Clinical trial NCT00867139: TCAD vs. Monotherapy for Influenza A in Immunocompromised Patients
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Influenza
Keywords: Influenza
Immunocompromised
Antiviral
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
First posted: 2009-03-23
Enrollment: 7
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility 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

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs), Drug Specific AEs or AEs Resulting in Treatment Interruption
timeFrame: 30 days after the final dose of study drug
Secondary outcomes:
measure: Number of Participants With Viral Load Decrease as a Function of Time
timeFrame: baseline and 28 days
measure: Number of Patients Not Shedding Virus at Day 5 +/-1 and Day 10 +/- 1
timeFrame: 10 days
measure: Number of Participants With Viral Resistance as a Function of Drug Exposure
timeFrame: 28 days
measure: Duration of Symptoms
timeFrame: from baseline up to 28 days
measure: Frequency of Confirmed Pneumonia
timeFrame: 58 days
measure: Duration of Hospitalization
timeFrame: from baseline up to 58 days
measure: Days on Supplemental Oxygen
timeFrame: 58 days
measure: Number of Participants With ICU Admissions
timeFrame: baseline and up to 58 days
measure: Number of Participants With Intubations
timeFrame: 58 days
measure: Number of Deaths
timeFrame: 58 days
measure: Pharmacokinetics (AUC0-last) of TCAD
timeFrame: 5 days
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Seattle Children's
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: Fred Hutchinson Cancer Center
name: Michael Boeckh, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Seo S, Englund JA, Nguyen JT, Pukrittayakamee S, Lindegardh N, Tarning J, Tambyah PA, Renaud C, Went GT, de Jong MD, Boeckh MJ. Combination therapy with amantadine, oseltamivir and ribavirin for influenza A infection: safety and pharmacokinetics. Antivir Ther. 2013;18(3):377-86. doi: 10.3851/IMP2475. Epub 2012 Dec 21.