TCAD vs. Monotherapy for Influenza A in Immunocompromised Patients

Phase 1

Completed

• Conditions: Influenza
• Interventions: Drug: Zanamivir or Oseltamivir; Drug: TCAD; Other: Open label treatment with TCAD

• Registration Number: NCT00867139
• Lead Sponsor: Fred Hutchinson Cancer 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

Detailed Description

Not available

Study Timeline

• Study Start: 2009-03
• Study First Submitted: 2009-03-20
• Study First Submitted QC: 2009-03-20
• Study First Posted: 2009-03-23
• Primary Completion: 2009-08
• Study Completion: 2010-01
• Results First Submitted: 2012-12-21
• Results First Submitted QC: 2013-04-26
• Results First Posted: 2013-06-04
• Status Verified: 2013-08
• Last Update Submitted: 2013-08-08
• Last Update Posted: 2013-08-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 7

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:

4. 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

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Neuraminidase Monotherapy Arm	Zanamivir or Oseltamivir	Zanamivir or Oseltamivir
TCAD-Randomized Arm	TCAD	TCAD (amantadine hydrocholoride, ribavirin and oseltamivir phosphate)
TCAD Open Label Arm	Open label treatment with TCAD	TCAD for subjects who cannot tolerate or are ineligible to receive zanamivir

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AEs), Drug Specific AEs or AEs Resulting in Treatment Interruption	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

Name	Time	Method
Number of Patients Not Shedding Virus at Day 5 +/-1 and Day 10 +/- 1	10 days
Number of Participants With Viral Load Decrease as a Function of Time	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.
Frequency of Confirmed Pneumonia	58 days
Number of Participants With Intubations	58 days
Number of Deaths	58 days
Duration of Symptoms	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
Days on Supplemental Oxygen	58 days
Pharmacokinetics (AUC0-last) of TCAD	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.
Number of Participants With Viral Resistance as a Function of Drug Exposure	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.
Duration of Hospitalization	from baseline up to 58 days
Number of Participants With ICU Admissions	baseline and up to 58 days	The number of participants with ICU admissions was evaluated.

Trial Locations

Locations (2)

Seattle Children's; 🇺🇸 Seattle, Washington, United States

Fred Hutchinson Cancer Research Center; 🇺🇸 Seattle, Washington, United States