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

• Plitidepsin (Drug): IV infusion over 60-minutes

Primary outcomes

• One-month All-cause Mortality Rate [Day 1 to Day 30 (±2)]: In the event of the participant initiating another non-protocol therapy, 1-month all-cause mortality rate was evaluated regardless of initiation of new non-protocol therapy.

Secondary outcomes

• Time to Confirmed Negativisation in SARS-CoV-2 Antigen Test or Real Time Polymerase Chain Reaction (RT-PCR) Cycle Threshold (Ct) > 30 [Day 1 to Day 60 (±3)]: Time to confirmed negativisation in SARS-CoV antigen test or RT-PCR Ct>30 was calculated as time from randomisation to the corresponding event using Kaplan-Meier (KM) estimates. Participants with no available data for any time to event efficacy endpoint were censored at time 0, end of study (Day 60 ±3), or date of early study termination. Also, participants who had not achieved the time to event endpoint were censored at the last valid assessment.
• Time to Sustained End of COVID-related Hospital Care [Day 1 to Day 60 (±3)]: Time to sustained end of COVID-related hospital care from the time of randomisation was calculated as time from randomisation to the corresponding event using KM estimates. Participants with no available data for any time to event efficacy endpoint were censored at time 0, end of study (Day 60 ±3), or date of early study termination. Also, participants who had not achieved the time to event endpoint were censored at the last valid assessment.
• Time to Sustained Improvement and Resolution of Selected COVID-19 Signs/Symptoms [Day 1 to Day 60 (±3)]: Time to sustained improvement and resolution of all targeted COVID-19 signs/symptoms was calculated as time from randomisation to the corresponding event using KM estimates. Corresponding events were defined as the event occurring on the first of 4 consecutive days when all symptoms scored as National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v5.0; category of moderate-severe intensity, or requiring medical intervention, or limiting instrumental activity of daily living are scored as mild or absent AND all symptoms scored mild or 0 (absent) at study entry are scored as 0. Participants with no available data for any time to event efficacy endpoint were censored at time 0, end of study (Day 60 ±3), or date of early study termination. Also, participants who had not achieved the time to event endpoint were censored at the last valid assessment.
• Number of Participants in Each Category of the World Health Organization (WHO) Clinical Progression Scale (CPS) [Days 4 (±1), 8 (±1), 15 (±1), 30 (±2), and 60 (±3)]: Distribution of participants according to their clinical status by the 11-category WHO CPS: * Uninfected; no viral ribonucleic acid (RNA) detected * Asymptomatic; viral RNA detected * Symptomatic; independent * Symptomatic; assistance needed * Hospitalised; no oxygen therapy * Hospitalised; oxygen by mask or nasal prongs * Hospitalised; oxygen by non-invasive ventilation (NIV) or high flow * Intubation and mechanical ventilation * Mechanical ventilation or vasopressors * Mechanical ventilation and vasopressors, dialysis, or extracorporeal membrane oxygenation (ECMO) OR * Death.
• Number of Participants Requiring Oxygen Therapy [Days 4 (±1), 8 (±1), 15 (±1), 30 (±2), and 60 (±3)]: The maximum number of participants requiring oxygen therapy on any day during each visit window is reported.
• Time to Sustained Discontinuation of Oxygen Supplementation [Day 1 to Day 60 (±3)]: Time to sustained discontinuation is calculated as time from randomisation to the corresponding event using KM estimates. Corresponding events were defined as discontinuation of oxygen supplementation for at least 7 days. Participants with no available data for any time to event efficacy endpoint were censored at time 0, end of study (Day 60 ±3), or date of early study termination. Also, participants who had not achieved the time to event endpoint were censored at the last valid assessment.
• Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE) [Day 1 to Day 60 (±3)]: Frequency of the following events (all-cause and treatment-related) are included: * TEAEs * TEAEs ≥ grade 3 according to the NCI CTCAE v5.0 * TEAEs of special interest * Serious TEAEs * Serious adverse reactions (SARs) * AEs leading to treatment discontinuation * Deaths (related to COVID-19/all) Clinically relevant/significant changes from Baseline in laboratory parameters and vital signs were reported as AEs.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Signed informed consent obtained prior to initiation of any study-specific procedures 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 study randomisation, with either a Ct value ≤30 or a positive antigen test.
  2. Presence of any of the selected signs/symptom listed in the COVID-19 signs/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 drug unavailability), after a minimum washout period of 24 hours for small molecules (e.g., remdesivir, molnupiravir, nirmaltrevir, ritonavir) and 5 days for antiviral monoclonal antibodies (e.g., tixagevimab + cilgavimab) or convalescent plasma.
* Adequate bone marrow, liver, kidney, and metabolic function, defined by the following 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 if preexistent liver involvement by the underlying disease).
  4. Serum bilirubin ≤1.5 x ULN (or direct bilirubin <1.5 x ULN when total bilirubin is 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 pregnancy test by local laboratory at screening and must be non-lactating.
* Females of child-bearing potential and fertile males with partners of child-bearing potential must use contraceptive methods as specified in the protocol.

Group-specific inclusion criteria:

* Group 1 - Patients receiving, within the last 30 days, immune-suppressive therapy due 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 not applicable).
* Group 3 - Participants receiving, within the last 30 days, other immune-suppressive therapies.
* Group 4 - Other situations with immunodeficiency.

  1. Primary immune deficiencies.
  2. Human immunodeficiency virus (HIV) infection, with CD4\^+ T lymphocyte < 200 cells/μL in the last month.
  3. Radiation therapy within the last 3 months- requires documentation of ALC < 500 cells/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 ejection fraction (LVEF) (<50%).
  4. 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 dexamethasone, 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 at least 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 participant or potentially impact on participant compliance or the safety/efficacy observations in the study.
* Participation in another clinical study involving an investigational drug within 30 days prior to screening.

Participant flow

Outcome results

• One-month All-cause Mortality Rate (Primary), Number, percentage of participants: Group 1: Plitidepsin 2.5 mg 0.0 (0.0 to 84.2); Group 1: Control 0.0 (0.0 to 97.5); Group 2: Plitidepsin 2.5 mg 20.0 (2.5 to 55.6); Group 2: Control 0.0 (0.0 to 70.8); Group 3: Plitidepsin 2.5 mg 0.0 (0.0 to 97.5); Group 3: Control 100.0 (2.5 to 100.0); Group 4: Plitidepsin 2.5 mg 14.3 (0.4 to 57.9)
• Time to Confirmed Negativisation in SARS-CoV-2 Antigen Test or Real Time Polymerase Chain Reaction (RT-PCR) Cycle Threshold (Ct) > 30 (Secondary), Median, days: Group 1: Plitidepsin 2.5 mg 61.0 (NA to NA); Group 1: Control 2.0 (NA to NA); Group 2: Plitidepsin 2.5 mg 14.0 (2.0 to NA); Group 2: Control 14.0 (4.0 to NA); Group 3: Plitidepsin 2.5 mg 13.0 (NA to NA); Group 3: Control 10.0 (NA to NA); Group 4: Plitidepsin 2.5 mg 14.0 (3.0 to NA)
• Time to Sustained End of COVID-related Hospital Care (Secondary), Median, days: Group 1: Plitidepsin 2.5 mg 20.5 (2.0 to NA); Group 1: Control 4.0 (NA to NA); Group 2: Plitidepsin 2.5 mg 4.5 (2.0 to NA); Group 2: Control 37.0 (13.0 to NA); Group 3: Plitidepsin 2.5 mg 24.0 (NA to NA); Group 3: Control 2.0 (NA to NA); Group 4: Plitidepsin 2.5 mg 7.0 (3.0 to NA)
• Time to Sustained Improvement and Resolution of Selected COVID-19 Signs/Symptoms (Secondary), Median, days: Group 1: Plitidepsin 2.5 mg NA (5.0 to NA); Group 1: Control NA (NA to NA); Group 2: Plitidepsin 2.5 mg NA (3.0 to NA); Group 2: Control 14.0 (4.0 to NA); Group 3: Plitidepsin 2.5 mg 17.0 (NA to NA); Group 3: Control 2.0 (NA to NA); Group 4: Plitidepsin 2.5 mg 37.0 (2.0 to NA)
• Number of Participants in Each Category of the World Health Organization (WHO) Clinical Progression Scale (CPS) (Secondary), Count of participants, Participants: Group 1: Plitidepsin 2.5 mg 0; Group 1: Control 0; Group 2: Plitidepsin 2.5 mg 0; Group 2: Control 0; Group 3: Plitidepsin 2.5 mg 0; Group 3: Control ; Group 4: Plitidepsin 2.5 mg 0
• Number of Participants Requiring Oxygen Therapy (Secondary), Count of participants, Participants: Group 1: Plitidepsin 2.5 mg 0; Group 1: Control 0; Group 2: Plitidepsin 2.5 mg 2; Group 2: Control 1; Group 3: Plitidepsin 2.5 mg 1; Group 3: Control 0; Group 4: Plitidepsin 2.5 mg 3
• Time to Sustained Discontinuation of Oxygen Supplementation (Secondary), Median, days: Group 1: Plitidepsin 2.5 mg 13.0 (NA to NA); Group 1: Control NA (NA to NA); Group 2: Plitidepsin 2.5 mg 63.0 (1.0 to NA); Group 2: Control NA (34.0 to NA); Group 3: Plitidepsin 2.5 mg NA (NA to NA); Group 3: Control 14.0 (NA to NA); Group 4: Plitidepsin 2.5 mg 14.0 (2.0 to NA)
• Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE) (Secondary), Count of participants, Participants: Group 1: Plitidepsin 2.5 mg 1; Group 1: Control 1; Group 2: Plitidepsin 2.5 mg 10; Group 2: Control 4; Group 3: Plitidepsin 2.5 mg 1; Group 3: Control 1; Group 4: Plitidepsin 2.5 mg 7

Adverse events

Time frame: Up to Day 60 (±3)

Serious adverse events by term

Other adverse events by term

12 more terms not shown.

• Results publication: Landete P, Caliman-Sturdza OA, Lopez-Martin JA, Preotescu L, Luca MC, Kotanidou A, Villares P, Iglesias SP, Guisado-Vasco P, Saiz-Lou EM, Del Carmen Farinas-Alvarez M, de Lucas EM, Perez-Alba E, Cisneros JM, Estrada V, Hidalgo-Tenorio C, Poulakou G, Torralba M, Fortun J, Garcia-Ocana P, Lemaignen A, Marcos-Martin M, Molina M, Paredes R, Perez-Rodriguez MT, Raev D, Ryan P, Meira F, Gomez J, Torres N, Lopez-Mendoza D, Jimeno J, Varona JF. A Phase III Randomized Controlled Trial of Plitidepsin, a Marine-Derived Compound, in Hospitalized Adults With Moderate COVID-19. Clin Infect Dis. 2024 Oct 15;79(4):910-919. doi: 10.1093/cid/ciae227. PMID 39182994

• Study Protocol (PDF, 2023-03-22)
• Statistical Analysis Plan (PDF, 2024-03-20)