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

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.

- 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.