TCAD vs. Monotherapy for Influenza A in Immunocompromised Patients

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

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

Study Overview

• Status: Completed
• Conditions: Influenza
• Intervention / Treatment: Drug: TCAD; Drug: Zanamivir or Oseltamivir; Other: Open label treatment with TCAD

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center
    • Seattle, Washington, United States, 98105
      • Seattle Children's

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / 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: Tamiflu; Relenza
Other: 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Investigators: Principal Investigator: Michael Boeckh, MD, Fred Hutchinson Cancer Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): August 1, 2009
• Study Completion (Actual): January 1, 2010

Study Registration Dates

• First Submitted: March 20, 2009
• First Submitted That Met QC Criteria: March 20, 2009
• First Posted (Estimate): March 23, 2009

Study Record Updates

• Last Update Posted (Estimate): August 15, 2013
• Last Update Submitted That Met QC Criteria: August 8, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Keywords: Influenza; Immunocompromised; Antiviral
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antimetabolites; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Ribavirin; Zanamivir; Oseltamivir; Amantadine; Thiazole-4-carboxamide adenine dinucleotide
• Other Study ID Numbers: 2323.00; 6895 (FHCRC/UW CC IRB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No