Interaction Between Etravirine or Darunavir/Ritonavir and Artemether / Lumefantrine (DDI Coartem)

June 11, 2013 updated by: Janssen Pharmaceutica N.V., Belgium

A Phase I, Partially Randomized, Open Label, Two-way, Two Period Cross-over Study to Investigate the Pharmacokinetic Interaction Between Etravirine or Darunavir/Rtv and Artemether/Lumefantrine at Steady-state in Healthy HIV-negative Subjects

The purpose of this study is to investigate the pharmacokinetic interaction between etravirine and artemether/lumefantrine and darunavir/ritonavir and artemether/lumefantrine in healthy Human Immunodeficiency Virus- (HIV-)negative patients. 'Pharmacokinetic interaction' means that one medication can influence the absorption and elimination from the body of the other medication.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

This is a Phase I, partially randomized, open-label, single-center, two-way, two-period cross-over study to investigate the pharmacokinetic interaction between etravirine (ETR) or darunavir/ritonavir (DRV/rtv) and the antimalarial drugs artemether/lumefantrine at steady-state in healthy human immunodeficiency virus (HIV)-negative patients. The study population will consist of 32 healthy patients, equally divided over 2 panels. Patients in Panel 1 will be treated with ETR and artemether/lumefantrine; patients in Panel 2 will be treated with DRV/rtv and artemether/lumefantrine. Treatment A will consist of 3 days of treatment with artemether/lumefantrine. Treatment B will consist of 200 mg ETR twice daily (b.i.d.) (Panel 1) or 600/100 mg DRV/rtv b.i.d. (Panel 2) from Day 1 to Day 21 with a single dose of ETR (Panel 1) or DRV/rtv (Panel 2) in the morning on Day 22. From Day 8, 3 days of treatment with artemether/lumefantrine. In a first stage of treatment in Panel 2, only 4 patients will be allowed to start Treatment B. Based on the ECG results of the first 4 patients with evaluable ECG data after assessments on Day 11 (66 hours after the combined intake of DRV/rtv and artemether/lumefantrine), the Sponsor will decide whether additional patients can be allowed to start Treatment B. There will be a washout period of at least 4 weeks between Treatments A and B. Half of the patients of Panel 1 (8 patients) and Panel 2 (8 patients) will be randomized to sequence AB and half will be randomized to sequence BA. Randomization in Panel 2 will occur in two steps. In Step 1, 4 patients will be allocated to sequence BA and evaluated for QTc prolongation. Based on the outcome of their ECG results, the Sponsor will decide whether the remainder of patients will be randomized in Step 2, i.e. 4 patients to BA and 8 patients to AB (1:2 randomization). Serial pharmacokinetic assessments will be determined for Panels 1 and 2 in Treatments A and B for artemether and its metabolite dihydroartemisinin (DHA) after the first intake of artemether/lumefantrine over 8 hours and after the last intake of artemether/lumefantrine over 72 hours (3 days), and for lumefantrine after the last intake of artemether/lumefantrine over 264 hours (11 days). Serial pharmacokinetic assessments will be determined for ETR (Panel 1) or DRV and rtv (Panel 2) over the 12-hour dosing interval on Day 8 (after the morning intake) and Day 11 (after the last dose of artemether/lumefantrine) of Treatment B. All ETR, DRV/rtv and artemether/lumefantrine treatments will be administered under fed conditions and will be taken within 10 minutes after completion of a meal. Safety and tolerability evaluations will be recorded on an ongoing basis.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
33

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 55 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • if of childbearing potential or if male, use a highly effective method of birth control.
  • Able to comply with protocol requirements.
  • A BMI (weight in kg divided by the square of height in meters) of 18.5 to 30.0 kg/m2, extremes included.
  • healthy on the basis of a medical evaluation
  • Non-smoking for at least 3 months prior to selection.

Exclusion Criteria:

  • previously demonstrated clinically significant allergy, hypersensitivity or intolerance to any of the investigational medications or its excipients
  • Use of concomitant medication, including over-the-counter products and dietary supplements.
  • Having participated in more than 1 study (single or multiple dose) with ETR (TMC125), DRV (TMC114), dapivirine (TMC120) and/or rilpivirine (TMC278, formerly known as R278474), or having developed a rash, erythema or urticaria while participating in a study with the aforementioned compounds.
  • A positive pregnancy test or breast feeding at screening or on Day 1.
  • Any condition that, in the opinion of the investigator, would compromise the study or the well-being of the patient or prevent the patient from meeting or performing study requirements

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

  • Primary Purpose: HEALTH_SERVICES_RESEARCH
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: ETR, artemether/lumefantrine
treatment with artemether/lumefantrine 80/480 mg during 3 days (treatment A) and treatment during 22 days with etravirine for 22 days and artemether/lumefantrine 80/480 mg from day 8 to day 11 (treatment B) with a washout of at least 4 weeks between the 2 treatment periods
Drug: Etravirine
200 mg ETR b.i.d. from Day 1 to Day 21 with a single 200 mg dose of ETR in the morning on Day 22
Drug: artemether/lumefantrine
3 days of treatment with artemether/lumefantrine 80/480 mg (6 doses of 4 tablets [20/120 mg] at 0, 8, 24, 36, 48, and 60 hours)
EXPERIMENTAL: DRV/rtv, artemether/lumefantrine
treatment with artemether/lumefantrine 80/480 mg during 3 days (treatment A) and treatment during 22 days with darunavir/ritonavir and artemether/lumefantrine 80/480 mg from day 8 to day 11 (treatment B) with a washout of at least 4 weeks between the 2 treatment periods
Drug: artemether/lumefantrine
3 days of treatment with artemether/lumefantrine 80/480 mg (6 doses of 4 tablets [20/120 mg] at 0, 8, 24, 36, 48, and 60 hours)
Drug: Darunavir/ritonavir
DRV/rtv 600/100 mg b.i.d. from Day 1 to Day 21 with a single dose of DRV/rtv in the morning on Day 22

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
effect of ETR or DRV/rtv on the plasma concentrations of artemether, lumefantrine and dihydroartemisinin
Time Frame: Treatment A: Day 1-2 & Day 4-15; Treatment B: Day 8-9 & Day 11-22
the effect of ETR or DRV/rtv on the pharmacokinetics of artemether, lumefantrine and the artemether metabolite dihydroartemisinin (DHA) after single and multiple dose(s) in healthy subjects. plasma concentrations: minimum (Cmin) and maximum (Cmax): artemether and DHA (Day 11 of Treatment B versus Day 4 of Treatment A, Days 11-14 of Treatment B versus Days 4-7 of Treatment A ), lumefantrine (Days 11-22 of Treatment B versus Days 4-15 of Treatment A ); Cmax artemether and DHA (Day 8-9 of Treatment B versus Day 1-2 of Treatment A )
Treatment A: Day 1-2 & Day 4-15; Treatment B: Day 8-9 & Day 11-22
effect of ETR or DRV/rtv on the Area under the concentration-time curve (AUC) in plasma for artemether, lumefantrine and dihydroartemisinin
Time Frame: Treatment A: Day 1-2 & Day 4-15; Treatment B: Day 8-9 & 11-22
effect of ETR or DRV/rtv on the AUC from time of administration (0 hours) to 8 hours after dosing (AUC8h): artemether and DHA (Day 8-9 of Treatment B versus Day 1-2 of Treatment A); AUC from 0 to 12 hours (AUC 12h) artemether and DHA (Day 11 of Treatment B versus Day 4 of Treatment A ); AUC from 0 to 264 hours (AUC264h) lumefantrine (Days 11-22 of Treatment B versus Days 4-15 of Treatment A ; AUC from 0 to the last time point with a measurable concentration post dosing (AUClast) artemether and DHA (Days 11-14 of Treatment B versus Days 4-7 of Treatment A )
Treatment A: Day 1-2 & Day 4-15; Treatment B: Day 8-9 & 11-22
Plasma concentrations of ETR, DRV and rtv
Time Frame: Treatment B: Day 8 & Day 11
Cmin and Cmax for ETR, DRV and ritonavir (Day 11 of Treatment B versus Day 8 of Treatment B )
Treatment B: Day 8 & Day 11
Area under the concentration-time curve (AUC) in plasma for ETR, DRV and rtv
Time Frame: Treatment B: Day 8 & Day 11
AUC from time of administration to 12 hours after dosing (AUC12h) for ETR, DRV and ritonavir (Day 11 of Treatment B versus Day 8 of Treatment B)
Treatment B: Day 8 & Day 11

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Time Frame: at screening, during treatment and at day 7 and 30, 31 or 32 after last study medication intake
short-term safety and tolerability of coadministration of ETR or DRV/rtv and artemether/lumefantrine in healthy subjects.
at screening, during treatment and at day 7 and 30, 31 or 32 after last study medication intake
Profile of pharmacokinetics of ETR by cytochrome P450 (CYP)2C9 and CYP2C19 genotype
Time Frame: Treatment B: Day 8
the effect of CYP2C9 and CYP2C19 genotypes will be evaluated by comparison of these genotypes with the Cmax and AUC12 for ETR
Treatment B: Day 8
Profile of pharmacokinetics of artemether and DHA after single and multiple dose(s)
Time Frame: Treatment A: Day 1-2 & Day 4-7
Cmax (both periods), AUC8h (Day 1-2) and AUClast (Day 4-7) for artemether and DHA
Treatment A: Day 1-2 & Day 4-7

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Janssen Pharmaceutica N.V., Belgium

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

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 1, 2011

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 1, 2011

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 1, 2011

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
November 19, 2012

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 11, 2013

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 13, 2013

Study Record Updates

Last Update Posted (ESTIMATE)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 13, 2013

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 11, 2013

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • CR018409
  • 2010-023289-31 (EUDRACT_NUMBER)
  • TMC125VIR1001 (OTHER: Janssen CTMS ID)

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