TCAD vs. Monotherapy for Influenza A in Immunocompromised Patients

Influenza Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00867139
• Other study ID #: 2323.00
• Secondary ID: 6895
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: March 20, 2009
• Last updated: August 8, 2013
• Start date: March 2009
• Est. completion date: January 2010

Study information

• Verified date: August 2013
• Source: Fred Hutchinson Cancer Research Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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

Other known NCT identifiers

• NCT00865800

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7
• Est. completion date: January 2010
• Est. primary completion date: August 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Influenza
• Influenza, Human

Intervention

Drug:
• TCAD
TCAD (amantadine hydrocholoride, ribavirin and oseltamivir phosphate)
• Zanamivir or Oseltamivir
Zanamivir or Oseltamivir

Other:
• Open label treatment with TCAD
TCAD(amantadine hydrocholoride, ribavirin and oseltamivir phosphate)

Locations

Country	Name	City	State
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Seattle Children's	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Research Center

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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)	30 days after the final dose of study drug	Yes
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.	baseline and 28 days	No
Secondary	Number of Patients Not Shedding Virus at Day 5 +/-1 and Day 10 +/- 1		10 days	No
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.	28 days	No
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	from baseline up to 28 days	No
Secondary	Frequency of Confirmed Pneumonia		58 days	No
Secondary	Duration of Hospitalization		from baseline up to 58 days	No
Secondary	Days on Supplemental Oxygen		58 days	No
Secondary	Number of Participants With ICU Admissions	The number of participants with ICU admissions was evaluated.	baseline and up to 58 days	No
Secondary	Number of Participants With Intubations		58 days	No
Secondary	Number of Deaths		58 days	No
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.	5 days	No