A Study on Emergence of Resistance With Oseltamivir (Tamiflu) in Participants With Seasonal Influenza

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00949533
• Collaborator: (none)
• Enrollment: 37
• Locations: 3
• Arms: 2
• Duration (Months): 14
• Patients Per Site: 12.3
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This open-label randomized 2 arm study will determine the emergence of viral resistance in participants with seasonal influenza A infection treated with oseltamivir. Eligible participants less than or equal to (</=) 5 years of age will be randomized to receive oseltamivir at either standard dose (30-75 milligrams [mg] orally twice daily [bid]) or double dose (60-150 mg orally bid) for 5 days. Target sample size is greater than (>) 100.

Condition or Disease	Intervention/Treatment	Phase
Influenza	Drug: Oseltamivir	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase IIIb, Open-label, Comparative, Randomized Study on Resistance of Influenza A/H1N1 2009 Virus to Treatment With Oseltamivir at Standard Dose Versus Double Dose
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Standard Dose Oseltamivir capsule will be administered orally at a dose of 75 mg BID in adult participants and children will receive oseltamivir powder for oral suspension dose (at 12 milligrams/ milliliter [mg/mL]) based on their body weight with a starting dose of 30 mg BID to a maximum dose of 75 mg BID; for 5 days.	Drug: Oseltamivir; Standard dose (30 - 75 mg orally bid) or double dose (60 - 150 mg orally bid); for 5 days; Other Names: Tamiflu
Active Comparator: Double Dose Oseltamivir capsule will be administered orally at a dose of 150 mg BID in adult participants and children will receive oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 60 mg BID to a maximum dose of 150 mg BID; for 5 days.	Drug: Oseltamivir; Standard dose (30 - 75 mg orally bid) or double dose (60 - 150 mg orally bid); for 5 days; Other Names: Tamiflu

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Excreting Resistant Virus [Day 5]

   Resistant virus included new influenza A virus subtype hemagglutinin type 1 and neuraminidase type 1 (New AH1N1).

Secondary Outcome Measures

1. Percentage of Participants With A Reduction in Viral Load [Baseline, Day 5]

   Viral load is defined as the amount of H1N1 virus in blood. As per investigator, a participant was considered as having viral load reduction at Day 5 if the Day 5 viral load was lower than the Baseline viral load.

2. Number of Participants With Various Clinical Signs and Symptoms [Day 5]

   Number of participants with various clinical signs and symptoms, as per investigator's discretion, were reported. Same participants were reported in more than 1 category. "Other" in the category included abdominal pain, breathlessness, thoracic pain and tired.

3. Number of Participants With Various Clinical Signs and Symptoms in Whom Resistant Virus Were Detected [Day 5]

   Number of participants with various clinical signs and symptoms, as per investigator's discretion, in whom new AH1N1 virus was detected, were reported. Same participants were reported in more than 1 category.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• positive rapid antigen test for influenza A

• onset of symptoms of influenza (fever, at least one respiratory symptom) </=48 hours

Exclusion Criteria:

• clinical suspicion of infection with a respiratory virus other than influenza

• suspicion of invasive bacterial infection

• evidence of poorly controlled underlying disease

• known immunosuppression

• known allergy to Oseltamivir

• women who are pregnant or planning to get pregnant during the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Curitiba		Brazil	80810-040
2		Sao Paulo		Brazil	04025-002
3		Sao Paulo		Brazil	05508-000

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00949533
• Other Study ID Numbers: ML22789
• First Posted: Jul 30, 2009
• Last Update Posted: Aug 8, 2016
• Last Verified: Jun 1, 2016

• Additional relevant MeSH terms: Influenza, Human; Oseltamivir

Study Results

Participant Flow

Pre-assignment Detail	Out of 199 participants, 162 were considered as screening failures, mainly due to the negative result detected by the quick test for Influenza A Antigen. Therefore, 37 participants included in the study.

Arm/Group Title	Standard Dose	Double Dose
Arm/Group Description	Oseltamivir (Tamiflu) capsule was administered orally at a dose of 75 milligrams (mg) twice a day (BID) in adult participants and children received oseltamivir powder for oral suspension dose (at 12 milligrams/ milliliter [mg/mL]) based on their body weight with a starting dose of 30 mg BID to a maximum dose of 75 mg BID; for 5 days.	Oseltamivir capsule was administered orally at a dose of 150 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 60 mg BID to a maximum dose of 150 mg BID; for 5 days.
Period Title: Overall Study
STARTED	19	18
COMPLETED	19	17
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Standard Dose	Double Dose	Total
Arm/Group Description	Oseltamivir capsule was administered orally at a dose of 75 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 30 mg BID to a maximum dose of 75 mg BID; for 5 days.	Oseltamivir capsule was administered orally at a dose of 150 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 60 mg BID to a maximum dose of 150 mg BID; for 5 days.	Total of all reporting groups
Overall Participants	19	18	37
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	21.6 (11.0)	22.0 (12.7)	21.8 (11.7)
Sex: Female, Male (Count of Participants)
Female	11 57.9%	9 50%	20 54.1%
Male	8 42.1%	9 50%	17 45.9%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Excreting Resistant Virus
Description	Resistant virus included new influenza A virus subtype hemagglutinin type 1 and neuraminidase type 1 (New AH1N1).
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

ITT population. Here "number of participants analyzed" included evaluable participants for the outcome measure.

Arm/Group Title	Standard Dose	Double Dose
Arm/Group Description	Oseltamivir capsule was administered orally at a dose of 75 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 30 mg BID to a maximum dose of 75 mg BID; for 5 days.	Oseltamivir capsule was administered orally at a dose of 150 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 60 mg BID to a maximum dose of 150 mg BID; for 5 days.
Measure Participants	19	17
Number [percentage of participants]	26.3 138.4%	35.3 196.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Standard Dose, Double Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.825
	Comments
	Method	Pearson Chi-Square
	Comments

2. Secondary Outcome

Title	Percentage of Participants With A Reduction in Viral Load
Description	Viral load is defined as the amount of H1N1 virus in blood. As per investigator, a participant was considered as having viral load reduction at Day 5 if the Day 5 viral load was lower than the Baseline viral load.
Time Frame	Baseline, Day 5

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Standard Dose	Double Dose
Arm/Group Description	Oseltamivir capsule was administered orally at a dose of 75 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 30 mg BID to a maximum dose of 75 mg BID; for 5 days.	Oseltamivir capsule was administered orally at a dose of 150 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 60 mg BID to a maximum dose of 150 mg BID; for 5 days.
Measure Participants	19	18
Number [percentage of participants]	100 526.3%	100 555.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Standard Dose, Double Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	> 0.05
	Comments
	Method	Chi-squared
	Comments

3. Secondary Outcome

Title	Number of Participants With Various Clinical Signs and Symptoms
Description	Number of participants with various clinical signs and symptoms, as per investigator's discretion, were reported. Same participants were reported in more than 1 category. "Other" in the category included abdominal pain, breathlessness, thoracic pain and tired.
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

ITT population. Here "number of participants analyzed" included evaluable participants for the outcome measure.

Arm/Group Title	Standard Dose	Double Dose
Arm/Group Description	Oseltamivir capsule was administered orally at a dose of 75 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 30 mg BID to a maximum dose of 75 mg BID; for 5 days.	Oseltamivir capsule was administered orally at a dose of 150 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 60 mg BID to a maximum dose of 150 mg BID; for 5 days.
Measure Participants	19	17
Cough	10 52.6%	9 50%
Rhinorrhea	10 52.6%	5 27.8%
Sore throat	2 10.5%	2 11.1%
Shortness of breath	2 10.5%	1 5.6%
Diarrhea	2 10.5%	0 0%
Headache	1 5.3%	2 11.1%
Conjunctivitis	1 5.3%	0 0%
Vomiting	1 5.3%	0 0%
Other	4 21.1%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Standard Dose, Double Dose
	Comments	Cough: statistical difference between 2 groups was based on chi-squared test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard Dose, Double Dose
	Comments	Rhinorrhea: statistical difference between 2 groups was based on chi-squared test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.284
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Standard Dose, Double Dose
	Comments	Sore throat: statistical difference between 2 groups was based on fisher-exact test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Standard Dose, Double Dose
	Comments	Shortness of breath: statistical difference between 2 groups was based on fisher-exact test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Standard Dose, Double Dose
	Comments	Diarrhea: statistical difference between 2 groups was based on fisher-exact test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.487
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Standard Dose, Double Dose
	Comments	Headache: statistical difference between 2 groups was based on fisher-exact test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.593
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Standard Dose, Double Dose
	Comments	Conjunctivitis: statistical difference between 2 groups was based on fisher-exact test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Standard Dose, Double Dose
	Comments	Vomiting: statistical difference between 2 groups was based on fisher-exact test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Standard Dose, Double Dose
	Comments	Other: statistical difference between 2 groups was based on fisher-exact test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.106
	Comments
	Method	Fisher Exact
	Comments

4. Secondary Outcome

Title	Number of Participants With Various Clinical Signs and Symptoms in Whom Resistant Virus Were Detected
Description	Number of participants with various clinical signs and symptoms, as per investigator's discretion, in whom new AH1N1 virus was detected, were reported. Same participants were reported in more than 1 category.
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

ITT population. Here "number of participants analyzed" included evaluable participants for the outcome measure.

Arm/Group Title	Standard Dose	Double Dose
Arm/Group Description	Oseltamivir capsule was administered orally at a dose of 75 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 30 mg BID to a maximum dose of 75 mg BID; for 5 days.	Oseltamivir capsule was administered orally at a dose of 150 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 60 mg BID to a maximum dose of 150 mg BID; for 5 days.
Measure Participants	5	6
Cough	3 15.8%	4 22.2%
Rhinorrhea	3 15.8%	3 16.7%
Shortness of breath	0 0%	1 5.6%

Adverse Events

Time Frame	Up to 12 months
Arm/Group Title	Standard Dose		Double Dose
Arm/Group Description	Oseltamivir capsule was administered orally at a dose of 75 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/ml) based on their body weight with a starting dose of 30 mg BID to a maximum dose of 75 mg BID; for 5 days.		Oseltamivir capsule was administered orally at a dose of 150 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/ml) based on their body weight with a starting dose of 60 mg BID to a maximum dose of 150 mg BID; for 5 days.
All Cause Mortality
	Standard Dose		Double Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Standard Dose		Double Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Standard Dose		Double Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/19 (42.1%)		7/18 (38.9%)
Gastrointestinal disorders
Abdominal cramps	0/19 (0%)		1/18 (5.6%)
Abdominal pain	1/19 (5.3%)		1/18 (5.6%)
Diarrhoea	1/19 (5.3%)		1/18 (5.6%)
Dyspepsia	1/19 (5.3%)		0/18 (0%)
Epigastric discomfort	1/19 (5.3%)		0/18 (0%)
Nausea	1/19 (5.3%)		1/18 (5.6%)
Vomiting	1/19 (5.3%)		2/18 (11.1%)
General disorders
Chest pain	0/19 (0%)		1/18 (5.6%)
Feeling hot	0/19 (0%)		1/18 (5.6%)
Tracheobronchitis	1/19 (5.3%)		0/18 (0%)
Infections and infestations
Pneumonia	1/19 (5.3%)		0/18 (0%)
Investigations
Weight decreased	1/19 (5.3%)		0/18 (0%)
Psychiatric disorders
Agitation	0/19 (0%)		1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/19 (5.3%)		0/18 (0%)
Skin and subcutaneous tissue disorders
Rash	1/19 (5.3%)		0/18 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.