HIVPhase 1NCT01479361
Antiretroviral Drug Interaction Study in Volunteers With HIV
A Phase 1 study testing Atovaquone 750 mg twice daily and Atovaquone 1500 mg twice daily in people with HIV and PCP, run by National Institutes of Health Clinical Center (CC) at 1 site in United States.
Trial summary
Background: People who are infected with the human immunodeficiency virus (HIV) are at risk of getting certain diseases. Two of these diseases are a type of pneumonia known as PCP and a brain infection called toxoplasmosis. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- HIV, PCP, Toxoplasmosis
- What is being tested?
- Atovaquone 750 mg twice daily and Atovaquone 1500 mg twice daily
- How many people
- 36 participants
- Where
- 1 siteUnited States
- Study dates
- 31 Oct 2011to 20 Feb 2014
- 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 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- A subject will be considered eligible for this study only if all of the following criteria are met:
- Between the ages of 18 and 70 years.
- HIV-infected patients stabilized (greater than or equal to 90 days) on ARV regimens containing efavirenz 600 mg daily, or atazanavir/ritonavir 300/100 mg daily or HIV-infected patients not receiving ARV therapy.
- CD4 cells greater than or equal to 350 cells/mm3 for HIV-infected patients not receiving ARV therapy.
- CD4 cells >200 cells/mm3 for HIV-infected patients receiving ARV therapy.
- Virologically suppressed patients receiving ARV therapy (<200 copies/mL on at least 2 consecutive occasions, within 6 months prior to enrollment).
- Females of child bearing potential who are able and willing to prevent pregnancy by (a) practicing abstinence or (b) using effective methods of birth control, such as condoms, during the study period and for 1 month after study completion.
- Subject agrees to storage of specimens for future research.
Who cannot join
- A subject will be ineligible for this study if 1 or more of the following criteria are met:
- Concomitant routine therapy with any prescription, over-the- counter, herbal, or holistic medications that are known or suspected to alter atovaquone including rifampin, rifabutin, and metoclopramide for 14 days prior to study participation.
- Subjects receiving primary or secondary prophylaxis for PCP or toxoplasmosis.
- ARV regimens containing both EFV and ATV/r.
- Subjects receiving hormonal contraceptives within 90 days of Study Day 1.
- Inability to obtain venous access for sample collection.
Show all 16Show fewer
- Laboratory and/or physical evidence of any active opportunistic infection.
- Diabetes mellitus requiring treatment with insulin, active tuberculosis, cardiac disease (uncontrolled hypertension and/or heart failure etc.), renal disease (chronic or acute renal failure or insufficiency resulting in baseline serum creatinine greater than 1.5 times upper limit of normal [ULN]), untreated/uncontrolled thyroid disease, untreated/uncontrolled psychiatric disease, active hepatitis (liver failure resulting in liver function tests greater than 3 times the ULN, ascites, or jaundice in the absence of ATV), or any other condition that may interfere with the interpretation of the study results or not be in the best interest of the subject in the opinion of the Investigator.
- Positive pregnancy test or breastfeeding female.
- The presence of persistent diarrhea or malabsorption that could interfere with the subject s ability to absorb drugs.
- Drug or alcohol use that may impair safety or adherence.
- History of intolerance or allergic reaction (rash; hives; swollen lips; difficulty breathing) to atovaquone.
- Bleeding disorders (hemophilia, G.I., or intracranial bleeding).
- Organ transplant recipient.
- Documented ongoing problems with medication adherence.
- High likelihood of switching ARV regimen within 12 weeks of the start of the study.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: The Influence of Atazanavir-ritonavir and Efavirenz on Atovaquone Pharmacokinetics in HIV-infected Volunteers
Background:
- People who are infected with the human immunodeficiency virus (HIV) are at risk of getting certain diseases. Two of these diseases are a type of pneumonia known as PCP and a brain infection called toxoplasmosis. Most people with HIV take antiretroviral (ARV) drugs to treat HIV and lower the risk of infections. However, some ARV drugs may make other drugs used to treat PCP and toxoplasmosis less effective. Researchers want to test specific ARV drugs to see if they affect atovaquone, a drug used to treat PCP and toxoplasmosis.
Read more
Objectives:
- To see if ARV drugs atazanavir-ritonavir or efavirenz lower the blood levels of atovaquone.
Eligibility:
- Individuals between 18 and 70 years of age who have HIV.
- Participants must be taking efavirenz or atazanavir-ritonavir, or not taking any ARV drugs.
Design:
- Participants will be screened with a physical exam and medical history. They will also have blood and urine tests.
- This study has a screening visit and five study visits. Two of the study visits will last about 12 hours; the other three visits will last about 1 hour each.
- Participants will receive either a low dose or high dose of atovaquone to take for 14 days. They will record doses and any symptoms on a diary card at home.
- After 14 days, participants will have a 12-hour visit to provide blood samples. There will be a wash-out period with no doses for up to 6 weeks.
- After the wash-out period, participants will switch dose levels to either the high or low dose.
- After 14 days, participants will have a 12-hour visit to provide blood samples.
Read the detailed description
The incidence of opportunistic infections such as Pneumocystis jirovecii pneumonia (PCP) and Toxoplasma gondii have substantially declined in patients with HIV infection due to potent combination antiretroviral (ARV) therapy and effective prophylaxis. The drug of choice for prophylaxis and treatment of PCP and toxoplasmosis is trimethoprim-sulfamethoxazole (TMP-SMX) and sulfadiazine, respectively. In patients who cannot tolerate these first line therapies, atovaquone is a common alternative. While generally considered safe and effective, a recent drug interaction study involving a single dose of combination tablet of atovaquone/proguanil (Malarone ) in HIV-infected patients showed that atovaquone plasma concentrations were significantly lowered (compared to healthy volunteers) by 75%, 74%, and 46% in patients taking the ARV medications efavirenz (EFV), lopinavir-ritonavir (LPV/r), and atazanavir-ritonavir (ATV/r), respectively. The mechanism of this drug interaction is unknown but is presumably due to induction of uridine diphosphate glucuronsosyltransferase (UGT) enzymes responsible for the metabolism of atovaquone. The magnitude of this interaction is such that it strongly suggests a clinically relevant drug interaction between atovaquone and the aforementioned ARVs. The purpose of this study is to determine whether HIV-infected subjects receiving ATV/r or EFV-containing ARV regimens, experience reductions in atovaquone exposure under steady state conditions compared to HIV-infected patients not receiving ARV therapy.
In this open-label study, 30 HIV-infected subjects will participate in 1 of 3 groups of 10 (Groups A, B, and C). Group A will consist of 10 subjects who are already receiving combination ARV therapy containing ATV/r; Group B will consist of 10 subjects already receiving combination ARV therapy containing EFV; and Group C will consist of 10 subjects who are not currently receiving ARV therapy. All subjects in Groups A, B, and C will be randomly assigned to either receive atovaquone 750 mg twice daily for 14 days (Phase 1) followed by a 2-6 week washout period, followed by atovaquone 1500 mg twice daily for 14 days (Phase 2), or vice versa. Pharmacokinetic (PK) sampling for atovaquone will occur on Day 14 of Phase 1 and 2.
Atovaquone PK parameters will be determined using non-compartmental methods with the WinNonlin professional computer program (version 5.2; Pharsight Corporation, Mountain View, CA). The following PK parameters will be compared among the groups: area under the concentration vs. time curve (AUC ?), maximum concentration (Cmax), apparent oral clearance (Cl/F), time to reach maximum concentration (Tmax), and half-life (T (Omega)). Data from this investigation will determine whether ATV/r and/or EFV alter the steady state PK of atovaquone in HIV-infected subjects. This information will assist clinicians in choosing appropriate alternative therapies for the treatment of PCP and toxoplasmosis in patients who are not candidates for first line therapies.
- Conditions
- HIV, PCP, Toxoplasmosis
- Being tested
- Atovaquone 750 mg twice daily, Atovaquone 1500 mg twice daily
- Keywords
- Atovaquone, Drug Interaction, Pharmacokinetics, Efavirenz, Atazanavir-Ritonavir, HIV
- Medical subject headings
- Toxoplasmosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Atovaquone 750 mg twice dailyDrug
Atovaquone 1500 mg twice dailyDrug
What is being measured
The primary outcome is the main question the study is designed to answer.
The primary objective of this study is to determine the steady state pharmacokinetics of 2 doses of atovaquone oral suspension in the presence of ATV/r, EFV, or no ARVs in HIV-infected patients.
Secondary outcomes (1)
To compare our PK results with the recently reported interaction between a single dose of atovaquone+proguanil and ATV/r and EFV, and the comparator group which consists of HIV-infected subjects, as opposed to a comparator group of healthy subje...
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Nov 2011 (estimated)
- Study start31 Oct 2011
- Primary completion20 Feb 2014
- Study completion20 Feb 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for HIVStudies 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
- Crossover
- Masking
- None (open label)
- Enrolment
- 36 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institutes of Health Clinical Center (CC)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Joseph A Kovacs, M.D., Principal investigator, National Institutes of Health Clinical Center (CC)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01479361
- Sponsor's protocol ID
- 120017
- Other IDs
- 12-CC-0017
- Status last verified
- 1 Jun 2016
- First submitted
- 22 Nov 2011
- Last updated
- 5 Jul 2018
- Results posted
- No
Publications
Pifer LL, Hughes WT, Stagno S, Woods D. Pneumocystis carinii infection: evidence for high prevalence in normal and immunosuppressed children. Pediatrics. 1978 Jan;61(1):35-41.
PubMed 400818Hughes WT, Feldman S, Chaudhary SC, Ossi MJ, Cox F, Sanyal SK. Comparison of pentamidine isethionate and trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia. J Pediatr. 1978 Feb;92(2):285-91. doi: 10.1016/s0022-3476(78)80028-6.
PubMed 304478Winston DJ, Lau WK, Gale RP, Young LS. Trimethoprim-sulfamethoxazole for the treatment of Pneumocystis carinii pneumonia. Ann Intern Med. 1980 Jun;92(6):762-9. doi: 10.7326/0003-4819-92-6-762.
PubMed 6966901Calderon MM, Penzak SR, Pau AK, Kumar P, McManus M, Alfaro RM, Kovacs JA. Efavirenz but Not Atazanavir/Ritonavir Significantly Reduces Atovaquone Concentrations in HIV-Infected Subjects. Clin Infect Dis. 2016 Apr 15;62(8):1036-1042. doi: 10.1093/cid/ciw028. Epub 2016 Jan 20.
PubMed 26797214
Study at a glance
From the registry record, last updated by the sponsor on 5 Jul 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Influence of Atazanavir-ritonavir and Efavirenz on Atovaquone Pharmacokinetics in HIV-infected Volunteers
- ClinicalTrials.gov ID
- NCT01479361
- Acronym / sponsor ID
- 120017
- Conditions
- HIV, PCP, Toxoplasmosis
- Keywords
- Atovaquone, Drug Interaction, Pharmacokinetics, Efavirenz, Atazanavir-Ritonavir, HIV
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 36 participants (actual)
- Lead sponsor
- National Institutes of Health Clinical Center (CC)US National Institutes of Health
- Study start
- 31 Oct 2011
- Primary completion
- 20 Feb 2014 (actual)
- Study completion
- 20 Feb 2014 (actual)
- First posted
- 24 Nov 2011 (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.
Background:
- People who are infected with the human immunodeficiency virus (HIV) are at risk of getting certain diseases. Two of these diseases are a type of pneumonia known as PCP and a brain infection called toxoplasmosis. Most people with HIV take antiretroviral (ARV) drugs to treat HIV and lower the risk of infections. However, some ARV drugs may make other drugs used to treat PCP and toxoplasmosis less effective. Researchers want to test specific ARV drugs to see if they affect atovaquone, a drug used to treat PCP and toxoplasmosis.
Objectives:
- To see if ARV drugs atazanavir-ritonavir or efavirenz lower the blood levels of atovaquone.
Eligibility:
- Individuals between 18 and 70 years of age who have HIV.
- Participants must be taking efavirenz or atazanavir-ritonavir, or not taking any ARV drugs.
Design:
- Participants will be screened with a physical exam and medical history. They will also have blood and urine tests.
- This study has a screening visit and five study visits. Two of the study visits will last about 12 hours; the other three visits will last about 1 hour each.
- Participants will receive either a low dose or high dose of atovaquone to take for 14 days. They will record doses and any symptoms on a diary card at home.
- After 14 days, participants will have a 12-hour visit to provide blood samples. There will be a wash-out period with no doses for up to 6 weeks.
- After the wash-out period, participants will switch dose levels to either the high or low dose.
- After 14 days, participants will have a 12-hour visit to provide blood samples.
Detailed description
The incidence of opportunistic infections such as Pneumocystis jirovecii pneumonia (PCP) and Toxoplasma gondii have substantially declined in patients with HIV infection due to potent combination antiretroviral (ARV) therapy and effective prophylaxis. The drug of choice for prophylaxis and treatment of PCP and toxoplasmosis is trimethoprim-sulfamethoxazole (TMP-SMX) and sulfadiazine, respectively. In patients who cannot tolerate these first line therapies, atovaquone is a common alternative. While generally considered safe and effective, a recent drug interaction study involving a single dose of combination tablet of atovaquone/proguanil (Malarone ) in HIV-infected patients showed that atovaquone plasma concentrations were significantly lowered (compared to healthy volunteers) by 75%, 74%, and 46% in patients taking the ARV medications efavirenz (EFV), lopinavir-ritonavir (LPV/r), and atazanavir-ritonavir (ATV/r), respectively. The mechanism of this drug interaction is unknown but is presumably due to induction of uridine diphosphate glucuronsosyltransferase (UGT) enzymes responsible for the metabolism of atovaquone. The magnitude of this interaction is such that it strongly suggests a clinically relevant drug interaction between atovaquone and the aforementioned ARVs. The purpose of this study is to determine whether HIV-infected subjects receiving ATV/r or EFV-containing ARV regimens, experience reductions in atovaquone exposure under steady state conditions compared to HIV-infected patients not receiving ARV therapy.
In this open-label study, 30 HIV-infected subjects will participate in 1 of 3 groups of 10 (Groups A, B, and C). Group A will consist of 10 subjects who are already receiving combination ARV therapy containing ATV/r; Group B will consist of 10 subjects already receiving combination ARV therapy containing EFV; and Group C will consist of 10 subjects who are not currently receiving ARV therapy. All subjects in Groups A, B, and C will be randomly assigned to either receive atovaquone 750 mg twice daily for 14 days (Phase 1) followed by a 2-6 week washout period, followed by atovaquone 1500 mg twice daily for 14 days (Phase 2), or vice versa. Pharmacokinetic (PK) sampling for atovaquone will occur on Day 14 of Phase 1 and 2.
Atovaquone PK parameters will be determined using non-compartmental methods with the WinNonlin professional computer program (version 5.2; Pharsight Corporation, Mountain View, CA). The following PK parameters will be compared among the groups: area under the concentration vs. time curve (AUC ?), maximum concentration (Cmax), apparent oral clearance (Cl/F), time to reach maximum concentration (Tmax), and half-life (T (Omega)). Data from this investigation will determine whether ATV/r and/or EFV alter the steady state PK of atovaquone in HIV-infected subjects. This information will assist clinicians in choosing appropriate alternative therapies for the treatment of PCP and toxoplasmosis in patients who are not candidates for first line therapies.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- A subject will be considered eligible for this study only if all of the following criteria are met:
- Between the ages of 18 and 70 years.
- HIV-infected patients stabilized (greater than or equal to 90 days) on ARV regimens containing efavirenz 600 mg daily, or atazanavir/ritonavir 300/100 mg daily or HIV-infected patients not receiving ARV therapy.
- CD4 cells greater than or equal to 350 cells/mm3 for HIV-infected patients not receiving ARV therapy.
- CD4 cells >200 cells/mm3 for HIV-infected patients receiving ARV therapy.
Key exclusion criteria (16 listed)
- A subject will be ineligible for this study if 1 or more of the following criteria are met:
- Concomitant routine therapy with any prescription, over-the- counter, herbal, or holistic medications that are known or suspected to alter atovaquone including rifampin, rifabutin, and metoclopramide for 14 days prior to study participation.
- Subjects receiving primary or secondary prophylaxis for PCP or toxoplasmosis.
- ARV regimens containing both EFV and ATV/r.
- Subjects receiving hormonal contraceptives within 90 days of Study Day 1.
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 |
|---|---|---|
| Atovaquone 750 mg twice daily | Drug | – |
| Atovaquone 1500 mg twice daily | Drug | – |
Primary outcome
The primary objective of this study is to determine the steady state pharmacokinetics of 2 doses of atovaquone oral suspension in the presence of ATV/r, EFV, or no ARVs in HIV-infected patients.
1 secondary outcome
To compare our PK results with the recently reported interaction between a single dose of atovaquone+proguanil and ATV/r and EFV, and the comparator group which consists of HIV-infected subjects, as opposed to a comparator group of healthy subje...
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 5 Jul 2018.
- Background: PubMed 400818Pifer LL, Hughes WT, Stagno S, Woods D. Pneumocystis carinii infection: evidence for high prevalence in normal and immunosuppressed children. Pediatrics. 1978 Jan;61(1):35-41.
- Background: PubMed 304478Hughes WT, Feldman S, Chaudhary SC, Ossi MJ, Cox F, Sanyal SK. Comparison of pentamidine isethionate and trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia. J Pediatr. 1978 Feb;92(2):285-91. doi: 10.1016/s0022-3476(78)80028-6.
- Background: PubMed 6966901Winston DJ, Lau WK, Gale RP, Young LS. Trimethoprim-sulfamethoxazole for the treatment of Pneumocystis carinii pneumonia. Ann Intern Med. 1980 Jun;92(6):762-9. doi: 10.7326/0003-4819-92-6-762.
- Derived from this study: PubMed 26797214Calderon MM, Penzak SR, Pau AK, Kumar P, McManus M, Alfaro RM, Kovacs JA. Efavirenz but Not Atazanavir/Ritonavir Significantly Reduces Atovaquone Concentrations in HIV-Infected Subjects. Clin Infect Dis. 2016 Apr 15;62(8):1036-1042. doi: 10.1093/cid/ciw028. Epub 2016 Jan 20.
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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.
Joseph A Kovacs, M.D. principal investigator
National Institutes of Health Clinical Center (CC)
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 Atovaquone 750 mg twice daily and Atovaquone 1500 mg twice daily in people with HIV and PCP, run by National Institutes of Health Clinical Center (CC) 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 8 inclusion and 16 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 5 Jul 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.
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?
The primary objective of this study is to determine the steady state pharmacokinetics of 2 doses of atovaquone oral suspension in the presence of ATV/r, EFV, or no ARVs in HIV-infected patients.. 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 NCT01479361, which also lists 4 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 5 Jul 2018.