FOCUS: Effect of Oseltamivir on Cognitive Function in Subjects With Influenza

• Sponsor: Trial Management Group Inc. (Other)
• Overall Status: Completed
• CT.gov ID: NCT01249833
• Collaborator: Hoffmann-La Roche (Industry)
• Enrollment: 122
• Locations: 16
• Arms: 2
• Duration (Months): 17
• Patients Per Site: 7.6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This study has been designed to determine if subjects treated with oseltamivir in addition to standard of care treatment for influenza demonstrate a greater improvement in attention / working memory / processing speed / mood as compared to subjects receiving standard of care alone. The cognitive tests employed are objective measures developed and administered online by HeadMinder Inc.

Condition or Disease	Intervention/Treatment	Phase
Influenza	Drug: Oseltamivir	Phase 4

Detailed Description

Primary Objective:

To determine if subjects treated with oseltamivir in addition to standard of care treatment for influenza demonstrate a greater improvement in attention as compared to subjects receiving standard of care alone.

Secondary Objectives:

To determine if subjects treated with oseltamivir in addition to standard of care treatment for influenza demonstrate a greater improvement in working memory and processing speed as compared to subjects receiving standard of care alone.

Supportive Objectives:

1. To determine if subjects treated with oseltamivir in addition to standard of care treatment for influenza demonstrate a greater improvement in self-rated alertness as compared to subjects receiving standard of care alone.

2. To determine if subjects treated with oseltamivir in addition to standard of care treatment for influenza demonstrate a greater improvement in self-rated calmness and contentment as compared to subjects receiving standard of care alone.

3. To determine if there is a correlation between the rate of improvement in symptom scores and the rate of change in attention and working memory.

Study Design

• Study Type: Interventional
• Actual Enrollment: 122 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Masking Description: Open Label
• Primary Purpose: Treatment
• Official Title: Randomised, Open-label, Multi-Centre, Phase IV Study Assessing the Effect of Oseltamivir Treatment on Cognitive Function in Subjects With Confirmed Influenza Virus Infection
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Oseltamivir Added to standard of care for influenza	Drug: Oseltamivir; Oseltamivir 75mg BID for 5 days; Other Names: Tamiflu
No Intervention: Standard of care alone Standard of care for influenza

Outcome Measures

Primary Outcome Measures

1. Change in Attention Assessment [Change from baseline at Day 4]

   Attention assessed using simple reaction time measured in milliseconds. Simple reaction time calculated as the mean of the following 2 sub-tests: Reaction Time Subtest Cued Reaction Time Subtest The lower the value, the better the attention.

Secondary Outcome Measures

1. Change in Working Memory Assessment [Change from baseline at Day 4]

   Working memory assessed with the Dot Memory Test. The higher the value, the better the working memory.

2. Change in Processing Speed Assessment [Change from baseline at Day 4]

   Processing speed assessed with the animal number decoding subtest The lower the value, the better the processing speed

Other Outcome Measures

1. Change in Mood Assessment [Change from baseline at Day 4]

   Mood was assessed using the Bond-Lader 10 cm (100 mm) visual analogue scales for mood (16 scales in total); factored for alertness (mean of 9 scales), calmness (mean of 2 scales) and contentment (mean of 5 scales). The range in score for each scale and for each factor (alertness, calmness and contentment) was 0 - 100 mm. Each scale was anchored such that the lower the value, the better the mood.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Adult men and women, 18 - 65 years of age (inclusive)

2. Indicative symptoms/signs of uncomplicated acute illness due to influenza infection (A or B strains) that started within a maximum of 2 days prior to Visit 1 as per the

Tamiflu® Canadian product label. Signs and symptoms may include the following:

• Fever

• Respiratory symptoms (cough, coryza, sore throat, rhinitis)

• Constitutional symptoms (headache, malaise, myalgia, sweats and/or chills, fatigue)

1. Positive rapid antigen test for influenza (A or B strains) at Visit 1

2. Negative urine pregnancy test at Visit 1 for women of childbearing potential; women of childbearing potential who are sexually active must agree to use a suitable form of contraception during the study. Acceptable birth control measures include: hysterectomy, birth control pills, tubal ligation, intrauterine device, hormonal injections and implants, double barrier methods (such as a condom with a diaphragm or a condom with spermicide), and abstinence. Oral contraceptives must be in stable use for 2 or more cycles prior to screening. Intrauterine device (IUD) must be in use at least 30 days prior to study drug administration. Barrier methods must be in use at least 14 days prior to study drug administration.

3. Subjects must:

• have daily access to a computer at home with: internet access (preferably high-speed for optimal performance but dial-up can be used as well); Microsoft operating system; Internet Explorer browser capability and an e-mail account. A Macintosh (Mac) computer cannot be used.

• be capable of and willing to complete the required online assessments in English according to the protocol schedule

• be willing to abstain from the use of an antiviral medication if they are randomised to the standard of care treatment arm

• have provided written informed consent prior to the initiation of any study procedures

Exclusion Criteria:

1. More than 2 days since the onset of influenza symptoms

2. Subjects who, in the Investigator's judgment, require treatment with an antiviral medication as per the Canadian "Clinical Recommendations for Patients Presenting with Respiratory Symptoms During the 2009 - 2010 Influenza Season" (see Appendix D)

3. Clinical suspicion of infection with a respiratory virus other than influenza

4. Any medical condition that is sufficiently severe or unstable such that the subject is considered to be at imminent risk of requiring hospitalisation

5. History of conditions that may potentially affect cognitive function during the study, such as underlying neurologic conditions, depression or depressive disorders (unless the condition and treatment have been stable for 3 months), seasonal affective disorder (SAD), or any other cognitive impairment or dementia

6. Intermittent use of sedative-hypnotics; subjects who have been taking a fixed dose of a sedative-hypnotic every day for a period of at least 30 days may be included provided that they continue the same regimen throughout the study.

7. Intermittent or chronic use of psychiatric medications (with the exception of antidepressants that have been stable for 3 months) or anti-epileptic drugs

8. Nursing home residents

9. Known allergy to oseltamivir phosphate or any of the inactive ingredients of Tamiflu®

10. Women who are pregnant, or planning to become pregnant, or who are lactating

11. Current alcohol or drug abuse or substance dependence

12. Participation in another clinical trial with an investigational drug within the last 30 days

13. Patients vaccinated for influenza within 6 months of study enrollment

14. In the Investigator's judgment, the subject will not be able to adhere to the protocol requirements or is not suitable for study participation for any reason

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dr. Collette	Vancouver	British Columbia	Canada
2	Dr. Lai	Vancouver	British Columbia	Canada
3	Topsail Road Medical Clinic	St. John's	Newfoundland and Labrador	Canada
4	Moran Medical Centre	Collingwood	Ontario	Canada
5	Dr. Kanani	Etobicoke	Ontario	Canada
6	Dr. Herman	London	Ontario	Canada
7	Milestone Research	London	Ontario	Canada
8	SKDS Research Inc	Newmarket	Ontario	Canada
9	Family First Medical Centre	Orleans	Ontario	Canada
10	Steeple Hill Medical Centre	Pickering	Ontario	Canada	L1V 2A6
11	Dr. Martyn Chilvers - London Road Diagnostic Clinic and Medical Centre	Sarnia	Ontario	Canada
12	Dr. Michael O'Mahony - London Road Diagnostic Clinic and Medical Centre	Sarnia	Ontario	Canada
13	DCTM Clinical Trials Group Ltd.	Strathroy	Ontario	Canada
14	Dr. Gupta	Toronto	Ontario	Canada
15	Devonshire Clinical Research Inc.	Woodstock	Ontario	Canada
16	Regina Medical Centre	Regina	Saskatchewan	Canada	S4P 3X1

Sponsors and Collaborators

• Trial Management Group Inc.
• Hoffmann-La Roche

Investigators

• Principal Investigator: Dr. O'Mahony, M.D., London Road Diagnostic Clinic and Medical Centre

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Trial Management Group Inc.
• ClinicalTrials.gov Identifier: NCT01249833
• Other Study ID Numbers: CAI-001-10
• First Posted: Nov 30, 2010
• Last Update Posted: Mar 9, 2017
• Last Verified: Jan 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Trial Management Group Inc.: Influenza; Cognition; Attention; Simple Reaction Time; Alertness; Calmness; Contentment; Mood
• Additional relevant MeSH terms: Influenza, Human; Oseltamivir

Study Results

Participant Flow

Arm/Group Title	Oseltamivir	Standard of Care Alone
Arm/Group Description	Added to standard of care for influenza Oseltamivir: Oseltamivir 75mg BID for 5 days	Standard of care for influenza
Period Title: Overall Study
STARTED	59	63
COMPLETED	59	62
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Oseltamivir	Standard of Care Alone	Total
Arm/Group Description	Added to standard of care for influenza Oseltamivir: Oseltamivir 75mg BID for 5 days	Standard of care for influenza	Total of all reporting groups
Overall Participants	59	63	122
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	37.0	32.0	34.0
Sex: Female, Male (Count of Participants)
Female	29 49.2%	33 52.4%	62 50.8%
Male	30 50.8%	30 47.6%	60 49.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.7%	0 0%	1 0.8%
Asian	12 20.3%	12 19%	24 19.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 1.7%	2 3.2%	3 2.5%
White	43 72.9%	49 77.8%	92 75.4%
More than one race	1 1.7%	0 0%	1 0.8%
Unknown or Not Reported	1 1.7%	0 0%	1 0.8%
Region of Enrollment (participants) [Number]
Canada	59 100%	63 100%	122 100%
Highest Education Level (Count of Participants)
Grade 5 - 11	7 11.9%	3 4.8%	10 8.2%
High School Graduate	12 20.3%	19 30.2%	31 25.4%
1 - 3 Years College	20 33.9%	24 38.1%	44 36.1%
Bachelor's Degree	16 27.1%	13 20.6%	29 23.8%
Post-Graduate	4 6.8%	4 6.3%	8 6.6%
Current Smoker (Count of Participants)
Count of Participants [Participants]	7 11.9%	14 22.2%	21 17.2%
Time from Symptom Onset (hours) [Median (Full Range) ]
Median (Full Range) [hours]	33.8	36.7	35.0
Baseline Symptom Score (symptom score) [Median (Full Range) ]
Median (Full Range) [symptom score]	13	14	14
Body Temperature (Degrees centigrade) [Median (Full Range) ]
Median (Full Range) [Degrees centigrade]	38.1	38.1	38.1
Health Assessment Question (Score) [Median (Full Range) ]
Median (Full Range) [Score]	3	3	3
Influenza Type (Count of Participants)
Strain A	53 89.8%	52 82.5%	105 86.1%
Strain B	6 10.2%	11 17.5%	17 13.9%
Cognitive/Mood Conditions (Count of Participants)
None	53 89.8%	60 95.2%	113 92.6%
ADHD	0 0%	1 1.6%	1 0.8%
Anxiety	1 1.7%	1 1.6%	2 1.6%
Depression	5 8.5%	1 1.6%	6 4.9%

Outcome Measures

1. Primary Outcome

Title	Change in Attention Assessment
Description	Attention assessed using simple reaction time measured in milliseconds. Simple reaction time calculated as the mean of the following 2 sub-tests: Reaction Time Subtest Cued Reaction Time Subtest The lower the value, the better the attention.
Time Frame	Change from baseline at Day 4

Outcome Measure Data

Analysis Population Description

All randomised subjects for whom data was collected at both baseline and Day 4. Oseltamivir group: baseline data available for 58 of 59 randomised subjects and Day 4 data for 53 subjects (53 subjects analysed). Standard of Care Alone group: baseline data available for 61 of 63 subjects and Day 4 data for 55 subjects (55 subjects analysed).

Arm/Group Title	Oseltamivir	Standard of Care Alone
Arm/Group Description	Added to standard of care for influenza Oseltamivir: Oseltamivir 75mg BID for 5 days	Standard of care for influenza
Measure Participants	53	55
Least Squares Mean (Standard Error) [milliseconds]	-70.0 (10.9)	-39.7 (10.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Standard of Care Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0492
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Means Difference
	Estimated Value	-30.4
	Confidence Interval	(2-Sided) 95%; -60.7 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	The LS means for Standard of Care Alone was subtracted from that of Oseltamivir.

2. Secondary Outcome

Title	Change in Working Memory Assessment
Description	Working memory assessed with the Dot Memory Test. The higher the value, the better the working memory.
Time Frame	Change from baseline at Day 4

Outcome Measure Data

Analysis Population Description

All randomised subjects with data collected at both Baseline and Day 4. Oseltamivir Group: Baseline values collected for all randomized subjects (59); Day 4 data available for 54 subjects (54 analysed). Standard of Care Alone Group: Baseline values collected for all randomized subjects (63); Day 4 data available for 58 subjects (58 analysed)

Arm/Group Title	Oseltamivir	Standard of Care Alone
Arm/Group Description	Added to standard of care for influenza Oseltamivir: Oseltamivir 75mg BID for 5 days	Standard of care for influenza
Measure Participants	54	58
Least Squares Mean (Standard Error) [Number of correct answers]	8.2 (0.95)	4.4 (0.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Standard of Care Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0054
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Means Difference
	Estimated Value	3.8
	Confidence Interval	(2-Sided) 95%; 1.14 to 6.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	The LS means for Standard of Care Alone was subtracted from that of Oseltamivir.

3. Secondary Outcome

Title	Change in Processing Speed Assessment
Description	Processing speed assessed with the animal number decoding subtest The lower the value, the better the processing speed
Time Frame	Change from baseline at Day 4

Outcome Measure Data

Analysis Population Description

All randomized subjects for whom data was collected at both Baseline and Day 4. Oseltamivr Group: Baseline data available for all randomized subjects (59); Day 4 data available for 54 subjects (54 analysed). Standard of Care Alone Group: Baseline data available for all randomized subjects (63); Day 4 data available for 58 subjects (58 analysed).

Arm/Group Title	Oseltamivir	Standard of Care Alone
Arm/Group Description	Added to standard of care for influenza Oseltamivir: Oseltamivir 75mg BID for 5 days	Standard of care for influenza
Measure Participants	54	58
Least Squares Mean (Standard Error) [Millliseconds]	-551.9 (77.6)	-555.8 (78.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Standard of Care Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.9685
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Means Difference
	Estimated Value	3.9
	Confidence Interval	(2-Sided) 95%; -190.1 to 197.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	The LS means for Standard of Care Alone was subtracted from that of Oseltamivir.

4. Other Pre-specified Outcome

Title	Change in Mood Assessment
Description	Mood was assessed using the Bond-Lader 10 cm (100 mm) visual analogue scales for mood (16 scales in total); factored for alertness (mean of 9 scales), calmness (mean of 2 scales) and contentment (mean of 5 scales). The range in score for each scale and for each factor (alertness, calmness and contentment) was 0 - 100 mm. Each scale was anchored such that the lower the value, the better the mood.
Time Frame	Change from baseline at Day 4

Outcome Measure Data

Analysis Population Description

All randomised subjects with data collected at both Baseline and Day 4. Baseline data was available for all randomized subjects in both groups; Day 4 data was available for 54 of 59 randomized subjects in the Oseltamivir Group (54 analysed) and for 58 of 63 randomized subjects in the Standard of Care Alone Group (58 analysed).

Arm/Group Title	Oseltamivir	Standard of Care Alone
Arm/Group Description	Added to standard of care for influenza Oseltamivir: Oseltamivir 75mg BID for 5 days	Standard of care for influenza
Measure Participants	54	58
Change in Alertness Assessment	19.1 (1.4)	17.2 (1.4)
Change in Calmness Assessment	3.0 (1.3)	3.6 (1.2)
Change in Contentedness Assessment	16.3 (1.5)	13.0 (1.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Standard of Care Alone
	Comments	Alertness: the higher the value, the greater the alertness.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.3195
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Means Difference
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95%; -1.9 to 5.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	The LS means for Standard of Care Alone was subtracted from that of Oseltamivir.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Standard of Care Alone
	Comments	Calmness: the higher the value, the greater the calmness.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.7219
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Means Difference
	Estimated Value	-.6
	Confidence Interval	(2-Sided) 95%; -4.1 to 2.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	The LS means for Standard of Care AL one was subtracted from that of Oseltamivir.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Oseltamivir, Standard of Care Alone
	Comments	Contentedness: the higher the value, the greater the contentedness.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.1162
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Means Difference
	Estimated Value	3.3
	Confidence Interval	(2-Sided) 95%; -.8 to 7.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	The LS means of Standard of Care Alone was subtracted from that of Oseltamivir.

Adverse Events

Time Frame	14 days
Arm/Group Title	Oseltamivir		Standard of Care Alone
Arm/Group Description	Added to standard of care for influenza Oseltamivir: Oseltamivir 75mg BID for 5 days		Standard of care for influenza
All Cause Mortality
	Oseltamivir		Standard of Care Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Oseltamivir		Standard of Care Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/59 (0%)		0/63 (0%)
Other (Not Including Serious) Adverse Events
	Oseltamivir		Standard of Care Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/59 (13.6%)		8/63 (12.7%)
Gastrointestinal disorders
Nausea	1/59 (1.7%)	1	0/63 (0%)	0
Diarrhoea	0/59 (0%)	0	1/63 (1.6%)	1
Infections and infestations
Bronchitis	1/59 (1.7%)	1	0/63 (0%)	0
Pharyngitis	1/59 (1.7%)	1	0/63 (0%)	0
Gastroenteritis viral	1/59 (1.7%)	1	0/63 (0%)	0
Pneumonia	0/59 (0%)	0	2/63 (3.2%)	2
Injury, poisoning and procedural complications
Fracture	1/59 (1.7%)	1	0/63 (0%)	0
Contusion	0/59 (0%)	0	1/63 (1.6%)	1
Nervous system disorders
Headache	1/59 (1.7%)	1	1/63 (1.6%)	1
Dizziness	1/59 (1.7%)	1	0/63 (0%)	0
Psychiatric disorders
Anxiety Disorder	0/59 (0%)	0	1/63 (1.6%)	1
Anger	0/59 (0%)	0	1/63 (1.6%)	1
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/59 (0%)	0	1/63 (1.6%)	1
Oropharyngeal Pain	0/59 (0%)	0	1/63 (1.6%)	1
Skin and subcutaneous tissue disorders
Rash	2/59 (3.4%)	4	1/63 (1.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If Sponsor has not submitted a manuscript for publication for this multi-center study within 12 months of study completion/termination, the PI will be free to publish separately. Sponsor can review results communications prior to public release and can embargo communications for up to 90 days if the proposed publication contains information relating to patentable items. If Sponsor believes proposed communications contain any confidential information, Sponsor has the right to remove it.