Comparing the Efficacy, Safety, and Tolerability of Combination Antivirals (Amantadine, Ribavirin, Oseltamivir) Versus Oseltamivir for the Treatment of Influenza in Adults at Risk for Complications
- Conditions
- Influenza
- Interventions
- Registration Number
- NCT01227967
- Brief Summary
Seasonal influenza is responsible for many hospitalizations and deaths each year, despite effective antiviral treatments. Some individuals have medical conditions such as heart or lung diseases that make them particularly at risk of severe influenza infections that may result in hospitalization or death. Oseltamivir (Tamiflu) is used most often to treat flu, but there are still many hospitalizations, complications, and deaths even with treatment. This study evaluated the use of combination antivirals (amantadine, oseltamivir, and ribavirin) compared to oseltamivir alone in the treatment of influenza in an at-risk population.
- Detailed Description
Seasonal influenza is responsible for approximately 226,000 excess hospitalizations annually and despite effective antivirals causes significant morbidity and mortality (estimated 24,000-50,000 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 percent of the deaths with the 2009 H1N1 occurred among people younger than 65 years of age. The CDC has defined an at-risk population that accounts for the majority of hospitalization and morbidity associated with influenza. This study evaluated the use of combination antivirals as compared to oseltamivir alone in the treatment of influenza in an at-risk population.
Subjects who met the CDC definition for being at-risk and that present with an influenza-like illness were screened for the study. Those subjects with a confirmatory test for influenza (rapid antigen or PCR) were randomized in a 1:1 manner to receive a blinded study treatment consisting of either the combination of amantadine, oseltamivir, and ribavirin or oseltamivir alone for 5 days. Clinical, virologic, and laboratory assessments on Days 1, 3, 7, 14, and 28 were used for both safety and efficacy analysis.
Design:
* Participants were screened with a physical examination and medical history, along with blood tests and throat swabs to confirm influenza infection.
* Eligible participants were randomly assigned to take either oseltamivir alone (the current standard treatment for influenza) or to take oseltamivir, amantadine, and ribavirin. Participants had additional blood samples and throat swabs taken at the start of the study, and were shown how to complete a study diary at home.
* Participants received a study medication kit containing the medication to take at home twice a day for 5 days.
* Participants returned, with the medication kit, to the clinic on days 1 (the first day after the start of the study), 3, 7, 14, and 28. The first visit took 2 to 3 hours, but each subsequent visit took approximately 1 to 2 hours. Additional blood samples and throat swabs were taken at these visits.
Pilot study:
Due to the lack of reliable data concerning the AUC virologic endpoint, an "external" pilot study was conducted in the first 47 patients randomized to identify a primary endpoint and method of analysis, and to possibly modify the sample size. To ensure no effect on the type I error rate, data from these 47 patients were excluded from the primary and secondary efficacy analyses but were used in other analyses of secondary objectives.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 881
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Combination Therapy Amantadine, Ribavirin, Oseltamivir Amantadine, Ribavirin, Oseltamivir Oseltamivir monotherapy Oseltamivir Oseltamivir
- Primary Outcome Measures
Name Time Method Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs At Day 3 The central laboratory performed a qualitative PCR test on the NP sample from Day 0 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
Name Time Method Time to Alleviation of Influenza Clinical Symptoms. 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 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). A measurement is considered to be the 8AM or 8PM assessment during Days 0 to 7 (so two measurements are obtained per day) and then the daily assessment thereafter. Time will then be calculated in half-days through to Day 7. If a subject's first two assessments on (baseline assessment and first subsequent diary card assessment) satisfy this criterion, then the duration will be 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.
Number of Participants by Virus Detection Status 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 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.)
Percentage of Participants With Clinical Failure at Day 5 From treatment initiation to Day 28 Clinical failure at Day 5 is defined as the need for continued (non-study) antiviral use after Day 5.
Number of Participants Shedding Virus 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 Feeling as Good as Before the Onset of the Influenza Illness 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.
Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. 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.
Time to Absence of Fever 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 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 Return to Pre-influenza Function 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.
Percentage of Participants Who Required New or Increased Use of Supplemental Oxygen From treatment initiation to Day 28 Percentage of participants who required new or increased use of supplemental oxygen
28-day Mortality From treatment initiation to Day 28 Number of deaths
Time to Return of Physical Function to Pre-illness Leve 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.
Percentage of Participants Who Required Hospitalization. From treatment initiation to Day 28 The percentage of participants hospitalized by 28 days was estimated from the Kaplan-Meier curves.
Trial Locations
- Locations (91)
Simon Williamson Clinic
🇺🇸Birmingham, Alabama, United States
East Valley Family Physicians
🇺🇸Chandler, Arizona, United States
Thomas Lenzmeier Family Practice
🇺🇸Glendale, Arizona, United States
Central Phoenix Medical Center
🇺🇸Phoenix, Arizona, United States
WCCT Global LLC
🇺🇸Costa Mesa, California, United States
Advanced Rx Clinical Research
🇺🇸Garden Grove, California, United States
Torrance Clinical Research Institute, Inc.
🇺🇸Lomita, California, United States
University of Southern California
🇺🇸Los Angeles, California, United States
University of California at San Diego
🇺🇸San Diego, California, United States
Westlake Medical Research (CA)
🇺🇸Thousand Oaks, California, United States
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