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Antiviral Agents

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
Shigeru Kohno
1Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki
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  • For correspondence: s-kohno@nagasaki-u.ac.jp
Muh-Yong Yen
2Taipei City Hospital, National Yang-Ming University, Taipei, Taiwan
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Hee-Jin Cheong
3Department of Internal Medicine, Korea University Guro Hospital, Seoul, South Korea
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Nobuo Hirotsu
4Hirotsu Clinic, St. Marianna University School of Medicine, Kawasaki
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Tadashi Ishida
5Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki
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Jun-ichi Kadota
6Department of Internal Medicine II, Oita University Faculty of Medicine, Yufu
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Masashi Mizuguchi
7Department of Developmental Medical Sciences, Graduate School of Medicine, University of Tokyo, Tokyo
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Hiroshi Kida
8Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
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Jingoro Shimada
9St. Marianna University School of Medicine, Kawasaki
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DOI: 10.1128/AAC.00360-11
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  • Fig. 1.
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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.

  • Fig. 3.
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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.

  • Fig. 4.
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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

    CharacteristicaValue for group receiving:
    PeramivirOseltamivir (n = 365)
    300 mg (n = 364)600 mg (n = 362)
    Region/countryb
        Japan247 (67.9)249 (68.8)246 (67.4)
        Taiwan81 (22.3)79 (21.8)84 (23.0)
        South Korea36 (9.9)34 (9.4)35 (9.6)
    Male sex180 (49.5)198 (54.7)184 (50.4)
    Age (yr)
        Mean ± SD34.9 ± 11.735.9 ± 12.034.6 ± 11.7
        Range20–7820–7820–80
    Wt (kg)
        Mean ± SD61.50 ± 13.0462.69 ± 13.0561.59 ± 13.09
        Range39.5–120.033.4–104.740.0–140.1
    Smokingb113 (31.0)111 (30.7)112 (30.7)
    Coexisting disease at baseline127 (34.9)146 (40.3)132 (36.2)
    Receipt of drugs from onset of influenza to randomization206 (56.6)212 (58.6)211 (57.8)
    Influenza vaccination64 (17.6)56 (15.5)63 (17.3)
    Duration of influenza
        0-12 h33 (9.1)24 (6.6)30 (8.2)
        >12-24 h129 (35.4)117 (32.3)131 (35.9)
        >24-36 h94 (25.8)114 (31.5)107 (29.3)
        >36-48 h108 (29.7)106 (29.3)95 (26.0)
        >48 h0 (0.0)1 (0.3)2 (0.5)
    Composite symptom score (mean ± SD)b12.5 ± 3.412.5 ± 3.312.5 ± 3.2
    Body temp (°C) (mean ± SD)38.53 ± 0.4938.48 ± 0.4938.56 ± 0.52
    Result of rapid antigen testb
        A335 (92.0)333 (92.0)338 (92.6)
        B27 (7.4)29 (8.0)25 (6.8)
        A and B2 (0.5)0 (0.0)2 (0.5)
    Influenza virus subtype
        A/H1197 (54.1)200 (55.2)201 (55.1)
        A/H1, H30 (0.0)0 (0.0)1 (0.3)
        A/H3112 (30.8)108 (29.8)108 (29.6)
        A/−21 (5.8)15 (4.1)17 (4.7)
        B21 (5.8)26 (7.2)23 (6.3)
        Unknown13 (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 populationa

    Influenza virus subtype (n) and treatment groupIC50 (nM)
    Mean ± SDMedian (range)b
    A/H1 (593)
        Peramivir22.25 ± 4.3721.59 (0.41–100.00)
        Oseltamivir87.70 ± 16.38100.00 (0.66–100.00)
        Zanamivir1.35 ± 0.181.34 (0.97–3.41)
    A/H3 (323)
        Peramivir0.83 ± 0.170.82 (0.45–2.13)
        Oseltamivir0.63 ± 0.170.62 (0.27–1.84)
        Zanamivir1.97 ± 0.371.91 (1.46–5.93)
    B (70)
        Peramivir3.51 ± 0.393.58 (2.18–4.33)
        Oseltamivir16.53 ± 2.3016.77 (8.77–22.33)
        Zanamivir9.74 ± 1.109.79 (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 intervalValue for group receiving:
    Peramivir (300 mg)Peramivir (600 mg)Oseltamivir
    No. of patients testedChange in virus titeraPbNo. of patients testedChange in virus titeraPbNo. of patients testedChange in virus titera
    Overall
        From day 1 to day 2201−1.10 ± 0.900.4278192−1.08 ± 0.820.2252195−1.04 ± 0.84
        From day 1 to day 3338−1.71 ± 1.210.1337349−1.71 ± 1.100.1778343−1.63 ± 1.11
        From day 1 to day 8323−2.97 ± 1.530.0674338−2.91 ± 1.440.2066331−2.82 ± 1.49
    A/H1
        From day 1 to day 2115−1.18 ± 0.950.6244117−1.15 ± 0.900.4678111−1.06 ± 0.97
        From day 1 to day 3190−1.79 ± 1.260.5092198−1.81 ± 1.190.5204195−1.71 ± 1.22
        From day 1 to day 8182−3.20 ± 1.550.1735191−3.17 ± 1.420.4007187−3.04 ± 1.57
    A/H3
        From day 1 to day 258−1.23 ± 0.680.038654−1.12 ± 0.520.312960−1.01 ± 0.60
        From day 1 to day 3106−1.87 ± 0.910.0218105−1.68 ± 0.710.2434107−1.58 ± 0.76
        From day 1 to day 8102−2.86 ± 1.280.0644103−2.57 ± 1.050.5459103−2.48 ± 1.01
    B
        From day 1 to day 213−0.82 ± 1.020.161210−1.13 ± 0.930.834216−1.21 ± 0.73
        From day 1 to day 321−1.68 ± 1.260.189125−2.08 ± 1.130.679423−2.08 ± 1.00
        From day 1 to day 820−3.46 ± 1.310.112824−3.92 ± 1.610.877823−3.99 ± 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)

    ParameteraValue for group
    PeramivirOseltamivir (n = 365)
    300 mg (n = 364)600 mg (n = 364)
    AEs
        Total
            No. of AEs272288297
            No. (% [95% CI]) of patients with ≥1170 (46.7 [41.5, 52.0])174 (47.8 [42.6, 53.1])178 (48.8 [43.5, 54.0])
            P0.60400.8242
        Mild
            No. of mild AEs909095
            No. (%) of patients with ≥169 (19.0)66 (18.1)74 (20.3)
        Moderate
            No. of moderate AEs161166177
            No. (%) of patients with ≥1119 (32.7)116 (31.9)121 (33.2)
        Severe
            No. of severe AEs213225
            No. (%) of patients with ≥119 (5.2)30 (8.2)24 (6.6)
    ADRs
        Total
            No. of ADRs8099104
            No. (% [95% CI]) of patients with ≥151 (14.0 [10.6, 18.0])66 (18.1 [14.3, 22.5])73 (20.0 [16.0, 24.5])
            P0.03820.5718
        Mild
            No. of mild ADRs404248
            No. (%) of patients with ≥129 (8.0)32 (8.8)40 (11.0)
        Moderate
            No. of moderate ADRs374747
            No. (%) of patients with ≥129 (8.0)34 (9.3)37 (10.1)
        Severe
            No. of severe ADRs3109
            No. (%) of patients with ≥13 (0.8)10 (2.7)9 (2.5)
    No. (%) of patients with the following AEb:
        Neutrophil count decreased39 (10.7)38 (10.4)34 (9.3)
        Diarrhea24 (6.6)30 (8.2)27 (7.4)
        Protein present in urine17 (4.7)16 (4.4)22 (6.0)
        Blood glucose increased11 (3.0)14 (3.8)12 (3.3)
        Urine positive for WBCs14 (3.8)8 (2.2)16 (4.4)
        Nausea8 (2.2)8 (2.2)20 (5.5)
        Vomiting2 (0.5)6 (1.6)15 (4.1)
    No. (%) of patients with the following ADRb:
        Diarrhea14 (3.8)20 (5.5)19 (5.2)
        Neutrophil count decreased9 (2.5)14 (3.8)13 (3.6)
        Nausea2 (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 studyaPhase III studyb
    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 neutropeniaaNo. (%) of patients
    Phase II studybPhase III studyc
    Peramivir (n = 198)Placebo (n = 100)Peramivir (n = 723)Oseltamivir (n = 363)
    10 (0.0)0 (0.0)0 (0.0)0 (0.0)
    2–30 (0.0)0 (0.0)0 (0.0)0 (0.0)
    4–90 (0.0)0 (0.0)66 (90.4)25 (73.5)
    10–1414 (77.8)2 (50.0)4 (5.5)6 (17.6)
    ≥154 (22.2)2 (50.0)3 (4.1)1 (2.9)
    No recovery0 (0.0)0 (0.0)0 (0.0)2 (5.9)d
    Total1847334
    • ↵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.

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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 for the S-021812 Clinical Study Group
Antimicrobial Agents and Chemotherapy Oct 2011, 55 (11) 5267-5276; DOI: 10.1128/AAC.00360-11

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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 for the S-021812 Clinical Study Group
Antimicrobial Agents and Chemotherapy Oct 2011, 55 (11) 5267-5276; DOI: 10.1128/AAC.00360-11
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    • ABSTRACT
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