Clinical trial NCT04784559: Trial to Determine the Efficacy/Safety of Plitidepsin vs Control in Patients With Moderate COVID-19 Infection
Official title: A Phase 3, Multicentre, Randomised, Controlled Trial to Determine the Efficacy and Safety of Two Dose Levels of Plitidepsin Versus Control in Adult Patient Requiring Hospitalisation for Management of Moderate COVID-19 Infection
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: COVID-19 Infection
Lead sponsor: PharmaMar
Sponsor class: INDUSTRY
First posted: 2021-03-05
Enrollment: 205
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients Will be randomised in 1:1:1 to: Plitidepsin 1.5 mg arm, Plitidepsin 2.5 mg arm and Control arm
Primary purpose: TREATMENT

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

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.

Primary outcomes:
measure: Time to Sustained Withdrawal of Supplementary Oxygen With no Subsequent Reutilisation During Remaining Study Period
timeFrame: From administration date to Day 31(±3)
Secondary outcomes:
measure: Time to Sustained (i.e., With no Subsequent Readmission to Day 31) Hospital Discharge (Since Randomisation).
timeFrame: From administration date to Day 31(±3)
measure: Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8
timeFrame: Day 8 (±1)
measure: Total Duration of Advanced Oxygen Support
timeFrame: From administration date to Day 31(±3)
measure: Number of Participants in Each Study Group Requiring Admission to ICU
timeFrame: Day 4, Day 8(±1) , Day 15(±1) and Day 31(±3)
measure: Frequency of Adverse Events
timeFrame: From administration date to Day 31(±3)
measure: Frequency of TEAEs of ≥Grade 3 According to NCI-CTCAE for Adverse Events (Version 5.0), TEAEs of Special Interest, Serious TEAEs, Serious Treatment-related TEAEs, TEAEs Leading to Treatment Discontinuation, and Deaths
timeFrame: From administration date to Day 31(±3)
Other outcomes:
Locations:
city: Belo Horizonte
country: Brazil
facility: Hospital Felicio Rocho
state: MG
city: Sofia
country: Bulgaria
facility: "MHAT "Sveta Anna"" - Sofia AD
city: Barranquilla
country: Colombia
facility: Clínica de la Costa Ltda.
state: Atlántico
city: Tours
country: France
facility: Centre Hospitalier Regional et Universitaire de Tours (CHRU Tours) - Hopital Bretonneau
city: Athens
country: Greece
facility: Evangelismos Hospital General Hospital of Athens Evangelismos, Intensive Care Unit
city: Athens
country: Greece
facility: Sotiria Hospital General Hospital of Chest Diseases of Athens "Sotiria" 3rd Department of Internal Medicine of University of Athens
city: Monterrey
country: Mexico
facility: Universidad Autonoma de Nuevo Leon - Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
state: NL
city: Bucharest
country: Romania
facility: Institutul National De Boli Infectioase "Prof. Dr. Matei Bals"
city: Bucharest
country: Romania
facility: Spitalul Clinic de Boli Infectioase si Tropicale Dr. Victor Babes - Bucharest
city: Iaşi
country: Romania
facility: Spitalul Clinic De Boli Infectioase "Sfanta Parascheva" IASI, Sectia Boli Infectioase III
city: Suceava
country: Romania
facility: Spitalul Judetean de Urgenta 'Sf. Ioan cel Nou' Suceava, Sectia de Boli Infectioase
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Hospitalet de Llobregat
country: Spain
facility: Hospital Universitari de Bellvitge
state: Barcelona
city: Jerez De La Frontera
country: Spain
facility: Hospital Universitario de Jerez de la Frontera
state: Cádiz
city: Boadilla Del Monte
country: Spain
facility: Hospital Universitario HM Montepríncipe
state: Madrid
city: Pozuelo De Alarcón
country: Spain
facility: Hospital Quirónsalud Madrid
state: Madrid
city: Vigo
country: Spain
facility: Hospital Álvaro Cunqueiro
state: Pontevedra
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves (HUVN)
city: Guadalajara
country: Spain
facility: Hospital Universitario de Guadalajara
city: Madrid
country: Spain
facility: Hospital Infanta Leonor
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: H. HM Sanchinarro
city: Madrid
country: Spain
facility: Hospital de Emergencias Enfermera Isabel Zendal
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Santander
country: Spain
facility: Instituto de Investigación Sanitaria Valdecilla (IDIVAL)
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
Study officials:
affiliation: PharmaMar
name: José Jimeno Doñaque, MD, PhD
role: STUDY_DIRECTOR
References: