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)

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

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.

Study Overview

• Status: Completed
• Conditions: Influenza
• Intervention / Treatment: Drug: Amantadine, Ribavirin, Oseltamivir; Drug: Oseltamivir

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.

• Study Type: Interventional
• Enrollment (Actual): 881
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Hospital Italiano de Buenos Aires
  • Buenos Aires, Argentina
    • Centro de Educación Médica e Investigaciones Clínicas (CEMIC)
  • Buenos Aires, Argentina
    • Fundación del Centro de Estudios Infectológicos (FUNCEI)
  • Buenos Aires, Argentina
    • Hospital General de Agudos J. M. Ramos Mejía
  • Cordoba, Argentina
    • Hospital Rawson
  • Santa Fe, Argentina
    • Instituto Centralizado de Asistencia e Investigación Clínica Integral (CAICI)
  • Buenos Aires
    • La Plata, Buenos Aires, Argentina
      • Instituto Medico Platense
  • Provincia De Buenos Aires
    • Vicente Lopez, Provincia De Buenos Aires, Argentina
      • Hospital Houssay
• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • Holdsworth House Med Practice
    • Darlinghurst, New South Wales, Australia, 2010
      • Taylor Square Private Clinic
    • Westmead, New South Wales, Australia
      • Westmead Hospital
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane
  • Victoria
    • Fitzroy North, Victoria, Australia, 3068
      • Northside Clinic
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
    • Parkville, Victoria, Australia, 3052
      • Royal Melbourne Hospital
• Mexico
  • México City, Mexico
    • Instituto Nacional de Ciencias Médicas y Nutrición (INCMN) Salvador Zubirán
  • Tlalpan, Mexico
    • Hospital General y de Alta Especialidad "Dr. Manuel GEA Gonzalez"
  • Tlalpan, Mexico
    • Instituto Nacional de Enfermedades Respiratorias (INER)
• Thailand
  • Bangkok
    • Bangkoknoi, Bangkok, Thailand, 10700
      • Siriraj Hospital, Mahidol University
    • Patumwan, Bangkok, Thailand, 10330
      • HIV-NAT, The Thai Red Cross AIDS
  • Khon Kaen
    • Muang, Khon Kaen, Thailand, 40002
      • Srinagarind Hospital, Khon Kaen University
  • Nonthaburi
    • Muang, Nonthaburi, Thailand, 11000
      • Bamrasnaradura Infectious Diseases Institute
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35211
      • Simon Williamson Clinic
  • Arizona
    • Chandler, Arizona, United States, 85224
      • East Valley Family Physicians
    • Glendale, Arizona, United States, 85308
      • Thomas Lenzmeier Family Practice
    • Phoenix, Arizona, United States, 85020
      • Central Phoenix Medical Center
  • California
    • Costa Mesa, California, United States, 92626
      • WCCT Global LLC
    • Garden Grove, California, United States, 92843
      • Advanced Rx Clinical Research
    • Lomita, California, United States, 90717
      • Torrance Clinical Research Institute, Inc.
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • San Diego, California, United States, 92103
      • University of California at San Diego
    • Thousand Oaks, California, United States, 91360
      • Westlake Medical Research (CA)
    • Torrance, California, United States, 90502
      • Los Angeles Biomedical Research Institute
    • Upland, California, United States, 91786
      • Empire Clinical Research
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
    • Centennial, Colorado, United States, 80112
      • Centennial - IMMUNOe International Research
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Hialeah, Florida, United States, 33016
      • Best Quality Research Inc.
    • Miami, Florida, United States, 33136
      • University of Miami
    • Miami, Florida, United States, 33015
      • San Marcus Research Clinic, Inc.
    • Miami, Florida, United States, 33135
      • Suncoast Research Group, LLC
    • Miami, Florida, United States, 33125
      • Medical Consulting Center
    • Pinellas Park, Florida, United States, 33782
      • DMI Research, Inc.
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Normal, Illinois, United States, 61761
      • Sneeze, Wheeze & Itch Associates, LLC
  • Iowa
    • Council Bluffs, Iowa, United States, 51503
      • Ridge Family Practice
    • Iowa City, Iowa, United States, 52246
      • University of Iowa
  • Kentucky
    • Owensboro, Kentucky, United States, 42303
      • Research Integrity, LLC
  • Louisiana
    • Eunice, Louisiana, United States, 70535
      • Horizon Research Group, of Opelousas, LLC
    • Lake Charles, Louisiana, United States, 70601
      • Centex Studies Inc. - Dr. Seep
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • NIH Clinical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Boston Medical Center
    • Worcester, Massachusetts, United States, 01655
      • UMass Medical School
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health Systems
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
  • Missouri
    • Bridgeton, Missouri, United States, 63044
      • West Florissant Internists
  • Nebraska
    • Elkhorn, Nebraska, United States, 68022
      • Clinical Research Advantage/ Skyline Medical Center
    • Fremont, Nebraska, United States, 68025
      • Prairie Fields Family Medicine
    • Omaha, Nebraska, United States, 68124
      • Southwest Family Physicians
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • New Jersey Medical School
  • New York
    • Bronx, New York, United States, 10468
      • James J. Peters, VA Medical Center
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina-Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Ohio
    • Middleburg Heights, Ohio, United States, 44130
      • Clinical Research Solutions - Dr. Panuto
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
    • Smithfield, Pennsylvania, United States, 15478
      • Montgomery Medical
  • South Dakota
    • Rapid City, South Dakota, United States, 57702
      • Health Concepts
  • Tennessee
    • Columbia, Tennessee, United States, 38401
      • Clinical Research Solutions - Dr. Bart
    • Franklin, Tennessee, United States, 37064
      • Clinical Research Solutions - Dr. Slandzicki
    • Jackson, Tennessee, United States, 38305
      • Clinical Research Solutions - Dr. Hoppers
    • Kingsport, Tennessee, United States, 37660
      • Holston Medical Group
    • Nashville, Tennessee, United States, 37211
      • Clinical Research Solutions - Dr. Rowe
    • Smyrna, Tennessee, United States, 37167
      • Clinical Research Solutions - Dr. Dar
  • Texas
    • Amarillo, Texas, United States, 79106
      • University of Texas Tech Amarillo
    • Carrollton, Texas, United States, 75010
      • Family Medicine Associates of Texas
    • Corpus Christi, Texas, United States, 78413
      • 3rd Coast Research Associates
    • Houston, Texas, United States, 77098
      • Pioneer Research Solutions, Inc.
    • Houston, Texas, United States, 77030
      • University of Texas at Houston
    • Houston, Texas, United States, 77062
      • Centex Studies Inc. - Dr. Pouzar
    • Lubbock, Texas, United States, 79430
      • Texas Tech HSC
    • Pharr, Texas, United States, 78577
      • Centex Studies Inc. - Dr. Garcia
    • Plano, Texas, United States, 75024
      • Village Health Partners
    • San Antonio, Texas, United States, 78229
      • Endeavor Clinical Trials
    • San Antonio, Texas, United States, 78249
      • Bandera Family Healthcare Research
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combination Therapy; Amantadine, Ribavirin, Oseltamivir	Drug: Amantadine, Ribavirin, Oseltamivir; 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.
Active Comparator: Oseltamivir monotherapy; Oseltamivir	Drug: Oseltamivir; Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Virus Detectable by Quantitative PCR (qPCR) in Nasopharyngeal (NP) Swabs	The central laboratory performed a qualitative PCR test on the NP sample from Day 0 in order to confirm influenza infection and to determine the influenza type and subtype. For participants with a positive influenza test result at Day 0 from this qualitative PCR testing, the laboratory then performed qPCR testing of subsequent samples to quantify viral shedding.	At Day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants by Virus Detection Status	Number of participants who had undetectable values (less than the limit of detection [LOD]), who had values between the LOD and the lower limit of quantification (LLOQ), and who had values ≥LLOQ	At Day 0, 3 and 7.
qPCR Viral Shedding	Median, 25% and 75% percentile of the value of viral shedding (Results <LOD were imputed as the LOD value, and Results >= LOD, <LLOQ were imputed as the LLOQ value.)	At Day 0, 3 and 7
Number of Participants Shedding Virus	Number of participants with undetectable viral load at both Day 3 and Day 7; detectable at Day 3 and undetectable at Day 7; detectable at Day 7 (irrespective of whether or not detectable at Day 3).	At day 3 and 7.
Time to Alleviation of Influenza Clinical Symptoms.	The assessed symptoms were cough, nasal obstruction (stuffy nose), sore throat, fatigue, headache, muscle aches, feverishness, rhinorrhea, nausea, vomiting, diarrhea. Duration of clinical symptoms is defined as the time from Day 0 to the first of two successive measurements at which all clinical symptoms are grade 0 (absent) or 1 (mild). A measurement is considered to be the 8AM or 8PM assessment during Days 0 to 7 (so two measurements are obtained per day) and then the daily assessment thereafter. Time will then be calculated in half-days through to Day 7. If a subject's first two assessments on (baseline assessment and first subsequent diary card assessment) satisfy this criterion, then the duration will be set to zero. For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with symptoms evaluated.	From treatment initiation to Day 28
Time to Absence of Fever	Fever was considered present based on the diary cards if a subject reported a maximal temperature ≥38.0°C (for the period since the diary card was previously completed) or reported having taken an antipyretic drug (also for the period since the diary card was previously completed). Otherwise, fever was considered not present during the period since the diary card was previously completed, except that the evaluation was considered missing if either the temperature or the antipyretic drug use entry was not completed on the diary card. The duration of fever was defined as the time from Day 0 to the first of two successive assessments (through to Day 7) or to the first assessment (Day 8 onwards) at which no fever was present according to this definition.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with fever evaluated.	From treatment initiation to Day 28
Time to Resolution of All Symptoms AND Fever	The assessed symptoms were cough, nasal obstruction (stuffy nose), sore throat, fatigue, headache, muscle aches, feverishness, rhinorrhea, nausea, vomiting, diarrhea. Fever was considered present based on the diary cards if a subject reported a maximal temperature ≥38.0°C (for the period since the diary card was previously completed) or reported having taken an antipyretic drug (also for the period since the diary card was previously completed). Time to resolution of all clinical symptoms and fever is defined as the time from Day 0 to the first of two successive measurements at which all clinical symptoms are grade 0 (absent) or 1(mild) and no fever >=38.0 C or antipyretic drug is reported. For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with symptoms and fever evaluated.	From treatment initiation to Day 28
Time to Feeling as Good as Before the Onset of the Influenza Illness	Time to feeling as good as before influenza is defined as time to the first of two successive 'yes' responses to the question of 'feeling as good as you did before you had the flu'.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with question answered.	From treatment initiation to Day 28
Time to Return to Pre-influenza Function	Time to return to pre-influenza function is defined as the time from Day 0 to the first of two successive 'Yes' answers to the global assessment question 'Are you functioning as well as you were before you had the flu'.For participants who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with question answered.	From treatment initiation to Day 28
Time to Return of Physical Function to Pre-illness Leve	Time to return of physical function to pre-illness level was defined as the time from Day 0 to the first of two successive measurements at which the physical function score equals or is better than the pre-illness score (obtained by recall at enrollment).For subjects who did not have two successive records meeting this criterion, follow-up was censored for analysis purposes at the time of the last but one diary card record with physical function evaluated.	From treatment initiation to Day 28
Percentage of Participants With Clinical Failure at Day 5	Clinical failure at Day 5 is defined as the need for continued (non-study) antiviral use after Day 5.	From treatment initiation to Day 28
Percentage of Participants Who Develop Bronchitis, Pneumonia, or Other Complications of Influenza After Day 0.	Participants were assessed for the signs/symptoms suggestive of one of the following complications: Sinusitis, Otitis Media ,Bronchitis / Bronchiolitis, Pneumonia and antibiotic use for reason other than above.	From treatment initiation to Day 28
Percentage of Participants Who Required New or Increased Use of Supplemental Oxygen	Percentage of participants who required new or increased use of supplemental oxygen	From treatment initiation to Day 28
Percentage of Participants Who Required Hospitalization.	The percentage of participants hospitalized by 28 days was estimated from the Kaplan-Meier curves.	From treatment initiation to Day 28
28-day Mortality	Number of deaths	From treatment initiation to Day 28

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: John Beigel, MD, Leidos Biomedical Research, Inc. in support of Clinical Research Section, LIR, NIAID, Natinal Institutes of Health; Study Chair: John Treanor, MD, University of Rochester

Publications and helpful links

General Publications

• 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.
• Monto AS. Vaccines and antiviral drugs in pandemic preparedness. Emerg Infect Dis. 2006 Jan;12(1):55-60. doi: 10.3201/eid1201.051068.
• 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.
• 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.

Helpful Links

• NIH Clinical Center Detailed Web Page
• The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009).

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): May 2, 2016
• Study Completion (Actual): March 30, 2017

Study Registration Dates

• First Submitted: October 22, 2010
• First Submitted That Met QC Criteria: October 22, 2010
• First Posted (Estimate): October 25, 2010

Study Record Updates

• Last Update Posted (Actual): February 4, 2019
• Last Update Submitted That Met QC Criteria: January 31, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Synergy; At Risk; H1N1; Adaptive Design; TCAD
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antimetabolites; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Ribavirin; Oseltamivir; Amantadine
• Other Study ID Numbers: 10-I-0210; IRC003