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

NCT ID: NCT01227967

Last Updated: 2019-02-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 881 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-09-30
• Study Completion Date: 2017-03-30

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.

Conditions

Influenza

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Combination Therapy

Amantadine, Ribavirin, Oseltamivir

Group Type: EXPERIMENTAL

Amantadine, Ribavirin, Oseltamivir

Intervention Type: DRUG

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.

Oseltamivir monotherapy

Oseltamivir

Group Type: ACTIVE_COMPARATOR

Oseltamivir

Intervention Type: DRUG

Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

Interventions

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.

Intervention Type: DRUG

Oseltamivir

Subjects were prescribed the medication twice daily for 5 days, and each dose consisted of one capsule of Oseltamivir 75 mg.

Intervention Type: DRUG

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
• Chronic lung disease (such as COPD and cystic fibrosis)
• Heart disease (such as congenital heart disease, congestive heart failure, and coronary artery disease)

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

(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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

John Beigel, MD

Role: STUDY_CHAIR

Leidos Biomedical Research, Inc. in support of Clinical Research Section, LIR, NIAID, Natinal Institutes of Health

John Treanor, MD

Role: STUDY_CHAIR

University of Rochester

Locations

Simon Williamson Clinic

Birmingham, Alabama, United States

East Valley Family Physicians

Chandler, Arizona, United States

Thomas Lenzmeier Family Practice

Glendale, Arizona, United States

Central Phoenix Medical Center

Phoenix, Arizona, United States

WCCT Global LLC

Costa Mesa, California, United States

Advanced Rx Clinical Research

Garden Grove, California, United States

Torrance Clinical Research Institute, Inc.

Lomita, California, United States

University of Southern California

Los Angeles, California, United States

University of California at San Diego

San Diego, California, 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

University of Colorado

Aurora, Colorado, United States

Centennial - IMMUNOe International Research

Centennial, Colorado, United States

University of Florida

Gainesville, Florida, United States

Best Quality Research Inc.

Hialeah, Florida, United States

San Marcus Research Clinic, Inc.

Miami, Florida, United States

Medical Consulting Center

Miami, Florida, United States

Suncoast Research Group, LLC

Miami, Florida, United States

University of Miami

Miami, Florida, United States

DMI Research, Inc.

Pinellas Park, Florida, United States

Northwestern University

Chicago, Illinois, United States

Sneeze, Wheeze & Itch Associates, LLC

Normal, Illinois, United States

Ridge Family Practice

Council Bluffs, Iowa, United States

University of Iowa

Iowa City, Iowa, United States

Research Integrity, LLC

Owensboro, Kentucky, United States

Horizon Research Group, of Opelousas, LLC

Eunice, Louisiana, United States

Centex Studies Inc. - Dr. Seep

Lake Charles, Louisiana, United States

NIH Clinical Center

Bethesda, Maryland, United States

Boston Medical Center

Boston, Massachusetts, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

UMass Medical School

Worcester, Massachusetts, United States

Henry Ford Health Systems

Detroit, Michigan, United States

Bronson Methodist Hospital

Kalamazoo, Michigan, United States

West Florissant Internists

Bridgeton, Missouri, United States

Clinical Research Advantage/ Skyline Medical Center

Elkhorn, Nebraska, United States

Prairie Fields Family Medicine

Fremont, Nebraska, United States

Southwest Family Physicians

Omaha, Nebraska, United States

New Jersey Medical School

Newark, New Jersey, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

University of Rochester Medical Center

Rochester, New York, United States

James J. Peters, VA Medical Center

The Bronx, New York, United States

University of North Carolina-Chapel Hill

Chapel Hill, North Carolina, United States

Duke University

Durham, North Carolina, United States

Clinical Research Solutions - Dr. Panuto

Middleburg Heights, Ohio, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Montgomery Medical

Smithfield, Pennsylvania, United States

Health Concepts

Rapid City, South Dakota, United States

Clinical Research Solutions - Dr. Bart

Columbia, Tennessee, United States

Clinical Research Solutions - Dr. Slandzicki

Franklin, Tennessee, United States

Clinical Research Solutions - Dr. Hoppers

Jackson, Tennessee, United States

Holston Medical Group

Kingsport, Tennessee, United States

Clinical Research Solutions - Dr. Rowe

Nashville, Tennessee, United States

Clinical Research Solutions - Dr. Dar

Smyrna, Tennessee, United States

University of Texas Tech Amarillo

Amarillo, Texas, United States

Family Medicine Associates of Texas

Carrollton, Texas, United States

3rd Coast Research Associates

Corpus Christi, Texas, United States

University of Texas at Houston

Houston, Texas, United States

Centex Studies Inc. - Dr. Pouzar

Houston, Texas, United States

Pioneer Research Solutions, Inc.

Houston, Texas, United States

Texas Tech HSC

Lubbock, Texas, United States

Centex Studies Inc. - Dr. Garcia

Pharr, Texas, United States

Village Health Partners

Plano, Texas, United States

Endeavor Clinical Trials

San Antonio, Texas, United States

Bandera Family Healthcare Research

San Antonio, Texas, United States

University of Virginia

Charlottesville, Virginia, United States

Virginia Commonwealth University

Richmond, Virginia, United States

Instituto Medico Platense

La Plata, Buenos Aires, Argentina

Hospital Houssay

Vicente López, Buenos Aires, 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

Córdoba, , Argentina

Instituto Centralizado de Asistencia e Investigación Clínica Integral (CAICI)

Santa Fe, , Argentina

Holdsworth House Med Practice

Darlinghurst, New South Wales, Australia

Taylor Square Private Clinic

Darlinghurst, New South Wales, Australia

Westmead Hospital

Westmead, New South Wales, Australia

Royal Brisbane

Herston, Queensland, Australia

Northside Clinic

Fitzroy North, Victoria, Australia

The Alfred Hospital

Melbourne, Victoria, Australia

Royal Melbourne Hospital

Parkville, Victoria, Australia

Instituto Nacional de Ciencias Médicas y Nutrición (INCMN) Salvador Zubirán

México, , Mexico

Hospital General y de Alta Especialidad "Dr. Manuel GEA Gonzalez"

Tlalpan, , Mexico

Instituto Nacional de Enfermedades Respiratorias (INER)

Tlalpan, , Mexico

Siriraj Hospital, Mahidol University

Bangkoknoi, Bangkok, Thailand

HIV-NAT, The Thai Red Cross AIDS

Patumwan, Bangkok, Thailand

Srinagarind Hospital, Khon Kaen University

Muang, Changwat Khon Kaen, Thailand

Bamrasnaradura Infectious Diseases Institute

Muang, Changwat Nonthaburi, Thailand

Countries

United States; Argentina; Australia; Mexico; Thailand

References

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.

Reference Type: BACKGROUND

PMID: 12517228 (View on PubMed)

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

Reference Type: BACKGROUND

PMID: 16494718 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16371626 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28958678 (View on PubMed)

Related Links

http://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2010-I-0210.html

NIH Clinical Center Detailed Web Page

https://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables

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).

Other Identifiers

10-I-0210

Identifier Type: -

Identifier Source: secondary_id

IRC003

Identifier Type: -

Identifier Source: secondary_id

10-I-0210

Identifier Type: -

Identifier Source: org_study_id