Influenza
Conditions
Keywords
Influenza, Immunocompromised, Antiviral
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
Interventions
DRUGTCAD
TCAD (amantadine hydrocholoride, ribavirin and oseltamivir phosphate)
DRUGZanamivir or Oseltamivir
Zanamivir or Oseltamivir
OTHEROpen label treatment with TCAD
TCAD(amantadine hydrocholoride, ribavirin and oseltamivir phosphate)
Sponsors
Fred Hutchinson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Not Shedding Virus at Day 5 +/-1 and Day 10 +/- 1 | 10 days | — |
| 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 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 |
| Frequency of Confirmed Pneumonia | 58 days | — |
| Duration of Hospitalization | from baseline up to 58 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. |
| Number of Participants With ICU Admissions | baseline and up to 58 days | The number of participants with ICU admissions was evaluated. |
| Number of Participants With Intubations | 58 days | — |
| Number of Deaths | 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. |
| Days on Supplemental Oxygen | 58 days | — |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from subjects who had a hematopoietic cell transplantation (HCT) within 2 years or combination chemotherapy within 3 months, those with chronic graft-versus-host disease (GVHD) requiring systemic treatment after 2 years post HCT, or with GVHD taking at least 2 immunosuppressive drugs between February - September, 2009
Participants by arm
| Arm | Count |
|---|---|
| TCAD This substudy was a randomized study comparing TCAD therapy and OSL monotherapy in immunocompromised patients with upper respiratory tract infection due to influenza A who were over 7 years of age and who were not asthmatic. | 2 |
| Neuraminidase Inhibitor Monotheraphy Neuraminidase inhibitors include zanamivir and oseltamivir phosphate in this study. | 1 |
| Open-Labeled TCAD Subjects with moderate respiratory symptoms and/or influenza-related lower respiratory tract disease, subjects who could not tolerate zanamivir, and children aged 1-6 years received open-label TCAD. | 4 |
| Total | 7 |
Baseline characteristics
| Characteristic | Neuraminidase Inhibitor Monotheraphy | Open-Labeled TCAD | TCAD | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Age Continuous | 17 years STANDARD_DEVIATION 0 | 29.5 years STANDARD_DEVIATION 26 | 59.5 years STANDARD_DEVIATION 17.7 | 36.3 years STANDARD_DEVIATION 25.7 |
| Region of Enrollment United States | 1 participants | 4 participants | 2 participants | 7 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 2 | 0 / 1 | 0 / 4 |
| serious Total, serious adverse events | 1 / 2 | 1 / 1 | 1 / 4 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs), Drug Specific AEs or AEs Resulting in Treatment Interruption
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)
Time frame: 30 days after the final dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TCAD | Number of Participants With Adverse Events (AEs), Drug Specific AEs or AEs Resulting in Treatment Interruption | 1 number of participants with AEs |
| Neuraminidase Inihibitor Monotherapy | Number of Participants With Adverse Events (AEs), Drug Specific AEs or AEs Resulting in Treatment Interruption | 1 number of participants with AEs |
| Open-labeled TCAD | Number of Participants With Adverse Events (AEs), Drug Specific AEs or AEs Resulting in Treatment Interruption | 1 number of participants with AEs |
Secondary
Days on Supplemental Oxygen
Time frame: 58 days
Population: One open-labeled TCAD patient withdrew on day 5.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TCAD | Days on Supplemental Oxygen | 2 days | Standard Deviation 1.4 |
| Neuraminidase Inihibitor Monotherapy | Days on Supplemental Oxygen | 0 days | — |
| Open-labeled TCAD | Days on Supplemental Oxygen | 0 days | Standard Deviation 0 |
Secondary
Duration of Hospitalization
Time frame: from baseline up to 58 days
Population: One open-labeled patient withdrew the study on day 5
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TCAD | Duration of Hospitalization | 6 days | Standard Deviation 8.5 |
| Neuraminidase Inihibitor Monotherapy | Duration of Hospitalization | 6 days | — |
| Open-labeled TCAD | Duration of Hospitalization | 1 days | Standard Deviation 1.7 |
Secondary
Duration of Symptoms
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
Time frame: from baseline up to 28 days
Population: one open labeled patient withdrew on day 5.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TCAD | Duration of Symptoms | 4.5 days | Standard Deviation 6.4 |
| Neuraminidase Inihibitor Monotherapy | Duration of Symptoms | 1 days | — |
| Open-labeled TCAD | Duration of Symptoms | 4.7 days | Standard Deviation 3.8 |
Secondary
Frequency of Confirmed Pneumonia
Time frame: 58 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TCAD | Frequency of Confirmed Pneumonia | 0 participants |
| Neuraminidase Inihibitor Monotherapy | Frequency of Confirmed Pneumonia | 0 participants |
| Open-labeled TCAD | Frequency of Confirmed Pneumonia | 1 participants |
Secondary
Number of Deaths
Time frame: 58 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TCAD | Number of Deaths | 0 participants |
| Neuraminidase Inihibitor Monotherapy | Number of Deaths | 0 participants |
| Open-labeled TCAD | Number of Deaths | 0 participants |
Secondary
Number of Participants With ICU Admissions
The number of participants with ICU admissions was evaluated.
Time frame: baseline and up to 58 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TCAD | Number of Participants With ICU Admissions | 0 participants |
| Neuraminidase Inihibitor Monotherapy | Number of Participants With ICU Admissions | 0 participants |
| Open-labeled TCAD | Number of Participants With ICU Admissions | 1 participants |
Secondary
Number of Participants With Intubations
Time frame: 58 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TCAD | Number of Participants With Intubations | 0 participants |
| Neuraminidase Inihibitor Monotherapy | Number of Participants With Intubations | 0 participants |
| Open-labeled TCAD | Number of Participants With Intubations | 1 participants |
Secondary
Number of Participants With Viral Load Decrease as a Function of Time
Viral loads were measured by quantitative Polymerase Chain Reaction (PCR) on day 1, 3, 5, 7, 9, 15, 20 and 28, if applicable.
Time frame: baseline and 28 days
Population: Three patients could not get viral load at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neuraminidase Inihibitor Monotherapy | Number of Participants With Viral Load Decrease as a Function of Time | 0 number of participants |
| Open-labeled TCAD | Number of Participants With Viral Load Decrease as a Function of Time | 2 number of participants |
Secondary
Number of Participants With Viral Resistance as a Function of Drug Exposure
Viral resistance was assessed within 28 days after drug administration by detecting resistance-conferring mutation genes and compared to the value at baseline.
Time frame: 28 days
Population: One open-labeled patient withdrew on day 5.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TCAD | Number of Participants With Viral Resistance as a Function of Drug Exposure | 0 Number of participants |
| Neuraminidase Inihibitor Monotherapy | Number of Participants With Viral Resistance as a Function of Drug Exposure | 1 Number of participants |
| Open-labeled TCAD | Number of Participants With Viral Resistance as a Function of Drug Exposure | 0 Number of participants |
Secondary
Number of Patients Not Shedding Virus at Day 5 +/-1 and Day 10 +/- 1
Time frame: 10 days
Population: Participants assessed for viral shedding were those with available baseline viral load data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Neuraminidase Inihibitor Monotherapy | Number of Patients Not Shedding Virus at Day 5 +/-1 and Day 10 +/- 1 | Day 5 +/-1 | 0 participants |
| Neuraminidase Inihibitor Monotherapy | Number of Patients Not Shedding Virus at Day 5 +/-1 and Day 10 +/- 1 | Day 10 +/- 1 | 0 participants |
| Open-labeled TCAD | Number of Patients Not Shedding Virus at Day 5 +/-1 and Day 10 +/- 1 | Day 5 +/-1 | 0 participants |
| Open-labeled TCAD | Number of Patients Not Shedding Virus at Day 5 +/-1 and Day 10 +/- 1 | Day 10 +/- 1 | 1 participants |
Secondary
Pharmacokinetics (AUC0-last) of TCAD
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.
Time frame: 5 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TCAD | Pharmacokinetics (AUC0-last) of TCAD | 304 ng*hr/mL | — |
| Neuraminidase Inihibitor Monotherapy | Pharmacokinetics (AUC0-last) of TCAD | 1497 ng*hr/mL | — |
| Open-labeled TCAD | Pharmacokinetics (AUC0-last) of TCAD | 2487 ng*hr/mL | Standard Deviation 2770 |