Proof of Concept Study to Evaluate the Safety Profile of Plitidepsin in Patients With COVID-19

Study Overview
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Brief Summary
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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
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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.

Official Title
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Multicenter, Randomized, Parallel and Proof of Concept Study to Evaluate the Safety Profile of Three Doses of Plitidepsin in Patients With COVID-19 Requiring Hospitalization

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Plitidepsin 1.5 mg/day
* Drug: Plitidepsin 2.0 mg/day
* Drug: Plitidepsin 2.5 mg/day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental 1<br>Plitidepsin 1.5 mg / day x 3 consecutive days | Drug: Plitidepsin 1.5 mg/day<br>* 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.<br>|
| Experimental: Experimental 2<br>Plitidepsin 2.0 mg / day x 3 consecutive days | Drug: Plitidepsin 2.0 mg/day<br>* 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.<br>|
| Experimental: Experimental 3<br>Plitidepsin 2.5 mg / day x 3 consecutive days | Drug: Plitidepsin 2.5 mg/day<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Occurrence of Neutropenia ≥ Grade 3 | Percentage of patients with Neutropenia ≥ grade 3 according to NCI-CTCAE v5.0 criteria. | At days 3, 7, 15 and 31 | 
| Frequency of Occurrence of Thrombocytopenia ≥ Grade 3 | Percentage of patients with Thrombocytopenia ≥ grade 3 according to NCI-CTCAE v5.0 criteria. | At days 3, 7, 15 and 31 | 
| Frequency of Occurrence of Anemia ≥ Grade 3 | Percentage of patients with Anemia ≥ grade 3 according to NCI-CTCAE v5.0 criteria. | At days 3, 7, 15 and 31 | 
| Frequency of Occurrence of Lymphopenia ≥ Grade 3 | Percentage of patients with Lymphopenia ≥ grade 3 according to NCI-CTCAE v5.0 criteria. | At days 3, 7, 15 and 31 | 
| Frequency of Occurrence of CPK Increase ≥ Grade 3 | Percentage of patients with CPK increase ≥ grade 3 according to NCI-CTCAE v5.0 criteria. | At days 3, 7, 15 and 31 | 
| Frequency of Occurrence of Increase ALT and / or AST ≥ Grade 3 | Percentage of patients with Increase ALT and / or AST ≥ grade 3 according to NCI-CTCAE v5.0 criteria. | At days 3, 7, 15 and 31 | 
| Frequency of Occurrence of Increase Total Bilirubin or Direct Bilirubin ≥ Grade 3 | Percentage of patients with Increase total bilirubin or direct bilirubin ≥ grade 3 according to NCI-CTCAE v5.0 criteria. | At days 3, 7, 15 and 31 | 
| Frequency of Occurrence of Neurotoxicity ≥ Grade 3 | Percentage of patients with Neurotoxicity ≥ grade 3 according to NCI-CTCAE v5.0 criteria. | At days 3, 7, 15 and 31 | 
| Frequency of Occurrence of QT-QTc Interval Extension ≥ Grade 3 | Percentage of patients with QT-QTc interval extension ≥ grade 3 according to NCI-CTCAE v5.0 criteria. | At days 3, 7, 15 and 31 | 
| Frequency of Occurrence of Other Adverse Events ≥ Grade 3 | Percentage of patients with Other adverse events ≥ grade 3 according to NCI-CTCAE v5.0 criteria. | At days 3, 7, 15 and 31. | 
| Percentage of Patients in Whom Treatment Cannot be Completed. | Percentage of patients in whom treatment cannot be completed and the reasons. | At 3 days from the first dose of study treatment | 
| Percentage of Patients With Adverse Events. | Percentage of patients with adverse events. | At days 3, 7, 15 and 31 | 
| Percentage of Patients With Serious Adverse Events. | Percentage of patients with serious adverse events. | At days 3, 7, 15 and 31 | 
| Percentage of Patients With ECG Abnormalities. | Percentage of patients with ECG abnormalities. | At days 2, 3, 4, 5, 6, 7, 15 and 31 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Viral Load of SARS-CoV-2 | Median change in the viral load of SARS-CoV-2 from baseline. | At days 4, 7, 15 and 31 | 
| Time to Negative PCR Test for COVID-19 | Time from inclusion/randomization to date of negative PCR test for COVID-19 | Up to 31 days + 3 days for window period | 
| Mortality | Percentage of patients who die during the study | At days 7, 15 and 31 | 
| Percentage of Patients Requiring Invasive Mechanical Ventilation and / or ICU Admission | Percentage of patients requiring invasive mechanical ventilation and / or ICU admission | At days 7, 15 and 31 | 
| Percentage of Patients Requiring Non-invasive Mechanical Ventilation | Percentage of patients requiring non-invasive mechanical ventilation | At days 7, 15 and 31 | 
| Percentage of Patients Requiring Oxygen Therapy | Percentage of patients requiring oxygen therapy | At days 7, 15 and 31 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Plitidepsin, COVID-19, SARS-COV-2, Coronavirus