High-Dose Versus Standard-Dose Oseltamivir to Treat Severe Influenza and Avian Influenza

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00298233
• Collaborator: Wellcome Trust (Other), World Health Organization (Other), University of Oxford (Other)
• Enrollment: 326
• Locations: 12
• Arms: 4
• Duration (Months): 47
• Patients Per Site: 27.2
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

Influenza, also known as the flu, is a contagious respiratory illness caused by influenza viruses. The illness can range in severity, from mild to severe to even death, and it causes an estimated 500,000 to 1,000,000 deaths worldwide each year. In the last several years, there have been increasing numbers of human cases of avian influenza, or bird flu. This trend may pose a threat of a future pandemic--worldwide outbreak of disease--with an avian influenza virus that can easily spread from person to person. Oseltamivir is an antiviral medication that is used to treat people with uncomplicated human influenza, and it may be effective in treating people with either severe human influenza or avian influenza. The purpose of this international study is to compare standard-dose oseltamivir versus high-dose oseltamivir for treating people who are hospitalized with severe human influenza or avian influenza.

Condition or Disease	Intervention/Treatment	Phase
Influenza; Avian Influenza; Severe Influenza	Drug: Oseltamivir	Phase 2

Detailed Description

Two main types of influenza virus--Types A and B--are responsible for the seasonal flu epidemics that occur each year. The influenza A viruses can be broken down into subtypes based on two proteins on the surface of the virus: hemagglutinin (H) and neuraminidase (N). The A subtypes usually found in humans are H1N1, H1N2, and H3N2. Other A subtypes are found primarily in animals. For example, the "avian influenza virus" refers to an influenza A virus that is found chiefly in birds.

Although avian influenza does not usually affect humans, increasing numbers of cases of human infection from avian influenza virus H5N1 have been reported in the last several years. Because all influenza viruses have the ability to modify, there is concern that this trend of increasing cases may pose a threat of a future pandemic with a new H5N1 virus that could spread easily from person to person.

The H5N1 virus that has caused human infection in Asia is resistant to amantadine and rimantadine, two antiviral medications commonly used for treating people with influenza. Another antiviral medication, oseltamivir, is currently used to treat people with uncomplicated human influenza. The purpose of this study is to compare standard-dose oseltamivir and high-does oseltamivir for treating people who are hospitalized with severe human influenza or avian influenza. The study will also attempt to identify how severe human influenza and avian influenza differ in the following factors: clinical manifestation, relationship between antiviral plasma concentrations and viral dynamics, and pathogenesis.

Upon meeting certain screening criteria, participants will be randomly assigned to receive oseltamivir either at a standard-dose level (75 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) or at a high-dose level (150 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function). Treatment will continue for 5 days, after which participants who meet clinical failure criteria will continue their assigned treatment for an additional 5 days. It is anticipated that participants will remain hospitalized through the course of treatment. On Day 0, which marks the first day of hospitalization, participants will undergo a medical review, physical examination, blood sampling, nasal swab, throat swab, anal swab, and chest x-ray. An endotracheal aspirate procedure and urine sampling may also be performed. During the hospital stay, most of the above procedures will be repeated regularly, and additional samples of lung fluid, cerebral spinal fluid, and pleural fluid may be obtained. On Day 5 and possibly on Day 10, participants will undergo a follow-up x-ray. If applicable, participants will attend outpatient study visits on Days 10, 14, and 28 for further evaluation; participants with avian influenza will also attend visits on Days 56 and 180.

Study Design

• Study Type: Interventional
• Actual Enrollment: 326 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: High-Dose Versus Standard-Dose Oseltamivir for the Treatment of Severe Influenza and Avian Influenza: A Phase II Double-Blind, Randomized Clinical Trial
• Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: Jan 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Standard Dose oseltamivir adult cohort All participants >= 15 years will receive standard-dose oseltamivir (75 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days.	Drug: Oseltamivir; Oseltamivir is a sialic acid analogue that potently and specifically inhibits the viral neuraminidases by competitively and reversibly interacting with the active enzyme site of influenza A and B viruses. Oseltamivir will be administered orally in standard formulations (capsules for adults and children at least 15 years of age; suspension for children younger than 15 years).; Other Names: Tamiflu
Active Comparator: Double Dose oseltamivir Adult cohort All participants >= 15 years will receive high-dose oseltamivir (150 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days.	Drug: Oseltamivir; Oseltamivir is a sialic acid analogue that potently and specifically inhibits the viral neuraminidases by competitively and reversibly interacting with the active enzyme site of influenza A and B viruses. Oseltamivir will be administered orally in standard formulations (capsules for adults and children at least 15 years of age; suspension for children younger than 15 years).; Other Names: Tamiflu
Active Comparator: Standard Dose Oseltamivir child cohort All participants <15 years will receive standard-dose oseltamivir (75 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days.	Drug: Oseltamivir; Oseltamivir is a sialic acid analogue that potently and specifically inhibits the viral neuraminidases by competitively and reversibly interacting with the active enzyme site of influenza A and B viruses. Oseltamivir will be administered orally in standard formulations (capsules for adults and children at least 15 years of age; suspension for children younger than 15 years).; Other Names: Tamiflu
Active Comparator: Double Dose Oseltamivir child cohort All Participants <15 years will receive high-dose oseltamivir (150 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days.	Drug: Oseltamivir; Oseltamivir is a sialic acid analogue that potently and specifically inhibits the viral neuraminidases by competitively and reversibly interacting with the active enzyme site of influenza A and B viruses. Oseltamivir will be administered orally in standard formulations (capsules for adults and children at least 15 years of age; suspension for children younger than 15 years).; Other Names: Tamiflu

Outcome Measures

Primary Outcome Measures

1. Proportion of All Participants Negative for Viral RNA on Day 5 [After 5 days of treatment]

   Proportion of all participants with no detectable viral RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) in a combined nasal and throat swab sample on day 5.

Secondary Outcome Measures

1. Participants Meeting Criteria for Day 5 Clinical Failure [After 5 days of treatment]

   Proportion of participants that have clinical failure by day 5. Subjects that meet one of the following on Day 5 will be classified as a clinical failure: Severe tachypnea (respiratory rate ≥ 30 for ages ≥12 years, rate ≥ 40 for ages 6 to 12 years, rate ≥45 for ages 3 to 6 years, rate ≥ 50 for ages 1 to 3 years) Severe dyspnea (unable to speak full sentences, or use of accessory respiratory muscles) Arterial oxygen saturation ≤92% on room air by trans-cutaneous method Need for mechanical ventilation or intensive care unit (ICU) admission For the purpose of endpoint definition, death prior to or on Day 5 will also be considered a clinical failure at Day 5.

2. In-hospital Mortality Rates [After up to 10 days of treatment]

   Standard therapy with oseltamivir is five days. Those patients with persistent symptoms on day five were continued on the randomized dose for an additional five days and assessments were performed up to day 10.

3. Median Time (Days) Receipt of Oxygen [Throughout study, 14 days]

4. Median Time (Days) in ICU [Throughout study, 14 days]

5. Median Time (Days) on Ventilation [Throughout study, 14 days]

   Use of mechanical ventilation at any time for subjects with severe influenza and avian influenza.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• At least one of the following respiratory symptoms: cough, dyspnea, sore throat

• Evidence of severe influenza or avian influenza, as defined below

• Severe influenza infection criteria:

1. Need for hospitalization

2. One of the following:

3. New infiltrate on chest x-ray (or any infiltrate if no prior chest x-ray or not known)

4. Severe tachypnea (more information on this criterion can be found in the protocol)

5. Severe dyspnea

6. Arterial oxygen saturation of 92% or less on room air by trans-cutaneous method

7. Positive diagnostic testing for influenza, as defined by either rapid influenza antigen (Ag) positive (A or B) or qualitative reverse transcriptase-polymerase chain reaction (RT-PCR) positive for any influenza

8. Illness (defined by onset of fever, respiratory symptoms, or constitutional symptoms) began within 10 days before study enrollment

• Avian influenza infection criteria:

1. Nasal wash, nasopharyngeal aspirate, endotracheal aspirate, nasal swab, or throat swab that is RT-PCR positive influenza for H5 influenza

2. Illness (defined by onset of fever, respiratory symptoms, or constitutional symptoms) began within 14 days before study enrollment

Exclusion Criteria:

• Received more than 72 hours of oseltamivir (six doses) within 14 days

• Received oseltamivir at higher than standard doses within the last 14 days or during current acute illness, whichever is longer

• History of allergy or severe intolerance of oseltamivir, as determined by the investigator

• Alternate explanation for the clinical findings, as determined by the investigator and with the information immediately available

• Creatine clearance less than 10 ml/minute

• Pregnant or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Changi General Hospital	Singapore		Singapore
2	National University Hospital, National University of Singapore	Singapore		Singapore
3	Tan Tock Seng Hospital	Singapore		Singapore
4	Queen Sirikit National Institute of Child Health	Bangkok		Thailand
5	Siriraj Hospital Mahidol University	Bangkok		Thailand
6	Bamrasnaradura Infectious Disease Institute	Nonthaburi		Thailand
7	Chest Disease Institute	Nonthaburi		Thailand
8	National Hospital of Pediatrics	Hanoi		Vietnam
9	National Institute fof Infectious and Tropical Diseases	Hanoi		Vietnam
10	Children's Hospital #1	Ho Chi Minh City		Vietnam
11	Hospital for Tropical Diseases	Ho Chi Minh City		Vietnam
12	Pediatric Hospital #2	Ho Chi Minh City		Vietnam

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Wellcome Trust
• World Health Organization
• University of Oxford

Investigators

• Principal Investigator: Tawee Chotpitayasunohdh, MD, Queen Sirikit National Institute of Child Health, Bangkok, Thailand
• Principal Investigator: Tran Tinh Hien, MD, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• South East Asian Infectious Diseases Clinical Research Network - Protocol and support documents available

Publications

• Colman PM. Influenza virus neuraminidase: structure, antibodies, and inhibitors. Protein Sci. 1994 Oct;3(10):1687-96. Review.
• de Jong MD, Bach VC, Phan TQ, Vo MH, Tran TT, Nguyen BH, Beld M, Le TP, Truong HK, Nguyen VV, Tran TH, Do QH, Farrar J. Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma. N Engl J Med. 2005 Feb 17;352(7):686-91.
• Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis. 1995 Jan-Mar;1(1):7-15. Review.

• Responsible Party: Jeremy Farrar, Director, Oxford University Clinical Research Unit, Oxford University Clinical Research Unit, Vietnam
• ClinicalTrials.gov Identifier: NCT00298233
• Other Study ID Numbers: SEA 001; N01A050042
• First Posted: Mar 1, 2006
• Last Update Posted: Jun 6, 2014
• Last Verified: May 1, 2014

• Keywords provided by Jeremy Farrar, Director, Oxford University Clinical Research Unit, Oxford University Clinical Research Unit, Vietnam: Antibody Response; Antiviral Efficacy; Bird Flu; Severe Respiratory Distress; Viral Replication and Shedding
• Additional relevant MeSH terms: Influenza, Human; Influenza in Birds; Oseltamivir

Study Results

Participant Flow

Arm/Group Title	Standard Dose Oseltamivir Adult Cohort	Double Dose Oseltamivir Adult Cohort	Standard Dose Oseltamivir Child Cohort	Double Dose Oseltamivir Child Cohort
Arm/Group Description	All participants >= 15 years received standard-dose oseltamivir (75 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days.	All Participants >= 15 years received high-dose oseltamivir (150 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days.	All participants <15 years received standard dose oseltamivir (75 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days.	All Participants <15 years received high-dose oseltamivir (150 mg twice daily orally or equivalent dose adjusted for age, weight, and kidney function) for 5 to 10 days.
Period Title: Overall Study
STARTED	39	41	122	124
COMPLETED	39	41	122	124
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Standarad Dose Oseltamivir	Double Dose Oseltamivir	Total
Arm/Group Description	All participants that were randomized and received standard dose oseltamivir	All participants that were randomized and received doubledose oseltamivir	Total of all reporting groups
Overall Participants	161	165	326
Age, Customized (participants) [Number]
Child cohort: ≥1 to <15 years	122 75.8%	124 75.2%	246 75.5%
Adult cohort: ≥15 years	39 24.2%	41 24.8%	80 24.5%
Sex: Female, Male (Count of Participants)
Female	72 44.7%	69 41.8%	141 43.3%
Male	89 55.3%	96 58.2%	185 56.7%

Outcome Measures

1. Primary Outcome

Title	Proportion of All Participants Negative for Viral RNA on Day 5
Description	Proportion of all participants with no detectable viral RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) in a combined nasal and throat swab sample on day 5.
Time Frame	After 5 days of treatment

Outcome Measure Data

Analysis Population Description

All randomized patients with RT-PCR proven influenza.

Arm/Group Title	Double Dose Oseltamivir	Standard Dose Oseltamivir
Arm/Group Description	All participants receiving double dose oseltamivir	All participants receiving standard dose oseltamivir
Measure Participants	159	154
Number [participants]	115 71.4%	105 63.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double Dose Oseltamivir, Standard Dose Oseltamivir
	Comments	Based on previous studies, assumption was made that 30% of children and 55% of adults treated with standard dose oseltamivir would test negative for virus on day five. This would require a sample size of 242 patients to show a 20% absolute improvement in cessation of viral shedding with 85% power and a two sided α of 0.05. To allow for study withdrawals, the target sample size was set at 300 patients.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.42
	Comments	Significance assessed at the 5% level for a two-sided comparison
	Method	conditional univariate logistic regressi
	Comments	analysis stratified by study site

2. Secondary Outcome

Title	Participants Meeting Criteria for Day 5 Clinical Failure
Description	Proportion of participants that have clinical failure by day 5. Subjects that meet one of the following on Day 5 will be classified as a clinical failure: Severe tachypnea (respiratory rate ≥ 30 for ages ≥12 years, rate ≥ 40 for ages 6 to 12 years, rate ≥45 for ages 3 to 6 years, rate ≥ 50 for ages 1 to 3 years) Severe dyspnea (unable to speak full sentences, or use of accessory respiratory muscles) Arterial oxygen saturation ≤92% on room air by trans-cutaneous method Need for mechanical ventilation or intensive care unit (ICU) admission For the purpose of endpoint definition, death prior to or on Day 5 will also be considered a clinical failure at Day 5.
Time Frame	After 5 days of treatment

Outcome Measure Data

Analysis Population Description

For the purpose of endpoint definition, death prior to or on Day 5 was also considered as clinical failure on day 5.In the double dose cohort, only 154 subjects completed fives days of drug and 7 died (total 161). In the standard dose cohort only 149 subjects completed 5 days of drug and 9 died (total 158).

Arm/Group Title	Double Dose Oseltamivir	Standard Dose Oseltamivir
Arm/Group Description	All participants receiving double dose oseltamivir	All participants receiving standard dose oseltamivir
Measure Participants	161	158
Number [participants]	16 9.9%	20 12.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double Dose Oseltamivir, Standard Dose Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.54
	Comments	Significance assessed at the 5% level for a two-sided comparison
	Method	Mantel Haenszel
	Comments

3. Secondary Outcome

Title	In-hospital Mortality Rates
Description	Standard therapy with oseltamivir is five days. Those patients with persistent symptoms on day five were continued on the randomized dose for an additional five days and assessments were performed up to day 10.
Time Frame	After up to 10 days of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Double Dose Oseltamivir	Standard Dose Oseltamivir
Arm/Group Description	All participants receiving double dose oseltamivir	All participants receiving standard dose oseltamivir
Measure Participants	165	161
Number [participants]	12 7.5%	9 5.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double Dose Oseltamivir, Standard Dose Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.54
	Comments	Significance assessed at the 5% level for a two-sided comparison
	Method	Mantel Haenszel
	Comments	Mantel-Haenszel chi-square stratified by study site

4. Secondary Outcome

Title	Median Time (Days) Receipt of Oxygen
Time Frame	Throughout study, 14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Double Dose Oseltamivir	Standard Dose Oseltamivir
Arm/Group Description	All participants receiving double dose oseltamivir	All participants receiving standard dose oseltamivir
Measure Participants	165	161
Median (95% Confidence Interval) [days]	3 (2-5)	3.5 (2-7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double Dose Oseltamivir, Standard Dose Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.48
	Comments	Significance assessed at the 5% level for a two-sided comparison
	Method	Kruskal-Wallis
	Comments

5. Secondary Outcome

Title	Median Time (Days) in ICU
Time Frame	Throughout study, 14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Double Dose Oseltamivir	Standard Dose Oseltamivir
Arm/Group Description	All participants receiving double dose oseltamivir	All participants receiving standard dose oseltamivir
Measure Participants	165	161
Median (95% Confidence Interval) [days]	4.4	5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double Dose Oseltamivir, Standard Dose Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.66
	Comments	Significance assessed at the 5% level for a two-sided comparison
	Method	Kruskal-Wallis
	Comments

6. Secondary Outcome

Title	Median Time (Days) on Ventilation
Description	Use of mechanical ventilation at any time for subjects with severe influenza and avian influenza.
Time Frame	Throughout study, 14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Double Dose Oseltamivir	Standard Dose Oseltamivir
Arm/Group Description	All participants receiving double dose oseltamivir	All participants receiving standard dose oseltamivir
Measure Participants	165	161
Median (95% Confidence Interval) [days]	2.5	5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double Dose Oseltamivir, Standard Dose Oseltamivir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments	Significance assessed at the 5% level for a two-sided comparison
	Method	Kruskal-Wallis
	Comments

Adverse Events

Time Frame	Through Day 28 for severe influenza, and Day 180 for avian influenza.
Adverse Event Reporting Description	The study recorded only cumulative data (total number of AEs per type, per Arm, but not number of subjects affected per AE type). Therefore data are the number of events and not the number of participants with events.
Arm/Group Title	Double Dose Oseltamivir		Standard Dose Oseltamivir
Arm/Group Description	The study recorded only cumulative data (total number of adverse events (AEs) per type, per Arm, but not number of subjects affected per AE type). Therefore data are the number of events and not the number of participants with events.		The study recorded only cumulative data (total number of adverse events (AEs) per type, per Arm, but not number of subjects affected per AE type). Therefore data are the number of events and not the number of participants with events.
All Cause Mortality
	Double Dose Oseltamivir		Standard Dose Oseltamivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Double Dose Oseltamivir		Standard Dose Oseltamivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/165 (0.6%)		0/161 (0%)
Respiratory, thoracic and mediastinal disorders
Septic shock	1/165 (0.6%)	1	0/161 (0%)	0
Other (Not Including Serious) Adverse Events
	Double Dose Oseltamivir		Standard Dose Oseltamivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/165 (22.4%)		38/161 (23.6%)
Blood and lymphatic system disorders
neutropenia	2/165 (1.2%)	2	1/161 (0.6%)	1
Thrombocytosis	3/165 (1.8%)	3	0/161 (0%)	0
Cardiac disorders
Septic shock	1/165 (0.6%)	1	2/161 (1.2%)	2
Gastrointestinal disorders
diarrhea	2/165 (1.2%)	2	9/161 (5.6%)	9
General disorders
multi-organ failures	3/165 (1.8%)	3	3/161 (1.9%)	3
Pyrexia	1/165 (0.6%)	1	1/161 (0.6%)	1
other	10/165 (6.1%)	10	11/161 (6.8%)	11
Respiratory, thoracic and mediastinal disorders
respiratory failure	10/165 (6.1%)	10	5/161 (3.1%)	5
acute respiratory distress syndrome	2/165 (1.2%)	2	1/161 (0.6%)	1
pneumothorax	1/165 (0.6%)	1	2/161 (1.2%)	2
Bronchitis	0/165 (0%)	0	2/161 (1.2%)	2
Skin and subcutaneous tissue disorders
Rash	2/165 (1.2%)	2	1/161 (0.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.