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

Phase 2

Terminated

• Conditions: COVID-19
• Interventions: Drug: Plitidepsin

• Registration Number: NCT05705167
• Lead Sponsor: PharmaMar

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-12-21
• Study First Submitted QC: 2023-01-27
• Study First Posted: 2023-01-30
• Study Start: 2023-04-19
• Primary Completion: 2024-03-19
• Study Completion: 2024-04-19
• Status Verified: 2024-09
• Results First Submitted: 2024-10-15
• Results First Submitted QC: 2024-10-15
• Last Update Submitted: 2024-10-15
• Results First Posted: 2024-12-02
• Last Update Posted: 2024-12-02

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 37

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Plitidepsin 2.5 mg	Plitidepsin	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (44)

IRCCS Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani; 🇮🇹 Roma, Rome, Italy

Universitair Ziekenhuis Leuven - Campus Gasthuisberg; 🇧🇪 Leuven, Flemish Brabant, Belgium

Centre Hospitalier de la Côte Basque; 🇫🇷 Bayonne, Pyrénées-Atlantiques, France

Les Hôpitaux Universitaires de Strasbourg; 🇫🇷 Strasbourg, France

Cancer Research Centre of Lyon; 🇫🇷 Lyon, Rhone-Alpes, France

The First University Clinic of the Tbilisi State Medical University; 🇬🇪 Tbilisi, Georgia

Academician Vakhtang Bochorishvili Clinic; 🇬🇪 Tbilisi, Georgia

Alexandra General Hospital; 🇬🇷 Athens, Attica, Greece

University Hospital of Ioannina; 🇬🇷 Ioannina, Epirus, Greece

Laiko General Hospital of Athens; 🇬🇷 Athens, Attica, Greece

General Hospital for Thoracic Diseases Sotiria; 🇬🇷 Athens, Greece

University General Hospital Attikon; 🇬🇷 Athens, Attica, Greece

Országos Korányi Pulmonológiai Intézet; 🇭🇺 Budapest, Hungary

Sheba Medical Center Hospital - Tel Hashomer; 🇮🇱 Ramat Gan, Tel Aviv, Israel

Wojewódzki Specjalistyczny Szpital im. Dr. Władysława Biegańskiego; 🇵🇱 Łódź, Lódzkie, Poland

Ente Ospedaliero Ospedali Galliera; 🇮🇹 Genova, Italy

Centro Hospitalar Universitário Lisboa Norte, E.P.E - Hospital De Santa Maria; 🇵🇹 Lisbon, Lisboa, Portugal

Hospital da Senhora da Oliveira - Guimarães; 🇵🇹 Guimaraes, Braga, Portugal

Hospital Universitario Quirónsalud Madrid; 🇪🇸 Pozuelo de Alarcón, Madrid, Spain

Centro Hospitalar de Vila Nova de Gaia/Espinho; 🇵🇹 Vila Nova de Gaia, Portugal

Hospital Alvaro Cunqueiro - Clinico Universitario Vigo; 🇪🇸 Vigo, Pontevedra, Spain

Hospital del Mar - Parc de Salut Mar; 🇪🇸 Barcelona, Spain

Hospital Clinic de Barcelona; 🇪🇸 Barcelona, Spain

Vall d'Hebron Institut de Recerca; 🇪🇸 Barcelona, Spain

Hospital San Pedro de Alcantara; 🇪🇸 Cáceres, Spain

Hospital Universitario de La Princesa; 🇪🇸 Madrid, Spain

Hospital Universitario Ramón y Cajal; 🇪🇸 Madrid, Spain

Hospital General Universitario Gregorio Marañón; 🇪🇸 Madrid, Spain

MD Anderson Cancer Center Madrid; 🇪🇸 Madrid, Spain

Hospital Universitario Fundación Jiménez Díaz; 🇪🇸 Madrid, Spain

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Spain

Hospital Clínico San Carlos; 🇪🇸 Madrid, Spain

Complejo Asistencial Universitario de Salamanca - Hospital Clínico; 🇪🇸 Salamanca, Spain

Hospital Universitario Miguel Servet; 🇪🇸 Zaragoza, Spain

Hospital Universitario HM Sanchinarro; 🇪🇸 Madrid, Spain

Hospital Regional Universitario de Málaga - Hospital General; 🇪🇸 Málaga, Spain

Hospital Pedro Hispano; 🇵🇹 Senhora da Hora, Portugal

Hospital Germans Trias i Pujol; 🇪🇸 Badalona, Barcelona, Spain

Hôpitaux Civils de Colmar - Centre Hospitalier Louis Pasteur; 🇫🇷 Colmar, Grand Est, France

Ltd Tbilisi State Medical University and Ingorokva High Medical Technology University Clinic; 🇬🇪 Tbilisi, Georgia

General Hospital of Athens Evangelismos; 🇬🇷 Athens, Attica, Greece

The Newcastle Upon Tyne Hospitals NHS Foundation Trust; 🇬🇧 Newcastle Upon Tyne, England, United Kingdom

University College London Hospitals NHS Foundation Trust; 🇬🇧 London, United Kingdom

Centre Hospitalier Régional Universitaire de Tours; 🇫🇷 Tours, Indre-et-Loire, France