Trial to Determine the Efficacy/Safety of Plitidepsin vs Control in Patients With Moderate COVID-19 Infection

NCT04784559 | Terminated Phase 3 Results DMC

• 2 other identifiers: APL-D-003-202020-005951-19
• Study Type: interventional
• Target: 205
• Locations: 8 countries
• Sites: 28

Brief Summary

Treatment of patients hospitalised for management of moderate COVID-19 infection

Conditions

COVID-19 Infection

Outcome Measures

Primary Outcomes (1)

• Time to Sustained Withdrawal of Supplementary Oxygen With no Subsequent Reutilisation During Remaining Study Period

  Time to sustained withdrawal of oxygen supplementation (in days) with no subsequent reutilisation during remaining study period is defined as the first day, from randomisation through completion of the study, on which a patient i. satisfies categories 0 to 4 on the 11-point WHO Clinical Progression Scale, and ii. has no subsequent reutilisation of oxygen supplementation (5 to 10 on the 11-point WHO Clinical Progression Scale). The WHO clinical progression scale provides a measure of illness severity across a range from 0 (uninfected) to 10 (dead).

  From administration date to Day 31(±3)

Secondary Outcomes (6)

• Time to Sustained (i.e., With no Subsequent Readmission to Day 31) Hospital Discharge (Since Randomisation).

  From administration date to Day 31(±3)

• Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8

  Day 8 (±1)

• Total Duration of Advanced Oxygen Support

  From administration date to Day 31(±3)

• Number of Participants in Each Study Group Requiring Admission to ICU

  Day 4, Day 8(±1) , Day 15(±1) and Day 31(±3)

• Frequency of Adverse Events

  From administration date to Day 31(±3)

Study Arms (3)

Plitidepsin 1.5 mg arm

EXPERIMENTAL

Patients will receive plitidepsin 1.5 mg/day intravenous (IV) in addition to dexamethasone on days 1 to 3.

Drug: Plitidepsin; Drug: Dexamethasone

Plitidepsin 2.5 mg arm

EXPERIMENTAL

Patients will receive plitidepsin 2.5 mg/day IV in addition to dexamethasone on days 1 to 3.

Drug: Plitidepsin; Drug: Dexamethasone

Control arm

ACTIVE COMPARATOR

Patients will receive dexamethasone IV on Days 1 to 3. Additionally, in accordance with local treatment guidelines, patients in this group may receive a regulatory-approved antiviral treatment.

Drug: Dexamethasone; Drug: Remdesivir; Drug: Favipiravir

Interventions

Plitidepsin DRUG

Plitidepsin 2 mg powder is provided as a sterile, preservative-free, and white to off-white lyophilised powder/cake comprising 2 mg plitidepsin and mannitol in a single-dose, 10 mL clear type 1 glass vial. Solvent for plitidepsin is provided as a sterile, preservative-free, clear, slightly viscous aqueous liquid (4 mL) containing macrogolglycerol ricinoleate and ethanol in a single-dose type 1 clear glass ampoule. For administration, vial contents are reconstituted by addition of 4 mL of solvent for plitidepsin to obtain a slightly yellowish solution containing 0.5 mg/mL plitidepsin with mannitol, macrogolglycerol ricinoleate and ethanol excipients. The required amount of plitidepsin reconstituted solution is added to bag containing 0.9% sodium chloride or 5% glucose for IV injection and administered as an IV infusion over 60 minutes.

Plitidepsin 1.5 mg arm; Plitidepsin 2.5 mg arm

Dexamethasone DRUG

Detailed information about the formulation, posology, packaging and labelling, storage, and manufacturer is provided in the current country-specific product information. The summary of product characteristics (SmPC) and/or leaflet provides detailed product information for investigators in the European Union and/or in other regions.

Control arm; Plitidepsin 1.5 mg arm; Plitidepsin 2.5 mg arm

Remdesivir DRUG

Detailed information about the formulation, posology, packaging and labelling, storage, and manufacturer is provided in the current country-specific product information. The summary of product characteristics (SmPC) and/or leaflet provides detailed product information for investigators in the European Union and/or in other regions.

Control arm

Favipiravir DRUG

Detailed information about the formulation, posology, packaging and labelling, storage, and manufacturer is provided in the current country-specific product information. The summary of product characteristics (SmPC) and/or leaflet provides detailed product information for investigators in the European Union and/or in other regions.

Control arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent obtained prior to initiation of any study-specific procedures and study treatment.
• Documented diagnosis of SARS-CoV-2 infection, determined by either qualitative polymerase chain reaction (PCR), antigen test by local laboratory, or any other validated method approved by the local health authority, from appropriate biological samples collected no more than 72 hours prior to study treatment on Day 1.
• Patient meets category 5 on the 11-point WHO Clinical Progression Scale: requires hospitalisation and oxygen by mask or nasal prongs/cannula.
• A maximum of 14 days from onset of COVID-19 symptoms to initiation of study treatment on Day 1.
• Male or female aged ≥18 years.
• Adequate bone marrow, liver, kidney, and metabolic function, defined by the following tests performed at local laboratory:
• Absolute neutrophil count ≥500/mm\^3 (0.5 x 10\^9/L).
• Platelet count ≥75,000/mm\^3 (75 x 10\^9/L).
• Alanine transaminase (ALT), aspartate transaminase (AST) ≤3 x upper limit of normal (ULN).
• Serum bilirubin ≤1 x ULN (or direct bilirubin \<1 x ULN when total bilirubin is above ULN).
• Calculated creatinine clearance ≥30 mL/min (Cockcroft-Gault equation).
• Creatine phosphokinase (CPK) ≤2.5 x ULN except if the patient has had recent (i.e., in the last week) shivering episodes or trauma. In that case, the level of CPK should be ≤5 x ULN.
• Agree not to participate in another interventional clinical trial through Day 31.
• Females of reproductive capacity must have a negative serum or urine pregnancy test by local laboratory at study enrolment and must be non-lactating.
• Females and males with partners of child-bearing potential must use effective contraception while on study treatment and for 6 months after last dose of plitidepsin. Patients in the control arm must use effective contraception during the time indicated in the approved product information (summary of product characteristics \[SmPC\] or leaflet). If no information is available in the approved product information, patients in the control arm must use effective contraception for at least one week after the study completion or the time indicated based on the investigator's discretion.

You may not qualify if:

• Subjects with a pre-baseline (i.e., in the month preceding the current COVID-19 infection) impairment in general health condition for whatever reason except COVID-19, with a severe dependency for daily living activities (Barthel index ≤ 60/100) or chronic oxygen therapy.
• Having received treatment for COVID-19 in another clinical trial in the prior 4 weeks, except documented allocation in a placebo arm.
• Evidence of respiratory failure at the time of randomisation, based on resource utilisation requiring at least one of the following: endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula, non-invasive positive pressure ventilation, ECMO, or clinical diagnosis of respiratory failure (i.e., clinical need for one of the aforementioned therapies, which could not be administered in a resource-limited setting).
• Patients with severe COVID-19, meeting score \>5 on the 11-point WHO Clinical Progression Scale or presenting, after an initial stabilisation prior to randomisation, any of clinical signs indicative of severe systemic illness, such as respiratory rate ≥30 per minute, heart rate ≥125 per minute, or PaO2/FiO2 \<300. In case a direct measure of PaO2 has not been obtained, it should be imputed according to a referenced formula. For sites located over 1000 m above sea level, PaO2/FiO2 ratio will be adjusted.
• Patients receiving, at randomisation, treatment with antiviral therapy against SARS-CoV-2 or requiring anti-inflammatory/immunomodulating drugs beyond glucocorticoids with the exceptions listed below:
• Prior administration of dexamethasone or equivalent glucocorticoid might be acceptable if:
• The total daily dose is not higher than 10 mg of dexamethasone phosphate (equivalent to dexamethasone base 8.25 mg/day) or equivalent glucocorticoids.
• The duration of the treatment does not exceed 72 hours prior to study treatment Day 1.
• Prior administration of dexamethasone or equivalent glucocorticoid might be acceptable if:
• The total daily dose is not higher than 10 mg of dexamethasone phosphate (equivalent to dexamethasone base 8.25 mg/day) or equivalent glucocorticoids.
• The duration of the treatment does not exceed 72 hours prior to study treatment Day 1.
• Prior administration of an antiviral might be acceptable in the following circumstances:
• For small molecules (e.g., remdesivir, molnupiravir, nirmaltrevir/ritonavir), they must have been given for an earlier stage of the disease, outside a clinical trial, and there should be a documentation of objective clinical deterioration plus evidence of persisting positivity for SARS-CoV-2 in appropriate biological samples. Last dose of previous antiviral drugs should have been administered at least 24 h before randomisation.
• For antiviral monoclonal antibodies, they must have been given for an earlier stage of the disease (including pre-exposure prophylaxis), outside a clinical trial, and there should be a documentation of objective clinical deterioration plus evidence of persisting positivity for SARS-CoV-2 in appropriate biological samples. Last dose of antiviral monoclonal antibodies should have been administered at least 1 week before randomisation.
• Patients receiving treatment with chloroquine or derivatives within 8 weeks before enrolment or during the study.

Sponsors & Collaborators

• PharmaMar: lead

Study Sites (28)

Hospital Felicio Rocho

Belo Horizonte, Minas Gerais, 30110-934, Brazil

Location

"MHAT "Sveta Anna"" - Sofia AD

Sofia, 1570, Bulgaria

Location

Clínica de la Costa Ltda.

Barranquilla, Atlántico, 80020, Colombia

Location

Centre Hospitalier Regional et Universitaire de Tours (CHRU Tours) - Hopital Bretonneau

Tours, 37044, France

Location

Evangelismos Hospital General Hospital of Athens Evangelismos, Intensive Care Unit

Athens, 106 76, Greece

Location

Sotiria Hospital General Hospital of Chest Diseases of Athens "Sotiria" 3rd Department of Internal Medicine of University of Athens

Athens, 115 27, Greece

Location

Universidad Autonoma de Nuevo Leon - Hospital Universitario "Dr. Jose Eleuterio Gonzalez"

Monterrey, Nuevo León, 64460, Mexico

Location

Institutul National De Boli Infectioase "Prof. Dr. Matei Bals"

Bucharest, 021105, Romania

Location

Spitalul Clinic de Boli Infectioase si Tropicale Dr. Victor Babes - Bucharest

Bucharest, 030303, Romania

Location

Spitalul Clinic De Boli Infectioase "Sfanta Parascheva" IASI, Sectia Boli Infectioase III

Iași, 700116, Romania

Location

Spitalul Judetean de Urgenta 'Sf. Ioan cel Nou' Suceava, Sectia de Boli Infectioase

Suceava, 720237, Romania

Location

Hospital Universitari Germans Trias i Pujol

Badalona, Barcelona, 08916, Spain

Location

Hospital Universitari de Bellvitge

L'Hospitalet de Llobregat, Barcelona, 08907, Spain

Location

Hospital Universitario de Jerez de la Frontera

Jerez de la Frontera, Cádiz, 11407, Spain

Location

Hospital Universitario HM Montepríncipe

Boadilla del Monte, Madrid, 28668, Spain

Location

Hospital Quirónsalud Madrid

Pozuelo de Alarcón, Madrid, 28223, Spain

Location

Hospital Álvaro Cunqueiro

Vigo, Pontevedra, 36213, Spain

Location

Hospital General Universitario de Alicante

Alicante, 3010, Spain

Location

Hospital Universitario Virgen de las Nieves (HUVN)

Granada, 18014, Spain

Location

Hospital Universitario de Guadalajara

Guadalajara, 19002, Spain

Location

Hospital Infanta Leonor

Madrid, 28032, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, 28034, Spain

Location

Hospital Clínico San Carlos

Madrid, 28040, Spain

Location

H. HM Sanchinarro

Madrid, 28050, Spain

Location

Hospital de Emergencias Enfermera Isabel Zendal

Madrid, 28055, Spain

Location

Hospital Universitario de Salamanca

Salamanca, 37007, Spain

Location

Instituto de Investigación Sanitaria Valdecilla (IDIVAL)

Santander, 39008, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

Related Publications (1)

• 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 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

plitidepsin; Dexamethasone; remdesivir; favipiravir

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Limitations and Caveats

The decision was made by the sponsor on 31 January 2023 to prematurely end the study (early termination) based on significant difficulties in the recruitment of patients, despite the implementation of corrective measures.

Results Point of Contact

• Title: Clinical Development Virology Business Unit
• Organization: PharmaMar

virologytrials@pharmamar.com

+34 918466000

Study Officials

• José Jimeno Doñaque, MD, PhD

  PharmaMar

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Patients Will be randomised in 1:1:1 to: Plitidepsin 1.5 mg arm, Plitidepsin 2.5 mg arm and Control arm

Study Record Dates

• First Submitted: March 4, 2021
• First Posted: March 5, 2021
• Study Start: June 4, 2021
• Primary Completion: March 1, 2023
• Study Completion: March 1, 2023
• Last Updated: February 21, 2025
• Results First Posted: February 21, 2025

Record last verified: 2025-01

Locations

GR (2); RO (4); ME (1); CO (1); ES (17); BR (1); BU (1); FR (1)