Proof of Concept Study to Evaluate the Safety Profile of Plitidepsin in Patients With COVID-19
- Conditions
- COVID-19
- Interventions
- Registration Number
- NCT04382066
- Lead Sponsor
- PharmaMar
- Brief 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.
- Detailed Description
In December 2019, a new infectious respiratory disease emerged in Wuhan, China. The agent that caused this pneumonia was identified as a new virus in the Coronaviridae family (SARS-CoV-2) and the clinical symptomatology associated with the virus has been named COVID-19. COVID-19 is currently a public health emergency.
Plitidepsin is an authorized drug in Australia for the treatment of multiple myeloma. Antiviral activity of plitidepsin has been analyzed in a human hepatoma cell line infected with the HCoV-229E-GFP virus, a virus similar to the SARS-CoV-2 virus.
Taking into account that the available safety data from plitidepsin comes from patients with solid tumors that received treatment with a regimen of administration of plitidepsin for 5 consecutive days, we propose a multicenter, randomized, proof-of-concept clinical trial to assess the safety profile of 3 different dose levels of plitidepsin administered three consecutive days, in adult patients with confirmed diagnosis of COVID-19 who require hospital admission.
This study aims to assess safety and toxicity profile and also preliminary efficacy of plitidepsin at each dose level administered according to the proposed administration scheme in patients with COVID-19 who require hospital admission. Main objective is to select the recommended dose levels of plitidepsin for a future phase II / III efficacy study.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 46
- Patient who agrees to participate in the study by signing the informed consent.
- Men and women (non-pregnant) aged ≥18 years.
- COVID-19 infection confirmed by PCR obtained from nasopharyngeal exudate or sample from the lower respiratory tract.
- Patients who require hospitalization for COVID-19.
- Symptom onset at most within 10 days prior to study inclusion.
- 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.
- In addition, women participating in the study with reproductive ability must have a negative pregnancy test at enrollment.
- Patients participating in some other clinical trial for COVID-19 infection.
- Patients who are receiving treatment with antivirals, interleukin 6 receptor inhibitors or immunomodulatory drugs for COVID-19.
- Patients who are receiving treatment with chloroquine and derivatives.
- Evidence of multi-organ failure.
- Patients who require support with mechanical ventilation (invasive or non-invasive) at the time of inclusion.
- D-dimer> 4 x UNL.
- Hb <9 g / dL.
- Neutrophils <1000 / mm3.
- Platelets <100,000 / mm3.
- Lymphopenia <800 / μL.
- GOT / GPT> 3 X UNL.
- Bilirubin> 1 X UNL.
- CPK> 2.5 X UNL.
- Creatinine clearance <30ml / min.
- Troponin elevation> 1.5 x ULN.
- Clinically relevant heart disease (NYHA> 2).
- Clinically relevant arrhythmia or previous history / presence of prolonged QT-QTc ≥ 450 ms.
- Pre-existing neuropathies of any type ≥ grade 2.
- Hypersensitivity to the active substance or to any of its excipients (macrogol glycerol ricinoleate and ethanol).
- Patients who require or are being treated with potent CYP3A4 inhibitors and inducers.
- Patients who for any reason should not be included in the study according to the evaluation of the research team.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Experimental 3 Plitidepsin 2.5 mg/day Plitidepsin 2.5 mg / day x 3 consecutive days Experimental 1 Plitidepsin 1.5 mg/day Plitidepsin 1.5 mg / day x 3 consecutive days Experimental 2 Plitidepsin 2.0 mg/day Plitidepsin 2.0 mg / day x 3 consecutive days
- Primary Outcome Measures
Name Time Method Frequency of Occurrence of Neutropenia ≥ Grade 3 At days 3, 7, 15 and 31 Percentage of patients with Neutropenia ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Frequency of Occurrence of Thrombocytopenia ≥ Grade 3 At days 3, 7, 15 and 31 Percentage of patients with Thrombocytopenia ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Frequency of Occurrence of Anemia ≥ Grade 3 At days 3, 7, 15 and 31 Percentage of patients with Anemia ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Frequency of Occurrence of Lymphopenia ≥ Grade 3 At days 3, 7, 15 and 31 Percentage of patients with Lymphopenia ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Frequency of Occurrence of CPK Increase ≥ Grade 3 At days 3, 7, 15 and 31 Percentage of patients with CPK increase ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Frequency of Occurrence of Increase ALT and / or AST ≥ Grade 3 At days 3, 7, 15 and 31 Percentage of patients with Increase ALT and / or AST ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Frequency of Occurrence of Increase Total Bilirubin or Direct Bilirubin ≥ Grade 3 At days 3, 7, 15 and 31 Percentage of patients with Increase total bilirubin or direct bilirubin ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Frequency of Occurrence of Neurotoxicity ≥ Grade 3 At days 3, 7, 15 and 31 Percentage of patients with Neurotoxicity ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Frequency of Occurrence of QT-QTc Interval Extension ≥ Grade 3 At days 3, 7, 15 and 31 Percentage of patients with QT-QTc interval extension ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Frequency of Occurrence of Other Adverse Events ≥ Grade 3 At days 3, 7, 15 and 31. Percentage of patients with Other adverse events ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Percentage of Patients in Whom Treatment Cannot be Completed. At 3 days from the first dose of study treatment Percentage of patients in whom treatment cannot be completed and the reasons.
Percentage of Patients With Adverse Events. At days 3, 7, 15 and 31 Percentage of patients with adverse events.
Percentage of Patients With Serious Adverse Events. At days 3, 7, 15 and 31 Percentage of patients with serious adverse events.
Percentage of Patients With ECG Abnormalities. At days 2, 3, 4, 5, 6, 7, 15 and 31 Percentage of patients with ECG abnormalities.
- Secondary Outcome Measures
Name Time Method Change in the Viral Load of SARS-CoV-2 At days 4, 7, 15 and 31 Median change in the viral load of SARS-CoV-2 from baseline.
Time to Negative PCR Test for COVID-19 Up to 31 days + 3 days for window period Time from inclusion/randomization to date of negative PCR test for COVID-19
Mortality At days 7, 15 and 31 Percentage of patients who die during the study
Percentage of Patients Requiring Invasive Mechanical Ventilation and / or ICU Admission At days 7, 15 and 31 Percentage of patients requiring invasive mechanical ventilation and / or ICU admission
Percentage of Patients Requiring Non-invasive Mechanical Ventilation At days 7, 15 and 31 Percentage of patients requiring non-invasive mechanical ventilation
Percentage of Patients Requiring Oxygen Therapy At days 7, 15 and 31 Percentage of patients requiring oxygen therapy
Trial Locations
- Locations (13)
Hospital Gregorio Marañón
🇪🇸Madrid, Spain
Hospital Clínic de Barcelona
🇪🇸Barcelona, Spain
Hospital Universitario Hm Montepríncipe
🇪🇸Boadilla Del Monte, Madrid, Spain
Hospital Germans Trias i Pujol
🇪🇸Badalona, Spain
Hospital Universitari Arnau de Vilanova
🇪🇸Lleida, Spain
Hospital Universitario de Guadalajara
🇪🇸Guadalajara, Spain
Hospital de la Santa Creu i Sant Pau
🇪🇸Barcelona, Spain
Hospital Ciudad Real
🇪🇸Ciudad Real, Spain
Hospital Universitario de Getafe
🇪🇸Getafe, Spain
Hospital La Princesa
🇪🇸Madrid, Spain
Hospital Clínico San Carlos
🇪🇸Madrid, Spain
Hospital Ramón Y Cajal
🇪🇸Madrid, Spain
Hosptial Quironsalud Madrid
🇪🇸Madrid, Spain