Proof of Concept Study to Evaluate the Safety Profile of Plitidepsin in Patients With COVID-19 (APLICOV-PC)
Primary Purpose
COVID-19
Status
Completed
Phase
Phase 1
Locations
Spain
Study Type
Interventional
Intervention
Plitidepsin 1.5 mg/day
Plitidepsin 2.0 mg/day
Plitidepsin 2.5 mg/day
Sponsored by
About this trial
This is an interventional treatment trial for COVID-19 focused on measuring Plitidepsin, COVID-19, SARS-COV-2, Coronavirus
Eligibility Criteria
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.
Sites / Locations
- Hospital Universitario Hm Montepríncipe
- Hospital Germans Trias i Pujol
- Hospital Clínic de Barcelona
- Hospital de la Santa Creu i Sant Pau
- Hospital Ciudad Real
- Hospital Universitario de Getafe
- Hospital Universitario de Guadalajara
- Hospital Universitari Arnau de Vilanova
- Hospital La Princesa
- Hospital Gregorio Marañón
- Hospital Ramón Y Cajal
- Hospital Clínico San Carlos
- Hosptial Quironsalud Madrid
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Experimental 1
Experimental 2
Experimental 3
Arm Description
Plitidepsin 1.5 mg / day x 3 consecutive days
Plitidepsin 2.0 mg / day x 3 consecutive days
Plitidepsin 2.5 mg / day x 3 consecutive days
Outcomes
Primary Outcome Measures
Frequency of Occurrence of Neutropenia ≥ Grade 3
Percentage of patients with Neutropenia ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Frequency of Occurrence of Thrombocytopenia ≥ Grade 3
Percentage of patients with Thrombocytopenia ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Frequency of Occurrence of Anemia ≥ Grade 3
Percentage of patients with Anemia ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Frequency of Occurrence of Lymphopenia ≥ Grade 3
Percentage of patients with Lymphopenia ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Frequency of Occurrence of CPK Increase ≥ Grade 3
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
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
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
Percentage of patients with Neurotoxicity ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
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.
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.
Percentage of Patients in Whom Treatment Cannot be Completed.
Percentage of patients in whom treatment cannot be completed and the reasons.
Percentage of Patients With Adverse Events.
Percentage of patients with adverse events.
Percentage of Patients With Serious Adverse Events.
Percentage of patients with serious adverse events.
Percentage of Patients With ECG Abnormalities.
Percentage of patients with ECG abnormalities.
Secondary Outcome Measures
Change in the Viral Load of SARS-CoV-2
Median change in the viral load of SARS-CoV-2 from baseline.
Time to Negative PCR Test for COVID-19
Time from inclusion/randomization to date of negative PCR test for COVID-19
Mortality
Percentage of patients who die during the study
Percentage of Patients Requiring Invasive Mechanical Ventilation and / or ICU Admission
Percentage of patients requiring invasive mechanical ventilation and / or ICU admission
Percentage of Patients Requiring Non-invasive Mechanical Ventilation
Percentage of patients requiring non-invasive mechanical ventilation
Percentage of Patients Requiring Oxygen Therapy
Percentage of patients requiring oxygen therapy
Full Information
NCT ID
NCT04382066
First Posted
May 7, 2020
Last Updated
July 28, 2022
Sponsor
PharmaMar
Collaborators
Apices Soluciones S.L.
1. Study Identification
Unique Protocol Identification Number
NCT04382066
Brief Title
Proof of Concept Study to Evaluate the Safety Profile of Plitidepsin in Patients With COVID-19
Acronym
APLICOV-PC
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
2. Study Status
Record Verification Date
July 2022
Overall Recruitment Status
Completed
Study Start Date
May 12, 2020 (Actual)
Primary Completion Date
November 26, 2020 (Actual)
Study Completion Date
November 26, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
PharmaMar
Collaborators
Apices Soluciones S.L.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19
Keywords
Plitidepsin, COVID-19, SARS-COV-2, Coronavirus
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
46 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Experimental 1
Arm Type
Experimental
Arm Description
Plitidepsin 1.5 mg / day x 3 consecutive days
Arm Title
Experimental 2
Arm Type
Experimental
Arm Description
Plitidepsin 2.0 mg / day x 3 consecutive days
Arm Title
Experimental 3
Arm Type
Experimental
Arm Description
Plitidepsin 2.5 mg / day x 3 consecutive days
Intervention Type
Drug
Intervention Name(s)
Plitidepsin 1.5 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.
Intervention Type
Drug
Intervention Name(s)
Plitidepsin 2.0 mg/day
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Plitidepsin 2.5 mg/day
Intervention Description
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.
Primary Outcome Measure Information:
Title
Frequency of Occurrence of Neutropenia ≥ Grade 3
Description
Percentage of patients with Neutropenia ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Time Frame
At days 3, 7, 15 and 31
Title
Frequency of Occurrence of Thrombocytopenia ≥ Grade 3
Description
Percentage of patients with Thrombocytopenia ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Time Frame
At days 3, 7, 15 and 31
Title
Frequency of Occurrence of Anemia ≥ Grade 3
Description
Percentage of patients with Anemia ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Time Frame
At days 3, 7, 15 and 31
Title
Frequency of Occurrence of Lymphopenia ≥ Grade 3
Description
Percentage of patients with Lymphopenia ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Time Frame
At days 3, 7, 15 and 31
Title
Frequency of Occurrence of CPK Increase ≥ Grade 3
Description
Percentage of patients with CPK increase ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Time Frame
At days 3, 7, 15 and 31
Title
Frequency of Occurrence of Increase ALT and / or AST ≥ Grade 3
Description
Percentage of patients with Increase ALT and / or AST ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Time Frame
At days 3, 7, 15 and 31
Title
Frequency of Occurrence of Increase Total Bilirubin or Direct Bilirubin ≥ Grade 3
Description
Percentage of patients with Increase total bilirubin or direct bilirubin ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Time Frame
At days 3, 7, 15 and 31
Title
Frequency of Occurrence of Neurotoxicity ≥ Grade 3
Description
Percentage of patients with Neurotoxicity ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Time Frame
At days 3, 7, 15 and 31
Title
Frequency of Occurrence of QT-QTc Interval Extension ≥ Grade 3
Description
Percentage of patients with QT-QTc interval extension ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Time Frame
At days 3, 7, 15 and 31
Title
Frequency of Occurrence of Other Adverse Events ≥ Grade 3
Description
Percentage of patients with Other adverse events ≥ grade 3 according to NCI-CTCAE v5.0 criteria.
Time Frame
At days 3, 7, 15 and 31.
Title
Percentage of Patients in Whom Treatment Cannot be Completed.
Description
Percentage of patients in whom treatment cannot be completed and the reasons.
Time Frame
At 3 days from the first dose of study treatment
Title
Percentage of Patients With Adverse Events.
Description
Percentage of patients with adverse events.
Time Frame
At days 3, 7, 15 and 31
Title
Percentage of Patients With Serious Adverse Events.
Description
Percentage of patients with serious adverse events.
Time Frame
At days 3, 7, 15 and 31
Title
Percentage of Patients With ECG Abnormalities.
Description
Percentage of patients with ECG abnormalities.
Time Frame
At days 2, 3, 4, 5, 6, 7, 15 and 31
Secondary Outcome Measure Information:
Title
Change in the Viral Load of SARS-CoV-2
Description
Median change in the viral load of SARS-CoV-2 from baseline.
Time Frame
At days 4, 7, 15 and 31
Title
Time to Negative PCR Test for COVID-19
Description
Time from inclusion/randomization to date of negative PCR test for COVID-19
Time Frame
Up to 31 days + 3 days for window period
Title
Mortality
Description
Percentage of patients who die during the study
Time Frame
At days 7, 15 and 31
Title
Percentage of Patients Requiring Invasive Mechanical Ventilation and / or ICU Admission
Description
Percentage of patients requiring invasive mechanical ventilation and / or ICU admission
Time Frame
At days 7, 15 and 31
Title
Percentage of Patients Requiring Non-invasive Mechanical Ventilation
Description
Percentage of patients requiring non-invasive mechanical ventilation
Time Frame
At days 7, 15 and 31
Title
Percentage of Patients Requiring Oxygen Therapy
Description
Percentage of patients requiring oxygen therapy
Time Frame
At days 7, 15 and 31
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vicente Estrada, MD
Organizational Affiliation
Hospital San Carlos, Madrid
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jesús Fortún, MD
Organizational Affiliation
Hospital Universitario Ramon y Cajal
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
José Barberán, MD
Organizational Affiliation
HOSPITAL UNIVERSITARIO HM MONTEPRÍNCIPE
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Universitario Hm Montepríncipe
City
Boadilla Del Monte
State/Province
Madrid
ZIP/Postal Code
28660
Country
Spain
Facility Name
Hospital Germans Trias i Pujol
City
Badalona
ZIP/Postal Code
08916
Country
Spain
Facility Name
Hospital Clínic de Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Hospital de la Santa Creu i Sant Pau
City
Barcelona
ZIP/Postal Code
08041
Country
Spain
Facility Name
Hospital Ciudad Real
City
Ciudad Real
ZIP/Postal Code
13005
Country
Spain
Facility Name
Hospital Universitario de Getafe
City
Getafe
ZIP/Postal Code
28905
Country
Spain
Facility Name
Hospital Universitario de Guadalajara
City
Guadalajara
ZIP/Postal Code
19002
Country
Spain
Facility Name
Hospital Universitari Arnau de Vilanova
City
Lleida
ZIP/Postal Code
25198
Country
Spain
Facility Name
Hospital La Princesa
City
Madrid
ZIP/Postal Code
28006
Country
Spain
Facility Name
Hospital Gregorio Marañón
City
Madrid
ZIP/Postal Code
28009
Country
Spain
Facility Name
Hospital Ramón Y Cajal
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Facility Name
Hospital Clínico San Carlos
City
Madrid
ZIP/Postal Code
28040
Country
Spain
Facility Name
Hosptial Quironsalud Madrid
City
Madrid
ZIP/Postal Code
28223
Country
Spain
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Data of the final publication of the study will be shared upon request.
Citations:
PubMed Identifier
35012962
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.
Results Reference
derived
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Proof of Concept Study to Evaluate the Safety Profile of Plitidepsin in Patients With COVID-19
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