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

NCT ID: NCT04784559

Last Updated: 2025-02-21

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 205 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-06-04
• Study Completion Date: 2023-03-01

Brief Summary

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

Detailed Description

This is a multicentre, open-label, controlled Phase 3 study in which adults requiring hospital admission and O2 supplementation for management of moderate COVID-19 infection will be randomised in 1:1:1 to: Plitidepsin 1.5 mg arm, Plitidepsin 2.5 mg arm and Control arm

Conditions

COVID-19 Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Plitidepsin 1.5 mg arm

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

Group Type: EXPERIMENTAL

Plitidepsin

Intervention Type: 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.

Dexamethasone

Intervention Type: 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.

Plitidepsin 2.5 mg arm

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

Group Type: EXPERIMENTAL

Plitidepsin

Intervention Type: 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.

Dexamethasone

Intervention Type: 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

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.

Group Type: ACTIVE_COMPARATOR

Dexamethasone

Intervention Type: 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.

Remdesivir

Intervention Type: 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.

Favipiravir

Intervention Type: 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.

Interventions

Plitidepsin

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.

Intervention Type: DRUG

Dexamethasone

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.

Intervention Type: DRUG

Remdesivir

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.

Intervention Type: DRUG

Favipiravir

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.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Signed informed consent obtained prior to initiation of any study-specific procedures and study treatment.

2. 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.

3. Patient meets category 5 on the 11-point WHO Clinical Progression Scale: requires hospitalisation and oxygen by mask or nasal prongs/cannula.

4. A maximum of 14 days from onset of COVID-19 symptoms to initiation of study treatment on Day 1.

5. Male or female aged ≥18 years.

6. 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.

7. Agree not to participate in another interventional clinical trial through Day 31.

8. Females of reproductive capacity must have a negative serum or urine pregnancy test by local laboratory at study enrolment and must be non-lactating.

9. 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.

Exclusion Criteria

1. 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.

2. Having received treatment for COVID-19 in another clinical trial in the prior 4 weeks, except documented allocation in a placebo arm.

3. 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).

4. 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.

5. 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:

1. The total daily dose is not higher than 10 mg of dexamethasone phosphate (equivalent to dexamethasone base 8.25 mg/day) or equivalent glucocorticoids.

2. 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:

1. The total daily dose is not higher than 10 mg of dexamethasone phosphate (equivalent to dexamethasone base 8.25 mg/day) or equivalent glucocorticoids.

2. 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:

1. 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.

2. 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.

6. Patients receiving treatment with chloroquine or derivatives within 8 weeks before enrolment or during the study.

7. Patients receiving treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers.

8. Viral illness (other than COVID-19) requiring therapy, except for patients with treated and adequately controlled (undetectable) human immunodeficiency virus infection.

9. Patients with uncontrolled known primary or secondary immunodeficiency, including chronic treatment with glucocorticoids (i.e., prednisone at a daily dose of >10 mg for >1 month, or another glucocorticoid at equipotent dose).

10. Any of the following cardiac conditions or risk factors:

• Sinus bradycardia (<50 beats/min), sinus nodal dysfunction (sick sinus disease), atrioventricular block of any degree (PR >200 msec), or any other bradyarrhythmia (<50 beats/min), except for patients with permanent pacemakers;
• Cardiac infarction, cardiac surgery or cardiac insufficiency episode within the last 6 months;
• Known abnormal value of left ventricular ejection fraction (LVEF <low limit of normal (LLN)), unless documented confirmation of recovery (LVEF >LLN) in the previous month;
• QT interval corrected using Fridericia's formula (QTcF) >450 msec for males or >470 msec for females;
• History of known congenital or acquired QT prolongation;
• Uncorrected hypokalaemia, hypocalcaemia (adjusted) and/or hypomagnesemia at screening;
• Troponin test performed at local laboratory >1.5 x ULN; or
• Need for an unreplaceable drug that prolongs QT and it is clearly associated with a known risk for torsades de pointes (TdP); in case of being already on treatment with these aforementioned drugs, a minimum of 4 half-lives of the drug is required before replacement (if feasible).

11. Hypersensitivity to the active ingredient or any of the excipients (mannitol, macrogolglycerol hydroxystearate, and ethanol) or patients for whom dexamethasone, antihistamine H1/H2 or antiserotoninergic agents are contraindicated.

12. Females who are pregnant (negative serum or urine pregnancy test required for all females of child-bearing potential at screening) or breast feeding.

13. Females and males with partners of child-bearing potential (females who are not surgically sterile or postmenopausal defined as amenorrhea for >12 months) who are not using at least 1 protocol specified method of contraception.

14. Any other clinically significant medical condition (including major surgery within the last 3 weeks before screening) or laboratory abnormality that, in the opinion of the investigator, would jeopardise the safety of the patient or potentially impact on patient compliance or the safety/efficacy observations in the study.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

PharmaMar

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

José Jimeno Doñaque, MD, PhD

Role: STUDY_DIRECTOR

PharmaMar

Locations

Hospital Felicio Rocho

Belo Horizonte, Minas Gerais, Brazil

"MHAT "Sveta Anna"" - Sofia AD

Sofia, , Bulgaria

Clínica de la Costa Ltda.

Barranquilla, Atlántico, Colombia

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

Tours, , France

Evangelismos Hospital General Hospital of Athens Evangelismos, Intensive Care Unit

Athens, , Greece

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

Athens, , Greece

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

Monterrey, Nuevo León, Mexico

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

Bucharest, , Romania

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

Bucharest, , Romania

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

Iași, , Romania

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

Suceava, , Romania

Hospital Universitari Germans Trias i Pujol

Badalona, Barcelona, Spain

Hospital Universitari de Bellvitge

L'Hospitalet de Llobregat, Barcelona, Spain

Hospital Universitario de Jerez de la Frontera

Jerez de la Frontera, Cádiz, Spain

Hospital Universitario HM Montepríncipe

Boadilla del Monte, Madrid, Spain

Hospital Quirónsalud Madrid

Pozuelo de Alarcón, Madrid, Spain

Hospital Álvaro Cunqueiro

Vigo, Pontevedra, Spain

Hospital General Universitario de Alicante

Alicante, , Spain

Hospital Universitario Virgen de las Nieves (HUVN)

Granada, , Spain

Hospital Universitario de Guadalajara

Guadalajara, , Spain

Hospital Infanta Leonor

Madrid, , Spain

Hospital Universitario Ramón y Cajal

Madrid, , Spain

Hospital Clínico San Carlos

Madrid, , Spain

H. HM Sanchinarro

Madrid, , Spain

Hospital de Emergencias Enfermera Isabel Zendal

Madrid, , Spain

Hospital Universitario de Salamanca

Salamanca, , Spain

Instituto de Investigación Sanitaria Valdecilla (IDIVAL)

Santander, , Spain

Hospital Universitario Virgen del Rocío

Seville, , Spain

Countries

Brazil; Bulgaria; Colombia; France; Greece; Mexico; Romania; Spain

References

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.

Reference Type: DERIVED

PMID: 39182994 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2020-005951-19

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

APL-D-003-20

Identifier Type: -

Identifier Source: org_study_id