COVID-19 trials registries data warehouse

https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-002489-34/HU

Pharma Mar S.A. - Clinical Development Virology Unit

clinicaltrials@pharmamar.com

2022-11-17

Terminated

RCT

Randomized

Parallel

Open label

multi-center

Treatment

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, or cannot be used‡, after a minimum washout period of 24h for small molecules (e.g., remdesivir, molnupiravir, nirmaltrevir/ritonavir) and 5 days for antiviral monoclonal antibodies (e.g., tixagevimab + cilgavimab) or convalescent plasma.*The definition of hospital care is based on the need to use a hospital environment (hospital ward, day hospital) for treatment administration and/or clinical monitoring of the patient with COVID-19. †Failure of a prior antiviral is defined as a documented lack of clinical response, plus evidence of persisting positivity for SARS-CoV-2 in an appropriate biological sample, determined by a regulatory approved test, collected no more than 3 days prior to study randomisation, with either a Ct value ≤ 30 (RT-PCR) or a positive antigen test. ‡Contraindication, absence of labelled indication, guidelines or drug unavailability. 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)]. 6.Females of childbearing potential must have a negative serum or urine pregnancy test by local laboratory at study enrolment and must be non-lactating. 7.Females of child-bearing potential must use highly effective contraceptive methods, while on study treatment and for 6 months after last dose of plitidepsin. Fertile males with partners of child bearing potential must use effective contraception while on study treatment and for 6 months after last dose of plitidepsin (See Appendix 2 - Contraception and pregnancy testing). Patients in the control arm must follow contraception methods 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 highly effective contraception for at least one week after the study completion (females of child-bearing potential) and effective (fertile males with partners of child-bearing potential) 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 6 months*. Includes (but is not limited to): o Monoclonal antibodies (mAbs) targeting CD19, CD20, CD38 or CD52 (e.g., rituximab, ocrelizumab, ofatumumab, daratumumab alemtuzumab). 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). *Time restriction is NA for CAR-T cell therapy. 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 neoplasia or myelodysplasia not currently receiving any therapy o Other situations with a documentation of ALC < 500 cells/µL. * NA in Spain.

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. Criterion eliminated and merged with inclusion criterion #4, based on AEMPS recommendations. 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 (<50%), Current clinical evidence of heart failure or acute cardiac ischaemia (New York Heart Association (NYHA) class III-IV). 4. Hypersensitivity to the active ingredient or any of the excipients (mannitol, macrogolglycerol hydroxystearate, and ethanol) or contraindication to receive dexamethasone, antihistamine H1/H2, or anti-serotoninergic 5HT3 agents. 5. Females who are pregnant or breast-feeding. 6. Females and males with partners of childbearing 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. 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 drug within 30 days prior to screening.

2

Pharma Mar, S.A.

18

100

Georgia;Israel;United Kingdom;Belgium;France;Greece;Hungary;Italy;Poland;Portugal;Spain

High risk patients

N/A

16

Efficacy primary endpoint 1-Month all-cause mortality rate.

Declared number of arm (2.0) differs from found arms (1.0)

Phase 2

[{"arm_notes": "Dose 1", "treatment_id": 1003, "treatment_name": "Plitidepsin", "treatment_type": "Others pharmacological treatment", "pharmacological_treatment": "Pharmacological treatment"}, {"arm_notes": "Dose 2", "treatment_id": 1003, "treatment_name": "Plitidepsin", "treatment_type": "Others pharmacological treatment", "pharmacological_treatment": "Pharmacological treatment"}]