Aspergillosis InvasivePhase 4NCT03731169
CYP2C19 Genotype-Specific Dosing Plus TDM on Reaching Therapeutic Voriconazole Blood Levels
A Phase 4 study testing Voriconazole genotype-specific dosing in people with Aspergillosis Invasive and Fungal Infection, run by University Health Network, Toronto at 2 sites in Canada.
Trial summary
Invasive aspergillosis is a fungal infection which left untreated, is a significant cause of morbidity and mortality. Immunocompromised patient populations such as solid organ transplant and malignant hematology patients are especially susceptible to invasive fungal infections. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Aspergillosis Invasive, Fungal Infection
- What is being tested?
- Voriconazole genotype-specific dosing
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 2 sitesCanada
- Study dates
- 10 Jan 2018to 28 Aug 2020
- 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
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- All adult malignant hematology patients who are prescribed voriconazole.
Who cannot join
- Patients that have previously taken voriconazole within the last 2 weeks
Trial locations and contacts
2 sites in 1 country.
Canada2 sites
Toronto General Hospital
Toronto, Ontario, M5G 2C4
Princess Margaret Cancer Care Centre
Toronto, Ontario, M5G 2M9
About this study
Official title: A Randomized Controlled Trial of the Effect of Cytochrome P450 2C19 Genotype-Specific Dosing Plus TDM vs. TDM Alone on Reaching Therapeutic Voriconazole Blood Levels
Invasive aspergillosis is a fungal infection which left untreated, is a significant cause of morbidity and mortality. Immunocompromised patient populations such as solid organ transplant and malignant hematology patients are especially susceptible to invasive fungal infections. Voriconazole is an anti-fungal agent that is frontline therapy for invasive aspergillosis. Treatment success is highly dependent on maintaining therapeutic voriconazole concentrations. The current published literature has established that treatment failure is associated with sub- and supra-therapeutic voriconazole concentrations.
Maintaining therapeutic voriconazole concentrations however, is challenging due to the high inter and intra-patient variability in voriconazole pharmacokinetics. The complex kinetics of voriconazole renders current manufacturers' dosing guidelines ineffective. Much of this complexity has been linked to genetic polymorphisms in the cytochrome P450 2C19 gene, and it has been found that CYP2C19 genotype plays an important role in determining voriconazole exposure levels. Therapeutic drug monitoring has been found to increase efficacy of voriconazole treatment through the monitoring of patients' voriconazole levels, allowing for dosage adjustments in response to supra- or sub-therapeutic levels.
Read more
There are few robust studies that have examined the effect of CYP2C19 genotype on voriconazole treatment outcomes. They have been unable to determine relationships between CYP2C19 genetic status, and clinical efficacy and safety. No studies to our knowledge have made dosing adjustments based on CYP2C19 genetic status.
The study aim is to explore the utility of voriconazole dosing that is based on the genetic status of the patient in conjunction with therapeutic drug monitoring. Over the course of one year, solid organ transplant recipients at Toronto General Hospital and malignant hematology patients at Princess Margaret Cancer Centre receiving voriconazole therapy will be randomized into one of two trial arms: a control arm receiving therapeutic drug monitoring only, or a treatment arm receiving genotype-specific dosing in conjunction with therapeutic drug monitoring. The investigators will compare the proportion of patients that achieve voriconazole therapeutic concentrations, the number of dose adjustments needed to achieve therapeutic voriconazole levels, and clinical outcomes between trial arms.
Read the detailed description
Purpose of Research:
Invasive aspergillosis (IA) is a fungal infection which left untreated, can cause dangerous complications and death. Transplant patients who have weakened immune systems are at higher risk of getting IA. Voriconazole is a medication that is prescribed for IA. In order for voriconazole to work, it is important to maintain the right amount of drug in the blood. The investigators check for the right amount of voriconazole in the blood by collecting blood samples. This process is called therapeutic drug monitoring (TDM) and usually done for transplant patients with weakened immune systems. However, maintaining the right amount of drug in the blood is still difficult since voriconazole is absorbed and excreted by the body differently for each person, depending on their genetic make-up. This study will try to understand if genetic testing early on in addition with TDM will be able to provide us with doses tailored to each individual.
Study Design:
Patients who consent to participate in this study and who are receiving voriconazole therapy for IA will be randomly split into one of two groups. The control group will receive voriconazole dosages and then TDM according to the usual treatment for the patient's condition. A treatment group will receive altered dosages that are specific to their genetic make-up for the first four days of treatment and will then receive routine TDM. This altered dosing for the treatment group is experimental and is not routinely used in patients' care. TDM will take place at approximately the fourth day after starting voriconazole for all patients, and from this point on the usual treatment will resume for all patients.
Participation in the study will be for the entire amount of time the patient is taking voriconazole. The study staff will meet with the patient once, provided they meet the study criteria. This will be the only visit from the study staff. This visit will take place immediately after being prescribed voriconazole and is estimated to take 1-2 hours.
Should the patient decide to participate in the study, basic demographic information will be collected at this time and the patient's medical records will be accessible to the study staff. One saliva sample will be collected from the patient at this time for the genetic testing portion of the study. The genetic testing used in this study will be specific to looking at the way the patient's body handles voriconazole and will not inform us of any other potential condition. No incidental findings will be discovered. This procedure will be done by Spartan Bioscience, a third party company. The patient's saliva sample will be sent with a code and will not show the patient's name or address, or any information that directly identifies them. The patient's saliva sample will be immediately destroyed after the genetic testing component has been completed. The patient's genetic information will remain confidential as no research data will be shared with Spartan Bioscience or anyone outside the study staff. No additional procedures outside of routine care will be done. As part of routine care, the patient's treatment will be regularly be assessed by a physician.
- Conditions
- Aspergillosis Invasive, Fungal Infection
- Being tested
- Voriconazole genotype-specific dosing, Standard of Care
- Medical subject headings
- Mycoses
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Voriconazole genotype-specific dosingGenetic
Also called Genotype-guided dosing
Those in the intervention arm will receive an experimental dosage regimen of voriconazole based on their genetic status.
URM: 6 mg/kg voriconazole twice on the first day followed by 5 mg/kg twice daily, rounded to the nearest 50mg for oral formulations up to day 4 post-start of voriconazole therapy.
EM: 6 mg/kg voriconazole twice on the first day followed by 4 mg/kg twice daily, rounded to the nearest 50mg for oral formulations up to day 4 post-start of voriconazole therapy.
HEM and PM: 6 mg/kg voriconazole twice on the first day followed by 2 mg/kg twice daily, rounded to the nearest 50mg for oral formulations up to day 4 post-start of voriconazole therapy.
Standard of CareDrug
Participants are given 6 mg/kg voriconazole twice on the first day followed by 4 mg/kg twice daily, rounded to the nearest 50mg for oral formulations up to day 4 post-start of voriconazole therapy. After TDM is conducted on day 4 for all patients, dosing in both trial arms will adhere to the following in order to reach the target therapeutic window: 1.0-5.5 mg/L.
| Study group | Role | What they receive |
|---|---|---|
| TDM Only | Active comparator | This is the standard of care trial arm. Patients receive voriconazole dosages according to the product monograph. After day 4, dosing in both trial arms will adhere to the following in order to reach the target therapeutic window: 1.0-5.5 mg/L. Receives: Drug: Standard of Care |
| Genotyping + TDM | Experimental | After ascertaining CYP2C19 genetic status, the participants will be categorized as having either the ultra-rapid metabolizer (URM), extensive metabolizer (EM), heterozygous extensive metabolizer (HEM) or poor metabolizer (PM) phenotype. They will receive an experimental dosage regimen based on their phenotype. receive the following dosing regimen until TDM is conducted on day 4. After day 4, dosing in both trial arms will adhere to the following in order to reach the target therapeutic window: 1.0-5.5 mg/L. Receives: Genetic: Voriconazole genotype-specific dosing |
What is being measured
The primary outcome is the main question the study is designed to answer.
Voriconazole trough concentrations at steady-state
To determine if the proportion of patients who achieve therapeutic voriconazole trough concentrations at steady-state through genotype-specific dosing in conjunction with TDM is greater than the proportion of patients who obtain therapeutic voriconazole concentrations via TDM alone.
Measured: 1 year
Number of dose adjustments
To determine if genotype-specific dosing in conjunction with TDM will result in a fewer number of dose adjustments needed to achieve therapeutic voriconazole levels, compared to TDM alone.
Measured: 1 year
Genotype-specific dosages
To evaluate the genotype-specific dosages suggested for the genotyping plus TDM trial arm.
Measured: 1 year
Secondary outcomes (1)
Genotype-specific dosing on treatment success/failure
To determine if genotyping can increase treatment success (complete or partial response), predict the incidence of voriconazole dose-related adverse events (AEs), severity of toxicity, and incidence of termination of voriconazole therapy due to voriconazole dose-related AEs.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Nov 2018
- Study start10 Jan 2018
- Primary completion31 Aug 2019
- Study completion28 Aug 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Aspergillosis InvasiveStudies of the same condition, open and under way.
- More trials run by University Health Network, TorontoThe 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
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Care provider
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Health Network, Toronto
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Marisa Battistella, University Health Network, Toronto
- Investigators
- Marisa Battistella, PharmD, Principal investigator, University Health Network, Toronto
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03731169
- Sponsor's protocol ID
- 15-9226
- Status last verified
- Nov 2020
- First submitted
- 2 Nov 2018
- Last updated
- 3 Nov 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Individual participant data (IPD) will not be shared with other researchers.
Study at a glance
From the registry record, last updated by the sponsor on 3 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Controlled Trial of the Effect of Cytochrome P450 2C19 Genotype-Specific Dosing Plus TDM vs. TDM Alone on Reaching Therapeutic Voriconazole Blood Levels
- ClinicalTrials.gov ID
- NCT03731169
- Acronym / sponsor ID
- 15-9226
- Conditions
- Aspergillosis Invasive, Fungal Infection
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- University Health Network, TorontoUniversity, hospital or other
- Study start
- 10 Jan 2018 (actual)
- Primary completion
- 31 Aug 2019 (actual)
- Study completion
- 28 Aug 2020 (actual)
- First posted
- 6 Nov 2018 (actual)
- 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.
Invasive aspergillosis is a fungal infection which left untreated, is a significant cause of morbidity and mortality. Immunocompromised patient populations such as solid organ transplant and malignant hematology patients are especially susceptible to invasive fungal infections. Voriconazole is an anti-fungal agent that is frontline therapy for invasive aspergillosis. Treatment success is highly dependent on maintaining therapeutic voriconazole concentrations. The current published literature has established that treatment failure is associated with sub- and supra-therapeutic voriconazole concentrations.
Maintaining therapeutic voriconazole concentrations however, is challenging due to the high inter and intra-patient variability in voriconazole pharmacokinetics. The complex kinetics of voriconazole renders current manufacturers' dosing guidelines ineffective. Much of this complexity has been linked to genetic polymorphisms in the cytochrome P450 2C19 gene, and it has been found that CYP2C19 genotype plays an important role in determining voriconazole exposure levels. Therapeutic drug monitoring has been found to increase efficacy of voriconazole treatment through the monitoring of patients' voriconazole levels, allowing for dosage adjustments in response to supra- or sub-therapeutic levels.
There are few robust studies that have examined the effect of CYP2C19 genotype on voriconazole treatment outcomes. They have been unable to determine relationships between CYP2C19 genetic status, and clinical efficacy and safety. No studies to our knowledge have made dosing adjustments based on CYP2C19 genetic status.
The study aim is to explore the utility of voriconazole dosing that is based on the genetic status of the patient in conjunction with therapeutic drug monitoring. Over the course of one year, solid organ transplant recipients at Toronto General Hospital and malignant hematology patients at Princess Margaret Cancer Centre receiving voriconazole therapy will be randomized into one of two trial arms: a control arm receiving therapeutic drug monitoring only, or a treatment arm receiving genotype-specific dosing in conjunction with therapeutic drug monitoring. The investigators will compare the proportion of patients that achieve voriconazole therapeutic concentrations, the number of dose adjustments needed to achieve therapeutic voriconazole levels, and clinical outcomes between trial arms.
Detailed description
Purpose of Research:
Invasive aspergillosis (IA) is a fungal infection which left untreated, can cause dangerous complications and death. Transplant patients who have weakened immune systems are at higher risk of getting IA. Voriconazole is a medication that is prescribed for IA. In order for voriconazole to work, it is important to maintain the right amount of drug in the blood. The investigators check for the right amount of voriconazole in the blood by collecting blood samples. This process is called therapeutic drug monitoring (TDM) and usually done for transplant patients with weakened immune systems. However, maintaining the right amount of drug in the blood is still difficult since voriconazole is absorbed and excreted by the body differently for each person, depending on their genetic make-up. This study will try to understand if genetic testing early on in addition with TDM will be able to provide us with doses tailored to each individual.
Study Design:
Patients who consent to participate in this study and who are receiving voriconazole therapy for IA will be randomly split into one of two groups. The control group will receive voriconazole dosages and then TDM according to the usual treatment for the patient's condition. A treatment group will receive altered dosages that are specific to their genetic make-up for the first four days of treatment and will then receive routine TDM. This altered dosing for the treatment group is experimental and is not routinely used in patients' care. TDM will take place at approximately the fourth day after starting voriconazole for all patients, and from this point on the usual treatment will resume for all patients.
Participation in the study will be for the entire amount of time the patient is taking voriconazole. The study staff will meet with the patient once, provided they meet the study criteria. This will be the only visit from the study staff. This visit will take place immediately after being prescribed voriconazole and is estimated to take 1-2 hours.
Should the patient decide to participate in the study, basic demographic information will be collected at this time and the patient's medical records will be accessible to the study staff. One saliva sample will be collected from the patient at this time for the genetic testing portion of the study. The genetic testing used in this study will be specific to looking at the way the patient's body handles voriconazole and will not inform us of any other potential condition. No incidental findings will be discovered. This procedure will be done by Spartan Bioscience, a third party company. The patient's saliva sample will be sent with a code and will not show the patient's name or address, or any information that directly identifies them. The patient's saliva sample will be immediately destroyed after the genetic testing component has been completed. The patient's genetic information will remain confidential as no research data will be shared with Spartan Bioscience or anyone outside the study staff. No additional procedures outside of routine care will be done. As part of routine care, the patient's treatment will be regularly be assessed by a physician.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, care provider)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| TDM Only | Active comparator | Drug: Standard of CareThis is the standard of care trial arm. Patients receive voriconazole dosages according to the product monograph. After day 4, dosing in both trial arms will adhere to the following in order to reach the target therapeutic window: 1.0-5.5 mg/L. |
| Genotyping + TDM | Experimental | Genetic: Voriconazole genotype-specific dosingAfter ascertaining CYP2C19 genetic status, the participants will be categorized as having either the ultra-rapid metabolizer (URM), extensive metabolizer (EM), heterozygous extensive metabolizer (HEM) or poor metabolizer (PM) phenotype. They will receive an experimental dosage regimen based on their phenotype. receive the following dosing regimen until TDM is conducted on day 4. After day 4, dosing in both trial arms will adhere to the following in order to reach the target therapeutic window: 1.0-5.5 mg/L. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- All adult malignant hematology patients who are prescribed voriconazole.
Key exclusion criteria (1 listed)
- Patients that have previously taken voriconazole within the last 2 weeks
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 |
|---|---|---|
| Voriconazole genotype-specific dosingAlso: Genotype-guided dosingThose in the intervention arm will receive an experimental dosage regimen of voriconazole based on their genetic status. URM: 6 mg/kg voriconazole twice on the first day followed by 5 mg/kg twice daily, rounded to the nearest 50mg for oral formulations up to day 4 post-start of voriconazole therapy. EM: 6 mg/kg voriconazole twice on the first day followed by 4 mg/kg twice daily, rounded to the nearest 50mg for oral formulations up to day 4 post-start of voriconazole therapy. HEM and PM: 6 mg/kg voriconazole twice on the first day followed by 2 mg/kg twice daily, rounded to the nearest 50mg for oral formulations up to day 4 post-start of voriconazole therapy. | Genetic | Genotyping + TDM |
| Standard of CareParticipants are given 6 mg/kg voriconazole twice on the first day followed by 4 mg/kg twice daily, rounded to the nearest 50mg for oral formulations up to day 4 post-start of voriconazole therapy. After TDM is conducted on day 4 for all patients, dosing in both trial arms will adhere to the following in order to reach the target therapeutic window: 1.0-5.5 mg/L. | Drug | TDM Only |
Primary outcome
Voriconazole trough concentrations at steady-state
Time frame: 1 year
To determine if the proportion of patients who achieve therapeutic voriconazole trough concentrations at steady-state through genotype-specific dosing in conjunction with TDM is greater than the proportion of patients who obtain therapeutic voriconazole concentrations via TDM alone.
Number of dose adjustments
Time frame: 1 year
To determine if genotype-specific dosing in conjunction with TDM will result in a fewer number of dose adjustments needed to achieve therapeutic voriconazole levels, compared to TDM alone.
Genotype-specific dosages
Time frame: 1 year
To evaluate the genotype-specific dosages suggested for the genotyping plus TDM trial arm.
1 secondary outcome
Genotype-specific dosing on treatment success/failure
Time frame: 1 year
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 3 Nov 2020.
- Individual participant dataSharing planned: No. Individual participant data (IPD) will not be shared with other researchers.
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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.
Marisa Battistella, PharmD principal investigator
University Health Network, Toronto
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Voriconazole genotype-specific dosing in people with Aspergillosis Invasive and Fungal Infection, run by University Health Network, Toronto at 2 sites in Canada.
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 1 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 3 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Canada. 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?
Voriconazole trough concentrations at steady-state (time frame: 1 year). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 3 Nov 2020.