Phase II Study to Evaluate the Efficacy and Safety of Baricitinib for Reduction of HIV in the Central Nervous System
概览
- 阶段
- 2 期
- 干预措施
- Baricitinib 2 MG Oral Tablet
- 疾病 / 适应症
- Human Immunodeficiency Virus
- 发起方
- William Tyor
- 入组人数
- 95
- 试验地点
- 2
- 主要终点
- Changes in CSF integrated proviral DNA
- 状态
- 招募中
- 最后更新
- 上个月
概览
简要总结
There is still no cure for the human immunodeficiency virus (HIV). While combination antiretroviral therapy (cART) is effective in decreasing deaths from HIV, infected individuals face a lifetime of treatment and many potential complications including end organ diseases such as HIV-associated neurocognitive disorders. HIV infection is controllable with antiretroviral therapy (ART), but ART cannot eliminate HIV reservoirs. Thus, there is no available cure for HIV. There is a large and growing body of evidence that the central nervous system (CNS) is an HIV reservoir site and a barrier to HIV eradication. Our group has done extensive pre-clinical work with janus-kinase (JAK 1/2) inhibitors. This includes baricitinib, which is an orally available, FDA-approved drug for rheumatoid arthritis. Evidence suggests that this drug has activity against HIV in the central nervous system (CNS). In our recently completed pilot study, we showed that baricitinib crosses the blood brain barrier (BBB) and decreases HIV CNS persistence in the brain.
Using bloodwork, neurocognitive testing, MRIs and lumbar punctures, we plan to evaluate the change in central nervous system HIV after treatment with baricitinib versus placebo. We will also evaluate changes in neuroimaging, inflammation in blood and cerebrospinal fluid (CSF), and neuropsychological performance after treatment with baricitinib versus placebo.
Evidence shows that the central nervous system is one of the reservoir sites that enables the HIV virus to persist in the body even after years of treatment. In order to attack this reservoir and eventually find a cure, it is vital to learn if certain medications can suppress HIV in the CNS.
详细描述
HIV infection is controllable with antiretroviral therapy (ART), but ART cannot eliminate HIV reservoirs. Thus, there is no available cure for HIV. There is a large and growing body of evidence that the central nervous system (CNS) is an HIV reservoir site and a barrier to HIV eradication. HIV DNA is commonly found in brain from people with HIV (PWH) on suppressive ART. HIV genetic compartmentalization occurs in both the brain and CSF, showing that CNS HIV is distinct from peripheral sources such as blood. Multiple studies have demonstrated that CSF HIV RNA can be detected at very low levels during suppressive ART. A study from the AIDS Clinical Trials Group (ACTG) found HIV DNA in CSF cells from approximately 50% of PWH on suppressive ART, a finding that was associated with neurocognitive impairment. The study team's group recently demonstrated a significant advance in quantitating HIV from the CSF. Specifically, CSF cell associated HIV RNA was quantifiable in 90% and CSF HIV DNA was quantifiable in 80% of PWH on suppressive ART. Based on these multiple lines of evidence that the CNS is an HIV reservoir, more research is needed on therapies that have the potential to target the CNS reservoir. The study team has performed extensive pre-clinical and clinical work on the Janus Kinase (Jak 1/2) inhibitor drug class for viral infections. This includes work on ruxolitinib and baricitinib, two FDA approved orally bioavailable agents for myelofibrosis and polycythemia vera (ruxolitinib) as well as rheumatoid arthritis (baricitinib). The investigators have evaluated their potential to target HIV in the CNS in vitro, ex vivo, and in vivo Specifically, the study team has demonstrated that these agents block HIV replication and infection in key CNS cells, reduce the lifespan of HIV CNS reservoirs, and block reservoir reseeding. In vivo, the study team has shown in the murine model that baricitinib decreases CNS HIV and reverses behavioral abnormalities associated with HIV, which correlates with reversal of phenotypic markers of brain inflammation. This has also demonstrated that baricitinib reaches therapeutic CNS concentrations in the rhesus macaque model (including in brain parenchyma) as well as in humans. In a recently published multi-site Phase 2a ACTG-sponsored study with ruxolitinib (A5336, n = 60),the research group demonstrated that ruxolitinib is safe, well-tolerated, and reduces key markers of immune activation. New data that ruxolitinib decreased the peripheral HIV reservoir in a subset of A5336 participants provides even more evidence for this drug class to be included in eradication strategies. However, A5336 did not have any CNS assessments. The investigators now propose to study baricitinib, one of the most promising Jak 1/2 inhibitors with once daily dosing, renal clearance, and a more favorable safety/ pharmacokinetic profile, as a therapy to decrease the HIV CNS reservoir in PWH with durable virologic suppression on ART.
研究者
William Tyor
Professor
Emory University
入排标准
入选标准
- •HIV infected on continuous ART with plasma HIV RNA \<200 copies/ml for at least 12 months (on at least two previous clinic visits and confirmed at screening). If a viral load is documented from a CLIA-certified laboratory 14 days before screening, then this result can be used in place of the screening lab result.
- •Current CD4+ \> 350 cells/microliter for at least twelve months (on at least two previous clinic visits and confirmed at screening). If a CD4 count is documented from a CLIA-certified laboratory 30 days before screening, then this result can be used in place of the screening lab result.
- •Women of reproductive age will have a negative pregnancy test at study entry and agree to contraception while on the study drug. Women who are at least 50 years of age and who have been amenorrheic for at least 12 months will not be required to agree to contraception to participate.
排除标准
- •\< 18 years of age or \> 65 years of age
- •Pregnancy or breastfeeding
- •Significant hematological abnormalities at screening (ANC \< 1000, Hgb\<10, platelet\< 100,000)
- •History of progressive multifocal leukoencephalopathy
- •Untreated latent tuberculosis infection (which will be screened for before entry). If there is a prior positive test, the test does not need to be repeated at screening.
- •Immunosuppressive medications (including corticosteroids) and anticoagulants (aspirin acceptable) within 1 month. A partial list is provided in the SOP for staff, but otherwise, if there is a question it will be adjudicated by the Investigator(s).
- •History of deep venous thrombosis
- •Cardiovascular disease:
- •Coronary artery disease or history of myocardial infarction, no exclusion if greater than 3 months
- •Congestive heart failure with left ventricular ejection fraction ≤40% per American Heart Association guidelines-- no exclusion if greater than 3 months
研究组 & 干预措施
Baricitinib
Potential participants will be pre-screened through review of the electronic medical record from Emory or Grady. Or if a potential participant receives care elsewhere, a release of medical information form will be signed and sent to the medical center that the individual goes to. The study team will enroll individuals who have well controlled HIV. Participants will then be randomized to either baricitinib or placebo. Patients randomized to Baricitinib group will receive Baricitinib at dose of 2 mg oral for ten weeks. Follow up visits will happen for both groups at weeks 1, 2, 4 and 10.
干预措施: Baricitinib 2 MG Oral Tablet
Placebo
Potential participants will be pre-screened through review of the electronic medical record from Emory or Grady. Or if a potential participant receives care elsewhere, a release of medical information form will be signed and sent to the medical center that the individual goes to. The study team will enroll individuals who have well controlled HIV. Participants will then be randomized to either baricitinib or placebo. Patients randomized to the placebo group will receive 2 mg oral daily placebo for ten weeks. Follow up visits will happen for both groups at weeks 1, 2, 4 and 10.
干预措施: Placebo
结局指标
主要结局
Changes in CSF integrated proviral DNA
时间窗: Baseline and study week 10
The study team will obtain up to 40 milliliters (ml) of CSF from individuals who weigh at least 60 kilograms, otherwise, they will draw up to 30 ml of CSF. CSF integrated proviral DNA (IPDA and Alu-PCR) will be assessed: Integrated proviral DNA will be performed using existing methods in the clinical research group, which employ the Alu-PCR real-time platform, with a limit of 3 copies. Integrated proviral DNA assay (IPDA) to measure the replication-competent reservoir will be used with digital droplet PCR methodology.
次要结局
- Changes in CSF HIV RNA by single copy assay(Baseline and study week 10)
- Changes in HIV tat protein in CSF(Baseline and study week 10)
- Changes in CSF HIV cell-associated RNA by Double-R assay.(Baseline and study week 10)
- Changes in CSF HIV cell associated CSF HIV DNA by Double-R assay.(Baseline and study week 10)
- Changes in CSF cell associated DNA(Baseline and study week 10)
- Changes in Blood HIV cell associated RNA by Double-R assay(Baseline and study week 10)
- Changes in Blood HIV cell associated DNA by Double-R assay(Baseline and study week 10)
- Changes in Blood cell associated DNA(Baseline and study week 10)
- Change in HIV DNA levels by Integrated proviral DNA assay(Baseline and study week 10)
- Changes in Blood HIV RNA by single copy assay(Baseline and study week 10)
- Changes in Blood indirect viral markers: anti-HIV antibody levels(Baseline and study week 10)
- Changes in Blood indirect viral markers: HIV specific T cells(Baseline and study week 10)
- Changes in Blood CXCL10(Baseline and study week 10)
- Changes in Blood Neopterin(Baseline and study week 10)
- Changes in Blood IL-7(Baseline and study week 10)
- Changes in Blood IL-15(Baseline and study week 10)
- Changes in Stroop Test (Color Naming and Color-Word)(Baseline and study week 10)
- Changes in Hopkins Verbal Learning Test II (Learning and Recall)(Baseline and study week 10)
- Changes in Brief Visuospatial Test (Learning and Recall)(Baseline and study week 10)
- Changes in Trailmaking(Baseline and study week 10)
- Changes in Digit Symbol Test(Baseline and study week 10)
- Changes in Letter Number Sequencing Test(Baseline and study week 10)
- Changes in Wisconsin Card Sorting Test(Baseline and study week 10)
- Changes in Grooved Pegboard Test(Baseline and study week 10)
- Changes in Letter and category fluency test(Baseline and study week 10)
- Changes in Beck Depression Inventory II (BDI-II)(Baseline and study week 10)
- Changes in MRI neuroimaging findings(Baseline and study week 10)