Curing HIV: Proof of Concept Randomized Clinical Trial With Pyrimethamine, Lenalidomide, TOpiramate
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 30
- 试验地点
- 4
- 主要终点
- Phase I primary outcome: Fold change in cell-associated HIV-RNA
研究概览
简要总结
The PLUTO trial aims to contribute to the worldwide search for a functional cure of HIV. One the strategies ("shock and kill' strategy) aims to reverse the HIV-reservoir from latency by increasing cell-associated HIV-RNA, which will lead to increased antigen presentation, trigger immune recognition, and facilitate the elimination of reservoir cells. Participants of the trial are adults with HIV with undetectable viral load that are able to give informed consent to participate in the trial, in total 30 patients will be recruited. The investigational medical compounds in this trial are topiramate, lenalidomide and pyrimethamine, which will be combined. These are all licensed drugs for other conditions.
The study consists of two phases. In phase I participants will receive a single dose of the IMPs, as combination therapy. Sampling will be performed before, during and after medical treatment to evaluate latency reversal and safety endpoints. In phase II, participants will receive the combination of IMPs which is the most potent and within safety limits selected from phase I during a four-week treatment. Sampling will take place on a weekly basis to assess latency reversal, reservoir reduction and safety.
Participants will be recruited from the Erasmus MC, Amsterdam university Medical Center, Radboud University Medical Center and the University Medical Center Utrecht.
详细描述
Rationale Though combined antiretroviral therapy (ART) has made HIV a clinically manageable chronic illness by preventing viral replication, HIV poses great burdens on PLWH and society to this day. Due to the presence of a stable, latent viral reservoir, the virus rebounds when ART is stopped. Additionally this reservoir fuels inflammation with related comorbidities. Finding therapies to reduce the reservoir are therefore an important research objective. One strategy to shrink or eliminate the latent reservoir aims to reverse the reservoir from latency, leading to increased antigen presentation and trigger immune recognition (the "shock and kill" strategy). Several latency reversal agents (LRA) have been identified. Though single LRA treatment are effective to a limited extent, they have not resulted in significant HIV reservoir reduction. PLUTO, aims to study novel combinations of promising LRAs with different targets to reactivate and reduce the latent viral reservoir by identifying the combination with strongest latency reversal of phase I of our study and assessing latency reversal and reservoir decay after prolonged treatment in phase II of our study.
Objectives
Primary objectives phase I:
- To assess the efficacy of LRA combinations during a one day treatment on HIV reservoir reactivation in people living with HIV.
Primary objectives phase II:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Documented HIV-1 infection, confirmed by 4th generation ELISA, Western Blot or PCR.
- •Age ≥ 18 years old.
- •Confirmed HIV1, subtype A, B, C or D.
- •Uninterrupted ART therapy for a minimum 6 months. .
- •Plasma HIV RNA <≤50 copies/ml prior to inclusion at two consecutive measurements at least three months apart.
- •No disclosed missed ART on more than 2 days per month.
- •Current blood CD4+T-cell count of ≥200 cells/mm3
- •No clinical signs of cellular immunodeficiency or AIDS.
- •Pre-ART plasma HIV RNA ≥1000 copies/mL.
- •Able to understand provided information and to give informed consent.
排除标准
- •Prior exposure to any of the studied LRAs in the previous 90 days
- •HIV-2 (double)infection
- •Co-infection with hepatitis B, unless resolved HBV (anti-HBc positive, anti-HBs positive and HBsAg negative) OR HBsAg positive and on continuous HBV-active antiviral therapy for ≥24 weeks prior to dosing, and HBV DNA undetectable or ≤ 200 IU/mL on two measurements (screening and within 4 weeks prior to enrolment), and no history of advanced fibrosis/cirrhosis (stage F2 and higher)
- •Co-infection with hepatitis C, measured by the presence of hepatitis C virus RNA in blood.
- •Co-medication with clinically significant interactions with LRA
- •mRNA vaccine or adjuvant vaccine (e.g. Shingrix) in the previous 8 weeks.
- •Megaloblastic anaemia due to folate deficiency and untreated haemolysis of any cause
- •Active malignancy during the past year with the exception of basal carcinoma of the skin, stage 0 cervical carcinoma, Kaposi's sarcoma treated with ART alone or other indolent malignancies.
- •History of suicide attempt or suicidal ideation.
- •History of ophthalmological medical problems leading to glaucoma or visual field disturbances (e.g. macula oedema). Refraction abnormalities that can be corrected by lenses are acceptable.
- •History of any medical condition with a causal relationship with hyperammonemia.
- •History of epileptic seizures in the previous year.
- •Registered allergies for any of the investigational medical products
- •Sexually active participants who do not fit any of the following:
- •a) Female subject of childbearing potential willing to comply with pregnancy tests before start and four weeks after end of treatment and willing to use of double contraceptive measures during and until 1 week after administration of study medication. Non-childbearing is defined by one of the following criteria: amenorrhoea for ≥ 1 year, premature ovarian failure, assigned male at birth, or having undergone bilateral salpingo-oophorectomy, or hysterectomy. b) Sexually active male PLWH who have sex with female partners of childbearing potential and willing to abstain from sex or willing to use condom protection during and until 1 week after administration of study medication.
- •c) Sexually active male PLWH who have sex with postmenopausal female partners and willing to abstain from sex or willing to use condom protection or with a postmenopausal female partner on pre-exposure prophylaxis during and until 1 week after administration of study medication.
- •d) Male PLWH who have sex with male partners and willing to abstain from sex or willing to use a condom protection during and until 1 week after administration of study medication.
- •e) Male PLWH who have sex with male partners on preexposure prophylaxis during and until 1 week after administration of study medication.
- •Any lab abnormalities at screening as listed below:
- •Moderate kidney impairment, defined as eGFR <50 mL/min. In PLWH on dolutegravir- or bictegravir-based ART regimens, cystatin C-based eGFR can be used, since possible drug interference with tubular creatinine excretion which leads to eGFR underestimation.
- •Moderate hepatic impairment, defined as bilirubin > 3 x upper limit of normal (ULN) or ALT > 3x ULN
- •Inadequate blood counts, defined as: haemoglobin <6.5 mmol/L (males) or <6.0 mmol/L (females), Absolute neutrophil count <1000 cells/mm3, thrombocytes <100 x109/L, international standardized ratio >1.6, activated partial thromboplastin time >40 seconds,
研究组 & 干预措施
PYR + LENA
Pyrimethamine 200mg oral administration + Lenalidomide 25mg oral administration
干预措施: Pyrimethamine (PYR) (Drug)
PYR + TOPI
Pyrimethamine 200mg oral administration + Topiramate 400mg oral administration
干预措施: Pyrimethamine (PYR) (Drug)
PYR + TOPI
Pyrimethamine 200mg oral administration + Topiramate 400mg oral administration
干预措施: Topiramate (drug) (Drug)
LENA + TOPI
Lenalidomide 25mg oral administration + Topiramate 400 mg oral administration
干预措施: Lenalidomide (Drug)
LENA + TOPI
Lenalidomide 25mg oral administration + Topiramate 400 mg oral administration
干预措施: Topiramate (drug) (Drug)
PYR + LENA
Pyrimethamine 200mg oral administration + Lenalidomide 25mg oral administration
干预措施: Lenalidomide (Drug)
结局指标
主要结局
Phase I primary outcome: Fold change in cell-associated HIV-RNA
时间窗: At time points 6 and 24 hours after treatment, compared to baseline
The fold change in cell-associated HIV-RNA within and between the study arms
Phase II primary outcome: Log transformed HIV-DNA
时间窗: At time point 4 weeks compared to baseline
The change in log transformed HIV-DNA within the treatment group. Measured using IPDA and SQuHIVLa
次要结局
- Phase I & II: Clinical safety and tolerability of the LRA drug combination.(Phase I: 1 week Phase II: 5 weeks)
- Phase I: Participant preference on the latency reversing agent (LRA) combinations.(At 0 hours, 24 hours and 7 days)
- Phase I: Participant quality of life during combination LRA treatment(Baseline, and at timepoint 7 days)
- Phase I: Plasma HIV-RNA kinetics during interventional treatment(At time points 6 hours, 24 hours and 7 days compared to baseline)
- Phase I: Change of the functionality of immune cells(At 7 days, compared to baseline)
- Phase I: Change of the phenotype of immune cells(At 7 days, compared to baseline)
- Phase I: Pharmacokinetics of LRA compounds(At time points 2 hours, 6 hours, 24 hours and 7 days compared to baseline)
- Phase I: Drug plasma levels of ART(At time points 0 hours, 6 hours, 24 hours and 7 days)
- Phase I: Drug plasma levels of ART(At baseline and at time points 6 hours, 24 hours and 7 days)
- Phase I: Ex vivo/ In vivo correlation of reservoir reactivation(From time points baseline to 24 hours)
- Phase II: Participant quality of life during LRA combination treatment.(At baseline and timepoint 4 weeks)
- Phase II: Plasma HIV-RNA kinetics during interventional treatment(At timepoints 24 hours, 1 week, 2 weeks, 3 weeks and 4 weeks compared to baseline)
- Phase II: functionality of innate and adaptive immune cells(At time points 1 week, 2 weeks, 3 weeks and 4 weeks compared to baseline)
- Phase II: Phenotype of innate and adaptive immune cells(At time points 1 week, 2 weeks, 3 weeks and 4 weeks compared to baseline)
- Phase II: Pharmacokinetics LRA compounds(At time points 1 week, 2 weeks, 3 weeks and 4 weeks compared to baseline)
- Phase II: Pharmacokinetics of LRA compounds(At time points 1week, 2 weeks, 3 weeks and 4 weeks compared to baseline)
- Phase II: Drug plasma levels of ART(At time points 1 week, 2 weeks, 3 weeks and 4 weeks)
- Phase II: Drug plasma levels of ART(At time points 1 week, 2 weeks, 3 weeks, 4 weeks)
研究者
Casper Rokx
Erasmus MC internist-infectious diseases specialist, principal investigator
Erasmus Medical Center