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 (IRC003)

• INCLUSION CRITERIA:

Enrollment (Screening)

1. Written informed consent prior to initiation of any study procedures
2. Age greater than or equal to 18 years of age
3. Presence of a underlying medical condition(s) that may increase risk of complications from influenza

4. History of an influenza-like illness defined as:

   • Subjective fever
   • 1 or more respiratory symptom (cough, sore throat, or nasal symptoms).
   • 1 or more constitutional symptom (headache, malaise, myalgia, sweats/chills or fatigue)
5. Onset of illness no more than 72 hours before randomization defined as either (1) when the temperature was first measured as elevated (greater than or equal to 38.0 degrees Celsius [greater than or equal to100.4 degrees Fahrenheit]), OR (2) when the subject experienced at least one respiratory symptom or at least one constitutional symptom
6. Willingness to have samples stored

Randomization

1. Written informed consent
2. Age greater than or equal to 18 years of age

3. Presence of a medical condition(s) that have 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 greater than or equal to 40
4. Onset of illness no more than 72 hours before randomization defined as either (1) when the temperature was first measured as elevated (greater than or equal to 38.0 degrees Celsius [greater than or equal to 100.4 degrees Fahrenheit]), OR (2) when the subject experienced at least one respiratory symptom or at least one constitutional symptom

5. Positive test for influenza (either rapid antigen or PCR)

   - Randomization may proceed in cases of discrepant results (one positive and one negative)

6. One of the following to avoid pregnancy:

   • Females who are 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 have 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
7. Willingness to have samples stored

EXCLUSION CRITERIA:

(for Enrollment or Randomization)

1. Hospitalization at the time of enrollment
2. Women who are pregnant or breast-feeding, and men whose female partner(s) is pregnant
3. Inability to take oral medication or a history of gastrointestinal malabsorption that would preclude the use of oral medication.
4. Hemoglobin < 10 g/dL
5. WBC < 1.5 times 10(9)/L
6. Neutrophils < 0.75 x 10(9)/L
7. Platelets < 50 x 10(9)/L
8. History of genetic hemoglobinopathy (e.g., thalassemia major or sickle cell anemia) or autoimmune hemolytic anemia
9. Received more than one dose of any antiviral influenza medications since onset of influenza symptoms
10. Received stavudine (d4T), didanosine (ddI), zidovudine (AZT), or azathioprine within 30 days prior to study entry
11. Creatinine clearance less than 50 mL/min (estimated by the Cockcroft-Gault equation using serum creatinine)
12. History of autoimmune hepatitis
13. Uncompensated liver disease (defined as AST > 3 times site upper limit of normal (ULN), ALT > 3 times ULN, or Direct Bilirubin > 2 times ULN)
14. Clinical signs of end-stage liver disease including jaundice, coagulopathy, portal hypertension, esophageal varices, ascites, peripheral edema, gastrointestinal bleeding, or encephalopathy
15. Chronic liver disease categorized as Child-Pugh class C (Child-Pugh score 10-15)
16. Known hypersensitivity to rimantadine, amantadine, ribavirin, oseltamivir, peramivir, or zanamivir
17. Received live attenuated virus vaccine (influenza or other) within 3 weeks prior to study entry
18. Use of any investigational drug within 30 days or 5 half-lives (whichever is longer) prior to study entry