Evaluation of Alternative Oseltamivir (Tamiflu) Dosing Strategies.

September 21, 2009 updated by: US Department of Veterans Affairs

Oseltamivir (Tamiflu) Dosing Strategies for Use During Influenza Prophylaxis (VA01)

Objective 1: Determine the safety and toxicity profile of Tamiflu administered in combination with probenecid in healthy adults.Objective 2: Determine the pharmacokinetic profile of Tamiflu and probenecid in healthy adults.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

In vitro studies have determined that the 50 % inhibitory concentrations (IC50) of Ro 64-0802 against influenza neuraminidases ranged from 0.3 to 22 nmol/L (0.08 - 0.28 g/L or 0.08 -0.28 ng/mL). IC50 values against influenza strains in cell culture were somewhat higher and more variable ranging from 0.6 to 155 nmol/L (0.17 - 32.8 g/L or 0.17 - 32.8 ng/mL). Tamiflu has also been shown to have in vitro and mouse challenge activity against the H5N1 virus. EC50 values against H5N1 strain replication in Madin Darby canine kidney (MDCK) cells ranged from 7.5-12 M and neuraminidase activity from 7.0-15 nM (IC50 values).

The current U.S. FDA approved recommendations for influenza A and B treatment using oseltamivir suggest a dose of 75mg taken orally twice daily for 5 days at the onset of symptoms or laboratory confirmation of infection. Prophylaxis against influenza A infection for those people exposed to or at high risk for exposure suggests a dose of 75 mg orally taken once daily for up to 6 weeks. No clinical trials in humans infected with or requiring prophylaxis for the H5N1 variant have been performed. Oseltamivir treatment in a human pediatric case of H5N1 influenza pneumonia has been published. Oseltamivir was given late in the course of illness and the child subsequently expired. Several people were given a prophylactic course of oseltamivir after avian influenza (H7N7, H7N3) outbreaks in the Netherlands and in British Columbia, which appeared to be effective in preventing additional human cases.

Clinical trials using oseltamivir for influenza treatment have recently been reviewed. Two phase III placebo controlled, blinded studies were performed in adults, three in geriatric populations, and one in pediatric patients. In general, flu symptoms were decreased by one day or greater in those patients who received Tamiflu compared to placebo. Several prophylaxis studies using oseltamivir have been conducted in healthy unvaccinated adults and have also been recently reviewed. In several trials involving either prophylaxis after household exposure or after exposure in the community have demonstrated that the incidence of influenza was significantly reduced (range 70-90%) in those patients receiving Tamiflu, 75mg orally once daily for 42 days compared to placebo. Side effect profiles in the prophylaxis studies indicate that nausea and vomiting were more commonly found in the Tamiflu arm when compared to placebo. There was no difference in side effect incidence in younger compared to older adult (> 65 years) populations.

Study Type

Interventional

Enrollment (Anticipated)

48

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Palo Alto, California, United States, 94304-1207
        • VA Palo Alto Health Care System

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Subjects will include males and non-pregnant females 18 years or older Subjects who can understand the study and potential safety concerns and can sign the informed consent form prior to admission to this study Subjects that are willing to complete all the required assessments, tests and evaluations and able to make all study visits Hemoglobin > 10.0 g/dL for males and > 9.0 g/dL for females; b) Platelet count of > 75,000 / L; c) Absolute neutrophil count > 1000 / L; SGOT and SGPT < than 2.5 times normal upper limit (UL); Serum uric acid WNL; Creatinine < 1.5 times normal upper limit (normal UL 1.5 mg/dL) for the < 65 years of age group and MUST be WNL for the > 65 years of age group; creatinine clearance > 50 mL/min

Exclusion Criteria:

Subjects with a creatinine clearance of < 50 mL/min Subjects who are pregnant or breast feeding females Subjects who are not employing adequate contraception Subjects who are drug or alcohol abusers and in the opinion of the investigator would interfere with subject compliance and safety Subjects who are currently participating in any other clinical research study Any acute serious infection requiring prescription therapy within 14 days prior to Day 1 of the study Subjects who may have or recently been exposed to influenza Subjects with gout, blood dyscrasias, or history of hypersensitivity to sulfonamide drugs Subjects with contraindications to the study medications History of allergic reaction to probenecid Have kidney disease, kidney stones, or poorly functioning kidneys Have active peptic ulcer disease On high dose aspirin or salicylate therapy

Receiving any of the following medications (relative contraindication for probenecid):

Acyclovir, allopurinol, penicillamine, clofibrate, rifampin, methotrexate, zidovudine, theophylline, dapsone, penicillins or cephalosporins, nonsteroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen (Motrin, Advil, Nuprin, others), ketoprofen (Orudis, Oruvail, Orudis KT), diclofenac (Cataflam, Voltaren), etodolac (Lodine), fenoprofen (Nalfon), flurbiprofen (Ansaid), indomethacin (Indocin), ketorolac (Toradol), nabumetone (Relafen), oxaprozin (Daypro), piroxicam (Feldene), sulindac (Clinoril), tolmetin (Tolectin), and naproxen (Aleve, Anaprox, Naprosyn); a sulfa-based medication such as sulfamethoxazole (Bactrim, Septra, Gantanol), sulfasalazine (Azulfidine), sulfinpyrazone (Anturane), sulfisoxazole (Gantrisin), and others; an oral diabetes medicine such as glipizide (Glucotrol), glyburide (Micronase, Diabeta, Glynase), tolbutamide (Orinase), or tolazamide (Tolinase); a barbiturate such as phenobarbital (Luminal, Solfoton), amobarbital (Amytal), secobarbital (Seconal), and others; or a benzodiazepine (used to treat anxiety and panic disorders and to induce sleep) such as alprazolam (Xanax), diazepam (Valium), lorazepam (Ativan), temazepam (Restoril), chlordiazepoxide (Librium), clonazepam (Klonopin), clorazepate (Tranxene), oxazepam (Serax), estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), or triazolam (Halcion).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: 1
Drug: Probenecid
Drug: Oseltamivir

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To determine whether the combination of oseltamivir and probenecid result in equivalent blood plasma concentrations compared to oseltamivir given alone
Time Frame: 15 days
15 days

Secondary Outcome Measures

Outcome Measure
The safety of combining oseltamivir and probenecid

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

US Department of Veterans Affairs

Collaborators

National Institutes of Health (NIH)
Brooke Army Medical Center

Investigators

  • Principal Investigator: Mark Holodniy, MD, VA Palo Alto Health Care System

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2005

Primary Completion (Actual)

February 1, 2007

Study Completion (Actual)

February 1, 2007

Study Registration Dates

First Submitted

March 16, 2006

First Submitted That Met QC Criteria

March 16, 2006

First Posted (Estimate)

March 17, 2006

Study Record Updates

Last Update Posted (Estimate)

September 23, 2009

Last Update Submitted That Met QC Criteria

September 21, 2009

Last Verified

September 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • INDA-014-05F

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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