IRC003: Comparing the Efficacy, Safety, and Tolerability of Combination Antivirals (Amantadine, Ribavirin, Oseltamivir) Versus Oseltamivir for the Treatment of Influenza in Adults at Risk for Complications

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01227967
• Collaborator: (none)
• Enrollment: 881
• Locations: 91
• Arms: 2
• Duration (Months): 78.9
• Patients Per Site: 9.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Seasonal influenza is responsible for many hospitalizations and deaths each year, despite effective antiviral treatments. Some individuals have medical conditions such as heart or lung diseases that make them particularly at risk of severe influenza infections that may result in hospitalization or death. Oseltamivir (Tamiflu) is used most often to treat flu, but there are still many hospitalizations, complications, and deaths even with treatment. This study evaluated the use of combination antivirals (amantadine, oseltamivir, and ribavirin) compared to oseltamivir alone in the treatment of influenza in an at-risk population.

Condition or Disease	Intervention/Treatment	Phase
Influenza	Drug: Amantadine, Ribavirin, Oseltamivir; Drug: Oseltamivir	Phase 2

Detailed Description

Seasonal influenza is responsible for approximately 226,000 excess hospitalizations annually and despite effective antivirals causes significant morbidity and mortality (estimated 24,000-50,000 deaths each year in the United States alone). The influenza virus that emerged in 2009 (A/California/07/2009 H1N1) caused fewer deaths (12,000 flu-related deaths in the U.S) but in contrast to seasonal flu, nearly 90 percent of the deaths with the 2009 H1N1 occurred among people younger than 65 years of age. The CDC has defined an at-risk population that accounts for the majority of hospitalization and morbidity associated with influenza. This study evaluated the use of combination antivirals as compared to oseltamivir alone in the treatment of influenza in an at-risk population.

Subjects who met the CDC definition for being at-risk and that present with an influenza-like illness were screened for the study. Those subjects with a confirmatory test for influenza (rapid antigen or PCR) were randomized in a 1:1 manner to receive a blinded study treatment consisting of either the combination of amantadine, oseltamivir, and ribavirin or oseltamivir alone for 5 days. Clinical, virologic, and laboratory assessments on Days 1, 3, 7, 14, and 28 were used for both safety and efficacy analysis.

Design:

• Participants were screened with a physical examination and medical history, along with blood tests and throat swabs to confirm influenza infection.

• Eligible participants were randomly assigned to take either oseltamivir alone (the current standard treatment for influenza) or to take oseltamivir, amantadine, and ribavirin. Participants had additional blood samples and throat swabs taken at the start of the study, and were shown how to complete a study diary at home.

• Participants received a study medication kit containing the medication to take at home twice a day for 5 days.

• Participants returned, with the medication kit, to the clinic on days 1 (the first day after the start of the study), 3, 7, 14, and 28. The first visit took 2 to 3 hours, but each subsequent visit took approximately 1 to 2 hours. Additional blood samples and throat swabs were taken at these visits.

Pilot study:

Due to the lack of reliable data concerning the AUC virologic endpoint, an "external" pilot study was conducted in the first 47 patients randomized to identify a primary endpoint and method of analysis, and to possibly modify the sample size. To ensure no effect on the type I error rate, data from these 47 patients were excluded from the primary and secondary efficacy analyses but were used in other analyses of secondary objectives.

Study Design

• Study Type: Interventional
• Actual Enrollment: 881 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized Double-Blind Phase 2 Study Comparing the Efficacy, Safety, and Tolerability of Combination Antivirals (Amantadine, Ribavirin, Oseltamivir) Versus Oseltamivir for the Treatment of Influenza in Adults at Risk for Complications
• Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: May 2, 2016
• Actual Study Completion Date: Mar 30, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Combination Therapy Amantadine, Ribavirin, Oseltamivir	Drug: Amantadine, Ribavirin, Oseltamivir; Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.
Active Comparator: Oseltamivir monotherapy Oseltamivir	Drug: Oseltamivir; Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs [At Day 3]

   The central laboratory performed a qualitative PCR test on the NP sample from Day 0 in order to confirm influenza infection and to determine the influenza type and subtype. For participants with a positive influenza test result at Day 0 from this qualitative PCR testing, the laboratory then performed qPCR testing of subsequent samples to quantify viral shedding.

Secondary Outcome Measures

1. Number of Participants by Virus Detection Status [At Day 0, 3 and 7.]

   Number of participants who had undetectable values (less than the limit of detection [LOD]), who had values between the LOD and the lower limit of quantification (LLOQ), and who had values ≥LLOQ

2. qPCR Viral Shedding [At Day 0, 3 and 7]

   Median, 25% and 75% percentile of the value of viral shedding (Results <LOD were imputed as the LOD value, and Results >= LOD, <LLOQ were imputed as the LLOQ value.)

3. Number of Participants Shedding Virus [At day 3 and 7.]

   Number of participants with undetectable viral load at both Day 3 and Day 7; detectable at Day 3 and undetectable at Day 7; detectable at Day 7 (irrespective of whether or not detectable at Day 3).

4. Time to Alleviation of Influenza Clinical Symptoms. [From treatment initiation to Day 28]

   The assessed symptoms were cough, nasal obstruction (stuffy nose), sore throat, fatigue, headache, muscle aches, feverishness, rhinorrhea, nausea, vomiting, diarrhea. Duration of clinical symptoms is defined as the time from Day 0 to the first of two successive measurements at which all clinical symptoms are grade 0 (absent) or 1 (mild). A measurement is considered to be the 8AM or 8PM assessment during Days 0 to 7 (so two measurements are obtained per day) and then the daily assessment thereafter. Time will then be calculated in half-days through to Day 7. If a subject's first two assessments on (baseline assessment and first subsequent diary card assessment) satisfy this criterion, then the duration will be set to zero. For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with symptoms evaluated.

5. Time to Absence of Fever [From treatment initiation to Day 28]

   Fever was considered present based on the diary cards if a subject reported a maximal temperature ≥38.0°C (for the period since the diary card was previously completed) or reported having taken an antipyretic drug (also for the period since the diary card was previously completed). Otherwise, fever was considered not present during the period since the diary card was previously completed, except that the evaluation was considered missing if either the temperature or the antipyretic drug use entry was not completed on the diary card. The duration of fever was defined as the time from Day 0 to the first of two successive assessments (through to Day 7) or to the first assessment (Day 8 onwards) at which no fever was present according to this definition.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with fever evaluated.

6. Time to Resolution of All Symptoms AND Fever [From treatment initiation to Day 28]

   The assessed symptoms were cough, nasal obstruction (stuffy nose), sore throat, fatigue, headache, muscle aches, feverishness, rhinorrhea, nausea, vomiting, diarrhea. Fever was considered present based on the diary cards if a subject reported a maximal temperature ≥38.0°C (for the period since the diary card was previously completed) or reported having taken an antipyretic drug (also for the period since the diary card was previously completed). Time to resolution of all clinical symptoms and fever is defined as the time from Day 0 to the first of two successive measurements at which all clinical symptoms are grade 0 (absent) or 1(mild) and no fever >=38.0 C or antipyretic drug is reported. For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with symptoms and fever evaluated.

7. Time to Feeling as Good as Before the Onset of the Influenza Illness [From treatment initiation to Day 28]

   Time to feeling as good as before influenza is defined as time to the first of two successive 'yes' responses to the question of 'feeling as good as you did before you had the flu'.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with question answered.

8. Time to Return to Pre-influenza Function [From treatment initiation to Day 28]

   Time to return to pre-influenza function is defined as the time from Day 0 to the first of two successive 'Yes' answers to the global assessment question 'Are you functioning as well as you were before you had the flu'.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with question answered.

9. Time to Return of Physical Function to Pre-illness Leve [From treatment initiation to Day 28]

   Time to return of physical function to pre-illness level was defined as the time from Day 0 to the first of two successive measurements at which the physical function score equals or is better than the pre-illness score (obtained by recall at enrollment).For subjects who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with physical function evaluated.

10. Percentage of Participants With Clinical Failure at Day 5 [From treatment initiation to Day 28]

    Clinical failure at Day 5 is defined as the need for continued (non-study) antiviral use after Day 5.

11. Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. [From treatment initiation to Day 28]

    Participants were assessed for the signs/symptoms suggestive of one of the following complications: Sinusitis, Otitis Media ,Bronchitis / Bronchiolitis, Pneumonia and antibiotic use for reason other than above.

12. Percentage of Participants Who Required New or Increased Use of Supplemental Oxygen [From treatment initiation to Day 28]

    Percentage of participants who required new or increased use of supplemental oxygen

13. Percentage of Participants Who Required Hospitalization. [From treatment initiation to Day 28]

    The percentage of participants hospitalized by 28 days was estimated from the Kaplan-Meier curves.

14. 28-day Mortality [From treatment initiation to Day 28]

    Number of deaths

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

Enrollment (Screening)

1. Signed informed consent prior to initiation of any study procedures

2. Presence of an underlying medical condition(s) that might increase risk of complications from influenza

3. History of an influenza-like illness defined as:

• One or more respiratory symptom (cough, sore throat, or nasal symptoms) AND

• Either

• Fever (subjective or documented >38 degrees C) OR

• 1 or more constitutional symptom (headache, malaise, myalgia, sweats/chills or fatigue)

1. Onset of illness no more than 96 hours before screening defined as when the subject experienced at least one respiratory symptom, constitutional symptom, or fever

2. Willingness to have samples stored

Randomization

1. Signed informed consent

2. Presence of a medical condition(s) that had been associated with increased risk of complications from influenza

• Age 65 years of age or older

• Asthma

• Neurological and neuro-developmental conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy [seizure disorders], stroke, moderate to severe developmental delay, muscular dystrophy, or spinal cord injury) [though still able to provide informed consent per inclusion criteria #1]

• Chronic lung disease (such as COPD and cystic fibrosis)

• Heart disease (such as congenital heart disease, congestive heart failure, and coronary artery disease)

• Blood disorders (excluding genetic causes of anemia, as noted in the exclusion criteria)

• Endocrine disorders (such as diabetes mellitus)

• Kidney disorders

• Liver disorders

• Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders)

• Weakened immune system due to disease or medication (such as people with HIV/AIDS, or cancer, chronic steroids or other medications causing immune suppression)

• BMI ≥ 40(kg/m²)

1. Onset of illness no more than 96 hours before screening defined as when the subject experienced at least one respiratory symptom, constitutional symptom, or fever

2. Positive test for influenza (either rapid antigen or PCR)

• Results from influenza testing obtained for clinical indications within 12 hours before screening/enrollment may be used if available. Randomization may proceed in cases of discrepant results (one positive and one negative)

1. One of the following to avoid pregnancy:

• Females who were able to become pregnant (i.e., are not postmenopausal, have not undergone surgical sterilization, and are sexually active with men) must agree to use at least 2 effective forms of contraception from the date of informed consent through 6 months after the last dose of study drug. At least one of the methods of contraception should be a barrier method

• Males who had not undergone surgical sterilization and are sexually active with women must agree to use condoms plus have a partner use at least one additional effective form of contraception from the date of informed consent through 6 months after the last dose of study drug

1. Willingness to have samples stored

EXCLUSION CRITERIA:

(for Enrollment or Randomization)

1. Women who were pregnant or breast-feeding, and men whose female partner(s) was pregnant

2. Inability to take oral medication or a history of gastrointestinal malabsorption that would preclude the use of oral medication.

3. Hemoglobin < 10 g/dL

4. WBC < 1.5 times 10(9)/L

5. Neutrophils < 0.75 x 10(9)/L

6. Platelets < 50 x 10(9)/L

7. History of genetic hemoglobinopathy (e.g., thalassemia major or sickle cell anemia) or autoimmune hemolytic anemia

8. Received more than 2 doses of any antiviral influenza medications since onset of influenza symptoms

9. Received stavudine (d4T), didanosine (ddI), zidovudine (AZT), or azathioprine within 30 days prior to study entry

10. Creatinine clearance less than 60 mL/min (estimated by the Cockcroft-Gault equation using serum creatinine)

11. History of autoimmune hepatitis

12. Uncompensated liver disease (defined as AST > 3 times site upper limit of normal (ULN), ALT > 3 times ULN, or Direct Bilirubin > 2 times ULN)

13. Clinical signs of end-stage liver disease including jaundice, coagulopathy, portal hypertension, esophageal varices, ascites, peripheral edema, gastrointestinal bleeding, or encephalopathy

14. Chronic liver disease categorized as Child-Pugh class C (Child-Pugh score 10-15)

15. Known hypersensitivity to rimantadine, amantadine, ribavirin, oseltamivir, peramivir, or zanamivir

16. Received live attenuated virus vaccine (influenza or other) within 3 weeks prior to study entry

17. Use of any investigational drug within 30 days or 5 half-lives (whichever was longer) prior to study entry

18. Participation in other research protocols that would require more than 100 mL of blood to be drawn in any 4-week period that overlaps with this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Simon Williamson Clinic	Birmingham	Alabama	United States	35211
2	East Valley Family Physicians	Chandler	Arizona	United States	85224
3	Thomas Lenzmeier Family Practice	Glendale	Arizona	United States	85308
4	Central Phoenix Medical Center	Phoenix	Arizona	United States	85020
5	WCCT Global LLC	Costa Mesa	California	United States	92626
6	Advanced Rx Clinical Research	Garden Grove	California	United States	92843
7	Torrance Clinical Research Institute, Inc.	Lomita	California	United States	90717
8	University of Southern California	Los Angeles	California	United States	90033
9	University of California at San Diego	San Diego	California	United States	92103
10	Westlake Medical Research (CA)	Thousand Oaks	California	United States	91360
11	Los Angeles BioMedical Research Institute	Torrance	California	United States	90502
12	Empire Clinical Research	Upland	California	United States	91786
13	University of Colorado	Aurora	Colorado	United States	80045
14	Centennial - IMMUNOe International Research	Centennial	Colorado	United States	80112
15	University of Florida	Gainesville	Florida	United States	32610
16	Best Quality Research Inc.	Hialeah	Florida	United States	33016
17	San Marcus Research Clinic, Inc.	Miami	Florida	United States	33015
18	Medical Consulting Center	Miami	Florida	United States	33125
19	Suncoast Research Group, LLC	Miami	Florida	United States	33135
20	University of Miami	Miami	Florida	United States	33136
21	DMI Research, Inc.	Pinellas Park	Florida	United States	33782
22	Northwestern University	Chicago	Illinois	United States	60611
23	Sneeze, Wheeze & Itch Associates, LLC	Normal	Illinois	United States	61761
24	Ridge Family Practice	Council Bluffs	Iowa	United States	51503
25	University of Iowa	Iowa City	Iowa	United States	52246
26	Research Integrity, LLC	Owensboro	Kentucky	United States	42303
27	Horizon Research Group, of Opelousas, LLC	Eunice	Louisiana	United States	70535
28	Centex Studies Inc. - Dr. Seep	Lake Charles	Louisiana	United States	70601
29	NIH Clinical Center	Bethesda	Maryland	United States	20892
30	Boston Medical Center	Boston	Massachusetts	United States	02111
31	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
32	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
33	UMass Medical School	Worcester	Massachusetts	United States	01655
34	Henry Ford Health Systems	Detroit	Michigan	United States	48202
35	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
36	West Florissant Internists	Bridgeton	Missouri	United States	63044
37	Clinical Research Advantage/ Skyline Medical Center	Elkhorn	Nebraska	United States	68022
38	Prairie Fields Family Medicine	Fremont	Nebraska	United States	68025
39	Southwest Family Physicians	Omaha	Nebraska	United States	68124
40	New Jersey Medical School	Newark	New Jersey	United States	07103
41	James J. Peters, VA Medical Center	Bronx	New York	United States	10468
42	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
43	University of Rochester Medical Center	Rochester	New York	United States	14642
44	University of North Carolina-Chapel Hill	Chapel Hill	North Carolina	United States	27514
45	Duke University	Durham	North Carolina	United States	27710
46	Clinical Research Solutions - Dr. Panuto	Middleburg Heights	Ohio	United States	44130
47	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
48	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
49	Montgomery Medical	Smithfield	Pennsylvania	United States	15478
50	Health Concepts	Rapid City	South Dakota	United States	57702
51	Clinical Research Solutions - Dr. Bart	Columbia	Tennessee	United States	38401
52	Clinical Research Solutions - Dr. Slandzicki	Franklin	Tennessee	United States	37064
53	Clinical Research Solutions - Dr. Hoppers	Jackson	Tennessee	United States	38305
54	Holston Medical Group	Kingsport	Tennessee	United States	37660
55	Clinical Research Solutions - Dr. Rowe	Nashville	Tennessee	United States	37211
56	Clinical Research Solutions - Dr. Dar	Smyrna	Tennessee	United States	37167
57	University of Texas Tech Amarillo	Amarillo	Texas	United States	79106
58	Family Medicine Associates of Texas	Carrollton	Texas	United States	75010
59	3rd Coast Research Associates	Corpus Christi	Texas	United States	78413
60	University of Texas at Houston	Houston	Texas	United States	77030
61	Centex Studies Inc. - Dr. Pouzar	Houston	Texas	United States	77062
62	Pioneer Research Solutions, Inc.	Houston	Texas	United States	77098
63	Texas Tech HSC	Lubbock	Texas	United States	79430
64	Centex Studies Inc. - Dr. Garcia	Pharr	Texas	United States	78577
65	Village Health Partners	Plano	Texas	United States	75024
66	Endeavor Clinical Trials	San Antonio	Texas	United States	78229
67	Bandera Family Healthcare Research	San Antonio	Texas	United States	78249
68	University of Virginia	Charlottesville	Virginia	United States	22908
69	Virginia Commonwealth University	Richmond	Virginia	United States	23298
70	Instituto Medico Platense	La Plata	Buenos Aires	Argentina
71	Hospital Houssay	Vicente Lopez	Provincia De Buenos Aires	Argentina
72	Centro de Educación Médica e Investigaciónes Clínicas (CEMIC)	Buenos Aires		Argentina
73	Fundación del Centro de Estudios Infectológicos (FUNCEI)	Buenos Aires		Argentina
74	Hospital General de Agudos J. M. Ramos Mejía	Buenos Aires		Argentina
75	Hospital Italiano de Buenos Aires	Buenos Aires		Argentina
76	Hospital Rawson	Cordoba		Argentina
77	Instituto Centralizado de Asistencia e Investigación Clínica Integral (CAICI)	Santa Fe		Argentina
78	Holdsworth House Med Practice	Darlinghurst	New South Wales	Australia	2010
79	Taylor Square Private Clinic	Darlinghurst	New South Wales	Australia	2010
80	Westmead Hospital	Westmead	New South Wales	Australia
81	Royal Brisbane	Herston	Queensland	Australia	4029
82	Northside Clinic	Fitzroy North	Victoria	Australia	3068
83	The Alfred Hospital	Melbourne	Victoria	Australia	3004
84	Royal Melbourne Hospital	Parkville	Victoria	Australia	3052
85	Instituto Nacional de Ciencias Médicas y Nutrición (INCMN) Salvador Zubirán	México City		Mexico
86	Hospital General y de Alta Especialidad "Dr. Manuel GEA Gonzalez"	Tlalpan		Mexico
87	Instituto Nacional de Enfermedades Respiratorias (INER)	Tlalpan		Mexico
88	Siriraj Hospital, Mahidol University	Bangkoknoi	Bangkok	Thailand	10700
89	HIV-NAT, The Thai Red Cross AIDS	Patumwan	Bangkok	Thailand	10330
90	Srinagarind Hospital, Khon Kaen University	Muang	Khon Kaen	Thailand	40002
91	Bamrasnaradura Infectious Diseases Institute	Muang	Nonthaburi	Thailand	11000

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: John Beigel, MD, Leidos Biomedical Research, Inc. in support of Clinical Research Section, LIR, NIAID, Natinal Institutes of Health
• Study Chair: John Treanor, MD, University of Rochester

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page
• The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009).

Publications

• Monto AS. Vaccines and antiviral drugs in pandemic preparedness. Emerg Infect Dis. 2006 Jan;12(1):55-60.
• Moscona A. Oseltamivir resistance--disabling our influenza defenses. N Engl J Med. 2005 Dec 22;353(25):2633-6.
• Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003 Jan 8;289(2):179-86.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT01227967
• Other Study ID Numbers: 10-I-0210; 10-I-0210; IRC003
• First Posted: Oct 25, 2010
• Last Update Posted: Feb 4, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Adaptive Design; At Risk; H1N1; Synergy; TCAD
• Additional relevant MeSH terms: Influenza, Human; Ribavirin; Oseltamivir; Amantadine

Study Results

Participant Flow

Recruitment Details	Outpatient or hospitalized participants at high risk for complications and morbidity, diagnosed with influenza by rapid antigen or PCR were recruited at 65 sites from 5 countries: 52 from the U.S., 2 from Australia, 3 from Mexico, and 4 each in Thailand and Argentina, between March 2011 to April 2016.
Pre-assignment Detail	Eight hundred eighty-one subjects were enrolled per protocol (signed consent). Two hundred fifty-one subjects were excluded during screening and did not participate in any other aspect of the trial. Three subjects were randomized improperly because they were given study drug kit prior to the randomization.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Period Title: Overall Study
STARTED	314	316
COMPLETED	298	303
NOT COMPLETED	16	13

Baseline Characteristics

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy	Total
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	Total of all reporting groups
Overall Participants	314	312	626
Age (Count of Participants)
<=18 years	1 0.3%	4 1.3%	5 0.8%
Between 18 and 65 years	252 80.3%	241 77.2%	493 78.8%
>=65 years	61 19.4%	67 21.5%	128 20.4%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	49.5	49.5	49.5
Sex: Female, Male (Count of Participants)
Female	187 59.6%	198 63.5%	385 61.5%
Male	127 40.4%	114 36.5%	241 38.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	55 17.5%	58 18.6%	113 18.1%
Not Hispanic or Latino	258 82.2%	254 81.4%	512 81.8%
Unknown or Not Reported	1 0.3%	0 0%	1 0.2%
Race/Ethnicity, Customized (Count of Participants)
White	203 64.6%	189 60.6%	392 62.6%
Asian	70 22.3%	73 23.4%	143 22.8%
Black or African American	18 5.7%	25 8%	43 6.9%
American Indian	1 0.3%	2 0.6%	3 0.5%
Race not available to clinic	21 6.7%	21 6.7%	42 6.7%
Subject does not want to report	1 0.3%	1 0.3%	2 0.3%
Subject does not know	0 0%	1 0.3%	1 0.2%
Region of Enrollment (participants) [Number]
Argentina	12 3.8%	10 3.2%	22 3.5%
United States	220 70.1%	216 69.2%	436 69.6%
Mexico	17 5.4%	18 5.8%	35 5.6%
Australia	0 0%	2 0.6%	2 0.3%
Thailand	65 20.7%	66 21.2%	131 20.9%
Influenza Diagnostic Test by Local Testing (Count of Participants)
RT-PCR/PCR	33 10.5%	30 9.6%	63 10.1%
Rapid antigen test	281 89.5%	281 90.1%	562 89.8%
Isothermal nucleic acid amplification technology	0 0%	1 0.3%	1 0.2%
Positive Influenza Test by Local Testing (Count of Participants)
Count of Participants [Participants]	314 100%	312 100%	626 100%
Result of Influenza Test By Local Testing (Count of Participants)
Influenza A/H1N1	13 4.1%	14 4.5%	27 4.3%
Influenza A/H3N2	1 0.3%	1 0.3%	2 0.3%
Influenza A unsubtypable	29 9.2%	22 7.1%	51 8.1%
Influenza A not typed	180 57.3%	180 57.7%	360 57.5%
Influenza B	75 23.9%	80 25.6%	155 24.8%
Influenza positive (unknown A or B)	10 3.2%	5 1.6%	15 2.4%
Multiple types/subtypes	6 1.9%	10 3.2%	16 2.6%
Confirmed Influenza Infection Status By Central Testing (Count of Participants)
Yes	230 73.2%	224 71.8%	454 72.5%
No	84 26.8%	88 28.2%	172 27.5%
Influenza Type/Subtype By Central Testing (Count of Participants)
Influenza A/H3N2	126 40.1%	118 37.8%	244 39%
Influenza A/H1N1	55 17.5%	49 15.7%	104 16.6%
Influenza B	49 15.6%	57 18.3%	106 16.9%
Negative	83 26.4%	86 27.6%	169 27%
Missing	1 0.3%	2 0.6%	3 0.5%
Quantitative PCR Viral Shedding (log10 copies/mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [log10 copies/mL]	6.4	6.7	6.5
Presence of fever (Count of Participants)
Yes	94 29.9%	93 29.8%	187 29.9%
No	216 68.8%	216 69.2%	432 69%
Missing	4 1.3%	3 1%	7 1.1%
Symptom Score (Count of Participants)
Absent	18 5.7%	14 4.5%	32 5.1%
Mild	68 21.7%	86 27.6%	154 24.6%
Moderate	139 44.3%	130 41.7%	269 43%
Severe	85 27.1%	78 25%	163 26%
Missing	4 1.3%	4 1.3%	8 1.3%
Absent	28 8.9%	15 4.8%	43 6.9%
Mild	33 10.5%	43 13.8%	76 12.1%
Moderate	117 37.3%	105 33.7%	222 35.5%
Severe	132 42%	145 46.5%	277 44.2%
Missing	4 1.3%	4 1.3%	8 1.3%
Absent	70 22.3%	62 19.9%	132 21.1%
Mild	61 19.4%	68 21.8%	129 20.6%
Moderate	111 35.4%	98 31.4%	209 33.4%
Severe	68 21.7%	80 25.6%	148 23.6%
Missing	4 1.3%	4 1.3%	8 1.3%
Absent	231 73.6%	253 81.1%	484 77.3%
Mild	36 11.5%	26 8.3%	62 9.9%
Moderate	26 8.3%	20 6.4%	46 7.3%
Severe	15 4.8%	10 3.2%	25 4%
Missing	6 1.9%	3 1%	9 1.4%
Absent	44 14%	30 9.6%	74 11.8%
Mild	51 16.2%	56 17.9%	107 17.1%
Moderate	100 31.8%	99 31.7%	199 31.8%
Severe	115 36.6%	124 39.7%	239 38.2%
Missing	4 1.3%	3 1%	7 1.1%
Absent	268 85.4%	269 86.2%	537 85.8%
Mild	18 5.7%	18 5.8%	36 5.8%
Moderate	16 5.1%	12 3.8%	28 4.5%
Severe	6 1.9%	9 2.9%	15 2.4%
Missing	6 1.9%	4 1.3%	10 1.6%
Absent	60 19.1%	55 17.6%	115 18.4%
Mild	76 24.2%	81 26%	157 25.1%
Moderate	99 31.5%	99 31.7%	198 31.6%
Severe	75 23.9%	74 23.7%	149 23.8%
Missing	4 1.3%	3 1%	7 1.1%
Absent	197 62.7%	198 63.5%	395 63.1%
Mild	54 17.2%	51 16.3%	105 16.8%
Moderate	38 12.1%	35 11.2%	73 11.7%
Severe	19 6.1%	24 7.7%	43 6.9%
Missing	6 1.9%	4 1.3%	10 1.6%
Absent	80 25.5%	80 25.6%	160 25.6%
Mild	94 29.9%	91 29.2%	185 29.6%
Moderate	102 32.5%	91 29.2%	193 30.8%
Severe	34 10.8%	47 15.1%	81 12.9%
Missing	4 1.3%	3 1%	7 1.1%
Absent	82 26.1%	66 21.2%	148 23.6%
Mild	62 19.7%	68 21.8%	130 20.8%
Moderate	107 34.1%	96 30.8%	203 32.4%
Severe	59 18.8%	78 25%	137 21.9%
Missing	4 1.3%	4 1.3%	8 1.3%
Absent	77 24.5%	54 17.3%	131 20.9%
Mild	79 25.2%	96 30.8%	175 28%
Moderate	96 30.6%	84 26.9%	180 28.8%
Severe	56 17.8%	74 23.7%	130 20.8%
Missing	6 1.9%	4 1.3%	10 1.6%
Overall Symptom Score (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	15	15	15
Functional status (Count of Participants)
Limited a lot = 0	238 75.8%	238 76.3%	476 76%
Limited a little = 50	58 18.5%	59 18.9%	117 18.7%
Not limited at all = 100	14 4.5%	12 3.8%	26 4.2%
Missing	4 1.3%	3 1%	7 1.1%
Limited a lot = 0	167 53.2%	171 54.8%	338 54%
Limited a little = 50	114 36.3%	107 34.3%	221 35.3%
Not limited at all = 100	29 9.2%	31 9.9%	60 9.6%
Missing	4 1.3%	3 1%	7 1.1%
Limited a lot = 0	99 31.5%	116 37.2%	215 34.3%
Limited a little = 50	129 41.1%	114 36.5%	243 38.8%
Not limited at all = 100	82 26.1%	79 25.3%	161 25.7%
Missing	4 1.3%	3 1%	7 1.1%
Limited a lot = 0	182 58%	172 55.1%	354 56.5%
Limited a little = 50	97 30.9%	105 33.7%	202 32.3%
Not limited at all = 100	31 9.9%	32 10.3%	63 10.1%
Missing	4 1.3%	3 1%	7 1.1%
Limited a lot = 0	97 30.9%	103 33%	200 31.9%
Limited a little = 50	146 46.5%	129 41.3%	275 43.9%
Not limited at all = 100	67 21.3%	77 24.7%	144 23%
Missing	4 1.3%	3 1%	7 1.1%
Limited a lot = 0	89 28.3%	82 26.3%	171 27.3%
Limited a little = 50	118 37.6%	133 42.6%	251 40.1%
Not limited at all = 100	103 32.8%	94 30.1%	197 31.5%
Missing	4 1.3%	3 1%	7 1.1%
Limited a lot = 0	199 63.4%	202 64.7%	401 64.1%
Limited a little = 50	81 25.8%	78 25%	159 25.4%
Not limited at all = 100	30 9.6%	29 9.3%	59 9.4%
Missing	4 1.3%	3 1%	7 1.1%
Limited a lot = 0	169 53.8%	177 56.7%	346 55.3%
Limited a little = 50	100 31.8%	91 29.2%	191 30.5%
Not limited at all = 100	41 13.1%	41 13.1%	82 13.1%
Missing	4 1.3%	3 1%	7 1.1%
Limited a lot = 0	101 32.2%	108 34.6%	209 33.4%
Limited a little = 50	123 39.2%	111 35.6%	234 37.4%
Not limited at all = 100	86 27.4%	90 28.8%	176 28.1%
Missing	4 1.3%	3 1%	7 1.1%
Limited a lot = 0	48 15.3%	54 17.3%	102 16.3%
Limited a little = 50	72 22.9%	83 26.6%	155 24.8%
Not limited at all = 100	190 60.5%	172 55.1%	362 57.8%
Missing	4 1.3%	3 1%	7 1.1%
Average Functional Status (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	35	35	35
Global assessment (Count of Participants)
Yes	9 2.9%	7 2.2%	16 2.6%
No	301 95.9%	302 96.8%	603 96.3%
Missing	4 1.3%	3 1%	7 1.1%
Yes	23 7.3%	20 6.4%	43 6.9%
No	287 91.4%	289 92.6%	576 92%
Missing	4 1.3%	3 1%	7 1.1%
Complications of Influenza (Count of Participants)
Yes	11 3.5%	14 4.5%	25 4%
No	298 94.9%	298 95.5%	596 95.2%
Unable to assess	2 0.6%	0 0%	2 0.3%
Missing	3 1%	0 0%	3 0.5%
Yes	2 0.6%	4 1.3%	6 1%
No	307 97.8%	308 98.7%	615 98.2%
Unable to assess	2 0.6%	0 0%	2 0.3%
Missing	3 1%	0 0%	3 0.5%
Yes	8 2.5%	14 4.5%	22 3.5%
No	301 95.9%	298 95.5%	599 95.7%
Unable to assess	2 0.6%	0 0%	2 0.3%
Missing	3 1%	0 0%	3 0.5%
Yes	5 1.6%	9 2.9%	14 2.2%
No	304 96.8%	303 97.1%	607 97%
Unable to assess	2 0.6%	0 0%	2 0.3%
Missing	3 1%	0 0%	3 0.5%
Yes	20 6.4%	21 6.7%	41 6.5%
No	291 92.7%	291 93.3%	582 93%
Unable to assess	0 0%	0 0%	0 0%
Missing	3 1%	0 0%	3 0.5%
Medical Conditions (Count of Participants)
Yes	251 79.9%	247 79.2%	498 79.6%
No	63 20.1%	65 20.8%	128 20.4%
Yes	214 68.2%	213 68.3%	427 68.2%
No	100 31.8%	99 31.7%	199 31.8%
Yes	297 94.6%	293 93.9%	590 94.2%
No	17 5.4%	19 6.1%	36 5.8%
Yes	297 94.6%	291 93.3%	588 93.9%
No	17 5.4%	21 6.7%	38 6.1%
Yes	284 90.4%	273 87.5%	557 89%
No	30 9.6%	39 12.5%	69 11%
Yes	306 97.5%	307 98.4%	613 97.9%
No	8 2.5%	5 1.6%	13 2.1%
Yes	227 72.3%	224 71.8%	451 72%
No	87 27.7%	88 28.2%	175 28%
Yes	306 97.5%	306 98.1%	612 97.8%
No	8 2.5%	6 1.9%	14 2.2%
Yes	311 99%	305 97.8%	616 98.4%
No	3 1%	7 2.2%	10 1.6%
Yes	302 96.2%	304 97.4%	606 96.8%
No	12 3.8%	8 2.6%	20 3.2%
Yes	270 86%	266 85.3%	536 85.6%
No	44 14%	46 14.7%	90 14.4%
Yes	240 76.4%	261 83.7%	501 80%
No	74 23.6%	51 16.3%	125 20%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs
Description	The central laboratory performed a qualitative PCR test on the NP sample from Day 0 in order to confirm influenza infection and to determine the influenza type and subtype. For participants with a positive influenza test result at Day 0 from this qualitative PCR testing, the laboratory then performed qPCR testing of subsequent samples to quantify viral shedding.
Time Frame	At Day 3

Outcome Measure Data

Analysis Population Description

The population analyzed was restricted to the 407 participants who had a confirmed positive test for influenza by qPCR in the central laboratory testing and were not in the pilot study for IRC003. 13 participants (5 in the Combination Therapy and 8 in the Oseltamivir Monotherapy) had missing endpoint samples so were excluded from the analysis.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	200	194
Number [percentage of participants analyzed]	40 12.7%	50 16%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy, Oseltamivir Monotherapy
	Comments	Assuming that pooled percentage of participants with virus detectable by PCR at Day 3 is 50%, assuming that the Combination Therapy was better than the Oseltamivir Monotherapy and that the detectable rate in the Combination Therapy was 42.5% compared to 57.5% in the Oseltamivir Monotherapy (a 15% reduction), and assuming 10% subjects with missing qPCR at Day 3, in a two-sided, two-sample 0.05-level t- test with 546 participants combined across both arms, there was 90% power.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.046
	Comments	P-value was not adjusted for multiple interim analyses.
	Method	Z-test, 2-sided
	Comments	Comparison of randomized arms was based on the normal approximation to the binomial distribution.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10
	Confidence Interval	(2-Sided) 95%; -19.8 to -0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5
	Estimation Comments	The difference in percents was calculated as the percent detectable in the Combination Therapy minus the percent detectable in the Oseltamivir Monotherapy.

2. Secondary Outcome

Title	Number of Participants by Virus Detection Status
Description	Number of participants who had undetectable values (less than the limit of detection [LOD]), who had values between the LOD and the lower limit of quantification (LLOQ), and who had values ≥LLOQ
Time Frame	At Day 0, 3 and 7.

Outcome Measure Data

Analysis Population Description

The population analyzed is the Primary Efficacy Population (PEP), which included all participants who were randomized properly, had received at least one dose of study drug, and had influenza virus isolated and typed in the qualitative PCR evaluation at Day 0 from central laboratory testing.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	230	224
>=LLOQ	221 70.4%	200 64.1%
>=LOD, <LLOQ	4 1.3%	9 2.9%
<LOD	5 1.6%	15 4.8%
Missing	0 0%	0 0%
>=LLOQ	65 20.7%	87 27.9%
>=LOD, <LLOQ	22 7%	25 8%
<LOD	134 42.7%	104 33.3%
Missing	9 2.9%	8 2.6%
>=LLOQ	19 6.1%	24 7.7%
>=LOD, <LLOQ	4 1.3%	7 2.2%
<LOD	193 61.5%	184 59%
Missing	14 4.5%	9 2.9%

3. Secondary Outcome

Title	qPCR Viral Shedding
Description	Median, 25% and 75% percentile of the value of viral shedding (Results <LOD were imputed as the LOD value, and Results >= LOD, <LLOQ were imputed as the LLOQ value.)
Time Frame	At Day 0, 3 and 7

Outcome Measure Data

Analysis Population Description

The population analyzed is the Primary Efficacy Population (PEP), which included all participants who were randomized properly, had received at least one dose of study drug, and had influenza virus isolated and typed in the qualitative PCR evaluation at Day 0 from central laboratory testing.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	230	224
Day 0	6.4	6.7
Day 3	3.4	3.9
Day 7	3.2	3.2

4. Secondary Outcome

Title	Number of Participants Shedding Virus
Description	Number of participants with undetectable viral load at both Day 3 and Day 7; detectable at Day 3 and undetectable at Day 7; detectable at Day 7 (irrespective of whether or not detectable at Day 3).
Time Frame	At day 3 and 7.

Outcome Measure Data

Analysis Population Description

The population analyzed is the Primary Efficacy Population (PEP), which included all participants who were randomized properly, had received at least one dose of study drug, and had influenza virus isolated and typed in the qualitative PCR evaluation at Day 0 from central laboratory testing.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	230	224
Undetectable at both Day 3 and 7	126 40.1%	95 30.4%
Detectable at Day 3 and undetectable at Day 7	67 21.3%	88 28.2%
Detectable at Day 7	23 7.3%	30 9.6%
Missing result at Day 3 and/or Day 7	14 4.5%	11 3.5%

5. Secondary Outcome

Title	Time to Alleviation of Influenza Clinical Symptoms.
Description	The assessed symptoms were cough, nasal obstruction (stuffy nose), sore throat, fatigue, headache, muscle aches, feverishness, rhinorrhea, nausea, vomiting, diarrhea. Duration of clinical symptoms is defined as the time from Day 0 to the first of two successive measurements at which all clinical symptoms are grade 0 (absent) or 1 (mild). A measurement is considered to be the 8AM or 8PM assessment during Days 0 to 7 (so two measurements are obtained per day) and then the daily assessment thereafter. Time will then be calculated in half-days through to Day 7. If a subject's first two assessments on (baseline assessment and first subsequent diary card assessment) satisfy this criterion, then the duration will be set to zero. For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with symptoms evaluated.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	314	312
Median (95% Confidence Interval) [Days]	4.5	4.0

6. Secondary Outcome

Title	Time to Absence of Fever
Description	Fever was considered present based on the diary cards if a subject reported a maximal temperature ≥38.0°C (for the period since the diary card was previously completed) or reported having taken an antipyretic drug (also for the period since the diary card was previously completed). Otherwise, fever was considered not present during the period since the diary card was previously completed, except that the evaluation was considered missing if either the temperature or the antipyretic drug use entry was not completed on the diary card. The duration of fever was defined as the time from Day 0 to the first of two successive assessments (through to Day 7) or to the first assessment (Day 8 onwards) at which no fever was present according to this definition.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with fever evaluated.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	314	312
Median (95% Confidence Interval) [Days]	0.5	0.5

7. Secondary Outcome

Title	Time to Resolution of All Symptoms AND Fever
Description	The assessed symptoms were cough, nasal obstruction (stuffy nose), sore throat, fatigue, headache, muscle aches, feverishness, rhinorrhea, nausea, vomiting, diarrhea. Fever was considered present based on the diary cards if a subject reported a maximal temperature ≥38.0°C (for the period since the diary card was previously completed) or reported having taken an antipyretic drug (also for the period since the diary card was previously completed). Time to resolution of all clinical symptoms and fever is defined as the time from Day 0 to the first of two successive measurements at which all clinical symptoms are grade 0 (absent) or 1(mild) and no fever >=38.0 C or antipyretic drug is reported. For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with symptoms and fever evaluated.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which includes all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	314	312
Median (95% Confidence Interval) [Days]	4.5	4.5

8. Secondary Outcome

Title	Time to Feeling as Good as Before the Onset of the Influenza Illness
Description	Time to feeling as good as before influenza is defined as time to the first of two successive 'yes' responses to the question of 'feeling as good as you did before you had the flu'.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with question answered.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	314	312
Median (95% Confidence Interval) [Days]	7.5	6.5

9. Secondary Outcome

Title	Time to Return to Pre-influenza Function
Description	Time to return to pre-influenza function is defined as the time from Day 0 to the first of two successive 'Yes' answers to the global assessment question 'Are you functioning as well as you were before you had the flu'.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with question answered.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	314	312
Median (95% Confidence Interval) [Days]	7.0	6.0

10. Secondary Outcome

Title	Time to Return of Physical Function to Pre-illness Leve
Description	Time to return of physical function to pre-illness level was defined as the time from Day 0 to the first of two successive measurements at which the physical function score equals or is better than the pre-illness score (obtained by recall at enrollment).For subjects who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with physical function evaluated.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	314	312
Median (95% Confidence Interval) [Days]	7.0	6.0

11. Secondary Outcome

Title	Percentage of Participants With Clinical Failure at Day 5
Description	Clinical failure at Day 5 is defined as the need for continued (non-study) antiviral use after Day 5.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	314	312
Number [percentage of participants analyzed]	7.0 2.2%	7.7 2.5%

12. Secondary Outcome

Title	Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0.
Description	Participants were assessed for the signs/symptoms suggestive of one of the following complications: Sinusitis, Otitis Media ,Bronchitis / Bronchiolitis, Pneumonia and antibiotic use for reason other than above.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug. The categories in the table are not mutually exclusive (because some participants had multiple complications) and the last row of the table summarizes all incidents.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	314	312
Sinustis	4.5 1.4%	4.5 1.4%
Otitis Media	0.3 0.1%	1.0 0.3%
Bronchitis Bronchiolitis	5.7 1.8%	3.5 1.1%
Pneumonia	2.2 0.7%	1.9 0.6%
Antibiotic use for other reasons	8.6 2.7%	9.3 3%
At least one complication and/or use of antibiotic	16.6 5.3%	15.4 4.9%

13. Secondary Outcome

Title	Percentage of Participants Who Required New or Increased Use of Supplemental Oxygen
Description	Percentage of participants who required new or increased use of supplemental oxygen
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	314	312
Number [percentage of participants analyzed]	1.91 0.6%	1.6 0.5%

14. Secondary Outcome

Title	Percentage of Participants Who Required Hospitalization.
Description	The percentage of participants hospitalized by 28 days was estimated from the Kaplan-Meier curves.
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	314	312
Number (95% Confidence Interval) [percentage of participants analyzed]	4.28 1.4%	0.98 0.3%

15. Secondary Outcome

Title	28-day Mortality
Description	Number of deaths
Time Frame	From treatment initiation to Day 28

Outcome Measure Data

Analysis Population Description

The population analyzed is the Intention To Treat (ITT) Population, which included all participants who were randomized properly and who had received at least one dose of study drug.

Arm/Group Title	Combination Therapy	Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Measure Participants	314	312
Number [participants]	0 0%	1 0.3%

Adverse Events

Time Frame	Adverse events were collected throughout the conduct of the study; from Day 0 to Day 28
Adverse Event Reporting Description	All worsening and new symptoms were evaluated as potential adverse events.If a diagnosis was clinically evident (or subsequently determined), the diagnosis, rather than the individual signs and symptoms or lab abnormalities, were recorded as the AE. All worsening laboratory values were also evaluated as potential adverse events. The DAIDS AE Grading Table (V1.0) was used.
Arm/Group Title	Combination Therapy		Oseltamivir Monotherapy
Arm/Group Description	Drug: Amantadine, Ribavirin, Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.		Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
All Cause Mortality
	Combination Therapy		Oseltamivir Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/314 (0%)		1/312 (0.3%)
Serious Adverse Events
	Combination Therapy		Oseltamivir Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/314 (4.5%)		6/312 (1.9%)
Blood and lymphatic system disorders
Febrile neutropenia	0/314 (0%)		1/312 (0.3%)
Cardiac disorders
Atrial fibrillation	1/314 (0.3%)		0/312 (0%)
Atrial tachycardia	1/314 (0.3%)		0/312 (0%)
Cardiac failure	0/314 (0%)		1/312 (0.3%)
Gastrointestinal disorders
Diarrhoea	2/314 (0.6%)		0/312 (0%)
Diarrhoea haemorrhagic	1/314 (0.3%)		0/312 (0%)
Nausea	1/314 (0.3%)		0/312 (0%)
Infections and infestations
Cellulitis	1/314 (0.3%)		0/312 (0%)
Gastroenteritis	1/314 (0.3%)		0/312 (0%)
Pneumonia	1/314 (0.3%)		1/312 (0.3%)
Injury, poisoning and procedural complications
Spinal compression fracture	1/314 (0.3%)		0/312 (0%)
Metabolism and nutrition disorders
Dehydration	1/314 (0.3%)		0/312 (0%)
Psychiatric disorders
Delirium	0/314 (0%)		1/312 (0.3%)
Personality change	0/314 (0%)		1/312 (0.3%)
Respiratory, thoracic and mediastinal disorders
Asthma	2/314 (0.6%)		0/312 (0%)
Bronchospasm	0/314 (0%)		1/312 (0.3%)
Pulmonary oedema	1/314 (0.3%)		0/312 (0%)
Respiratory distress	1/314 (0.3%)		0/312 (0%)
Skin and subcutaneous tissue disorders
Diabetic foot	1/314 (0.3%)		0/312 (0%)
Other (Not Including Serious) Adverse Events
	Combination Therapy		Oseltamivir Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	148/314 (47.1%)		163/312 (52.2%)
Gastrointestinal disorders
Diarrhoea	40/314 (12.7%)		52/312 (16.7%)
Nausea	52/314 (16.6%)		50/312 (16%)
Vomiting	34/314 (10.8%)		22/312 (7.1%)
General disorders
Fatigue	18/314 (5.7%)		12/312 (3.8%)
Pyrexia	16/314 (5.1%)		18/312 (5.8%)
Musculoskeletal and connective tissue disorders
Myalgia	17/314 (5.4%)		13/312 (4.2%)
Nervous system disorders
Dizziness	23/314 (7.3%)		22/312 (7.1%)
Headache	14/314 (4.5%)		19/312 (6.1%)
Respiratory, thoracic and mediastinal disorders
Cough	14/314 (4.5%)		22/312 (7.1%)
Oropharyngeal pain	15/314 (4.8%)		11/312 (3.5%)
Rhinorrhoea	13/314 (4.1%)		17/312 (5.4%)
Vascular disorders
Hypertension	12/314 (3.8%)		15/312 (4.8%)

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.