HIV InfectionsPhase 1NCT00697892
Pharmacokinetic Interactions Between Antiretroviral Agents and Antimalarial Drug Combinations
A Phase 1 study testing lopinavir/ritonavir, efavirenz and artemether/lumefantrine in people with HIV Infections and Malaria, run by Fran Aweeka at 1 site in United States.
Trial summary
The purpose of the study is to determine in healthy volunteers whether certain anti-HIV medications (lopinavir/ritonavir and efavirenz) affect the drug levels of certain anti-malarial medications (artesunate/ amodiaquine and artemether/ lumefantrine) and vice versa. Read more about this study
- Who is it for?
- Ages 21 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- HIV Infections, Malaria
- What is being tested?
- lopinavir/ritonavir, efavirenz and artemether/lumefantrine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 38 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2005to Dec 2010
- Phase
- Phase 1
- 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 21 to 60 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Absence of HIV infection prior to study entry
- Male or female aged 21-60 who are able to provide informed consent
- Subject is within 20% (+/-) of ideal body weight and weighs at least 50 kg.
- Healthy, without evidence of acute or chronic illness including diabetes, hypertension, CAD, psychiatric illnesses, renal or hepatic impairment.
- Screening laboratory tests that are normal or deemed not clinically significant by the study physician.
- Female subjects of reproductive potential must agree to the use of two forms of birth control methods for at least one month prior to study enrollment and for 6 weeks following study completion
- Female subjects must have a negative pregnancy test within 24 hours before receiving any study drugs.
Who cannot join
- Use of illicit drugs or alcohol that could interfere with the completion of the study
- Use of any over-the-counter or prescribed drugs unless approved by the principal investigator or study physician
- Use of drugs that are known to inhibit/induce CYP450 isozymes or are substrates of CYP3A4, CYP2D6, CYP2C8 enzymes (use of hormonal contraceptives is permitted).
- Pregnant or breastfeeding
- History of acute or chronic illnesses, such as diabetes, hypertension, CAD, psychiatric illnesses, renal or hepatic impairment.
- Evidence of acute illness
- Family history of congenital prolongation of QTc interval or with any conditions known to prolong QTc interval such as cardiac arrhythmias, bradycardia, or severe heart disease
- History of hypokalemia, hypomagnesemia, or hypercholesteremia
Trial locations and contacts
1 site in 1 country.
United States1 site
San Francisco General Hospital
San Francisco, California, 94110
About this study
Official title: Pharmacokinetic Interactions Between Antiretroviral Agents, Lopinavir/Ritonavir and Efavirenz and Antimalarial Drug Combinations, Artesunate/Amodiaquine and Artemether/Lumefantrine.
The purpose of the study is to determine in healthy volunteers whether certain anti-HIV medications (lopinavir/ritonavir and efavirenz) affect the drug levels of certain anti-malarial medications (artesunate/ amodiaquine and artemether/ lumefantrine) and vice versa. Since these drugs are degraded using overlapping pathways in the liver, it is predicted that changes in both drug level and overall drug exposure will be observed.
Read the detailed description
HIV and malaria are two of the most pernicious diseases facing developing countries. Malaria affects 300 to 500 million individuals annually in developing countries and it is estimated that 25.8 million people in Africa live with HIV. Current therapy recommended by the World Health Organization includes the use of artemisinin derivatives, such as artesunate and artemether. To minimize the risk of resistance, these drugs are used in combination with older drugs with longer half-lives including amodiaquine and lumefantrine.
Treatment of malaria is further complicated by the increasing availability of antiretroviral (ARV) medications for HIV in that clinically important drug-drug interactions may occur in co-infected patients. Protease inhibitor (e.g. lopinavir and ritonavir) and non-nucleoside reverse transcriptase (e.g. efavirenz) based treatment commonly affects pharmacokinetic exposure of drugs metabolized by cytochrome P450 (CYP) metabolic pathways.
Artemether is metabolized by the CYP3A4 to active dihydroartemisinin (DHA), while artesunate is hydrolyzed to DHA. Lumefantrine is an active compound that is metabolized by CYP3A4. Amodiaquine is an active "prodrug" that is quickly metabolized to an active metabolite N-desethylamodiaquine (DEAQ) by CYP2C8. In addition, these antimalarial drugs may also affect the metabolism of CYP substrates, such as ARVs.
The primary objective of this study is to investigate the effects of ARV agents (ritonavir/ lopinavir (Kaletra) and efavirenz) on the pharmacokinetics of antimalarial drug combinations [artesunate/ amodiaquine and their active metabolites, and artemether/ lumefantrine (Coartem®) and their active metabolites]. The secondary objective is to investigate the effects of antimalarial drug combinations [artesunate/amodiaquine and artemether/lumefantrine (Coartem®)] on the pharmacokinetics of ARV drugs [lopinavir/ritonavir (Kaletra®) and efavirenz].
If clinically important interactions occur, net effects may include improved or diminished antimalarial activity (as activity is attributed to both the parent drug and the active metabolite(s)) and drug toxicity. The study in HIV negative healthy volunteers will allow rapid assessment of these potential interactions and will provide essential data for optimizing a future clinical study and the use of ARVs and antimalarials for children and adults in Uganda.
Currently the components of the study involving the impact of ARVs on artesunate/amodiaquine are not being pursued (and recruitment for those arms was conducted separately), so there are only two groups in the presently-approved trial: one in which the effects of lopinavir/ritonavir on artemether/lumefantrine are studied and another in which the effects of efavirenz on artemether/lumefantrine are studied.
- Conditions
- HIV Infections, Malaria
- Being tested
- lopinavir/ritonavir, efavirenz, artemether/lumefantrine
- Keywords
- Human Immunodeficiency Virus, Drug Interactions
- Medical subject headings
- HIV Infections, Malaria, Acquired Immunodeficiency Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
lopinavir/ritonavirDrug
Also called Kaletra
Two tablets of lopinavir 200mg / ritonavir 50mg orally twice daily with food for 26 days
efavirenzDrug
Also called Sustiva
One 600mg tablet orally once daily before bedtime on an empty stomach for 26 days
artemether/lumefantrineDrug
Also called Coartem
4 tablets of artemether 20mg/lumefantrine 120mg twice daily with food. 2 three-day courses will be administered (with washout in between) during the duration of the trial.
| Study group | Role | What they receive |
|---|---|---|
| Group A4 | Experimental | healthy volunteers assigned to the efavirenz with artemether/lumefantrine intervention Receives: Drug: efavirenz; Drug: artemether/lumefantrine |
| Group A3 | Experimental | healthy volunteers assigned to the lopinavir/ritonavir with artemether/lumefantrine intervention Receives: Drug: lopinavir/ritonavir; Drug: artemether/lumefantrine |
What is being measured
The primary outcome is the main question the study is designed to answer.
AUC (zero to infinity) of the antimalarial agent
Measured: Each 3-day antimalarial treatment course throughout study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jun 2008 (estimated)
- Study startJul 2005
- Primary completionDec 2008
- Study completionDec 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HIV InfectionsStudies 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 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 38 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fran Aweeka
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Fran Aweeka, University of California, San Francisco
- Investigators
- Francesca T Aweeka, PharmD, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00697892
- Sponsor's protocol ID
- H6930-27654
- Status last verified
- May 2013
- First submitted
- 2 Jun 2008
- Last updated
- 6 Jun 2013
- Results posted
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Jun 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacokinetic Interactions Between Antiretroviral Agents, Lopinavir/Ritonavir and Efavirenz and Antimalarial Drug Combinations, Artesunate/Amodiaquine and Artemether/Lumefantrine.
- ClinicalTrials.gov ID
- NCT00697892
- Acronym / sponsor ID
- H6930-27654
- Conditions
- HIV Infections, Malaria
- Keywords
- Human Immunodeficiency Virus, Drug Interactions
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 38 participants (actual)
- Lead sponsor
- Fran AweekaUniversity, hospital or other
- Study start
- Jul 2005
- Primary completion
- Dec 2008 (actual)
- Study completion
- Dec 2010 (actual)
- First posted
- 16 Jun 2008 (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 purpose of the study is to determine in healthy volunteers whether certain anti-HIV medications (lopinavir/ritonavir and efavirenz) affect the drug levels of certain anti-malarial medications (artesunate/ amodiaquine and artemether/ lumefantrine) and vice versa. Since these drugs are degraded using overlapping pathways in the liver, it is predicted that changes in both drug level and overall drug exposure will be observed.
Detailed description
HIV and malaria are two of the most pernicious diseases facing developing countries. Malaria affects 300 to 500 million individuals annually in developing countries and it is estimated that 25.8 million people in Africa live with HIV. Current therapy recommended by the World Health Organization includes the use of artemisinin derivatives, such as artesunate and artemether. To minimize the risk of resistance, these drugs are used in combination with older drugs with longer half-lives including amodiaquine and lumefantrine.
Treatment of malaria is further complicated by the increasing availability of antiretroviral (ARV) medications for HIV in that clinically important drug-drug interactions may occur in co-infected patients. Protease inhibitor (e.g. lopinavir and ritonavir) and non-nucleoside reverse transcriptase (e.g. efavirenz) based treatment commonly affects pharmacokinetic exposure of drugs metabolized by cytochrome P450 (CYP) metabolic pathways.
Artemether is metabolized by the CYP3A4 to active dihydroartemisinin (DHA), while artesunate is hydrolyzed to DHA. Lumefantrine is an active compound that is metabolized by CYP3A4. Amodiaquine is an active "prodrug" that is quickly metabolized to an active metabolite N-desethylamodiaquine (DEAQ) by CYP2C8. In addition, these antimalarial drugs may also affect the metabolism of CYP substrates, such as ARVs.
The primary objective of this study is to investigate the effects of ARV agents (ritonavir/ lopinavir (Kaletra) and efavirenz) on the pharmacokinetics of antimalarial drug combinations [artesunate/ amodiaquine and their active metabolites, and artemether/ lumefantrine (Coartem®) and their active metabolites]. The secondary objective is to investigate the effects of antimalarial drug combinations [artesunate/amodiaquine and artemether/lumefantrine (Coartem®)] on the pharmacokinetics of ARV drugs [lopinavir/ritonavir (Kaletra®) and efavirenz].
If clinically important interactions occur, net effects may include improved or diminished antimalarial activity (as activity is attributed to both the parent drug and the active metabolite(s)) and drug toxicity. The study in HIV negative healthy volunteers will allow rapid assessment of these potential interactions and will provide essential data for optimizing a future clinical study and the use of ARVs and antimalarials for children and adults in Uganda.
Currently the components of the study involving the impact of ARVs on artesunate/amodiaquine are not being pursued (and recruitment for those arms was conducted separately), so there are only two groups in the presently-approved trial: one in which the effects of lopinavir/ritonavir on artemether/lumefantrine are studied and another in which the effects of efavirenz on artemether/lumefantrine are studied.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group A4 | Experimental | Drug: efavirenz, Drug: artemether/lumefantrinehealthy volunteers assigned to the efavirenz with artemether/lumefantrine intervention |
| Group A3 | Experimental | Drug: lopinavir/ritonavir, Drug: artemether/lumefantrinehealthy volunteers assigned to the lopinavir/ritonavir with artemether/lumefantrine intervention |
Who may qualify
- Ages
- 21 to 60 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- Absence of HIV infection prior to study entry
- Male or female aged 21-60 who are able to provide informed consent
- Subject is within 20% (+/-) of ideal body weight and weighs at least 50 kg.
- Healthy, without evidence of acute or chronic illness including diabetes, hypertension, CAD, psychiatric illnesses, renal or hepatic impairment.
- Screening laboratory tests that are normal or deemed not clinically significant by the study physician.
Key exclusion criteria (8 listed)
- Use of illicit drugs or alcohol that could interfere with the completion of the study
- Use of any over-the-counter or prescribed drugs unless approved by the principal investigator or study physician
- Use of drugs that are known to inhibit/induce CYP450 isozymes or are substrates of CYP3A4, CYP2D6, CYP2C8 enzymes (use of hormonal contraceptives is permitted).
- Pregnant or breastfeeding
- History of acute or chronic illnesses, such as diabetes, hypertension, CAD, psychiatric illnesses, renal or hepatic impairment.
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 |
|---|---|---|
| lopinavir/ritonavirAlso: KaletraTwo tablets of lopinavir 200mg / ritonavir 50mg orally twice daily with food for 26 days | Drug | Group A3 |
| efavirenzAlso: SustivaOne 600mg tablet orally once daily before bedtime on an empty stomach for 26 days | Drug | Group A4 |
| artemether/lumefantrineAlso: Coartem4 tablets of artemether 20mg/lumefantrine 120mg twice daily with food. 2 three-day courses will be administered (with washout in between) during the duration of the trial. | Drug | Group A3, Group A4 |
Primary outcome
AUC (zero to infinity) of the antimalarial agent
Time frame: Each 3-day antimalarial treatment course throughout study
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 6 Jun 2013.
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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.
Francesca T Aweeka, PharmD principal investigator
University of California, San Francisco
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing lopinavir/ritonavir, efavirenz and artemether/lumefantrine in people with HIV Infections and Malaria, run by Fran Aweeka 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 7 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 6 Jun 2013. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
AUC (zero to infinity) of the antimalarial agent (time frame: Each 3-day antimalarial treatment course throughout study). 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 6 Jun 2013.