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

• ClinicalTrials.gov Identifier: NCT04382066
• Recruitment Status: Completed
• First Posted: May 11, 2020
• Results First Posted: September 24, 2021
• Last Update Posted: August 23, 2022
• Sponsor: PharmaMar
• Collaborator: Apices Soluciones S.L.
• Information provided by (Responsible Party): PharmaMar

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.

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: Plitidepsin 1.5 mg/day; Drug: Plitidepsin 2.0 mg/day; Drug: Plitidepsin 2.5 mg/day	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 12, 2020
• Actual Primary Completion Date: November 26, 2020
• Actual Study Completion Date: November 26, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Experimental 1; Plitidepsin 1.5 mg / day x 3 consecutive days	Drug: Plitidepsin 1.5 mg/day; 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.
Experimental: Experimental 2; Plitidepsin 2.0 mg / day x 3 consecutive days	Drug: Plitidepsin 2.0 mg/day; 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.
Experimental: Experimental 3; Plitidepsin 2.5 mg / day x 3 consecutive days	Drug: Plitidepsin 2.5 mg/day; 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.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

Spain

Hospital Universitario Hm Montepríncipe

Boadilla Del Monte, Madrid, Spain, 28660

Hospital Germans Trias i Pujol

Badalona, Spain, 08916

Hospital Clínic de Barcelona

Barcelona, Spain, 08036

Hospital de la Santa Creu i Sant Pau

Barcelona, Spain, 08041

Hospital Ciudad Real

Ciudad Real, Spain, 13005

Hospital Universitario de Getafe

Getafe, Spain, 28905

Hospital Universitario de Guadalajara

Guadalajara, Spain, 19002

Hospital Universitari Arnau de Vilanova

Lleida, Spain, 25198

Hospital La Princesa

Madrid, Spain, 28006

Hospital Gregorio Marañón

Madrid, Spain, 28009

Hospital Ramón Y Cajal

Madrid, Spain, 28034

Hospital Clínico San Carlos

Madrid, Spain, 28040

Hosptial Quironsalud Madrid

Madrid, Spain, 28223

Sponsors and Collaborators

PharmaMar

Apices Soluciones S.L.

Investigators

• Principal Investigator: Vicente Estrada, MD; Hospital San Carlos, Madrid
• Principal Investigator: Jesús Fortún, MD; Hospital Universitario Ramon y Cajal
• Principal Investigator: José Barberán, MD; HOSPITAL UNIVERSITARIO HM MONTEPRÍNCIPE

  Study Documents (Full-Text)

Documents provided by PharmaMar:

Study Protocol  [PDF] September 29, 2020

Statistical Analysis Plan  [PDF] March 22, 2021

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: PharmaMar
• ClinicalTrials.gov Identifier: NCT04382066
• Other Study ID Numbers: APL-D-002-20; 2020-001993-31 ( EudraCT Number )
• First Posted: May 11, 2020
• Results First Posted: September 24, 2021
• Last Update Posted: August 23, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Data of the final publication of the study will be shared upon request.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by PharmaMar:

Plitidepsin; COVID-19; SARS-COV-2; Coronavirus

Additional relevant MeSH terms:

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases