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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04382066
Recruitment Status : Recruiting
First Posted : May 11, 2020
Last Update Posted : May 15, 2020
Sponsor:
Collaborator:
Apices Soluciones S.L.
Information provided by (Responsible Party):
PharmaMar

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:

Last December, 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 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
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : November 2020

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.

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.

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.




Primary Outcome Measures :
  1. Frequency of occurrence of Neutropenia ≥ grade 3 [ Time Frame: Up to 31 days ]
    Percentage of patients with Neutropenia ≥ grade 3

  2. Frequency of occurrence of Thrombocytopenia ≥ grade 3 [ Time Frame: Up to 31 days ]
    Percentage of patients with Thrombocytopenia ≥ grade 3

  3. Frequency of occurrence of Anemia ≥ grade 3 [ Time Frame: Up to 31 days ]
    Percentage of patients with Anemia ≥ grade 3

  4. Frequency of occurrence of Lymphopenia ≥ grade 3 [ Time Frame: Up to 31 days ]
    Percentage of patients with Lymphopenia ≥ grade 3

  5. Frequency of occurrence of CPK increase ≥ grade 3 [ Time Frame: Up to 31 days ]
    Percentage of patients with CPK increase ≥ grade 3

  6. Frequency of occurrence of Increase ALT and / or AST ≥ grade 3 [ Time Frame: Up to 31 days ]
    Percentage of patients with Increase ALT and / or AST ≥ grade 3

  7. Frequency of occurrence of Increase total bilirubin or direct bilirubin ≥ grade 3 [ Time Frame: Up to 31 days ]
    Percentage of patients with Increase total bilirubin or direct bilirubin ≥ grade 3

  8. Frequency of occurrence of Neurotoxicity ≥ grade 3 [ Time Frame: Up to 31 days ]
    Percentage of patients with Neurotoxicity ≥ grade 3

  9. Frequency of occurrence of QT-QTc interval extension ≥ grade 3 [ Time Frame: Up to 31 days ]
    Percentage of patients with QT-QTc interval extension ≥ grade 3

  10. Frequency of occurrence of Other adverse events ≥ grade 3 [ Time Frame: Up to 31 days ]
    Percentage of patients with Other adverse events ≥ grade 3

  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: Up to 31 days ]
    Percentage of patients with adverse events.

  13. Percentage of patients with serious adverse events. [ Time Frame: Up to 31 days ]
    Percentage of patients with serious adverse events.

  14. Percentage of patients with ECG abnormalities. [ Time Frame: Up to 31 days ]
    Percentage of patients with ECG abnormalities.


Secondary Outcome Measures :
  1. Change in the viral load of SARS-CoV-2 [ Time Frame: Up to 31 days ]
    Percentage of 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 ]
    Time from inclusion/randomization to date of negative PCR test for COVID-19

  3. Mortality [ Time Frame: Up to 31 days ]
    Percentage of patients who die during the study

  4. Percentage of patients requiring invasive mechanical ventilation and / or ICU admission [ Time Frame: Up to 31 days ]
    Percentage of patients requiring invasive mechanical ventilation and / or ICU admission

  5. Percentage of patients requiring non-invasive mechanical ventilation [ Time Frame: Up to 31 days ]
    Percentage of patients requiring non-invasive mechanical ventilation

  6. Percentage of patients requiring oxygen therapy [ Time Frame: Up to 31 days ]
    Percentage of patients requiring oxygen therapy



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 6 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> 1500 ng / ml.
  7. Hb <9 g / dL.
  8. Neutrophils <1000 / mm3.
  9. Platelets <100,000 / mm3.
  10. Lymphopenia <1200 / μL.
  11. GOT / GPT> 3 X LSN.
  12. Bilirubin> 1 X LSN.
  13. CPK> 2.5 X LSN.
  14. Creatinine clearance <30ml / min.
  15. Troponin elevation> 1.5 x ULN.
  16. Coagulation parameters outside normal limits, except D-dimer.
  17. Clinically relevant heart disease (NYHA> 2).
  18. Clinically relevant arrhythmia or previous history / presence of prolonged QT-QTc ≥ 450 ms.
  19. Pre-existing neuropathies of any type ≥ grade 2.
  20. Hypersensitivity to the active substance or to any of its excipients (macrogol glycerol ricinoleate and ethanol).
  21. Patients who require or are being treated with potent CYP3A4 inhibitors and inducers.
  22. Patients who for any reason should not be included in the study according to the evaluation of the research team.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04382066


Contacts
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Contact: Maria J Pontes + 34 91 8234631 mjpontes@pharmamar.com
Contact: María A Fores mafores@pharmamar.com

Locations
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Spain
Hospital Universitario Hm Montepríncipe Recruiting
Boadilla Del Monte, Madrid, Spain, 28660
Contact: José Barberán, Md       barberan60@gmail.com   
Principal Investigator: José Barberán, MD         
Hospital Ramón Y Cajal Recruiting
Madrid, Spain, 28034
Contact: Jesús Fortún, MD       fortunabete@gmail.com   
Principal Investigator: Jesús Fortún, MD         
Hospital Clínico San Carlos Recruiting
Madrid, Spain, 28040
Contact: Vicente Estrada, MD       vicente.estrada@salud.madrid.org   
Principal Investigator: Vicente Estrada, MD         
Sponsors and Collaborators
PharmaMar
Apices Soluciones S.L.
Investigators
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Principal Investigator: Vicente Estrada, MD Hospital Clínico San Carlos
Principal Investigator: Jesús Fortún, MD Hospital Universitario Ramon y Cajal
Principal Investigator: José Barberán, MD HOSPITAL UNIVERSITARIO HM MONTEPRÍNCIPE
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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    Key Record Dates
Last Update Posted: May 15, 2020
Last Verified: May 2020
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.

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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