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Monto AS, Robinson DP, Herlocher ML, Hinson, Jr JM, Elliott MJ, Crisp A. Zanamivir in the Prevention of Influenza Among Healthy Adults: A Randomized Controlled Trial. JAMA. 1999;282(1):31–35. doi:10.1001/jama.282.1.31
Author Affiliations: School of Public Health, University of Michigan, Ann Arbor (Drs Monto and Herlocher); University of Missouri, Columbia (Drs Robinson and Hinson); Glaxo Wellcome Inc, Research Triangle Park, NC (Dr Elliot); and Glaxo Wellcome Inc, Greenford, England (Dr Crisp).
Context The neuraminidase inhibitor zanamivir, a sialic acid analog administered
directly to the respiratory tract, has been demonstrated in clinical studies
to be effective in treatment of type A and B influenza. It has also been shown
to prevent influenza infection and disease in an experimental model.
Objective To examine the efficacy of zanamivir, administered once daily, in the
prevention of influenza infection and disease.
Design Double-blind, randomized, placebo-controlled trial.
Setting Two midwestern university communities.
Participants A total of 1107 healthy adults (mean age [range], 29 [18-69] years)
were recruited in November 1997, before the influenza season.
Intervention At the start of the influenza outbreak, 554 subjects were randomized
to receive placebo and 553 to receive zanamivir. The drug, 10 mg once per
day, or identical placebo was administered by oral inhalation for a 4-week
Main Outcome Measures Illness occurrence was recorded by participants daily and records were
evaluated weekly. Specimens were collected for viral isolation when symptoms
were reported within 3 days of illness onset. Infection was also identified
by testing paired serum samples for rise in antibody titer against the circulating
Results Zanamivir was 67% efficacious (95% confidence interval [CI], 39%-83%; P<.001) in preventing laboratory-confirmed clinical
influenza meeting the case definition and 84% efficacious (95% CI, 55%-94%; P=.001) in preventing laboratory-confirmed illnesses with
fever. All influenza infections occurring during the season, with or without
symptoms, were prevented with an efficacy of 31% (95% CI, 4%-50%; P=.03). The nature and incidence of adverse events in the zanamivir
group did not differ from placebo. Compliance with the once-daily dosage was
Conclusions Zanamivir administered once daily is efficacious and well tolerated
in the prevention of influenza for a 4-week period in healthy adults.
Twenty years ago, the antiviral drug amantadine was reported
to be 70% efficacious in prevention of symptomatic influenza during an epidemic
associated with the reappearance of type A(H1N1) virus.1
A few years later, amantadine and the related compound rimantadine were demonstrated
to be efficacious in preventing illnesses associated with type A(H3N2) and
type A(H1N1) viruses.2 However, while clearly
effective, there has been a long-standing controversy about appropriate use
of these drugs dating to the 1960s.3,4
Concerns raised include the lack of effectiveness against type B viruses,
occurrence of adverse effects mainly related to amantadine, and the rapid
development of resistance to both agents.5-7
A new class of antivirals, with a different mechanism of antiviral
action, has been designed and developed to provide another approach to the
control of influenza.8,9 The compounds
specifically inhibit the action of the viral neuraminidase enzyme, essential
for replication of both type A and B viruses. The sites affected are conserved;
thus, the antiviral action is independent of antigenic change.8,9
Zanamivir (GG167), a sialic acid analog, has been demonstrated to be efficacious
in clinical trials in shortening the duration and reducing the severity of
type A and B influenza illness.10 Experimental
studies have suggested promise in the prevention of influenza.11
We report use of zanamivir administered once daily for a period of 4 weeks
during the course of an influenza season in which the predominant circulating
virus was A/Sydney/5/97 (H3N2), a variant not contained in the vaccine used
The study was a randomized, double-blind, placebo-controlled trial conducted
at 2 sites in the United States during the 1997-1998 influenza season. The
study was approved by the institutional review boards at both participating
universities. Prophylaxis began when an increase in occurrence of influenza
was documented in each geographic area based on frequency of influenzalike
illnesses and identification of influenza viruses circulating. As a result,
randomization took place and active prophylaxis began at the University of
Missouri site approximately 1 week before it began at the University of Michigan
site. Otherwise, eligibility criteria, drug use, and data collection were
identical at the 2 locations.
Zanamivir or an identically packaged placebo, both containing lactose
as the principal base, was administered by self-activated inhalation once
daily using a Diskhaler device (Glaxo Wellcome, Ware, England). The daily
dosage of zanamivir used was 10 mg; the micronized drug powder was estimated
to have an aerodynamic mass median diameter of approximately 3.0 µm.
The first dose was taken under the supervision of the study staff. Participants
returned weekly for study drug resupply, to have diary cards evaluated, and
for inspection of the used medication to ensure appropriate use. If the drug
or placebo had not been used for 6 days or more during the 28-day period,
that individual was considered noncompliant with the protocol.
The study was conducted in the midwestern US university communities
of Ann Arbor, Mich, and Columbia, Mo. Participants were mainly students or
community volunteers. Persons aged 18 to 64 years were eligible for participation
if they did not have chronic conditions that put them in the groups at risk
for complications and for which influenza vaccination was recommended. Therefore,
individuals with hypertension were eligible. Eligibility was not restricted
to unvaccinated participants. Pregnant and lactating women were excluded,
as were those unable to return to the study office at the scheduled times.
To ensure that prophylaxis would begin when the influenza outbreak began,
participants were recruited during November 1997. At enrollment, the study
design was reviewed and informed consent obtained. Blood samples were collected
for initial safety evaluations, which included blood counts, electrolyte and
liver enzyme determinations, and a metabolic profile. An aliquot of serum
was frozen at −70°C for serologic testing.
Surveillance of influenza virus occurrence was conducted in the enrolled
study panel, in the surrounding community, and in university-associated student
health services. Specimens at the Michigan site were processed for viral isolation
using standard techniques at the World Health Organization Collaborating Center
for Influenza in the School of Public Health. At the Missouri site, a commercial
laboratory was used. In January, the number of specimens increased. After
influenza occurrence was detected, the active phase of the study began. Participants
were called to the study offices, where exclusions were reevaluated and consent
to participate was reviewed. Any subject presenting with a respiratory illness
at this visit was excluded. Subjects were sequentially assigned treatment
numbers corresponding to a box of disks containing prerandomized drug or identical
placebo to maintain the blind. Randomization was stratified for vaccination
states in blocks of 10 at each site. All participants were blindly randomized
to drug or placebo in a 1:1 ratio and prophylaxis began.
Participants were given a diary card to record twice daily any symptoms
occurring during the following week, using a severity scale of 0 to 3 (representing
none, mild, moderate, and severe). At the same time, subjects obtained and
recorded their temperatures by tympanic methods. Participants returned to
the centers, where each 7-day diary card was checked and any other symptoms
were sought. Subjects then received a new diary card and a new supply of study
drug or placebo. The procedure was repeated during the 28 days of prophylaxis,
after which time drug administration ended. At day 35, participants returned
for the final visit, at which a second blood specimen was obtained for safety
determinations and viral serology.
Throughout the study period, the subjects were asked to report
to the study center should they have any respiratory symptoms. At that point,
a culture for virus isolation was obtained. Collected serum samples from both
sites were treated with receptor-destroying enzyme and tested as pairs in
the laboratory at the University of Michigan.13
Antigens used were obtained from the Centers for Disease Control and Prevention
(CDC) or produced in the laboratory from seed viruses obtained from the same
source. The hemagglutination-inhibition tests were carried out using antigens
of A/Sydney/5/97 (H3N2), A/Wuhan/359/95 (H3N2), and A/Johannesburg/82/96 (H1N1).
A 20% subset of serum samples was tested with B/Guangdong/8/93. A 4-fold rise
in titer or appearance of inhibition 2 dilutions higher than the initial dilution,
when negative, was considered to represent infection.
Individuals were classified as infected with influenza if they had a
rise in titer with 1 or more of the antigens used and/or isolation of an influenza
virus during the period of prophylaxis. An influenza-associated illness (laboratory-confirmed
clinical influenza) was considered to have occurred in those with documented
infection who also had 2 or more of the following signs or symptoms recorded
concurrently on 3 or more successive diary card entries: cough, headache,
sore throat, myalgia, feverishness, or a temperature of at least 37.8°C.
Febrile laboratory-confirmed influenza required that a temperature of at least
37.8°C be recorded in individuals with rise in antibody titer and/or isolation
of virus. Total febrile illness required only the occurrence of a temperature
of at least 37.8°C.
The primary efficacy end point was the proportion of randomized
subjects who, during prophylaxis, developed laboratory-confirmed clinical
influenza. The sample size was based on the assumption that the attack rate
in the placebo group would be 10% and the effectiveness of zanamivir would
be 70%. On this basis, 270 subjects were required in each group to give 90%
power at the 2-sided P=.05 level of significance.14 Because an influenza outbreak was declared at both
study sites, the planned sample size was exceeded. The analysis was performed
using an exact test15,16 for stratified
2 × 2 tables. Analyses were conducted on the intent-to-treat population
(all randomized subjects, regardless of whether study drug was taken or if
the subject completed the planned duration of the study) with stratification
by study sites and vaccination status and on the nonvaccinated population
(all nonvaccinated, randomized subjects who took at least 1 dose of study
medication), stratified by study site. Statistical tests were performed at
the 2-sided P=.05 level of significance. Corresponding
estimates of the odds ratios (ORs) of laboratory-confirmed clinical influenza
were obtained, together with 95% confidence intervals (CIs).17
Approximate risk ratios (RRs) were also calculated based on stratified analyses,
using Mantel-Haenszel estimates with test-based CIs. Efficacy was expressed
as 1 − RR.
A total of 1107 individuals were randomized to receive either placebo
or zanamivir (Figure 1). As shown
in Table 1, there were 554 and
553 subjects in each of those groups, respectively, with mean ages of 28.6
and 29.0 years, with an age range of 18-69 years, reflecting the nature of
the pool from which the participants were recruited. (Although the initial
age range was 18-64 years, 1 individual older than 64 years was recruited
in each group and retained in the analysis.) (Although the initial age range
was 18-64 years, 1 individual older than 64 years was recruited in each group
and retained in the analysis.) Women predominated, and 14% of each group had
received vaccine prior to randomization. Slightly more than half of the population
was at the Michigan site.
Reports of the sporadic occurrence of influenza began to appear in both
areas in November. Virus was first isolated in December, but illness frequency
did not start to increase until January 6, 1998, with the wave of illnesses
continuing until February 12, 1998. There were 19 viral isolates at the Michigan
site. All were type A(H3N2); with the assistance of the Influenza Branch of
the CDC, 15 were further identified: 12 (80%) as A/Sydney/5/97 (H3N2) and
3 (20%) as A/Wuhan/359/95 (H3N2). At the Missouri site, there was only 1 type
A(H3N2) influenza isolate, but the frequency of rises in titer among the type
A subtypes and variants was similar to that seen in Michigan.
The frequency of illnesses of various characteristics and of infection
in the overall randomized, or intent-to-treat, population is shown in Table 2. The primary end point was prevention
of laboratory-confirmed clinical influenza meeting the case definition. The
number of events observed demonstrated that this was an outbreak of moderate
size. The OR of the illness frequencies between study groups was 0.31. As
shown, this approximates an RR of 0.33 (95% CI, 0.17-0.61) or an efficacy
of 67% (95% CI, 39%-83%). Fever is one of the best predictors of influenza
positivity when respiratory illnesses among adults are tested for presence
of virus.18 When those illnesses considered
were restricted to those with temperatures of at least 37.8°C that were
laboratory-confirmed as influenza, the efficacy was 84% (95% CI, 55%-94%).
When all febrile episodes were considered with or without confirmation of
influenza etiology, a significant efficacy could still be demonstrated and
was 43% (95% CI, 14%-62%). Finally, influenza infections, with or without
illness, were prevented with a lower efficacy than symptomatic infections
of 31% (95% CI, 4%-50%). This is in agreement with the lower efficacy in the
prevention of influenza infection characteristic of amantadine and rimantadine.1,2
The results were consistent between the 2 sites, with the exact test
for homogeneity of ORs between centers demonstrating P=.73.
The viruses circulating at the 2 sites also appeared to be similar based on
similar serologic data. There were 52 rises in titer detected for A/Sydney/5/97
(H3N2), 50 rises for A/Wuhan/395/95 (H3N2), and 6 for A/Johannesburg/82/96
(H1N1) in serum samples collected from Michigan; results for Missouri were
59, 40, and 5, respectively. Many individuals had rises in titer for both
A(H3N2) strains, indicating cross-reactivity. There were no rises in titer
detected in specimens from either site for type B virus.
Only 14% of the participants were vaccinated, and the vaccine minimally
protected against the A/Sydney/5/97 (H3N2) virus.12
When the analysis was restricted to unvaccinated persons, the OR for laboratory-confirmed
clinical influenza was 0.38 (95% CI, 0.17-0.80), with an estimated RR of 0.40,
which translates to an efficacy of 60% (95% CI, 24%-80%; P=.009). For laboratory-confirmed influenza with fever, the efficacy
was 81% (95% CI, 46%-96%; P=.004). The number of
vaccinated individuals was too small to draw conclusions about the interaction
of the antiviral with even a marginally protective vaccine.
Several measures were examined in an attempt to identify any adverse
effects associated with use of zanamivir in the 4-week period of administration.
Because this was a prophylactic study, any symptoms occurring during the period
could possibly be related to drug use and, thus, were recorded. In both placebo
and zanamivir groups, some symptoms were reported by 75% of individuals. When
examined as a whole or by system, there were no significant differences observed.
The systems examined were ear, nose, and throat; endocrine and metabolic;
eye; gastrointestinal tract; lower respiratory tract; musculoskeletal; neurologic;
reproductive; and non–site specific. Adverse effects thought by the
investigators to be potentially drug-related were observed in 27 (5%) of the
placebo group and 30 (5%) of the zanamivir group. Potential adverse effects
that were considered severe were seen in 1 (<1%) of the placebo recipients
and 1 (<1%) of the zanamivir recipients. Withdrawals from the trial for
any reason occurred in 17 subjects (3%) from the placebo group and 10 (2%)
from the zanamivir group; those thought by the participants to be potentially
drug related occurred among 7 (1%) and 4 (<1%) subjects in the 2 groups,
respectively. The remaining 10 and 6 withdrawals, respectively, were related
to voluntary withdrawal of consent or by loss to follow-up (Figure 1). Thus, adverse events were not associated with drug prophylaxis.
The study staff assessed compliance by the number of doses that each subject
used from the disks. In the placebo group, 525 (95%) were recorded as taking
doses for 23 to 28 or more days and in the zanamivir group, the number was
There were a number of paradoxes associated with the 1997-1998 influenza
year in the United States. The predominant strain was A/Sydney/5/97 (H3N2),
a virus significantly different from that in the vaccine. This was the first
time in many years that such an event happened, especially since it began
almost at the start of the season. Not surprisingly, there was excess mortality
documented during 9 consecutive weeks, as well as major community outbreaks
in the western states in early winter.12 However,
much of the rest of the country had more modest outbreaks, which sometimes
occurred over a long period. Thus, the frequencies in the placebo group of
laboratory-confirmed clinical influenza of 6% and of influenza infection of
14% is lower than might have been expected in many influenza seasons. Still,
the demonstrated clinical protective efficacy of 67% was consistent between
the 2 sites.
When laboratory-confirmed episodes with documented
fever were considered, the efficacy estimate rose to 84%. Fever is a major
predictor of the ability to isolate influenza virus from respiratory illnesses
with cough, and this value may be a better estimate of the ability of zanamivir
to prevent typical influenza.18 The difference
in efficacy estimates might also suggest that zanamivir is better in preventing
disease—in particular, more severe disease—than infection. Supporting
this observation is the lower efficacy of 31% of the drug in preventing all
influenza infections, clinical and inapparent. In any event, because asymptomatic
infection still occurs in those receiving prophylaxis, antibodies will be
produced that could protect individuals against a later infection. Interestingly,
the same pattern of a better ability to prevent symptomatic than asymptomatic
infection has been previously observed with amantadine and rimantadine.1,2
Zanamivir is a neuraminidase
inhibitor and, thus, has a totally different mechanism of action than amantadine
or rimantadine, compounds that are limited in activity to type A influenza.
While only type A influenza circulated during the conduct of the current trial,
zanamivir's demonstrated activity in therapy of type B infections plus in
vitro data suggest that it would be equally efficacious against type B infections.8,19 This broader spectrum would be an
advantage over the current influenza antiviral drugs, especially in years
with mixed or overlapping type A and B outbreaks.
to amantadine and rimantadine develops rapidly and can be managed by careful
use, but concern regarding this issue has been widely expressed.4,20,21
Resistance to zanamivir has been sought in specimens resulting from trials
in therapy, a situation in which resistant strains would have been routinely
identified if amantadine had been used, but none has yet been found. Obviously,
continued surveillance for resistance is required as use increases. The 1
instance in which resistance has been demonstrated occurred when the drug
was given for a prolonged period to an immunosuppressed individual.21 The leading advantage of zanamivir in prophylaxis
is its safety and its once-daily use. This study did not demonstrate any excess
adverse events vs placebo in the healthy adults who received the drug, and
the observed compliance was high. It should be remembered that this drug will
be used in practice in other populations and in less-than-ideal settings,
where it might function differently; however, initial results in nursing home
residents have been encouraging.22
Antiviral prophylaxis of influenza has been considered an adjunct to vaccination,
useful in specific situations, and this will continue to be the case.23 One of these situations was exhibited in 1997-1998,
when a change in the circulating virus limited the efficacy of the vaccine.
Another would be when a person in the risk groups recommended for vaccination
is found to be unvaccinated by medical personnel after influenza transmission
has started. In this case, vaccine could be administered and the drug given
and continued for at least the limited period while antibody develops. Also,
outside the high-risk group, a decision may sometimes be made between a patient
and medical personnel to use drug prophylaxis for a short period of exposure,
such as when traveling, or for longer periods, when virus is known to be transmitting.
These approaches have been used in the past with amantadine and rimantadine,
and they should serve as guidelines for the use of zanamivir, recognizing
its advantages over the older compounds.
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