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

NCT04382066 | Completed Phase 1 Results

• 2 other identifiers: APL-D-002-202020-001993-31
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 13

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.

Conditions

COVID-19

Keywords

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

Outcome Measures

Primary Outcomes (14)

• 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 Outcomes (6)

• Change in the Viral Load of SARS-CoV-2

  At days 4, 7, 15 and 31

• Time to Negative PCR Test for COVID-19

  Up to 31 days + 3 days for window period

• Mortality

  At days 7, 15 and 31

• 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

  At days 7, 15 and 31

Study Arms (3)

Experimental 1

EXPERIMENTAL

Plitidepsin 1.5 mg / day x 3 consecutive days

Drug: Plitidepsin 1.5 mg/day

Experimental 2

EXPERIMENTAL

Plitidepsin 2.0 mg / day x 3 consecutive days

Drug: Plitidepsin 2.0 mg/day

Experimental 3

EXPERIMENTAL

Plitidepsin 2.5 mg / day x 3 consecutive days

Drug: Plitidepsin 2.5 mg/day

Interventions

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.

Experimental 1

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.

Experimental 2

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.

Experimental 3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• PharmaMar: lead
• Apices Soluciones S.L.: collaborator

Study Sites (13)

Hospital Universitario Hm Montepríncipe

Boadilla del Monte, Madrid, 28660, Spain

Location

Hospital Germans Trias i Pujol

Badalona, 08916, Spain

Location

Hospital Clínic de Barcelona

Barcelona, 08036, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, 08041, Spain

Location

Hospital Ciudad Real

Ciudad Real, 13005, Spain

Location

Hospital Universitario de Getafe

Getafe, 28905, Spain

Location

Hospital Universitario de Guadalajara

Guadalajara, 19002, Spain

Location

Hospital Universitari Arnau de Vilanova

Lleida, 25198, Spain

Location

Hospital La Princesa

Madrid, 28006, Spain

Location

Hospital Gregorio Marañón

Madrid, 28009, Spain

Location

Hospital Ramón Y Cajal

Madrid, 28034, Spain

Location

Hospital Clínico San Carlos

Madrid, 28040, Spain

Location

Hosptial Quironsalud Madrid

Madrid, 28223, Spain

Location

Related Publications (1)

• 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.

  PMID: 35012962 DERIVED

MeSH Terms

Conditions

COVID-19; Coronavirus Infections

Interventions

plitidepsin

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Limitations and Caveats

Small number of patients. No control group.

Results Point of Contact

• Title: Clinical Development Virology Business Unit PharmaMar
• Organization: PharmaMar, S.A.

clinicaltrials@pharmamar.com

+34 91 846 60 00

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 7, 2020
• First Posted: May 11, 2020
• Study Start: May 12, 2020
• Primary Completion: November 26, 2020
• Study Completion: November 26, 2020
• Last Updated: August 23, 2022
• Results First Posted: September 24, 2021

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will share

Locations

ES (13)