COVID-19 Infection
Conditions
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
Interventions
DRUGPlitidepsin
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.
DRUGDexamethasone
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.
DRUGRemdesivir
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.
DRUGFavipiravir
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.
Sponsors
PharmaMar
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Sustained Withdrawal of Supplementary Oxygen With no Subsequent Reutilisation During Remaining Study Period | From administration date to Day 31(±3) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | Day 8 (±1) | The WHO clinical progression scale provides a measure of illness severity across a range from 0 (uninfected) to 10 (dead). 0 = Uninfected; no viral RNA detected 1. = Ambulatory mild disease. Asymptomatic; viral RNA detected 2. = Ambulatory mild disease. Symptomatic; independent 3. = Ambulatory mild disease. Symptomatic; assistance needed 4. = Hospitalized: moderate disease. Hospitalized; no oxygen therapy 5. = Hospitalized: moderate disease. Hospitalized; oxygen by mask or nasal prongs 6. = Hospitalized: severe diseases. Hospitalized; oxygen by NIV or high flow 7. = Hospitalized: severe diseases. Intubation and mechanical ventilation pO2/FIO2 \> 150 or SpO2/FIO2 \> 200 8. = Hospitalized: severe diseases. Mechanical ventilation pO2 /FIO2 \<150 (SpO2 /FiO2 \<200) or vasopressors 9. = Hospitalized: severe diseases. Mechanical ventilation pO2 /FiO2 \<150 and vasopressors, dialysis, or ECMO 10. = dead |
| Total Duration of Advanced Oxygen Support | From administration date to Day 31(±3) | Total duration of advanced oxygen support (high-flow nasal oxygen, extracorporeal membrane oxygenation -ECMO-, non-invasive ventilation or mechanical ventilation). |
| Time to Sustained (i.e., With no Subsequent Readmission to Day 31) Hospital Discharge (Since Randomisation). | From administration date to Day 31(±3) | Time to sustained (i.e., with no subsequent readmission to Day 31) hospital discharge (since randomization) |
| Frequency of Adverse Events | From administration date to Day 31(±3) | Adverse Event Types according to the National Cancer Institute \[NCI\]-Common Terminology Criteria for AEs (CTCAE v.5.0): The number of participants who experienced treatment-emergent adverse events (TEAEs) are presented. |
| 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 | From administration date to Day 31(±3) | Frequency of treatment-emergent adverse events (TEAEs) of ≥grade 3 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0), TEAEs of special interest, serious TEAEs, serious treatment-related TEAEs, TEAEs leading to treatment discontinuation, and deaths |
| Number of Participants in Each Study Group Requiring Admission to ICU | Day 4, Day 8(±1) , Day 15(±1) and Day 31(±3) | Number of participants in each study group requiring admission to intensive care unit |
Countries
Brazil, Bulgaria, Colombia, France, Greece, Mexico, Romania, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Plitidepsin 2.5 mg Arm Participants received plitidepsin 2.5 mg/day intravenous (IV) in addition to dexamethasone on days 1 to 3. | 68 |
| Plitidepsin 1.5 mg Arm Participants received plitidepsin 1.5 mg/day IV in addition to dexamethasone on days 1 to 3. | 70 |
| Control Arm Participants received dexamethasone IV on Days 1 to 3. Additionally, in accordance with local treatment guidelines, participants in this group may have received a regulatory-approved antiviral treatment. | 67 |
| Total | 205 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 2 | 1 | 2 |
| Overall Study | Did not meet all inclusion criteria | 0 | 1 | 0 |
| Overall Study | Discontinued as was found to be ineligible | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 2 |
| Overall Study | Participant admitted in other hospital due to a serious adverse event | 1 | 0 | 0 |
| Overall Study | Participant deterioration becoming a candidate for treatment with TZB | 1 | 0 | 0 |
| Overall Study | Participant worsened, PI decision | 1 | 0 | 0 |
| Overall Study | SAE | 0 | 1 | 0 |
| Overall Study | The participant was transferred to IRCU | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 2 | 1 |
Baseline characteristics
| Characteristic | Plitidepsin 1.5 mg Arm | Plitidepsin 2.5 mg Arm | Total | Control Arm |
|---|---|---|---|---|
| Age, Continuous | 58.1 years STANDARD_DEVIATION 14.8 | 58.9 years STANDARD_DEVIATION 13.33 | 58.7 years STANDARD_DEVIATION 14.34 | 59.3 years STANDARD_DEVIATION 15.02 |
| Age, Customized ≥18 to 59 years | 34 Participants | 32 Participants | 98 Participants | 32 Participants |
| Age, Customized ≥60 to 64 years | 9 Participants | 13 Participants | 28 Participants | 6 Participants |
| Age, Customized ≥65 to 69 years | 11 Participants | 8 Participants | 30 Participants | 11 Participants |
| Age, Customized ≥70 to 74 years | 8 Participants | 9 Participants | 21 Participants | 4 Participants |
| Age, Customized ≥75 to 79 years | 6 Participants | 3 Participants | 16 Participants | 7 Participants |
| Age, Customized ≥80 years | 2 Participants | 3 Participants | 12 Participants | 7 Participants |
| Body mass index at screening | 29.68 kg/m^2 STANDARD_DEVIATION 5.617 | 29.45 kg/m^2 STANDARD_DEVIATION 4.555 | 29.79 kg/m^2 STANDARD_DEVIATION 5.448 | 30.26 kg/m^2 STANDARD_DEVIATION 6.116 |
| Body mass index group at screening ≥18.5 and <25 kg/m^2 | 10 Participants | 10 Participants | 30 Participants | 10 Participants |
| Body mass index group at screening ≥25 and <30 kg/m^2 | 35 Participants | 31 Participants | 92 Participants | 26 Participants |
| Body mass index group at screening ≥30 and <35 kg/m^2 | 13 Participants | 15 Participants | 45 Participants | 17 Participants |
| Body mass index group at screening ≥35 and <40 kg/m^2 | 4 Participants | 9 Participants | 21 Participants | 8 Participants |
| Body mass index group at screening ≥40 kg/m^2 | 5 Participants | 1 Participants | 10 Participants | 4 Participants |
| Body mass index group at screening Missing | 3 Participants | 2 Participants | 7 Participants | 2 Participants |
| Body surface area at screening | 1.961 m^2 STANDARD_DEVIATION 0.2252 | 1.922 m^2 STANDARD_DEVIATION 0.1787 | 1.950 m^2 STANDARD_DEVIATION 0.2123 | 1.968 m^2 STANDARD_DEVIATION 0.2299 |
| Child-bearing potential, n (%) No, other | 3 Participants | 0 Participants | 5 Participants | 2 Participants |
| Child-bearing potential, n (%) No, surgically sterile/post-menopausal | 18 Participants | 21 Participants | 58 Participants | 19 Participants |
| Child-bearing potential, n (%) Yes | 5 Participants | 4 Participants | 13 Participants | 4 Participants |
| Diastolic blood pressure (mmHg) at screening | 76.1 mmHg STANDARD_DEVIATION 9.36 | 74.2 mmHg STANDARD_DEVIATION 9.53 | 75.1 mmHg STANDARD_DEVIATION 10.05 | 75.0 mmHg STANDARD_DEVIATION 11.26 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 35 Participants | 33 Participants | 89 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 35 Participants | 116 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Fraction of inspired oxygen (%) at screening | 26.91 Percentage STANDARD_DEVIATION 3.37 | 26.92 Percentage STANDARD_DEVIATION 3.861 | 27.25 Percentage STANDARD_DEVIATION 6.191 | 27.94 Percentage STANDARD_DEVIATION 9.526 |
| Height at screening | 169.56 Centimeter STANDARD_DEVIATION 8.534 | 167.79 Centimeter STANDARD_DEVIATION 8.067 | 168.87 Centimeter STANDARD_DEVIATION 8.921 | 169.25 Centimeter STANDARD_DEVIATION 10.095 |
| Oxygen saturation (%) at screening | 96.26 Percentage STANDARD_DEVIATION 1.721 | 96.29 Percentage STANDARD_DEVIATION 1.779 | 96.33 Percentage STANDARD_DEVIATION 1.743 | 96.44 Percentage STANDARD_DEVIATION 1.749 |
| Periods of inclusion April 2022 - End of accrual | 14 Participants | 10 Participants | 38 Participants | 14 Participants |
| Periods of inclusion Beginning of accrual - August 2021 | 1 Participants | 2 Participants | 5 Participants | 2 Participants |
| Periods of inclusion September 2021 - March 2022 | 55 Participants | 56 Participants | 162 Participants | 51 Participants |
| Pulse rate (beats/min) at screening | 83.9 beats/min STANDARD_DEVIATION 11.36 | 81.6 beats/min STANDARD_DEVIATION 13.72 | 83.2 beats/min STANDARD_DEVIATION 12.88 | 84.2 beats/min STANDARD_DEVIATION 13.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 4 Participants | 12 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 62 Participants | 63 Participants | 189 Participants | 64 Participants |
| Respiration rate (breaths/min) at screening | 19.0 breaths/min STANDARD_DEVIATION 3.4 | 19.5 breaths/min STANDARD_DEVIATION 3.49 | 19.4 breaths/min STANDARD_DEVIATION 3.41 | 19.9 breaths/min STANDARD_DEVIATION 3.32 |
| SARS-CoV-2 viral load at Day 1 | 4.97 log10 copies/mL STANDARD_DEVIATION 1.985 | 5.02 log10 copies/mL STANDARD_DEVIATION 1.88 | 5.01 log10 copies/mL STANDARD_DEVIATION 2.04 | 5.06 log10 copies/mL STANDARD_DEVIATION 2.253 |
| Sex: Female, Male Female | 26 Participants | 25 Participants | 76 Participants | 25 Participants |
| Sex: Female, Male Male | 44 Participants | 43 Participants | 129 Participants | 42 Participants |
| Systolic blood pressure (mmHg) at screening | 126.9 mmHg STANDARD_DEVIATION 16.25 | 123.4 mmHg STANDARD_DEVIATION 18.44 | 126.1 mmHg STANDARD_DEVIATION 17.04 | 127.9 mmHg STANDARD_DEVIATION 16.24 |
| Temperature (C) at screening | 36.90 celsius STANDARD_DEVIATION 0.899 | 36.91 celsius STANDARD_DEVIATION 0.878 | 36.91 celsius STANDARD_DEVIATION 0.88 | 36.92 celsius STANDARD_DEVIATION 0.875 |
| Vaccination status Fully vaccinated | 36 Participants | 35 Participants | 103 Participants | 32 Participants |
| Vaccination status Fully vaccinated + Non-fully vaccinated | 39 Participants | 41 Participants | 116 Participants | 36 Participants |
| Vaccination status Non-fully vaccinated | 3 Participants | 6 Participants | 13 Participants | 4 Participants |
| Vaccination status Not vaccinated | 31 Participants | 27 Participants | 89 Participants | 31 Participants |
| Weight at screening | 86.05 kilogram STANDARD_DEVIATION 19.778 | 82.72 kilogram STANDARD_DEVIATION 14.38 | 85.36 kilogram STANDARD_DEVIATION 18.12 | 87.38 kilogram STANDARD_DEVIATION 19.672 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 63 | 1 / 67 | 2 / 65 |
| other Total, other adverse events | 43 / 63 | 43 / 67 | 38 / 65 |
| serious Total, serious adverse events | 11 / 63 | 6 / 67 | 5 / 65 |
Outcome results
Primary
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).
Time frame: From administration date to Day 31(±3)
Population: Intent-to-treat Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Plitidepsin 2.5 mg Arm | Time to Sustained Withdrawal of Supplementary Oxygen With no Subsequent Reutilisation During Remaining Study Period | 5 Days |
| Plitidepsin 1.5 mg Arm | Time to Sustained Withdrawal of Supplementary Oxygen With no Subsequent Reutilisation During Remaining Study Period | 5 Days |
| Control Arm | Time to Sustained Withdrawal of Supplementary Oxygen With no Subsequent Reutilisation During Remaining Study Period | 7 Days |
Comparison: Plitidepsin 2.5 mg arm versus Control armp-value: 0.875195% CI: [0.727, 1.53]Log Rank
Comparison: Plitidepsin 1.5 mg arm versus Control armp-value: 0.062595% CI: [0.96, 1.96]Log Rank
Secondary
Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8
The WHO clinical progression scale provides a measure of illness severity across a range from 0 (uninfected) to 10 (dead). 0 = Uninfected; no viral RNA detected 1. = Ambulatory mild disease. Asymptomatic; viral RNA detected 2. = Ambulatory mild disease. Symptomatic; independent 3. = Ambulatory mild disease. Symptomatic; assistance needed 4. = Hospitalized: moderate disease. Hospitalized; no oxygen therapy 5. = Hospitalized: moderate disease. Hospitalized; oxygen by mask or nasal prongs 6. = Hospitalized: severe diseases. Hospitalized; oxygen by NIV or high flow 7. = Hospitalized: severe diseases. Intubation and mechanical ventilation pO2/FIO2 \> 150 or SpO2/FIO2 \> 200 8. = Hospitalized: severe diseases. Mechanical ventilation pO2 /FIO2 \<150 (SpO2 /FiO2 \<200) or vasopressors 9. = Hospitalized: severe diseases. Mechanical ventilation pO2 /FiO2 \<150 and vasopressors, dialysis, or ECMO 10. = dead
Time frame: Day 8 (±1)
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Plitidepsin 2.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 6 = hospitalised, oxygen by NIV or high flow | 5 Participants |
| Plitidepsin 2.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 0 = uninfected, no viral RNA detected | 6 Participants |
| Plitidepsin 2.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 1 = asymptomatic, viral RNA detected | 12 Participants |
| Plitidepsin 2.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 2 = symptomatic, independent | 20 Participants |
| Plitidepsin 2.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 3 = symptomatic, assistance needed | 0 Participants |
| Plitidepsin 2.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 4 = hospitalised, no oxygen therapy | 4 Participants |
| Plitidepsin 2.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 5 = hospitalised, oxygen by mask or nasal prongs | 10 Participants |
| Plitidepsin 2.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 7 = intubation and mechanical ventilation. pO2/FiO2 >150 or SpO2/FiO2 >200 | 4 Participants |
| Plitidepsin 2.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 8 = mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or vasopressors | 1 Participants |
| Plitidepsin 2.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 9 = mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO | 0 Participants |
| Plitidepsin 2.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 10 = dead | 1 Participants |
| Plitidepsin 1.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 3 = symptomatic, assistance needed | 1 Participants |
| Plitidepsin 1.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 10 = dead | 0 Participants |
| Plitidepsin 1.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 4 = hospitalised, no oxygen therapy | 8 Participants |
| Plitidepsin 1.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 9 = mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO | 0 Participants |
| Plitidepsin 1.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 5 = hospitalised, oxygen by mask or nasal prongs | 8 Participants |
| Plitidepsin 1.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 6 = hospitalised, oxygen by NIV or high flow | 7 Participants |
| Plitidepsin 1.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 7 = intubation and mechanical ventilation. pO2/FiO2 >150 or SpO2/FiO2 >200 | 1 Participants |
| Plitidepsin 1.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 0 = uninfected, no viral RNA detected | 10 Participants |
| Plitidepsin 1.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 1 = asymptomatic, viral RNA detected | 15 Participants |
| Plitidepsin 1.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 8 = mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or vasopressors | 0 Participants |
| Plitidepsin 1.5 mg Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 2 = symptomatic, independent | 17 Participants |
| Control Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 1 = asymptomatic, viral RNA detected | 12 Participants |
| Control Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 3 = symptomatic, assistance needed | 1 Participants |
| Control Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 7 = intubation and mechanical ventilation. pO2/FiO2 >150 or SpO2/FiO2 >200 | 2 Participants |
| Control Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 2 = symptomatic, independent | 19 Participants |
| Control Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 4 = hospitalised, no oxygen therapy | 7 Participants |
| Control Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 0 = uninfected, no viral RNA detected | 3 Participants |
| Control Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 10 = dead | 0 Participants |
| Control Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 5 = hospitalised, oxygen by mask or nasal prongs | 20 Participants |
| Control Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 8 = mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or vasopressors | 0 Participants |
| Control Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 6 = hospitalised, oxygen by NIV or high flow | 1 Participants |
| Control Arm | Clinical Status by the 11-category WHO Clinical Progression Scale on Day 8 | 9 = mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO | 0 Participants |
Comparison: Plitidepsin 2.5 mg arm versus Control armp-value: 0.725295% CI: [0.604, 2.06]p-value based on proportional odds model
Comparison: Plitidepsin 1.5 mg arm versus Control armp-value: 0.09195% CI: [0.92, 3.11]p-value based on proportional odds model
Secondary
Frequency of Adverse Events
Adverse Event Types according to the National Cancer Institute \[NCI\]-Common Terminology Criteria for AEs (CTCAE v.5.0): The number of participants who experienced treatment-emergent adverse events (TEAEs) are presented.
Time frame: From administration date to Day 31(±3)
Population: As Treated Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Plitidepsin 2.5 mg Arm | Frequency of Adverse Events | 45 Participants |
| Plitidepsin 1.5 mg Arm | Frequency of Adverse Events | 44 Participants |
| Control Arm | Frequency of Adverse Events | 40 Participants |
Secondary
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
Frequency of treatment-emergent adverse events (TEAEs) of ≥grade 3 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0), TEAEs of special interest, serious TEAEs, serious treatment-related TEAEs, TEAEs leading to treatment discontinuation, and deaths
Time frame: From administration date to Day 31(±3)
Population: As Treated Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Plitidepsin 2.5 mg Arm | 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 | Any TEAE Grade ≥3 | 22 Participants |
| Plitidepsin 2.5 mg Arm | 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 | Any TEAE of special interest | 22 Participants |
| Plitidepsin 2.5 mg Arm | 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 | Any serious TEAE | 11 Participants |
| Plitidepsin 2.5 mg Arm | 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 | Any serious treatment-related TEAE to any study treatment | 1 Participants |
| Plitidepsin 2.5 mg Arm | 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 | Any TEAE leading to discontinuation of any study treatment | 1 Participants |
| Plitidepsin 2.5 mg Arm | 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 | Any TEAE leading to death | 2 Participants |
| Plitidepsin 1.5 mg Arm | 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 | Any TEAE leading to death | 1 Participants |
| Plitidepsin 1.5 mg Arm | 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 | Any TEAE Grade ≥3 | 17 Participants |
| Plitidepsin 1.5 mg Arm | 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 | Any serious treatment-related TEAE to any study treatment | 1 Participants |
| Plitidepsin 1.5 mg Arm | 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 | Any TEAE leading to discontinuation of any study treatment | 1 Participants |
| Plitidepsin 1.5 mg Arm | 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 | Any TEAE of special interest | 25 Participants |
| Plitidepsin 1.5 mg Arm | 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 | Any serious TEAE | 6 Participants |
| Control Arm | 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 | Any TEAE of special interest | 18 Participants |
| Control Arm | 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 | Any serious TEAE | 5 Participants |
| Control Arm | 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 | Any TEAE leading to death | 2 Participants |
| Control Arm | 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 | Any serious treatment-related TEAE to any study treatment | 0 Participants |
| Control Arm | 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 | Any TEAE Grade ≥3 | 11 Participants |
| Control Arm | 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 | Any TEAE leading to discontinuation of any study treatment | 1 Participants |
Secondary
Number of Participants in Each Study Group Requiring Admission to ICU
Number of participants in each study group requiring admission to intensive care unit
Time frame: Day 4, Day 8(±1) , Day 15(±1) and Day 31(±3)
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Plitidepsin 2.5 mg Arm | Number of Participants in Each Study Group Requiring Admission to ICU | From Day 1 to Day 8 | 7 participants |
| Plitidepsin 2.5 mg Arm | Number of Participants in Each Study Group Requiring Admission to ICU | From Day 1 to Day 15 | 7 participants |
| Plitidepsin 2.5 mg Arm | Number of Participants in Each Study Group Requiring Admission to ICU | From Day 1 to Day 4 | 1 participants |
| Plitidepsin 2.5 mg Arm | Number of Participants in Each Study Group Requiring Admission to ICU | From Day 1 to Day 31 | 7 participants |
| Plitidepsin 1.5 mg Arm | Number of Participants in Each Study Group Requiring Admission to ICU | From Day 1 to Day 8 | 3 participants |
| Plitidepsin 1.5 mg Arm | Number of Participants in Each Study Group Requiring Admission to ICU | From Day 1 to Day 4 | 1 participants |
| Plitidepsin 1.5 mg Arm | Number of Participants in Each Study Group Requiring Admission to ICU | From Day 1 to Day 15 | 4 participants |
| Plitidepsin 1.5 mg Arm | Number of Participants in Each Study Group Requiring Admission to ICU | From Day 1 to Day 31 | 5 participants |
| Control Arm | Number of Participants in Each Study Group Requiring Admission to ICU | From Day 1 to Day 15 | 4 participants |
| Control Arm | Number of Participants in Each Study Group Requiring Admission to ICU | From Day 1 to Day 4 | 3 participants |
| Control Arm | Number of Participants in Each Study Group Requiring Admission to ICU | From Day 1 to Day 8 | 4 participants |
| Control Arm | Number of Participants in Each Study Group Requiring Admission to ICU | From Day 1 to Day 31 | 4 participants |
Secondary
Time to Sustained (i.e., With no Subsequent Readmission to Day 31) Hospital Discharge (Since Randomisation).
Time to sustained (i.e., with no subsequent readmission to Day 31) hospital discharge (since randomization)
Time frame: From administration date to Day 31(±3)
Population: Intent-to-treat Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Plitidepsin 2.5 mg Arm | Time to Sustained (i.e., With no Subsequent Readmission to Day 31) Hospital Discharge (Since Randomisation). | 7 Days |
| Plitidepsin 1.5 mg Arm | Time to Sustained (i.e., With no Subsequent Readmission to Day 31) Hospital Discharge (Since Randomisation). | 7 Days |
| Control Arm | Time to Sustained (i.e., With no Subsequent Readmission to Day 31) Hospital Discharge (Since Randomisation). | 7 Days |
Comparison: Plitidepsin 2.5 mg arm versus Control armp-value: 0.594595% CI: [0.655, 1.37]Log Rank
Comparison: Plitidepsin 1.5 mg arm versus Control armp-value: 0.335895% CI: [0.827, 1.7]Log Rank
Secondary
Total Duration of Advanced Oxygen Support
Total duration of advanced oxygen support (high-flow nasal oxygen, extracorporeal membrane oxygenation -ECMO-, non-invasive ventilation or mechanical ventilation).
Time frame: From administration date to Day 31(±3)
Population: Full Analysis Set; number of participants who received advanced oxygen support are presented
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Plitidepsin 2.5 mg Arm | Total Duration of Advanced Oxygen Support | 12.2 Days | Standard Deviation 9.71 |
| Plitidepsin 1.5 mg Arm | Total Duration of Advanced Oxygen Support | 10 Days | Standard Deviation 8.21 |
| Control Arm | Total Duration of Advanced Oxygen Support | 8.3 Days | Standard Deviation 12.66 |