HealthyPhase 2NCT02435563
Dose Adaptation to Offset the Interaction Between Ticagrelor and Ritonavir by Population-based PK Modeling
A Phase 2 study testing ticagrelor 180 mg administrated alone and Ticagrelor adjusted dose + ritonavir 100mg in people with Healthy, run by University Hospital, Geneva at 1 site in Switzerland.
Trial summary
Ticagrelor is a new generation antiplatelet agent with higher efficacy as compared to clopidogrel and prasugrel in treatment of patients with moderate and high ischemic risks. Ticagrelor is active as such and its hepatic metabolism by CYP3A generates also an active metabolite. Read more about this study
- Who is it for?
- Ages 18 to 60 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Healthy
- What is being tested?
- ticagrelor 180 mg administrated alone and Ticagrelor adjusted dose + ritonavir 100mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 1 siteSwitzerland
- Study dates
- Aug 2014to Apr 2015
- Phase
- Phase 2
- 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 to 60 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy male volunteers
- Aged between 18 and 60 years
- BMI between 18 and 27
- Understanding of French language and able to give an inform consent.
Who cannot join
- Hypersensitivity to ticagrelor or ritonavir or any constituents of the tablets
- Concomitant diseases
- Smokers (> 20 cigarettes per day)
- Intake of any drug or food (grapefruit) that is metabolized by or can affect CYP3A or P-glycoprotein activity within the last 10 days
- Pathologies or drugs associated with an increased bleeding risk such as aspirin, non-steroidal anti-inflammatory drugs, steroids and serotonin reuptake inhibitors
- Bleeding familial history or antecedent or hemorrhagic disease
- Previous or active gastro-intestinal ulcer
- Alteration of hepatic tests (ASAT>100 U/l, ALAT >100 U/l, GGT >80 U/l, BILI > 50 μmol/l)
Trial locations and contacts
1 site in 1 country.
Switzerland1 site
Centre de Recherche Clinique, HUG, Rue Gabrielle Perret-Gentil 4
Geneva, 1211
About this study
Official title: Dose Adaptation to Offset the Pharmacokinetic Interaction Between Ticagrelor and Ritonavir in Healthy Volunteers by Population-based PK Modeling (Simcyp®)
Ticagrelor is a new generation antiplatelet agent with higher efficacy as compared to clopidogrel and prasugrel in treatment of patients with moderate and high ischemic risks. Ticagrelor is active as such and its hepatic metabolism by CYP3A generates also an active metabolite. Because of the remarkable progress in HIV therapies the number of older age patients is on the rise, requiring adequate cardiovascular treatment. Since frontline HIV therapies include ritonavir, a strong inhibitor of CYP3A enzyme, ticagrelor is contraindicated in these patients because of the expected interaction and bleeding risk. A lower efficacy of clopidogrel and prasugrel, which are both pro-drugs, in the presence of ritonavir has been already demonstrated. Therefore, administration of a lower dose of ticagrelor may be a good alternative in HIV patients in order to lessen the impact of this pharmacokinetic interaction. The aim of this study is to adjust the dose of ticagrelor in case of co-treatment with ritonavir to achieve the same pharmacokinetic profile as administered alone using a physiologically-based pharmacokinetic (PBPK) model.
As the first step, a pharmacokinetic (PK) model for ticagrelor and its active metabolite will be created based on available in vitro and in vivo parameters in healthy volunteers.
Read more
An open-label, 2 sessions cross over study will be conducted with 20 healthy male volunteers at Clinical Research Center (CRC) of Geneva University Hospitals (HUG). During the first session of the clinical trial, a single dose 180 mg ticagrelor will be administered to the volunteers and obtained pharmacokinetic data will be fitted into the model for optimization. Thereafter a simulated trial by the Simcyp® simulator in presence of a single dose 100 mg ritonavir will allow evaluating the impact of CYP3A inhibition on the concentration-time profile of ticagrelor and its active metabolite. The necessary dose of ticagrelor to minimize the magnitude of this interaction will be calculated. This new dose will be co-administered with ritonavir in the same volunteers during the second session of the clinical trial. The purpose is to obtain the same PK profile with single dose of 180 mg ticagrelor administered alone and with an adapted dose of ticagrelor co-administered with a single dose 100 mg ritonavir. Moreover, the pharmacodynamic effect of ticagrelor will be measured in both sessions of the clinical trial using two specific platelet function tests: the VAsodilator-Stimulated Phosphoprotein assay (VASP) and VerifyNow® P2Y12. With the same PK profile, the same pharmacodynamic activity is expected. The modulation of activity of CYP3A and P-gp by ritonavir will be also monitored using micro dose midazolam and fexofenadine as probe substrates.
The purpose of this study is to use the Simcyp® Simulator mechanistic PBPK modeling to broaden the application field of ticagrelor, especially in HIV patients. Since PK models are often created after clinical observations, the prospective aspect of this study is of particular value as the model will be first created and then applied to an unknown clinical scenario.
- Conditions
- Healthy
- Being tested
- ticagrelor 180 mg administrated alone, Ticagrelor adjusted dose + ritonavir 100mg
- Keywords
- Anti-HIV Agents, cardiovascular agents, drug interactions
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ticagrelor 180 mg administrated aloneDrug
Ticagrelor adjusted dose + ritonavir 100mgDrug
| Study group | Role | What they receive |
|---|---|---|
| Ticagrelor 180 mg | Experimental | Single dose of 180mg ticagrelor administered orally Receives: Drug: ticagrelor 180 mg administrated alone |
| Ticagrelor adjusted dose+ritonavir 100mg | Experimental | adpated dose of ticagrelor calculated after PK modelisation with the Simcyp® simulator administered simultaneously with 100 mg ritonavir Receives: Drug: Ticagrelor adjusted dose + ritonavir 100mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in AUC of ticagrelor and its metabolite from baseline
Venous blood samples will be taken to assess the baseline pharmacokinetic parameters of ticagrelor and its metabolite, prior to ticagrelor administration (time zero) and at the following post dosage times: 0.5, 1, 2, 3, 4, 6, 8, and 24 hours
Measured: 30 min 1hr 2hr 3hr 4hr 6hr 8hr 24hr
Secondary outcomes (3)
Measure of the pharmacodynamic response to ticagrelor by two platelet reactivity tests VASP and VerifyNow® P2Y12
4 hours after administration of ticagrelor the pharmacodynamic, response of ticagrelor will be assessed by the VAsodilator-Stimulated Phosphoprotein Assay (VASP) and VerifyNow® P2Y12 tests
Measured: 4hr
Change in P-gp phenotyping from baseline (0 min)
Venous blood samples will be taken to assess the P-gp phenotyping, prior to fexofenadine administration (time zero) and at the following post dosage times: 0.5, 1, 2, 3, 4, 6, 8, and 24 hours
Measured: 30 min 1hr 2hr 3hr 4hr 6hr 8hr 24hr
Change in CYP3A4 phenotyping from baseline (0 min)
Venous blood samples will be taken to assess the CYP3A4 phenotyping, prior to midazolam administration (time zero) and at the following post dosage time: 1 hour
Measured: 1hr
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 May 2015 (estimated)
- Study startAug 2014
- Primary completionApr 2015
- Study completionApr 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HealthyStudies 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 2
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Geneva
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Jules Desmeules, University Hospital, Geneva
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02435563
- Sponsor's protocol ID
- 13-182
- Status last verified
- Feb 2017
- First submitted
- 15 Sep 2014
- Last updated
- 7 Feb 2017
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 7 Feb 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Dose Adaptation to Offset the Pharmacokinetic Interaction Between Ticagrelor and Ritonavir in Healthy Volunteers by Population-based PK Modeling (Simcyp®)
- ClinicalTrials.gov ID
- NCT02435563
- Acronym / sponsor ID
- 13-182
- Conditions
- Healthy
- Keywords
- Anti-HIV Agents, cardiovascular agents, drug interactions
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- University Hospital, GenevaUniversity, hospital or other
- Study start
- Aug 2014
- Primary completion
- Apr 2015 (actual)
- Study completion
- Apr 2015 (actual)
- First posted
- 6 May 2015 (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.
Ticagrelor is a new generation antiplatelet agent with higher efficacy as compared to clopidogrel and prasugrel in treatment of patients with moderate and high ischemic risks. Ticagrelor is active as such and its hepatic metabolism by CYP3A generates also an active metabolite. Because of the remarkable progress in HIV therapies the number of older age patients is on the rise, requiring adequate cardiovascular treatment. Since frontline HIV therapies include ritonavir, a strong inhibitor of CYP3A enzyme, ticagrelor is contraindicated in these patients because of the expected interaction and bleeding risk. A lower efficacy of clopidogrel and prasugrel, which are both pro-drugs, in the presence of ritonavir has been already demonstrated. Therefore, administration of a lower dose of ticagrelor may be a good alternative in HIV patients in order to lessen the impact of this pharmacokinetic interaction. The aim of this study is to adjust the dose of ticagrelor in case of co-treatment with ritonavir to achieve the same pharmacokinetic profile as administered alone using a physiologically-based pharmacokinetic (PBPK) model.
As the first step, a pharmacokinetic (PK) model for ticagrelor and its active metabolite will be created based on available in vitro and in vivo parameters in healthy volunteers.
An open-label, 2 sessions cross over study will be conducted with 20 healthy male volunteers at Clinical Research Center (CRC) of Geneva University Hospitals (HUG). During the first session of the clinical trial, a single dose 180 mg ticagrelor will be administered to the volunteers and obtained pharmacokinetic data will be fitted into the model for optimization. Thereafter a simulated trial by the Simcyp® simulator in presence of a single dose 100 mg ritonavir will allow evaluating the impact of CYP3A inhibition on the concentration-time profile of ticagrelor and its active metabolite. The necessary dose of ticagrelor to minimize the magnitude of this interaction will be calculated. This new dose will be co-administered with ritonavir in the same volunteers during the second session of the clinical trial. The purpose is to obtain the same PK profile with single dose of 180 mg ticagrelor administered alone and with an adapted dose of ticagrelor co-administered with a single dose 100 mg ritonavir. Moreover, the pharmacodynamic effect of ticagrelor will be measured in both sessions of the clinical trial using two specific platelet function tests: the VAsodilator-Stimulated Phosphoprotein assay (VASP) and VerifyNow® P2Y12. With the same PK profile, the same pharmacodynamic activity is expected. The modulation of activity of CYP3A and P-gp by ritonavir will be also monitored using micro dose midazolam and fexofenadine as probe substrates.
The purpose of this study is to use the Simcyp® Simulator mechanistic PBPK modeling to broaden the application field of ticagrelor, especially in HIV patients. Since PK models are often created after clinical observations, the prospective aspect of this study is of particular value as the model will be first created and then applied to an unknown clinical scenario.
Study design
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Ticagrelor 180 mg | Experimental | Drug: ticagrelor 180 mg administrated aloneSingle dose of 180mg ticagrelor administered orally |
| Ticagrelor adjusted dose+ritonavir 100mg | Experimental | Drug: Ticagrelor adjusted dose + ritonavir 100mgadpated dose of ticagrelor calculated after PK modelisation with the Simcyp® simulator administered simultaneously with 100 mg ritonavir |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Healthy male volunteers
- Aged between 18 and 60 years
- BMI between 18 and 27
- Understanding of French language and able to give an inform consent.
Key exclusion criteria (8 listed)
- Hypersensitivity to ticagrelor or ritonavir or any constituents of the tablets
- Concomitant diseases
- Smokers (> 20 cigarettes per day)
- Intake of any drug or food (grapefruit) that is metabolized by or can affect CYP3A or P-glycoprotein activity within the last 10 days
- Pathologies or drugs associated with an increased bleeding risk such as aspirin, non-steroidal anti-inflammatory drugs, steroids and serotonin reuptake inhibitors
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 |
|---|---|---|
| ticagrelor 180 mg administrated alone | Drug | Ticagrelor 180 mg |
| Ticagrelor adjusted dose + ritonavir 100mg | Drug | Ticagrelor adjusted dose+ritonavir 100mg |
Primary outcome
Change in AUC of ticagrelor and its metabolite from baseline
Time frame: 30 min 1hr 2hr 3hr 4hr 6hr 8hr 24hr
Venous blood samples will be taken to assess the baseline pharmacokinetic parameters of ticagrelor and its metabolite, prior to ticagrelor administration (time zero) and at the following post dosage times: 0.5, 1, 2, 3, 4, 6, 8, and 24 hours
3 secondary outcomes
Measure of the pharmacodynamic response to ticagrelor by two platelet reactivity tests VASP and VerifyNow® P2Y12
Time frame: 4hr
Change in P-gp phenotyping from baseline (0 min)
Time frame: 30 min 1hr 2hr 3hr 4hr 6hr 8hr 24hr
Change in CYP3A4 phenotyping from baseline (0 min)
Time frame: 1hr
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 7 Feb 2017.
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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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing ticagrelor 180 mg administrated alone and Ticagrelor adjusted dose + ritonavir 100mg in people with Healthy, run by University Hospital, Geneva at 1 site in Switzerland.
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 4 inclusion and 8 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 7 Feb 2017. 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 Switzerland. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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?
Change in AUC of ticagrelor and its metabolite from baseline (time frame: 30 min 1hr 2hr 3hr 4hr 6hr 8hr 24hr). 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 7 Feb 2017.