| 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 |
Comparing plitidepsin 1.5 or 2.5 mg vs control on the percentage of patients who achieve complete recovery by Day 8 (±1), defined as (i) meeting categories 0 to 2 on the 11-point WHO Clinical Progression Scale below, (ii) having Barthel Index >90/100 at the time of discharge, (iii) with no re-admission for COVID-19 signs and symptoms through Day31
0: uninfected, no viral RNA detected
1: asymptomatic, viral RNA detected
2: symptomatic, independent
3: symptomatic, assistance needed
4: hospitalised, no oxygen therapy (if hospitalised for isolation only, record status as for ambulatory patient)
5: hospitalised, oxygen by mask or nasal prongs
6: hospitalised, oxygen by noninvasive ventilation (NIV) or high flow
7: intubation and mechanical ventilation. pO2/FIO2 ≥150 or SpO2/FIO2 ≥200
8: mechanical ventilation pO2/FIO2 <150 (SpO2/FIO2 <200) or vasopressors
9: mechanical ventilation pO2/FIO2 <150 and vasopressors, dialysis, or extracorporeal membrane oxygenation (ECMO)
10: dead |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objectives of this study are to compare plitidepsin 1.5 and 2.5 mg versus control on the following::
*Time to complete recovery (in days), defined as the first day, from Day 1 through follow-up on Day 31, on which a patient (i) satisfies categories 0 to 2 on the 11-point WHO Clinical Progression Scale above, (ii) has Barthel Index >90/100 at the time of discharge, and (iii) has no subsequent re-admission for COVID-19 signs and symptoms
*Clinical status, as assessed by the 11-category WHO Clinical Progression Scale, at Day 8 (±1) |
|
| 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. Laboratory confirmed SARS-CoV-2 infection as determined by qualitative polymerase chain reaction (PCR) by local laboratory from oro/nasopharyngeal exudate (or other respiratory specimen) collected no more than 24 hours prior to study treatment on Day 1
3. Admitted to hospital as clinically indicated for management of moderate SARS-CoV-2 (COVID-19) infection, defined by the following criteria:
• Positive PCR test for SARS-CoV-2
• Symptoms of moderate illness with COVID-19, which could include any symptoms of mild illness or shortness of breath with exertion
• Clinical signs suggestive of moderate illness with COVID-19 such as respiratory rate ≥20 breaths but <30 breaths per minute, SpO2 >93% but <95% on room air at sea level, heart rate ≥90 but <125 beats per minute, and requiring O2 supplementation. If SpO2 on room air is not possible to be measured, the ratio PaO2/FiO2 should be >= 300 mm Hg (see Appendix 9); in addition, if the site is located at high altitude over sea level (> 1000 m), the ratio PaO2/FiO2 should be adjusted
• No clinical signs indicative of severe illness, which could include shortness of breath at rest or respiratory distress, or PaO2/FiO2 ratio < 300 mm Hg (sea level).
4. Onset of COVID-19 symptoms no later than 6 days prior 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 ≥1000/mm3 (1.0 x 109/L)
• Lymphocyte count ≥500/mm3 (0.5 x 109/L)
• Platelet count ≥100 000/mm3 (100 x 109/L)
• Haemoglobin >9.0 g/dL
• Alanine transaminase (ALT), aspartate transaminase (AST) ≤3 x upper limit of normal (ULN)
• Serum bilirubin ≤1 x ULN
• Calculated creatinine clearance ≥30 mL/min (Cockcroft and Gault formula)
• Creatine phosphokinase ≤2.5 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 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. |
|
| E.4 | Principal exclusion criteria |
1. Subjects with a pre-baseline (ie, in the prior month) impairment in general health condition for whatever reason except COVID-19, requiring either assistance for daily living activities or chronic oxygen therapy
2. Participating in another clinical trial for treatment of COVID-19 infection or patients previously enrolled in clinical trials and currently in follow-up, or patients previously vaccinated for COVID-19
3. Evidence of respiratory failure at the time of randomisation, based on resource utilisation requiring at least 1 of the following: endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula, noninvasive positive pressure ventilation, ECMO, or clinical diagnosis of respiratory failure (ie, clinical need for 1 of the preceding therapies, but preceding therapies not able to be administered in setting of resource limitation)
4. Patients clinically indicated for management of SARS-CoV-2 (COVID-19), with baseline disease severity rated as severe (if positive testing by standard RT-PCR assay or equivalent test, symptoms suggestive of severe illness with COVID-19, which could include any symptom of moderate illness or shortness of breath at rest, or respiratory distress, clinical signs indicative of severe systemic illness with COVID-19, such as respiratory rate ≥30 per minute, heart rate ≥125 per minute, SpO2 ≤93% on room air at sea level, or PaO2/FiO2 <300)
5. Patients receiving treatment with antivirals, IL-6 receptor inhibitor, corticosteroids, or immunomodulatory drugs for COVID-19 infection within 4 weeks before enrolment
6. History of live vaccination within the last 4 weeks prior to study enrolment; subjects must not receive live, attenuated influenza vaccine within 4 weeks before enrolment or at any time during the study
7. Patients receiving treatment with chloroquine or derivatives within 8 weeks before enrolment or during the study
8. Receiving treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers (see Appendix 4)
9. Viral illness (other than COVID-19) requiring therapy, except for patients with treated and adequately controlled (undetectable) human immunodeficiency virus infection are eligible
10. Any of the following cardiac conditions or risk factors:
- Sinus bradycardia (<50 beats/min), sinus nodal dysfunction (sick sinus disease), atrio-ventricular block of any degree (PR >200 msec), or any other bradyarrhthymia (< 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 < 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, based on triplicate ECG at screening;
- History of known congenital or acquired QT prolongation;
- Uncorrected hypokalaemia, hypocalcaemia (adjusted) and/or hypomagnesemia at baseline;
- Concomitant treatments with drugs known to be associated with a risk of QT prolongation or cardiac arrhythmia (Appendix 8a); or
- Troponin test performed at local laboratory > 1.5 x ULN.
11. Pre-existing neuropathies of any type Grade ≥2
12. Hypersensitivity to the active ingredient or any of the excipients (mannitol, macrogolglycerol hydroxystearate, and ethanol).
13. Females who are pregnant (negative serum pregnancy test required for all females of child-bearing potential at screening) or breast feeding
14. Females and males with partners of child-bearing potential (females who are not surgically sterile or postmenopausal defined as amenorrhoea for >12 months) who are not using at least 1 protocolspecified method of contraception
15. Any other clinically significant medical condition or laboratory abnormality that, in the opinion of the investigator, would jeopardise the safety of the patient or potentially impact patient compliance or the safety/efficacy observations in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Compare plitidepsin 1.5 or 2.5 mg versus control on the percentage of patients who achieve complete recovery by Day 8 (±1), defined as (i) meeting categories 0 to 2 on the 11-point WHO Clinical Progression Scale below, (ii) having Barthel Index >90/100 at the time of discharge, and (iii) with no re-admission for COVID-19 signs and symptoms through Day 31.
0. uninfected, no viral RNA detected
1. asymptomatic, viral RNA detected
2. symptomatic, independent
3. symptomatic, assistance needed
4. hospitalised, no oxygen therapy (if hospitalised for isolation only, record status as for ambulatory patient)
5. hospitalised, oxygen by mask or nasal prongs
6. hospitalised, oxygen by NIV or high flow
7. intubation and mechanical ventilation. pO2/FIO2 ≥150 or SpO2/FIO2 ≥200
8. mechanical ventilation pO2/FIO2 <150 (SpO2/FIO2 <200) or vasopressors
9. mechanical ventilation pO2/FIO2 <150 and vasopressors, dialysis, or ECMO
10. dead |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key secondary objectives of this study are to compare plitidepsin 1.5 and 2.5 mg versus control on the following:
• Time to complete recovery (in days), defined as the first day, from Day 1 through follow-up on Day 31, on which a patient (i) satisfies categories 0 to 2 on the 11-point WHO Clinical Progression Scale above, (ii) has Barthel Index >90/100 at the time of discharge, and (iii) has no subsequent re-admission for COVID-19 signs and symptoms
• Clinical status, as assessed by the 11-category WHO Clinical Progression Scale, at Day 8 (±1)
Other secondary objectives of this study are:
• Safety and tolerability, based on treatment-emergent adverse events (TEAEs), Grade ≥3 TEAEs, serious adverse events (SAEs), serious adverse reactions (SARs) and adverse events (AEs) of special interest
• Compare the efficacy and safety/tolerability between plitidepsin arms (1.5 versus 2.5 mg) in case both arms are significantly better than the control arm on the primary endpoint
• Compare the percentage of patients who achieve complete recovery by Day 8 (±1), as defined above, for the pooled plitidepsin arms versus control
• Percentage of patients in each study arm requiring re-admission for COVID-19 signs and symptoms
• Clinical status in each study arm, as assessed by the 11-category WHO Clinical Progression Scale, at Days 4, 15, and 31
• Duration of oxygen therapy (in days) for each study arm
• Percentage of patients in each study arm requiring high-flow oxygen at Days 4, 8, 15, and 31
• Percentage of patients in each study arm requiring noninvasive mechanical ventilation at Days 4, 8, 15, and 31
• Percentage of patients in each study arm requiring invasive mechanical ventilation or ECMO at Days 4, 8, 15, and 31
• Percentage of patients in each study arm requiring intensive care unit (ICU) admission at Days 4, 8, 15, and 31
• Duration of hospitalisation in ICU for each study arm
• Percentage of patients receiving subsequent antiviral therapies or immunomodulatory drugs at Days 4, 8, 15, and 31
• Percentage of patients in each study arm with nosocomial infection
• Mortality in each study arm at Days 4, 8, 15, and 31
• Change in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in each study arm from Day 1 before administration of study drug to Day 8 as measured by quantitative polymerase chain reaction (qPCR) from samples of oro-nasopharyngeal exudate
• Percentage of patients in each study arm with undetectable SARS-CoV-2 viral load on Day 8, as measured by qPCR from samples of oro-nasopharyngeal exudate
• Change in proinflammatory biomarkers (C-reactive protein [CRP], lactate dehydrogenase [LDH], ferritin, interleukin [IL]-6, IL-1β, IL-10, and tumour necrosis factor alpha [TNFα]) in each study arm from baseline to Days 2, 3, 4, 8, 15, and 31
• Proportion of patients with a serologic response anti-SARS-CoV-2 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| France |
| Portugal |
| Sweden |
| United Kingdom |
| Bulgaria |
| Romania |
| Spain |
| Italy |
|
| 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 31follow-up or until resolution/stabilization of AEs 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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