Comparing the Efficacy, Safety, and Tolerability of Combi... | NCT01227967

Status Module

Description Module

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.

Label	Type	Description	Intervention Names
Combination Therapy	Experimental	Amantadine, Ribavirin, Oseltamivir	Drug: Amantadine, Ribavirin, Oseltamivir
Oseltamivir monotherapy	Active Comparator	Oseltamivir	Drug: Oseltamivir

Name	Type	Description	Arm Group Labels	Other Names
Amantadine, Ribavirin, Oseltamivir	Drug	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.

Measure	Description	Time Frame
Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs	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.	At Day 3

Measure	Description	Time Frame
Number of Participants by Virus Detection Status	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	At Day 0, 3 and 7.
qPCR Viral Shedding

Eligibility Module

Eligibility Criteria

INCLUSION CRITERIA:

Enrollment (Screening)

Signed informed consent prior to initiation of any study procedures
Presence of an underlying medical condition(s) that might increase risk of complications from influenza
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)
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
Willingness to have samples stored

Randomization

Signed informed consent
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)
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
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)
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
Willingness to have samples stored

EXCLUSION CRITERIA:

(for Enrollment or Randomization)

Women who were pregnant or breast-feeding, and men whose female partner(s) was pregnant
Inability to take oral medication or a history of gastrointestinal malabsorption that would preclude the use of oral medication.
Hemoglobin < 10 g/dL
WBC < 1.5 times 10(9)/L
Neutrophils < 0.75 x 10(9)/L
Platelets < 50 x 10(9)/L
History of genetic hemoglobinopathy (e.g., thalassemia major or sickle cell anemia) or autoimmune hemolytic anemia
Received more than 2 doses of any antiviral influenza medications since onset of influenza symptoms
Received stavudine (d4T), didanosine (ddI), zidovudine (AZT), or azathioprine within 30 days prior to study entry
Creatinine clearance less than 60 mL/min (estimated by the Cockcroft-Gault equation using serum creatinine)
History of autoimmune hepatitis
Uncompensated liver disease (defined as AST > 3 times site upper limit of normal (ULN), ALT > 3 times ULN, or Direct Bilirubin > 2 times ULN)
Clinical signs of end-stage liver disease including jaundice, coagulopathy, portal hypertension, esophageal varices, ascites, peripheral edema, gastrointestinal bleeding, or encephalopathy
Chronic liver disease categorized as Child-Pugh class C (Child-Pugh score 10-15)
Known hypersensitivity to rimantadine, amantadine, ribavirin, oseltamivir, peramivir, or zanamivir
Received live attenuated virus vaccine (influenza or other) within 3 weeks prior to study entry
Use of any investigational drug within 30 days or 5 half-lives (whichever was longer) prior to study entry
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.

Name	Affiliation	Role
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 Chair

Facility	Status	City	State	ZIP	Country	Contacts
Simon Williamson Clinic		Birmingham	Alabama	35211	United States
East Valley Family Physicians

PubMed Identifier	Type	Citation	Retractions
12517228	Background	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. doi: 10.1001/jama.289.2.179.
16494718	Background	Monto AS. Vaccines and antiviral drugs in pandemic preparedness. Emerg Infect Dis. 2006 Jan;12(1):55-60. doi: 10.3201/eid1201.051068.

Label	URL
NIH Clinical Center Detailed Web Page	View source

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Combination Therapy	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.
FG001

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Categorical

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
	OG00040 OG00150

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.	Z-test, 2-sided	Comparison of randomized arms was based on the normal approximation to the binomial distribution.	0.046	P-value was not adjusted for multiple interim analyses.	Mean Difference (Final Values)	-10	Standard Error of the Mean	5	2-Sided	95	-19.8	-0.2

Secondary

Number of Participants by Virus Detection Status

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

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.

Posted

Count of Participants

Participants

At Day 0, 3 and 7.

ID	Title	Description
OG000	Combination Therapy	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.
OG001	Oseltamivir Monotherapy	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

Units	Counts
Participants

Secondary

qPCR Viral Shedding

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

Posted

Median

Inter-Quartile Range

Log10 copies/mL

At Day 0, 3 and 7

ID	Title	Description
OG000	Combination Therapy	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.
OG001	Oseltamivir Monotherapy	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

Units	Counts
Participants

Secondary

Number of Participants Shedding Virus

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).

Posted

Count of Participants

Participants

At day 3 and 7.

ID	Title	Description
OG000	Combination Therapy	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.
OG001	Oseltamivir Monotherapy	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

Units	Counts
Participants

Secondary

Time to Alleviation of Influenza Clinical Symptoms.

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.

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.

Posted

Median

95% Confidence Interval

Days

From treatment initiation to Day 28

ID	Title	Description
OG000	Combination Therapy	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.
OG001

Secondary

Time to Absence of Fever

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.

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.

Posted

Median

95% Confidence Interval

Days

From treatment initiation to Day 28

ID	Title	Description
OG000	Combination Therapy	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.
OG001

Secondary

Time to Resolution of All Symptoms AND Fever

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.

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.

Posted

Median

95% Confidence Interval

Days

From treatment initiation to Day 28

ID	Title	Description
OG000	Combination Therapy	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.
OG001	Oseltamivir Monotherapy

Secondary

Time to Feeling as Good as Before the Onset of the Influenza Illness

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.

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.

Posted

Median

95% Confidence Interval

Days

From treatment initiation to Day 28

ID	Title	Description
OG000	Combination Therapy	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.
OG001	Oseltamivir Monotherapy	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

Units

Secondary

Time to Return to Pre-influenza Function

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.

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.

Posted

Median

95% Confidence Interval

Days

From treatment initiation to Day 28

ID	Title	Description
OG000	Combination Therapy	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.
OG001	Oseltamivir Monotherapy	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

Secondary

Time to Return of Physical Function to Pre-illness Leve

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.

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.

Posted

Median

95% Confidence Interval

Days

From treatment initiation to Day 28

ID	Title	Description
OG000	Combination Therapy	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.
OG001	Oseltamivir Monotherapy	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

Secondary

Percentage of Participants With Clinical Failure at Day 5

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

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.

Posted

Number

percentage of participants analyzed

From treatment initiation to Day 28

ID	Title	Description
OG000	Combination Therapy	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.
OG001	Oseltamivir Monotherapy	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

Units	Counts
Participants

Secondary

Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0.

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.

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.

Posted

Number

percentage of participants analyzed

From treatment initiation to Day 28

ID	Title	Description
OG000	Combination Therapy	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.
OG001	Oseltamivir Monotherapy	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

Secondary

Percentage of Participants Who Required New or Increased Use of Supplemental Oxygen

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

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.

Posted

Number

percentage of participants analyzed

From treatment initiation to Day 28

ID	Title	Description
OG000	Combination Therapy	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.
OG001	Oseltamivir Monotherapy	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

Units	Counts
Participants

Secondary

Percentage of Participants Who Required Hospitalization.

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

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.

Posted

Number

95% Confidence Interval

percentage of participants analyzed

From treatment initiation to Day 28

ID	Title	Description
OG000	Combination Therapy	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.
OG001	Oseltamivir Monotherapy	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

Units	Counts
Participants

Secondary

28-day Mortality

Number of deaths

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.

Posted

Number

participants

From treatment initiation to Day 28

ID	Title	Description
OG000	Combination Therapy	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.
OG001	Oseltamivir Monotherapy	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA (19.1)	Systematic Assessment	EG0000 affected314 at risk EG0011 affected312 at risk
Atrial fibrillation	Cardiac disorders	MedDRA (19.1)	Systematic Assessment	EG0001 affected314 at risk EG0010 affected312 at risk
Atrial tachycardia	Cardiac disorders	MedDRA (19.1)	Systematic Assessment	EG0001 affected314 at risk EG0010 affected312 at risk
Cardiac failure	Cardiac disorders	MedDRA (19.1)	Systematic Assessment	EG0000 affected314 at risk EG0011 affected312 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (19.1)	Systematic Assessment	EG0002 affected314 at risk EG0010 affected312 at risk
Diarrhoea haemorrhagic	Gastrointestinal disorders	MedDRA (19.1)	Systematic Assessment	EG0001 affected314 at risk EG0010 affected312 at risk
Nausea	Gastrointestinal disorders	MedDRA (19.1)	Systematic Assessment	EG0001 affected314 at risk EG0010 affected312 at risk
Cellulitis	Infections and infestations	MedDRA (19.1)	Systematic Assessment	EG0001 affected314 at risk EG0010 affected312 at risk
Gastroenteritis	Infections and infestations	MedDRA (19.1)	Systematic Assessment	EG0001 affected314 at risk EG0010 affected312 at risk
Pneumonia	Infections and infestations	MedDRA (19.1)	Systematic Assessment	EG0001 affected314 at risk EG0011 affected312 at risk
Spinal compression fracture	Injury, poisoning and procedural complications	MedDRA (19.1)	Systematic Assessment	EG0001 affected314 at risk EG0010 affected312 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA (19.1)	Systematic Assessment	EG0001 affected314 at risk EG0010 affected312 at risk
Delirium	Psychiatric disorders	MedDRA (19.1)	Systematic Assessment	EG0000 affected314 at risk EG0011 affected312 at risk
Personality change	Psychiatric disorders	MedDRA (19.1)	Systematic Assessment	EG0000 affected314 at risk EG0011 affected312 at risk
Asthma	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Systematic Assessment	EG0002 affected314 at risk EG0010 affected312 at risk
Bronchospasm	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Systematic Assessment	EG0000 affected314 at risk EG0011 affected312 at risk
Pulmonary oedema	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Systematic Assessment	EG0001 affected314 at risk EG0010 affected312 at risk
Respiratory distress	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Systematic Assessment	EG0001 affected314 at risk EG0010 affected312 at risk
Diabetic foot	Skin and subcutaneous tissue disorders	MedDRA (19.1)	Systematic Assessment	EG0001 affected314 at risk EG0010 affected312 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Diarrhoea	Gastrointestinal disorders	MedDRA (19.1)	Systematic Assessment	EG00040 affected314 at risk EG00152 affected312 at risk
Nausea	Gastrointestinal disorders	MedDRA (19.1)	Systematic Assessment	EG00052 affected314 at risk EG00150 affected312 at risk
Vomiting	Gastrointestinal disorders	MedDRA (19.1)	Systematic Assessment	EG00034 affected314 at risk EG00122 affected312 at risk
Fatigue	General disorders	MedDRA (19.1)	Systematic Assessment	EG00018 affected314 at risk EG00112 affected312 at risk
Pyrexia	General disorders	MedDRA (19.1)	Systematic Assessment	EG00016 affected314 at risk EG00118 affected312 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA (19.1)	Systematic Assessment	EG00017 affected314 at risk EG00113 affected312 at risk
Dizziness	Nervous system disorders	MedDRA (19.1)	Systematic Assessment	EG00023 affected314 at risk EG00122 affected312 at risk
Headache	Nervous system disorders	MedDRA (19.1)	Systematic Assessment	EG00014 affected314 at risk EG00119 affected312 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Systematic Assessment	EG00014 affected314 at risk EG00122 affected312 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Systematic Assessment	EG00015 affected314 at risk EG00111 affected312 at risk
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Systematic Assessment	EG00013 affected314 at risk EG00117 affected312 at risk
Hypertension	Vascular disorders	MedDRA (19.1)	Systematic Assessment	EG00012 affected314 at risk EG00115 affected312 at risk

ID	Term
D012141	Respiratory Tract Infections
D007239	Infections
D009976	Orthomyxoviridae Infections
D012327	RNA Virus Infections
D014777	Virus Diseases
D012140	Respiratory Tract Diseases

ID	Term
D000218	Adamantane
D001952	Bridged-Ring Compounds
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D009930	Organic Chemicals
D012263	Ribonucleosides
D009705	Nucleosides
D009706	Nucleic Acids, Nucleotides, and Nucleosides
D000081	Acetamides
D000577	Amides
D053138	Cyclohexenes
D003510	Cyclohexanes
D003516	Cycloparaffins
D006840	Hydrocarbons, Alicyclic

ID	Title	Description
BG000	Combination Therapy	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.
BG001	Oseltamivir Monotherapy	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Combination Therapy	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.	0	314	14	314	148	314
EG001	Oseltamivir Monotherapy	Drug: Oseltamivir Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.	1	312	6	312	163	312

ID	Type	Description	Link
10-I-0210
IRC003