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

COVID-19 Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04382066
• Other study ID #: APL-D-002-20
• Secondary ID: 2020-001993-31
• Status: Completed
• Phase: Phase 1
• Start date: May 12, 2020
• Est. completion date: November 26, 2020

Study information

• Verified date: July 2022
• Source: PharmaMar
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: November 26, 2020
• Est. primary completion date: November 26, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• COVID-19

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
Spain	Hospital Germans Trias i Pujol	Badalona
Spain	Hospital Clínic de Barcelona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitario Hm Montepríncipe	Boadilla Del Monte	Madrid
Spain	Hospital Ciudad Real	Ciudad Real
Spain	Hospital Universitario de Getafe	Getafe
Spain	Hospital Universitario de Guadalajara	Guadalajara
Spain	Hospital Universitari Arnau de Vilanova	Lleida
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital Gregorio Marañón	Madrid
Spain	Hospital La Princesa	Madrid
Spain	Hospital Ramón Y Cajal	Madrid
Spain	Hosptial Quironsalud Madrid	Madrid

Sponsors (2)

Lead Sponsor	Collaborator
PharmaMar	Apices Soluciones S.L.

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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.
Primary	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
Primary	Percentage of Patients With Adverse Events.	Percentage of patients with adverse events.	At days 3, 7, 15 and 31
Primary	Percentage of Patients With Serious Adverse Events.	Percentage of patients with serious adverse events.	At days 3, 7, 15 and 31
Primary	Percentage of Patients With ECG Abnormalities.	Percentage of patients with ECG abnormalities.	At days 2, 3, 4, 5, 6, 7, 15 and 31
Secondary	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
Secondary	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
Secondary	Mortality	Percentage of patients who die during the study	At days 7, 15 and 31
Secondary	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
Secondary	Percentage of Patients Requiring Non-invasive Mechanical Ventilation	Percentage of patients requiring non-invasive mechanical ventilation	At days 7, 15 and 31
Secondary	Percentage of Patients Requiring Oxygen Therapy	Percentage of patients requiring oxygen therapy	At days 7, 15 and 31