Roche trials database

Protocol number:

ML22789

Title of Study:

An unblinded, comparative, randomized study of influenza A/H1N1 2009 resistance in patients with standard and double dose oseltamivir treatment

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

Tamiflu

Generic name:

oseltamivir [Tamiflu]

Therapeutic area:

• Influenza

Clinical study summary:

This phase IIIb, comparative, randomized, open-label and interventional study was designed to evaluate the efficacy and safety of Tamiflu in patients with Influenza.

Study center(s):

3 centers in Brazil

Phase of development:

IV

Objectives:

The primary objective was to evaluate the difference in the proportion of patients excreting resistant virus with each dosage scheme at the end of treatment.

The secondary objectives were as follows: To evaluate the differences in viral load reduction, as measured on Day 5, in subjects receiving standard dose and double dose of Tamiflu;  To evaluate the determination of any existing difference in frequency of clinical signs and symptoms on the 5th treatment day between patients treated with a standard dose and double dose of Tamiflu; To evaluate the determination of any existing difference between both dose groups (standard and double dose) in the frequency of clinical signs and symptoms reported on Day 5, in patients detected with resistant viruses.

Methodology:

A total of 125 randomized patients was planned, or at least 90, positive for Influenza A H1N1 as confirmed by PCR test. A total of 37 patients with positive results on the quick test for Influenza H1N1 were randomized at 1:1 ratio to receive treatment with Tamiflu at the following dosage schemes: Standard dose: 75mg twice a day for 5 days, or double dose: 150mg twice a day for 5 days. Viral load, viral excretion, clinical signs and symptoms and laboratory parameters were measured during the treatment period.

Number of patients (planned/analyzed):

199 patients enrolled, 37 patients treated

Diagnosis and main criteria for inclusion:

Male and female patients ≥ 5 years of age with positive rapid antigen test for influenza A and onset of symptoms of influenza (fever, at least one respiratory symptom) ≤48 hours.

Test product, dose and mode of administration or test procedure:

Oseltamivir dose was varied according to randomization, either 75mg twice a day or 150mg twice a day in adults, or a proper dose for children (see table 1 and 2 below).

Table 1. Standard doses for treatment with Tamiflu in children
Children	15 kg or less	60mg daily split in two doses
	15–23 Kg	90mg daily split in two doses
	24–40 Kg	120mg daily split in two doses
	>40 kg	150mg daily split in two doses

 

Table 2. Double doses for treatment with Tamiflu in children
Children	15 kg or less	120mg daily split in two doses
	15–23 Kg	180mg daily split in two doses
	24–40 Kg	240mg daily split in two doses
	>40 kg	300mg daily split in two doses

 

Duration of treatment:

5 days

Reference therapy, dose and mode of administration or reference procedure:

N/A

Criteria for evaluation (efficacy, safety):

Efficacy:

• Proportion of patients excreting resistant viruses in each dosage scheme.
• Proportion of patients showing a pattern of viral resistance in each dosage scheme.
• Proportion of patients with reduction in viral load, as analyzed on Day 5, in subjects receiving standard dose and double dose of Tamiflu.
• Frequency and percentage of clinical signs and symptoms on Day 5 between patients treated with a standard dose and double dose of Tamiflu.
• Frequency and percentage of clinical signs and symptoms on Day 5 between patients treated with a standard dose and double dose of Tamiflu in patients in whom resistant virus were detected.
• Values of H1N1 concentration in patients evaluated on days 1 and 5.
• Proportion of patients presenting adverse events in each dosage scheme
• Frequency and percentage of clinical signs and symptoms on Day 5 between patients treated with a standard dose and double dose of Tamiflu.

Safety:

• Proportion of patients presenting adverse events in each dosage scheme
• Frequency and percentage of clinical signs and symptoms on Day 5 between patients treated with a standard dose and double dose of Tamiflu.

Statistical methods:

The following hypotheses were made in order to estimate the sample size for this study:
- Assuming a discontinuation rate of 20%, 125 patients were intended for recruitment, reaching at least 100 subjects at the end of study.

- It was conservatively assumed that 40% of patients or more would meet the selection criteria, that was PCR-positive, then it would be possible to reach a number equal or higher than 80 patients eligible for virological analysis.

- Using a two-sided test, suited for testing the hypothesis that a double dose of Tamiflu suppresses the appearance of resistant viruses (detected by PCR), at a significance level of 0.05, there was an 80% probability of detecting a difference of 20% in the frequency of resistant viruses between both doses at the end of study (25% with standard dose versus 5% with double dose)

Summary (efficacy, safety, other results):

One hundred ninety-nine (199) patients were evaluated during the study. Among those, 162 were considered as screening failures, mainly due to the negative result detected by the quick test for Influenza A antigen.

From the 199 patients selected, 37 composed ITT population: 19 in the group receiving oseltamivir standard dose and 18 in the group receiving the double dose. Thirty-five patients composed PP population: 18 in the standard dose group and 17 in the double dose group.

Patients' mean age in the standard dose group was 21.6 ± 11.1 years, ranging from 6 to 47 years. Patients' mean age in the double dose group was 22.0 ± 12.7 years, ranging from 7 to 53 years. The majority of patients are White (89.8% in standard dose group and 72.2% in double dose group). Both groups were homogeneous regarding race, when considering two classes - "White” and “non-White”. As for sex and weight, the groups were balanced (p > 0.05).

Groups were considered homogeneous regarding the time to onset of symptoms for visit 01 as well as concerning signs and symptoms reported on visit 1 (p > 0.05).

PCR results for pandemic H1N1, seasonal H1N1, and H3N2 Influenza A viruses and responses on genetic sequencing and viral culture were equal for both treatment groups at study start.

By day 5, five (26.3%) in the standard dose group and six patients (35.3%) in the double dose group tested positive for pandemic Influenza A H1N1 virus. Four (21.1%) in the standard dose group and five patients (29.4%) in the double dose group showed positive results for Influenza A virus. There was no significant difference between groups as for the proportion of positive responses detected (p > 0.05).

Seasonal H1N1 and H3N2 viruses were not detected, either at study start or on the fifth treatment day.

In both treatment groups, there was a marked reduction in patients testing positive for the virus on the 5th treatment day relative to the 1st day, without a statistically significant difference.

Between visits 1 and 2, viremia (H1N1 genome /uL) in the samples had decreased for all patients. There were no significant differences between groups in relation to H1N1 genome /uL (p > 0.05).

Both groups showed reductions of approximately 100% in this parameter. There is no difference between groups in viral load reduction (p > 0.05).

Eight patients (42.1%) in the standard dose group and 7 patients (38.9%) in the double dose group reported an adverse event. Based on the total of adverse events, the number of events related to the investigational drug was 7 (63.6%) in the standard dose group and 5 (55.6%) in the double dose group.

Conclusions:

In this study we could notice the drug's clear action, demonstrated by a reduction in viremia for both treatment groups.

Improvement in the disease's symptoms was quite evident and no drug-resistant strains were found.

New studies are required to assess the drug in patients infected with mutated and drug-resistant strains.

Date of report:

16.04.2011

Click here for the protocol registry listing of this trial.