Impact of a Monoamine Oxidase Inhibitor on the Phenotype of Blood Mononucleated Cells in Patients With COVID-19
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 51
- 试验地点
- 2
- 主要终点
- levels of lymphocytes T DR + CD38 + and of monocytes CD14 dim + CD16 +.
研究概览
简要总结
The principal objective is to determine the impact of phenelzine on the activation phenotype of T cells and myeloid cells during SARS-CoV2 infection
详细描述
Investigators want to test in vitro (in France Stage 1), and in vivo in a phase 1b/2 clinical trial (Stage 2 in Australia) a widely used antidepressant (the monoamine oxidase inhibitor (MAOi) Phenelzine (Nardil*), repurposed as an antiviral drug to treat SARS-CoV-2. Indeed this proposal leverages extensive existing data on the epigenetic mechanism of action of phenelzine and new data suggesting that it has an anti-viral action against the SARS-CoV-2 virus.
Epigenetic drugs are promising antiviral treatments capable of modifying epigenetic tags and re-programming host and viral genomes. Epigenetic modulation could be useful at least at two steps: the entry of the virus, and the regulation of the immune response. The SARS-Cov-2 depends on ACE2 and TMPRSS2 to gain cellular entry. The reduction of the expression of these proteins could therefore be protective.
Recent clinical studies have demonstrated that, in addition to their effects on neurotransmitter regulation, anti-depressants also possess anti-inflammatory characteristics via impacting pro inflammatory cytokines production which are involved in the 'cytokines storm' during severe disease. (2). These patients also have fewer circulating functional T cells and NK cells and greater numbers of dysfunctional, exhausted CD8+ T cells (3). These abnormalities are probably deleterious and reduce the efficacy of anti-viral responses.
The in-depth and patented epigenetic, cellular, and structural analyses of human cell lines harbouring the SARS-CoV-2 infective machinery and capable of propagating the virus have shown that:
- The epigenetic enzyme (histone demethylase) LSD1 directly regulates the SARS-CoV-2-binding domain of ACE2 and the protease active sites of TMPRSS2 (patented), which are critical for viral entry and propagation within the host.
- MAOi, which target LSD1 activity, inhibit the ACE2/TMPRSS2 machinery, which investigators hypothesize will prevent viral entry into the host cell to reduce viral load, disease burden, and the emergence of cytokine storms. In support of novel dual targeting viral blockage strategy recent work have shown that targeting TMPRSS2 or ACE2 alone has anti-viral activity (4).
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Prospective
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
- •1. Individuals male or female ≥18 years of age at time of enrolment
- •2.Subject (or legally authorized representative provides non opposition form prior to initiation of any study procedure.
- •3. Understands and agrees to comply with planned study procedure. (Agrees to the collection of venous blood per protocol).
- •4. Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other commercial or public health assay in any specimen<72hours prior to enrollment and/or a chest CT scan reported as highly likely SARS-CoV2 infection.
- •The different scales for severity are as follows:
- •5. Non severe patients: Clinical assessment (evidence of rales/crackles on exam) or CT scan involvement AND SpO2> 94% on room air, or ≤ 94% on room air but > 94% with nasal Oxygen with a flow rate <= 3l O2/min
- •For the severe infection's patients' group:
- •6. Patients requiring mechanical ventilation and/or supplemental oxygen >= 6l O2/min
- •For the obese patients 'group:
- •7. Obese patients will be defined as an BMI > 30
- •8. Co inclusion in non-interventional researches is possible
排除标准
- •Pregnant and breast-feeding women
- •Patients previously treated by phenelzine (Nardil®)
- •Persons unable to give their no opposition
- •Persons under guardianship or curatorship
- •No affiliated to social insurance.
- •Inclusion in interventional researches
研究组 & 干预措施
Female, BMI<30, severe
Females:
Non-Obese BMI<30 With severe infection n = 10
干预措施: blood sample (Other)
male, BMI≥30, mild
males: Obese BMI≥30 With Mild infection n = 10
干预措施: blood sample (Other)
Female, BMI≥30, mild
Females:
Obese BMI≥30 With Mild infection n = 10
干预措施: blood sample (Other)
Female, BMI≥30, severe
Females:
Obese BMI≥30 With severe infection n = 10
干预措施: blood sample (Other)
Female, BMI<30, mild
Females:
Non-Obese BMI<30 With Mild infection n = 10
干预措施: blood sample (Other)
male, BMI≥30, severe
males: Obese BMI≥30 With severe infection n = 10
干预措施: blood sample (Other)
male, BMI<30, mild
males: Non-Obese BMI<30 With Mild infection n = 10
干预措施: blood sample (Other)
male, BMI<30, severe
males: Non-Obese BMI<30 With severe infection n = 10
干预措施: blood sample (Other)
Healthy donors from the EFS (Etablissement Français du Sang, St Louis)
Healthy donors from the EFS (Etablissement Français du Sang, St Louis) including 5 men and 5 women
干预措施: blood sample (Other)
结局指标
主要结局
levels of lymphocytes T DR + CD38 + and of monocytes CD14 dim + CD16 +.
时间窗: through study completion, an average of 1 year
evaluate the levels of the activation of T cells and myeloid cells after phenelzine exposure by the levels of the % of DR+ CD38+ T cells and CD14+dim CD16+ monocytes.
次要结局
- cytokine production and proliferation(through study completion, an average of 1 year)
- level of immune checkpoints(through study completion, an average of 1 year)
- level of immune responses for men and women(through study completion, an average of 1 year)
- levels of neutrophils(through study completion, an average of 1 year)
- level of immune responses in obese patients(through study completion, an average of 1 year)