Oseltamivir Randomised Controlled Efficacy Trial
Information source: International Centre for Diarrhoeal Disease Research, Bangladesh
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Influenza; Pneumonia; Lower Respiratory Tract Infection; Upper Respiratory Tract Infection; Viral Shedding
Intervention: Oseltamivir (Drug); Placebo (Drug)
Phase: Phase 3
Status: Completed
Sponsored by: International Centre for Diarrhoeal Disease Research, Bangladesh Official(s) and/or principal investigator(s): W. Abdullah Brooks, MD, MPH, Principal Investigator, Affiliation: International Centre for Diarrhoeal Disease Research, Bangladesh
Summary
Background In preparation for a global influenza pandemic, there is an urgent need for
representative data from populations and settings where the pandemic is most likely to
arise. There are no data on oseltamivir efficacy from Asian urban slum populations
concerning duration of illness and viral shedding, nor whether efficacy depends on starting
treatment < 48 hours or ≥ 48 hours after illness onset. Finally, there are no data on the
capacity of the drug, in such settings, to affect household and community transmission
rates.
Aims and Objectives This proposal aims to compare the duration of clinical illness among
patients treated with oseltamivir vs placebo < 48 hours and ≥ 48 hours after illness onset.
It will compare the duration of viral shedding among all treatment groups vs placebo, risk
of transmission to household contacts by treatment group and whether neuraminidase inhibitor
use creates resistance. Secondarily it aims to measure the effect on influenza.
Design and Methods A double-blind placebo controlled clinical trial design among a
population in an urban slum under current influenza disease burden surveillance will be
enrolled. Infection status will be confirmed by rRT-PCR. Patients ≥ 1 year old will be
randomised to < 48 hour and ≥ 48 hour treatment arms. Family members and neighbours will
also be assessed by PCR and a basic reproductive number calculated (R0).
Relevance These findings will address whether oseltamivir can affect illness duration and
severity, affect transmission, incidence and resistance in high risk urban Asian settings
where a pandemic is most likely to arise.
Clinical Details
Official title: Efficacy of Oseltamivir in Reducing the Duration of Clinical Illness, Viral Shedding, and Transmissibility Reduction Within Households Among Participants in an Influenza Disease Burden Surveillance Cohort in Urban Dhaka, Bangladesh
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Duration of clinical illness among patients treated with oseltamivir vs placebo < 48 hours as well as ≥48 hours after illness onsetDuration of viral shedding among all treatment groups vs placebo Compare the risk of transmission to household contacts by treatment group vs placebo The effect of neuraminidase inhibitor use on the emergence of resistance Clinical complications associated with influenza among all treatment groups vs placebo
Secondary outcome: Effect of acute neuraminidase inhibitor treatment on influenza incidence in the populationTransmission of resistant mutations within households Viral shedding in stool and effect of oseltamivir on stool shedding if present
Detailed description:
Purpose Influenza is a disease of global importance, having caused three pandemics in the
20th Century. Although concerns persist about a new pandemic, possibly from an avian
influenza A strain, more people died during the 20th Century from seasonal epidemic
influenza than from any single pandemic, thus global preparedness must address both epidemic
and pandemic influenza. It is generally believed that if a pandemic emerges, an efficacious
vaccine will either not be either generally available or broadly protective. Additional
strategies are required for effective control. Neuraminidase inhibitors, including
oseltamivir, have shown efficacy in limited controlled trials against both human influenza,
and have been used in avian influenza cases. Numerous questions, however, persist about the
extent of their efficacy. These include whether or not they are effective if given after 48
hours post-symptom onset, whether they reduce the duration and titre of viral shedding,
their effect on transmission to household contacts, and how quickly - or even if -
resistance will emerge in a high endemic setting during seasonal use. Finally, clinical
trials to date have used small samples sizes under controlled settings in industrialized
countries. There are no data on the efficacy of neuraminidase inhibitors in over-crowded
urban settings with rates of influenza and other respiratory infections, like Dhaka,
Bangladesh. The findings from this study will enable better assessment of the performance of
neuraminidase inhibitors under the conditions similar to those from which a global pandemic
is likely to occur.
This study will evaluate whether oseltamivir is effective at reducing illness and household
transmission during the seasonal influenza epidemic in a crowded urban setting in Dhaka,
Bangladesh.
Design/Methods This will be a double-blind placebo randomised controlled clinical trial that
will identify study subjects in clinic who present with signs/symptoms suggestive of
influenza. Patients will be screened using a commercial rapid diagnostic test of high
sensitivity and specificity (QuickVue A + B, Quidel, Inc., San Diego, CA, USA), and their
status will be confirmed using RT-PCR. Rapid test-positive patients will be randomised to
oseltamivir or placebo for the standard twice daily, five-day course. A total of 512
PCR-confirmed patients will be recruited and treated. Patients will provide nasopharyngeal
specimens on the day of presentation (day 0), and on days 2, 4 and 7 to determine duration
of viral shedding. All patients will be followed up at home daily by field research
assistants (FRAs), who will monitor their progress using standardised forms, and refer back
to clinic anyone who meets criteria for treatment failure. Once a patient meets criteria for
recovery, they will be referred back to clinic for an exit interview with the physician. At
the end of the study, comparisons will be made between groups on duration of illness,
duration of viral shedding and household and inter-household transmission rates, as well as
whether there were differences between those who started oseltamivir < 48 hour or ≥ 48 hours
from the onset of illness.
1. Requirements for subject population, rationale for use: The influenza virus, once
suspected to primarily attack older persons, is now recognised to cause more illness in
children, particularly those < 5 years. Indeed, both hospitalisation rates, serious
complications, and even mortality among healthy children < 5 years approach those of
older persons with chronic conditions that place them at high risk [1]. Children are
also the most potent spreaders of influenza infection in the community [2]. However, in
order to model the impact of neuraminidase inhibitors on duration of illness, and
especially on intra and inter-household transmission, the entire age spectrum must be
examined, as in the early stages of an epidemic, adults may be among the first to show
infection signs and seek treatment, even though children will be more important in the
spread of the epidemic in its early stages [3].
2. Potential risks, likelihood, seriousness and impact of methodology: The risk is greater
than minimal, in that oseltamivir is not routinely prescribed for influenza infection
in Bangladesh, and as with any licensed drug, there are potential side effects, the
most common being gastrointestinal upset, nausea and vomiting - all of which are rare
but reported, as well as sleep or behaviour disturbances, which are even less common
and not causally linked to oseltamivir. Likewise, nasopharyngeal washes and swabs are
not routinely collected in Bangladesh, and cause minor discomfort during the procedure,
however complications, primarily from nasopharyngeal swabs, such as nosebleeds, are
also uncommon. There are no alternatives to these procedures for these samples, which
are needed to document whether a person had influenza and for how long.
3. Procedures for minimising risks, effectiveness assessments: 1) All physicians have been
trained on the procedures for specimen collection, as this has been ongoing in
Kamalapur since 2004. A refresher course will be provided to all study physicians prior
to the new study to ensure correct procedure. 2) All physicians will be trained about
potential side effects, and will relate these to the patients and their caregivers, as
they currently do with any medication. 3) FRAs will be trained to look for signs of
illness as well as complications to the medication during their daily home visits, and
will refer back to clinic any patient with signs suggestive of complication (e. g. skin
rash, repeated vomiting).
4. Confidentiality and anonymity: All patient information, which is recorded on a case
report form, (CRF) will be kept in a locked cabinet. Only project staff will see it.
Patients' name and other potential identifiers will be removed from data shared in
public fora. Published data will be aggregated and anonymised.
5. Description of consent procedures: One consent form will be for household consent for
participation in weekly home visits for influenza surveillance, and collection of
samples for rapid diagnostics (nasal swab) and nasopharyngeal wash or nasopharyngeal
swab specimens for index cases, and for subsequent household suspected cases (Household
consent, Appendix 1), This form will be obtained by the field research assistant (FRA),
as are all surveillance forms used in Kamalapur. This is the same format as the current
influenza surveillance for children < 5 years of age. The FRA will read the consent
form in its entirety to any responsible adults (those with legal responsibility for the
children in the home, or if there are no children, for home itself) in the home, and
answer their questions using standardised responses (key points). The second consent
form will obtain consent for the index case to receive antiviral or placebo
administration, and to provide subsequent NPW or NPS specimens on days 2, 4 and 7
(Oseltamivir Study, Appendix 2). A study physician will obtain this consent form in
clinic. If the subject (index case) is an adult (age ≥ 18 years), consent will be
obtained from the subject himself/herself; if the subject is a child, consent will be
sought from his/her parents or legal guardian. The Oseltamivir study consent form
readability score is Flesh-Kincaid Grade level = 7. 8. An Assent form will be read to
children aged 7-14 years. The Assent form readability score is Flesh-Kincaid Grade
level = 5. 6. The methodology of obtaining consent for both forms will be standardised.
The FRA using the home visits consent form, or the study physician using the antiviral
administration form, will read the entire consent form to the patient or parent if the
patient is a minor, as this is an illiterate population. If parents have questions, the
study physician will provide clarification of the consent form from a standardised set
of key points that cover each section of the consent form. Patients, or parents if the
patient is a minor, who indicate that they understand and agree to the terms of the
study will be asked to provide written consent. If they cannot sign the form, a thumb
impression will be taken.
6. Interviews: The only interviews will be those conducted in the home by the FRA to
either screen for illness or follow-up ill patients at home, and will focus on illness
signs using standardised screening calendar questionnaires or follow-up questionnaires.
The other interviews occur in clinic with the study physician, and again focus on
history of present illness, past medical history, physical exam, follow-up and an exit
interview, as described above. These physician-patient interviews are fundamentally the
same as between any physician and patient, except that they are standardised.
7. Potential benefit to individual and society, risk/benefit: Patients may receive direct
benefit if they receive the treatment drug, including a mild reduction in the duration
of influenza symptoms. In addition, household members of persons treated with
oseltamivir may experience fewer influenza illnesses, if transmission is reduced.
Patients will receive routine medical care regardless of treatment group, even if they
refuse to participate in the study. The daily home follow-up by the trained FRA is
another benefit, as she can help to identify any signs indicating the need for medical
attention. The information collected will be valuable to inform future pandemic
planning in Bangladesh and globally, as there is no information available for this
regimen from the developing world. The potential and real benefits thus outweigh the
potential and real risks.
8. Drug status: Oseltamivir (Tamiflu®) is not an experimental drug, but is US Federal Drug
Administration (FDA) approved, having passed Good Clinical Practices licensing trials,
under the terms for use as in this trial. Furthermore, oseltamivir is manufactured by
Roche Pharmaceuticals, which has a branch in Bangladesh, which currently supplies local
pharmacies with the drug for sale.
9. Experimental new drugs: N/A
10. Placebo, indications for use in the study: In order to objectively demonstrate the
efficacy of the drug on duration of illness specifically, but household transmission
more generally, both patient and observer have to blinded to the intervention, as
knowledge of intervention assignment can affect recorded outcome (observational bias).
Although it is known that oseltamivir affects illness duration under controlled
settings and in settings with lower disease burden than those documented in Dhaka,
Bangladesh, it is not known how effective it will be under these conditions, nor is it
known whether it will work for patients who present later in the illness (≥48 hours).
For this reason, patients will be allocated to a study arm by pre-allotment using block
randomisation, along with the blinding by use of a placebo. No patient will be denied
standard of care, as any focal illness, such as pneumonia, bronchitis, bronchiolitis,
otitis media, sinusitis, or other common complications of influenza and similar
pathogens, will be treated with standard, WHO-recommended or approved regimens.
11. Experimental 'new' drug sponsorship: N/A
12. Use of records, organs, tissues, body fluids, and faetus/abortus: The study will
acquire nasopharyngeal wash and/or swab specimens, the objective of which is to collect
nasopharyngeal epithelial cells, which will be used in cell culture to isolate
influenza virus. The purpose of isolating the influenza virus is to validate whether or
not a patient actually had influenza, and if so, for how long was it shed.
Eligibility
Minimum age: 1 Year.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Persons at least one year old residing in randomly selected households with at least
one major illness sign, or if absent at least two minor illness signs who are rapid
test positive for either influenza A or influenza B.
Exclusion Criteria:
- Persons with a history of non-febrile convulsions or
- Persons who are taking anticonvulsive agents, or
- Persons who have a nonrespiratory comorbid condition requiring immediate medical
intervention, or
- Persons who are pregnant.
Locations and Contacts
Kamalapur Urban Site, ICDDR,B, Dhaka 1000, Bangladesh
Additional Information
Click here for more information about ICDDR,B Click here for more information about seasonal and pandemic influenza
Related publications: Abdullah Brooks W, Terebuh P, Bridges C, Klimov A, Goswami D, Sharmeen AT, Azim T, Erdman D, Hall H, Luby S, Breiman RF. Influenza A and B infection in children in urban slum, Bangladesh. Emerg Infect Dis. 2007 Oct;13(10):1507-8. doi: 10.3201/eid1310.070368. Abdullah Brooks W, Erdman D, Terebuh P, Klimov A, Goswami D, Sharmeen AT, Azim T, Luby S, Bridges C, Breiman R. Human metapneumovirus infection among children, Bangladesh. Emerg Infect Dis. 2007 Oct;13(10):1611-3. doi: 10.3201/eid1310.070337. Brooks WA, Breiman RF, Goswami D, Hossain A, Alam K, Saha SK, Nahar K, Nasrin D, Ahmed N, El Arifeen S, Naheed A, Sack DA, Luby S. Invasive pneumococcal disease burden and implications for vaccine policy in urban Bangladesh. Am J Trop Med Hyg. 2007 Nov;77(5):795-801.
Starting date: May 2008
Last updated: July 11, 2011
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