Clinical Trials Register

Summary
EudraCT Number:	2022-002489-34
Sponsor's Protocol Code Number:	AV-APL-B-002-22
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2023-01-24
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Belgium - FPS Health-DGM

A.2

EudraCT number

2022-002489-34

A.3

Full title of the trial

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 (NEREIDA)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A.4.1

Sponsor's protocol code number

AV-APL-B-002-22

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pharma Mar, S.A.
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pharma Mar, S.A.
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pharma Mar S.A.
B.5.2	Functional name of contact point	Clinical Development Virology Unit
B.5.3	Address:
B.5.3.1	Street Address	Avenida de los Reyes, 1
B.5.3.2	Town/ city	Colmenar Viejo. Madrid
B.5.3.3	Post code	28770
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34918466000
B.5.6	E-mail	clinicaltrials@pharmamar.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	plitidepsin
D.3.2	Product code	SAPL01
D.3.4	Pharmaceutical form	Powder and solvent for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Plitidepsin
D.3.9.1	CAS number	137219-37-5
D.3.9.2	Current sponsor code	SAPL01
D.3.9.3	Other descriptive name	Aplidin drug substance, Aplidine, dehydrodidemnin-B, DDB, APLD, PM90001
D.3.9.4	EV Substance Code	SUB33502
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Immunocompromised Adult Patients with Symptomatic COVID-19 requiring Hospital Care

E.1.1.1

Medical condition in easily understood language

Immunocompromised Adult Patients with Symptomatic COVID-19 requiring Hospital Care

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.0
E.1.2	Level	LLT
E.1.2	Classification code	10084272
E.1.2	Term	SARS-CoV-2 infection
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Efficacy primary objective
To evaluate efficacy of plitidepsin in pre-specified groups of immunocompromised patients with symptomatic COVID-19 requiring hospital care vs control in terms of mortality.

E.2.2

Secondary objectives of the trial

Key efficacy secondary objective:
Plitidepsin vs the control in terms of viral clearance, in each group.

Efficacy secondary objective:
Plitidepsin vs the control (in each group) in terms of:
-Sustained end of hospital care
- Symptomatic improvement
- Clinical status (WHO)
-the need of any kind of supplementary oxygen

Safety/tolerability secondary objective
Plitidepsin vs the control in terms of adverse events, adverse reactions and mortality, abnormal laboratory parameters, of variations of vital signs in each group.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent obtained prior to initiation of any study-specific procedures and study treatment;
2. Patient aged ≥18 years;
3. Patient diagnosed COVID-19, with the following characteristics:
a) 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;
b) Presence of any of the selected signs/symptom listed in Appendix 10 - COVID-19 signs/symptoms checklist within the last 24 h;
4. Patient already admitted or requiring hospital care for symptomatic COVID-19, for which at least one registered antiviral has failed, or cannot be
used‡, after a minimum washout period of 24h for small molecules (e.g., remdesivir, molnupiravir, nirmaltrevir/ritonavir) and 5 days for antiviral
monoclonal antibodies (e.g., tixagevimab + cilgavimab) or convalescent plasma.
*The definition of hospital care is based on the need to use a hospital environment (hospital ward, day hospital) for treatment administration and/or clinical monitoring of the patient with COVID-19.
†Failure of a prior antiviral is defined as a documented lack of clinical response, plus evidence of persisting positivity for SARS-CoV-2 in an appropriate biological sample, determined by a regulatory approved test, collected no more than 3 days prior to study randomisation, with either a Ct value ≤ 30 (RT-PCR) or a positive antigen test.
‡Contraindication, absence of labelled indication, guidelines or drug unavailability.
5. Adequate bone marrow, liver, kidney, and metabolic function, defined by the following tests performed at local laboratory:
o Absolute neutrophil count ≥500/mm3 (0.5 x 10exp9/L);
o Platelet count ≥ 50 000/mm3 (50 x 10exp9/L);
o Alanine transaminase (ALT) ≤3 x upper limit of normal (ULN) (≤5 x ULN if pre-existent liver involvement by the underlying disease);
o Serum bilirubin ≤1.5 x ULN (or direct bilirubin <1.5 x ULN when total bilirubin is above ULN);
o Estimated glomerular filtration rate ≥30 mL/min [CKD-EPI Creatinine Equation (2021)].
6. Females of childbearing potential must have a negative serum or urine pregnancy test by local laboratory at study enrolment and must be non-lactating.
7. Females of child-bearing potential must use highly effective contraceptive methods, while on study treatment and for 6 months after
last dose of plitidepsin. Fertile males with partners of child bearing potential must use effective contraception while on study treatment and for 6 months after last dose of plitidepsin (See Appendix 2 - Contraception and pregnancy testing). Patients in the control arm must follow contraception methods indicated in the approved product information (summary of product characteristics [SmPC] or leaflet). If no information is available in the approved product information, patients in the control arm must use highly effective contraception (females of child-bearing potential) and effective (fertile males with partners of child-bearing potential) for at least one week after the study completion or the time indicated based on the investigator’s discretion.

Group-specific inclusion criteria:
• Group 1 – Patients receiving, within the last 30 days, immune-suppressive therapy due to haematopoietic or organ transplantation.
o Haematopoietic transplantation.
o Solid Organ Transplantation: Lung / intestinal, Other.
• Group 2 – Patients receiving B-cell depleting therapies within the last 6 months*.
Includes (but is not limited to):
o Monoclonal antibodies (mAbs) targeting CD19, CD20, CD38 or CD52 (e.g., rituximab, ocrelizumab, ofatumumab, daratumumab, alemtuzumab).
o B-cell activating factor (BAFF) inhibitors (e.g., belimumab).
o Bruton's tyrosine kinase (BTK) inhibitors (e.g., evobrutinib, ibrutinib).
o Chimeric antigen receptor T cell therapy (CAR-T) (e.g., anti-CD19 CAR-T cell).
*Time restriction is NA for CAR-T cell therapy.
• Group 3 – Patients receiving, within the last 30 days, other immune-suppressive therapies.
o Other immunosuppressive therapies not including B-cell depleting agents for the treatment of auto-immune disorders.
o Chemotherapy or targeted therapies with immunosuppressive potential for solid tumours or haematological disorders.
o Chronic glucocorticoids (i.e., equivalent to prednisone ≥ 20 mg/day for more than 1 month).
•Group 4 – Other situations with immunodeficiency.
Includes (but is not limited to):
o Primary immune deficiencies.
o Human immunodeficiency virus (HIV) infection, with CD4+ T lymphocytes < 200 cells/µL in the last month.
o Radiation therapy within the last 3 months- requires documentation of ALC < 500 cells/µL.
o Haematological neoplasia or myelodysplasia not currently receiving any therapy
o Other situations with a documentation of ALC < 500 cells/µL.
*NA in Spain

E.4

Principal exclusion criteria

1. Evidence of critical illness, defined by at least one of the following:
• Respiratory failure defined based on resource utilization requiring at least one of the following: endotracheal intubation and mechanical ventilation, ECMO, or clinical diagnosis of severe acute respiratory distress syndrome with PaO2*/FiO2 ≤ 100.
*In case a direct measure of PaO2 has not been obtained, it should be imputed according to a referenced formula (Ellis or Rice) (Appendix 5 - Imputation of PaO2/FiO2 ratio). For sites located over 1000 m altitude above sea level, PaO2/FiO2 ratio will be adjusted (Appendix 6- Adjustment of PaO2 from a Site at High Altitude; See also Appendix 7 for FiO2 imputations from oxygen flow rates).
• Shock requiring vasopressors.
• Multi-organ dysfunction/failure.
2.Criterion eliminated and merged with inclusion criterion #4, based on AEMPS recommendations).
3. Any of the following cardiac conditions or risk factors:
• Cardiac infarction or cardiac surgery episode within the last month;
• History of known congenital QT prolongation;
• Known structural cardiomyopathy with abnormal LVEF (<50%);
• Current clinical evidence of heart failure or acute cardiac ischaemia (New York Heart Association (NYHA) class III-IV).
4. 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.
5. Females who are pregnant or breast-feeding.
6. Females and males with partners of childbearing potential (females who are not surgically sterile or postmenopausal defined as amenorrhoea for >12 months) who are not using at least 1 protocolspecified method of contraception.
7. Any situation currently requiring increasing needs of immune suppressive agents (e.g. acute graft rejection, flare of autoimmune disorder, or cytokine storm syndrome).
8. Any other clinically significant medical condition (including major surgery within the last 3 weeks before screening) or laboratory abnormality that, in the opinion of the investigator, would jeopardise the safety of the patient or potentially impact on patient compliance or the safety/efficacy observations in the study.
9. Participation in another clinical study involving an investigational drug within 30 days prior to screening.

E.5 End points

E.5.1

Primary end point(s)

Efficacy primary endpoint
1-Month all-cause mortality rate.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 30 since randomisation

E.5.2

Secondary end point(s)

Key secondary endpoint
Time to confirmed negativisation in SARS-CoV-2 antigen test or RT-PCR Ct > 30.

Efficacy secondary endpoints
Time to sustained end of COVID-related hospital care from the time of randomisation
Time to sustained improvement and resolution of selected COVID-19 signs/symptoms
Time to sustained discontinuation (i.e., at least 7 days) of oxygen supplementation
Distribution of patients according to their clinical status
Percentage of patients requiring oxygen therapy

Safety secondary endpoints
Frequency of the following events (all-cause and drug-related): TEAEs, TEAEs ≥ grade 3, AESIs, SAEs, SARs, Adverse events leading to treatment discontinuation, Deaths (COVID-19-related/all)
Change respect to baseline* in individual study-defined laboratory parameters
Change respect to baseline* in individual vital signs

E.5.2.1

Timepoint(s) of evaluation of this end point

Within 30 days of initial end of hospital care [up to day 60 (±3)
On Days 4 (±1), 8 (±1), 15 (±1), 30 (±2), and 60 (±3).
Throughout the study duration

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Basket trial

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Israel

Georgia

Belgium

Czechia

France

Greece

Hungary

Italy

Netherlands

Poland

Portugal

Spain

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The End of Trial (EOT) will be when the Last Patient Last Visit (LPLV) has occurred.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

140

F.4.2.2

In the whole clinical trial

150

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2023-03-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-05-30

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-04-19

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IMP with orphan designation in the indication
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