InfluenzaPhase 4NCT00304434
Evaluation of Alternative Oseltamivir (Tamiflu) Dosing Strategies.
A Phase 4 study testing Oseltamivir and Probenecid in people with Influenza, run by US Department of Veterans Affairs at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Influenza
- What is being tested?
- Oseltamivir and Probenecid
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 48 participants
- Where
- 1 siteUnited States
- Study dates
- Feb 2005to Feb 2007
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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).
Trial locations and contacts
1 site in 1 country.
United States1 site
VA Palo Alto Health Care System
Palo Alto, California, 94304-1207
About this study
Official title: 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.
Read the 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.
- Conditions
- Influenza
- Being tested
- Oseltamivir, Probenecid
- Keywords
- Adverse effects, Antiviral, Clinical trial, Oseltamivir, Pharmacokinetics, Probenecid
- Medical subject headings
- Influenza, Human
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OseltamivirDrug
ProbenecidDrug
| Study group | Role | What they receive |
|---|---|---|
| 1 | Other | Not described Receives: Drug: Oseltamivir; Drug: Probenecid |
What is being measured
The primary outcome is the main question the study is designed to answer.
To determine whether the combination of oseltamivir and probenecid result in equivalent blood plasma concentrations compared to oseltamivir given alone
Measured: 15 days
Secondary outcomes (1)
The safety of combining oseltamivir and probenecid
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Mar 2006 (estimated)
- Study startFeb 2005
- Primary completionFeb 2007
- Study completionFeb 2007
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for InfluenzaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 48 participants (estimated)
Sponsor and investigators
- Lead sponsor
- US Department of Veterans Affairs
- Sponsor type
- US federal agency
- Collaborators
- Brooke Army Medical Center, National Institutes of Health (NIH)
- Investigators
- Mark Holodniy, MD, Principal investigator, VA Palo Alto Health Care System
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00304434
- Sponsor's protocol ID
- INDA-014-05F
- Status last verified
- Sep 2009
- First submitted
- 16 Mar 2006
- Last updated
- 23 Sep 2009
- Results posted
- No
Publications
He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet. 1999 Dec;37(6):471-84. doi: 10.2165/00003088-199937060-00003.
PubMed 10628898Massarella JW, He GZ, Dorr A, Nieforth K, Ward P, Brown A. The pharmacokinetics and tolerability of the oral neuraminidase inhibitor oseltamivir (Ro 64-0796/GS4104) in healthy adult and elderly volunteers. J Clin Pharmacol. 2000 Aug;40(8):836-43. doi: 10.1177/00912700022009567.
PubMed 10934667Hill G, Cihlar T, Oo C, Ho ES, Prior K, Wiltshire H, Barrett J, Liu B, Ward P. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies. Drug Metab Dispos. 2002 Jan;30(1):13-9. doi: 10.1124/dmd.30.1.13.
PubMed 11744606Holodniy M, Penzak SR, Straight TM, Davey RT, Lee KK, Goetz MB, Raisch DW, Cunningham F, Lin ET, Olivo N, Deyton LR. Pharmacokinetics and tolerability of oseltamivir combined with probenecid. Antimicrob Agents Chemother. 2008 Sep;52(9):3013-21. doi: 10.1128/AAC.00047-08. Epub 2008 Jun 16.
PubMed 18559644Raisch DW, Straight TM, Holodniy M. Thrombocytopenia from combination treatment with oseltamivir and probenecid: case report, MedWatch data summary, and review of the literature. Pharmacotherapy. 2009 Aug;29(8):988-92. doi: 10.1592/phco.29.8.988.
PubMed 19637952
Study at a glance
From the registry record, last updated by the sponsor on 23 Sep 2009. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Oseltamivir (Tamiflu) Dosing Strategies for Use During Influenza Prophylaxis (VA01)
- ClinicalTrials.gov ID
- NCT00304434
- Acronym / sponsor ID
- INDA-014-05F
- Conditions
- Influenza
- Keywords
- Adverse effects, Antiviral, Clinical trial, Oseltamivir, Pharmacokinetics, Probenecid
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 48 participants (estimated)
- Lead sponsor
- US Department of Veterans AffairsUS federal agency
- Collaborators
- Brooke Army Medical Center, National Institutes of Health (NIH)
- Study start
- Feb 2005
- Primary completion
- Feb 2007 (actual)
- Study completion
- Feb 2007 (actual)
- First posted
- 17 Mar 2006 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1 | Other | Drug: Oseltamivir, Drug: Probenecid |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- 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
Key exclusion criteria (3 listed)
- 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
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Oseltamivir | Drug | 1 |
| Probenecid | Drug | 1 |
Primary outcome
To determine whether the combination of oseltamivir and probenecid result in equivalent blood plasma concentrations compared to oseltamivir given alone
Time frame: 15 days
1 secondary outcome
The safety of combining oseltamivir and probenecid
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Sep 2009.
- Results publication: PubMed 10628898He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet. 1999 Dec;37(6):471-84. doi: 10.2165/00003088-199937060-00003.
- Results publication: PubMed 10934667Massarella JW, He GZ, Dorr A, Nieforth K, Ward P, Brown A. The pharmacokinetics and tolerability of the oral neuraminidase inhibitor oseltamivir (Ro 64-0796/GS4104) in healthy adult and elderly volunteers. J Clin Pharmacol. 2000 Aug;40(8):836-43. doi: 10.1177/00912700022009567.
- Results publication: PubMed 11744606Hill G, Cihlar T, Oo C, Ho ES, Prior K, Wiltshire H, Barrett J, Liu B, Ward P. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies. Drug Metab Dispos. 2002 Jan;30(1):13-9. doi: 10.1124/dmd.30.1.13.
- Results publication: PubMed 18559644Holodniy M, Penzak SR, Straight TM, Davey RT, Lee KK, Goetz MB, Raisch DW, Cunningham F, Lin ET, Olivo N, Deyton LR. Pharmacokinetics and tolerability of oseltamivir combined with probenecid. Antimicrob Agents Chemother. 2008 Sep;52(9):3013-21. doi: 10.1128/AAC.00047-08. Epub 2008 Jun 16.
- Results publication: PubMed 19637952Raisch DW, Straight TM, Holodniy M. Thrombocytopenia from combination treatment with oseltamivir and probenecid: case report, MedWatch data summary, and review of the literature. Pharmacotherapy. 2009 Aug;29(8):988-92. doi: 10.1592/phco.29.8.988.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mark Holodniy, MD principal investigator
VA Palo Alto Health Care System
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Oseltamivir and Probenecid in people with Influenza, run by US Department of Veterans Affairs at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Sep 2009. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To determine whether the combination of oseltamivir and probenecid result in equivalent blood plasma concentrations compared to oseltamivir given alone (time frame: 15 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00304434, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Sep 2009.