Clinical trial NCT01227967: 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
Official title: A Randomized Double-Blind Phase 2 Study 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Influenza
Keywords: Adaptive Design
At Risk
H1N1
Synergy
TCAD
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2010-10-25
Enrollment: 881
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

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.

Primary outcomes:
measure: Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs
timeFrame: At Day 3
Secondary outcomes:
measure: Number of Participants by Virus Detection Status
timeFrame: At Day 0, 3 and 7.
measure: qPCR Viral Shedding
timeFrame: At Day 0, 3 and 7
measure: Number of Participants Shedding Virus
timeFrame: At day 3 and 7.
measure: Time to Alleviation of Influenza Clinical Symptoms.
timeFrame: From treatment initiation to Day 28
measure: Time to Absence of Fever
timeFrame: From treatment initiation to Day 28
measure: Time to Resolution of All Symptoms AND Fever
timeFrame: From treatment initiation to Day 28
measure: Time to Feeling as Good as Before the Onset of the Influenza Illness
timeFrame: From treatment initiation to Day 28
measure: Time to Return to Pre-influenza Function
timeFrame: From treatment initiation to Day 28
measure: Time to Return of Physical Function to Pre-illness Leve
timeFrame: From treatment initiation to Day 28
measure: Percentage of Participants With Clinical Failure at Day 5
timeFrame: From treatment initiation to Day 28
measure: Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0.
timeFrame: From treatment initiation to Day 28
measure: Percentage of Participants Who Required New or Increased Use of Supplemental Oxygen
timeFrame: From treatment initiation to Day 28
measure: Percentage of Participants Who Required Hospitalization.
timeFrame: From treatment initiation to Day 28
measure: 28-day Mortality
timeFrame: From treatment initiation to Day 28
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Simon Williamson Clinic
state: Alabama
city: Chandler
country: United States
facility: East Valley Family Physicians
state: Arizona
city: Glendale
country: United States
facility: Thomas Lenzmeier Family Practice
state: Arizona
city: Phoenix
country: United States
facility: Central Phoenix Medical Center
state: Arizona
city: Costa Mesa
country: United States
facility: WCCT Global LLC
state: California
city: Garden Grove
country: United States
facility: Advanced Rx Clinical Research
state: California
city: Lomita
country: United States
facility: Torrance Clinical Research Institute, Inc.
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: San Diego
country: United States
facility: University of California at San Diego
state: California
city: Thousand Oaks
country: United States
facility: Westlake Medical Research (CA)
state: California
city: Torrance
country: United States
facility: Los Angeles BioMedical Research Institute
state: California
city: Upland
country: United States
facility: Empire Clinical Research
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Centennial
country: United States
facility: Centennial - IMMUNOe International Research
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Hialeah
country: United States
facility: Best Quality Research Inc.
state: Florida
city: Miami
country: United States
facility: San Marcus Research Clinic, Inc.
state: Florida
city: Miami
country: United States
facility: Medical Consulting Center
state: Florida
city: Miami
country: United States
facility: Suncoast Research Group, LLC
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Pinellas Park
country: United States
facility: DMI Research, Inc.
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Normal
country: United States
facility: Sneeze, Wheeze & Itch Associates, LLC
state: Illinois
city: Council Bluffs
country: United States
facility: Ridge Family Practice
state: Iowa
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Owensboro
country: United States
facility: Research Integrity, LLC
state: Kentucky
city: Eunice
country: United States
facility: Horizon Research Group, of Opelousas, LLC
state: Louisiana
city: Lake Charles
country: United States
facility: Centex Studies Inc. - Dr. Seep
state: Louisiana
city: Bethesda
country: United States
facility: NIH Clinical Center
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Worcester
country: United States
facility: UMass Medical School
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health Systems
state: Michigan
city: Kalamazoo
country: United States
facility: Bronson Methodist Hospital
state: Michigan
city: Bridgeton
country: United States
facility: West Florissant Internists
state: Missouri
city: Elkhorn
country: United States
facility: Clinical Research Advantage/ Skyline Medical Center
state: Nebraska
city: Fremont
country: United States
facility: Prairie Fields Family Medicine
state: Nebraska
city: Omaha
country: United States
facility: Southwest Family Physicians
state: Nebraska
city: Newark
country: United States
facility: New Jersey Medical School
state: New Jersey
city: Bronx
country: United States
facility: James J. Peters, VA Medical Center
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina-Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Middleburg Heights
country: United States
facility: Clinical Research Solutions - Dr. Panuto
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Smithfield
country: United States
facility: Montgomery Medical
state: Pennsylvania
city: Rapid City
country: United States
facility: Health Concepts
state: South Dakota
city: Columbia
country: United States
facility: Clinical Research Solutions - Dr. Bart
state: Tennessee
city: Franklin
country: United States
facility: Clinical Research Solutions - Dr. Slandzicki
state: Tennessee
city: Jackson
country: United States
facility: Clinical Research Solutions - Dr. Hoppers
state: Tennessee
city: Kingsport
country: United States
facility: Holston Medical Group
state: Tennessee
city: Nashville
country: United States
facility: Clinical Research Solutions - Dr. Rowe
state: Tennessee
city: Smyrna
country: United States
facility: Clinical Research Solutions - Dr. Dar
state: Tennessee
city: Amarillo
country: United States
facility: University of Texas Tech Amarillo
state: Texas
city: Carrollton
country: United States
facility: Family Medicine Associates of Texas
state: Texas
city: Corpus Christi
country: United States
facility: 3rd Coast Research Associates
state: Texas
city: Houston
country: United States
facility: University of Texas at Houston
state: Texas
city: Houston
country: United States
facility: Centex Studies Inc. - Dr. Pouzar
state: Texas
city: Houston
country: United States
facility: Pioneer Research Solutions, Inc.
state: Texas
city: Lubbock
country: United States
facility: Texas Tech HSC
state: Texas
city: Pharr
country: United States
facility: Centex Studies Inc. - Dr. Garcia
state: Texas
city: Plano
country: United States
facility: Village Health Partners
state: Texas
city: San Antonio
country: United States
facility: Endeavor Clinical Trials
state: Texas
city: San Antonio
country: United States
facility: Bandera Family Healthcare Research
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: La Plata
country: Argentina
facility: Instituto Medico Platense
state: Buenos Aires
city: Vicente Lopez
country: Argentina
facility: Hospital Houssay
state: Provincia De Buenos Aires
city: Buenos Aires
country: Argentina
facility: Centro de Educación Médica e Investigaciónes Clínicas (CEMIC)
city: Buenos Aires
country: Argentina
facility: Fundación del Centro de Estudios Infectológicos (FUNCEI)
city: Buenos Aires
country: Argentina
facility: Hospital General de Agudos J. M. Ramos Mejía
city: Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
city: Cordoba
country: Argentina
facility: Hospital Rawson
city: Santa Fe
country: Argentina
facility: Instituto Centralizado de Asistencia e Investigación Clínica Integral (CAICI)
city: Darlinghurst
country: Australia
facility: Holdsworth House Med Practice
state: New South Wales
city: Darlinghurst
country: Australia
facility: Taylor Square Private Clinic
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane
state: Queensland
city: Fitzroy North
country: Australia
facility: Northside Clinic
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: México City
country: Mexico
facility: Instituto Nacional de Ciencias Médicas y Nutrición (INCMN) Salvador Zubirán
city: Tlalpan
country: Mexico
facility: Hospital General y de Alta Especialidad "Dr. Manuel GEA Gonzalez"
city: Tlalpan
country: Mexico
facility: Instituto Nacional de Enfermedades Respiratorias (INER)
city: Bangkoknoi
country: Thailand
facility: Siriraj Hospital, Mahidol University
state: Bangkok
city: Patumwan
country: Thailand
facility: HIV-NAT, The Thai Red Cross AIDS
state: Bangkok
city: Muang
country: Thailand
facility: Srinagarind Hospital, Khon Kaen University
state: Khon Kaen
city: Muang
country: Thailand
facility: Bamrasnaradura Infectious Diseases Institute
state: Nonthaburi
Study officials:
affiliation: Leidos Biomedical Research, Inc. in support of Clinical Research Section, LIR, NIAID, Natinal Institutes of Health
name: John Beigel, MD
role: STUDY_CHAIR
affiliation: University of Rochester
name: John Treanor, MD
role: STUDY_CHAIR
References:
citation: 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. doi: 10.1001/jama.289.2.179.
citation: Monto AS. Vaccines and antiviral drugs in pandemic preparedness. Emerg Infect Dis. 2006 Jan;12(1):55-60. doi: 10.3201/eid1201.051068.
citation: Moscona A. Oseltamivir resistance--disabling our influenza defenses. N Engl J Med. 2005 Dec 22;353(25):2633-6. doi: 10.1056/NEJMp058291. No abstract available.
citation: Beigel JH, Bao Y, Beeler J, Manosuthi W, Slandzicki A, Dar SM, Panuto J, Beasley RL, Perez-Patrigeon S, Suwanpimolkul G, Losso MH, McClure N, Bozzolo DR, Myers C, Holley HP Jr, Hoopes J, Lane HC, Hughes MD, Davey RT; IRC003 Study Team. Oseltamivir, amantadine, and ribavirin combination antiviral therapy versus oseltamivir monotherapy for the treatment of influenza: a multicentre, double-blind, randomised phase 2 trial. Lancet Infect Dis. 2017 Dec;17(12):1255-1265. doi: 10.1016/S1473-3099(17)30476-0. Epub 2017 Sep 22.