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 (IRC003)

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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 Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
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.
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.

Participant Flow:   Overall Study

	Combination Therapy	Oseltamivir Monotherapy
STARTED	314	316
COMPLETED [1]	298	303
NOT COMPLETED	16	13
Protocol Violation	3	1
Death	0	1
Lost to Follow-up	8	3
Withdrawal by Subject	4	3
Physician Decision	0	1
Never Started Treatment	0	4
Taking Additional Antiviral Drug	1	0

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent To Treat (ITT) Population: all participants who were randomized properly and who had received at least one dose of study drug.

Reporting Groups

	Description
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.
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.
Total	Total of all reporting groups

Baseline Measures

	Combination Therapy	Oseltamivir Monotherapy	Total
Overall Participants Analyzed  [Units: Participants]	314	312	626
Age  [Units: Participants] Count of Participants
Participants Analyzed  [Units: Participants]	314	312	626
<=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  [Units: Years] Median (Inter-Quartile Range)
Participants Analyzed  [Units: Participants]	314	312	626
	49.5   (37 to 61)	49.5   (35.5 to 61)	49.5   (36 to 61)
Sex: Female, Male  [Units: Participants] Count of Participants
Participants Analyzed  [Units: Participants]	314	312	626
Female	187  59.6%	198  63.5%	385  61.5%
Male	127  40.4%	114  36.5%	241  38.5%
Ethnicity (NIH/OMB)  [Units: Participants] Count of Participants
Participants Analyzed  [Units: Participants]	314	312	626
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   0.0%	1   0.2%
Race/Ethnicity, Customized  [Units: Participants] Count of Participants
Participants Analyzed  [Units: Participants]	314	312	626
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   8.0%	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   0.0%	1   0.3%	1   0.2%
Region of Enrollment  [Units: Participants]
Argentina
Participants Analyzed  [Units: Participants]	314	312	626
Argentina	12	10	22
United States
Participants Analyzed  [Units: Participants]	314	312	626
United States	220	216	436
Mexico
Participants Analyzed  [Units: Participants]	314	312	626
Mexico	17	18	35
Australia
Participants Analyzed  [Units: Participants]	314	312	626
Australia	0	2	2
Thailand
Participants Analyzed  [Units: Participants]	314	312	626
Thailand	65	66	131
Influenza Diagnostic Test by Local Testing  [Units: Participants] Count of Participants
Participants Analyzed  [Units: Participants]	314	312	626
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   0.0%	1   0.3%	1   0.2%
Positive Influenza Test by Local Testing  [Units: Participants] Count of Participants
Participants Analyzed  [Units: Participants]	314	312	626
	314	312	626
Result of Influenza Test By Local Testing  [Units: Participants] Count of Participants
Participants Analyzed  [Units: Participants]	314	312	626
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  [Units: Participants] Count of Participants
Participants Analyzed  [Units: Participants]	314	312	626
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 [1]  [Units: Participants] Count of Participants
Participants Analyzed  [Units: Participants]	314	312	626
Influenza A/H3N2	126  40.1%	118  37.8%	244  39.0%
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  27.0%
Missing	1   0.3%	2   0.6%	3   0.5%
[1] Influenza type/subtype by central lab testing was from site-collected swab on Day 0 (the first one if more than one was collected) and if that was missing, then from a Day -1 sample, if collected
Quantitative PCR Viral Shedding [1] [2]  [Units: Log10 copies/mL] Median (Inter-Quartile Range)
Participants Analyzed  [Units: Participants]	230	224	454
	6.4   (5.6 to 7.2)	6.7   (5.1 to 7.7)	6.5   (5.4 to 7.4)
[1] Limit of detection (LOD)/lower limit of quantification (LLOQ) for Flu A and Flu B by qPCR is 3.2/3.9 and 3.4/4.0, respectively. Results <LOD were imputed as LOD; results >=LOD and <LLOQ were imputed as LLOQ, and results >ULOQ were imputed as ULOQ [2] The results are for the 454 participants with a confirmed positive test for influenza on a Day 0 sample from the central laboratory using a RT-PCR for influenza type and subtype.
Presence of fever  [Units: Participants] Count of Participants
Participants Analyzed  [Units: Participants]	314	312	626
Yes	94  29.9%	93  29.8%	187  29.9%
No	216  68.8%	216  69.2%	432  69.0%
Missing	4   1.3%	3   1.0%	7   1.1%
Symptom Score [1]  [Units: Participants] Count of Participants
Cough
Participants Analyzed  [Units: Participants]	314	312	626
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  43.0%
Severe	85  27.1%	78  25.0%	163  26.0%
Missing	4   1.3%	4   1.3%	8   1.3%
Fatigue
Participants Analyzed  [Units: Participants]	314	312	626
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  42.0%	145  46.5%	277  44.2%
Missing	4   1.3%	4   1.3%	8   1.3%
Feverishness
Participants Analyzed  [Units: Participants]	314	312	626
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%
Diarrhea
Participants Analyzed  [Units: Participants]	314	312	626
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   4.0%
Missing	6   1.9%	3   1.0%	9   1.4%
Muscle aches
Participants Analyzed  [Units: Participants]	314	312	626
Absent	44  14.0%	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   1.0%	7   1.1%
Vomiting
Participants Analyzed  [Units: Participants]	314	312	626
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%
Headache
Participants Analyzed  [Units: Participants]	314	312	626
Absent	60  19.1%	55  17.6%	115  18.4%
Mild	76  24.2%	81  26.0%	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   1.0%	7   1.1%
Nausea
Participants Analyzed  [Units: Participants]	314	312	626
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%
Sore throat
Participants Analyzed  [Units: Participants]	314	312	626
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   1.0%	7   1.1%
Stuffy nose
Participants Analyzed  [Units: Participants]	314	312	626
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  25.0%	137  21.9%
Missing	4   1.3%	4   1.3%	8   1.3%
Rhinorrhea
Participants Analyzed  [Units: Participants]	314	312	626
Absent	77  24.5%	54  17.3%	131  20.9%
Mild	79  25.2%	96  30.8%	175  28.0%
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%
[1] Symptoms were scored on a 4-point scale : 0=absent, 1=mild, 2=moderate, 3=severe
Overall Symptom Score [1]  [Units: Units on a scale] Median (Inter-Quartile Range)
Participants Analyzed  [Units: Participants]	314	312	626
	15   (11 to 19)	15   (11 to 19)	15   (11 to 19)
[1] Overall symptom score was the sum of available scores for each of the 11 symptoms assessed (so ignoring missing values). The possible range of the overall symptom score is therefore 0 (no symptoms) to 44 (severe for all 10 symptoms). Participants with missing evaluations for all symptoms were given a missing overall symptom score.
Functional status  [Units: Participants] Count of Participants
Vigorous activities
Participants Analyzed  [Units: Participants]	314	312	626
Limited a lot = 0	238  75.8%	238  76.3%	476  76.0%
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   1.0%	7   1.1%
Moderate activities
Participants Analyzed  [Units: Participants]	314	312	626
Limited a lot = 0	167  53.2%	171  54.8%	338  54.0%
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   1.0%	7   1.1%
Lifting groceries
Participants Analyzed  [Units: Participants]	314	312	626
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   1.0%	7   1.1%
Climbing stairs
Participants Analyzed  [Units: Participants]	314	312	626
Limited a lot = 0	182  58.0%	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   1.0%	7   1.1%
Climbing 1 flight
Participants Analyzed  [Units: Participants]	314	312	626
Limited a lot = 0	97  30.9%	103  33.0%	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  23.0%
Missing	4   1.3%	3   1.0%	7   1.1%
Bending or kneeling
Participants Analyzed  [Units: Participants]	314	312	626
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   1.0%	7   1.1%
Walking > 1 mile
Participants Analyzed  [Units: Participants]	314	312	626
Limited a lot = 0	199  63.4%	202  64.7%	401  64.1%
Limited a little = 50	81  25.8%	78  25.0%	159  25.4%
Not limited at all = 100	30   9.6%	29   9.3%	59   9.4%
Missing	4   1.3%	3   1.0%	7   1.1%
Walking blocks
Participants Analyzed  [Units: Participants]	314	312	626
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   1.0%	7   1.1%
Walking a block
Participants Analyzed  [Units: Participants]	314	312	626
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   1.0%	7   1.1%
Bathing/dressing self
Participants Analyzed  [Units: Participants]	314	312	626
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   1.0%	7   1.1%
Average Functional Status [1]  [Units: Units on a scale] Median (Inter-Quartile Range)
Participants Analyzed  [Units: Participants]	314	312	626
	35   (20 to 60)	35   (15 to 55)	35   (15 to 60)
[1] Average functional status was calculated as the average of the ten items assessed (so ignoring missing values), scoring 0='yes, limited a lot', 50='yes, limited a little', 100='no, not limited at all'. The possible range of the functional status score is therefore 0 (worst possible status) to 100 (best possible status). Participants with missing evaluations for all items were given a missing average functional status.
Global assessment  [Units: Participants] Count of Participants
Subject feels as good today as before flu
Participants Analyzed  [Units: Participants]	314	312	626
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   1.0%	7   1.1%
Subject functions as well today as before flu
Participants Analyzed  [Units: Participants]	314	312	626
Yes	23   7.3%	20   6.4%	43   6.9%
No	287  91.4%	289  92.6%	576  92.0%
Missing	4   1.3%	3   1.0%	7   1.1%
Complications of Influenza  [Units: Participants] Count of Participants
Sinusitis
Participants Analyzed  [Units: Participants]	314	312	626
Yes	11   3.5%	14   4.5%	25   4.0%
No	298  94.9%	298  95.5%	596  95.2%
Unable to assess	2   0.6%	0   0.0%	2   0.3%
Missing	3   1.0%	0   0.0%	3   0.5%
Otitis Media
Participants Analyzed  [Units: Participants]	314	312	626
Yes	2   0.6%	4   1.3%	6   1.0%
No	307  97.8%	308  98.7%	615  98.2%
Unable to assess	2   0.6%	0   0.0%	2   0.3%
Missing	3   1.0%	0   0.0%	3   0.5%
Bronchitis/Bronchiolitis
Participants Analyzed  [Units: Participants]	314	312	626
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   0.0%	2   0.3%
Missing	3   1.0%	0   0.0%	3   0.5%
Pneumonia
Participants Analyzed  [Units: Participants]	314	312	626
Yes	5   1.6%	9   2.9%	14   2.2%
No	304  96.8%	303  97.1%	607  97.0%
Unable to assess	2   0.6%	0   0.0%	2   0.3%
Missing	3   1.0%	0   0.0%	3   0.5%
Using antibiotic for other reasons
Participants Analyzed  [Units: Participants]	314	312	626
Yes	20   6.4%	21   6.7%	41   6.5%
No	291  92.7%	291  93.3%	582  93.0%
Unable to assess	0   0.0%	0   0.0%	0   0.0%
Missing	3   1.0%	0   0.0%	3   0.5%
Medical Conditions [1]  [Units: Participants] Count of Participants
>= 65 years
Participants Analyzed  [Units: Participants]	314	312	626
Yes	251  79.9%	247  79.2%	498  79.6%
No	63  20.1%	65  20.8%	128  20.4%
Asthma
Participants Analyzed  [Units: Participants]	314	312	626
Yes	214  68.2%	213  68.3%	427  68.2%
No	100  31.8%	99  31.7%	199  31.8%
Neurological condition
Participants Analyzed  [Units: Participants]	314	312	626
Yes	297  94.6%	293  93.9%	590  94.2%
No	17   5.4%	19   6.1%	36   5.8%
Chronic Lung disease
Participants Analyzed  [Units: Participants]	314	312	626
Yes	297  94.6%	291  93.3%	588  93.9%
No	17   5.4%	21   6.7%	38   6.1%
Heart disease
Participants Analyzed  [Units: Participants]	314	312	626
Yes	284  90.4%	273  87.5%	557  89.0%
No	30   9.6%	39  12.5%	69  11.0%
Blood disorder
Participants Analyzed  [Units: Participants]	314	312	626
Yes	306  97.5%	307  98.4%	613  97.9%
No	8   2.5%	5   1.6%	13   2.1%
Endocrine
Participants Analyzed  [Units: Participants]	314	312	626
Yes	227  72.3%	224  71.8%	451  72.0%
No	87  27.7%	88  28.2%	175  28.0%
Kidney
Participants Analyzed  [Units: Participants]	314	312	626
Yes	306  97.5%	306  98.1%	612  97.8%
No	8   2.5%	6   1.9%	14   2.2%
Liver disorder
Participants Analyzed  [Units: Participants]	314	312	626
Yes	311  99.0%	305  97.8%	616  98.4%
No	3   1.0%	7   2.2%	10   1.6%
Metabolic
Participants Analyzed  [Units: Participants]	314	312	626
Yes	302  96.2%	304  97.4%	606  96.8%
No	12   3.8%	8   2.6%	20   3.2%
Weakened immune system
Participants Analyzed  [Units: Participants]	314	312	626
Yes	270  86.0%	266  85.3%	536  85.6%
No	44  14.0%	46  14.7%	90  14.4%
BMI >= 40
Participants Analyzed  [Units: Participants]	314	312	626
Yes	240  76.4%	261  83.7%	501  80.0%
No	74  23.6%	51  16.3%	125  20.0%
[1] Medication conditions that may increase risk of complications from influenza which are used to determine eligibility for the study.

1.  Primary:

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

2.  Secondary:

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

3.  Secondary:

qPCR Viral Shedding   [ Time Frame: At Day 0, 3 and 7 ]

4.  Secondary:

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

5.  Secondary:

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

6.  Secondary:

Time to Absence of Fever   [ Time Frame: From treatment initiation to Day 28 ]

7.  Secondary:

Time to Resolution of All Symptoms AND Fever   [ Time Frame: From treatment initiation to Day 28 ]

8.  Secondary:

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

9.  Secondary:

Time to Return to Pre-influenza Function   [ Time Frame: From treatment initiation to Day 28 ]

10.  Secondary:

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

11.  Secondary:

Percentage of Participants With Clinical Failure at Day 5   [ Time Frame: From treatment initiation to Day 28 ]

12.  Secondary:

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

13.  Secondary:

Percentage of Participants Who Required New or Increased Use of Supplemental Oxygen   [ Time Frame: From treatment initiation to Day 28 ]

14.  Secondary:

Percentage of Participants Who Required Hospitalization.   [ Time Frame: From treatment initiation to Day 28 ]

15.  Secondary:

28-day Mortality   [ Time Frame: From treatment initiation to Day 28 ]

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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