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)

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 will evaluate the use of combination antivirals (amantadine, oseltamivir, and ribavirin) compared to oseltamivir alone in the treatment of influenza in an at-risk population.

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 is responsible for the majority of hospitalization and morbidity associated with influenza. This study will evaluate the use of combination antivirals as compared to oseltamivir alone in the treatment of influenza in an at-risk population.

Subjects who meet the CDC definition for being at-risk and that present with an influenza-like illness will be screened for the study. Those subjects with a confirmatory test for influenza (rapid antigen or PCR) will be 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 will be used for both safety and efficacy analysis.

Objectives:

- To evaluate the effectiveness of combined treatment with oseltamivir, amantadine, and ribavirin compared with oseltamivir alone for at-risk individuals with confirmed influenza infection.

Eligibility:

- Individuals at least 18 years of age who have one or more medical conditions that may cause complications from influenza, and have developed an influenza-like illness.

Design:

• Participants will be screened with a physical examination and medical history, along with blood tests and throat swabs to confirm influenza infection.
• Eligible participants will be randomly assigned to take either oseltamivir alone (the current standard treatment for influenza) or to take oseltamivir, amantadine, and ribavirin. Participants will have additional blood samples and throat swabs taken at the start of the study, and will be shown how to complete a study diary at home.
• Participants will receive a study medication kit containing the medication to take at home twice a day for 5 days.
• Participants will return, 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 may take 2 to 3 hours, but each subsequent visit should take approximately 1 to 2 hours. Additional blood samples and throat swabs will be taken at these visits.

• Drug: Amantadine, Ribavirin, Oseltamivir
  One capsule of Oseltamivir 75 mg x 2 - Total dose: 150 mg/day for 5 days; Three capsules of Ribavirin 200 mg for total of 600 mg x 2 - Total dose: 1200 mg/day for 5 days; One capsule of Amantadine 100 mg x 2 Total dose: 200 mg/day for 5 days
• Drug: Oseltamivir
  75 mg x 2 Total dose: 150 mg/day for 5 days

• Experimental: Combination Therapy
  Amantadine, Ribavirin, Oseltamivir
  Intervention: Drug: Amantadine, Ribavirin, Oseltamivir
• Active Comparator: Oseltamivir monotherapy
  Oseltamivir
  Intervention: Drug: Oseltamivir

• Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003 Jan 8;289(2):179-86.
• Monto AS. Vaccines and antiviral drugs in pandemic preparedness. Emerg Infect Dis. 2006 Jan;12(1):55-60.
• Moscona A. Oseltamivir resistance--disabling our influenza defenses. N Engl J Med. 2005 Dec 22;353(25):2633-6. No abstract available.

• INCLUSION CRITERIA:

Enrollment (Screening)

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

4. 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)
5. 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
6. Willingness to have samples stored

Randomization

1. Signed 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 ≥ 40
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. 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)

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. Women who are pregnant or breast-feeding, and men whose female partner(s) is 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 50 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 is longer) prior to study entry