A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Plitidepsin in Adults with Post COVID-19 Condition

2023-504087-42-00 Protocol THALASA Therapeutic confirmatory (Phase III) Not authorised

Status Not authorised · 1 EU/EEA countries · 1 sites · Protocol THALASA

Overview

Sponsor-declared trial summary

Phase Therapeutic confirmatory (Phase III)
Status Not authorised
Participants planned 260
Countries 1
Sites 1

Post COVID-19

To compare plitidepsin 2.5 mg vs placebo in terms of improvement of functional status in patients with post COVID-19 condition (PCC).

Key facts

Sponsor
Fundacion Fls De Lucha Contra El Sida Las Enfermedades Infecciosas Y La Promocion De La Salud Y La Ciencia
Participant type
Patients
Age range
18-64 years
Gender
Male and Female
Therapeutic area
Diseases [C] - Virus Diseases [C02]
Decision date (initial)
2023-08-10
Transition trial
No
Low-intervention
No
Rare-disease indication
No
Vulnerable population
No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To compare plitidepsin 2.5 mg vs placebo in terms of improvement of functional status in patients with post COVID-19 condition (PCC).

Secondary objectives 14

  1. To compare plitidepsin 2.5 mg vs placebo in terms of improvement of functional status in patients with post COVID-19 condition (PCC).
  2. To compare the patients in the Plitidepsin group vs the patients in the placebo group with Grade 0 or 1 functional disability, according to PCFS
  3. To compare safety/tolerability of plitidepsin vs placebo in terms of adverse events in patients with PCC.
  4. To compare efficacy of plitidepsin vs placebo in terms of symptomatic improvement in patients with PCC.
  5. To compare efficacy of plitidepsin vs placebo in terms of quality of life (QoL) in patients with PCC.
  6. To compare efficacy of plitidepsin vs placebo in terms of neurocognitive symptoms in patients with PCC
  7. To compare efficacy of plitidepsin vs placebo in terms of physical activity in patients with PCC
  8. To compare efficacy of plitidepsin vs placebo in terms of fatigue in patients with PCC.
  9. To compare efficacy of plitidepsin vs placebo in terms of the evolution of inflammatory markers in patients with PCC.
  10. To compare efficacy of plitidepsin vs placebo in terms of immune response in patients with PCC.
  11. To compare efficacy of plitidepsin vs placebo in terms of markers of immune response (including autoimmunity) in patients with PCC
  12. To compare efficacy of plitidepsin vs placebo in terms of the presence of viral components in plasma in patients with PCC.
  13. To compare efficacy of plitidepsin vs placebo in terms of the immune response markers in patients with PCC
  14. To explore effects of plitidepsin vs placebo in terms of intestinal microbiota in patients with PCC.

Conditions and MedDRA coding

Post COVID-19

Study design 1 period

#TitleAllocationBlindingRoles blindedArms
1 overall trial
Randomized (1:1), Double-blind, Placebo-controlled Study
 Randomised Controlled Double [{"id":18124,"code":3,"name":"Monitor"},{"id":18127,"code":5,"name":"Carer"},{"id":18125,"code":2,"name":"Investigator"},{"id":18126,"code":1,"name":"Subject"}] Plitidepsin arm: Plitidepsin 2.5 mg/day 1-h IV infusion on Days 1 to 3.
Placebo arm: Placebo 1-h IV infusion, 1 vial/day on Days 1 to 3.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

  1. Male or female individuals 18 years old or older.
  2. Evidence of SARS-CoV-2 infection at least 90 days prior to study recruitment, defined by either (a) nasopharyngeal SARS-CoV-2 nucleic acid test [polymerase chain reaction (PCR) or transcription mediated amplification (TMA)], (b) validated Nasopharyngeal Lateral Flow Assay rapid antigen test (RAT), or (c) positive serology against SARS-CoV-2 N protein regardless vaccination status.
  3. Symptoms of PCC affecting at least two organs, after 90 days from the onset of SARS-CoV2 infection and that last for at least 2 months and cannot explained by an alternative diagnosis
  4. Unable to perform all usual duties/activities, defined as grades 3 or 4 in PCFS.
  5. Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study.
  6. Having understood the information provided and capable of providing informed consent.

Exclusion criteria 11

  1. Last SARS-CoV-2 vaccine dose during the previous 30 days.
  2. Females of childbearing potential (females who are not surgically sterile or postmenopausal defined as amenorrhea for >12 months) who are not using highly effective contraceptive methods, while on study treatment and for 6 months after last dose of plitidepsin. Fertile males with partners of childbearing potential must use condom during treatment and for 6 months after last dose of plitidepsin.
  3. Unable to consent and/or comply with study requirements, in the opinion of the investigator.
  4. Currently participating or participated in a clinical trial within the prior 30 days, or a planned participation in any other clinical trial within the next 90 days.
  5. Patients with active uncontrolled infections.
  6. Patients receiving treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers throughout plitidepsin treatment period and until 24-h washout period.
  7. Any of the following cardiac conditions or risk factors: 1. Cardiac infarction or cardiac surgery episode within the last six months; 2. History of known congenital QT prolongation; 3. Known structural cardiomyopathy with abnormal LVEF (<50%); 4. Current clinical evidence of heart failure or acute cardiac ischaemia (New York Heart Association (NYHA) class III-IV).
  8. Hypersensitivity to the active ingredient or any of the excipients (mannitol, macrogolglycerol hydroxystearate, and ethanol) or contraindication to receive systemic glucocorticoids, antihistamine H1/H2 receptor agents, or antiserotonine 5HT3 receptors drugs.
  9. Mast cell activation syndrome
  10. Females who are pregnant (negative serum or urine pregnancy test required for all females of childbearing potential at screening) or breast-feeding.
  11. Pacients receiving chronic glucocorticoid therapy

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

  1. Percentage of patients with PPC who improve at least one grade on the functional status measured with Post COVID-19 Functional Status Scale (PCFS https://medicaljournalssweden.se/jrm-cc/article/view/2652) at 28+/-2 days post-drug infusion.

Secondary endpoints 14

  1. Percentage of patients with PCC who improve at least one grade on the PCFS at 10+/-2 days post-drug infusion
  2. Percentage of patients with PCC with Grade 0 or 1 functional disability, according to PCFS, at 10+/-2, 28+/-2 and 90+/-5 days post-drug infusion
  3. Proportion of adverse events (AEs) (coded by MedDRA) through at 1-3, 10+/-2, 28+/-2 and 90+/-5 days post-drug infusion considering: 1) All AEs; 2) AEs leading to study discontinuation; 3) AEs of special interest (AESI): cardiac, liver, acute post-infusional reactions.
  4. Proportion of subjects with ≥10 points reduction in Can Ruti´s Questionnaire scale at 10+/-2, 28+/-2 and 90+/-5 days post-drug infusion
  5. Proportion of subjects with improvement in Quality of Life (QoL) according to European Quality of life-5D (EuroQol-5D) questionnaire at10+/-2, 28 +/-2, and 90+/-5 days post-drug infusion.
  6. Change respect to baseline in neurocognitive symptoms by 28 +/-2, and 90+/-5 days post-drug infusion assessed with the following questionnaires: Neu Screen (velocidad psicomotora y función ejecutora); MEF-30 (discapacidad cognitiva percibida); HADS (síntomas depresivos y ansiosos); PSQI (valoración del insomnio) y WHODAS 2.0.
  7. Change respect to baseline in physical activity by 10+/-2, 28 +/-2, and 90+/-5 days post-drug infusion assessed with the International Activity Questionary (IPAQ).
  8. Change respect to baseline in physical activity by 10+/-2, 28 +/-2, and 90+/-5 days post-drug infusion assessed with the Fatigue severe scale (FSS) and Five Times Sit to Stand Test (5xSTS).
  9. Change respect to baseline in inflammatory, microbiological and immunological biomarkers by Days 10 +/-2, 28 +/-2, and 90+/-5 days post-drug infusion.
  10. Change respect to baseline in immune cells by 10 +/-2, 28 +/-2, and 90+/-5 days post-drug infusion
  11. Change respect to baseline in individual serological assessments at 90+/-5 days post-drug infusion.
  12. Change respect to baseline in viral components in plasma by 10 +/-2, 28 +/-2, and 90+/-5 days post-drug infusion.
  13. Change respect to baseline in immune response markers by 10 +/-2, 28 +/-2, and 90+/-5 days post-drug infusion.
  14. Change respect to visit 2 (first infusion) in faecal microbiota by 10 +/-2, 28 +/-2, and 90+/-5 days post-drug infusion.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Aplidin

PRD164450 · Product

Active substance
Plitidepsin
Pharmaceutical form
POWDER AND SOLVENT FOR CONCENTRATE FOR SOLUTION FOR INFUSION
Route of administration
INTRAVENOUS USE
Max daily dose
2.5 mg milligram(s)
Max total dose
7.5 mg milligram(s)
Max treatment duration
3 Day(s)
Authorisation status
Not Authorised
MA holder
PHARMA MAR S.A.
Paediatric formulation
No
Orphan designation
No

Placebo 1

Placebo

SUB21402 · Substance

Active substance
Placebo
Pharmaceutical form
POWDER AND SOLVENT FOR SOLUTION FOR INJECTION
Route of administration
INTRAVENOUS
Max daily dose
0 mg milligram(s)
Max total dose
0 mg milligram(s)
Max treatment duration
3 Day(s)
Authorisation status
Authorised
ATC code
- — -
Marketing authorisation
-
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Auxiliary 4

Palonosetron

SUB09593MIG · Substance

Active substance
Palonosetron
Pharmaceutical form
SOLUTION FOR INJECTION
Route of administration
INTRAVENOUS
Max daily dose
250 µg microgram(s)
Max total dose
750 µg microgram(s)
Max treatment duration
3 Day(s)
Authorisation status
Authorised
ATC code
- — -
Marketing authorisation
-
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Famotidine

SUB07503MIG · Substance

Active substance
Famotidine
Pharmaceutical form
TABLET
Route of administration
ORAL
Max daily dose
40 mg milligram(s)
Max total dose
120 mg milligram(s)
Max treatment duration
3 Day(s)
Authorisation status
Authorised
ATC code
- — -
Marketing authorisation
-
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Dexchlorpheniramine

SUB07022MIG · Substance

Active substance
Dexchlorpheniramine
Pharmaceutical form
SOLUTION FOR INJECTION
Route of administration
INTRAVENOUS
Max daily dose
5 mg milligram(s)
Max total dose
15 mg milligram(s)
Max treatment duration
3 Day(s)
Authorisation status
Authorised
ATC code
- — -
Marketing authorisation
-
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Dexamethasone Phosphate

SUB01612MIG · Substance

Active substance
Dexamethasone Phosphate
Pharmaceutical form
SOLUTION FOR INJECTION
Route of administration
INTRAVENOUS
Max daily dose
8 mg milligram(s)
Max total dose
24 mg milligram(s)
Max treatment duration
3 Day(s)
Authorisation status
Authorised
ATC code
- — -
Marketing authorisation
-
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion Fls De Lucha Contra El Sida Las Enfermedades Infecciosas Y La Promocion De La Salud Y La Ciencia

6 Total trials 5 Ended
Academic / Non-commercial
Sponsor organisation
Fundacion Fls De Lucha Contra El Sida Las Enfermedades Infecciosas Y La Promocion De La Salud Y La Ciencia
Address
Carretera Canyet S/n
City
Badalona
Postcode
08916
Country
Spain

Scientific contact point

Organisation
Fundacion Fls De Lucha Contra El Sida Las Enfermedades Infecciosas Y La Promocion De La Salud Y La Ciencia
Contact name
Lourdes Pruñonosa

Public contact point

Organisation
Fundacion Fls De Lucha Contra El Sida Las Enfermedades Infecciosas Y La Promocion De La Salud Y La Ciencia
Contact name
Silvia Gel

Locations

1 EU/EEA country · 1 investigational sites

By country

CountryMS statusPlanned subjectsSites
Spain Not authorised 260 1
Rest of world — 0 —

Investigational sites

Spain

1 site · Not authorised
Hospital Universitari Germans Trias I Pujol
Infectious Diseases, Carretera Canyet 1a Planta, 08916, Badalona

Application history

1 submissions — initial application plus substantial / non-substantial modifications

#TypeCodeSubmittedReference MSConclusionDecision date
1 INITIAL IN 2023-05-04 Spain Not acceptable
2023-08-07
 2023-08-10

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