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

Influenza A Virus Clinical Trial

— ROSII  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01010087
• Other study ID #: 133312
• Status: Terminated
• Phase: Phase 2
• First received: November 5, 2009
• Last updated: June 9, 2011
• Start date: November 2009
• Est. completion date: May 2011

Study information

• Verified date: June 2011
• Source: University of Manitoba
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical Trial Summary

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

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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 59
• Est. completion date: May 2011
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Influenza A Virus
• Influenza, Human

Intervention

Drug:
• Oseltamivir
standard (75 mg bid) or high-dose (225 mg bid) oseltamivir

Locations

Country	Name	City	State
Canada	Winnipeg Regional Health Authority; Health Sciences Centre	Winnipeg	Manitoba

Sponsors (2)

Lead Sponsor	Collaborator
University of Manitoba	Hoffmann-La Roche

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Ventilator days up to 60 d (main clinical endpoint),		60 days	No