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TCAD vs. Monotherapy for Influenza A in Immunocompromised Patients

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ClinicalTrials.gov Identifier: NCT00867139
Recruitment Status : Completed
First Posted : March 23, 2009
Results First Posted : June 4, 2013
Last Update Posted : August 15, 2013
Sponsor:
Information provided by (Responsible Party):
Michael Boeckh, Fred Hutchinson Cancer Research Center

Brief Summary:
The purpose of this study is to assess the safety and tolerability of triple combination antiviral drug (TCAD) for use in immunocompromised patients with Influenza A infection, and to gain data on the effectiveness of TCAD

Condition or disease Intervention/treatment Phase
Influenza Drug: TCAD Drug: Zanamivir or Oseltamivir Other: Open label treatment with TCAD Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot, Randomized Study Comparing the Safety, Tolerability and Pharmacokinetics of Combination Therapy (Amantadine, Ribavirin, Oseltamivir) Versus Neuraminidase Inhibitor Monotherapy to Influenza Virus Infected Immunocompromised Patients
Study Start Date : March 2009
Actual Primary Completion Date : August 2009
Actual Study Completion Date : January 2010

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Flu Flu Shot

Arm Intervention/treatment
Experimental: TCAD-Randomized Arm
TCAD (amantadine hydrocholoride, ribavirin and oseltamivir phosphate)
Drug: TCAD
TCAD (amantadine hydrocholoride, ribavirin and oseltamivir phosphate)
Other Names:
  • Symmetrel
  • Rebetol
  • Tamiflu

Active Comparator: Neuraminidase Monotherapy Arm
Zanamivir or Oseltamivir
Drug: Zanamivir or Oseltamivir
Zanamivir or Oseltamivir
Other Names:
  • Relenza
  • Tamiflu

TCAD Open Label Arm
TCAD for subjects who cannot tolerate or are ineligible to receive zanamivir
Other: Open label treatment with TCAD
TCAD(amantadine hydrocholoride, ribavirin and oseltamivir phosphate)
Other Names:
  • Symmetrel
  • Rebetol
  • Tamiflu




Primary Outcome Measures :
  1. Number of Participants With Adverse Events (AEs), Drug Specific AEs or AEs Resulting in Treatment Interruption [ Time Frame: 30 days after the final dose of study drug ]

    Abnormal lab data or newly appeared symptoms & signs were considered as AEs.

    Examined lab data:

    Blood cell count (WBC, differential count, Red Blood Cell (RBC), Hemoglobin, Hematocrit, Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin Concentration (MCHC), platelets), Chemistry (Cl, bicarbonate (HCO3), K, Na), Renal function test (BUN, Creatinine, Creatinine clearance), Liver function test (AST, Alanine aminotransferase(ALT), T.Bil, gamma-glutamyltransferase)



Secondary Outcome Measures :
  1. Number of Participants With Viral Load Decrease as a Function of Time [ Time Frame: baseline and 28 days ]
    Viral loads were measured by quantitative Polymerase Chain Reaction (PCR) on day 1, 3, 5, 7, 9, 15, 20 and 28, if applicable.

  2. Number of Patients Not Shedding Virus at Day 5 +/-1 and Day 10 +/- 1 [ Time Frame: 10 days ]
  3. Number of Participants With Viral Resistance as a Function of Drug Exposure [ Time Frame: 28 days ]
    Viral resistance was assessed within 28 days after drug administration by detecting resistance-conferring mutation genes and compared to the value at baseline.

  4. Duration of Symptoms [ Time Frame: from baseline up to 28 days ]

    Calculated as the number of days (mean) any persistent symptom lasted per patient as listed below.

    overall health, short of breath, chills, cough, diarrhea, ear pain, fatigue, fever, headache, hoarseness, muscle ache, phlegm, runny nose, sinus congestion, sneezing, sore throat, watery eyes, wheezing


  5. Frequency of Confirmed Pneumonia [ Time Frame: 58 days ]
  6. Duration of Hospitalization [ Time Frame: from baseline up to 58 days ]
  7. Days on Supplemental Oxygen [ Time Frame: 58 days ]
  8. Number of Participants With ICU Admissions [ Time Frame: baseline and up to 58 days ]
    The number of participants with ICU admissions was evaluated.

  9. Number of Participants With Intubations [ Time Frame: 58 days ]
  10. Number of Deaths [ Time Frame: 58 days ]
  11. Pharmacokinetics (AUC0-last) of TCAD [ Time Frame: 5 days ]
    Only 5 patients had partial pharmacokinetic (PK) data available. Plasma concentration of oseltamivir was measured at several time points in one patient receiving neuraminidase inhibitor monotherapy. Plasma concentration of oseltamivir, amantadine, and ribavirin were measured at several time points in four patients receiving TCAD therapy. Area under the time-concentration curve up to the last measured time point (AUC0-last) was calculated from the plasma concentration-time profiles by non-compartmental analysis.



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Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

i. Inclusion criteria for randomized arms (both needed):

  1. Age ≥7 years, male or female; AND
  2. Influenza infection (i.e. upper respiratory tract infection)

ii. Inclusion criteria for open-label arm (at least one criteria required):

  1. Young age (1-6 years) with any influenza severity, proven or probable influenza A (H1N1)(H274Y); OR
  2. History of asthma; OR
  3. Older age (≥ 7 years), with no asthma; AND

    • moderate to severe influenza; AND/OR
    • failure in randomized study monotherapy arm iii. Inclusion criteria for all subjects:

1. Able to provide informed consent, or for whom consent may be provided by guardian 2. Immunocompromised, as defined by one of the following:

  • Recent hematopoietic cell transplantation (HCT) (within 2 years, all conditioning regimens, allogeneic, autologous, syngeneic; after 2 years patients with chronic graft-versus-host disease (GVHD) requiring systemic treatment may be included) or solid organ transplantation
  • Patients taking at least 2 immunosuppressants
  • Patients undergoing combination chemotherapy within the past 3 month 3. One or more of the following:
  • Presence of fever at time of screening of ≥ 38.0°C (≥ 100.0°F) taken orally.
  • presence of at least one constitutional symptom (headache, myalgia, malaise, or fatigue) of any severity (mild, moderate, or severe),
  • presence of at least one respiratory symptoms (e.g. cough, or sore throat) of any severity (mild, moderate, or severe),
  • other flu-like symptoms, where the clinician orders a respiratory virus test including influenza A or B 4. Positive test for influenza A (if available) 5. Onset of illness no more than 5 days prior to diagnosis. 6. Females patients of child-bearing age who are capable of conception (i.e. previously have not undergone surgical sterilization) must meet the following criteria:
  • Have been sexually abstinent or have used contraceptive agents (oral contraceptive or other hormonal contraceptives including vaginal rings or transdermal patches, intrauterine device (IUD), or barrier methods including condoms) during the 4 weeks prior to date of screening (3 months prior to enrollment for oral/hormonal contraceptives)
  • Agree to be sexually abstinent or use contraceptive agents (oral contraceptive or other hormonal contraceptives including vaginal rings or transdermal patches, intrauterine device (IUD), or barrier methods including condoms) from the date of screening through 24 weeks after the last dose of study drug

Exclusion Criteria(all subjects):

  1. Nausea that prevents taking oral medications
  2. Use of antiviral influenza medication within 10 days(unless switched from randomized to open-label TCAD). An exception to this exclusion criterion may be made by site investigators for patients admitted after hours who receive one or two initial doses of antiviral influenza medication prior to enrollment.
  3. Creatinine clearance (estimated by serum creatinine) less than 30 ml/min
  4. Current clinical evidence of a recognized or suspected uncontrolled non-influenza infectious illness with onset prior to screening
  5. Known hypersensitivity to amantadine, ribavirin, oseltamivir or zanamivir
  6. Women who are pregnant (positive serum or urine pregnancy test), who are attempting to become pregnant, or who are breast-feeding
  7. Psychiatric or cognitive illness, or recreational drug/alcohol use that, in the opinion of the principal investigator, would affect patient safety and/or compliance
  8. Uncontrolled seizure disorder or history of a seizure activity within 12 months prior to study participation
  9. Any significant finding in the patient's medical history or physical exam on Day 1 that, in the opinion of the investigator, would affect patient safety or compliance with the dosing schedule
  10. Documented Influenza B viral co-infection

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00867139


Locations
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United States, Washington
Seattle Children's
Seattle, Washington, United States, 98105
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
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Principal Investigator: Michael Boeckh, MD Fred Hutchinson Cancer Research Center

Publications of Results:
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Responsible Party: Michael Boeckh, Member, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00867139     History of Changes
Obsolete Identifiers: NCT00865800
Other Study ID Numbers: 2323.00
6895 ( Other Identifier: FHCRC/UW CC IRB )
First Posted: March 23, 2009    Key Record Dates
Results First Posted: June 4, 2013
Last Update Posted: August 15, 2013
Last Verified: August 2013
Keywords provided by Michael Boeckh, Fred Hutchinson Cancer Research Center:
Influenza
Immunocompromised
Antiviral
Additional relevant MeSH terms:
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Oseltamivir
Influenza, Human
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Ribavirin
Amantadine
Zanamivir
Thiazole-4-carboxamide adenine dinucleotide
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents