| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| moderate COVID-19 infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| moderate COVID-19 infection |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10084272 |
| E.1.2 | Term | SARS-CoV-2 infection |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Efficacy primary objective; To compare efficacy of plitidepsin 1.5 mg or
2.5 mg versus the control assessing the need of supplementary oxygen. |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objective:
Efficacy key secondary objective:
* To compare efficacy of plitidepsin 1.5 mg or 2.5 mg versus the control
assessing the time to sustained hospital discharge.
Secondary objectives:
Efficacy secondary objectives: To compare efficacy of plitidepsin 1.5 mg
or 2.5 mg vs the control
* assessing clinical status by the 11 category WHO Clinical Progression
Scale
* in terms of the need of advanced oxygen support
* in terms of the need for intensive care support
Safety secondary objectives: To compare safety/tolerability of
plitidepsin 1.5 mg or 2.5 mg vs the control in terms of
* adverse events, adverse reactions and mortality.
* abnormal lab parameters
* variations of vital signs
* ECG variations |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Evaluation of the Effect of Plitidepsin on Cardiac Repolarisation (QTc Duration) in Patients with COVID-19 Treated in Study APL-D-003-20
This QT corrected (QTc) substudy associated with clinical trial APL-D-003-20 will determine whether plitidepsin at 1.5 and 2.5 mg flat dose on Days 1 to 3 has any effects on the QT interval in patients with coronavirus disease 2019 (COVID-19).
The primary objective of the present substudy is to assess the potential effects of plitidepsin at a therapeutic dose on the duration of the QTc interval, measured by continuous 12-lead ECG automated monitoring, in patients with COVID-19.
Secondary objectives are:
To characterise the plitidepsin concentration/QTc relationship.
To explore waveform morphology-related ECG parameters
To explore plitidepsin pharmacokinetics in patients with COVID-19 |
|
| E.3 | Principal 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 (Appendix 13): requires hospitalization 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/mm3 (0.5 x 10^9/L)
• Platelet count ≥75,000/mm3 (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. |
|
| E.4 | Principal exclusion criteria |
1. Subjects with a pre-baseline impairment in general health condition for whatever reason except COVID-19, with a severe dependancy 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 randomisation, based on resource utilisation requiring at least one of the following: endotracheal intubation and mechanical ventilation, O2 delivered by high-flow nasal cannula, non-invasive positive pressure ventilation, ECMO, or clinical diagnosis of respiratory failure
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: respiratory rate ≥30/min, heart rate ≥125/min, 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 1000m 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:
o The total daily dose is not higher than 10mg of dexamethasone phosphate (equivalent to dexamethasone base 8.25 mg/day) or equivalent glucocorticoids
o The duration of the treatment does not exceed 72h prior to study treatment Day 1
Prior administration of an antiviral might be acceptable in the following circumstances:
o 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.
o 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 inhibitors or inducers
8. Viral illness (other than COVID-19) requiring therapy, except for patients with treated and adequately controlled (undetectable) HIV infection
9. Patients with uncontrolled known primary or secondary immunodeficiency, including chronic treatment with glucocorticoids
10. Any of the following cardiac conditions or risk
Any of the following cardiac conditions or risk factors:
- Sinus bradycardia (<50beats/min), sinus nodal dysfunction, atrioventricular block of any degree (PR >200 msec), or any other bradyarrhythmia (<50beats/min), except for patients with permanent pacemakers;
- Cardiac infarction, cardiac surgery or cardiac insufficiency episode within 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 >450msec for males or >470msec 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 >1.5xULN; 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, or patients for whom dexamethasone, antihistamine H1/H2 or antiserotoninergic agents are contraindicated
12. Females who are pregnant or breastfeeding
13. Females and males with partners of childbearing potential who are not using at least 1 protocol-specified method of contraception
14. Any other clinically significant medical condition (including major surgery within 3 weeks before screening) or lab 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Efficacy primary endpoint: Time to sustained withdrawal of supplementary oxygen (11 category WHO Clinical Progression Scale ≤4) with no subsequent reutilisation during remaining study period (See Appendix 13 - World Health Organization (WHO) Clinical Progression Scale). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key secondary objective:
Efficacy key secondary endpoint:
Time to sustained (i.e., with no subsequent readmission to Day 31) hospital discharge (since randomisation).
Efficacy secondary endpoints:
* Clinical status by the 11 category WHO Clinical Progression Scale, at Day 8 (±1) (See Appendix 13 - World Health Organization (WHO) Clinical Progression Scale).
* Total duration of advanced oxygen support (high-flow nasal oxygen, extracorporeal membrane oxygenation -ECMO-, non-invasive ventilation or mechanical ventilation).
* Percentage of patients in each study group requiring admission to ICU on Days 4, 8, 15 and 31.
Safety secondary endpoints: * Frequency of:
• Treatment-emergent adverse events (TEAEs);
• TEAEs ≥ grade 3 according to the National Cancer Institute [NCI]-Common Terminology Criteria for AEs (CTCAE v.5.0);
• Adverse events of special interest (AESIs);
• Serious adverse events (SAEs);
• Drug-releated serious adverse events (i.e., SARs)
• Adverse events leading to treatment discontinuation; and
• Deaths
Change respect to baseline in individual study-defined laboratory parameters
* Change respect to baseline in individual vital signs
* Change respect to baseline in individual ECG parameters |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 31. Other timepoint evaluations have been included in section E.5.2. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 63 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Brazil |
| Mexico |
| Peru |
| South Africa |
| France |
| Sweden |
| Bulgaria |
| Romania |
| Spain |
| Greece |
| Portugal |
| Turkey |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study is considered completed after the last patient has completed all protocol-specified evaluations, including the protocol-specified Day 31 (±3 days) follow-up or until resolution/stabilisation of treatment-related adverse events, treatment-emergent adverse events of special interest, and SAEs that occurred through Day 31, whichever is longer. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 19 |
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