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

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

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.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Plitidepsin 1.5 mg/day; Drug: Plitidepsin 2.0 mg/day; Drug: Plitidepsin 2.5 mg/day

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 Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 1

Contacts and Locations

Study Locations

• Spain
  • Badalona, Spain, 08916
    • Hospital Germans Trias i Pujol
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau
  • Ciudad Real, Spain, 13005
    • Hospital Ciudad Real
  • Getafe, Spain, 28905
    • Hospital Universitario de Getafe
  • Guadalajara, Spain, 19002
    • Hospital Universitario de Guadalajara
  • Lleida, Spain, 25198
    • Hospital Universitari Arnau de Vilanova
  • Madrid, Spain, 28009
    • Hospital Gregorio Marañón
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal
  • Madrid, Spain, 28006
    • Hospital La Princesa
  • Madrid, Spain, 28223
    • Hosptial Quironsalud Madrid
  • Madrid
    • Boadilla Del Monte, Madrid, Spain, 28660
      • Hospital Universitario HM Monteprincipe

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: PharmaMar
• Collaborators: 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 Monteprincipe

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2020
• Primary Completion (Actual): November 26, 2020
• Study Completion (Actual): November 26, 2020

Study Registration Dates

• First Submitted: May 7, 2020
• First Submitted That Met QC Criteria: May 8, 2020
• First Posted (Actual): May 11, 2020

Study Record Updates

• Last Update Posted (Actual): August 23, 2022
• Last Update Submitted That Met QC Criteria: July 28, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Coronavirus; COVID-19; SARS-COV-2; Plitidepsin
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: APL-D-002-20; 2020-001993-31 (EudraCT Number)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No