HIV InfectionsPhase 4NCT01340950
Clinical Trial of Brain-Penetrating HIV Drugs to Prevent Cognitive Impairment in China
A Phase 4 study testing zidovudine-lamivudine-nevirapine and tenofovir-lamivudine-efavirenz in people with HIV Infections and Central Nervous System Diseases, run by University of California, San Diego at 2 sites in China.
Trial summary
This primary aim of the project is to determine the association between antiretroviral therapy that better distributes into the central nervous system and prevention of HIV-associated neurocognitive impairment. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- HIV Infections, Central Nervous System Diseases, Dementia
- What is being tested?
- zidovudine-lamivudine-nevirapine and tenofovir-lamivudine-efavirenz
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 250 participants
- Where
- 2 sitesChina
- Study dates
- Jul 2010to Jul 2015
- Phase
- Phase 4
- 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
- Men and women of at least 18 years of age.
- Ability and willingness of subject to give written informed consent.
- HIV-1 infection, as documented by enzyme-linked immunosorbent assay (ELISA) and confirmed by Western blot at any time prior to study entry. Plasma HIV-1 RNA is acceptable as an alternative confirmatory test.
- Antiretroviral drug-naïve, defined as ≤10 days of ART at any time prior to entry.
- Clinical HIV-1 RNA ≥1000 copies/mL obtained within 90 days of study screening.
- Clinical blood CD4+ cell count < 350/mm3 (for men) or <250/mm3 (for women) within 60 days of study screening.
- Performance within the expected normal range on the project's comprehensive, standardized battery of neuropsychological tests within 4 weeks.
- For women of child-bearing potential (WOCBP), negative serum or urine pregnancy test at screening and within 48 hours prior to initiating study medications.
Who cannot join
- Serious illness requiring systemic treatment or hospitalization within 4 weeks.
- Unacceptable laboratory values obtained within 4 weeks prior to study entry.
- Untreated syphilis.
- Child Pugh Class C hepatic impairment.
- Active Hepatitis B Virus infection.
- Known allergy/sensitivity to study drugs or their formulations.
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- Severe or untreated conditions that could affect NP test performance.
- Such conditions include but are not limited to current substance use disorder, poorly controlled diabetes, uncontrolled seizure disorder, and any progressive CNS disorder (e.g., multiple sclerosis, CNS neoplasm) and evidence of acute intoxication or withdrawal, in the opinion of the study clinician.
- Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry.
- Currently breast-feeding.
- Requirement for any medications that have an absolute contraindication with any study drugs. In addition, we will exclude people taking rifampin.
- Current imprisonment or involuntary incarceration in a medical facility for psychiatric or physical illness.
- Prior use of nucleoside analogues, such as tenofovir, adefovir, or lamivudine, for treatment of hepatitis B for greater than 8 weeks while the subject was known to be HIV-infected.
- Any condition that, in the opinion of the investigators, would compromise the subject's ability to participate in the study.
Trial locations and contacts
2 sites in 1 country.
China2 sites
Beijing Ditan Hospital
Beijing, Beijing Municipality
Beijing YouAn Hospital
Beijing, Beijing Municipality
About this study
Official title: Clinical Trial of CNS Penetrating ART to Prevent NeuroAIDS in China
This primary aim of the project is to determine the association between antiretroviral therapy that better distributes into the central nervous system and prevention of HIV-associated neurocognitive impairment.
Read the detailed description
Advances in treatment have transformed HIV disease to a chronic illness in most individuals in the U.S. The most common central nervous system (CNS) complication of chronic HIV disease is HIV-associated neurocognitive disorder (HAND). In the U.S., HAND prevalence estimates range up to 55% of treated individuals. HAND is also common outside the U.S. For example, our prior project in China identified that more than a third of nearly 150 treated HIV(+) individuals in Anhui and Yunnan provinces had HAND. Data such as these support that the benefits of antiretroviral therapy (ART) can be incomplete, with many patients not returning to normal neurocognitive performance or, worse, developing new neurocognitive impairment while taking ART.
One explanation for this is the limited penetration of some antiretrovirals into the nervous system. Recent reports have identified that worse antiretroviral penetration characteristics are associated with worse control of HIV replication and worse neurocognitive performance. Most reports, however, have focused on treatment - rather than prevention - of HAND. Like many other medical conditions, prevention of HAND may be a more cost-effective public health goal than treating disease that has already occurred.
We are building on our prior work in China by performing a phase 4, randomized, controlled clinical trial of the safety and effectiveness of ART that differs in its penetration characteristics in 250 ART-naive individuals who have normal neurocognitive performance. The primary objective will be to determine the effects of better penetrating (BP) ART (zidovudine-lamivudine-nevirapine) compared with worse penetrating (WP) ART (tenofovir-lamivudine-efavirenz) on the prevention of HAND. We hypothesize that volunteers who are randomized to BP-ART will be less likely to neurocognitively decline over 96 weeks of observation than those who are randomized to WP-ART. The secondary objective will be to assess the influence on study outcomes of two conditions: persistent immune activation and viral hepatitis. In an exploratory aim, the project will also assess the influence on study outcomes of a concise panel of drug disposition-associated genetic polymorphisms.
Demonstrating that HAND can be prevented by using BP-ART should influence HIV treatment guidelines in the U.S., China, and elsewhere and ultimately lead to preservation of normal neurocognitive functioning in people afflicted with HIV/AIDS.
- Conditions
- HIV Infections, Central Nervous System Diseases, Dementia
- Being tested
- zidovudine-lamivudine-nevirapine, tenofovir-lamivudine-efavirenz
- Keywords
- Prevention, Anti-Retroviral Agents, Neuropsychological Tests
- Medical subject headings
- HIV Infections, Central Nervous System Diseases, Dementia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
zidovudine-lamivudine-nevirapineDrug
Also called Retrovir, Epivir, Viramune
96 weeks of zidovudine 300 mg orally twice daily, lamivudine 300 mg orally daily, nevirapine 200 mg orally daily for the first 14 days then 200 mg orally twice daily
tenofovir-lamivudine-efavirenzDrug
Also called Viread, Epivir, Sustiva
96 weeks of tenofovir disoproxil fumarate 300 mg orally daily, lamivudine 300 mg orally daily, efavirenz 600 mg orally daily
| Study group | Role | What they receive |
|---|---|---|
| Better-Penetrating ART | Active comparator | zidovudine 300 mg orally every 12 hours lamivudine 300 mg orally daily nevirapine 200 mg orally every 12 hours Receives: Drug: zidovudine-lamivudine-nevirapine |
| Worse-Penetrating ART | Active comparator | tenofovir disoproxil fumarate 300 mg orally daily lamivudine 150 mg orally every 12 hours efavirenz 600 mg orally daily Receives: Drug: tenofovir-lamivudine-efavirenz |
What is being measured
The primary outcome is the main question the study is designed to answer.
Decline in neuropsychological performance at 96 weeks
Comparison of decline in NP performance between treatment groups.
Measured: 96 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Apr 2011 (estimated)
- Study startJul 2010
- Primary completionJul 2014
- Study completionJul 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- More trials run by University of California, San DiegoThe 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 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 250 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Diego
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH), National Center for AIDS/STD Control and Prevention, China CDC, Beijing YouAn Hospital, Beijing Ditan Hospital, Peking University
- Responsible party
- Principal investigator, Scott Letendre, University of California, San Diego
- Investigators
- Scott L Letendre, M.D., Principal investigator, University of California, San Diego
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01340950
- Sponsor's protocol ID
- R01MH092225
- Other IDs
- 1R01MH092225-01
- Status last verified
- Mar 2016
- First submitted
- 21 Apr 2011
- Last updated
- 4 Apr 2016
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: Data will be shared in conference presentations and peer-reviewed publications. Data will also be made available on approval of requests for appropriate use.
Publications
Heaton RK, Cysique LA, Jin H, Shi C, Yu X, Letendre S, Franklin DR, Ake C, Vigil O, Atkinson JH, Marcotte TD, Grant I, Wu Z; San Diego HIV Neurobehavioral Research Center Group. Neurobehavioral effects of human immunodeficiency virus infection among former plasma donors in rural China. J Neurovirol. 2008 Nov;14(6):536-49. doi: 10.1080/13550280802378880.
PubMed 18991068Cysique LA, Letendre SL, Ake C, Jin H, Franklin DR, Gupta S, Shi C, Yu X, Wu Z, Abramson IS, Grant I, Heaton RK; HIV Neurobehavioral Research Center group. Incidence and nature of cognitive decline over 1 year among HIV-infected former plasma donors in China. AIDS. 2010 Apr 24;24(7):983-90. doi: 10.1097/QAD.0b013e32833336c8.
PubMed 20299964Spector SA, Singh KK, Gupta S, Cystique LA, Jin H, Letendre S, Schrier R, Wu Z, Hong KX, Yu X, Shi C, Heaton RK; HNRC Group. APOE epsilon4 and MBL-2 O/O genotypes are associated with neurocognitive impairment in HIV-infected plasma donors. AIDS. 2010 Jun 19;24(10):1471-9. doi: 10.1097/QAD.0b013e328339e25c.
PubMed 20442634Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, Gelman BB, McArthur JC, McCutchan JA, Morgello S, Simpson D, Grant I, Ellis RJ; CHARTER Group. Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008 Jan;65(1):65-70. doi: 10.1001/archneurol.2007.31.
PubMed 18195140Letendre SL, McCutchan JA, Childers ME, Woods SP, Lazzaretto D, Heaton RK, Grant I, Ellis RJ; HNRC Group. Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders. Ann Neurol. 2004 Sep;56(3):416-23. doi: 10.1002/ana.20198.
PubMed 15349869
Study at a glance
From the registry record, last updated by the sponsor on 4 Apr 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clinical Trial of CNS Penetrating ART to Prevent NeuroAIDS in China
- ClinicalTrials.gov ID
- NCT01340950
- Acronym / sponsor ID
- R01MH092225
- Conditions
- HIV Infections, Central Nervous System Diseases, Dementia
- Keywords
- Prevention, Anti-Retroviral Agents, Neuropsychological Tests
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 250 participants (actual)
- Lead sponsor
- University of California, San DiegoUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH), National Center for AIDS/STD Control and Prevention, China CDC, Beijing YouAn Hospital, Beijing Ditan Hospital, Peking University
- Study start
- Jul 2010
- Primary completion
- Jul 2014 (actual)
- Study completion
- Jul 2015 (actual)
- First posted
- 25 Apr 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.
This primary aim of the project is to determine the association between antiretroviral therapy that better distributes into the central nervous system and prevention of HIV-associated neurocognitive impairment.
Detailed description
Advances in treatment have transformed HIV disease to a chronic illness in most individuals in the U.S. The most common central nervous system (CNS) complication of chronic HIV disease is HIV-associated neurocognitive disorder (HAND). In the U.S., HAND prevalence estimates range up to 55% of treated individuals. HAND is also common outside the U.S. For example, our prior project in China identified that more than a third of nearly 150 treated HIV(+) individuals in Anhui and Yunnan provinces had HAND. Data such as these support that the benefits of antiretroviral therapy (ART) can be incomplete, with many patients not returning to normal neurocognitive performance or, worse, developing new neurocognitive impairment while taking ART.
One explanation for this is the limited penetration of some antiretrovirals into the nervous system. Recent reports have identified that worse antiretroviral penetration characteristics are associated with worse control of HIV replication and worse neurocognitive performance. Most reports, however, have focused on treatment - rather than prevention - of HAND. Like many other medical conditions, prevention of HAND may be a more cost-effective public health goal than treating disease that has already occurred.
We are building on our prior work in China by performing a phase 4, randomized, controlled clinical trial of the safety and effectiveness of ART that differs in its penetration characteristics in 250 ART-naive individuals who have normal neurocognitive performance. The primary objective will be to determine the effects of better penetrating (BP) ART (zidovudine-lamivudine-nevirapine) compared with worse penetrating (WP) ART (tenofovir-lamivudine-efavirenz) on the prevention of HAND. We hypothesize that volunteers who are randomized to BP-ART will be less likely to neurocognitively decline over 96 weeks of observation than those who are randomized to WP-ART. The secondary objective will be to assess the influence on study outcomes of two conditions: persistent immune activation and viral hepatitis. In an exploratory aim, the project will also assess the influence on study outcomes of a concise panel of drug disposition-associated genetic polymorphisms.
Demonstrating that HAND can be prevented by using BP-ART should influence HIV treatment guidelines in the U.S., China, and elsewhere and ultimately lead to preservation of normal neurocognitive functioning in people afflicted with HIV/AIDS.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Better-Penetrating ART | Active comparator | Drug: zidovudine-lamivudine-nevirapinezidovudine 300 mg orally every 12 hours lamivudine 300 mg orally daily nevirapine 200 mg orally every 12 hours |
| Worse-Penetrating ART | Active comparator | Drug: tenofovir-lamivudine-efavirenztenofovir disoproxil fumarate 300 mg orally daily lamivudine 150 mg orally every 12 hours efavirenz 600 mg orally daily |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Men and women of at least 18 years of age.
- Ability and willingness of subject to give written informed consent.
- HIV-1 infection, as documented by enzyme-linked immunosorbent assay (ELISA) and confirmed by Western blot at any time prior to study entry. Plasma HIV-1 RNA is acceptable as an alternative confirmatory test.
- Antiretroviral drug-naïve, defined as ≤10 days of ART at any time prior to entry.
- Clinical HIV-1 RNA ≥1000 copies/mL obtained within 90 days of study screening.
Key exclusion criteria (14 listed)
- Serious illness requiring systemic treatment or hospitalization within 4 weeks.
- Unacceptable laboratory values obtained within 4 weeks prior to study entry.
- Untreated syphilis.
- Child Pugh Class C hepatic impairment.
- Active Hepatitis B Virus infection.
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 |
|---|---|---|
| zidovudine-lamivudine-nevirapineAlso: Retrovir, Epivir, Viramune96 weeks of zidovudine 300 mg orally twice daily, lamivudine 300 mg orally daily, nevirapine 200 mg orally daily for the first 14 days then 200 mg orally twice daily | Drug | Better-Penetrating ART |
| tenofovir-lamivudine-efavirenzAlso: Viread, Epivir, Sustiva96 weeks of tenofovir disoproxil fumarate 300 mg orally daily, lamivudine 300 mg orally daily, efavirenz 600 mg orally daily | Drug | Worse-Penetrating ART |
Primary outcome
Decline in neuropsychological performance at 96 weeks
Time frame: 96 weeks
Comparison of decline in NP performance between treatment groups.
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 4 Apr 2016.
- Background: PubMed 18991068Heaton RK, Cysique LA, Jin H, Shi C, Yu X, Letendre S, Franklin DR, Ake C, Vigil O, Atkinson JH, Marcotte TD, Grant I, Wu Z; San Diego HIV Neurobehavioral Research Center Group. Neurobehavioral effects of human immunodeficiency virus infection among former plasma donors in rural China. J Neurovirol. 2008 Nov;14(6):536-49. doi: 10.1080/13550280802378880.
- Background: PubMed 20299964Cysique LA, Letendre SL, Ake C, Jin H, Franklin DR, Gupta S, Shi C, Yu X, Wu Z, Abramson IS, Grant I, Heaton RK; HIV Neurobehavioral Research Center group. Incidence and nature of cognitive decline over 1 year among HIV-infected former plasma donors in China. AIDS. 2010 Apr 24;24(7):983-90. doi: 10.1097/QAD.0b013e32833336c8.
- Background: PubMed 20442634Spector SA, Singh KK, Gupta S, Cystique LA, Jin H, Letendre S, Schrier R, Wu Z, Hong KX, Yu X, Shi C, Heaton RK; HNRC Group. APOE epsilon4 and MBL-2 O/O genotypes are associated with neurocognitive impairment in HIV-infected plasma donors. AIDS. 2010 Jun 19;24(10):1471-9. doi: 10.1097/QAD.0b013e328339e25c.
- Background: PubMed 18195140Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, Gelman BB, McArthur JC, McCutchan JA, Morgello S, Simpson D, Grant I, Ellis RJ; CHARTER Group. Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008 Jan;65(1):65-70. doi: 10.1001/archneurol.2007.31.
- Background: PubMed 15349869Letendre SL, McCutchan JA, Childers ME, Woods SP, Lazzaretto D, Heaton RK, Grant I, Ellis RJ; HNRC Group. Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders. Ann Neurol. 2004 Sep;56(3):416-23. doi: 10.1002/ana.20198.
- UCSD Division of Infectious Diseases International Program - ChinaLink provided by the sponsor.
- UCSD HIV Neurobehavioral Research ProgramLink provided by the sponsor.
- China Center for Disease Control and PreventionLink provided by the sponsor.
- Beijing Youan HospitalLink provided by the sponsor.
- Beijing Ditan HospitalLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. Data will be shared in conference presentations and peer-reviewed publications. Data will also be made available on approval of requests for appropriate use.
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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.
Scott L Letendre, M.D. principal investigator
University of California, San Diego
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing zidovudine-lamivudine-nevirapine and tenofovir-lamivudine-efavirenz in people with HIV Infections and Central Nervous System Diseases, run by University of California, San Diego at 2 sites in China.
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 14 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 4 Apr 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in China. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
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?
Decline in neuropsychological performance at 96 weeks (time frame: 96 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 NCT01340950, which also lists 5 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 4 Apr 2016.