Immunocompromised Adult Patients with Symptomatic COVID-19 requiring Hospital Care MedDRA version: 23.0 Level: LLT Classification code 10084272 Term: SARS-CoV-2 infection System Organ Class: 100000004862
Conditions
Sponsors
Pharma Mar, S.A.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed informed consent obtained prior to initiation of any study-specific procedures and study treatment; 2. Patient aged =18 years; 3. Patient diagnosed COVID-19, with the following characteristics: a) A regulatory approved test, collected no more than 3 days prior to study randomisation, with either a Ct value =30 or a positive antigen test; b) Presence of any of the selected signs/symptom listed in Appendix 10 - COVID-19 signs/symptoms checklist within the last 24 h; 4. Patient already admitted or requiring hospital care for symptomatic COVID-19, for which at least one registered antiviral has failed, unless it is either contraindicated or not feasible according to the investigator; 5. Adequate bone marrow, liver, kidney, and metabolic function, defined by the following tests performed at local laboratory: o Absolute neutrophil count =500/mm3 (0.5 x 10exp9/L); o Platelet count = 50 000/mm3 (50 x 10exp9/L); o Alanine transaminase (ALT) =3 x upper limit of normal (ULN) (=5 x ULN if pre-existent liver involvement by the underlying disease); o Serum bilirubin =1.5 x ULN (or direct bilirubin <1.5 x ULN when total bilirubin is above ULN); o Estimated glomerular filtration rate =30 mL/min [CKD-EPI Creatinine Equation (2021)]. • Females of childbearing potential 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 at 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. Group-specific inclusion criteria: • Group 1 – Patients receiving, within the last 30 days, immune-suppressive therapy due to haematopoietic or organ transplantation. o Haematopoietic transplantation. o Solid Organ Transplantation: Lung / intestinal, Other. • Group 2 – Patients receiving B-cell depleting therapies within the last 3 months*. Includes (but is not limited to): o Monoclonal antibodies (mAbs) targeting CD19, CD20 or CD38 (e.g., rituximab, ocrelizumab, ofatumumab, daratumumab). o B-cell activating factor (BAFF) inhibitors (e.g., belimumab). o Bruton's tyrosine kinase (BTK) inhibitors (e.g., evobrutinib, ibrutinib). o Chimeric antigen receptor T cell therapy (CAR-T) (e.g., anti-CD19 CAR-T cell). *Within the last 6 months for anti-CD20. • Group 3 – Patients receiving, within the last 30 days, other immune-suppressive therapies. o Other immunosuppressive therapies not including B-cell depleting agents for the treatment of auto-immune disorders. o Chemotherapy or targeted therapies with immunosuppressive potential for solid tumours or haematological disorders. o Chronic glucocorticoids (i.e., equivalent to prednisone = 20 mg/day for more than 1 month). •Group 4 – Other situations with immunodeficiency. Includes (but is not limited to): o Primary immune deficiencies. o Human immunodeficiency virus (HIV) infection, with CD4+ T lymphocytes < 200 cells/µL in the last month. o Radiation therapy within the last 3 months- requires documentation of ALC < 500 cells/µL. o Haematological
Exclusion criteria
Exclusion criteria: 1. Evidence of critical illness, defined by at least one of the following: • Respiratory failure defined based on resource utilization requiring at least one of the following: endotracheal intubation and mechanical ventilation, ECMO, or clinical diagnosis of severe acute respiratory distress syndrome with PaO2*/FiO2 = 100. *In case a direct measure of PaO2 has not been obtained, it should be imputed according to a referenced formula (Ellis or Rice) (Appendix 5 - Imputation of PaO2/FiO2 ratio). For sites located over 1000 m altitude above sea level, PaO2/FiO2 ratio will be adjusted (Appendix 6- Adjustment of PaO2 from a Site at High Altitude; See also Appendix 7 for FiO2 imputations from oxygen flow rates). • Shock requiring vasopressors. • Multi-organ dysfunction/failure. 2. Patients already receiving concomitant treatment with antiviral therapy against SARS-CoV-2. 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, there should be a documentation of lack of clinical improvement plus evidence of persisting positivity for SARS-CoV-2 in appropriate biological samples (determined by a regulatory approved test, collected no more than 3 days prior to study randomisation, with either a Ct value =30 or a positive antigen test), and a washout period > 24 h. • For antiviral monoclonal antibodies, they must have been given for an earlier stage of the disease (including pre-exposure prophylaxis), there should be a documentation of lack of clinical improvement plus evidence of persisting positivity for SARS-CoV-2 in appropriate biological samples (determined by a regulatory approved test, collected no more than 3 days prior to study randomisation, with either a Ct value =30 or a positive antigen test), and a washout period of = 5 days. 3. Any of the following cardiac conditions or risk factors: • Cardiac infarction or cardiac surgery episode within the last month; • History of known congenital QT prolongation; • Known structural cardiomyopathy with abnormal LVEF (12 months) who are not using at least 1 protocolspecified method of contraception. 7. Any situation currently requiring increasing needs of immune suppressive agents (e.g. acute graft rejection, flare of autoimmune disorder, or cytokine storm syndrome). 8. 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. 9. Participation in another clinical study involving an investigational dru
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Efficacy primary objective To evaluate efficacy of plitidepsin in pre-specified groups of immunocompromised patients with symptomatic COVID-19 requiring hospital care vs control in terms of mortality.;Secondary Objective: Key efficacy secondary objective: Plitidepsin vs the control in terms of viral clearance, in each group. Efficacy secondary objective: Plitidepsin vs the control (in each group) in terms of: -Sustained end of hospital care - Symptomatic improvement - Clinical status (WHO) -the need of any kind of supplementary oxygen Safety/tolerability secondary objective Plitidepsin vs the control in terms of adverse events, adverse reactions and mortality, abnormal laboratory parameters, of variations of vital signs in each group.;Primary end point(s): Efficacy primary endpoint 1-Month all-cause mortality rate.;Timepoint(s) of evaluation of this end point: Day 30 since randomisation | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key secondary endpoint Time to confirmed negativisation in SARS-CoV-2 antigen test or RT-PCR Ct > 30. Efficacy secondary endpoints Time to sustained end of COVID-related hospital care from the time of randomisation Time to sustained improvement and resolution of selected COVID-19 signs/symptoms Time to sustained discontinuation (i.e., at least 7 days) of oxygen supplementation Distribution of patients according to their clinical status Percentage of patients requiring oxygen therapy Safety secondary endpoints Frequency of the following events (all-cause and drug-related): TEAEs, TEAEs = grade 3, AESIs, SAEs, SARs, Adverse events leading to treatment discontinuation, Deaths (COVID-19-related/all) Change respect to baseline* in individual study-defined laboratory parameters Change respect to baseline* in individual vital signs;Timepoint(s) of evaluation of this end point: Within 30 days of initial end of hospital care [up to day 60 (±3) On Days 4 (±1), 8 (±1), 15 (±1), 30 (±2), and 60 (±3). Throughout the study duration | — |
Countries
Belgium, Czechia, France, Greece, Hungary, Italy, Netherlands, Poland, Portugal, Spain, United Kingdom
Contacts
Public ContactClinical Development Virology Unit
Pharma Mar S.A.
Outcome results
None listed