Plitidepsin Versus Control in Immunocompromised Adult Participants With Symptomatic COVID-19 Requiring Hospital Care (NEREIDA)

Inclusion Criteria:

• Signed informed consent obtained prior to initiation of any study-specificprocedures and study treatment.

• Participant aged ≥18 years.

• Participant diagnosed COVID-19, with the following characteristics:

1. A regulatory-approved test, collected no more than 3 days prior to studyrandomisation, with either a Ct value ≤30 or a positive antigen test.

2. Presence of any of the selected signs/symptom listed in the COVID-19signs/symptoms checklist within the last 24 hours.

• Participant already admitted or requiring hospital care for symptomatic COVID-19,for which at least one antiviral has failed or cannot be used (i.e.,contraindication, absence of labelled indication, guidelines or drugunavailability), after a minimum washout period of 24 hours for small molecules (e.g., remdesivir, molnupiravir, nirmaltrevir, ritonavir) and 5 days for antiviralmonoclonal antibodies (e.g., tixagevimab + cilgavimab) or convalescent plasma.

• Adequate bone marrow, liver, kidney, and metabolic function, defined by thefollowing tests performed at local laboratory:

1. Absolute neutrophil count ≥500/mm^3 (0.5 x 109/L).

2. Platelet count ≥ 50 000/mm3 (50 x 109/L).

3. Alanine transaminase (ALT) ≤3 x upper limit of normal (ULN) (≤5 x ULN ifpreexistent liver involvement by the underlying disease).

4. Serum bilirubin ≤1.5 x ULN (or direct bilirubin <1.5 x ULN when total bilirubinis above ULN).

5. Estimated glomerular filtration rate ≥30 mL/min (CKD-EPI Creatinine Equation [2021]).

• Females of child-bearing potential must have a negative serum or urine pregnancytest by local laboratory at screening and must be non-lactating.

• Females of child-bearing potential and fertile males with partners of child-bearingpotential must use contraceptive methods as specified in the protocol.

Group-specific inclusion criteria:

• Group 1 - Patients receiving, within the last 30 days, immune-suppressive therapydue to haematopoietic or organ transplantation.

• Group 2 - Participants receiving B-cell depleting therapies within the last 6 months (with the exception of CAR-T cell therapy for which time restriction is notapplicable).

• Group 3 - Participants receiving, within the last 30 days, other immune-suppressivetherapies.

• Group 4 - Other situations with immunodeficiency.

1. Primary immune deficiencies.

2. Human immunodeficiency virus (HIV) infection, with CD4^+ T lymphocyte < 200cells/μL in the last month.

3. Radiation therapy within the last 3 months- requires documentation of ALC < 500cells/μL.

4. Haematological neoplasia or myelodysplasia not currently receiving any therapy.

5. Other situations with a documentation of ALC < 500 cells/μL.

Exclusion Criteria:

• Evidence of critical illness.

• Any of the following cardiac conditions or risk factors:

1. Cardiac infarction or cardiac surgery episode within the last month.

2. History of known congenital QT prolongation.

3. Known structural cardiomyopathy with abnormal left ventricular ejectionfraction (LVEF) (<50%).

4. Current clinical evidence of heart failure or acute cardiac ischaemia (New YorkHeart Association (NYHA) class III-IV).

• Hypersensitivity to the active ingredient or any of the excipients (mannitol,macrogolglycerol hydroxystearate, and ethanol) or contraindication to receivedexamethasone, antihistamine H1/H2, or anti-serotoninergic 5HT3 agents.

• Females who are pregnant or breast-feeding.

• Females and males with partners of child-bearing potential who are not using atleast 1 protocol-specified method of contraception.

• Any situation currently requiring increasing needs of immune-suppressive agents.

• Any other clinically significant medical condition or laboratory abnormality that,in the opinion of the investigator, would jeopardise the safety of the participantor potentially impact on participant compliance or the safety/efficacy observationsin the study.

• Participation in another clinical study involving an investigational drug within 30days prior to screening.