Phase III Randomized, Double-Blind Study Comparing Single-Dose Intravenous Peramivir with Oral Oseltamivir in Patients with Seasonal Influenza Virus Infection

Shigeru Kohno; Muh-Yong Yen; Hee-Jin Cheong; Nobuo Hirotsu; Tadashi Ishida; Jun-ichi Kadota; Masashi Mizuguchi; Hiroshi Kida; Jingoro Shimada

doi:10.1128/AAC.00360-11

DOI: 10.1128/AAC.00360-11

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Fig. 1.
Study profiles. *, One patient assigned to the 600-mg-peramivir group received 300 mg peramivir. This patient's data were included in the analyses according to the treatment actually administered.
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Fig. 2.
Proportions of patients in the intent-to-treat infected population reporting normal temperatures. Asterisks indicate significant differences (P < 0.05) between peramivir and oseltamivir as determined by the Mantel-Haenszel test, which was stratified by current smoking behavior, composite symptom score at baseline, country/region, and influenza virus type.
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Fig. 3.
Mean influenza virus titers (log₁₀ TCID₅₀/ml) and SD over time in the intent-to-treat infected population. The data analyzed were from the subset of patients who were positive for the influenza virus at baseline. Virus titers below the lower limit of quantification were set to 0.5. The asterisk indicates a significant difference (P < 0.05) between peramivir and oseltamivir as determined by the van Elteren test, which was stratified by current smoking behavior, composite symptom score at baseline, country/region, and influenza virus type.
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Fig. 4.
Plasma peramivir concentrations after administration of 300 mg (top) or 600 mg (bottom) peramivir. The conversion factor between the plasma concentration (in nanograms per milliliter) and the IC₅₀ (nanomolar concentration) was as follows: 1 ng/ml = 2.84 nM.

Tables

Figures

Table 1.

Baseline characteristics for the intent-to-treat infected population

Characteristic^{^a}	Value for group receiving:
	Peramivir		Oseltamivir (n = 365)
	300 mg (n = 364)	600 mg (n = 362)	Oseltamivir (n = 365)
Region/country^{^b}
Japan	247 (67.9)	249 (68.8)	246 (67.4)
Taiwan	81 (22.3)	79 (21.8)	84 (23.0)
South Korea	36 (9.9)	34 (9.4)	35 (9.6)
Male sex	180 (49.5)	198 (54.7)	184 (50.4)
Age (yr)
Mean ± SD	34.9 ± 11.7	35.9 ± 12.0	34.6 ± 11.7
Range	20–78	20–78	20–80
Wt (kg)
Mean ± SD	61.50 ± 13.04	62.69 ± 13.05	61.59 ± 13.09
Range	39.5–120.0	33.4–104.7	40.0–140.1
Smoking^{^b}	113 (31.0)	111 (30.7)	112 (30.7)
Coexisting disease at baseline	127 (34.9)	146 (40.3)	132 (36.2)
Receipt of drugs from onset of influenza to randomization	206 (56.6)	212 (58.6)	211 (57.8)
Influenza vaccination	64 (17.6)	56 (15.5)	63 (17.3)
Duration of influenza
0-12 h	33 (9.1)	24 (6.6)	30 (8.2)
>12-24 h	129 (35.4)	117 (32.3)	131 (35.9)
>24-36 h	94 (25.8)	114 (31.5)	107 (29.3)
>36-48 h	108 (29.7)	106 (29.3)	95 (26.0)
>48 h	0 (0.0)	1 (0.3)	2 (0.5)
Composite symptom score (mean ± SD)^{^b}	12.5 ± 3.4	12.5 ± 3.3	12.5 ± 3.2
Body temp (°C) (mean ± SD)	38.53 ± 0.49	38.48 ± 0.49	38.56 ± 0.52
Result of rapid antigen test^{^b}
A	335 (92.0)	333 (92.0)	338 (92.6)
B	27 (7.4)	29 (8.0)	25 (6.8)
A and B	2 (0.5)	0 (0.0)	2 (0.5)
Influenza virus subtype
A/H1	197 (54.1)	200 (55.2)	201 (55.1)
A/H1, H3	0 (0.0)	0 (0.0)	1 (0.3)
A/H3	112 (30.8)	108 (29.8)	108 (29.6)
A/−	21 (5.8)	15 (4.1)	17 (4.7)
B	21 (5.8)	26 (7.2)	23 (6.3)
Unknown	13 (3.6)	13 (3.6)	15 (4.1)

↵a Unless otherwise indicated, each value is the number (percentage) of patients with the characteristic.
↵b Randomization ensured balance for this factor.

Table 2.

IC₅₀ in NA inhibition assays at baseline for the intent-to-treat infected population^{^a}

Influenza virus subtype (n) and treatment group	IC₅₀ (nM)
Influenza virus subtype (n) and treatment group	Mean ± SD	Median (range)^{^b}
A/H1 (593)
Peramivir	22.25 ± 4.37	21.59 (0.41–100.00)
Oseltamivir	87.70 ± 16.38	100.00 (0.66–100.00)
Zanamivir	1.35 ± 0.18	1.34 (0.97–3.41)
A/H3 (323)
Peramivir	0.83 ± 0.17	0.82 (0.45–2.13)
Oseltamivir	0.63 ± 0.17	0.62 (0.27–1.84)
Zanamivir	1.97 ± 0.37	1.91 (1.46–5.93)
B (70)
Peramivir	3.51 ± 0.39	3.58 (2.18–4.33)
Oseltamivir	16.53 ± 2.30	16.77 (8.77–22.33)
Zanamivir	9.74 ± 1.10	9.79 (5.92–12.17)

↵a The reliability of each assay was confirmed by the observation that the IC₅₀ of peramivir ranged from 0.2 to 2 nM for the standard strain (A/PR/8/34).
↵b Minimum to maximum IC₅₀. The upper limit of the IC₅₀ was 100.0 nM.

Table 3.

Time to alleviation of symptoms for the intent-to-treat infected population

Population and treatment (n)	Median time to alleviation (h) (95% CI)	Hazard ratio (97.5% CI)^{^a}
Overall
Peramivir
300 mg (364)	78.0 (68.4, 88.6)	0.946 (0.793, 1.129)^{^b}
600 mg (362)	81.0 (72.7, 91.5)	0.970 (0.814, 1.157)^{^b}
Oseltamivir (365)	81.8 (73.2, 91.1)
A/H1
Peramivir
300 mg (197)	80.2 (69.3, 90.6)	0.854 (0.672, 1.085)
600 mg (200)	83.6 (72.7, 101.9)	0.927 (0.730, 1.176)
Oseltamivir (201)	88.8 (73.1, 102.2)
A/H3
Peramivir
300 mg (112)	69.9 (54.4, 97.1)	1.039 (0.745, 1.448)
600 mg (108)	70.6 (47.7, 91.9)	0.958 (0.687, 1.335)
Oseltamivir (108)	75.1 (63.4, 92.6)
B
Peramivir
300 mg (21)	55.3 (43.9, 86.4)	0.445 (0.202, 0.982)
600 mg (26)	92.8 (57.4, 116.1)	0.706 (0.341, 1.460)
Oseltamivir (23)	92.7 (70.2, 138.5)

↵a Hazard ratios compared to the oseltamivir group were estimated using Cox proportional-hazards models, which were adjusted for current smoking behavior, composite symptom score at baseline, country/region, influenza virus type, sex, complications, and previous therapy.
↵b Both peramivir groups were noninferior to the oseltamivir group, with a noninferiority margin of 0.170.

Table 4.

Time-weighted change from baseline in virus titer for the intent-to-treat infected population

Population and time interval	Value for group receiving:
	Peramivir (300 mg)			Peramivir (600 mg)			Oseltamivir
	No. of patients tested	Change in virus titer^{^a}	P^{^b}	No. of patients tested	Change in virus titer^{^a}	P^{^b}	No. of patients tested	Change in virus titer^{^a}
Overall
From day 1 to day 2	201	−1.10 ± 0.90	0.4278	192	−1.08 ± 0.82	0.2252	195	−1.04 ± 0.84
From day 1 to day 3	338	−1.71 ± 1.21	0.1337	349	−1.71 ± 1.10	0.1778	343	−1.63 ± 1.11
From day 1 to day 8	323	−2.97 ± 1.53	0.0674	338	−2.91 ± 1.44	0.2066	331	−2.82 ± 1.49
A/H1
From day 1 to day 2	115	−1.18 ± 0.95	0.6244	117	−1.15 ± 0.90	0.4678	111	−1.06 ± 0.97
From day 1 to day 3	190	−1.79 ± 1.26	0.5092	198	−1.81 ± 1.19	0.5204	195	−1.71 ± 1.22
From day 1 to day 8	182	−3.20 ± 1.55	0.1735	191	−3.17 ± 1.42	0.4007	187	−3.04 ± 1.57
A/H3
From day 1 to day 2	58	−1.23 ± 0.68	0.0386	54	−1.12 ± 0.52	0.3129	60	−1.01 ± 0.60
From day 1 to day 3	106	−1.87 ± 0.91	0.0218	105	−1.68 ± 0.71	0.2434	107	−1.58 ± 0.76
From day 1 to day 8	102	−2.86 ± 1.28	0.0644	103	−2.57 ± 1.05	0.5459	103	−2.48 ± 1.01
B
From day 1 to day 2	13	−0.82 ± 1.02	0.1612	10	−1.13 ± 0.93	0.8342	16	−1.21 ± 0.73
From day 1 to day 3	21	−1.68 ± 1.26	0.1891	25	−2.08 ± 1.13	0.6794	23	−2.08 ± 1.00
From day 1 to day 8	20	−3.46 ± 1.31	0.1128	24	−3.92 ± 1.61	0.8778	23	−3.99 ± 1.24

↵a Expressed as log₁₀ TCID₅₀/ml. Values are means ± SD.
↵b Determined by the van Elteren test, which was stratified by current smoking behavior, composite symptom score at baseline, and country/region.

Table 5.

Summary of adverse events and adverse drug reactions (safety population)

Parameter^{^a}	Value for group
	Peramivir		Oseltamivir (n = 365)
	300 mg (n = 364)	600 mg (n = 364)	Oseltamivir (n = 365)
AEs
Total
No. of AEs	272	288	297
No. (% [95% CI]) of patients with ≥1	170 (46.7 [41.5, 52.0])	174 (47.8 [42.6, 53.1])	178 (48.8 [43.5, 54.0])
P	0.6040	0.8242
Mild
No. of mild AEs	90	90	95
No. (%) of patients with ≥1	69 (19.0)	66 (18.1)	74 (20.3)
Moderate
No. of moderate AEs	161	166	177
No. (%) of patients with ≥1	119 (32.7)	116 (31.9)	121 (33.2)
Severe
No. of severe AEs	21	32	25
No. (%) of patients with ≥1	19 (5.2)	30 (8.2)	24 (6.6)
ADRs
Total
No. of ADRs	80	99	104
No. (% [95% CI]) of patients with ≥1	51 (14.0 [10.6, 18.0])	66 (18.1 [14.3, 22.5])	73 (20.0 [16.0, 24.5])
P	0.0382	0.5718
Mild
No. of mild ADRs	40	42	48
No. (%) of patients with ≥1	29 (8.0)	32 (8.8)	40 (11.0)
Moderate
No. of moderate ADRs	37	47	47
No. (%) of patients with ≥1	29 (8.0)	34 (9.3)	37 (10.1)
Severe
No. of severe ADRs	3	10	9
No. (%) of patients with ≥1	3 (0.8)	10 (2.7)	9 (2.5)
No. (%) of patients with the following AE^{^b}:
Neutrophil count decreased	39 (10.7)	38 (10.4)	34 (9.3)
Diarrhea	24 (6.6)	30 (8.2)	27 (7.4)
Protein present in urine	17 (4.7)	16 (4.4)	22 (6.0)
Blood glucose increased	11 (3.0)	14 (3.8)	12 (3.3)
Urine positive for WBCs	14 (3.8)	8 (2.2)	16 (4.4)
Nausea	8 (2.2)	8 (2.2)	20 (5.5)
Vomiting	2 (0.5)	6 (1.6)	15 (4.1)
No. (%) of patients with the following ADR^{^b}:
Diarrhea	14 (3.8)	20 (5.5)	19 (5.2)
Neutrophil count decreased	9 (2.5)	14 (3.8)	13 (3.6)
Nausea	2 (0.5)	7 (1.9)	16 (4.4)

↵a AEs, adverse events; ADRs, adverse drug reactions; WBCs, white blood cells. P values were calculated by intergroup comparison between the peramivir and oseltamivir groups using Fisher's exact test.
↵b Data are shown only for AEs or ADRs that occurred at a frequency of >3% in any of the three groups.

Table 6.

Summary of postbaseline minimum neutrophil count by grade (safety population)

Grade (no. of neutrophils/μl)	No. (%) of patients
	Phase II study^{^a}		Phase III study^{^b}
	Peramivir (n = 198)	Placebo (n = 100)	Peramivir (n = 723)	Oseltamivir (n = 363)
Grade 0 (≥1,300/μl)	151 (76.3)	89 (89.0)	557 (77.0)	288 (79.3)
Grade 1 (≥1,000 and <1,300/μl)	29 (14.6)	7 (7.0)	93 (12.9)	41 (11.3)
Grade 2 (≥750 and <1,000/μl)	14 (7.1)	3 (3.0)	60 (8.3)	25 (6.9)
Grade 3 (≥500 and <750/μl)	3 (1.5)	1 (1.0)	10 (1.4)	7 (1.9)
Grade 4 (<500/μl)	1 (0.5)	0 (0.0)	3 (0.4)	2 (0.6)

↵a A placebo-controlled randomized study (12).
↵b An oseltamivir-controlled randomized study (our present study).

Table 7.

Summary of time (duration) to recovery from grade 2 or more-severe neutropenia to grade 1 or less (safety population)

Duration (days) of ≥grade 2 neutropenia^{^a}	No. (%) of patients
	Phase II study^{^b}		Phase III study^{^c}
	Peramivir (n = 198)	Placebo (n = 100)	Peramivir (n = 723)	Oseltamivir (n = 363)
1	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
2–3	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
4–9	0 (0.0)	0 (0.0)	66 (90.4)	25 (73.5)
10–14	14 (77.8)	2 (50.0)	4 (5.5)	6 (17.6)
≥15	4 (22.2)	2 (50.0)	3 (4.1)	1 (2.9)
No recovery	0 (0.0)	0 (0.0)	0 (0.0)	2 (5.9)^{^d}
Total	18	4	73	34

↵a Calculated as (date of recovery to grade 1 or less-severe neutropenia) − (date of onset of grade 2 or more-severe neutropenia) + 1.
↵b A placebo-controlled randomized study (12).
↵c An oseltamivir-controlled randomized study (our present study).
↵d Patients were categorized as “not recovered” because follow-up was discontinued.