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

Study Overview
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Brief Summary
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Treatment of patients hospitalised for management of moderate COVID-19 infection

Detailed Description
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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

Official Title
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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

Conditions
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COVID-19 Infection

Intervention / Treatment
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* Drug: Plitidepsin
* Drug: Dexamethasone
* Drug: Remdesivir
* Drug: Favipiravir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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. Patients receiving treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers. Viral illness (other than COVID-19) requiring therapy, except for patients with treated and adequately controlled (undetectable) human immunodeficiency virus infection. 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). 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). 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. Females who are pregnant (negative serum or urine pregnancy test required for all females of child-bearing potential at screening) or breast feeding. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients Will be randomised in 1:1:1 to: Plitidepsin 1.5 mg arm, Plitidepsin 2.5 mg arm and Control arm
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Plitidepsin 1.5 mg arm<br>Patients will receive plitidepsin 1.5 mg/day intravenous (IV) in addition to dexamethasone on days 1 to 3. | Drug: Plitidepsin<br>* 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.<br>Drug: Dexamethasone<br>* 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.<br>|
| Experimental: Plitidepsin 2.5 mg arm<br>Patients will receive plitidepsin 2.5 mg/day IV in addition to dexamethasone on days 1 to 3. | Drug: Plitidepsin<br>* 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.<br>Drug: Dexamethasone<br>* 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.<br>|
| Active Comparator: Control arm<br>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<br>* 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.<br>Drug: Remdesivir<br>* 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.<br>Drug: Favipiravir<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare efficacy of plitidepsin 1.5 mg or 2.5 mg versus the control assessing the need of supplementary oxygen: Time to sustained withdrawal of supplementary oxygen with no subsequent reutilisation during remaining study period | Time to sustained withdrawal of supplementary oxygen (as defined by the WHO clinical progression scale (Score ≤4). 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | The WHO clinical progression scale provides a measure of illness severity across a range from 0 (uninfected) to 10 (dead). | Day 8 (±1) | 
| Total duration of advanced oxygen support (high-flow nasal oxygen, extracorporeal membrane oxygenation -ECMO-, non-invasive ventilation or mechanical ventilation). |  | From administration date to Day 31(±3) | 
| Percentage of patients in each study group requiring admission to ICU |  | Day 4, Day 8(±1) , Day 15(±1) and Day 31(±3) | 
| Frequency of adverse events | Adverse Event Types according to the National Cancer Institute [NCI]-Common Terminology Criteria for AEs (CTCAE v.5.0): treatment-emergent adverse events (TEAEs), TEAEs ≥ grade 3, adverse events of special interest (AESIs), serious adverse events (SAEs), drug-related serious adverse events (i.e., SARs) and adverse events leading to treatment discontinuation | From administration date to Day 31(±3) | 
| Frequency of deaths |  | From administration date to Day 31(±3) | 
| Change from baseline in haematology laboratory parameters | Haematology laboratory parameters: red blood cell (RBC) [cells10^6/µL], haemoglobin [g/dL], haematocrit [%], white blood cell (WBC) with differential [cells10^3/µL], and platelet count [cells10^3/µL] | Screening (Day 0-1), Days 1, 2, 3, 4, Day 8(±1), and Day 31(±3) | 
| Change from baseline in coagulation laboratory parameter: D-dimer [mg/L] |  | Day 1, 2, 3, 4, Day 8(±1) and Day 31(±3) | 
| Change from baseline in serum chemistry parameters | Serum chemistry parameters: alanine transaminase (ALT) [U/L], aspartate transaminase (AST) [U/L], alkaline phosphatase [U/L], gamma glutamyl transferase (GGT) [U/L], lactate dehydrogenase (LDH) [U/L], total bilirubin [mg/dL], direct bilirubin [mg/dL], glucose (fasting) (mg/dL), sodium [mEq/L], potassium [mEq/L], calcium (albumin adjusted calculation) [mEq/L], magnesium [mEq/L], blood urea nitrogen (BUN) [mg/dL], creatinine [mg/dL], calculated creatinine clearance (Cockcroft-Gault equation) [ml/min], creatine-phosphokinase (CPK) [U/L], albumin [g/dL], amylase [U/L], lipase [U/L], procalcitonin [ng/mL], and Troponin [ng/L] (I or T according to local practice for screening) | Screening (Day 0-1), Days 1, 2, 3, 4, Day 8(±1) and Day 31(±3) | 
| Change from baseline in serum chemistry parameter: Troponin T [ng/L] (high sensitivity) |  | Day 1, Day 8(±1) and Day 31(±3) | 
| Change from baseline in serum chemistry parameter: N-terminal pro b-type natriuretic peptide (NT-pro BNP: pmol/L) |  | Day 1, Day 8(±1) and Day 31(±3) | 
| Safety/Tolerability: Change from baseline in serological SARS CoV 2 testing (immunoglobulin [Ig]G) [UA/ml] |  | Day 1 and Day 31(±3) | 
| Safety/Tolerability: Change from baseline in inflammatory biomarkers | Proinflammatory biomarkers: C-reactive protein (CRP) [mg/L], ferritin [ng/L], IL-1β [pg/mL], IL-6 [pg/mL], IL-10 [pg/mL] and tumour necrosis factor alpha (TNFα) [pg/mL] | Days 1, 2, 3, 4, Day 8(±1) and Day 31(±3) | 
| Change from baseline in vital signs | Vital signs: temperature [°C or °F], sitting blood pressure [mmHg], heart rate [beats per minute], respiratory rate [breaths per minute], saturation of oxygen (SpO2) at room air [%]by pulse oximetry or arterial blood gas analyses and its respective FiO2 [%], | Screening (Day 0-1), Once daily while the patient is hospitalized, and on Day 8(±1) and Day 31(±3) | 
| Change from baseline in electrocardiogram (ECG) findings | ECG findings: QTcF prolongation and any QTcF values >500 msec | Screening and on Days 1, 3, and Day 31(±3) |