The study aims to prove that plitidepsin could be an efficacious, safe, andwell-tolerated therapy for PCC. To this end, we will perform a randomized, double-blindstudy comparing the clinical and laboratory benefits of plitidepsin vs. placebo in 90subjects with moderate to severe functional disability. The study consists of anintervention period and a follow-up period, with a total of 135 +/-3 days approximatelybetween both periods.During the intervention period, four treatment cycles will be administered, scheduledevery 15 days (every 2 weeks), with intravenous (IV) infusion over three consecutivedays. After completing the intervention period, a 90-day (+/-5) follow-up period will beconducted.Subjects in arm A will receive the plitidepsin 1.5 mg/day 1h-IV during the four treatmentperiods on Days 1 to 3, Days 15 to 17, Days 29 to 31 and Days 43 to 45. Subjects in arm Bwill receive 1h-IV placebo 1 vial /day during the first two treatment periods and willreceive the plitidepsin 1.5 mg/day 1h-IV during the last two treatment periods. Subjectsin arm C will receive 1h-IV placebo 1 vial/day during the four treatment periods.
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
Drug: Plitidepsin 1.5 mg/day
Receive 1.5 mg/day of plitidepsin intravenously (IV) over a 1-hour infusion for 3
consecutive days every 15 days during 4 treatment periods.
The participant will receive the following pre-medication before receiving the study
treatment:
- Palonosetron 0.25 mg IV
- Dexchlorpheniramine maleate 5 mg IV (or equivalent to H1 receptor antihistamines)
- Famotidine 40 mg oral (60 minutes before starting the plitidepsin/placebo infusion)
- Dexamethasone phosphate 8 mg IV (equivalent to 6.6 mg of dexamethasone)
Premedication should be completed 20-30 minutes before starting the plitidepsin/placebo
infusion.
Drug: Placebo
Receive placebo intravenously (IV) over a 1-hour infusion for 3 consecutive days every 15
days during 4 treatment periods.
The participant will receive the following pre-medication before receiving the study
treatment:
- Palonosetron 0.25 mg IV
- Dexchlorpheniramine maleate 5 mg IV (or equivalent to H1 receptor antihistamines)
- Famotidine 40 mg oral (60 minutes before starting the plitidepsin/placebo infusion)
- Dexamethasone phosphate 8 mg IV (equivalent to 6.6 mg of dexamethasone)
Premedication should be completed 20-30 minutes before starting the plitidepsin/placebo
infusion.
Drug: Placebo and Plitidepsin 1.5mg/day
Receive placebo intravenously (IV) over a 1-hour infusion for 3 consecutive days every 15
days during two treatment periods and receive plitidepsin 1.5mg/day during the last two
treatment periods.
The participant will receive the following pre-medication before receiving the study
treatment:
- Palonosetron 0.25 mg IV
- Dexchlorpheniramine maleate 5 mg IV (or equivalent to H1 receptor antihistamines)
- Famotidine 40 mg oral (60 minutes before starting the plitidepsin/placebo infusion)
- Dexamethasone phosphate 8 mg IV (equivalent to 6.6 mg of dexamethasone)
Premedication should be completed 20-30 minutes before starting the plitidepsin/placebo
infusion.
1. Male or female individuals 18 years old or older.
2. 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. 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.
4. Unable to perform all usual duties/activities, defined as grades 3 or 4 in PCFS
(Annex 3).
5. Willing to comply with the requirements of the protocol and available for follow-up
for the planned duration of the study.
6. Having understood the information provided and capable of providing informed consent
EXCLUSION CRITERIA
1. Last SARS-CoV-2 vaccine dose during the previous 30 days.
2. Patients with active uncontrolled infections.
3. Patients infected by SARS-CoV-2 virus in the last 90 days prior to the screening
visit.
4. Patients receiving treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or
inducers (Annex 1) throughout plitidepsin treatment period and until 24-h washout
period.
5. Pacients receiving chronic glucocorticoid therapy (high-dose corticosteroids [ie, 20
mg of prednisone daily or equivalent for ≥2 weeks)
6. 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).
7. 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.
8. Mast cell activation syndrome.
9. Females who are pregnant (negative serum or urine pregnancy test required for all
females of childbearing potential at screening) or breast-feeding.
10. 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.
11. Unable to consent and/or comply with study requirements, in the opinion of the
investigator.
12. Currently participating or participated in a clinical trial within the prior
Hospital Universitari Germans Trias i Pujol
Badalona, Barcelona, Spain
Investigator: Lourdes Mateu Pruñonosa, phD, MD
Contact: (+34) 934657897
assaigs@scienhub.org
Lourdes Mateu Pruñonosa, phD, MD
+34 93 465 78 97
lmateu@lluita.org
Cora Loste, phD, MD
+34 93 465 78 97
closte@lluita.org
Not Provided