Trial Comparing High Versus Standard Dose Oseltamivir in Severe Influenza Infection in ICU (ROSII)

This study has been terminated.
(Patient population no longer available.)
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by:
University of Manitoba
ClinicalTrials.gov Identifier:
NCT01010087
First received: November 5, 2009
Last updated: June 9, 2011
Last verified: June 2011
  Purpose

Primary Objectives:

The primary objective of the trial is to compare the antiviral efficacy of a 10 day course of standard (75 mg bid) and high-dose (225 mg bid) oseltamivir (or equivalent doses in mild-moderate renal failure) in the treatment of severe influenza infections.

The hypothesis is that high dose oseltamivir will increase the proportion of patients with negative reverse transcriptase (RT)-PCR detection of influenza viral RNA (and viral culture, at selected sites) at Day 5 post-treatment.

An important secondary objective of the trial, which reflects the main clinical objective, is to determine the difference in the numbers of ventilator days between the standard-dose and high-dose groups


Condition Intervention Phase
Influenza A Virus
Drug: Oseltamivir
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blinded Controlled Trial Comparing High vs Standard Dose Oseltamivir in Severe, Influenza Infection in ICU. "ROSII Study"

Resource links provided by NLM:


Further study details as provided by University of Manitoba:

Primary Outcome Measures:
  • Negative reverse transcriptase (RT)-PCR detection of viral RNA in nasopharyngeal and tracheal aspirate (intubated) or oropharyngeal (non-intubated) samples at Day 5 among patients who require ICU admission due to respiratory distress. [ Time Frame: Day 5 on study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Ventilator days up to 60 d (main clinical endpoint), [ Time Frame: 60 days ] [ Designated as safety issue: No ]

Enrollment: 59
Study Start Date: November 2009
Study Completion Date: May 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Standard Oseltamivir dose 75 mg bid
Standard dosing
Drug: Oseltamivir
standard (75 mg bid) or high-dose (225 mg bid) oseltamivir
Other Name: Tamiflu
Experimental: High Dose Oseltamivir arm 225mg bid
High dose arm of the study
Drug: Oseltamivir
standard (75 mg bid) or high-dose (225 mg bid) oseltamivir
Other Name: Tamiflu

  Hide Detailed Description

Detailed Description:

Primary Objectives:

The primary objective of the trial is to compare the antiviral efficacy of a 10 day course of standard (75 mg bid) and high-dose (225 mg bid) oseltamivir (or equivalent doses in mild-moderate renal failure) in the treatment of severe influenza infections.

The hypothesis is that high dose oseltamivir will increase the proportion of patients with negative reverse transcriptase (RT)-PCR detection of influenza viral RNA (and viral culture, at selected sites) at Day 5 post-treatment.

An important secondary objective of the trial, which reflects the main clinical objective, is to determine the difference in the numbers of ventilator days between the standard-dose and high-dose groups.

Secondary Objectives:

  • Laboratory objectives:

    1. Assess viral RNA load and clearance from nasopharyngeal and tracheal aspirate (intubated) or oropharyngeal (non-intubated) samples by RT-PCR on days 1, 3, 5, 7, 10, 14 and 28 days
    2. Determine viral clearance by culture from nasopharyngeal and tracheal aspirate (intubated) or oropharyngeal (non-intubated) samples on days 1, 3, 5, 7, 10, 14 and 28 days at select hospital sites with culture capability
    3. Assess the pharmacokinetics of oseltamivir carboxylate and phosphate on Day 3 in suspected H1N1 patients with respiratory distress and/or critical illness requiring ICU care
    4. Characterize the inflammatory cytokine response on Day 1-3, 5, 7, 10, 14, 21 and 28 days to severe influenza stratified by standard-dose versus high-dose oseltamivir therapy.
    5. Assess leukocyte gene expression at day 1, 3, 5, 10 and 21 days using high throughput RNA assessment techniques
    6. Examine urine for biomarkers of disease and severe disease
  • Clinical and Safety Objectives:

    1. Determine the difference in the number of ventilator days in the standard-dose and high-dose groups
    2. Determine tolerability of high-dose versus standard-dose oseltamivir as assessed by the number of serious, atypical and drug-related adverse events that are possibly or probably related to oseltamivir
    3. Assess other secondary efficacy variables including survival duration, hospital free days to day 60, ICU free days to day 60, and shock (ie vasopressor) and renal failure free (ie not requiring hemodialysis; ultrafiltration acceptable) days to day 28 in relation to high vs standard dose oseltamivir therapy
    4. Assess 60 day mechanical ventilation and ICU-free days stay in relation to high vs standard dose oseltamivir therapy
    5. Determine clinical criteria used by clinicians when electing to continue or re-initiate oseltamivir therapy beyond 10 study day treatment course

Tertiary Objectives: Exploratory Analyses

  • Laboratory Objectives:

    1. Assess the relationship between pharmacokinetic variables on day 3 and measures of viral clearance
    2. Assess the frequency and genetic basis of antiviral resistance to oseltamivir during and after therapy
    3. Determine possible host genetic factors including HLA type that predispose to severe influenza
  • Clinical and Safety Objectives:

    1. Determine differences in development and persistence of adverse clinical signs (fever, heart rate, hypotension), requirement for and duration of organ support (supplemental oxygen, vasopressor/inotropes, continuous renal replacement therapy) and occurrence and resolution of organ failure by Sequential Organ Failure Assessment (SOFA) score at days 7, 10, 14 and 28 as a consequence of high-dose versus standard-dose oseltamivir
    2. Determine impact of oseltamivir dosing on frequency of progression to mechanical ventilation among non-ventilated patients
  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients age 12 and older and 45 kg or more
  2. Suspected or confirmed influenza (Appendix A)
  3. Requirement for ICU admission due to respiratory distress or critical illness defined as one of:

    1. Inspired oxygen need of >50% for at least 4 hours (For FiO2 for non-intubated patients see Appendix B)
    2. mechanical ventilation
    3. Patient is receiving inotrope or vasopressor
  4. Negative b-HCG test or negative bedside urine test pending a confirmatory b-HCG test for pregnancy in women of childbearing age (12-60 years of age) will allow study entry

Exclusion Criteria:

  1. Inability to obtain consent
  2. Patients receiving more than two doses of 150 mg or higher oseltamivir in 36 hours before study entry
  3. Patients having received more than 3 doses of 75 mg oseltamivir immediately in 36 hours before study entry
  4. Age less than 12 years, or age <16 and weight less than 45 kg
  5. Unlikely to absorb enteral study drug (e.g. patients with partial or complete mechanical bowel obstruction, intestinal ischemia, infarction, and short bowel syndrome)
  6. Known allergy or hypersensitivity to oseltamivir
  7. Pregnancy or breast feeding
  8. Previous enrollment in current study
  9. Concurrent involvement in an RCT examining an antiviral agent including other neuraminidase inhibitors, interferon-a and/or ribavirin
  10. Chronic renal failure requiring chronic hemodialysis
  11. Severe chronic liver disease (Child-Pugh Score 11-15)
  12. Anticipated death within 24 hours as judged by attending physician or local PI
  13. Patient carrying "do not intubate" order (a "no CPR" or "no defibrillate" or "no chest compressions" order alone is allowed)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01010087

Locations
Canada, Manitoba
Winnipeg Regional Health Authority; Health Sciences Centre
Winnipeg, Manitoba, Canada, R3E 0Z3
Sponsors and Collaborators
University of Manitoba
Hoffmann-La Roche
Investigators
Principal Investigator: Anand Kumar, MD University of Manitoba
  More Information

No publications provided

Responsible Party: Anand Kumar MD, Winnipeg Regional Health Authority; Health Sciences Centre
ClinicalTrials.gov Identifier: NCT01010087     History of Changes
Other Study ID Numbers: 133312
Study First Received: November 5, 2009
Last Updated: June 9, 2011
Health Authority: Canada: Health Canada

Keywords provided by University of Manitoba:
patients admitted to ICU

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
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 20, 2014