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NCT Number: NCT04382066

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

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.

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Key information

Conditions

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

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Hospital Universitario Hm Montepríncipe, Boadilla del Monte, Madrid, Spain

Loading trial locations.

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Plitidepsin 1.5 mg/day

Drug

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.

Plitidepsin 2.0 mg/day

Drug

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.

Plitidepsin 2.5 mg/day

Drug

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 outcomes

  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 outcomes

  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

Sponsors and collaborators

Lead sponsor

PharmaMar

Industry

Collaborators

  • Apices Soluciones S.L.

Registry information

Official study 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

Acronym: APLICOV-PC

Important dates

Study start
2020
Primary completion
2020
Study completion
2020
First posted
May 11, 2020
Registry last updated
Aug 23, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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