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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Influenza

Intervention / Treatment
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* Drug: Amantadine, Ribavirin, Oseltamivir
* Drug: Oseltamivir


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Enrollment (Screening) Signed informed consent prior to initiation of any study procedures Presence of an underlying medical condition(s) that might increase risk of complications from influenza History of an influenza-like illness defined as: One or more respiratory symptom (cough, sore throat, or nasal symptoms) AND Either Fever (subjective or documented >38 degrees C) OR 1 or more constitutional symptom (headache, malaise, myalgia, sweats/chills or fatigue) Onset of illness no more than 96 hours before screening defined as when the subject experienced at least one respiratory symptom, constitutional symptom, or fever Willingness to have samples stored Randomization Signed informed consent Presence of a medical condition(s) that had been associated with increased risk of complications from influenza Age 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) [though still able to provide informed consent per inclusion criteria #1] Chronic lung disease (such as COPD and cystic fibrosis) Heart disease (such as congenital heart disease, congestive heart failure, and coronary artery disease) Blood disorders (excluding genetic causes of anemia, as noted in the exclusion criteria) Endocrine disorders (such as diabetes mellitus) Kidney disorders Liver disorders Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders) Weakened immune system due to disease or medication (such as people with HIV/AIDS, or cancer, chronic steroids or other medications causing immune suppression) BMI ≥ 40(kg/m²) Onset of illness no more than 96 hours before screening defined as when the subject experienced at least one respiratory symptom, constitutional symptom, or fever Positive test for influenza (either rapid antigen or PCR) - Results from influenza testing obtained for clinical indications within 12 hours before screening/enrollment may be used if available. Randomization may proceed in cases of discrepant results (one positive and one negative) One of the following to avoid pregnancy: Females who were able to become pregnant (i.e., are not postmenopausal, have not undergone surgical sterilization, and are sexually active with men) must agree to use at least 2 effective forms of contraception from the date of informed consent through 6 months after the last dose of study drug. At least one of the methods of contraception should be a barrier method Males who had not undergone surgical sterilization and are sexually active with women must agree to use condoms plus have a partner use at least one additional effective form of contraception from the date of informed consent through 6 months after the last dose of study drug Willingness to have samples stored EXCLUSION CRITERIA: (for Enrollment or Randomization) Women who were pregnant or breast-feeding, and men whose female partner(s) was pregnant Inability to take oral medication or a history of gastrointestinal malabsorption that would preclude the use of oral medication. Hemoglobin < 10 g/dL WBC < 1.5 times 10(9)/L Neutrophils < 0.75 x 10(9)/L Platelets < 50 x 10(9)/L History of genetic hemoglobinopathy (e.g., thalassemia major or sickle cell anemia) or autoimmune hemolytic anemia Received more than 2 doses of any antiviral influenza medications since onset of influenza symptoms Received stavudine (d4T), didanosine (ddI), zidovudine (AZT), or azathioprine within 30 days prior to study entry Creatinine clearance less than 60 mL/min (estimated by the Cockcroft-Gault equation using serum creatinine) History of autoimmune hepatitis Uncompensated liver disease (defined as AST > 3 times site upper limit of normal (ULN), ALT > 3 times ULN, or Direct Bilirubin > 2 times ULN) Clinical signs of end-stage liver disease including jaundice, coagulopathy, portal hypertension, esophageal varices, ascites, peripheral edema, gastrointestinal bleeding, or encephalopathy Chronic liver disease categorized as Child-Pugh class C (Child-Pugh score 10-15) Known hypersensitivity to rimantadine, amantadine, ribavirin, oseltamivir, peramivir, or zanamivir Received live attenuated virus vaccine (influenza or other) 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 Participation in other research protocols that would require more than 100 mL of blood to be drawn in any 4-week period that overlaps with this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination Therapy<br>Amantadine, Ribavirin, Oseltamivir | Drug: Amantadine, Ribavirin, Oseltamivir<br>* Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg, three capsules of Ribavirin 200 mg for total of 600 mg, and one capsule of Amantadine 100 mg.<br>|
| Active Comparator: Oseltamivir monotherapy<br>Oseltamivir | Drug: Oseltamivir<br>* Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs | 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. | At Day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants by Virus Detection Status | 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 | At Day 0, 3 and 7. | 
| qPCR Viral Shedding | 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.) | At Day 0, 3 and 7 | 
| Number of Participants Shedding Virus | 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). | At day 3 and 7. | 
| Time to Alleviation of Influenza Clinical Symptoms. | 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. | From treatment initiation to Day 28 | 
| Time to Absence of Fever | 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. | From treatment initiation to Day 28 | 
| Time to Resolution of All Symptoms AND Fever | 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. | From treatment initiation to Day 28 | 
| Time to Feeling as Good as Before the Onset of the Influenza Illness | 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. | From treatment initiation to Day 28 | 
| Time to Return to Pre-influenza Function | 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. | From treatment initiation to Day 28 | 
| Time to Return of Physical Function to Pre-illness Leve | 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. | From treatment initiation to Day 28 | 
| Percentage of Participants With Clinical Failure at Day 5 | Clinical failure at Day 5 is defined as the need for continued (non-study) antiviral use after Day 5. | From treatment initiation to Day 28 | 
| Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0. | 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. | From treatment initiation to Day 28 | 
| Percentage of Participants Who Required New or Increased Use of Supplemental Oxygen | Percentage of participants who required new or increased use of supplemental oxygen | From treatment initiation to Day 28 | 
| Percentage of Participants Who Required Hospitalization. | The percentage of participants hospitalized by 28 days was estimated from the Kaplan-Meier curves. | From treatment initiation to Day 28 | 
| 28-day Mortality | Number of deaths | From treatment initiation to Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adaptive Design, At Risk, H1N1, Synergy, TCAD