TCAD vs. Monotherapy for Influenza A in Immunocompromised Patients

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Influenza

Intervention / Treatment
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* Drug: TCAD
* Drug: Zanamivir or Oseltamivir
* Other: Open label treatment with TCAD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: i. Inclusion criteria for randomized arms (both needed): Age ≥7 years, male or female; AND Influenza infection (i.e. upper respiratory tract infection) ii. Inclusion criteria for open-label arm (at least one criteria required): Young age (1-6 years) with any influenza severity, proven or probable influenza A (H1N1)(H274Y); OR History of asthma; OR 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): Nausea that prevents taking oral medications 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. Creatinine clearance (estimated by serum creatinine) less than 30 ml/min Current clinical evidence of a recognized or suspected uncontrolled non-influenza infectious illness with onset prior to screening Known hypersensitivity to amantadine, ribavirin, oseltamivir or zanamivir Women who are pregnant (positive serum or urine pregnancy test), who are attempting to become pregnant, or who are breast-feeding Psychiatric or cognitive illness, or recreational drug/alcohol use that, in the opinion of the principal investigator, would affect patient safety and/or compliance Uncontrolled seizure disorder or history of a seizure activity within 12 months prior to study participation 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 Documented Influenza B viral co-infection

Ages Eligible for Study
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Minimum Age: 1 Year

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TCAD-Randomized Arm<br>TCAD (amantadine hydrocholoride, ribavirin and oseltamivir phosphate) | Drug: TCAD<br>* TCAD (amantadine hydrocholoride, ribavirin and oseltamivir phosphate)<br>* Other names: Tamiflu;|
| Active Comparator: Neuraminidase Monotherapy Arm<br>Zanamivir or Oseltamivir | Drug: Zanamivir or Oseltamivir<br>* Zanamivir or Oseltamivir<br>* Other names: Tamiflu;|
| Other: TCAD Open Label Arm<br>TCAD for subjects who cannot tolerate or are ineligible to receive zanamivir | Other: Open label treatment with TCAD<br>* TCAD(amantadine hydrocholoride, ribavirin and oseltamivir phosphate)<br>* Other names: Tamiflu;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 30 days after the final dose of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | baseline and 28 days | 
| 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 | Viral resistance was assessed within 28 days after drug administration by detecting resistance-conferring mutation genes and compared to the value at baseline. | 28 days | 
| 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 | from baseline up to 28 days | 
| Frequency of Confirmed Pneumonia |  | 58 days | 
| Duration of Hospitalization |  | from baseline up to 58 days | 
| Days on Supplemental Oxygen |  | 58 days | 
| Number of Participants With ICU Admissions | The number of participants with ICU admissions was evaluated. | baseline and up to 58 days | 
| Number of Participants With Intubations |  | 58 days | 
| Number of Deaths |  | 58 days | 
| 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. | 5 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Influenza, Immunocompromised, Antiviral