Phase II Proof-of-concept, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Plitidepsin in Adults With Post-COVID-19 Condition (PCC)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 90
- 试验地点
- 2
- 主要终点
- Change in the overall health in patients from each group using patient reported outcomes measurement information system score (PROMIS-29®).
研究概览
简要总结
The study aims to prove that plitidepsin could be an efficacious, safe, and well-tolerated therapy for PCC. To this end, we will perform a randomized, double-blind study comparing the clinical and laboratory benefits of plitidepsin vs. placebo in 90 subjects with moderate to severe functional disability. The study consists of an intervention period and a follow-up period, with a total of 135 +/-3 days approximately between both periods.
During the intervention period, four treatment cycles will be administered, scheduled every 15 days (every 2 weeks), with intravenous (IV) infusion over three consecutive days. After completing the intervention period, a 90-day (+/-5) follow-up period will be conducted.
Subjects in arm A will receive the plitidepsin 1.5 mg/day 1h-IV during the four treatment periods on Days 1 to 3, Days 15 to 17, Days 29 to 31 and Days 43 to 45. Subjects in arm B will receive 1h-IV placebo 1 vial /day during the first two treatment periods and will receive the plitidepsin 1.5 mg/day 1h-IV during the last two treatment periods. Subjects in arm C will receive 1h-IV placebo 1 vial/day during the four treatment periods.
详细描述
Plitidepsin, a marine-derived cyclic depsipeptide that inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A, could be a suitable candidate treatment for "Long COVID" because of a triple mechanism of action; a) it has demonstrated potent anti-SARS-CoV-2 in vitro activity, (b) it has a systemic anti-inflammatory effect, detailed in the text below, and (c) has an anti-herpes antiviral effect, which could provide additional therapeutic benefits to prevent herpesvirus reactivation seen in Long-COVID.
An interim analysis will be conducted upon reaching 30% and 50% of recruitment (patients treated with at least one dose and 28 days (+/- 2 days) of FUP)). The first interim analysis will focus exclusively on safety assessment, based on adverse events reported to date. The second interim analysis (50%) will evaluate safety and futility. A blinded safety report will be prepared, summarizing adverse events, and submitted to the Data Safety Monitoring Board (DSMB) for review and to determine whether to continue, modify, or terminate the study
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Masking of investigational products will ensure that both the investigator and the participant are blinded to the product administered. The pharmacist service will be responsible for masking the study treatments. Both treatments (Plitidepsin and placebo) have the same route of administration. All the participants (from all arms) will receive the pre-medication required for the plitidepsin treatment.
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
- •Male or female individuals 18 years old or older.
- •Evidence of SARS-CoV-2 infection at least 90 days prior to study recruitment, defined by either (a) nasopharyngeal SARS-CoV-2 nucleic acid test [polymerase chain reaction (PCR) or transcription mediated amplification (TMA)], (b) validated Nasopharyngeal Lateral Flow Assay rapid antigen test (RAT), or (c) or positive serology against SARS-CoV-2 N protein regardless vaccination status.
- •3 or more symptoms of PCC affecting at least two organs, after 90 days from the onset of SARS-CoV2 infection and that last for at least 2 months and cannot be explained by an alternative diagnosis. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.
- •Unable to perform all usual duties/activities, defined as grades 3 or 4 in PCFS (Annex 3).
- •Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study.
- •Having understood the information provided and capable of providing informed consent
排除标准
- •Last SARS-CoV-2 vaccine dose during the previous 30 days.
- •Patients with active uncontrolled infections.
- •Patients infected by SARS-CoV-2 virus in the last 90 days prior to the screening visit.
- •Patients receiving treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers (Annex 1) throughout plitidepsin treatment period and until 24-h washout period.
- •Pacients receiving chronic glucocorticoid therapy (high-dose corticosteroids [ie, 20 mg of prednisone daily or equivalent for ≥2 weeks)
- •Any of the following cardiac conditions or risk factors:
- •Cardiac infarction or cardiac surgery episode within the last six months 14
- •History of known congenital QT prolongation;
- •Known structural cardiomyopathy with abnormal left ventricular ejection fraction (LVEF) <50%;
- •Current clinical evidence of heart failure or acute cardiac ischaemia (New York Heart Association (NYHA) class III-IV).
- •Hypersensitivity to the active ingredient or any of the excipients (mannitol, macrogolglycerol hydroxystearate, and ethanol) or contraindication to receive systemic glucocorticoids, antihistamine H1/H2 receptor agents, or antiserotonine 5HT3 receptors drugs.
- •Mast cell activation syndrome.
- •Females who are pregnant (negative serum or urine pregnancy test required for all females of childbearing potential at screening) or breast-feeding.
- •Females of childbearing potential (females who are not surgically sterile or postmenopausal defined as amenorrhea for >12 months) who are not using highly effective contraceptive methods, while on study treatment and for 6 months after last dose of plitidepsin. Fertile males with partners of childbearing potential must use condom during treatment and for 6 months after last dose of plitidepsin. Refer to Annex 2 for contraception requirements.
- •Unable to consent and/or comply with study requirements, in the opinion of the investigator.
- •Currently participating or participated in a clinical trial within the prior
研究组 & 干预措施
B. Placebo/Plitidepsin
Subjects in arm B will receive 1h-IV placebo 1 vial /day during the first two treatment periods (Days 1 to 3 and Days 15 to 17) and plitidepsin 1.5 mg/day 1h-IV during the last two treatment periods (Days 29 to 31 and Days 43 to 45).
干预措施: Placebo and Plitidepsin 1.5mg/day (Drug)
C. Placebo Arm
Subjects in arm C will receive 1h-IV placebo 1 vial/day during the four treatment periods on Days 1 to 3, Days 15 to 17, Days 29 to 31, and Days 43 to 45.
干预措施: Placebo (Drug)
A. Plitidepsin Arm
Subjects in arm A will receive the plitidepsin 1.5 mg/day 1h-IV during the four treatment periods on Days 1 to 3, Days 15 to 17, Days 29 to 31 and Days 43 to 45.
干预措施: Plitidepsin 1.5 mg/day (Drug)
结局指标
主要结局
Change in the overall health in patients from each group using patient reported outcomes measurement information system score (PROMIS-29®).
时间窗: On day 90 of follow-up period
Difference between groups on the patient-reported outcomes measurement information system (PROMIS-29®) score health scale measured by T-Score; Each domain is scored on a 5-point scale, (without any difficulty, with a little difficulty, with some difficulty, with much difficulty, unable to do), in case of the pain domain is on a 10-point scale; from no pain to the worse pain. on day 90 (±5) of the follow-up period\* (after the intervention).
次要结局
- To compare the safety/tolerability of Plitidepsin Vs placebo in terms of adverse events in patients with PCC.(On day 90 of follow-up period)
- To compare the incidence of Treatment-Emergent Adverse Events (TEAEs) between groups.(On day 10, day 30 and day 90 of follow-up period)
- To compare changes in the overall health in patients from each group using patient reported outcomes measurement information system score (PROMIS-29®).(On day 10, day 30 and day 90 of follow-up period)
- To compare functional capacity changes in patients from each group using the post-COVID-19 Functional State (PCFS) scale.(On day 10, day 30 and day 90 of follow-up period)
- To compare symptomatic changes in patients from each group using the Can Ruti Questionnaire.(On day 10, day 30 and day 90 of follow-up period)
- To compare changes in terms of Quality of Life (QoL) for each group.(On day 10, day 30 and day 90 of follow-up period)
- To compare neuropsychological symptomatology [psychomotor speed and executive function] in patients with PCC among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare neuropsychological symptomatology [depressive symptoms] in patients with PCC among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare neuropsychological symptomatology [ anxiety symptoms] in patients with PCC among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare neuropsychological symptomatology [sleep quality] in patients with PCC among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare neuropsychological symptomatology [disability] in patients with PCC among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare changes in terms of physical activity in patients with PCC among the three arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare changes in terms of fatigue (Fatigue scale) in patients with PCC among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare changes in terms of fatigue (Five times sit to stant test) in patients with PCC among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare the evolution of inflammation markers in patients with PCC among the three arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare immune response markers: Antinuclear antibodies (ANAs) in patients with persistent COVID among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare immune response markers: antiphospholipid antibodies (Abs) in patients with persistent COVID among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare immune response markers: antimitochondrial antibodies in patients with persistent COVID among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare alterations in thromboinflammatory components (activated partial thromboplastin time (aPTT)), among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare the SARS-CoV-2 RNA antigenemia (presence of viral components) in plasma with persistent COVID among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare alterations in Complement Activitation: Hemolytic Complement CH50 in patients with persistent COVID among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare alterations in thromboinflammatory components (prothrombin time (PT)), among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare alterations in thromboinflammatory components (D-Dimer), among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare alterations in thromboinflammatory components (Fibrinogen), among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare alterations in thromboinflammatory components (Antithrombin III (ATIII)), among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare alterations in thromboinflammatory components (Factor de Von willebrand), among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare alterations in hormonal components (Serotonin) among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)
- To compare alterations in hormonal components (Dopamine) among the three treatment arms.(On day 10, day 30 and day 90 of follow-up period)