Evaluating the Use of Oseltamivir for the Treatment of Influenza in Adults
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| ClinicalTrials.gov Identifier: NCT01314911 |
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Recruitment Status :
Completed
First Posted : March 15, 2011
Results First Posted : February 5, 2019
Last Update Posted : February 5, 2019
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Sponsor:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
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Brief Summary:
People who are infected with the influenza virus may develop respiratory illnesses, such as pneumonia, or other life-threatening complications. Currently, there are four antiviral medications that are used to treat influenza. This study will examine one of these medications, oseltamivir, to examine how it affects the shedding of influenza virus in infected people.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Influenza, Human | Drug: Oseltamivir Drug: Placebo | Not Applicable |
Seasonal influenza is responsible for excess hospitalizations and, despite effective antivirals, causes significant morbidity and mortality (about 24,000 deaths each year in the United States alone). The influenza virus that emerged in 2009 (A/California/07/2009 H1N1) caused fewer deaths (12,000 flu-related deaths in the U.S.) but in contrast to seasonal flu, nearly 90% of the deaths with the 2009 H1N1 occurred among people younger than 65 years of age. Although there are four currently licensed anti-influenza medications (amantadine and rimantadine, oseltamivir, and zanamivir), previous studies have not demonstrated conclusively to what extent these medications affect influenza viral shedding. This study will evaluate whether oseltamivir modifies the viral shedding during the treatment of uncomplicated influenza in an adult population and also assess methods to detect viral replication in the upper respiratory tract.
Subjects who presented with an influenza-like illness without any risk factors for severe disease were screened for the study. Those with a confirmatory test for influenza (rapid antigen or polymerase chain reaction [PCR]) were randomized in a 1:1 manner to receive a blinded study treatment consisting of either the oseltamivir or placebo for 5 days. Clinical, virologic, and laboratory assessments on Days 1, 3, 7, and 28 were used for both safety and efficacy analysis.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 716 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | A Randomized Double-Blind Study Comparing Oseltamivir Versus Placebo for the Treatment of Influenza in Low Risk Adults |
| Study Start Date : | April 2011 |
| Actual Primary Completion Date : | November 18, 2017 |
| Actual Study Completion Date : | November 18, 2017 |
Resource links provided by the National Library of Medicine
Drug Information available for:
Oseltamivir
| Arm | Intervention/treatment |
|---|---|
| Experimental: Oseltamivir |
Drug: Oseltamivir
Subjects were prescribed Oseltamivir twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg. |
| Placebo Comparator: Placebo |
Drug: Placebo
Subjects were prescribed the matching placebo twice daily for 5 days, and each dose consisted of one capsule of placebo. |
Primary Outcome Measures :
- Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs at Day 3 -- Team Collected Samples [ Time Frame: At Day 3 ]The central laboratory performed a qualitative PCR test on the NP sample from Day 0 team collected swap in order to confirm influenza infection and to determine the influenza type and subtype. For participants with a positive influenza test result at Day 0 from this qualitative PCR testing, the laboratory then performed qPCR testing of subsequent samples to quantify viral shedding.
Secondary Outcome Measures :
- Number of Participants by Virus Detection Status--Team Collected Samples [ Time Frame: At Day 0, 3 and 7 ]Number of participants who had undetectable values (less than the limit of detection [LOD]), who had values between the LOD and the lower limit of quantification (LLOQ), and who had values ≥LLOQ
- qPCR Viral Shedding -- Team Collected Samples [ Time Frame: At Day 0, 3 and 7 ]Median, 25% and 75% percentile of the value of viral shedding (Results <LOD were imputed as the LOD value, and Results >= LOD, <LLOQ were imputed as the LLOQ value.)
- Number Of Participants Shedding Virus -- Team Collected Samples [ Time Frame: At day 3 and 7. ]Number of participants with undetectable viral load at both Day 3 and Day 7; detectable at Day 3 and undetectable at Day 7; detectable at Day 7 (irrespective of whether or not detectable at Day 3).
- Time to Alleviation of Influenza Clinical Symptoms [ Time Frame: From treatment initiation to Day 28 ]The assessed symptoms were cough, nasal obstruction (stuffy nose), sore throat, fatigue, headache, muscle aches, feverishness, rhinorrhea, nausea, vomiting, diarrhea. Duration of clinical symptoms was defined as the time from Day 0 to the first of two successive measurements at which all clinical symptoms were grade 0 (absent) or 1 (mild). A measurement was considered to be the 8AM or 8PM assessment during Days 0 to 7 (so two measurements were obtained per day) and then the daily assessment thereafter. Time was calculated in half-days through to Day 7. If a subject's first two assessments on (baseline assessment and first subsequent diary card assessment) satisfied this criterion, then the duration was set to zero. For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with symptoms evaluated.
- Time to Absence of Fever [ Time Frame: From treatment initiation to Day 28 ]Fever was considered present based on the diary cards if a subject reported a maximal temperature ≥38.0°C (for the period since the diary card was previously completed) or reported having taken an antipyretic drug (also for the period since the diary card was previously completed). Otherwise, fever was considered not present during the period since the diary card was previously completed, except that the evaluation was considered missing if either the temperature or the antipyretic drug use entry was not completed on the diary card. The duration of fever was defined as the time from Day 0 to the first of two successive assessments (through to Day 7) or to the first assessment (Day 8 onwards) at which no fever was present according to this definition.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with fever evaluated.
- Time to Resolution of All Symptoms AND Fever [ Time Frame: From treatment initiation to Day 28 ]The assessed symptoms were cough, nasal obstruction (stuffy nose), sore throat, fatigue, headache, muscle aches, feverishness, rhinorrhea, nausea, vomiting, diarrhea. Fever was considered present based on the diary cards if a subject reported a maximal temperature ≥38.0°C (for the period since the diary card was previously completed) or reported having taken an antipyretic drug (also for the period since the diary card was previously completed). Time to resolution of all clinical symptoms and fever is defined as the time from Day 0 to the first of two successive measurements at which all clinical symptoms are grade 0 (absent) or 1(mild) and no fever >=38.0 C or antipyretic drug is reported. For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with symptoms and fever evaluated.
- Time to Feeling as Good as Before the Onset of the Influenza Illness [ Time Frame: From treatment initiation to Day 28 ]Time to feeling as good as before influenza is defined as time to the first of two successive 'yes' responses to the question of 'feeling as good as you did before you had the flu'.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with question answered.
- Time to Return to Pre-influenza Function [ Time Frame: From treatment initiation to Day 28 ]Time to return to pre-influenza function is defined as the time from Day 0 to the first of two successive 'Yes' answers to the global assessment question 'Are you functioning as well as you were before you had the flu'.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with question answered.
- Time to Return of Physical Function to Pre-illness Level [ Time Frame: From treatment initiation to Day 28 ]Time to return of physical function to pre-illness level was defined as the time from Day 0 to the first of two successive measurements at which the physical function score equals or is better than the pre-illness score (obtained by recall at enrollment). For subjects who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with physical function evaluated.
- Number of Participants With Treatment Compliance Status [ Time Frame: From treatment initiation to Day 5 ]For each of the 5 days of treatment, participants were asked whether they took all study drug for that day. All participants were assumed to have taken at least some study drug even if they had zero days with all study drug reported as taken. Missing reports for some or all days were imputed as not having taken all study drug for the days concerned.
- Percentage of Participants Who Required Hospitalization. [ Time Frame: From treatment initiation to Day 28 ]The percentage of participants hospitalized by 28 days was constructed by inverting an exact binomial test of the actual percentages (ignoring loss to follow-up).
- Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications Requiring An Antibiotic Use, After Day 0. [ Time Frame: From treatment initiation to Day 28 ]Participants were assessed for the signs/symptoms suggestive of one of the following complications: Sinusitis, Otitis Media ,Bronchitis / Bronchiolitis, Pneumonia and antibiotic use for reason other than above.
- 28-day Mortality [ Time Frame: From treatment initiation to Day 28 ]Number of deaths
- Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs --Self Collected Samples [ Time Frame: At Day 3 ]For participants with a positive influenza test result at Day 0 from qualitative PCR testing on the team collected sample, the laboratory then performed qPCR testing of self-collected samples to quantify viral shedding.
- Number of Participants by Virus Detection Status --Self Collected Samples [ Time Frame: At Day 0, Day 0 evening, Day 1, Day 1 evening, Day 2, Day 2 evening and Day 3 ]Number of participants who had undetectable values (less than the limit of detection [LOD]), who had values between the LOD and the lower limit of quantification (LLOQ), and who had values ≥LLOQ. Evening samples on Day 0, 1 and 2 were only required under protocol versions 1.0-4.0 and so were only collected for about 20% of participants.
- qPCR Viral Shedding -- Self Collected Samples [ Time Frame: At Day 0, Day 0 evening, Day 1, Day 1 evening, Day 2, Day 2 evening and Day 3 ]Median, 25% and 75% percentile of the value of viral shedding (Results <LOD were imputed as the LOD value, and Results >= LOD, <LLOQ were imputed as the LLOQ value.). Evening samples on Day 0, 1 and 2 were only required under protocol versions 1.0-4.0 and so were only collected for about 20% of participants.
- Area Under The Curve (AUC) Of Viral Shedding For Self Collected Samples [ Time Frame: From Day 0 to Day 3 ]This AUC was calculated using the trapezoidal rule and the units of measurement are (days*log10 copies/mL) with the fact that it was the level of virus above the LLOQ being considered. The calculation of AUC was undertaken using measurements from Day 0 to Day 3 which were collected under all versions of the protocol (i.e. evening measurements on Days 0, 1 and 2 were not used as these were collected for only about 20% of subjects). Missing values during follow-up were ignored. This is equivalent to imputing a missing value using linear interpolation between the preceding and succeeding available values. For the five subjects with missing values following a last available measurement which was above the LLOQ, the remaining values were assumed to be the mean of preceding value and LLOQ in calculating the AUC.
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| Ages Eligible for Study: | 18 Years to 64 Years (Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Written informed consent prior to initiation of any study procedures
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History of an influenza-like illness defined as:
1) One or more respiratory symptom (cough, sore throat, or nasal symptoms)
- Onset of illness no more than 48 hours before screening, defined as when the participant experienced at least one respiratory symptom
- Willing to have samples stored
- Positive test for influenza (either rapid antigen or polymerase chain reaction [PCR]); randomization could proceed in cases of discrepant results (one positive and one negative)
Exclusion Criteria:
- Hospitalization at the time of screening
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Presence of a medical condition(s) that had been associated with increased risk of complications from influenza
- Aged 65 years of age or older
- Asthma
- Neurological and neuro-developmental conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle, such as cerebral palsy, epilepsy [seizure disorders], stroke, moderate to severe developmental delay, muscular dystrophy, or spinal cord injury)
- Chronic lung disease (such as chronic obstructive pulmonary disease [COPD] or cystic fibrosis)
- Heart disease (such as congenital heart disease, congestive heart failure, or coronary artery disease)
- Blood disorders
- Endocrine disorders (such as diabetes mellitus)
- Kidney disorders
- Liver disorders
- Metabolic disorders (such as inherited metabolic disorders or mitochondrial disorders)
- Weakened immune system due to disease or medication (such as people with HIV/AIDS or cancer, or use of chronic steroids or other medications causing immune suppression)
- Pregnant or 4 weeks postpartum
- Body mass index (BMI) greater than or equal to 40
- Breastfeeding
- Inability to take oral medication or a history of gastrointestinal malabsorption that would preclude the use of oral medication
- Received more than one dose of any antiviral influenza medication since onset of influenza symptoms
- Known end stage kidney dysfunction (e.g., creatinine clearance less than 30 mL/min)
- Known hypersensitivity to oseltamivir, peramivir, or zanamivir
- Received live attenuated influenza virus vaccine within 3 weeks prior to study entry
- Use of any investigational drug within 30 days or 5 half-lives (whichever was longer) prior to study entry
- Participated in other research protocols that required more than 100mL of blood to be drawn in a 4-week period that overlapped with this study.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01314911
Locations
Show 51 study locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
| Study Chair: | John Beigel, MD | Leidos Biomedical Research, Inc. in support of Clinical Research Section, LIR, NIAID, National Institutes of Health | |
| Study Chair: | Michael Ison, MD, MS | Division of Infectious Disease, Feinberg School of Medicine, Northwestern University |
Study Documents (Full-Text)
Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):
Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):
Statistical Analysis Plan [PDF] August 3, 2016
Study Protocol [PDF] August 3, 2016
Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | National Institute of Allergy and Infectious Diseases (NIAID) |
| ClinicalTrials.gov Identifier: | NCT01314911 |
| Other Study ID Numbers: |
IRC 004 11-I-0031 IRC004 |
| First Posted: | March 15, 2011 Key Record Dates |
| Results First Posted: | February 5, 2019 |
| Last Update Posted: | February 5, 2019 |
| Last Verified: | January 2019 |
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
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H1N1 Complications PCR Seasonal Influenza Viral Shedding |
Additional relevant MeSH terms:
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Influenza, Human Respiratory Tract Infections Infections Orthomyxoviridae Infections RNA Virus Infections Virus Diseases |
Respiratory Tract Diseases Oseltamivir Antiviral Agents Anti-Infective Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |