PharmacokineticsNCT01976078
Development of Voriconazole Pharmacokinetics and Metabolism in Children and Adolescents
An observational study of Pharmacokinetics and Voriconazole, run by Children's Hospital Los Angeles at 1 site in United States.
Trial summary
The death rate in children from the invasive fungal infection called aspergillosis is more than 50%. Voriconazole is the first-line therapy for this infection. In a previous publication the investigators have shown a highly significant relationship between voriconazole plasma concentrations and survival. Read more about this study
- Who is it for?
- Ages Up to 18 years
- Conditions the study is for
- Pharmacokinetics, Voriconazole
- What is being tested?
- Midazolam/Ranitidine/Esomeprazole
- How many people
- 45 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2012to 22 Apr 2015
- Phase
- Observational
- 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 Up to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Study population: Children with an invasive fungal infection
Who may be able to join
- Participants will be enrolled before their 18th birthday.
- Participant/parent/legal guardian must be able and willing to provide signed informed consent.
- Laboratory values obtained within 7 days prior to study entry (obtained for clinical purposes)
- Hemoglobin ≥ 7.0 g/dL (transfusion dependence acceptable)
- Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) (SGPT), and total bilirubin ≤ 5 X upper limit of age-appropriate normal (ULN)
- Serum creatinine ≤ 3 X ULN
Who cannot join
- Pregnancy
- Active substance abuse or other psychiatric illness that would prevent adherence to the study protocol. Investigators will not record this information in the screening log, and the information will be obtained from existing documents in the medical record only.
- Known hypersensitivity or intolerance to study medications
- Not expected to survive >1 week.
- Weight < 4.5 kg (blood volume draw limitations)
Trial locations and contacts
1 site in 1 country.
United States1 site
Children's Hospital Los Angeles
Los Angeles, California, 90027
About this study
Official title: Ontogeny of Voriconazole Pharmacokinetics and Metabolism in Children and Adolescents
The death rate in children from the invasive fungal infection called aspergillosis is more than 50%. Voriconazole is the first-line therapy for this infection. In a previous publication the investigators have shown a highly significant relationship between voriconazole plasma concentrations and survival. However, voriconazole dosing is currently poorly established, and plasma drug exposure varies between children by 400% or more, even after intravenous dosing. The objective of this study is to investigate the reasons for this variability in voriconazole pharmacokinetics (PK).In two studies, the investigators will enroll 80 children/adolescents receiving oral or intravenous voriconazole, divided by age under 2 years (n=15), and 2-18 years (n=65). From each patient the investigators will collect the following: 1) a blood sample for detection of several genetic changes known to affect drug metabolizing enzyme (DME) activity; 2) up to 9 blood samples after a voriconazole dose for measurement of voriconazole ("PK sampling"); 3) follow-up samples after each PK sampling visit if necessary to adjust the dose so that voriconazole concentrations in the blood are satisfactory (known as therapeutic drug monitoring or TDM). At the time of the voriconazole dose prior to the PK sampling, we will also give single IV or oral (corresponding to the route of voriconazole administration) low doses of esomeprazole (an antacid), midazolam (a sedative), and ranitidine (an antacid) as a cocktail to test or probe DME activity. All of these medications are used commonly in children already. The investigators will estimate DME activity or phenotype using ratios of probe drug metabolite to parent drug concentrations, while simultaneously quantifying the amount of DME genetic material (mRNA) and protein in white blood cells. The investigators will test associations between DME activity, mRNA, protein, voriconazole PK, age, sex, and degree of illness. The investigators will also use a computer program to integrate all these data to develop a comprehensive model that will predict blood concentrations of voriconazole in children of all ages, as well as assist physicians and pharmacists to dose voriconazole more accurately.The total study duration for each subject will be until after the TDM follow up visit, generally about one week.
- Conditions
- Pharmacokinetics, Voriconazole
- Being tested
- Midazolam/Ranitidine/Esomeprazole
- Keywords
- Voriconazole, Pharmacokinetics, Ontogeny, Modeling, Bayesian
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Midazolam/Ranitidine/EsomeprazoleDrug
Each of the three drugs will be given at 10% of their usual doses for age/weight.
| Study group | Role | What they receive |
|---|---|---|
| Midazolam/Ranitidine/Esomeprazole | All enrolled subjects will have a study pharmacokinetic visit where they will be given the above cocktail of drugs along with their clinically indicated voriconazole dose, followed by blood sampling over the next 12 hours. Receives: Drug: Midazolam/Ranitidine/Esomeprazole |
What is being measured
The primary outcome is the main question the study is designed to answer.
Voriconazole steady-state pharmacokinetics
8 (after intravenous dosing) or 9 (after oral dosing) samples are taken after a voriconazole dose over a 12 hour timeframe.
Measured: During the 12 hours after a dose
Secondary outcomes (1)
Voriconazole drug metabolizing enzyme activity
At the time of the voriconazole dose used for the primary outcome, an intravenous or oral cocktail of "probe drugs", depending on the route of the voriconazole dose, consisting of midazolam, ranitidine, and esomeprazole will be administered. Using the samples collected for the primary outcome, concentrations of all three probe drugs and their major metabolites will be measured and used to compute activity of the relevant drug metabolizing enzymes.
Measured: Within 12 hours after a study medication dosing
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Nov 2013 (estimated)
- Study startSep 2012
- Primary completion22 Apr 2015
- Study completion22 Apr 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for PharmacokineticsStudies of the same condition, open and under way.
- More trials run by Children's Hospital Los AngelesThe sponsor's other registered studies.
- 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 45 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Hospital Los Angeles
- Sponsor type
- University, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Principal investigator, Michael Neely, Children's Hospital Los Angeles
- Investigators
- Michael N Neely, MD, Principal investigator, Children's Hospital Los Angeles
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01976078
- Sponsor's protocol ID
- CCI-11-00334
- Other IDs
- R01HD070996
- Status last verified
- Feb 2018
- First submitted
- 18 Sep 2013
- Last updated
- 20 Feb 2018
- Results posted
- No
- Data monitoring committee
- No
Publications
Hope WW, Vanguilder M, Donnelly JP, Blijlevens NM, Bruggemann RJ, Jelliffe RW, Neely MN. Software for dosage individualization of voriconazole for immunocompromised patients. Antimicrob Agents Chemother. 2013 Apr;57(4):1888-94. doi: 10.1128/AAC.02025-12. Epub 2013 Feb 4.
PubMed 23380734Neely M, Rushing T, Kovacs A, Jelliffe R, Hoffman J. Voriconazole pharmacokinetics and pharmacodynamics in children. Clin Infect Dis. 2010 Jan 1;50(1):27-36. doi: 10.1086/648679.
PubMed 19951112Neely M, Margol A, Fu X, van Guilder M, Bayard D, Schumitzky A, Orbach R, Liu S, Louie S, Hope W. Achieving target voriconazole concentrations more accurately in children and adolescents. Antimicrob Agents Chemother. 2015;59(6):3090-7. doi: 10.1128/AAC.00032-15. Epub 2015 Mar 16.
PubMed 25779580
Study at a glance
From the registry record, last updated by the sponsor on 20 Feb 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Ontogeny of Voriconazole Pharmacokinetics and Metabolism in Children and Adolescents
- ClinicalTrials.gov ID
- NCT01976078
- Acronym / sponsor ID
- CCI-11-00334
- Conditions
- Pharmacokinetics, Voriconazole
- Keywords
- Voriconazole, Pharmacokinetics, Ontogeny, Modeling, Bayesian
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 45 participants (actual)
- Lead sponsor
- Children's Hospital Los AngelesUniversity, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Study start
- Sep 2012 (actual)
- Primary completion
- 22 Apr 2015 (actual)
- Study completion
- 22 Apr 2015 (actual)
- First posted
- 5 Nov 2013 (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.
The death rate in children from the invasive fungal infection called aspergillosis is more than 50%. Voriconazole is the first-line therapy for this infection. In a previous publication the investigators have shown a highly significant relationship between voriconazole plasma concentrations and survival. However, voriconazole dosing is currently poorly established, and plasma drug exposure varies between children by 400% or more, even after intravenous dosing. The objective of this study is to investigate the reasons for this variability in voriconazole pharmacokinetics (PK).In two studies, the investigators will enroll 80 children/adolescents receiving oral or intravenous voriconazole, divided by age under 2 years (n=15), and 2-18 years (n=65). From each patient the investigators will collect the following: 1) a blood sample for detection of several genetic changes known to affect drug metabolizing enzyme (DME) activity; 2) up to 9 blood samples after a voriconazole dose for measurement of voriconazole ("PK sampling"); 3) follow-up samples after each PK sampling visit if necessary to adjust the dose so that voriconazole concentrations in the blood are satisfactory (known as therapeutic drug monitoring or TDM). At the time of the voriconazole dose prior to the PK sampling, we will also give single IV or oral (corresponding to the route of voriconazole administration) low doses of esomeprazole (an antacid), midazolam (a sedative), and ranitidine (an antacid) as a cocktail to test or probe DME activity. All of these medications are used commonly in children already. The investigators will estimate DME activity or phenotype using ratios of probe drug metabolite to parent drug concentrations, while simultaneously quantifying the amount of DME genetic material (mRNA) and protein in white blood cells. The investigators will test associations between DME activity, mRNA, protein, voriconazole PK, age, sex, and degree of illness. The investigators will also use a computer program to integrate all these data to develop a comprehensive model that will predict blood concentrations of voriconazole in children of all ages, as well as assist physicians and pharmacists to dose voriconazole more accurately.The total study duration for each subject will be until after the TDM follow up visit, generally about one week.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Midazolam/Ranitidine/Esomeprazole | – | Drug: Midazolam/Ranitidine/EsomeprazoleAll enrolled subjects will have a study pharmacokinetic visit where they will be given the above cocktail of drugs along with their clinically indicated voriconazole dose, followed by blood sampling over the next 12 hours. |
Who may qualify
- Ages
- Up to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
- Study population
- Children with an invasive fungal infection
Key inclusion criteria (6 listed)
- Participants will be enrolled before their 18th birthday.
- Participant/parent/legal guardian must be able and willing to provide signed informed consent.
- Laboratory values obtained within 7 days prior to study entry (obtained for clinical purposes)
Key exclusion criteria (5 listed)
- Pregnancy
- Active substance abuse or other psychiatric illness that would prevent adherence to the study protocol. Investigators will not record this information in the screening log, and the information will be obtained from existing documents in the medical record only.
- Known hypersensitivity or intolerance to study medications
- Not expected to survive >1 week.
- Weight < 4.5 kg (blood volume draw limitations)
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 |
|---|---|---|
| Midazolam/Ranitidine/EsomeprazoleEach of the three drugs will be given at 10% of their usual doses for age/weight. | Drug | Midazolam/Ranitidine/Esomeprazole |
Primary outcome
Voriconazole steady-state pharmacokinetics
Time frame: During the 12 hours after a dose
8 (after intravenous dosing) or 9 (after oral dosing) samples are taken after a voriconazole dose over a 12 hour timeframe.
1 secondary outcome
Voriconazole drug metabolizing enzyme activity
Time frame: Within 12 hours after a study medication dosing
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 20 Feb 2018.
- Background: PubMed 23380734Hope WW, Vanguilder M, Donnelly JP, Blijlevens NM, Bruggemann RJ, Jelliffe RW, Neely MN. Software for dosage individualization of voriconazole for immunocompromised patients. Antimicrob Agents Chemother. 2013 Apr;57(4):1888-94. doi: 10.1128/AAC.02025-12. Epub 2013 Feb 4.
- Background: PubMed 19951112Neely M, Rushing T, Kovacs A, Jelliffe R, Hoffman J. Voriconazole pharmacokinetics and pharmacodynamics in children. Clin Infect Dis. 2010 Jan 1;50(1):27-36. doi: 10.1086/648679.
- Derived from this study: PubMed 25779580Neely M, Margol A, Fu X, van Guilder M, Bayard D, Schumitzky A, Orbach R, Liu S, Louie S, Hope W. Achieving target voriconazole concentrations more accurately in children and adolescents. Antimicrob Agents Chemother. 2015;59(6):3090-7. doi: 10.1128/AAC.00032-15. Epub 2015 Mar 16.
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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.
Michael N Neely, MD principal investigator
Children's Hospital Los Angeles
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Pharmacokinetics and Voriconazole, run by Children's Hospital Los Angeles 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 6 inclusion and 5 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 20 Feb 2018. 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.
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?
Voriconazole steady-state pharmacokinetics (time frame: During the 12 hours after a dose). 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 NCT01976078, which also lists 3 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 20 Feb 2018.