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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

Information source: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Influenza

Intervention: Amantadine, Ribavirin, Oseltamivir (Drug); Oseltamivir (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
John Beigel, MD, Study Chair, Affiliation: Leidos Biomedical Research, Inc. in support of Clinical Research Section, LIR, NIAID, Natinal Institutes of Health
John Treanor, MD, Study Chair, Affiliation: University of Rochester, School of Medicine and Dentistry

Overall contact:
Patient Recruitment and Public Liaison Office, Phone: (800) 411-1222, Email: prpl@mail.cc.nih.gov

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 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.

Clinical Details

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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome: Evaluate the reproducibility of virologic samples, comparison between culture and PCR, and the impact of missing data between randomized groups.

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 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.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

- 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

Locations and Contacts

Patient Recruitment and Public Liaison Office, Phone: (800) 411-1222, Email: prpl@mail.cc.nih.gov

Centro de Educación Médica e Investigaciónes Clínicas (CEMIC), Buenos Aires, Argentina; Completed

Fundación del Centro de Estudios Infectológicos (FUNCEI), Buenos Aires, Argentina; Recruiting
Gustavo Daniel Lopardo, Phone: (011) 4809-4206

Hospital General de Agudos J. M. Ramos Mejía, Buenos Aires, Argentina; Recruiting
Marcelo Losso, MD, Phone: 5411-4931-5252, Email: mlosso@hivramos.org.ar

Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; Completed

Hospital Rawson, Cordoba, Argentina; Recruiting
Daniel David, MD, Phone: (54 351) 422-7452, Email: danielo.david@gmail.com

Instituto Centralizado de Asistencia e Investigación Clínica Integral (CAICI), Santa Fe, Argentina; Recruiting
Sergio Horacia Lupo, Phone: (54-341) 424-8045

Instituto Nacional de Ciencias Médicas y Nutrición (INCMN) Salvador Zubirán, México City, Mexico; Recruiting
Francisco Astudillo, MD, Phone: (52-55) 5487-0900, Ext: 2420
Itzel Cruz, MD, Phone: (52-55) 5487-0900, Ext: 2420

Hospital General y de Alta Especialidad "Dr. Manuel GEA Gonzalez", Tlalpan, Mexico; Completed

Instituto Nacional de Enfermedades Respiratorias (INER), Tlalpan, Mexico; Recruiting
Javier Romo Garcia, MD, Phone: 52 (55) 5487-1700, Ext: 5295
Roberto Sanchez, MD, Phone: 52 (55) 5487-1700, Ext: 5295

Simon Williamson Clinic, Birmingham, Alabama 35211, United States; Completed

Thomas Lenzmeier Family Practice, Glendale, Arizona 85308, United States; Recruiting
Meghan Caldron, Phone: 623-295-1711, Email: mcaldron@crastudies.com

Siriraj Hospital, Mahidol University, Bangkoknoi, Bangkok 10700, Thailand; Recruiting
Winai Ratanasuwan, MD, Phone: +66-24-197-388, Email: srwrt@mahidol.ac.th

HIV-NAT, The Thai Red Cross AIDS, Patumwan, Bangkok 10330, Thailand; Recruiting
Anchalee Avihingsanon, Phone: +66-26-523-040, Ext: 107, Email: anchalee.a@hivnat.org

Instituto Medico Platense, La Plata, Buenos Aires, Argentina; Recruiting
Analia Mykietiuk, Phone: 0221-15-419-4421

WCCT Global LLC, Costa Mesa, California 92626, United States; Completed

Advanced Rx Clinical Research, Garden Grove, California 92843, United States; Recruiting
Dianne Huynh, Phone: 714-554-8080, Email: dlhuynh@advancedrxclinicalresearch.com

Torrance Clinical Research Institute, Inc., Lomita, California 90717, United States; Completed

University of Southern California, Los Angeles, California 90033, United States; Recruiting
Luis M. Mendez, BS, Phone: 323-343-8283, Email: lmendez@usc.edu

University of California at San Diego, San Diego, California 92103, United States; Recruiting
Jill Kunkell, RN, Phone: 619-543-8080, Email: jkunkell@ucsd.edu

Westlake Medical Research (CA), Thousand Oaks, California 91360, United States; Completed

Los Angeles BioMedical Research Institute, Torrance, California 90502, United States; Terminated

University of Colorado, Aurora, Colorado 80045, United States; Completed

University of Florida, Gainesville, Florida 32610, United States; Recruiting
Ashley Babinski, Phone: 352-213-9924, Email: babina@shands.ufl.edu

Best Quality Research Inc., Hialeah, Florida 33016, United States; Completed

Medical Consulting Center, Miami, Florida 33125, United States; Completed

San Marcus Research Clinic, Inc., Miami, Florida 33015, United States; Completed

Suncoast Research Group, LLC, Miami, Florida 33135, United States; Recruiting
Carolina Ramirez, Phone: 305-631-6704, Email: eramirez@suncoastresearch.com

University of Miami, Miami, Florida 33136, United States; Completed

DMI Research, Inc., Pinellas Park, Florida 33782, United States; Completed

Northwestern University, Chicago, Illinois 60611, United States; Completed

Sneeze, Wheeze & Itch Associates, LLC, Normal, Illinois 61761, United States; Completed

Ridge Family Practice, Council Bluffs, Iowa 51503, United States; Recruiting
Kylie Scheideler, Phone: 712-352-0423, Email: kyliescheideler@crastudies.com

University of Iowa, Iowa City, Iowa 52246, United States; Recruiting
Patricia Winokur, Phone: 319-384-1735, Email: patricia-winokur@uiowa.edu

Research Integrity, LLC, Owensboro, Kentucky 42303, United States; Completed

Srinagarind Hospital, Khon Kaen University, Muang, Khon Kaen 40002, Thailand; Recruiting
Ploenchan Chetchotisakd, MD, Phone: +66-43-363-168, Email: ploencha@kku.ac.th

Horizon Research Group, of Opelousas, LLC, Eunice, Louisiana 70535, United States; Recruiting
Rachael Boudreaux, Phone: 337-457-8841, Email: rachael@horizonresearchgroup.com

Centex Studies Inc. - Dr. Seep, Lake Charles, Louisiana 70601, United States; Recruiting
Louis Charles, Phone: 337-244-6374, Email: lcharles@centexstudies.com

NIH Clinical Center, Bethesda, Maryland 20892, United States; Active, not recruiting

Boston Medical Center, Boston, Massachusetts 02111, United States; Completed

Brigham and Women's Hospital, Boston, Massachusetts 02115, United States; Recruiting
Siddharth Parmar, M.D., Phone: 617-525-8466, Email: sparmar@partners.org

Massachusetts General Hospital, Boston, Massachusetts 02114, United States; Recruiting
Josalyn Cho, Phone: 617-726-1721, Email: jlcho@partners.org

UMass Medical School, Worcester, Massachusetts 01655, United States; Recruiting
Celia Hartigan, RN, Phone: 508-856-2800, Email: celia.hartigan@umassmed.edu

Henry Ford Health Systems, Detroit, Michigan 48202, United States; Completed

Bronson Methodist Hospital, Kalamazoo, Michigan 49007, United States; Recruiting
Gail Massey, RN, BS, CCRP, Phone: 269-341-8774, Email: masseyg@bronsonhg.org

West Florissant Internists, Bridgeton, Missouri 63044, United States; Completed

Clinical Research Advantage/ Skyline Medical Center, Elkhorn, Nebraska 68022, United States; Recruiting
William Patrick Fitzgibbons, M.D., Phone: 402-393-2727

Prairie Fields Family Medicine, Freemont, Nebraska 68025, United States; Recruiting
Shayla Addison, Phone: 402-753-6034, Email: shaylaaddison@crastudies.com

Southwest Family Physicians, Omaha, Nebraska 68124, United States; Recruiting
Jan Mitchell, Phone: 402-505-4497, Email: JanMitchell@crastudies.com

New Jersey Medical School, Newark, New Jersey 07103, United States; Completed

Holdsworth House Med Practice, Darlinghurst, New South Wales 2010, Australia; Completed

Taylor Square Private Clinic, Darlinghurst, New South Wales 2010, Australia; Completed

Westmead Hospital, Westmead, New South Wales, Australia; Completed

James J. Peters, VA Medical Center, Bronx, New York 10468, United States; Completed

Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States; Recruiting
Judith Aberg, MD, Phone: 212-824-7714

University of Rochester Medical Center, Rochester, New York 14642, United States; Completed

Bamrasnaradura Infectious Diseases Institute, Muang, Nonthaburi 11000, Thailand; Recruiting
Weerawat Manosuthi, Phone: +66-25-903-632, Email: drweerawat@hotmail.com

University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27514, United States; Recruiting
Cheryl Marcus, Phone: 919-843-8761, Email: cjm@med.unc.edu

Duke University, Durham, North Carolina 27710, United States; Recruiting
Cameron Wolfe, MD, Phone: 919-970-3885, Email: cameron.wolfe@duke.edu

Clinical Research Solutions - Dr. Panuto, Middleburg Heights, Ohio 44130, United States; Recruiting
Amie Demming, Phone: 440-340-9010, Email: ademming@crssites.com

University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States; Recruiting
Joseph Quinn, Phone: 215-349-8092, Email: joseph.quinn@uphs.upenn.edu

University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States; Completed

Hospital Houssay, Vicente Lopez, Provincia de Buenos Aires, Argentina; Recruiting
Laura Barcelona, Phone: (54-341) 424-8045

Royal Brisbane, Herston, Queensland 4029, Australia; Completed

Health Concepts, Rapid City, South Dakota 57702, United States; Recruiting
Marty Beasley, Phone: 605-348-4141, Email: healthconcepts104@hotmail.com

Clinical Research Solutions - Dr. Bart, Columbia, Tennessee 38401, United States; Recruiting
Beverly Harris, Phone: 931-255-0177, Email: bharris@crssites.com

Clinical Research Solutions - Dr. Slandzicki, Franklin, Tennessee 37064, United States; Recruiting
Debra Adamson, Phone: 615-577-4017, Email: dadamson@crssites.com

Clinical Research Solutions - Dr. Hoppers, Jackson, Tennessee 38305, United States; Recruiting
Amy Arnold, Phone: 731-431-5027, Email: aarnold@crssites.com

Holston Medical Group, Kingsport, Tennessee 37660, United States; Completed

Clinical Research Solutions - Dr. Rowe, Nashville, Tennessee 37211, United States; Recruiting
Ashley Adamson, Phone: 615-693-9742, Email: aadamson@crssites.com

Clinical Research Solutions - Dr. Dar, Smyrna, Tennessee 37167, United States; Recruiting
Ashley Adamson, Phone: 615-577-4017, Email: aadamson@crssites.com

University of Texas Tech Amarillo, Amarillo, Texas 79106, United States; Recruiting
Joann Urben, Phone: 806-354-5582, Email: joann.urben@ttuhsc.edu

3rd Coast Research Associates, Corpus Christi, Texas 78413, United States; Recruiting
Michael Winnie, M.D., Phone: 361-288-4668, Email: mwinnie@3cra.net

Centex Studies Inc. - Dr. Pouzar, Houston, Texas 77062, United States; Recruiting
Shruti Konda, Phone: 281-282-0808, Email: skonda@centexstudies.com

Pioneer Research Solutions, Inc., Houston, Texas 77098, United States; Completed

University of Texas at Houston, Houston, Texas 77030, United States; Completed

Texas Tech HSC, Lubbock, Texas 79430, United States; Completed

Centex Studies Inc. - Dr. Garcia, Pharr, Texas 78577, United States; Recruiting
Norma Sanchez, Phone: 956-342-2626, Email: nsanchez@centexstudies.com

Bandera Family Healthcare Research, San Antonio, Texas 78249, United States; Completed

Endeavor Clinical Trials, San Antonio, Texas 78229, United States; Recruiting
Diego Ceniceros, Phone: 210-949-0807, Email: dceniceros@endeavorct.com

Northside Clinic, Fitzroy North, Victoria 3068, Australia; Completed

The Alfred Hospital, Melbourne, Victoria 3004, Australia; Completed

Royal Melbourne Hospital, Parkville, Victoria 3052, Australia; Completed

University of Virginia, Charlottesville, Virginia 22908, United States; Completed

Virginia Commonwealth University, Richmond, Virginia 23298, United States; Completed

Additional Information

NIH Clinical Center Detailed Web Page

Related 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.

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.

Starting date: September 2010
Last updated: June 11, 2015

Page last updated: August 23, 2015

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