TCAD vs. Monotherapy for Influenza A in Immunocompromised Patients

• ClinicalTrials.gov Identifier: NCT00867139
• Recruitment Status: Completed
• First Posted: March 23, 2009
• Results First Posted: June 4, 2013
• Last Update Posted: August 15, 2013
• Sponsor: Fred Hutchinson Cancer Research Center
• Information provided by (Responsible Party): Michael Boeckh, Fred Hutchinson Cancer Research Center

Study Description

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

Condition or disease	Intervention/treatment	Phase
Influenza	Drug: TCAD; Drug: Zanamivir or Oseltamivir; Other: Open label treatment with TCAD	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 7 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: March 2009
• Actual Primary Completion Date: August 2009
• Actual Study Completion Date: January 2010

Arms and Interventions

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: Relenza; Tamiflu
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

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Adverse Events (AEs), Drug Specific AEs or AEs Resulting in Treatment Interruption [ Time Frame: 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 :

1. Number of Participants With Viral Load Decrease as a Function of Time [ Time Frame: 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.
2. Number of Patients Not Shedding Virus at Day 5 +/-1 and Day 10 +/- 1 [ Time Frame: 10 days ]
3. Number of Participants With Viral Resistance as a Function of Drug Exposure [ Time Frame: 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.
4. Duration of Symptoms [ Time Frame: 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

5. Frequency of Confirmed Pneumonia [ Time Frame: 58 days ]
6. Duration of Hospitalization [ Time Frame: from baseline up to 58 days ]
7. Days on Supplemental Oxygen [ Time Frame: 58 days ]
8. Number of Participants With ICU Admissions [ Time Frame: baseline and up to 58 days ]
   The number of participants with ICU admissions was evaluated.
9. Number of Participants With Intubations [ Time Frame: 58 days ]
10. Number of Deaths [ Time Frame: 58 days ]
11. Pharmacokinetics (AUC0-last) of TCAD [ Time Frame: 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.

Eligibility Criteria

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

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

Contacts and Locations

Locations

United States, Washington

Seattle Children's

Seattle, Washington, United States, 98105

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States, 98109

Sponsors and Collaborators

Fred Hutchinson Cancer Research Center

Investigators

• Principal Investigator: Michael Boeckh, MD; Fred Hutchinson Cancer Research Center

More Information

Publications of Results:

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.

• Responsible Party: Michael Boeckh, Member, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center
• ClinicalTrials.gov Identifier: NCT00867139
• Obsolete Identifiers: NCT00865800
• Other Study ID Numbers: 2323.00; 6895 ( Other Identifier: FHCRC/UW CC IRB )
• First Posted: March 23, 2009
• Results First Posted: June 4, 2013
• Last Update Posted: August 15, 2013
• Last Verified: August 2013

Keywords provided by Michael Boeckh, Fred Hutchinson Cancer Research Center:

Influenza; Immunocompromised; Antiviral

Additional relevant MeSH terms:

Influenza, Human; Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Oseltamivir; Ribavirin; Zanamivir; Amantadine; Thiazole-4-carboxamide adenine dinucleotide; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Antiparkinson Agents; Anti-Dyskinesia Agents; Dopamine Agents; Neurotransmitter Agents; Physiological Effects of Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents