Clinical Trial Result Information
Title of Study:
A Double-Blind, Randomized, Stratified, Placebo-Controlled Study of Oseltamivir in the Treatment of Influenza in Children with Asthma
Fast Facts:
| Protocol number: | NV16871 |
| Sponsor: | F Hoffmann-La Roche Ltd |
| Company division: | Pharmaceutical |
| Product name: | Tamiflu |
| Generic name: | oseltamivir |
| Phase of development: | IV |
| Therapeutic area, approved indication: | Influenza |
| Date of report: | 12/15/2004 |
Clinical study summary:
This was a randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy of oseltamivir (Tamiflu) in the treatment of influenza-mediated asthma symptoms in pediatric and adolescent patients with asthma.
Study center(s) :
Subjects were recruited from 50 centers in 10 countries.
Objectives:
To investigate the effect of treatment with Tamiflu (1) on improving the rate of recovery from influenza-mediated asthma symptoms and exacerbations in patients with asthma; (2) on pulmonary function in this population; (3) on the need for medical and other health care resources associated with influenza infection in this population; (4) on viral activity in this population.
Methodology:
Patients were randomized to receive either placebo or Tamiflu (dose based on body weight). Ten consecutive doses were to be taken at approximately 12-hour intervals. At baseline (Day 1) and on Days 2, 6, and 10, measurements of forced expiratory volume in 1 second (FEV1) were made in the clinic (or at a home visit). From Day 1 to Day 28, patients completed their own diaries of asthma and influenza symptoms, and recorded their own FEV1 and measurements of peak expiratory flow rate (PEFR) using a hand-held device.. Nose/throat swabs for the determination of influenza viral shedding were taken at baseline and on Days 2, 6, and 10. Safety was assessed through the monitoring of adverse events, vital signs, and physical examination.
Number of patients (planned/analyzed):
329 randomized
Diagnosis and main criteria for inclusion:
Subjects 6 to17 years of age, inclusive; with >=3 episodes of infection-induced wheezing in the previous year or with asthma severe enough to require regular medical follow-up or hospital care; rapid onset of influenza-like symptoms (oral temperature >=37.8°C plus >=1 respiratory symptom [cough or coryza]); and <48 hours between onset of symptoms and start of treatment.
Test product, dose and mode of administration or test procedure:
Tamiflu, 45 mg (if weight >15–23 kg), 60 mg (>23–40 kg), or 75 mg (>40 kg), po/bid/5 days.
Duration of treatment:
Twice daily for 5 days.
Reference therapy, dose and mode of administration or reference procedure:
Placebo, po/bid/5 days.
Criteria for evaluation (efficacy, safety):
Primary efficacy parameter: Percentage change in FEV1 from the patient’s worst (on Days 1–2) over the dosing period (Day 6), as measured by spirometry.
Secondary efficacy parameters: (1) Time to alleviation of influenza symptoms; (2) percentage change in FEV1 to Day 10; (3) proportion of patients with asthma exacerbation; (4) time to 50% recovery in FEV1 from patient’s worst value; (5) proportion with 20% recovery in FEV1 by Day 6; (6) proportion of patients developing secondary illness (sinusitis, otitis media, bronchitis, pneumonia); (7) percentage change in PEFR from baseline to Day 6; (8) time to 50% recovery from patient’s worst asthma symptoms on Days 1–2; (9) time to first asthma-free day.
Safety parameters: Adverse events, vital signs, and physical examination.
Statistical methods:
The study was stratified for asthma severity at baseline (mild or moderate/severe) and the time from influenza symptom onset to the time to first dose of study medication (<24 hours or >=24 hours). Time to treatment intervention was compared for the primary and secondary efficacy parameters to determine if earlier intervention provided increased treatment benefit. For all endpoints that involved alleviation of symptoms, alleviation was defined as occurring at the start of the period in which the symptom was rated as 0 (no problem/not present) or 1 (mild problem) and remained so for >=21.5 hours. The percentage change in FEV1 from the patient’s worst value (recorded on Days 1–2) to Day 6 was compared between groups using an extended Wilcoxon rank sum (van Elteren) test.
Summary (efficacy, safety, other results):
Efficacy – Only 28.6% of the randomized population (N=329) had laboratory-confirmed influenza, and the resulting intent-to-treat-infected (ITTI) population comprised 51 placebo patients and 43 Tamiflu patients. The primary efficacy endpoint (the percentage change in clinic FEV1 from the patient’s worst value on Day 1 or 2 up to Day 6) showed a trend in favor of the Tamiflu group (P=0.098), with a difference between group medians of 3.6%. The proportion of patients achieving a 20% recovery in FEV1 by Day 6 was also greater in the Tamiflu group (23% vs 12%). These results were consistent with patients’ diary assessments of asthma symptoms, which suggested faster recovery in the Tamiflu group: the median time to 25% recovery was decreased by 9.5 hours (11.8 hours vs 21.3 hours), and the median time to 50% recovery decreased by 23.5 hours (32.5 hours vs 56.0 hours). Time to full recovery was equally reduced, by 27.6 hours (103.3 hours vs 130.9 hours). The incidence of secondary complications of influenza (bronchitis, sinusitis, otitis media, and pneumonia) was significantly reduced in the Tamiflu population relative to the placebo population (2% vs 16%; P=0.036). The proportion of patients requiring antibiotics was correspondingly reduced (2% vs 14% in the placebo group).
Daily self-assessments of FEV1 and PEFR were recorded by patients at home in patient diaries. These measurements of FEV1, using a hand-held device, suggested a consistently higher percentage improvement in the Tamiflu group compared with the placebo group. While the median percentage change in PEFR appeared to be higher in the Tamiflu group (12% vs 6%), there was no difference between the groups when using pairwise comparisons. The area of the PEFR versus time curve, however, did suggest higher values in the Tamiflu group (54608 %hours vs 50901 %hours).
Viral shedding was assessed at baseline and on Days 2, 6, and 10. Most patients (88%–91%) were still shedding virus on Day 2; however, at later time points the proportion was lower in the Tamiflu group (7% vs 14% on Day 6, and 2% vs 4% on Day 10).
Influenza symptoms resolved quickly in both groups. Tamiflu treatment did not lead to an earlier resolution of influenza symptoms in infected patients (67.0 hours vs 71.7 hours) but, surprisingly, did so in the overall intent-to-treat (ITT) population (56.4 hours vs 66.3 hours; P=0.014). Similarly, Tamiflu treatment failed to lead to an earlier resolution of fever in infected patients.
Safety – The overall incidence of adverse events was slightly higher in the Tamiflu group than the placebo group (24% vs 21%). This was mainly due to a higher incidence of gastrointestinal events (10% vs 6%), of which vomiting (8% vs 2%) was most significant. Most of the vomiting events in the Tamiflu group were single events on the first day of dosing and were of mild intensity. The incidences of nervous system disorders and respiratory disorders were also slightly elevated in the Tamiflu group (cases of headache and migraine were recorded on active treatment only, together with slight increases in asthma and allergic rhinitis). Almost all adverse events were considered as mild or moderate in intensity, and none led to premature withdrawal from treatment. Two patients (1 in each treatment group) experienced serious adverse events during the “off-treatment” phase of the study, both considered by the investigators to be unrelated to treatment: acute sinusitis in a placebo patient and fever in a Tamiflu patient. No meaningful changes were observed in vital signs or physical examinations.
Conclusions:
It is concluded from this under-recruited study that despite the low numbers of patients with confirmed influenza infection, there is evidence that treatment of asthmatic children and adolescents with Tamiflu had beneficial effects. These beneficial effects were manifested by a greater improvement in clinic-measured FEV1, an enhanced rate of recovery from asthma symptoms, and a significant reduction in the incidence of secondary complications. Despite these, an earlier resolution of influenza-symptoms was not demonstrated in the infected population. Side effects were few and limited to the known gastrointestinal effects of Tamiflu reported in other studies.
