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
Condition: Influenza
MeSH terms: Influenza, Human
Intervention: Amantadine, Ribavirin, Oseltamivir; Oseltamivir
Intervention description: 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.; Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.
Intervention MeSH terms: Ribavirin; Oseltamivir; Amantadine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 881.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Adaptive Design; At Risk; H1N1; Synergy; TCAD

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Enrollment (Screening)

          1. Signed informed consent prior to initiation of any study procedures

          2. Presence of an underlying medical condition(s) that might increase risk of
             complications from influenza

          3. 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)

          4. 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

          5. Willingness to have samples stored

        Randomization

          1. Signed informed consent

          2. 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)

          3. 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

          4. 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)

          5. 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

          6. Willingness to have samples stored

        EXCLUSION CRITERIA:

        (for Enrollment or Randomization)

          1. Women who were pregnant or breast-feeding, and men whose female partner(s) was
             pregnant

          2. Inability to take oral medication or a history of gastrointestinal malabsorption that
             would preclude the use of oral medication.

          3. Hemoglobin < 10 g/dL

          4. WBC < 1.5 times 10(9)/L

          5. Neutrophils < 0.75 x 10(9)/L

          6. Platelets < 50 x 10(9)/L

          7. History of genetic hemoglobinopathy (e.g., thalassemia major or sickle cell anemia) or
             autoimmune hemolytic anemia

          8. Received more than 2 doses of any antiviral influenza medications since onset of
             influenza symptoms

          9. Received stavudine (d4T), didanosine (ddI), zidovudine (AZT), or azathioprine within
             30 days prior to study entry

         10. Creatinine clearance less than 60 mL/min (estimated by the Cockcroft-Gault equation
             using serum creatinine)

         11. History of autoimmune hepatitis

         12. Uncompensated liver disease (defined as AST > 3 times site upper limit of normal
             (ULN), ALT > 3 times ULN, or Direct Bilirubin > 2 times ULN)

         13. Clinical signs of end-stage liver disease including jaundice, coagulopathy, portal
             hypertension, esophageal varices, ascites, peripheral edema, gastrointestinal
             bleeding, or encephalopathy

         14. Chronic liver disease categorized as Child-Pugh class C (Child-Pugh score 10-15)

         15. Known hypersensitivity to rimantadine, amantadine, ribavirin, oseltamivir, peramivir,
             or zanamivir

         16. Received live attenuated virus vaccine (influenza or other) within 3 weeks prior to
             study entry

         17. Use of any investigational drug within 30 days or 5 half-lives (whichever was longer)
             prior to study entry

         18. 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.