Influenza Clinical Trial
— IRC003Official 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
Verified date | January 2019 |
Source | National Institute of Allergy and Infectious Diseases (NIAID) |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 881 |
Est. completion date | March 30, 2017 |
Est. primary completion date | May 2, 2016 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility |
- 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. |
Country | Name | City | State |
---|---|---|---|
Argentina | Centro de Educación Médica e Investigaciónes Clínicas (CEMIC) | Buenos Aires | |
Argentina | Fundación del Centro de Estudios Infectológicos (FUNCEI) | Buenos Aires | |
Argentina | Hospital General de Agudos J. M. Ramos Mejía | Buenos Aires | |
Argentina | Hospital Italiano de Buenos Aires | Buenos Aires | |
Argentina | Hospital Rawson | Cordoba | |
Argentina | Instituto Medico Platense | La Plata | Buenos Aires |
Argentina | Instituto Centralizado de Asistencia e Investigación Clínica Integral (CAICI) | Santa Fe | |
Argentina | Hospital Houssay | Vicente Lopez | Provincia De Buenos Aires |
Australia | Holdsworth House Med Practice | Darlinghurst | New South Wales |
Australia | Taylor Square Private Clinic | Darlinghurst | New South Wales |
Australia | Northside Clinic | Fitzroy North | Victoria |
Australia | Royal Brisbane | Herston | Queensland |
Australia | The Alfred Hospital | Melbourne | Victoria |
Australia | Royal Melbourne Hospital | Parkville | Victoria |
Australia | Westmead Hospital | Westmead | New South Wales |
Mexico | Instituto Nacional de Ciencias Médicas y Nutrición (INCMN) Salvador Zubirán | México City | |
Mexico | Hospital General y de Alta Especialidad "Dr. Manuel GEA Gonzalez" | Tlalpan | |
Mexico | Instituto Nacional de Enfermedades Respiratorias (INER) | Tlalpan | |
Thailand | Siriraj Hospital, Mahidol University | Bangkoknoi | Bangkok |
Thailand | Bamrasnaradura Infectious Diseases Institute | Muang | Nonthaburi |
Thailand | Srinagarind Hospital, Khon Kaen University | Muang | Khon Kaen |
Thailand | HIV-NAT, The Thai Red Cross AIDS | Patumwan | Bangkok |
United States | University of Texas Tech Amarillo | Amarillo | Texas |
United States | University of Colorado | Aurora | Colorado |
United States | NIH Clinical Center | Bethesda | Maryland |
United States | Simon Williamson Clinic | Birmingham | Alabama |
United States | Boston Medical Center | Boston | Massachusetts |
United States | Brigham and Women's Hospital | Boston | Massachusetts |
United States | Massachusetts General Hospital | Boston | Massachusetts |
United States | West Florissant Internists | Bridgeton | Missouri |
United States | James J. Peters, VA Medical Center | Bronx | New York |
United States | Family Medicine Associates of Texas | Carrollton | Texas |
United States | Centennial - IMMUNOe International Research | Centennial | Colorado |
United States | East Valley Family Physicians | Chandler | Arizona |
United States | University of North Carolina-Chapel Hill | Chapel Hill | North Carolina |
United States | University of Virginia | Charlottesville | Virginia |
United States | Northwestern University | Chicago | Illinois |
United States | Clinical Research Solutions - Dr. Bart | Columbia | Tennessee |
United States | 3rd Coast Research Associates | Corpus Christi | Texas |
United States | WCCT Global LLC | Costa Mesa | California |
United States | Ridge Family Practice | Council Bluffs | Iowa |
United States | Henry Ford Health Systems | Detroit | Michigan |
United States | Duke University | Durham | North Carolina |
United States | Clinical Research Advantage/ Skyline Medical Center | Elkhorn | Nebraska |
United States | Horizon Research Group, of Opelousas, LLC | Eunice | Louisiana |
United States | Clinical Research Solutions - Dr. Slandzicki | Franklin | Tennessee |
United States | Prairie Fields Family Medicine | Fremont | Nebraska |
United States | University of Florida | Gainesville | Florida |
United States | Advanced Rx Clinical Research | Garden Grove | California |
United States | Thomas Lenzmeier Family Practice | Glendale | Arizona |
United States | Best Quality Research Inc. | Hialeah | Florida |
United States | Centex Studies Inc. - Dr. Pouzar | Houston | Texas |
United States | Pioneer Research Solutions, Inc. | Houston | Texas |
United States | University of Texas at Houston | Houston | Texas |
United States | University of Iowa | Iowa City | Iowa |
United States | Clinical Research Solutions - Dr. Hoppers | Jackson | Tennessee |
United States | Bronson Methodist Hospital | Kalamazoo | Michigan |
United States | Holston Medical Group | Kingsport | Tennessee |
United States | Centex Studies Inc. - Dr. Seep | Lake Charles | Louisiana |
United States | Torrance Clinical Research Institute, Inc. | Lomita | California |
United States | University of Southern California | Los Angeles | California |
United States | Texas Tech HSC | Lubbock | Texas |
United States | Medical Consulting Center | Miami | Florida |
United States | San Marcus Research Clinic, Inc. | Miami | Florida |
United States | Suncoast Research Group, LLC | Miami | Florida |
United States | University of Miami | Miami | Florida |
United States | Clinical Research Solutions - Dr. Panuto | Middleburg Heights | Ohio |
United States | Clinical Research Solutions - Dr. Rowe | Nashville | Tennessee |
United States | Icahn School of Medicine at Mount Sinai | New York | New York |
United States | New Jersey Medical School | Newark | New Jersey |
United States | Sneeze, Wheeze & Itch Associates, LLC | Normal | Illinois |
United States | Southwest Family Physicians | Omaha | Nebraska |
United States | Research Integrity, LLC | Owensboro | Kentucky |
United States | Centex Studies Inc. - Dr. Garcia | Pharr | Texas |
United States | University of Pennsylvania | Philadelphia | Pennsylvania |
United States | Central Phoenix Medical Center | Phoenix | Arizona |
United States | DMI Research, Inc. | Pinellas Park | Florida |
United States | University of Pittsburgh | Pittsburgh | Pennsylvania |
United States | Village Health Partners | Plano | Texas |
United States | Health Concepts | Rapid City | South Dakota |
United States | Virginia Commonwealth University | Richmond | Virginia |
United States | University of Rochester Medical Center | Rochester | New York |
United States | Bandera Family Healthcare Research | San Antonio | Texas |
United States | Endeavor Clinical Trials | San Antonio | Texas |
United States | University of California at San Diego | San Diego | California |
United States | Montgomery Medical | Smithfield | Pennsylvania |
United States | Clinical Research Solutions - Dr. Dar | Smyrna | Tennessee |
United States | Westlake Medical Research (CA) | Thousand Oaks | California |
United States | Los Angeles BioMedical Research Institute | Torrance | California |
United States | Empire Clinical Research | Upland | California |
United States | UMass Medical School | Worcester | Massachusetts |
Lead Sponsor | Collaborator |
---|---|
National Institute of Allergy and Infectious Diseases (NIAID) |
United States, Argentina, Australia, Mexico, Thailand,
Monto AS. Vaccines and antiviral drugs in pandemic preparedness. Emerg Infect Dis. 2006 Jan;12(1):55-60. — View Citation
Moscona A. Oseltamivir resistance--disabling our influenza defenses. N Engl J Med. 2005 Dec 22;353(25):2633-6. — View 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. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | 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. | |
Secondary | qPCR Viral Shedding | Median, 25% and 75% percentile of the value of viral shedding (Results At Day 0, 3 and 7 |
| |
Secondary | 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. | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 28-day Mortality | Number of deaths | From treatment initiation to Day 28 |
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