International network to study high-dose Tamiflu

Mar 29, 2007 (CIDRAP News) – A network of clinical researchers stretching from Southeast Asia to the United States is about to begin testing whether doubling the standard dosage of oseltamivir (Tamiflu) will help patients overcome either the often-deadly H5N1 avian influenza or severe seasonal flu.

Researchers in Indonesia, Thailand, Vietnam, and the United States hope to enroll up to 400 patients over the next 2 years and treat them with either the standard regimen or twice that amount for up to 10 days.

The trial will be run by the Southeast Asia Influenza Clinical Research Network (SEA ICRN), a multinational partnership launched about a year and a half ago. The network has published the full study protocol on its Web site (see link below).

H5N1 disease in humans is fatal about 60% of the time, and experts have been suggesting for some time that higher doses of the antiviral drug might give patients a better chance of surviving. The results of the trial could affect not only recommendations for use of the drug, but also government decisions about how much of it to stockpile for use in a flu pandemic. Oseltamivir is considered the first-line treatment for H5N1 patients.

Patients will be randomly assigned to receive either the standard dosage of oseltamivir—75 mg twice a day—or 150 mg twice a day, according to the study protocol. Patients won't know which regimen they are on; placebo capsules will be used to pad the regimen for the standard-treatment group.

Elizabeth Higgs, MD, deputy of the Collaborative Clinical Research Branch of the National Institute of Allergy and Infectious Diseases (NIAID), an associate investigator with the trial, told CIDRAP News that patients will be treated for 5 days and then assessed. "Then we'll continue [the treatment] if the patient isn't clinically better. We're really trying to look at both the dose and the length of time. The hypothesis is the higher dose for a longer period of time will work better."

Higgs said Dr. Menno de Jong, a clinical researcher at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam, found evidence that the virus reaches higher levels and invades more systems and organs in H5N1 disease than in seasonal flu. The hope is that a higher dose of oseltamivir will be more effective in countering the high viral load in H5N1 patients, she said.

De Jong was the first author of a December 2005 report on two fatal H5N1 cases in Vietnam in which the virus showed signs of resistance to oseltamivir. One of the patients died despite receiving the drug within the recommended window of 2 days after symptom onset. De Jong and colleagues said their findings implied that some patients may need a higher dose or longer treatment regimen.

In animal studies, higher doses of oseltamivir have yielded higher cure rates for H5N1, according to Tawee Chotpitayasunondh of Thailand's Ministry of Public Health, who was quoted in a Reuters report published yesterday.

Besides testing whether high-dose oseltamivir will better control the virus, the trial aims to uncover differences between human and avian influenza in their clinical manifestations, the relationship between viral blood concentration and viral dynamics, and pathogenesis, according to the protocol.

The protocol calls for enrolling up to 100 patients with avian flu and up to 300 with severe seasonal flu. The aim is to enroll all laboratory-identified avian flu patients who seek treatment within 1 week of illness onset.

The participating hospitals include five in Vietnam, two in Indonesia, four in Thailand, and one in the United States—the National Institutes of Health Clinical Center in Bethesda, Md. Five labs in Indonesia, Thailand, and Vietnam will also be involved.

The study is supported by the NIAID, the Wellcome Trust in London, and the University of Oxford. The World Health Organization (WHO) is also a partner in the network.

Roche, the manufacturer of oseltamivir, is not participating in the study but is supplying the drug for it, according to the protocol.

Amid controversy over access to H5N1 virus samples and vaccines, Higgs described the network as a remarkable example of international cooperation in flu research. Indonesia promised this week to resume sharing its H5N1 samples with the WHO, after withholding them for several months because of concern that vaccine producers would use them to make vaccines priced beyond Indonesia's reach.

"This [network] is the only group of its type that has this type of cooperation among countries," Higgs said. "Here we are at a clinical science level cooperating very nicely. It's significant that all of these countries want to cooperate at a scientific level and everybody has the same information."

She said the network was born about 18 months ago, after years of discussion among Southeast Asian researchers and also between the NIAID and the WHO. Since then, much work has been done to build capacity at the various sites involved, she said.

"A lot of these sites had a tremendous amount of experience with research before they joined the network," Higgs said. "Wellcome has been supporting clinical research in these countries for decades."

See also:

Dec 22, 2005, CIDRAP News story "Tamiflu resistance in avian flu victims sparks concern"

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