| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| SARS-CoV-2 pneumonia |
| Polmonite da SARS-CoV-2 |
|
| E.1.1.1 | Medical condition in easily understood language |
| COVID-19 pneumonia |
| Polmonite da COVID-19 |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10061229 |
| E.1.2 | Term | Lung infection |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Evaluation of the feasibility and safety of the use of allogeneic Mesenchymal stromal cells (MSC) to treat SARS-CoV-2 related severe pneumonia through the capability to treat all enrolled patients and monitoring the rate of adverse events |
| Valutazione della fattibilità e della sicurezza dell’impiego di cellule stromali mesenchimali (MSC) allogeniche per il trattamento della polmonite severa da infezione da SARS-CoV-2 attraverso la capacità di trattare tutti i pazienti arruolati e il monitoraggio della quota di eventi avversi |
|
| E.2.2 | Secondary objectives of the trial |
Evaluation of the efficacy of MSC in terms of:
mortality rate
trend of the daily PaO2/FiO2 ratio
evaluation of the days to intubation
date of independence from non-invasive mechanical ventilation
date of independence from oxygen therapy
hospitalization lenght
radiological pattern response
Evaluation of: neutrophil, lymphocyte and platelet counts, platelet mean volume, C-reactive protein, ferritin, procalcitonin, LDH, fibrinogen, and D-dimer.
Comparative immunological study of the cytokine pattern and the immunophenotyphic cell profile of bronchoalveolar lavage fluid and peripheral blood samples will be carried out in order to establish the pathogenic mechanisms of COVID-19 tissue injury and the mechanism of action of MSC in this specific clinical setting.
Establish which IMP used, as stratified according to the tissue origin, is associated with the best result in terms of safety and efficacy. |
Valutazione dell’efficacia di MSC in termini di:
mortalità
andamento di PaO2/FiO2 giornaliero
valutazione del tempo all’intubazione
tempo all’indipendenza dalla ventilazione meccanica non invasiva
tempo all’indipendenza dall’ossigeno-terapia
durata ospedalizzazione
risposta radiologica
Valutazione di: rapporto tra conte assolute di polimorfonucleati neutrofili e linfociti, conta piastrinica, volume piastrinico, proteina C-reattiva, ferritinemia, procalcitonina, LDH, fibrinogeno, D-dimero.
Valutazione del pattern citochinico e profilo immunofenotipico cellulare su campioni di liquido di lavaggio broncoalveolare, e di sangue periferico per definire i meccanismi patogenetici del danno in corso di COVID-19 e il meccanismo d’azione delle MSC in questo specifico setting clinico.
Stabilire quale sia tra le tipologie di IMP utilizzati, stratificati in base all’origine tissutale delle MSC, quello associato a miglior risultato in termini di sicurezza ed efficacia. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Adult patients suffering from SARS-CoV-2 induced severe pneumonia admitted to semi-intensive or intensive COVID Units because of the need of ventilation support.
• Sign of the informed consent,
• Patients of either sex, aged 18-80 years (inclusive),
• Patient with a confirmed virological diagnosis of SARS-CoV2 infection by means of real-time Polymerase Chain Reaction,
• Hospitalization due to clinical and radiological diagnosis of pneumonia,
• PaO2/FiO2 value between 150-300 with impending necessity of noninvasive positive pressure respiratory support (nCPAP) or ventilator support through nasal pressure support ventilation (nPSV),
• Systolic artery pressure >90 mmHg without amine support,
• Modified Early Warning Score (MEWS) score <3,
• Absence of known active malignancy. |
Pazienti adulti ricoverati in COVID Unit intensive e semi-intensive a causa della necessità di supporto ventilatorio per polmonite da SARS-CoV-2.
• Firma del consenso informato,
• Pazienti di entrambi i generi, di età compresa tra 18 e gli 80 anni (incluse),
• Pazienti con una diagnosi virologica di infezione da SARS-CoV-2 confermata mediante real time-Polymerase Chain Reaction,
• Ospedalizzazione per diagnosi clinica e radiologica di polmonite,
• Valore di PaO2/FiO2 compreso tra 150-300 tale da richiedere ossigenoterapia e indicazione a supporto respiratorio non invasivo tramite CPAP (positive pressure respiratory) o ventilatorio tramite NPSV (nasal pressure support ventilation),
• Pressione arteriosa sistolica >90 mm Hg in assenza di supporto aminico,
• Modified Early Warning Score (MEWS) <3,
• Assenza di neoplasia attive note. |
|
| E.4 | Principal exclusion criteria |
• Deny to informed consent,
• Known history of alcohol or drug abuse in the 12 months prior to inclusion,
• Presence of significant comorbidities, such as uncontrolled hypertension, invalidating psychiatric or neurological disorders, organ failure (renal impairment defined by creatinine clearance below 50 ml/min or by serum creatinine =2.0 mg/dl; hepatic impairment defined by total bilirubin =2.0 mg/dl and AST + ALT = 2.5 x upper normal value; cardiac failure with an output fraction =40%), or any other clinically significant condition, as determined by the Principal Investigator,
• Presence of chronic advanced cardio-pulmonary diseases, such as ILDs (obstructive pneumonia, severe pulmonary interstitial fibrosis, alveolar proteinosis, allergic alveolitis),
• Patient has a clinically relevant abnormality on electrocardiogram, as determined by the Principal Investigator,
• History of previous embolism,
• Known active malignancy,
• Patient with a history of severe allergic reactions (e.g., swelling of the mouth and throat, difficulty breathing, hypotension, or shock) requiring medical intervention,
• Patient with a positive test for human immunodeficiency virus or active hepatitis B or C disease or tuberculosis or further viral infections (influenza virus, adenovirus and other respiratory viruses),
• Patient is known to be pregnant, has a positive pregnancy test or is nursing,
• Patient has had major surgery, either open or laparoscopic, within the 3 months prior to screening,
• Previous haematopoietic stem cell or organ transplantation,
• Patient under immunosuppressive agents,
• Patients currently receiving, or having received within 2 months prior to enrolment into this clinical study, any other investigational drug. |
• Non volontà a dare il consenso,
• Storia nota di abuso alcolico o di stupefacenti nei 12 mesi precedenti l’inclusione,
• Presenza di comorbidità significative, come ipertensione arteriosa incontrollata, patologie psichiatriche o neurologiche invalidanti, insufficienza d’organo (insufficienza renale definite come valore di clearance della creatinine al di sotto di 50 ml/min o da un valore di creatinine sierica =2.0 mg/dl; insufficienza epatica definite da un valore di bilirubina totale =2.0 mg/dl e di AST + ALT = 2.5 x il valore massimo normale; insufficienza cardiaca definite da una frazione di eiezione =40%), o qualunque altra condizione clinica rilevante, come stabilito dal Principal Investigator,
• Presenza di malattie cardio-polmonari croniche avanzate, come ILD (pneumopatia ostruttiva, fibrosi interstiziale polmonare, proteinosi alveolare, alveolite allergica),
• Pazienti con anormalità elettrocardiografiche clinicamente rilevanti, come stabilito dal Principal Investigator,
• Pre-esistente patologia trombo-embolica,
• Neoplasia attiva nota,
• Pazienti con anamnesi positiva per reazione allergica severa (ad esempio, gonfiore della bocca e della gola, difficoltà respiratorie, ipotensione, o shock) che hanno richiesto intervento medico,
• Pazienti con test positive per virus dell’immunodeficienza umana o epatite B o C attiva o tubercolosi o qualunque altra infezione virale (virus influenzali, adenovirus e altri virus respiratori),
• Pazienti in stato di gravidanza, o con test di gravidanza positive, o in allattamento,
• Pazienti che hanno subito interventi chirurgici maggiori, sia open sia per via laparoscopica, entro i 3 mesi prima dello screening,
• Precedente trapianto di cellule staminali emopoietiche,
• Pazienti in terapia immunosoppressiva,
• Pazienti che stanno ricevendo o che hanno ricevuto entro 2 mesi prima dell’arruolamento in questo studio clinico, qualunque altra terapia sperimentale. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The feasibility will be assessed through the evaluation of the production capacity of each Cell Factory participating in the study in terms of an adequate amount of cellular product lots sufficient to treat 100% of the patients recruited. In addition, the process of transfer of the cellular product to the Clinical Unit will be validated, so that all the quality, safety and therapeutic properties will be guaranteed, with particular reference to its viability. Finally, a protocol for the bedside preparation of the final suspension for administration will be implemented according to the Good Clinical Practice.
The safety will be assessed by recording all adverse events as coded by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, based on their duration, intensity, and possible association with the treatment under study. More in depth, the absolute number/percentage of Suspected Unexpected Sever Adverse Reactions (SUSARs) and Severe Adverse Reactions (SARs) recorded after 2 and 4 weeks from the MSC treatment that will not exceed 10% will be considered the cutoff to be met. |
La fattibilità verrà valutata attraverso la valutazione della capacità di produzione da parte delle Cell Factory partecipanti allo studio di un’adeguata quantità di lotti di prodotto cellulare sufficienti a trattare il 100% dei pazienti reclutati. Inoltre, verrà validato il processo di trasferimento del prodotto cellulare presso l’Unità Clinica di impiego, affinché siano garantiti tutti i requisiti di qualità, sicurezza e proprietà terapeutiche con particolare riferimento al mantenimento della vitalità dello stesso. Verrà, infine, implementato un protocollo di impiego al letto del paziente che rispetti le Good Clinical Practice, incluse le dovute misure di contenimento.
La sicurezza verrà valutata mediante la registrazione di tutti gli eventi avversi come codificato dal¿Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0, sulla base della durata, intensità, e possibile associazione con il trattamento oggetto dello studio. In particolare, si terrà conto del numero assoluto/percentuale di Suspected Unexpected Sever Adverse Reactions (SUSAR) e di Severe Adverse Reactions (SAR) registrate nel corso del trial a 2 e 4 settimane dal trattamento con MSC che non devono superare il limite del 10%. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End points will be assessed at 4 hours, 48 ¿¿hours, 7, 14, 28 and 180 days from the end of treatment or enrollment, as appropriate |
| Gli end point verranno valutati a 4 ore, 48 ore, 7, 14, 28 e 180 giorni dal termine del trattamento o dall’arruolamento, come appropriato |
|
| E.5.2 | Secondary end point(s) |
The efficacy will be assessed through the evaluation of
a) mortality rate (%) at 2 and 4 weeks from the end of the treatmentfollow-up,
b) percentage of change of the daily PaO2/FiO2 ratio in comparison with the basal value,
c) percentage of patients under invasive mechanical ventilation,
d) days under non-invasive mechanical ventilation,
e) days under oxygen therapy,
f) radiological response,
g) days of hospitalization,
h) percentage change of the radiologic score with respect to the basal value; Change of the following laboratory values after 2 and 4 weeks from the end of the MSC treatment of follow-up in comparison to the basal values and expressed as percentages: neutrophil, lymphocyte and platelet counts, platelet mean volume, C-reactive protein, ferritin, procalcitonin, LDH, fibrinogen, and D-dimer.; Modification of the cytokine pattern and of the immunophenotyphic cell profile on both BALF and peripheral blood samples as assessed by means of ELISA, flow cytometry and single cell RNAseq before and after 1 and 2 weeks from the end of MSC treatment follow-up will be carried outevaluated.; We have planned to treat a group of 10 cases with umbilical cord MSCs, a group of 10 cases with umbilical cord blood MSCs, a group of 10 cases with bone marrow MSCs, and a group of 10 cases with adipose tissue MSCs. The percentages of total adverse events, SUSARs, and SARs related to the MSC treatment, together with the efficacy parameters will be compared among the groups. |
L’efficacia verrà testata mediante la valutazione di:
a) mortalità (%) a 2 e 4 settimane,
b) percentuale di variazione del rapporto PaO2/FiO2 quotidiano rispetto al basale,
c) percentuale di pazienti in ventilazione invasiva meccanica,
d) giorni in ventilazione meccanica non invasiva,
e) giorni in ossigenoterapia,
f) risposta radiologica
g) giorni di ospedalizzazione
h) percentuale di cambio di score radiologico rispetto al basale; Variazione dei parametri di laboratorio (rapporto tra conte assolute di polimorfonucleati neutrofili e linfociti, conta piastrinica, volume piastrinico, proteina C-reattiva, ferritinemia, procalcitonina, LDH, fibrinogeno, D-dimero).; Modifiche del pattern citochinico e del profilo immunofenotipico cellulare su campioni di BAL e sangue periferico, valutati tramite ELISA, citofluorimetria e single cell RNAseq, prima e dopo 1 e 2 settimane di follow-up rispetto al basale; Prevediamo di trattare un gruppo di 10 casi con MSC da cordone ombelicale, un gruppo di 10 casi con MSC da sangue di cordone ombelicale, un gruppo di 10 casi con MSC da midollo e un gruppo di 10 casi con MSC da tessuto adiposo. Valuteremo il confronto percentuale del numero totale di eventi avversi, SUSAR e SAR relati al trattamento, unitamente ai parametri di efficacia registrati a seguito dell’impiego dei diversi IMP nei vari gruppi |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Endpoints will be assessed at 4 hours, 48 ¿¿hours, 7, 14, and 28 days from the end of treatment or enrollment, as appropriate; End points will be assessed after 2 and 4 weeks from the end of the MSC treatment; End points will be assessed after 1 and 2 weeks from the end of the MSC treatment; End points will be assessed at 4 hours, 48 ¿¿hours, 7, 14, 28 and 180 days from the end of treatment or enrollment |
| Gli obiettivi verranno valutati a 4 ore, 48 ore, 7, 14, e 28 giorni dal termine del trattamento o dall’arruolamento, come appropriato; Gli end point verranno valutati dopo 2 e 4 settimane dal termine del trattamento; Gli end point verranno valutati dopo 1 e 2 settimane dal termine del trattamento; Gli end point verranno valutati a 4 ore, 48 ore, 7, 14, 28 e 180 giorni dal termine del trattamento o dall’arruolamento |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Terapia standard |
| Standard of care |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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