Clinical trial NCT04382066: Proof of Concept Study to Evaluate the Safety Profile of Plitidepsin in Patients With COVID-19
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: COVID-19
Keywords: Plitidepsin
COVID-19
SARS-COV-2
Coronavirus
Lead sponsor: PharmaMar
Sponsor class: INDUSTRY
Collaborators: name: Apices Soluciones S.L.
First posted: 2020-05-11
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Frequency of Occurrence of Neutropenia ≥ Grade 3
timeFrame: At days 3, 7, 15 and 31
measure: Frequency of Occurrence of Thrombocytopenia ≥ Grade 3
timeFrame: At days 3, 7, 15 and 31
measure: Frequency of Occurrence of Anemia ≥ Grade 3
timeFrame: At days 3, 7, 15 and 31
measure: Frequency of Occurrence of Lymphopenia ≥ Grade 3
timeFrame: At days 3, 7, 15 and 31
measure: Frequency of Occurrence of CPK Increase ≥ Grade 3
timeFrame: At days 3, 7, 15 and 31
measure: Frequency of Occurrence of Increase ALT and / or AST ≥ Grade 3
timeFrame: At days 3, 7, 15 and 31
measure: Frequency of Occurrence of Increase Total Bilirubin or Direct Bilirubin ≥ Grade 3
timeFrame: At days 3, 7, 15 and 31
measure: Frequency of Occurrence of Neurotoxicity ≥ Grade 3
timeFrame: At days 3, 7, 15 and 31
measure: Frequency of Occurrence of QT-QTc Interval Extension ≥ Grade 3
timeFrame: At days 3, 7, 15 and 31
measure: Frequency of Occurrence of Other Adverse Events ≥ Grade 3
timeFrame: At days 3, 7, 15 and 31.
measure: Percentage of Patients in Whom Treatment Cannot be Completed.
timeFrame: At 3 days from the first dose of study treatment
measure: Percentage of Patients With Adverse Events.
timeFrame: At days 3, 7, 15 and 31
measure: Percentage of Patients With Serious Adverse Events.
timeFrame: At days 3, 7, 15 and 31
measure: Percentage of Patients With ECG Abnormalities.
timeFrame: At days 2, 3, 4, 5, 6, 7, 15 and 31
Secondary outcomes:
measure: Change in the Viral Load of SARS-CoV-2
timeFrame: At days 4, 7, 15 and 31
measure: Time to Negative PCR Test for COVID-19
timeFrame: Up to 31 days + 3 days for window period
measure: Mortality
timeFrame: At days 7, 15 and 31
measure: Percentage of Patients Requiring Invasive Mechanical Ventilation and / or ICU Admission
timeFrame: At days 7, 15 and 31
measure: Percentage of Patients Requiring Non-invasive Mechanical Ventilation
timeFrame: At days 7, 15 and 31
measure: Percentage of Patients Requiring Oxygen Therapy
timeFrame: At days 7, 15 and 31
Other outcomes:
Locations:
city: Boadilla Del Monte
country: Spain
facility: Hospital Universitario Hm Montepríncipe
state: Madrid
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Ciudad Real
country: Spain
facility: Hospital Ciudad Real
city: Getafe
country: Spain
facility: Hospital Universitario de Getafe
city: Guadalajara
country: Spain
facility: Hospital Universitario de Guadalajara
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova
city: Madrid
country: Spain
facility: Hospital La Princesa
city: Madrid
country: Spain
facility: Hospital Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Ramón Y Cajal
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hosptial Quironsalud Madrid
Study officials:
affiliation: Hospital San Carlos, Madrid
name: Vicente Estrada, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Ramon y Cajal
name: Jesús Fortún, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: HOSPITAL UNIVERSITARIO HM MONTEPRÍNCIPE
name: José Barberán, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Varona JF, Landete P, Lopez-Martin JA, Estrada V, Paredes R, Guisado-Vasco P, Fernandez de Orueta L, Torralba M, Fortun J, Vates R, Barberan J, Clotet B, Ancochea J, Carnevali D, Cabello N, Porras L, Gijon P, Monereo A, Abad D, Zuniga S, Sola I, Rodon J, Vergara-Alert J, Izquierdo-Useros N, Fudio S, Pontes MJ, de Rivas B, Giron de Velasco P, Nieto A, Gomez J, Aviles P, Lubomirov R, Belgrano A, Sopesen B, White KM, Rosales R, Yildiz S, Reuschl AK, Thorne LG, Jolly C, Towers GJ, Zuliani-Alvarez L, Bouhaddou M, Obernier K, McGovern BL, Rodriguez ML, Enjuanes L, Fernandez-Sousa JM, Krogan NJ, Jimeno JM, Garcia-Sastre A. Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19. Life Sci Alliance. 2022 Jan 10;5(4):e202101200. doi: 10.26508/lsa.202101200. Print 2022 Apr.