Plitidepsin Versus Control in Immunocompromised Adult Participants With Symptomatic COVID-19 Requiring Hospital Care (NEREIDA)

• ClinicalTrials.gov Identifier: NCT05705167
• Recruitment Status: Terminated
• First Posted: January 30, 2023
• Last Update Posted: April 26, 2024
• Sponsor: PharmaMar
• Information provided by (Responsible Party): PharmaMar

Tracking Information

• First Submitted Date: December 21, 2022
• First Posted Date: January 30, 2023
• Last Update Posted Date: April 26, 2024
• Actual Study Start Date: April 19, 2023
• Actual Primary Completion Date: March 19, 2024 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: January 27, 2023): All-cause Mortality Rate [ Time Frame: Day 1 to Day 30 (±2) ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 8, 2023)

• Key Secondary Outcome Measure: Time to Confirmed Negativisation in SARS-CoV-2 Antigen Test or Real Time Polymerase Chain Reaction (RT-PCR) Cycle Threshold (Ct) > 30 [ Time Frame: Day 1 to Day 60 (±3) ]
• Time to Sustained End of COVID-related Hospital Care [ Time Frame: Day 1 to Day 60 (±3) ]
• Time to Sustained Improvement of Selected COVID-19 Signs/Symptoms. [ Time Frame: Day 1 to Day 60 (±3) ]
• Time to Resolution of Selected COVID-19 Signs/Symptoms [ Time Frame: Day 1 to Day 60 (±3) ]
• Percentage of Participants in Each Category of the World Health Organization (WHO) Clinical Progression Scale [ Time Frame: Days 4 (±1), 8 (±1), 15 (±1), 30 (±2) and 60 (±3) ]
• Percentage of Participants Requiring Oxygen Therapy [ Time Frame: Days 4 (±1), 8 (±1), 15 (±1), 30 (±2) and 60 (±3) ]
• Time to Sustained Discontinuation of Oxygen Supplementation [ Time Frame: Day 1 to Day 60 (±3) ]
• Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE) [ Time Frame: Day 1 to Day 60 (±3) ]
  Frequency of the following events (all-cause and drug-related) are included:

  • TEAEs
  • TEAEs ≥ grade 3 according to the National Cancer Institute [NCI]-Common Terminology Criteria for adverse events (CTCAE v.5.0)
  • Adverse events of special interest (AESIs)
  • Serious adverse events (SAEs)
  • Serious adverse reactions (SARs)
  • Adverse events leading to treatment discontinuation
  • Deaths (related to COVID-19/all)
• Number of Participants with a Clinically Relevant/Significant Change from Baseline in Individual Laboratory Parameters [ Time Frame: Baseline to Day 60 (±3) ]
• Number of Participants with a Clinically Relevant/Significant Change from Baseline in Individual Vital Signs [ Time Frame: Baseline to Day 60 (±3) ]

Original Secondary Outcome Measures (submitted: January 27, 2023)

• Key Secondary Outcome Measure: Time to Confirmed Negativisation in SARS-CoV-2 Antigen Test or Real Time Polymerase Chain Reaction (RT-PCR) Cycle Threshold (Ct) > 30 [ Time Frame: Day 1 to Day 60 (±3) ]
• Time to Sustained End of COVID-related Hospital Care [ Time Frame: Day 1 to Day 60 (±3) ]
• Time to Sustained Improvement of Selected COVID-19 Signs/Symptoms. [ Time Frame: Day 1 to Day 60 (±3) ]
• Time to Resolution of Selected COVID-19 Signs/Symptoms [ Time Frame: Day 1 to Day 60 (±3) ]
• Percentage of Participants in Each Category of the World Health Organization (WHO) Clinical Progression Scale [ Time Frame: Days 4 (±1), 8 (±1), 15 (±1), 30 (±2) and 60 (±3) ]
• Percentage of Participants Requiring Oxygen Therapy [ Time Frame: Days 4 (±1), 8 (±1), 15 (±1), 30 (±2) and 60 (±3) ]
• Time to Sustained Discontinuation of Oxygen Supplementation [ Time Frame: Day 1 to Day 60 (±3) ]
• Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE) [ Time Frame: Day 1 to Day 60 (±3) ]
  Frequency of the following events (all-cause and drug-related) are included:

  • TEAEs
  • TEAEs ≥ grade 3 according to the National Cancer Institute [NCI]-Common Terminology Criteria for adverse events (CTCAE v.5.0)
  • Adverse events of special interest (AESIs)
  • Serious adverse events (SAEs)
  • Adverse events leading to treatment discontinuation
  • Deaths (related to COVID-19/all)
• Number of Participants with a Clinically Relevant/Significant Change from Baseline in Individual Laboratory Parameters [ Time Frame: Baseline to Day 60 (±3) ]
• Number of Participants with a Clinically Relevant/Significant Change from Baseline in Individual Vital Signs [ Time Frame: Baseline to Day 60 (±3) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Plitidepsin Versus Control in Immunocompromised Adult Participants With Symptomatic COVID-19 Requiring Hospital Care
• Official Title: A Multicentre, Open Label, Randomised, Controlled, Basket, Pragmatic, Phase II, Clinical and Translational Study to Determine the Efficacy and Safety of Plitidepsin Versus Control in Immunocompromised Adult Patients With Symptomatic COVID-19 Requiring Hospital Care
• Brief Summary: The primary objective of this study is to evaluate efficacy of plitidepsin in pre-specified groups of immunocompromised patients with symptomatic COVID-19 requiring hospital care versus control in terms of mortality.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: COVID-19

Intervention

Drug: Plitidepsin

IV infusion over 60-minutes

Study Arms

• Experimental: Plitidepsin 2.5 mg

  Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute intravenous (IV) infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) will be administered to participants of the following groups:

  • Group 1 - Participants receiving immune-suppression due to haematopoietic or organ transplantation.
  • Group 2 - Participants receiving B-cell depleting therapies.
  • Group 3 - Participants receiving other immune-suppressive therapies.
  • Group 4 - Other situations with immune deficiencies.
  Intervention: Drug: Plitidepsin
• No Intervention: Control

  Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) ± other regulatory-approved antiviral (if clinically indicated) will be administered to participants of the following groups:

  • Group 1 - Participants receiving immune-suppression due to haematopoietic or organ transplantation.
  • Group 2 - Participants receiving B-cell depleting therapies.
  • Group 3 - Participants receiving other immune-suppressive therapies.

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: April 24, 2024): 37
• Original Estimated Enrollment (submitted: January 27, 2023): 150
• Actual Study Completion Date: April 19, 2024
• Actual Primary Completion Date: March 19, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Signed informed consent obtained prior to initiation of any study-specific procedures and study treatment.
• Participant aged ≥18 years.

• Participant diagnosed COVID-19, with the following characteristics:

  1. A regulatory-approved test, collected no more than 3 days prior to study randomisation, with either a Ct value ≤30 or a positive antigen test.
  2. Presence of any of the selected signs/symptom listed in the COVID-19 signs/symptoms checklist within the last 24 hours.
• Participant already admitted or requiring hospital care for symptomatic COVID-19, for which at least one antiviral has failed or cannot be used (i.e., contraindication, absence of labelled indication, guidelines or drug unavailability), after a minimum washout period of 24 hours for small molecules (e.g., remdesivir, molnupiravir, nirmaltrevir, ritonavir) and 5 days for antiviral monoclonal antibodies (e.g., tixagevimab + cilgavimab) or convalescent plasma.

• Adequate bone marrow, liver, kidney, and metabolic function, defined by the following tests performed at local laboratory:

  1. Absolute neutrophil count ≥500/mm^3 (0.5 x 109/L).
  2. Platelet count ≥ 50 000/mm3 (50 x 109/L).
  3. Alanine transaminase (ALT) ≤3 x upper limit of normal (ULN) (≤5 x ULN if preexistent liver involvement by the underlying disease).
  4. Serum bilirubin ≤1.5 x ULN (or direct bilirubin <1.5 x ULN when total bilirubin is above ULN).
  5. Estimated glomerular filtration rate ≥30 mL/min (CKD-EPI Creatinine Equation [2021]).
• Females of child-bearing potential must have a negative serum or urine pregnancy test by local laboratory at screening and must be non-lactating.
• Females of child-bearing potential and fertile males with partners of child-bearing potential must use contraceptive methods as specified in the protocol.

Group-specific inclusion criteria:

• Group 1 - Patients receiving, within the last 30 days, immune-suppressive therapy due to haematopoietic or organ transplantation.
• Group 2 - Participants receiving B-cell depleting therapies within the last 6 months (with the exception of CAR-T cell therapy for which time restriction is not applicable).
• Group 3 - Participants receiving, within the last 30 days, other immune-suppressive therapies.

• Group 4 - Other situations with immunodeficiency.

  1. Primary immune deficiencies.
  2. Human immunodeficiency virus (HIV) infection, with CD4^+ T lymphocyte < 200 cells/μL in the last month.
  3. Radiation therapy within the last 3 months- requires documentation of ALC < 500 cells/μL.
  4. Haematological neoplasia or myelodysplasia not currently receiving any therapy.
  5. Other situations with a documentation of ALC < 500 cells/μL.

Exclusion Criteria:

• Evidence of critical illness.

• Any of the following cardiac conditions or risk factors:

  1. Cardiac infarction or cardiac surgery episode within the last month.
  2. History of known congenital QT prolongation.
  3. Known structural cardiomyopathy with abnormal left ventricular ejection fraction (LVEF) (<50%).
  4. Current clinical evidence of heart failure or acute cardiac ischaemia (New York Heart Association (NYHA) class III-IV).
• Hypersensitivity to the active ingredient or any of the excipients (mannitol, macrogolglycerol hydroxystearate, and ethanol) or contraindication to receive dexamethasone, antihistamine H1/H2, or anti-serotoninergic 5HT3 agents.
• Females who are pregnant or breast-feeding.
• Females and males with partners of child-bearing potential who are not using at least 1 protocol-specified method of contraception.
• Any situation currently requiring increasing needs of immune-suppressive agents.
• Any other clinically significant medical condition or laboratory abnormality that, in the opinion of the investigator, would jeopardise the safety of the participant or potentially impact on participant compliance or the safety/efficacy observations in the study.
• Participation in another clinical study involving an investigational drug within 30 days prior to screening.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, France, Georgia, Greece, Hungary, Israel, Italy, Poland, Portugal, Spain, United Kingdom

Administrative Information

• NCT Number: NCT05705167
• Other Study ID Numbers: AV-APL-B-002-22; 2022-002489-34 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: PharmaMar
• Original Responsible Party: Same as current
• Current Study Sponsor: PharmaMar
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: PharmaMar
• Verification Date: April 2024