HIVPhase 2/3NCT03019783
Atazanavir and Endothelial Function in Older HIV Patients
A Phase 2/3 study testing Atazanavir in people with HIV, run by Brigham and Women's Hospital at 1 site in United States.
Trial summary
The investigators hypothesize that older subjects with HIV randomly assigned to atazanavir will have increased bilirubin levels, reduced oxidative stress, and improved flow-mediated, endothelium-dependent vasodilation compared to subjects not switched to atazanavir. Read more about this study
- Who is it for?
- Ages 45 years and older
- Conditions the study is for
- HIV
- What is being tested?
- Atazanavir
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 60 participants
- Where
- 1 siteUnited States
- Study dates
- Dec 2011to Jun 2016
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 45 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 45 years
- Stable non-atazanavir-containing regimen consisting of co-formulated tenofovir/emtricitabine as the NRTIs plus a third agent for 3 months or longer. The third agent can be any FDA-approved PI, NNRTI, or raltegravir.
- HIV RNA < 200 cop/mL at screening and at least once within the prior year,
- No treatment interruptions > 7 days in the 3 months prior to study entry
- The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
- Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)
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- Signed Written Informed Consent. Before any study procedures are performed, subjects will have the details of the study described to them, and they will be given a written informed consent document to read. Then, if subjects consent to participate in the study, they will indicate that consent by signing and dating the informed consent document in the presence of study personnel.
- Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of study drug to minimize the risk of pregnancy.
- WOCBP include any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined as:
- Amenorrhea that has lasted for 12 consecutive months without another cause, or
- For women with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.
- Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or who are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential.
- WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of the investigational product.
Who cannot join
- Sex and Reproductive Status
- WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 4 weeks after the last dose of study drug.
- Women who are pregnant or breastfeeding.
- Women with a positive pregnancy test.
- Target Disease Exceptions
- Prior treatment failure on or intolerance to atazanavir
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- Known or suspected resistance to atazanavir
- Receiving ART different from co-formulated tenofovir/emtricitabine plus third agent (PI, NNRTI, or raltegravir) regimen
- Receiving Viagra, Levitra, or Cialis
- A new AIDS-defining condition diagnosed within the 30 days prior to screening
- Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to baseline
- Medical History and Concurrent Diseases
- Patients with Gilbert's Syndrome or elevated bilirubin levels (>1.5 mg/dL) at baseline (for the randomized trial)
- Patients with uncontrolled diabetes (hemoglobin A1c > 11%)
- Patients allergic to nitroglycerin
- Prohibited Treatments and/or Therapies
- Recent initiation of hormones or immunomodulators (3 months)
- Current receipt of proton-pump inhibitor therapy
- Other Exclusion Criteria
- Prisoners, or subjects who are involuntarily incarcerated.
- Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
- Subjects for whom the investigators believe there will be a low likelihood of medication compliance.
Trial locations and contacts
1 site in 1 country.
United States1 site
Brigham and Women's Hospital
Boston, Massachusetts, 02115
About this study
The investigators hypothesize that older subjects with HIV randomly assigned to atazanavir will have increased bilirubin levels, reduced oxidative stress, and improved flow-mediated, endothelium-dependent vasodilation compared to subjects not switched to atazanavir.
Read the detailed description
The mortality induced by HIV has dropped significantly due to effective antiretroviral therapy. Epidemiological data suggest a less than 5% 10-year mortality for patients treated with HAART. As a result of the reduction in early AIDS-related deaths, HIV has become a chronic disease manifesting the common components of chronic disease such as inflammation, vascular dysfunction, and oxidative stress. The combination of these trends put HIV patients at increased risk of myocardial infarction compared with age-matched subjects over the long term. Several studies suggest that some protease inhibitors might increase the risk of myocardial infarction. The leading theory behind this association derives from the relationship between protease inhibitor use and the onset of an atherogenic dysmetabolism including the development of insulin resistance, dyslipidemia, and oxidative stress.
In contrast to the older protease inhibitors, atazanavir induces neither insulin resistance nor dyslipidemia. In addition, atazanavir has a property unique among protease inhibitors: elevation of unconjugated bilirubin by inhibiting the enzyme uridine diphosphate glucuronyltransferase (UGT) 1A1. Bilirubin is a potent intracellular antioxidant. The investigators have demonstrated that higher levels of bilirubin within the normal range are associated with reduced rates of stroke and peripheral artery disease. Patients with Gilbert's Syndrome (chronic elevations of bilirubin as a result of genetically reduced UGT 1A1) have a lower rate of myocardial infarction compared with age-matched controls. It is plausible that use of atazanavir compared with other protease inhibitors, by reducing oxidative stress, may improve vascular function and, ultimately, reduce the rate of cardiovascular complications with chronic therapy.
The benefit of atazanavir may be particularly important now with the aging of the HIV population. Aging is associated with higher levels of oxidative stress and endothelial dysfunction, both of which are associated with heightened rates of cardiovascular morbidity and mortality. Accordingly, the investigators hypothesize that the use of atazanavir in stable HIV patients age 45 years or older will improve endothelial dysfunction and reduce oxidative stress compared with continuing the current therapy.
- Conditions
- HIV
- Being tested
- Atazanavir, Placebo
- Keywords
- Endothelial function
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AtazanavirDrug
Also called Reyataz
The active group will switch from a non-atazanavir regimen to an atazanavir-based regimen.
PlaceboOther
The control group will stay on their baseline regimen
| Study group | Role | What they receive |
|---|---|---|
| Remains on baseline HIV regimen | Placebo comparator | Subjects are enrolled and either kept on their baseline regimen. This is being designated the placebo comparator. Receives: Other: Placebo |
| Atazanavir switch | Active comparator | These subjects are switched to an atazanavir-based regimen. Receives: Drug: Atazanavir |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Flow-mediated, Endothelium-dependent Vasodilation
The investigators will evaluate flow-mediated, brachial artery vasodilation (percentage increase in diameter in response to a 5 minute ischemic challenge) at study entry and then after 28 days, with the change between the two measurements being the primary endpoint.
Measured: 4 weeks
Secondary outcomes (1)
Change in Plasma Total Antioxidant Capacity
The investigators will evaluate plasma total antioxidant capacity at study entry and then after 28 days, with the change between the two measurements being the secondary endpoint.
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jan 2017 (estimated)
- Study startDec 2011
- Primary completionJun 2015
- Study completionJun 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HIVStudies of the same condition, open and under way.
- More trials run by Brigham and Women's HospitalThe 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 2/3
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 60 participants (actual)
Sponsor and investigators
- Lead sponsor
- Brigham and Women's Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Joshua A. Beckman, MD, Brigham and Women's Hospital
- Investigators
- Joshua Beckman, Principal investigator, Brigham and Women's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03019783
- Sponsor's protocol ID
- AI424-469
- Status last verified
- Apr 2017
- First submitted
- 8 Dec 2016
- Last updated
- 16 May 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Beckman JA, Wood BR, Ard KL, Price CN, Solomon DA, Zuflacht JP, Milian J, Prenner JC, Sax PE. Conflicting effects of atazanavir therapy on atherosclerotic risk factors in stable HIV patients: A randomized trial of regimen switch to atazanavir. PLoS One. 2017 Oct 12;12(10):e0181993. doi: 10.1371/journal.pone.0181993. eCollection 2017.
PubMed 29023508
Study at a glance
From the registry record, last updated by the sponsor on 16 May 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Atazanavir and Endothelial Function in Older HIV Patients
- ClinicalTrials.gov ID
- NCT03019783
- Acronym / sponsor ID
- AI424-469
- Conditions
- HIV
- Keywords
- Endothelial function
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 60 participants (actual)
- Lead sponsor
- Brigham and Women's HospitalUniversity, hospital or other
- Study start
- Dec 2011
- Primary completion
- Jun 2015 (actual)
- Study completion
- Jun 2016 (actual)
- First posted
- 13 Jan 2017 (estimated)
- Results
- Posted 18 Apr 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The investigators hypothesize that older subjects with HIV randomly assigned to atazanavir will have increased bilirubin levels, reduced oxidative stress, and improved flow-mediated, endothelium-dependent vasodilation compared to subjects not switched to atazanavir.
Detailed description
The mortality induced by HIV has dropped significantly due to effective antiretroviral therapy. Epidemiological data suggest a less than 5% 10-year mortality for patients treated with HAART. As a result of the reduction in early AIDS-related deaths, HIV has become a chronic disease manifesting the common components of chronic disease such as inflammation, vascular dysfunction, and oxidative stress. The combination of these trends put HIV patients at increased risk of myocardial infarction compared with age-matched subjects over the long term. Several studies suggest that some protease inhibitors might increase the risk of myocardial infarction. The leading theory behind this association derives from the relationship between protease inhibitor use and the onset of an atherogenic dysmetabolism including the development of insulin resistance, dyslipidemia, and oxidative stress.
In contrast to the older protease inhibitors, atazanavir induces neither insulin resistance nor dyslipidemia. In addition, atazanavir has a property unique among protease inhibitors: elevation of unconjugated bilirubin by inhibiting the enzyme uridine diphosphate glucuronyltransferase (UGT) 1A1. Bilirubin is a potent intracellular antioxidant. The investigators have demonstrated that higher levels of bilirubin within the normal range are associated with reduced rates of stroke and peripheral artery disease. Patients with Gilbert's Syndrome (chronic elevations of bilirubin as a result of genetically reduced UGT 1A1) have a lower rate of myocardial infarction compared with age-matched controls. It is plausible that use of atazanavir compared with other protease inhibitors, by reducing oxidative stress, may improve vascular function and, ultimately, reduce the rate of cardiovascular complications with chronic therapy.
The benefit of atazanavir may be particularly important now with the aging of the HIV population. Aging is associated with higher levels of oxidative stress and endothelial dysfunction, both of which are associated with heightened rates of cardiovascular morbidity and mortality. Accordingly, the investigators hypothesize that the use of atazanavir in stable HIV patients age 45 years or older will improve endothelial dysfunction and reduce oxidative stress compared with continuing the current therapy.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Remains on baseline HIV regimen | Placebo comparator | Other: PlaceboSubjects are enrolled and either kept on their baseline regimen. This is being designated the placebo comparator. |
| Atazanavir switch | Active comparator | Drug: AtazanavirThese subjects are switched to an atazanavir-based regimen. |
Who may qualify
- Ages
- 45 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- Age ≥ 45 years
- Stable non-atazanavir-containing regimen consisting of co-formulated tenofovir/emtricitabine as the NRTIs plus a third agent for 3 months or longer. The third agent can be any FDA-approved PI, NNRTI, or raltegravir.
- HIV RNA < 200 cop/mL at screening and at least once within the prior year,
- No treatment interruptions > 7 days in the 3 months prior to study entry
- The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
Key exclusion criteria (22 listed)
- Sex and Reproductive Status
- Target Disease Exceptions
- Medical History and Concurrent Diseases
- Prohibited Treatments and/or Therapies
- Other Exclusion Criteria
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 |
|---|---|---|
| AtazanavirAlso: ReyatazThe active group will switch from a non-atazanavir regimen to an atazanavir-based regimen. | Drug | Atazanavir switch |
| PlaceboThe control group will stay on their baseline regimen | Other | Remains on baseline HIV regimen |
Primary outcome
Change in Flow-mediated, Endothelium-dependent Vasodilation
Time frame: 4 weeks
The investigators will evaluate flow-mediated, brachial artery vasodilation (percentage increase in diameter in response to a 5 minute ischemic challenge) at study entry and then after 28 days, with the change between the two measurements being the primary endpoint.
1 secondary outcome
Change in Plasma Total Antioxidant Capacity
Time frame: 4 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 May 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 29023508Beckman JA, Wood BR, Ard KL, Price CN, Solomon DA, Zuflacht JP, Milian J, Prenner JC, Sax PE. Conflicting effects of atazanavir therapy on atherosclerotic risk factors in stable HIV patients: A randomized trial of regimen switch to atazanavir. PLoS One. 2017 Oct 12;12(10):e0181993. doi: 10.1371/journal.pone.0181993. eCollection 2017.
- Individual participant dataSharing planned: No
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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.
Joshua Beckman principal investigator
Brigham and Women's Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Atazanavir in people with HIV, run by Brigham and Women's Hospital 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 13 inclusion and 22 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 16 May 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 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined 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.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Apr 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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 Flow-mediated, Endothelium-dependent Vasodilation (time frame: 4 weeks). 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 NCT03019783, which also lists 1 linked publication.
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 16 May 2017.