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

A Randomized, Double-Blinded Controlled Trial Comparing High vs Standard Dose Oseltamivir in Severe, Influenza Infection in ICU. "ROSII Study"

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

Study Overview

• Status: Terminated
• Conditions: Influenza A Virus
• Intervention / Treatment: Drug: Oseltamivir

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

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0Z3
      • Winnipeg Regional Health Authority; Health Sciences Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard Oseltamivir dose 75 mg bid; Standard dosing	Drug: Oseltamivir; standard (75 mg bid) or high-dose (225 mg bid) oseltamivir; Other Names: 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 Names: Tamiflu

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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.	Day 5 on study

Secondary Outcome Measures

Outcome Measure	Time Frame
Ventilator days up to 60 d (main clinical endpoint),	60 days

Collaborators and Investigators

• Sponsor: University of Manitoba
• Collaborators: Hoffmann-La Roche
• Investigators: Principal Investigator: Anand Kumar, MD, University of Manitoba

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: November 5, 2009
• First Submitted That Met QC Criteria: November 6, 2009
• First Posted (Estimate): November 9, 2009

Study Record Updates

• Last Update Posted (Estimate): June 10, 2011
• Last Update Submitted That Met QC Criteria: June 9, 2011
• Last Verified: June 1, 2011

More Information

Terms related to this study

• Keywords: patients admitted to ICU
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Oseltamivir
• Other Study ID Numbers: 133312