A Randomized Double-Blind Phase 2 Study 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
Overview
- Phase
- Phase 2
- Intervention
- Amantadine, Ribavirin, Oseltamivir
- Conditions
- Influenza
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 881
- Locations
- 91
- Primary Endpoint
- Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs
- Status
- Completed
- Last Updated
- 7 years ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Combination Therapy
Amantadine, Ribavirin, Oseltamivir
Intervention: Amantadine, Ribavirin, Oseltamivir
Oseltamivir monotherapy
Oseltamivir
Intervention: Oseltamivir
Outcomes
Primary Outcomes
Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs
Time Frame: 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 Outcomes
- Time to Alleviation of Influenza Clinical Symptoms.(From treatment initiation to Day 28)
- Number of Participants by Virus Detection Status(At Day 0, 3 and 7.)
- qPCR Viral Shedding(At Day 0, 3 and 7)
- Percentage of Participants With Clinical Failure at Day 5(From treatment initiation to Day 28)
- Number of Participants Shedding Virus(At day 3 and 7.)
- Time to Feeling as Good as Before the Onset of the Influenza Illness(From treatment initiation to Day 28)
- Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0.(From treatment initiation to Day 28)
- Time to Absence of Fever(From treatment initiation to Day 28)
- Time to Resolution of All Symptoms AND Fever(From treatment initiation to Day 28)
- Time to Return to Pre-influenza Function(From treatment initiation to Day 28)
- Percentage of Participants Who Required New or Increased Use of Supplemental Oxygen(From treatment initiation to Day 28)
- 28-day Mortality(From treatment initiation to Day 28)
- Time to Return of Physical Function to Pre-illness Leve(From treatment initiation to Day 28)
- Percentage of Participants Who Required Hospitalization.(From treatment initiation to Day 28)