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

• 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 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 (whiche