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A Multicentre, Randomized, Controlled Trial of Oseltamivir in the Treatment of Influenza in a High-Risk Chinese Population*

Posted on: Thursday, 9 February 2006, 06:00 CST

By Lin, Jiang-tao; Yu, Xue-zhong; Cui, De-jian; Chen, Xu-yan; Et al

Key words: High-risk population * Influenza * Oseltamivir * Randomized controlled trial

ABSTRACT

Objective: To evaluate the efficacy and safety of oseltamivir treatment in a population at high risk for influenza.

Research design and methods: This was a randomized, open-label, controlled trial involving Chinese patients with chronic respiratory diseases (chronic bronchitis, obstructive emphysema, bronchial asthma or bronchiectasis) or chronic cardiac disease. Patients showing symptoms of influenza were randomly assigned to receive oral oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or symptomatic treatment (control group) within 48 h after symptom onset.

Main outcome measures: The main outcome measures were duration and severity of illness in influenza-infected patients. Other outcome measures included incidence of complications, antibiotic use, hospitalization and total medical cost.

Results: Of the 118 recruited patients, 56 were identified as influenza-infected through laboratory tests (oseltamivir, N = 27; control, N = 29). Relative to symptomatic treatment, oseltamivir significantly reduced the duration of influenza symptoms by 36.8% (p = 0.0479), and the severity by 43.1 % (p = 0.0002). In addition, oseltamivir significantly reduced the duration of fever by 45.2% (p = 0.0051), and the time to return to baseline health status by 5 days (p = 0.0011). The incidence of complications (11% vs. 45%, p= 0.0053) and antibiotic use (37% vs. 69%, p = 0.0167) were also significantly lower in the oseltamivir group compared with the control group. The cost of treating influenza and its complications was comparable between the two groups (p =0.2462).

Conclusions: Oseltamivir is effective and well tolerated in high- risk patients with chronic respiratory or cardiac diseases. It can reduce the duration and severity of influenza symptoms and decrease the incidence of secondary complications and antibiotic use, without increasing the total medical cost.

Introduction

Each year, influenza causes worldwide epidemics of respiratory illness in people of all ages2. In healthy adults, the illness is usually self-limiting with symptoms persisting for about 1 week3'4. However, the infection may be more protracted in high-risk populations, such as the elderly, immuno-compromised individuals and those with underlying chronic diseases such as asthma, cardiovascular disease and diabetes mellitus3. In these high-risk patients, influenza is associated with increased risk of complications and death3-5.

Oseltamivir, a neuraminidase inhibitor, is effective against influenza virus types A and B in adults and children6-10. Clinical studies have shown that oseltamivir can reduce the median duration of influenza-related symptoms in otherwise healthy adults if treatment is initiated within 48h of onset of symptoms6,7,11. Oseltamivir may also reduce the incidence of influenzarelated complications and allow patients to return to normal activities up to 2 days earlier than untreated patients7.

Reports on the effects of oseltamivir in high-risk patients with chronic diseases are lacking. The aim of this study was to evaluate the efficacy and safety of oseltamivir in the treatment of influenza in patients with cardiac or pulmonary diseases, and to provide a reference for its application in other high-risk infected populations.

Patients and methods

This was a randomized, open-label, controlled trial carried out at nine university tertiary teaching hospitals in China during the flu season of 2002-2003. The participating hospitals included Peking Sino-Japan Friendship Hospital, Peking United Medical Center Hospital, No. 1 Hospital Affiliated to Peking University, People's Hospital Affiliated to Peking University, Tianjin Thoracic Hospital, Tianjin No. 3 Medical Center, General Air Force Hospital (People's Liberation Army), Shanghai Changhai Hospital and Shanghai Renji Hospital.

Patients

Patients with chronic respiratory disease (bronchial asthma, bronchiectasis or obstructive pulmonary emphysema) or chronic cardiac disease (coronary heart disease or chronic heart insufficiency) who displayed symptoms consistent with influenza infection (fever ≥ 37.8C and at least two of the following seven symptoms: sore throat, cough, nasal snuffle, myalgia, fatigue, headache, chills/sweating) were invited to participate in the study if they presented within 48 h of illness onset. Chronic obstructive pulmonary disease (COPD) and asthma were diagnosed according to the criteria of the National Heart, Lung and Blood Institute of the National Institutes of Health and the World Health Organization's (NHLBI/WHO) Global Initiative for Chronic Obstructive Lung Disease (GOLD) and Global Initiative for Asthma (GINA). Bronchiectasis was diagnosed by high-resolution computed tomography. Coronary heart disease and chronic heart insufficiency were diagnosed based on disease history, ultrasound cardiography and coronary arteriography. Patients with a high suspicion of bacterial infection (based on signs, symptoms, leukocyte count > 10.0 x 109/L or neutrophil granulocyte level ≥ 0.8%) were excluded from the study. Pregnant or nursing women were also excluded, as were patients with a history of alcohol or drug abuse and those who had been vaccinated for influenza within 12 months prior to the start of the study. The trial protocol was approved by the Ethics Committee for each participating trial centre and written informed consent was obtained from all patients prior to their participation in the study.

Study design

A physical examination was performed at baseline. Other baseline assessments included case history, viral culture from naso- pharyngeal secretions and determination of influenza antibody titre. Eligible patients were randomized to receive 75mg of oral oseltamivir twice a day for 5 consecutive days (oseltamivir group), or routine symptomatic treatment (control group). Block randomization was used, where randomization numbers were allocated by the admitting physician according to the sequence of enrolment. All patients were followed up for 21 days, or until they recovered from the infection. All patients received symptom diary cards to record influenza-related symptoms, temperature and adverse reactions. This information was recorded by the patients themselves, or by a family member who had been briefed on how to record information on the diary card. The diary cards formed the basis for collection of efficacy data. Each symptom was graded as O = no problem; 1 = mild; 2 = moderate; 3 = severe. secondary complications such as tracheitis, bronchitis or pneumonia were also recorded. Patients were required to complete all diary cards for at least 8 days, or until remission of all symptoms was achieved. Remission of fever was defined as a temperature of ≤ 37.3C lasting for ≥ 24 h. Remission of other symptoms was defined as a score of 0-1 lasting for > 24 h. Patients were allowed acetaminophen and antibiotics as required within the first 8 days. Usage of antibiotics and acetaminophen was also recorded on the diary card.

Virologic assessments

Naso-pharyngeal secretions were collected at screening for viral culture. Specimens were inoculated onto Madin-Darby canine kidney cells and isolates were detected and typed using fluorescein- labelled influenza A and B monoclonal antibodies (Chemicon International, Inc.). Duplicate serum samples were collected in the acute phase (Day 1, baseline) and recovery phase (Day 21) and stored at -20C until they were analyzed. Antibody titres were measured using the serum haemagglutinin inhibition assay. Antigens used in the assay were from influenza virus strains known to be circulating during the 2002-2003 influenza season (A/Shanghai/7/99, A^sub 3^/ Fujian/151/2000, B/Zhejiang/2/2001, B/Shanghai/20/2001). These were provided by the Chinese National Influenza Center (100 Yingxin Street, Beijing, China). Influenza infection was defined by recovery of virus from naso-pharyngeal secretions and/or a 4-fold rise in serum antibody titres between Day 1 and Day 21 of the study.

Data analyses

Efficacy analyses were performed on the intention-totreat infected (ITTI) population, which consisted of all randomized patients who received at least one dose of study medication and had laboratory-confirmed influenza. Safety analyses were performed on the safety population, which included all patients who received at least one dose of study medication and who had at least one safety follow-up, whether or not they were withdrawn prematurely.

The primary endpoint was duration of illness, defined as the time from symptom onset to remission of fever and all the seven symptoms (sore throat, cough, nasal snuffle, myalgia, fatigue, headache, chills/sweating). The cumulative remission rate was calculated according to the remission status in different groups. Other endpoints included severity of illness (measured by the area under the curve of total symptom scores), recovery, incidence of complications, antibiotic use, hospitalization and recovery time, and total medical cost, including cost of antibiotics.

Figure 1. Flow diagram of study population

All analyses were performed using SAS version 8.2. Measurement data showing a normalized distribution were described as mean stan\dard deviation and analysed with analysis of variance to determine the difference between the oseltamivir and control groups. Measurement data in non-normalized distributions were described as median and analysed using the Wilcoxon test. Frequency data were analysed using the chi-squared (χ2) and F tests. Statistical significance was tested at the 5% level. Fever and the other seven symptoms were analysed using the survival method. Kaplan-Meier curves were constructed and significance-tested using the log-rank method.

Results

A total of 118 patients (58 oseltamivir group; 60 control group) were enrolled into the study (Figure 1). Influenza was diagnosed by virus isolation and serological analysis in 56 (51.9%) of these patients, 27 of whom were in the oseltamivir group and 29 in the control group (ITTI population). A total of 13 patients (6 oseltamivir group; seven control group) were over 65 years old.

The basic health status of the ITTI population is shown in Table 1. The majority of patients in the two groups had chronic obstructive pulmonary disease and there was no significant difference between the two groups in the distribution (χ^sup 2^ = 6.974, p = 0.223) and severity of existing diseases. The baseline characteristics of the two groups were also similar (Table 2). At the start of the study, 10 patients were using bronchodilators (oseltamivir group, n =5 [18.5%]; control group, n =5 [17.2%], p = 0.90), and four patients were using steroids (oseltamivir group, n =2 [7.4%]; control group, n =2 [6.9%], p = 0.94). The body temperature, score of each symptom and duration of illness prior to enrolment were similar for both groups (Table 3).

Clinical efficacy

Time to remission of all influenza symptoms: there was a significant difference in the time to remission of all symptoms between the two groups as revealed through the survival curve log- rank test (p = 0.0479, Figure 2). Compared with the control group, oseltamivir reduced the duration of influenza by 64 h (36.8%, Table 4).

Time to remission of fever: the cumulative proportion for fever remission in the two groups is shown in Figure 3. There was a significant difference in time to remission of fever between the two groups (F = 7.85, p = 0.0051). Oseltamivir treatment reduced the mean duration of fever by 47.2 h (45.2%, Table 4).

Severity of influenza symptoms: the severity of illness, measured by the area under the curve of the overall symptom score, was reduced by 617.9 points (43.1%) in the oseltamivir group compared with the control group (Table 4). The difference between the two groups was statistically significant (F = 16.58, p = 0.0002).

Table 1. Basic health status of the intention-to-treat infected population

Table 2. Baseline characteristics of the intention-to-treat infected population

Incidence of complications: a total of 16 patients in the ITTI population (oseltamivir group, three of 27, 11%; control group, 13 of 29, 45%) developed complications, which included tracheitis, bronchitis, pneumonia, nasosinusitis and pharyngitis. The difference in the incidence of complications between the groups was statistically significant (χ^sup 2^ = 7.7885, p = 0.0053).

Antibiotic use: the proportion of patients receiving antibiotic treatment during their illness was significantly lower in the oseltamivir group (10 of 27, 37%) compared with the control group (20 of 29, 69%; χ^sup 2^ = 5.7308, p = 0.0167). The average duration of antibiotic use was also significantly lower in the oseltamivir group (3.7 2.5 vs. 7.3 4.0 days, respectively; F = 6.69, p = 0.0152).

Hospitalization: of the patients who developed complications, seven (oseltamivir, n = 2; control, n = 5) were hospitalized for influenza during this study. Patients with complications who were not hospitalized were treated with oral or intravenous antibiotics at a clinic. There was no significant difference between the two groups in the proportion of patients hospitalized (χ^sup 2^ = 1.2363, p = 0.2662).

Recovery to basic health status: the mean time to recovery to basic health status was significantly reduced by 5 days in the oseltamivir group compared with the control group (Table 4; F = 11.95, p = 0.0011).

Table 3. Duration and severity of influenza symptoms before treatment, intention-to-treat infected population

Figure 2. Time to alleviation of all symptoms in influenza- infected patients, intention-to-treat infected population. Patients received either 75 mg oseltamivir twice a day for 5 days (oseltamivir group) or routine symptomatic treatment (control group)

Table 4. Clinical outcomes in the intention-to-treat infected population

Figure 3. Time to alleviation of fever in influenza-infected patients, intention-to-treat infected population. Patients received either 75 mg oseltamivir twice a day for 5 days (oseltamivir group) or routine symptomatic treatment (control group)

Cost of treatment

The total cost per patient of treating influenza, including the cost of oseltamivir, antibiotics and acetaminophen, was US$24.06 (= CNY99 [CNY: China Yuan Renminbi]; US$1 = CNY 8.27, November 2002- February 2003) lower in the oseltamivir group compared with the control group (70.98 55.99 vs. 95.16 US$92.01, respectively). Despite the lower cost in the oseltamivir group, the difference between the two groups was not statistically significant (F = 1.37, p = 0.2462).

Safety and tolerability

Oseltamivir treatment was generally well tolerated, with the incidence of adverse events in the oseltamivir group being comparable to that of the control group. Of the 118 patients enrolled in the study, only two (both in the oseltamivir group) reported adverse events (nausea [grade 1] and stomach discomfort [grade 2]). Both events were mild in intensity, and both patients completed the course of oseltamivir treatment.

Discussion

The results of the current study demonstrate that oseltamivir is effective and safe for the treatment of influenza in high-risk patients.

While the efficacy and safety of oseltamivir in otherwise healthy adults with naturally acquired infection have been previously demonstrated in two large trials6,7, this is the first report describing its effectiveness in patients with chronic respiratory and cardiac disease. Oseltamivir [75 mg) given twice daily for 5 days reduced the duration of influenza symptoms by 36.8% and the severity of symptoms by 43.1%. Patients receiving oseltamivir also benefited from a 5-day reduction in the amount of time before returning to basic health status compared with patients on symptomatic treatment. In addition, the incidence of secondary complications was significantly lower in the oseltamivir group compared with the control group. Consistent with this, the use of antibiotics was significantly reduced in the oseltamivirtreated patients. Thus, oseltamivir was of significant benefit in this patient population.

The average age of the high-risk patients included in this study was 48.1 years for the oseltamivir group and 52.3 years for the control group, with 13 patients (6 oseltamivir group; seven control group) aged over 65 years. There was no significant difference between the two groups in terms of age (p = 0.700). In addition, based on regression analysis, age was found to have no effect on physiological parameters (data not shown). Patients ≥ 65 years of age with underlying conditions are at increased risk of developing complications, and can experience significant morbidity and mortality12,13. Significant correlations have been demonstrated between the presence of influenza virus and admissions of the elderly for pneumonia and chronic lung disease14. In addition, a retrospective study in patients with congestive heart failure indicated that during the 1998 influenza pandemic, the death rate of hospitalized patients, especially those aged 75 years and older, was significantly higher when compared to the same season in past years, suggesting a causal relationship between influenza infection and increased mortality due to congestive heart failure among older Japanese patients15. Oseltamivir administration has been shown to significantly reduce the incidence of influenza-related complications and the mortality rate among elderly patients following an influenza outbreak16,17, and the present study demonstrates that oseltamivir is also effective in patients with co- morbidities.

In a study by Kaiser et al.18, oseltamivir significantly reduced the incidence of influenza-related respiratory tract complications, antibiotic use and hospitalization rates in otherwise healthy adults as well as in 'at-risk' adults. In addition, in a recent retrospective study based on a large US claims database, Nordstrom et al.19 showed that the risk of pneumonia, antibiotic use and hospitalization was reduced in patients with influenzalike illness who received oseltamivir. The present study also demonstrated significant reductions in the incidence of complications and antibiotic use with oseltamivir. The reduced antibiotic usage in the oseltamivir group is important in light of the increasing bacterial resistance3,9. Unlike the Kaiser et al.18 and Nordstrom et al.19 studies, there was no statistical difference in hospitalization rate between the oseltamivir group and the control group in the present study, probably due to the small sample size.

The rate of antibiotic use in both the oseltamivir and control groups (37% vs. 69%, respectively) was higher than the incidence of secondary complications in both groups (11% vs. 45%, respectively). In China, many clinicians prescribe antibiotics for respiratory tract infections even when the patient has no evidence of bacterial infection. In addition, patients can selfmedicate, as they do not require a prescription in order to purchase antibiotics20. This easy access to antibiotics, coupled with the prescribing practices, may account for the increased antibiotic usage relative to theincidence of secondary complications.

The significantly higher rate of antibiotic usage in the control group (69%) relative to the oseltamivir group (37%) may explain the lack of difference in the cost of treatment between the two groups, suggesting that in high-risk patients, oseltamivir reduces the incidence of secondary complications, thereby reducing the cost associated with treating such complications.

A limitation of this study was its open-label design. However, this design was deemed appropriate because all patients enrolled had underlying chronic conditions, and it would have been difficult for physicians to provide appropriate care for any complications that may have arisen had they been blinded to treatment groups. Moreover, efficacy assessments were based on diary card information provided by the patients, thereby reducing the likelihood of bias.

Oseltamivir is well tolerated in otherwise healthy adults and children, as well as in frail older individuals6,7,9,16. In the present study, oseltamivir was well tolerated, with the incidence of adverse events in the oseltamivir group being comparable to that of the control group.

Conclusion

Oseltamivir, given twice daily for 5 days and within 48 h of symptom onset, can reduce the duration and severity of influenza and its associated complications in patients with chronic respiratory and cardiac diseases at no additional cost. Thus, oseltamivir provides a new option for effective influenza treatment in high- risk patients with chronic respiratory and cardiac diseases.

Acknowledgements

Declaration of interest: This study was sponsored by Shanghai Roche.

The authors would like to thank the following investigators for their invaluable help with this study: Gao He, General Air Force Hospital, People's Liberation Army, China; Huo Zhenglu, Shanghai Changhai Hospital, China; Zhu Shunhe, Shanghai Renji Hospital, China; Hu Shanlian, Fudan University, China; Wang Aixia, Peking United Medical Center Hospital, China. Editorial assistance was provided by Annete Njue-Doswell and Adis International Ltd, Chester, UK (financially supported by Roche Pharmaceuticals).

Original publication of material: This article is based on an article previously published in Chinese in the journal Zhonghua Jie He He Hu Xi Za Zhi1

* This material was previously presented at the 9th Congress of the Asian Pacific Society of Respirology Abstract (No. 360), 10-13 December 2004, Hong Kong. This article is based on an article previously published in Chinese in the journal Zhonghua Jie He He Hu Xi Za Zhi1

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7. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial [US Oral Neuraminidase Study Group]. J Am Med Assoc 2000;283(8):1016-24

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14. Upshur RE, Knight K, Goel V. Time-series analysis of the relation between influenza virus and hospital admissions of the elderly in Ontario, Canada, for pneumonia, chronic lung disease, and congestive heart failure. Am J Epidemiol 1999;149(1): 85-92

15. Narukawa M, Minezaki K, Okubo M, Kario K. Impact of an influenza pandemic on the mortality of congestive heart failure in older Japanese: the 1998 Japanese influenza pandemic. J Am Geriatr Soc 2001;49(5):689-90

16. Peters Jr PH, Gravenstein S, Norwood P, et al. Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population. J Am Geriatr Soc 2001;49(8): 1025-31

17. Bowles SK, Lee W, Simor AE, et al. Use of oseltamivir during influenza outbreaks in Ontario nursing homes, 1999-2000. J Am Geriatr Soc 2002)50:608-16

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19. Nordstrom BL, Sung I, Suter P, et al. Risk of pneumonia and other complications of influenza-like illness in patients treated with oseltamivir. Curr Med Res Opin 2005;21:761-8

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3112_3, Accepted for publication: 02 November 2005

Published Online: 21 November 2005

doi: 10.1185/030079906X80297

Jiang-tao Lin(a), Xue-zhong Yu(b), De-jian Cui(c), Xu-yan Chen(d), Ji-hong Zhu(e), Yu-zhen Wang(f) and Xiao-di Wu(g)

a China-Japan Friendship Hospital, Beijing, China

b Peking United Medical Center Hospital, China

c No. 304 Hospital, People's Liberation Army, China

d No. 1 Hospital Affiliated to Beijing University, China

e People's Hospital Affiliated to Beijing University, China

f Tianjin Hospital for Thoracic Diseases, China

g Tianjin No. 3 Medical Center, China

Address for correspondence: Lin Jiang-tao, Chief and Professor, Department of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, 100029, China. Tel.: +86 10 8420 6187; Fax: +86 10 8420 6187; email: Jiangtao_l@263.net

Copyright Librapharm Jan 2006

Source: Current Medical Research and Opinion

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