    Defined as the time between the initiation of the study treatment and the resolution of fever. The resolution of fever is defined as the time when the patient's self-measured temperature becomes less than 37ºC.

  12. Percentage of participants reporting normal temperature at each time point [ Time Frame: Days 1 to 3 at morning, noon, evening and bedtime, Days 4 to 14 morning and evening ]
    Defined as the percentage of patients whose self-measured temperature drops to less than 37ºC after the initiation of the study treatment.

  13. Body temperature at each time point [ Time Frame: Days 1 to 3 at morning, noon, evening and bedtime, Days 4 to 14 morning and evening ]
  14. Time to improvement of each influenza symptom [ Time Frame: Day 1 pretreatment up to Day 14 ]
    Defined as the time between the initiation of the study treatment and the alleviation of each influenza symptom.

  15. Time to return to preinfluenza health status [ Time Frame: Day 1 pretreatment up to Day 14 ]
    Patients will be asked to record their preinfluenza health status (for someone your age and your health condition). Return to preinfluenza health status is defined as time from the initiation of the study treatment to time to return to preinfluenza health status.

  16. Percentage of participants requiring systemic antibiotics for infections secondary to influenza infection [ Time Frame: Day 2 to Day 22 ]
  17. Percentage of participants with influenza-related complications [ Time Frame: Day 1 to Day 22 ]
    Defined as the percentage of patients who experience each influenza-related complication (hospitalization, death, sinusitis, otitis media, bronchitis, and radiologically-confirmed pneumonia) as an adverse event after the initiation of study treatment.

  18. Number of participants with adverse events [ Time Frame: Day 1 to Day 22 plus or minus 3 days ]
    The frequency of AEs in patients with influenza after Baloxavir Marboxil, after oseltamivir, and after placebo.



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Ages Eligible for Study:   12 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02949011


  Show 454 Study Locations
Sponsors and Collaborators
Shionogi
Investigators
Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line Shionogi

Responsible Party: Shionogi
ClinicalTrials.gov Identifier: NCT02949011     History of Changes
Other Study ID Numbers: 1602T0832
2016-002688-32 ( EudraCT Number )
First Posted: October 31, 2016    Key Record Dates
Last Update Posted: May 3, 2018
Last Verified: May 2018

Keywords provided by Shionogi Inc. ( Shionogi ):
Tamiflu®
Influenza
Oseltamivir
Flu
S-033188

Additional relevant MeSH terms:
Influenza, Human
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Oseltamivir
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action