Proof of Concept Study to Evaluate the Safety Profile of Plitidepsin in Patients With COVID-19
Condition: COVID-19
MeSH terms: COVID-19
Intervention: Plitidepsin 1.5 mg/day; Plitidepsin 2.0 mg/day; Plitidepsin 2.5 mg/day
Intervention description: Plitidepsin 1.5 mg/day will be IV infused through a pump device over 1 hour and 30 minutes, 3 consecutive days.
All patients must receive the following prophylactic medications 20-30 minutes before the infusion of plitidepsin:
Diphenhydramine hydrochloride 25 mg iv or equivalent.
Ranitidine 50 mg iv or equivalent.
Dexamethasone 8 mg iv.
Ondansetron 8 mg i.v. 15 minutes infusion or equivalent.
Ondansetron 4 mg p.o. administered every 12 hours until 48 hours after the last administration of plitidepsin.; Plitidepsin 2.0 mg/day will be IV infused through a pump device over 1 hour and 30 minutes, 3 consecutive days.
All patients must receive the following prophylactic medications 20-30 minutes before the infusion of plitidepsin:
Diphenhydramine hydrochloride 25 mg iv or equivalent.
Ranitidine 50 mg iv or equivalent.
Dexamethasone 8 mg iv.
Ondansetron 8 mg i.v. 15 minutes infusion or equivalent.
Ondansetron 4 mg p.o. administered every 12 hours until 48 hours after the last administration of plitidepsin.; Plitidepsin 2.5 mg/day will be IV infused through a pump device over 1 hour and 30 minutes, 3 consecutive days.
All patients must receive the following prophylactic medications 20-30 minutes before the infusion of plitidepsin:
Diphenhydramine hydrochloride 25 mg iv or equivalent.
Ranitidine 50 mg iv or equivalent.
Dexamethasone 8 mg iv.
Ondansetron 8 mg i.v. 15 minutes infusion or equivalent.
Ondansetron 4 mg p.o. administered every 12 hours until 48 hours after the last administration of plitidepsin.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 46.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Plitidepsin; COVID-19; SARS-COV-2; Coronavirus

Summary:

      In December 2019, Wuhan, in Hubei province, China, became the center of an outbreak of
      pneumonia of unknown cause. In a short time, Chinese scientists had shared the genome
      information of a novel coronavirus (SARS-CoV-2) from these pneumonia patients and developed a
      real-time reverse transcription PCR (real-time RT-PCR) diagnostic assay.

      Given no specific antiviral therapy for COVID-19 and the ready availability of plitidepsin as
      a potential antiviral agent, based on pre-clinical studies, this randomized, parallel and
      proof of concept trial will evaluate the safety of three doses of plitidepsin in patients
      hospitalized with COVID-19.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patient who agrees to participate in the study by signing the informed consent.

          2. Men and women (non-pregnant) aged ≥18 years.

          3. COVID-19 infection confirmed by PCR obtained from nasopharyngeal exudate or sample
             from the lower respiratory tract.

          4. Patients who require hospitalization for COVID-19.

          5. Symptom onset at most within 10 days prior to study inclusion.

          6. Men and women with reproductive capacity should agree to use highly effective
             contraceptive methods during their participation in the study and in the 6 months
             following the last administration of plitidepsin.

          7. In addition, women participating in the study with reproductive ability must have a
             negative pregnancy test at enrollment.

        Exclusion Criteria:

          1. Patients participating in some other clinical trial for COVID-19 infection.

          2. Patients who are receiving treatment with antivirals, interleukin 6 receptor
             inhibitors or immunomodulatory drugs for COVID-19.

          3. Patients who are receiving treatment with chloroquine and derivatives.

          4. Evidence of multi-organ failure.

          5. Patients who require support with mechanical ventilation (invasive or non-invasive) at
             the time of inclusion.

          6. D-dimer> 4 x UNL.

          7. Hb <9 g / dL.

          8. Neutrophils <1000 / mm3.

          9. Platelets <100,000 / mm3.

         10. Lymphopenia <800 / μL.

         11. GOT / GPT> 3 X UNL.

         12. Bilirubin> 1 X UNL.

         13. CPK> 2.5 X UNL.

         14. Creatinine clearance <30ml / min.

         15. Troponin elevation> 1.5 x ULN.

         16. Clinically relevant heart disease (NYHA> 2).

         17. Clinically relevant arrhythmia or previous history / presence of prolonged QT-QTc ≥
             450 ms.

         18. Pre-existing neuropathies of any type ≥ grade 2.

         19. Hypersensitivity to the active substance or to any of its excipients (macrogol
             glycerol ricinoleate and ethanol).

         20. Patients who require or are being treated with potent CYP3A4 inhibitors and inducers.

         21. Patients who for any reason should not be included in the study according to the
             evaluation of the research team.