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Microsoft word - protocol.doc

1.0 TITLE PAGE FOR 2008 PILOT (STOP-FLU 2)
Study title:
A pilot study for a randomized controlled trial comparing trivalent split virus
influenza vaccine to seasonal antiviral prophylaxis in healthcare workers and other healthy
adults: assessment of zanamivir versus vaccine.
Products to be used:
1. Licensed, trivalent split virus influenza vaccine (Vaxigrip®, Fluviral®) 2. Zanamivir (Relenza®)
Investigators:
Dr. Steven Drews Dr. Michael Gardam Dr. Kevin Katz Dr. Jeffrey Kwong Investigator/coordinators:

Study contact:
Development phase: Phase IV
Date:
____________________________________ PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 2.0 BACKGROUND

Despite substantial progress in vaccination, and new medications for both treatment and
prophylaxis of influenza, this viral infection remains the most common infectious disease cause
of death in the developed world (1-3). Influenza infections are due to two types of influenza, A
and B. Several different strains of influenza circulate at any given time. Currently, influenza
infections are due to the A(H3N2), A(H1N1) and B strains. In any given year, most influenza
illness is due to one or two specific influenza strains; these strains change from year to year (3).
In Canada, influenza is responsible for an estimated 4000 to 8000 deaths annually, as well as
50,000 to 75,000 hospitalizations (2). Morbidity and mortality due to influenza are highest in
pandemic years. In these years, which occur approximately three times per century, a new strain
of influenza A emerges, and both the incidence and severity of infection are substantially higher
than usual; as many as 70% of the population may be infected in a one-year period. Between
pandemic years, influenza continues to evolve, and the genetic changes from year to year are
enough that people with immunity to last year’s strain may be infected and become ill with this
year’s. The annual rate of infection in healthy young adults between pandemics ranges from 5%
to 25%; approximately 50% of infections are asymptomatic (3, 4). In children, the rate of
infection is higher. In at risk persons the infection rate is unchanged, but the severity and rate of
complications are higher. Part of the variation in the incidence and severity of infection is
explained by the degree of antigenic change from one strain to the next, part by differences in
virulence, and part is unexplained.
In the northern and southern hemispheres, influenza is a seasonal disease. Most influenza activity
is concentrated in an 8 to 15 week period during the winter (2, 5-7). The exact timing of onset,
the duration, and the overall rate of infection are unpredictable. In the northern hemisphere, the
season usually starts between December 15th and January 15th, but may start as early as
November, or as late as mid-February. In some years, there is no detectable influenza activity at
all. Influenza activity is measured in a number of ways (e.g. number of institutional respiratory
outbreaks, school or workplace absenteeism, proportion of healthcare provider or emergency
department visits that are due to influenza-like illness, proportion of mortality that is due to
pneumonia and influenza, and proportion of respiratory specimens submitted for viral testing that
are positive for influenza) (7). All of these result in approximately the same assessment of
activity. As influenza testing becomes more common, determination of season has increasingly
been based on the results of laboratory testing since data is more easily and quickly available,
and less subjective.
Immunization is the main strategy for the prevention of influenza (8). In Canada, only
inactivated influenza vaccines are licensed, and only split-virion vaccines are routinely used in
public health vaccination programs. Vaccines are made semi-annually (for the northern and
southern hemisphere seasons, respectively), with the antigenic composition being determined by
a World Health Organization consensus group (see 9).
In healthy adults, vaccine is about 80% effective against infection due to influenza which
matches antigenically (10). In older adults, vaccination is substantially less effective;
nonetheless, it has still been shown in randomized controlled trials to be protective, and the best
estimate of the Cochrane review is that vaccination prevents 42% of all cause mortality in the
elderly during the influenza season (11). For this reason, in Canada, vaccines are offered free of
____________________________________
PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 charge to all persons over the age of 6 months who are at risk of complications from influenza (children under 2 years of age, adults over 65 years of age, persons with chronic underlying conditions, and pregnant women), and all those who have close contact with persons in these risk groups, including all healthcare workers (8). In Ontario, annual influenza vaccine is universally offered to all residents. There are two classes of medication with activity against influenza that have been used as an adjunct to vaccine (12-14). The first are the adamantanes (M2 inhibitors): amantadine and rimantadine (only amantadine is licensed in Canada). These medications have been used for the control of influenza outbreaks in healthcare institutions for more than 20 years; however, a relative lack of efficacy data, significant side effects, and antiviral resistance has limited their use. Influenza type B strains are intrinsically resistant to adamantanes. In the last three years, adamantane resistance in A(H3N2) strains identified in Canada has ranged from 15 to 90%, and in 2006/7, the first resistant strains of A(H1N1) were identified (15,16). Thus, expert bodies, including the US Centers for Disease Control and Prevention and the Canadian National Advisory Committee on Immunization recommends that adamantanes no longer be used for influenza treatment or prophylaxis (8,13). In the late 1990s, the first of a new class of antivirals, the neuraminidase inhibitors, were licensed for use in humans. Two drugs in this class are currently licensed in Canada: oseltamivir (Tamiflu®) and zanamivir (Relenza®). Oseltamivir is available as a capsule and suspension to be taken orally. Zanamivir is available as a dry powder for inhalation. Both medications are licensed for use for both treatment and prophylaxis. If treatment is started within 48 hours of the onset of symptoms, use of either of these medications reduces the severity and duration of illness due to influenza by 25-35% and the rate of complications by 40-65% (12, 14). Several large, randomized controlled trials have demonstrated that zanamivir and oseltamivir are effective in preventing influenza infection and illness when used either as prophylaxis after exposure to a household contact with influenza, or when taken for several weeks at the height of influenza activity in the general community (14, 17-23). In general, both oseltamivir and zanamivir are 70-90% effective in preventing symptomatic influenza infection due to either influenza A or B. This activity against influenza makes neuraminidase inhibitors useful adjuncts to vaccination in a number of situations. In the vulnerable elderly resident in healthcare institutions, influenza outbreaks are common, and antivirals are routinely recommended for the prevention of illness and the control of outbreaks (1, 8, 13). Expert groups also recommend that consideration be given to the use of antiviral prophylaxis for at-risk household contacts of influenza cases, and for seasonal prophylaxis for high-risk patients who will not respond well to vaccine (8,13). However, because the longest duration of prophylaxis in clinical trials to date has been six weeks, and because a few studies have assessed the efficacy of six weeks of prophylaxis (22,24), neither neuraminidase inhibitor is licensed in Canada for seasonal prophylaxis for the entire influenza season, and data on prolonged use of these medications are very limited. Antiviral medications will also likely have an important role in the response to the next influenza pandemic. Because the time from recognition of which strain will cause the next pandemic to the onset of the first major wave of illness is expected to be significantly less than 6 months, and because it will take at least five to six months to produce sufficient vaccine to protect the ____________________________________ PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 Canadian population from serious illness, antiviral medications are likely to be important in initial pandemic response. Many countries, including Canada, are building stockpiles of antivirals to treat pandemic influenza (25, 26). Most stockpiles include both zanamivir and oseltamivir, because some persons may not be able to tolerate one or the other, and because resistance may arise differentially. More recently, growing attention is being paid to the potential for use of antivirals for prophylaxis. Two scenarios for prophylaxis are being considered: “ring” prophylaxis of close contacts of influenza cases, to attempt to slow community spread (25), and continuous prophylaxis of healthcare and other essential service providers to maintain services (27, 28). There are a number of important unanswered questions about the potential value of antiviral prophylaxis for healthcare workers, and its benefits relative to the use of personal protective equipment used at work. One of the important pieces of information that is missing is the extent to which influenza in healthcare workers is occupationally acquired: healthcare workers are obviously exposed to influenza both while they are at work and while they are not, and we do not know the relative contribution of work to their rate of illness, or even whether healthcare workers are at higher risk of influenza infection than other adults. There may also be additional indications for the use of antivirals during seasons in which the major infecting strain is not one whose antigen is well-covered by the vaccine. This type of difference, known as a “mismatch,” occurs on occasion because influenza viruses evolve continuously, and because a decision about a vaccine to be ready in October has to be made at the end of February (7 months prior). At the moment, our ability to assess antigenic differences and their impact on the efficacy of vaccine in real-time is limited (29). As yet, we have not known before the end of the season (or near the end of the season) either the frequency or the degree of mismatch. However, this is changing rapidly, and, over the next few seasons, it is likely that we will, increasingly quickly, be able to assess mismatch during the season, or even before the season starts. This ability will create significant challenges related to adjunctive use of antivirals. If vaccine efficacy is low enough, seasonal prophylaxis for high risk persons and healthcare workers, despite its cost, may be an option that should be considered. This pilot study is intended to assess the feasibility of a larger double-blind, randomized
controlled trial designed to obtain the answers to a number of questions related to antiviral
prophylaxis of influenza. In the randomized controlled trial, we are interested in understanding
the relative benefits of vaccine and antiviral prophylaxis, in determining risk factors for influenza
infection in healthy adults, particularly risk factors related to exposure to children and patients
with acute respiratory illness; and in assessing the safety and tolerability of seasonal zanamivir
prophylaxis in healthcare workers. The objectives and methods for the randomized controlled
trial are attached as Appendix 1.
3.0 OBJECTIVES

The objectives of this pilot proposal are to:
(i) assess the feasibility of recruitment for the study; (ii) pilot study procedures, specifically web-based diary management and real-time analysis, (iii) assess whether the proposed four serologic measurements will be adequate to serologically assess influenza infection during the study; (iv) determine rates of acute respiratory illness using different criteria for acute respiratory ____________________________________ PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 (v) assess the feasibility of obtaining nasopharyngeal (NP) or nasal swabs within 48 hours of symptom onset and the results of PCR testing within 24 hours of obtaining the swab; (vi) assess adherence rates (and reasons) to long term zanamivir in healthy adults; and (vii) provide a preliminary assessment of the safety of prolonged zanamivir prophylaxis in
4.0 INVESTIGATIONAL PLAN
4.1 Overall study design

The study will be an randomized, unblinded pilot study of 50 individuals, aged 18 to 69 years.
Subjects will receive either zanamivir 10mg once daily during the influenza season or licensed
trivalent inactivated influenza vaccine in October/November. The ratio will be 4:1; that is, four
subjects will receive zanamivir prophylaxis for every person who receives influenza vaccine.
The study will be submitted for review by the institutional review board of the Mount Sinai
Hospital and any other participating institutions, as well as to the Therapeutic Products
Directorate before September 10, 2008.

4.2 Study population:

Subjects will be 18-69 year old residents of Ontario who meet all inclusion/exclusion criteria.
Recruitment will be directed primarily to healthcare workers, although up to 10 subjects may be
other healthy adults. Specifically, healthcare workers will be primarily recruited from among
employees and other workers (e.g. physicians) at Mount Sinai Hospital in Toronto. Recruitment
will occur via the Mount Sinai intranet, emails, and information pamphlets sent via the internal
mail or attached to pay stubs. Recruitment for non-staff healthy adults will also occur via posters
in Mount Sinai.
4.2.1 Inclusion criteria:
1. Aged 18 to 69 years inclusive, as of November 1, 2008. 2. Have an understanding of the study, agree to its provisions, and give written informed 3. Available for follow-up during the study period. 4. Employed full- or part-time (>8 hours per week), or a full- or part-time student. 5. If a woman of child-bearing years, must meet one of the following criteria: a. be surgically sterile; b. agree to be abstinent from November 1, 2008 until completion of the study c. be using oral contraceptives or some other form of hormonal birth control (e.g. transdermal patches) from start to completion of study drug administration; d. be using an intrauterine device from start of the study to completion of study drug e. both partners are using barrier protection; that is the male partner uses a condom, and the female uses a diaphragm, a female condom, or vaginal foam, from start of the study until study medication is complete.
____________________________________
PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 4.2.2 Exclusion criteria:
1. Allergic to any components of influenza vaccine or zanamivir. 2. Previous serious adverse events associated with influenza vaccination such that influenza 3. Received any influenza vaccine after March 1st, 2008 and before study start. 4. Previous serious adverse events associated with the use of antiviral medications. 5. Expecting to be unable to take zanamivir for more than 72 hours during the study period (e.g. major surgery booked or anticipated). 6. Planning to spend more than 2 consecutive weeks outside of Canada or more than 100km from the study site during the study period. 7. Pregnant, or planning to become pregnant, between November 1, 2008 and end of study 8. Planning to be breastfeeding a child under 12 months of age between November 15, 2008 9. Receipt of immunoglobulin within six months of study entry. 10. Immunocompromising condition or therapy that would be expected to reduce the efficacy a) HIV infection; b) lymphoma, multiple myeloma, leukemia or other blood dyscrasia; c) systemic lupus erythematosis or other connective tissue disorder; d) renal failure (baseline serum creatinine >150uM, or requires dialysis); e) nephrotic syndrome; f) active neoplastic disease (except localized skin cancer); g) any requirement for corticosteroids >20mg/day for >1 week in the six months h) cytotoxic therapy (e.g. chemotherapy for cancer) received within the six months i) radiation therapy received in the six months prior to randomization; j) hemoglobinopathy; k) any immunodeficiency disorder; or l) prior solid organ or allogeneic stem cell or bone marrow transplant. 11. Plans to receive cytotoxic therapy or radiation therapy during the study period. 12. History of cardiovascular or pulmonary disease that has required hospital admission within 13. History of asthma or other chronic respiratory disease. 14. Participating in a trial that will result in the receipt of investigational medication during the period that zanamivir may be taken (i.e. November 15, 2008 to May 31, 2009).
4.3 Removal of subjects from treatment or assessment

Subjects may withdraw their consent to participate at any time without prejudice. Subjects who
are to receive zanamivir and who wish to withdraw from the study medication for any reason, or
who discontinue the medication due to an adverse event, will be offered vaccine but will be
asked to continue to be followed as per the study protocol. They will also be asked to have blood
drawn for antibody titres on the day of vaccination, and two weeks later. Investigators may also
withdraw a subject from the study if, in the investigator’s best clinical judgment, it is in the best
interest of the study subject to be withdrawn.
____________________________________
PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 4.4 Treatments administered
4.4.1 Study vaccine
The vaccine to be used in the study will be any one of the two split virus vaccines licensed in
Canada (Fluviral® or Vaxigrip®), depending on what is supplied to the study pharmacies from
the Ontario Ministry of Health.
Vaccine will be administered intramuscularly into the deltoid muscle of either arm, using a 1½
inch needle.
4.4.2 Study medication
Medication to be used in this study will be standard, commercially available inhalant containing
10mg zanamivir. Zanamivir will be packaged for each subject in packages containing either 20
or 40 days’ supply. Each package will be labelled with the study title, “zanamivir 10mg, 20 (or
40) doses”, the name of the subject, the date of packaging and expiry, and the dates during which
medication in the package should be used.
The first package of study medication will be dispensed during a study visit at the onset of
influenza season (see section 4.4.3). The second package will be dispensed at the study visit 4-6
weeks after the start of prophylaxis. The third package will be dispensed at the visit 9-11 weeks
after the start of prophylaxis. Remaining medication will be returned at the end of the study.
4.4.3 Determination of the start and end of influenza season
The start of influenza season will be defined by the influenza activity and three study
investigators (AM, JK, and ML) based on FluWatch reports from other areas of Canada and the
world, and influenza outbreak activity and laboratory reporting from local virology laboratories.
In general, it will be the first week after the rate of influenza identified from respiratory
specimens is >3% for one week or >2.5% for two consecutive weeks. However, this guideline
may be overridden by the investigator group.
Study medication and follow-up will continue until the proportion of respiratory specimens
yielding influenza is below 2% for 2 consecutive weeks.

4.4.4 Blinding
Study participants and investigators will not be blinded. However, technologists performing all
laboratory tests will be blinded to subject allocation. In addition, the interpretation of serologic
results will be performed in a blinded fashion.

4.4.5 Prior, concomitant, and disallowed therapy
During the study, use of prescription, over the counter, and natural/herbal medications is
permitted. Use of all of these medications will be recorded at the first study visit, and any change
in medication or new medication will be recorded using weekly diaries.
____________________________________
PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 Subjects may not be enrolled if the use of an investigational medication is planned or likely
during the period that study medication will be taken. During the course of the study, if a subject
elects to enter another study for any reason (e.g. treatment of a newly identified cancer), the
subject, their attending physician, and the three investigators (AM, JK, and ML) may agree to
permit them to continue in the study if it is deemed best for the subject.
Should a vaccinated subject be involved in an outbreak for which antiviral prophylaxis is
recommended (usually either medication OR vaccine is required; however, in a year in which
vaccine antigen and infecting strain may be mismatched, prophylaxis may be recommended for
vaccinated persons), subjects who have received vaccine will take antiviral prophylaxis as
recommended.
4.4.6 Treatment compliance

Adherence to zanamivir will be assessed by:
1. self-report during weekly diaries; and 2. count of doses of zanamivir returned at exit interview.
4.5 Monitoring of acute respiratory illness during the study
4.5.1 Clinical assessment
All study subjects will report to the study once weekly. This will be done by web data entry. Any
report of fever or acute respiratory symptoms will be followed-up. Subjects will also be asked to
call the study immediately if they have symptoms of acute respiratory illness (at least two of
runny or stuffy nose, sneezing, sore or scratchy throat, hoarseness, or cough) or fever.
Every attempt will be made to obtain a nasopharyngeal (NP) or nasal swab from each ill subject
within 24-48 hours of the onset of acute respiratory symptoms or unexplained fever. When this is
not possible, self-obtained nasal swabs will be obtained, and/or NP swabs will be obtained
between 48 and 96 hours after symptom onset.
With each acute respiratory illness, subjects will record severity of symptoms daily until all
symptoms scores have been mild or none for 2 consecutive days. Visits to healthcare providers,
and use of prescription and non-prescription medication will also be recorded.
4.5.2 Laboratory testing
All NP and nasal swabs will be processed in the MSH laboratory, which will use PCR for
detection of influenza A and B. Viral culture will also be performed. An aliquot of each
specimen will be frozen for future testing. If situations arise in which the results of PCR testing
cannot be made available within 24 hours of testing, a rapid antigen method (either direct
fluorescent antigen or enzyme immunoassay, depending on availability) will be used as a rapid
diagnostic test.
All viral isolates will be saved. Upon completion of the study, all influenza isolates will be tested
for resistance to adamantanes and neuraminidase inhibitors.
____________________________________
PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 Serum will be drawn on day 0, two weeks post vaccination (for those receiving vaccine only) or
at visit #3 (for those receiving antiviral medication), mid season (visit #5), and end of study (visit
#6). This blood will be used for the measurement of antibodies to influenza to detect
asymptomatic infection.
4.5.3 Treatment of influenza
If influenza is diagnosed by rapid testing or PCR in a vaccinated study subject, they will be
offered therapy with zanamivir. If they elect to be treated, zanamivir will be prescribed (10 mg
bid x 5 days). If influenza is diagnosed in a subject taking zanamivir, they will be offered
treatment with oseltamivir (75 mg bid x 5 days). (These recommendations may be changed if
additional information becomes available during the study about antiviral resistance).
4.5.4 Completion of pilot study assessment
At the end of the study, participants will be asked to repeat the data collection from their baseline
assessments. There will also be a 30-40 minute interview in which subjects will be asked about
the ease and comfort of study procedures and about any changes they would recommend to the
study procedures. Finally, the data from their baseline and exit data collected related to influenza
exposure variables will be reviewed with them to elicit potential reasons for any discrepancies.
5.0 OUTCOMES
The overall goal of the pilot is to assess all study procedures and data collection forms.
Outcomes of particular interest will be:
(i) adherence to zanamivir over time during a 10-23 week period (ii) number and description of adverse events associated with zanamivir (iii) number and description of adverse events associated with influenza vaccine administration (iv) number and rate of reported acute respiratory illness episodes, proportion of episodes of acute respiratory illness in which an NP or nasal swab is obtained, and proportion in which this swab is obtained within 48 hours of symptom onset (v) rates of adherence to study reporting procedures (vi) rate of withdrawal from the study, and (vii) whether four serological measurements is adequate to determine influenza infection. 6.0 SAFETY
6.1 Safety at study enrolment
Influenza vaccine is known to have reduced efficacy in immunocompromised persons and the
elderly, and expert recommendations suggest that seasonal antiviral prophylaxis might be
considered for such persons (although no medication is licensed in Canada for seasonal
prophylaxis). Thus, immunocompromised persons and those 70 years of age and over will be
excluded from the study. In a year in which there is mismatch between vaccine antigen and
infecting influenza strains, antiviral prophylaxis may be recommended for patients with
____________________________________ PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 relatively normal immune systems at particularly high risk of influenza complications. For these
reasons, persons with severe cardiopulmonary disease will be excluded from the study.

Every effort will be made during the enrolment process to emphasize that non-adherence with
antiviral prophylaxis will result in lack of protection from influenza. Potential subjects will also
be warned that if they are taking zanamivir for prophylaxis and withdraw from the study,
protection against influenza will not start for several days after vaccination, and not be adequate
for 10-14 days (note that seasonal prophylaxis will be deliberately started early in the season, so
that those who do not tolerate medication can be vaccinated before the season is truly underway).
Subjects will be advised to contact the principal investigator immediately if they experience
wheezing, shortness of breath, or other signs of bronchospasm.
6.2 Safety considerations during the study

A urine pregnancy test will be performed on all women of child-bearing potential before they
start on the study drug.

Subjects who cannot tolerate zanamivir will be offered vaccine but will remain in the study for
follow-up.

For the duration of the study, the weekly diaries will solicit any serious adverse events and any
events thought by the subject to potentially be due to study medication. Any subject experiencing
wheezing, shortness of breath, or other signs of bronchspasm will be advised to discontinue
medication and to call the principal investigator immediately.
6.3 Solicited local and systemic reactogenicity to influenza vaccine
Subjects who are vaccinated will be asked to document local and systemic reactions daily for one
week following vaccination. A centimetre ruler will be provided for measurement of
redness/swelling at the injection site.
6.4 Solicited adverse events associated with study medication
For the first week on study medication and the week after the mid-influenza season study visit
(approximately week 7 of study medication), subjects will be asked to document all potential
medication side effects daily.
7.0 STUDY PROCEDURES

Potential study subjects will be interviewed to inform them of the study purpose, design,
methods, procedures, requirements, and potential risks and benefits. Individuals who continue to
express an interest will be screened for eligibility. Those who are eligible will be asked if they
wish to enroll in the study. After providing informed consent, those who are willing will
participate in the study, as described in the following pages.
STUDY VISIT 1 (Day 0):
____________________________________
PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 • Obtain informed consent • Collect baseline information (abbreviated medical history, current medication list, information about exposure to children, exposure to the general public, exposure to patients with respiratory illness) • Obtain unique study number • Provide subject with study binder (includes study description, copy of informed consent, contact telephone numbers/e-mail, nasal swabs and mailing information) • Review study procedures and scheduled visits • Obtain contact information for notification of onset of influenza season and study • Obtain study blood work
• Provide vaccine if subject to receive vaccine
• Have subject complete first daily diary entry
• Book study visit #2 (vaccine group only)
Week 1:
• Monitor completion of daily diary in subjects receiving vaccine • Contact subjects with any reports of serious adverse events • First weekly study email re: illness during the week, completion of daily and/or weekly diaries, reporting of any adverse event STUDY VISIT 2 (Day 14, Window -1 to +5):
Vaccine group only

• Review diary entries for completeness, correctness
• Check for problems with study reporting
• Review study procedures for weekly diaries and reporting illness
• Obtain study blood work (5mL serum)
Contact between study visit 2 and visit 3
• Weekly diaries for illness, medical visits, serious adverse events • Weekly study email re: diaries and reporting of illnesses or adverse events • If acute respiratory illness or unexplained febrile illness develops: o Study visit to obtain NP or nasal swab for PCR and culture (nasal swab if o Daily diary until symptoms have abated
o Treatment offered if influenza diagnosed


STUDY VISIT 3 (Start of influenza season, Window day 0 to + 13 days):
Antiviral prophylaxis group only
*NOTE: Subjects to receive vaccine, will continue through the vaccination season with weekly
reporting. Their next study visit will be visit #4, for mid-season blood work.
____________________________________ PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 When the influenza season starts, subjects who are to receive zanamivir will be asked to book an
appointment to pick up their study medication. Every effort will be made to ensure that subjects
are started on antiviral prophylaxis within 6 days of notification (study visits will be available
evenings and weekends); however, if subjects are on holiday or unavailable, antiviral dispensing
will begin as soon as possible but may be at any time after season start.


Visit procedures:
• Review any problems with weekly reporting of illness
• Review data from weekly diaries
• Review on-going study procedures
• Perform urine pregnancy test
• Obtain early season blood work
• Dispense first package of study medication (40 days)
• Have subject self-administer first dose prophylaxis and complete first daily medication
• Book study visit #4

Week 1 of study medication
• Monitor completion of daily diary • Contact subjects with any reports of serious adverse events or reports of Contact between study visit 3 and 4
• As previously, for illness
• Weekly study email re: diaries and reporting of illnesses or adverse events
• If unable to tolerate study medication, vaccination offered (see section 4.3), and
blood drawn day 0 and 14 post-vaccination STUDY VISIT 4 (Day 30-35 after start of study medication; Window: days 24-38):
Both groups
– (note: if visit 4a is needed, prophylaxis group needs two visits, vaccine group
requires only visit #4a)

• Dispense second medication package (40 days), check medication adherence • Review data from weekly diary entries • Review study procedures • Check for serious adverse events, unreported respiratory illness • Draw mid-season blood work Study visit 4a (Required if season starts more slowly than expected, and mid-season
blood work is not appropriate at study visit 4)

• Review data from weekly diary entries
• Review study procedures
• Check for serious adverse events, unreported respiratory illness
• Draw mid-season blood work

Week 6-7 of study medication (one week period, starting after visit 4)

____________________________________ PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 • Monitor completion of daily diary • Contact subjects with any reports of serious adverse events • Contact subjects more than 2 weeks late with diary entries Contact between study visit 4 and 5
• As previously, for illness
• Weekly study email re: diaries and reporting of illnesses or adverse events
• If unable to tolerate study medication, vaccination offered (see section 4.3), and
blood drawn day 0 and 14 post-vaccination
STUDY VISIT 5 (Day 70-80 after start of study medication; Window: day 65-84:
Antiviral prophylaxis group only

• Dispense third medication package (either 1 or 2 – 20-day refills)
• Review data from weekly diary entries
• Review study procedures
• Check for serious adverse events, unreported respiratory illness

Contact between study visit 5 and 6
• As previously, for illness
• Weekly study email re: diaries and reporting of illnesses or adverse events:
• If unable to tolerate study medication, vaccination offered (see section 4.3), and
blood drawn day 0 and 14 post-vaccination • Study visit 5a may be booked for prophylaxis group to dispense additional STUDY VISIT 6 (2-3 weeks after end of influenza season):
Both groups

• Review data from weekly study contact
• Check for serious adverse events, unreported respiratory illness
• Collect final package of study medication
• Draw end-of-study blood work
• Complete exit interview
8.0 SAMPLE SIZE
This is a pilot study meant to determine the feasibility of study procedures.
We estimate that the rate of acute respiratory infection will be 0.8 per 100 study days during the
influenza season: with 100 participants and a 13 week season, this results in an estimated 72
infections (95% CI: +/- 8) in 4,550 days. We anticipate that 1 to 2% of subjects will not be able
to tolerate zanamivir, with 80 subjects, 1 to 2 subjects (95% CI +/- 0.5) will likely have to
discontinue zanamivir.
9.0 REFERENCES
____________________________________ PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 1. Hota S, McGeer A. Antivirals for the control of influenza outbreaks. In press, Clin Infect 2. Schanzer DL, Tam TW, Langley JM, Winchester BT. Influenza-attributable deaths, Canada 1990-1999. Epidemiol Infect. 2007 Feb 19:1-8 [Epub ahead of print]. 3. Kilbourne ED. The epidemiology of influenza. Chapter 10 in Kilbourne, ED. Influenza. Plenum Medical Book Company, New York, 1987. pp 255-89. 4. Fox, JP, Hall CE, Cooney MK, Foy HM. Influenza virus infections in Seattle families. 1975-1979 I. Study design, methods and the occurrence of inflections by time and age. American Journal of Epidemiology, 1982 Aug; 116(2): 212-27. 5. Reyes F, Macey J, Aziz S. Influenza in Canada: 2005-2006 season. CCDR 2007; 33(03): February 1, 2007. Available at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/07vol33/dr3303ea.html. 6. Influenza season in 2007 for Australia and New Zealand. WHO Collaborating Centre for Reference and Research on Influenza. Available at: http://www.influenzacentre.org/index.html. 7. Fluwatch (reports from Canadian influenza surveillance system). Available at: http://www.phac-aspc.gc.ca/fluwatch/index.html. 8. National Advisory Committee on Immunization. Statement on Influenza Vaccination for the 2007-2008 Season. 2007; 33: ACS7. Available at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/07vol33/acs-07/index_e.html. 9. World Health Organization. Recommended composition of influenza virus vaccines for use in the 2007-2008 influenza season. Geneva, 2007. Available at: http://www.who.int/csr/disease/influenza/20078anorthreport.pdf. 10. Jefferson TO, Rivetti D, Di Pietrantonj C, Rivetti A, Demicheli V. Vaccines for preventing influenza in healthy adults. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD001269. DOI: 10.1002/14651858.CD001269.pub3. 11. Rivetti D, Jefferson T, Thomas R, Rudin M, Rivetti A, Di Pietrantonj C, Demicheli V. Vaccines for preventing influenza in the elderly. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004876. DOI: 10.1002/14651858.CD004876.pub2. 12. Jefferson T, Demicheli V, Rivetti D, Jones M, Di Pietrantonj C, Rivetti A. Antivirals for infleunza in healthly adults: systematic review. Lancet 2006; 367: 303-313. 13. Advisory Committee on Immunization Practices. Recommendations on the prevention of influenza 2007. MMWR 2007; 56 (RR06); 1-54. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5606a1.htm 14. Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med. 2005 Sep 29; 15. CDC Health Alert. January 14, 2006, 3:25 PM EST. CDC Recommends against the Use of Amantadine and Rimantadine for the Treatment or Prophylaxis of Influenza in the United States during the 2005–06 Influenza Season. Available at: http://www.cdc.gov/flu/han011406.htm. 16. Public Health Agency of Canada. FluWatch Report, June 17, 2007 to June 30, 2007 (Week 25 & 26). Available at: http://www.phac-aspc.gc.ca/fluwatch/06-07/w25_26_07/index.html. 17. Hayden F, Belshe R, Villaneuva C, et al. Management of influenza in households: a prospective randomized comparison of osetltamivir treatment with or without post-exposure prophylaxis. J Infect Dis 2004; 189: 440-9. ____________________________________ PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 18. Hayden FG, Gubareva LV, Monto AS, et al. Inhaled zanamivir for the prevention of influenza in families. N Engl J Med 2000; 343: 1282-9. 19. Welliver R, Monto AS, Carewicz O, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA 2001; 285: 748-54. 20. Monto AS, Robinson DP, Hierholcher ML, et al. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA 1999; 282: 31-5. 21. Monto AS, Pichchero ME, Blanckenberg SJ et al. Zanamivir prophylaxis: an effective strategy for the prevention of influenza types A and B within households. J Infect Dis 2002; 186: 1582-8. 22. Peters PH Jr, 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: 1025-31. 23. Ambrozaitis A, Gravenstein S,van Essen GA, et al. Inhaled zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population. J Am Med Dir Assoc. 2005 Nov-Dec; 6(6): 367-74. 24. Hayden FG, Atmar RL, Schilling M, Johnson C, Poretz D, Paar D, Huson L, Ward P, Mills RG. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza N Engl J Med. 1999 Oct 28; 341(18): 1336-43. 25. Harrod ME, Emery S, Dwyer DE. Antivirals in the management of an influenza pandemic. Med J Aust. 2006 Nov 20; 185(10 Suppl): S58-61. 26. Hayden FG, Pavia AT Antiviral management of seasonal and pandemic influenza. J Infect Dis. 2006 Nov 1; 194 Suppl 2: S119-26. 27. Gardam M, Liang D, Moghadas SM, Wu J, Zeng Q, Zhu H. The impact of prophylaxis of healthcare workers on influenza pandemic burden. J R Soc Interface. 2007 Aug 22; 4(15): 727-34. 28. Lee VJ, Chen MI. Effectiveness of neuraminidase inhibitors for preventing staff absenteeism during pandemic influenza. Emerg Infect Dis. 2007 Mar; 13(3): 449-57. 29. Skowronski DM, Masaro C, Kwindt TL, et al. Estimating vaccine effectiveness against laboratory-confirmed influenza using a sentinel physician network: results from the 2005-2006 season of dual A and B vaccine mismatch in Canada. Vaccine. 2007 Apr 12; 25(15): 2842-51. Epub 2006 Oct 16. ____________________________________ PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008
APPENDIX I: SYNOPSIS OF PROPOSAL FOR PLANNED FUTURE RANDOMIZED
CONTROLLED TRIAL
Title:
A double-blind, double-dummy, randomized controlled trial to compare trivalent split
virus influenza vaccine to seasonal antiviral prophylaxis in healthcare workers and other healthy
adults in a year with predicted vaccine antigen/infecting strain mismatch.

Hypothesis:
That in a year with mismatch between influenza vaccine antigen and infecting H3N2 strain,
seasonal (10-13 weeks) antiviral prophylaxis in adults will provide better protection from
symptomatic influenza infection than trivalent inactivated split virus influenza vaccine.
Primary objective:
1. To compare the efficacy of standard influenza vaccine and seasonal (10-13 weeks) antiviral prophylaxis in preventing symptomatic influenza infection in adults during an influenza season with mismatch between influenza vaccine antigen and infecting H3N2 strain.
Secondary objectives:

1. To compare the efficacy of standard influenza vaccine and seasonal antiviral prophylaxis against symptomatic influenza infection in adults during an influenza season in which mismatch between vaccine and infecting influenza strains is expected to occur. 2. To compare days of acute respiratory illness, days of febrile respiratory illness, and days of missed work/school due to acute respiratory illness in vaccinated adults versus those receiving seasonal antiviral prophylaxis. 3. To assess the safety and tolerability of 10-13 weeks of seasonal antiviral prophylaxis in 4. To compare rates of and risk factors for influenza infection in healthcare workers and 5. To compare rates of acute respiratory illness in household contacts of healthcare workers. 6. To assess rates of asymptomatic influenza infection in persons prescribed seasonal 7. To assess issues surrounding the logistics of delivery of antiviral prophylaxis to healthcare workers during the next influenza pandemic. Study period: October 15 to April 30 of the next mismatch year
Design: Randomized, double-blinded trial

Study sites:
Five to ten hospitals; two other workplaces in Canada

Sample size:
Total number of enrolled subjects: 1325. Powered to distinguish an expected rate
of symptomatic infection of 9% in the vaccine group and 4.5% in the prophylaxis group
(alpha=0.05, power 80%) with a 20% drop out rate.
____________________________________ PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 Population: 60-80% healthcare workers (persons who work in healthcare institutions, or who
provide healthcare to patients outside institutions) or healthcare professional students; 20-35%
other employed adults or students in practical training.
Inclusion criteria:
1. Aged 18 to 69 years inclusive, as of November 1st of the next mismatch year 2. Have an understanding of the study, agree to its provisions, and give written informed 3. Available for follow-up during the study period 4. Employed full or part time (>8 hours per week), or a full or part-time student 5. If a woman of child-bearing years, must meet one of the following criteria: a) Be surgically sterile b) Agree to be abstinent from November 1st of the next mismatch year until c) Be using oral contraceptives or some other form of hormonal birth control (e.g. transdermal patches) from start to completion of study drug administration d) Be using adequate barrier protection (e.g. IUD, double barrier such as condom and diaphragm or diaphragm with spermicidal gel of foam) as birth control from the start of the study until study medication is complete.
Exclusion criteria:
1. Allergic to any components of influenza vaccine or to the antiviral medication 2. Previous serious adverse event associated with influenza vaccination, such that influenza 3. Received any influenza vaccine after March 1st of the next mismatch year and before 4. Expecting to be unable to take antiviral prophylaxis for more than 72 hours consecutively during the study period (e.g. major surgery booked or anticipated) 5. Planning to spend more than 2 consecutive weeks outside of Canada or more than 100km from the closest study site during the study period 6. Pregnant, or planning to become pregnant during the season 7. Planning to be breastfeeding a child <1 year of age between November 15th of the next mismatch year and the end of the study period 8. Receipt of immunoglobulin within six months of study entry 9. Immunocompromising condition or therapy that would be expected to reduce the efficacy a) HIV infection b) Co-existing: lymphoma, multiple myeloma, leukemia, or other blood dyscrasia c) Systemic lupus erythematosis or other connective tissue disorder d) Renal failure (baseline serum creatinine >150uM, or requires dialysis) e) Nephrotic syndrome f) Active neoplastic disease (except localized skin cancer) g) Any requirement for corticosteroids >20mg/day for >1 week in the six months h) Cytotoxic therapy (e.g. chemotherapy for cancer) received within the past six i) Radiation therapy received in the past six months j) Hemoglobinopathy ____________________________________ PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 k) Any immunodeficiency disorder l) Prior solid organ or allogeneic stem cell or bone marrow transplant 10. Plans to receive cytotoxic therapy or radiation therapy during the study period 11. History of cardiovascular or pulmonary disease that has required hospital admission 12. Participating in a trial that will result in the receipt of investigational medication during the period that antiviral prophylaxis may be taken
Methodology
This will be a double-blind, double dummy, randomized controlled trial. Potential study subjects
will be informed of the study purpose, design, methods, procedures, risks, and benefits. After
being screened for eligibility, subjects who provide written, informed consent will be enrolled.
Study participants will be randomized to receive either trivalent split influenza virus vaccine (as
provided by respective provincial Ministries of Health) plus placebo study medication, or sterile
normal saline injection plus active antiviral prophylaxis. The study injection will be received in
October or November of the next mismatch year. When the influenza season starts, subjects will
start taking study medication. This will be continued for 13 weeks, or until the season is over
(whichever is shorter). Serum for measurement of anti-influenza antibodies will be drawn at
baseline, 2-3 weeks after injection, mid-influenza season, and at the end of the study. Weekly
study reporting will occur during the study, and all acute respiratory illness will be assessed, with
nasopharyngeal or nasal swabs obtained for influenza PCR and culture.

Primary outcome:
Laboratory confirmed influenza infection (fourfold increase in antibody titer
from blood drawn two weeks post injection and end of study period, or positive laboratory test
for influenza during the study).

Secondary outcomes:
• Laboratory confirmed, symptomatic influenza infection
• Acute febrile respiratory illness
• Rate of discontinuation of medication due to side effects
• Rate of reported adverse events to vaccination
• Adherence to antiviral prophylaxis (measured as percent of capsules taken within 24 hours of

Analyses:
The primary analysis will be a modified intention-to-treat analysis, which will include all
patients who have adequate adherence to the initial regimen, and for whom any antiviral
prophylaxis is dispensed.
Safety: A safety monitoring board will be appointed. This board will have access to blinded
data, and the capacity to unblind if they deem it necessary. Their role will be to monitor:
rates of symptomatic influenza infection They will have the authority to stop the trial if they deem continuing unsafe. They will also be responsible for assessing whether the study will need to be terminated at week 12-13. ____________________________________ PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 Ethics:
This protocol will be approved by the research ethics board of all participating hospitals.
Influenza vaccine is strongly recommended for healthcare workers and close contacts of persons
at risk of complications of influenza (e.g. children under the age of two years, adults over 65
years of age, and those with chronic underlying illnesses). There is good evidence that
vaccination of healthcare workers working in long term care facilities for the elderly reduces
mortality in patients they care for. However, only about 50% of healthcare workers receive
influenza vaccine annually, so that it is not currently standard of care for persons at risk to
receive care from vaccinated providers.
Nonetheless, in research studies, the standard of protection for subjects who are healthcare
workers (and their patients) is that provided by inactivated influenza vaccine. The protective
efficacy of vaccine against influenza has been studied extensively, and recently summarized in a
Cochrane review (10). In years in which vaccine antigen is well matched to the major infecting
strains of influenza, the efficacy of influenza vaccine against symptomatic influenza is 80%
(95% CI, 56-91%) (10). In years in which the vaccine is not well matched, the efficacy against
symptomatic influenza is 50% (95% CI 27-65%). The proposed alternative to vaccine in this
study is seasonal antiviral prophylaxis. “Seasonal” oseltamivir prophylaxis has been studied in
healthy adults in one randomized controlled trial. This trial did not include an entire season, but
rather, a six week period during the 1999-2000 season. Overall, 1599 unvaccinated subjects were
randomized to oseltamivir (75 or 150 mg/day) or placebo. The protective efficacy of oseltamivir
against symptomatic influenza was 74% (95% CI 53- 88%), and against culture-confirmed
disease was 82% (95% CI 60-93%) (24). In this study, 90% of subjects took >90% of their
prescribed doses of medication (24).
In a well-matched year, then, it is most likely that vaccination and antiviral prophylaxis are
approximately equivalent in their efficacy against influenza. However, confidence intervals are
relatively wide, so that a true difference may exist; it is not possible to determine which would be
more efficacious. For the small proportion of influenza (perhaps 10-15%) that occurs outside of
the regular influenza season, vaccine will offer protection, but seasonal prophylaxis will not. In
addition, if adherence to medication is poor, then the probability that vaccine is more efficacious
increases. On balance, then, vaccine is favoured.
In a year in which the vaccine strain is, or may be, poorly matched to the major infecting antigen,
the balance shifts significantly away from vaccine, and may favour seasonal antiviral
prophylaxis. Whether antiviral prophylaxis will be favoured depends on the degree of mismatch,
the distribution of influenza infections (proportion in season and out-of-season, by infecting
type), and adherence to the prophylaxis regimen. The former two are not known before the
season starts, and the latter has not been studied in healthcare workers (although it is likely to be
high). Because the degree of mismatch is not known before the season is over, and because
vaccine retains substantial efficacy, experts do not currently recommend adding seasonal
prophylaxis to vaccine for healthy adult healthcare workers even when a mismatch season may
occur.
Over the next few years, it is likely that we will be able to assess mismatch during the season, or
even before the season starts. This ability will create significant challenges related to adjunctive
____________________________________
PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008 use of antivirals. If vaccine efficacy is low enough, seasonal prophylaxis for high risk persons and healthcare workers, despite its cost, may be an option that should be considered. In the next mismatch year, the antigens of a significant fraction of strains will not match the antigens contained in the vaccine. Vaccine efficacy will likely be reduced, and prophylaxis may be more effective than vaccination in that influenza season. Therefore, it is reasonable, for the next mismatch influenza year, to compare the efficacy of influenza vaccine (standard of care) with antiviral prophylaxis. A number of precautions will be put in place to ensure protection of healthcare workers and other participants from the impact of influenza: (i) A data safety monitoring board will monitor rates of infection in the two treatment arms, (ii) If subjects are involved in an outbreak in which mismatch is suspected, and antiviral prophylaxis is recommended, they will discontinue study medication for the outbreak duration so that they can take active antiviral prophylaxis. (iii) Subjects who cannot comply with weekly reporting before influenza season starts (and who might therefore be less adherent to study medication) will be withdrawn from the trial and offered vaccine at the onset of influenza season. (iv) All healthcare workers with acute respiratory illness will be offered influenza testing, and those who have influenza will be offered treatment. Every effort will be made to have this testing done and results available within 48 hours of onset of symptoms. ____________________________________ PILOT - Vaccine vs. seasonal antiviral prophylaxis Protocol for 2008 pilot, v2, August 19, 2008

Source: http://www.idresearchmsh.com/stopflu/protocol.pdf

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