Effect of peramivir on respiratory symptom improvement in patients with influenza virus infection and pre‐existing chronic respiratory disease: Findings of a randomized, open‐label study

Abstract Background The efficacy of neuraminidase inhibitors on improvement of respiratory symptoms triggered by influenza in patients with pre‐existing chronic respiratory diseases is unknown. Methods This 2‐week, randomized, open‐label study evaluated intravenous peramivir 600 mg on two consecutive days (peramivir‐repeat), peramivir 300 mg single dose (peramivir‐single), and oral oseltamivir 75 mg twice daily for 5 days in patients with confirmed influenza and chronic respiratory diseases. Patients recorded symptom scores daily. The primary endpoint of cumulative area of time vs symptoms (CATVS) was expressed as an index value of area under the curve vs time of the total score of cough, sore throat, and nasal congestion from baseline to 2 weeks. Results Of 214 randomized patients, 209 (56% female, 77% aged <65 years, 94% outpatients, 91% bronchial asthma, 62% influenza A) received ≥1 dose of study drug. Mean (standard deviation) CATVS was similar for peramivir‐repeat (782.78 [487.17]) vs peramivir‐single (717.35 [347.55]; P = .4371), and for peramivir‐repeat vs oseltamivir (856.34 [404.99]; P = 1.00). However, CATVS was significantly shorter for peramivir‐single vs oseltamivir, with an estimated treatment difference (TD) of −145.07 (95% confidence interval: −284.57, −5.56; P = .0416). In subgroup analyses, CATVS was significantly shorter for peramivir‐single vs oseltamivir among patients with influenza A (TD: −206.31 [−383.86, −28.76]; P = .0231), bronchial asthma (TD: −156.57 [−300.22, −12.92]; P = .0328), baseline respiratory severity score <5 (TD: −265.32 [−470.42, −60.21]; P = .0120), and age <65 (TD: −184.30 [−345.08, −23.52]; P = .0249). Conclusions In patients with chronic respiratory diseases, peramivir‐single was not significantly different from peramivir‐repeat and was more effective than oseltamivir at alleviating respiratory symptoms.


| INTRODUC TI ON
Influenza is a potentially life-threatening illness associated with seasonal epidemics that result in significant societal disruption and morbidity. 1,2 Progression of infection to the lower respiratory tract can prove fatal, particularly in patients with chronic respiratory diseases such as bronchial asthma, chronic bronchitis, and chronic obstructive pulmonary disease (COPD). 3,4 Susceptible individuals have a high risk of acute respiratory distress syndrome, which is typically triggered by influenza A infection. 3 Antiviral treatment with a neuraminidase inhibitor (NAI) can bring clinical benefits, including clearing virus, alleviating symptoms, reducing transmission, 5 and potentially improving survival. 1,6 NAI efficacy has been explored predominantly in patients with uncomplicated seasonal influenza. [7][8][9][10][11] Among these agents, intravenous peramivir, including a single-dose 300 mg regimen, showed more rapid symptom alleviation compared with placebo 11 and other NAIs. [8][9][10] However, further data are needed for highrisk patients with chronic respiratory diseases that can be aggravated by influenza, leading to delayed recovery from influenza symptoms. 12,13 A phase III trial previously investigated intravenous peramivir 300 or 600 mg/d for 1-5 days as needed in high-risk patients. 14  Saisho, H. Tanaka, T. Bando, unpublished results). Peramivir 600 mg appeared to be more effective than peramivir 300 mg, with the former demonstrating a higher reduction from baseline in total symptoms at 2 weeks.
The primary objective of this study was to compare peramivir 600 mg repeat dose (1200 mg total dose) with peramivir 300 mg single dose and oseltamivir 75 mg twice daily in patients with influenza A or B infection and chronic respiratory diseases. The study also compared the effect of peramivir 300 mg single dose with oseltamivir. Secondary objectives reported here include changes in respiratory symptom scores over time, virus titer, and safety; additional outcomes will be reported separately.

| Study design
This was a 2-week, multicenter, randomized, open-label study to evaluate intravenous peramivir 600 mg repeat dose, intravenous peramivir 300 mg single dose, or oral oseltamivir 75 mg twice-daily treatment in patients with confirmed influenza A or B together with concomitant bronchial asthma, COPD, or pulmonary fibrosis. The study was conducted between October 2017 and February 2019, encompassing two influenza seasons, across 50 sites in Japan. Enrollment occurred within 48 hours from influenza onset defined as an initial ≥1°C increase in axillary body temperature above normal or worsening of ≥1 systemic or respiratory symptom compared with normal. All patients had ≥4 clinic visits (Figure 1). During a screening visit, influenza diagnosis was confirmed using the rapid antigen test. Patients were instructed in the use of a daily diary to record influenza symptom scores and temperature. A COPD assessment test (CAT) was conducted together with oxygen saturation and respiratory function testing. Patients were assigned to treatment, and the study drug was administered. Patients assigned to peramivir 600 mg repeat dose had an additional visit to receive the repeat treatment on Day 2. Adverse events (AEs) were monitored throughout the 14-day study period.

| Study population
Eligible patients were male or female inpatients or outpatients diagnosed with influenza aged 16-79 years, with those aged 16-19 years requiring consent from a legal guardian. Other key inclusion criteria were the following: a total symptom score for cough, sore throat, and nasal congestion of ≥3 including a score of ≥1 for cough, and ≥1 systemic symptom that scored ≥2 for headache, muscle or joint pain, heat or chills, or fatigue; nasal or throat swab with a positive rapid influenza test; maximum axillary temperature ≥37.5°C for ≥12 hours before screening; and receiving treatment for bronchial asthma, pulmonary fibrosis, or COPD. Key exclusion criteria were the following: concomitant infectious disease requiring treatment with a systemic antibacterial, antifungal, or antiviral drug; history of convulsions or other neurological symptoms within the past 2 years; chronic respiratory failure requiring management on a mechanical ventilator; diabetes with glycated hemoglobin A1c >10% within 4 weeks prior to screening; previous treatment with an NAI, amantadine hydrochloride, or baloxavir marboxil within the previous 7 days; cardiovascular disease requiring hospitalization, and other serious diseases requiring treatment, including congestive heart failure, central nervous system diseases, metabolic diseases, malignancies, renal dialysis, and transplantation within the previous 12 months.

| Randomization and treatment
Patients were randomized (1:1:1) to peramivir 600 mg repeat dose administered as two 300 mg intravenous infusions on two consecutive days (ie, 1200 mg total dose), peramivir 300 mg single dose administered as a single 300 mg infusion, or oral oseltamivir 75 mg twice daily for 5 days (Figure 1). Infusion time was 15-75 minutes for peramivir 600 mg repeat dose and 15-45 minutes for peramivir 300 mg single dose. Randomization was conducted using the minimization method, stratified by total score of respiratory symptoms (≥5, <5) and underlying respiratory disease (bronchial asthma, COPD, or pulmonary fibrosis). Concomitant drugs (except topical medicines) such as antivirals, antifungals, antipyretics (except acetaminophen), general cold drugs, antihistaminic drugs, immunosuppressive drugs, Chinese medicine for influenza virus, and investigational drugs were not permitted. Patients could take a chemical mediator release inhibitor or leukotriene receptor antagonist as an alternative to antihistaminic drugs.

| Outcome measures
The primary efficacy endpoint was "cumulative area of time vs symptoms" (CATVS) expressed as an index AUC of the total score of three respiratory symptoms (cough, sore throat, and nasal congestion) for 2 weeks (from Visit 1 [baseline] to Visit 5 [Day 14]). Influenza symptom severity was assessed using seven items including the three respiratory symptoms and four systemic symptoms (headache, muscle or joint pain, feverishness or chills, and fatigue) by patient diary.
Symptom severity was scored as 0 (no symptoms), 1 (mild), 2 (moderate), or 3 (severe). Secondary efficacy endpoints were mean change from baseline over Visits 2-5 in the total score of three respiratory symptoms, and mean change from baseline over Visits 2, 3, and 4 in virus titer, expressed as median 50% tissue culture infectious dose (TCID 50 ) per mL. Nasal or throat swabs were sent to a central laboratory for viral titer measurement (LSI Medience Corporation). Safety assessments included the frequency of treatment-emergent AEs (TEAEs), serious TEAEs (SAEs), and discontinuations due to TEAEs.

| Statistical analysis
The planned sample size of 70 patients per treatment group was based on an estimate of 64 patients per group needed to provide 80% power to detect a difference between treatments with a twosided significance level of .05. Assumptions were further based on the results of a post hoc analysis of a phase III study of high-risk patients, 14 which showed a difference in index AUC for the total scores of cough, sore throat, and nasal congestion between peramivir 600 mg/d and peramivir 300 mg/d of 11.5; the standard deviation of each treatment group was 24.0. Oseltamivir was assumed to have the same effect on index AUC as peramivir 300 mg/d.
The primary efficacy analyses were conducted using the intentto-treat (ITT) population, which included all randomized patients who received ≥1 dose of study drug and were eligible for efficacy analysis. The primary efficacy endpoint was analyzed using analysis of covariance with the weighted Holm method for multiplicity adjustment (with two-sided significance level of .05 split into .04 F I G U R E 1 Study design. Screening visit (Day 1): patient consent, evaluation of patient demographics and clinical characteristics, physical examination, axillary body temperature, assessment of influenza symptoms, nasal cavity evaluation and throat swab, and confirmation of influenza using the rapid antigen test. Day 2: patients assigned to peramivir 600 mg received repeat treatment; if available, patients in any arm had physical examination and virus test. Day 3: physical examination, virus testing, and CAT, oxygen saturation, and respiratory function assessments in all patients, and clinical examination in patients in the two peramivir groups. Day 7: physical examination, virus testing, and testing for CAT, oxygen saturation, and respiratory function in all patients; clinical examination in patients in the oseltamivir arm. Day 14: physical examination, clinical examination (where possible), CAT, oxygen saturation, and respiratory function assessments in all patients. Patients were instructed to record their axillary body temperature four times per day on Days 1-3 and twice per day from Day 4, and to record their influenza symptom scores twice per day on Days 1-7, then once daily from Day 8. CAT, chronic obstructive pulmonary disease assessment test . .

| Demographic and baseline clinical characteristics
Of 214 patients randomized, 209 received ≥1 dose of study drug and comprised the SAS ( Figure S1). Screening data before obtaining consent were not available, but the major reason for patient ineligibility was not having a body temperature ≥37.5°C during the previous 12 hours. In the peramivir 600 mg repeat-dose arm, one patient who withdrew consent was not included in the safety or ITT analyses. In the peramivir 300 mg single-dose arm, four patients (two without written consent, one who withdrew consent, and one who required a prohibited drug) were not included in the SAS; in addition, one patient who received the allocated treatment was not included in the ITT population because they did not have a body temperature ≥37.5°C within 12 hours before screening and therefore did not meet this inclusion criterion. Patient demographics and baseline clinical characteristics were well balanced between treatment arms, with no significant differences (Table 1). Most patients were outpatients, aged <65 years, never smokers, with comorbid bronchial asthma, a total score of three respiratory symptoms ≥5, and a predominance of infection by influenza A.

| Peramivir 600 mg repeat-dose vs peramivir 300 mg single-dose treatment (primary analysis)
There was no difference between peramivir 600 mg repeat dose and 300 mg single dose with respect to the primary outcome of CATVS (

| Peramivir 300 mg single-dose vs oseltamivir treatment
Cumulative area of time vs symptoms was significantly shorter for peramivir 300 mg single dose compared with oseltamivir ( Table 2).
TA B L E 2 Cumulative area of time vs symptoms expressed as an index value for area under the curve of the total score of cough, sore throat, and nasal congestion from the start of study drug administration to 2 wk post-administration (ITT population)

| Subgroup analyses
Compared with peramivir 600 mg repeat dose or oseltamivir, treatment with peramivir 300 mg single dose was associated with shorter CATVS across a range of subgroups, including virus type, those with bronchial asthma or pulmonary fibrosis, symptom severity score <5 or ≥5, and age <65 years (

| Changes in symptoms
Peramivir 300 mg single dose was associated with significantly greater decreases from baseline in total symptom score compared  Figure 2B). Decreases in sore throat scores were significantly greater with peramivir 300 mg single dose than with oseltamivir (Days 5 and 10) and peramivir 600 mg repeat dose (Days 8-11) ( Figure 2C). Decreases in nasal congestion score were similar in the three groups, except for a greater decrease with peramivir 300 mg single dose compared with oseltamivir on Day 10 ( Figure 2D).

| Virus titer
The reduction in symptom score was associated with a decrease in viral titer at Days 2, 3, and 7 (Figure 3). At Day 3 following completion of dosing in the two peramivir arms but not oseltamivir, the mean (standard deviation) reduction from baseline in virus titer (expressed as log 10 TCID 50 /mL) was −3.74 (2.45) for peramivir 600 mg repeat dose, −3.49 (2.34) for peramivir 300 mg single dose, and −3.08 (2.23) for oseltamivir.
In a subanalysis of viral titer by influenza type, patients with influenza A had a more rapid reduction in viral titer vs those with influenza B (data not shown). Among patients with influenza A, peramivir 300 mg single dose compared with peramivir 600 mg repeat dose was associated with a significantly greater reduction in viral titer at Day 2 (P = .0268), and peramivir 600 mg repeat dose compared with oseltamivir was associated with a significantly greater reduction in viral titer at Day 3 (P = .0313). There were no differences in viral titer between the three arms at Day 7.

| Safety and tolerability measures
Treatment with peramivir 600 mg repeat dose, peramivir 300 mg single dose, or oseltamivir was well tolerated (Table S2). The incidence of any TEAEs was higher among patients treated with peramivir 600 mg repeat dose (25.7%) compared with either peramivir 300 mg single dose (13.4%) or oseltamivir (13.9%). However, the only TEAEs that occurred in ≥2 patients in any arm were diarrhea, hepatic function abnormal, vomiting, and decreased appetite. Three patients experienced SAEs: one patient each with vomiting and pneumonia in the peramivir 600 mg repeat-dose arm, and one patient with pneumococcal pneumonia in the peramivir 300 mg single-dose arm.

| D ISCUSS I ON
This is the first prospective, randomized, head-to-head study of oseltamivir and peramivir 600 mg repeat-dose and 300 mg single-dose regimens in high-risk patients with chronic respiratory diseases. peramivir 300 mg single dose or 600 mg repeat dose as an effective antiviral option in patients with chronic respiratory diseases.
In particular, peramivir 300 mg single dose offered greater efficacy than oseltamivir in patients with bronchial asthma and influenza A.
Although a potential benefit for the 600 mg repeat-dose regimen could not be established, with the 300 mg single-dose regimen providing significant antiviral effect and symptom reduction, the former regimen may be more appropriate for the inpatient setting. Thus, it is relevant that the majority of patients treated in this study were outpatients. Our findings also confirm the safety of intravenous peramivir in patients with high-risk features, with overall safety consistent with post-marketing safety evaluations of peramivir. 18 In addition to providing superior symptom relief overall, peramivir 300 mg single dose also had an impact on cough.
Influenza symptoms are triggered in response to upper airway infection, damage to the respiratory epithelium, and the subsequent host immune response. 23 Peramivir's mechanism of action is explained by its potent inhibition of influenza neuraminidase enzyme, with prolonged binding compared with either oseltamivir or zanamivir. 24 Given peramivir's effect on cough was superior to oseltamivir, this indicates that its strong antiviral effect may reduce damage to the airway epithelium leading to earlier alleviation of symptoms. Viruses such as influenza are implicated in the majority of asthma and COPD exacerbations. 25 The diminished cough associated with peramivir in the present context may reflect reductions in virus-associated epithelial activation and degeneration, which stimulate persistent cough through mechanisms involving inflammatory mediators 26 and stimulation of C-fibers, 27 respectively.

| Study strengths and limitations
This study permitted robust comparison between peramivir and oseltamivir while minimizing the potential for selection bias through randomization.

| CON CLUS ION
In the main analysis, there were no significant differences in CATVS between peramivir 600 mg repeat dose and either peramivir 300 mg single dose or oseltamivir. Secondary analysis showed a significant difference between peramivir 300 mg single dose and oseltamivir.
Significant differences between peramivir and oseltamivir were seen for several secondary endpoints, including changes in respiratory symptoms (especially cough). Differential effects of peramivir and oseltamivir on other outcomes, including the COPD Assessment Test, will be reported elsewhere. for Good Publication Practice (GPP3).

CO N FLI C T O F I NTE R E S T
MK is a steering committee member for AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd, GlaxoSmithKline K.K., and Shionogi & Co., Ltd., and has given lectures for AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., GlaxoSmithKline K.K., Novartis