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

A Multicentre, Open Label, Randomised, Controlled, Basket, Pragmatic, Phase II, Clinical and Translational Study to Determine the Efficacy and Safety of Plitidepsin Versus Control in Immunocompromised Adult Patients With Symptomatic COVID-19 Requiring Hospital Care

The primary objective of this study is to evaluate efficacy of plitidepsin in pre-specified groups of immunocompromised patients with symptomatic COVID-19 requiring hospital care versus control in terms of mortality.

Study Overview

• Status: Terminated
• Conditions: COVID-19
• Intervention / Treatment: Drug: Plitidepsin

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Flemish Brabant
    • Leuven, Flemish Brabant, Belgium, 3000
      • Universitair Ziekenhuis Leuven - Campus Gasthuisberg
• France
  • Strasbourg, France, 67091
    • Les Hôpitaux Universitaires de Strasbourg
  • Grand Est
    • Colmar, Grand Est, France, 68024
      • Hôpitaux Civils de Colmar - Centre Hospitalier Louis Pasteur
  • Indre-et-Loire
    • Tours, Indre-et-Loire, France, 37044
      • Centre Hospitalier Régional Universitaire de Tours
  • Pyrénées-Atlantiques
    • Bayonne, Pyrénées-Atlantiques, France, 64109
      • Centre Hospitalier de la Cote Basque
  • Rhone-Alpes
    • Lyon, Rhone-Alpes, France, 69373
      • Cancer Research Centre of Lyon
• Georgia
  • Tbilisi, Georgia, 0141
    • The First University Clinic of the Tbilisi State Medical University
  • Tbilisi, Georgia, 0144
    • Ltd Tbilisi State Medical University and Ingorokva High Medical Technology University Clinic
  • Tbilisi, Georgia, 4600
    • Academician Vakhtang Bochorishvili Clinic
• Greece
  • Athens, Greece, 11527
    • General Hospital for Thoracic Diseases Sotiria
  • Attica
    • Athens, Attica, Greece, 11527
      • Laiko General Hospital of Athens
    • Athens, Attica, Greece, 10676
      • General Hospital of Athens Evangelismos
    • Athens, Attica, Greece, 11528
      • Alexandra General Hospital
    • Athens, Attica, Greece, 124 62
      • University General Hospital Attikon
  • Epirus
    • Ioannina, Epirus, Greece, 45500
      • University Hospital of Ioannina
• Hungary
  • Budapest, Hungary, 1121
    • Orszagos Koranyi Pulmonologiai Intezet
• Israel
  • Tel Aviv
    • Ramat Gan, Tel Aviv, Israel, 52621
      • Sheba Medical Center Hospital - Tel Hashomer
• Italy
  • Genova, Italy, 16128
    • Ente Ospedaliero Ospedali Galliera
  • Rome
    • Roma, Rome, Italy, 00149
      • IRCCS Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani
• Poland
  • Lódzkie
    • Łódź, Lódzkie, Poland, 91-347
      • Wojewódzki Specjalistyczny Szpital im. Dr. Władysława Biegańskiego
• Portugal
  • Senhora da Hora, Portugal, 4464-513
    • Hospital Pedro Hispano
  • Vila Nova de Gaia, Portugal, 4434-502
    • Centro Hospitalar de Vila Nova de Gaia/Espinho
  • Braga
    • Guimaraes, Braga, Portugal, 4835-044
      • Hospital da Senhora da Oliveira - Guimarães
  • Lisboa
    • Lisbon, Lisboa, Portugal, 1649-035
      • Centro Hospitalar Universitário Lisboa Norte, E.P.E - Hospital De Santa Maria
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08003
    • Hospital del Mar - Parc de Salut Mar
  • Barcelona, Spain, 08035
    • Vall D'hebron Institut De Recerca
  • Cáceres, Spain, 10003
    • Hospital San Pedro De Alcantara
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28006
    • Hospital Universitario de la Princesa
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
  • Madrid, Spain, 28033
    • MD Anderson Cancer Center Madrid
  • Madrid, Spain, 28050
    • Hospital Universitario HM Sanchinarro
  • Málaga, Spain, 29010
    • Hospital Regional Universitario de Malaga - Hospital General
  • Salamanca, Spain, 37007
    • Complejo Asistencial Universitario de Salamanca - Hospital Clínico
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Germans Trias i Pujol
  • Madrid
    • Pozuelo de Alarcón, Madrid, Spain, 28223
      • Hospital Universitario Quirónsalud Madrid
  • Pontevedra
    • Vigo, Pontevedra, Spain, 36213
      • Hospital Alvaro Cunqueiro - Clinico Universitario Vigo
• United Kingdom
  • London, United Kingdom, NW1 2BU
    • University College London Hospitals Nhs Foundation Trust
  • England
    • Newcastle Upon Tyne, England, United Kingdom, NE1 4LP
      • The Newcastle upon Tyne Hospitals NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Plitidepsin 2.5 mg; Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute intravenous (IV) infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) will be administered to participants of the following groups: Group 1 - Participants receiving immune-suppression due to haematopoietic or organ transplantation.; Group 2 - Participants receiving B-cell depleting therapies.; Group 3 - Participants receiving other immune-suppressive therapies.; Group 4 - Other situations with immune deficiencies.	Drug: Plitidepsin; IV infusion over 60-minutes
No Intervention: Control; Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) ± other regulatory-approved antiviral (if clinically indicated) will be administered to participants of the following groups: Group 1 - Participants receiving immune-suppression due to haematopoietic or organ transplantation.; Group 2 - Participants receiving B-cell depleting therapies.; Group 3 - Participants receiving other immune-suppressive therapies.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
One-month All-cause Mortality Rate	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.	Day 1 to Day 30 (±2)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Confirmed Negativisation in SARS-CoV-2 Antigen Test or Real Time Polymerase Chain Reaction (RT-PCR) Cycle Threshold (Ct) > 30	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.	Day 1 to Day 60 (±3)
Time to Sustained End of COVID-related Hospital Care	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.	Day 1 to Day 60 (±3)
Time to Sustained Improvement and Resolution of Selected COVID-19 Signs/Symptoms	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.	Day 1 to Day 60 (±3)
Number of Participants in Each Category of the World Health Organization (WHO) Clinical Progression Scale (CPS)	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.	Days 4 (±1), 8 (±1), 15 (±1), 30 (±2), and 60 (±3)
Number of Participants Requiring Oxygen Therapy	The maximum number of participants requiring oxygen therapy on any day during each visit window is reported.	Days 4 (±1), 8 (±1), 15 (±1), 30 (±2), and 60 (±3)
Time to Sustained Discontinuation of Oxygen Supplementation	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.	Day 1 to Day 60 (±3)
Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE)	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.	Day 1 to Day 60 (±3)

Collaborators and Investigators

• Sponsor: PharmaMar

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2023
• Primary Completion (Actual): March 19, 2024
• Study Completion (Actual): April 19, 2024

Study Registration Dates

• First Submitted: December 21, 2022
• First Submitted That Met QC Criteria: January 27, 2023
• First Posted (Actual): January 30, 2023

Study Record Updates

• Last Update Posted (Estimated): December 2, 2024
• Last Update Submitted That Met QC Criteria: October 15, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: COVID-19; Plitidepsin
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; COVID-19
• Other Study ID Numbers: AV-APL-B-002-22; 2022-002489-34 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No