| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The study objective is to evaluate the efficacy and safety of NexoBrid in removing burn eschar in hospitalized subjects with thermal burns. |
| Dimostrare l'efficacia e la sicurezza di NexoBrid nella rimozione dell'escara in pazienti ospedalizzati con ustioni termiche. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Dead tissue of a burn wound has to be removed to promote healing of the wound. |
| Tessuto morto di una ferita da ustione che deve essere rimosso per promuovere la guarigione della ferita. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Injuries, poisonings, and occupational diseases [C21] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10043418 |
| E.1.2 | Term | Thermal burns |
| E.1.2 | System Organ Class | 100000004863 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing complete eschar removal as compared with Gel Vehicle. |
| Dimostrare l'efficacia della rimozione enzimatica dell'escara con NexoBrid fornendo una rimozione dell'escara completa rispetto al veicolo in gel. |
|
| E.2.2 | Secondary objectives of the trial |
To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing earlier complete eschar removal, reduction in patients¿ surgical burden and its related blood loss as compared to SOC,
and to assess the safety of NexoBrid compared to SOC, including demonstration that treatment with NexoBrid does not cause an unacceptable level of harm on wound closure outcome and long term outcomes of cosmesis and function.
|
Dimostrare l'efficacia della rimozione enzimatica dell'escara con NexoBrid fornendo una rimozione dell'escara completa pi¿ precoce e una riduzione del carico chirurgico per i pazienti e della relativa perdita ematica rispetto al trattamento SOC;
Valutare la sicurezza di NexoBrid rispetto al trattamento SOC, ivi inclusa la dimostrazione che il trattamento con NexoBrid non causa un livello di danno inaccettabile sull'esito della cicatrizzazione della ferita e sugli esiti a lungo termine di estetica e funzionalit¿.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria- Patient level
1. Males and females; = 18 years of age,
2. Thermal burns caused by fire/flame, scalds or contact,
3. Patient total burns area = 3% DPT and / or FT,
4. Patient total burns area should be = 30% TBSA; SPT, DPT and/or FT in depth,
5. Informed consent can be obtained within 84 hours of the burn injury,
6. Patients who are willing and able to sign a written consent form.
Inclusion Criteria – Wound level
1. At least one wound (a continuous burn area) that is =0.5% TBSA (DPT and/or FT) (this minimal wound size should not include face, perineal or genital),
All planned target wounds (TWs) should meet the following criteria:
2. SPT areas that cannot be demarcated from DPT and FT areas should be less than 50% of the % TBSA of the TW
3. Wound’s blisters can be removed/unroofed, as judged by the investigator. |
Criteri di inclusione - Livello paziente
1. Uomini e donne di età = 18 anni;
2. Ustioni termiche provocate da fuoco o fiamme, scottature o contatto;
3. Area totale ustionata del paziente = 3% DPT e/o FT;
4. Area totale ustionata del paziente = 30% della TBSA e di profondità SPT, DPT e/o FT;
5. Consenso informato ottenuto entro 84 ore dalla lesione da ustione;
6. Volontà e capacità del paziente di firmare un modulo di consenso scritto.
Criteri di inclusione - Livello ferita
1. Almeno una ferita (un'area ustionata continua) di dimensioni =0,5% di TBSA (DPT e/o FT) (questa dimensione minima della ferita non deve includere il viso o la zona genitale o perineale) .
Tutte le ferite target (TW) previste devono soddisfare i seguenti criteri:
1. Le aree SPT che non possono essere delimitate dalle aree DPT e FT devono essere inferiori al 50% della % di TBSA interessata dalla TW;
2. Le vescicole delle ferite possono essere rimosse/aperte, secondo il giudizio dello sperimentatore.
|
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria- Patient level
1. Patients who are unable to follow study procedures and follow up period,
2. Modified Baux index14 = 80,
3. Patients with burned charred fingers, 3rd degree in depth and possibly devoid of circulation,
4. Patients with abraded wound/s that cannot be treated by an enzymatic debrider application (NexoBrid) will be excluded from the study,
5. Patients with electrical or chemical burns,
6. Patients with circumferential (= 80% of the limb circumference) DPT and/or FT burns defined as Extremities at Risk (EAR) as described in section 11.8,
7. The following pre-enrollment dressings: a. Flammacerium, b. Silver Nitrate (AgNO3),
8. Patients with pre-enrolment wounds which are covered by eschar heavily saturated with iodine or by SSD pseudoeschar (e.g. pseudoeschar as a result of >12 h SSD treatment),
9. Patients with pre-enrollment escharotomy,
10. Patients with diagnosed infections as described in Section 11.9 of study protocol,
11. Diagnosis of smoke inhalation injury,
12. Pregnant women (positive pregnancy test) or nursing mothers,
13. Poorly controlled diabetes mellitus (HbA1c>11%) in patients with known diabetes as captured in the medical history,
14. BMI greater than 39.0 kg/m2 in patients with burns area of up to 15% TBSA or BMI greater than 34.0 kg/m2 in patients with burns area of more than 15% %TBSA,
15. ASA greater than 2 (Appendix 13- ASA classification system),
16. Cardio-pulmonary disease (MI within 6 months prior to injury, severe pulmonary hypertension,
severe COPD or pre-existing oxygen-dependent pulmonary diseases, severe broncho-pneumonia within 1 month prior to injury, steroid dependent asthma or uncontrolled asthma),
17. Pre-existing diseases which interfere with circulation (severe peripheral vascular disease, severe edema and/or lymphedema, regional lymph nodes dissection, significant varicose veins),
18. Any conditions that would preclude safe participation in the study or adding further risk to the basic acute burn trauma (such as severe immuno-compromising diseases, life threatening trauma, severe pre-existing coagulation disorder, severe cardiovascular disorder, significant pulmonary disorder, significant liver disorder including post alcoholic abuse impaired function or neoplastic disease, blast injury),
19. Chronic systemic steroid intake,
20. History of allergy and/or known sensitivity to pineapples, papaya, Bromelain or papain,
21. Current (within 12 months prior to screening) suicide attempt,
22. Mentally incapacitated adults who are incapable of giving legal consent
23. Enrollment in any investigational drug trial within 4 weeks prior to screening,
24. Current (within 12 months prior to screening) severe alcohol or drug use disorder (see Definition in section 1.1),
25. Prisoners and incarcerated,
26. Patients who might depend on the clinical study site or investigator. |
Criteri di esclusione - Livello paziente
1. Pazienti non in grado di seguire le procedure dello studio e il periodo di follow-up;
2. Indice di Baux modificato = 80;
3. Pazienti con dita bruciate, carbonizzate, di 3o grado di profondità ed eventualmente prive di circolazione;
4. Pazienti con ferita/e abrasa/e che non può/possono essere trattata/e con l'applicazione di un agente di sbrigliamento enzimatico (NexoBrid);
5. Pazienti con ustioni elettriche o chimiche;
6. Pazienti con ustioni DPT e /o FT circonferenziali (> 80% della circonferenza dell'arto) definite come Estremità a Rischio (EAR), come descritto nella sezione 11.8;
7. Pazienti sottoposti prima dell'arruolamento alle seguenti medicazioni: a. Flammacerium, b. Nitrato d'argento (AgNO3),
8. Pazienti con ferite pre-arruolamento coperte da escara fortemente satura con iodio o da pseudoescara SSD (ovvero, pseudoescara conseguente a trattamento SSD > 12 ore);
9. Pazienti sottoposti ad escarotomia prima dell'arruolamento;
10. Pazienti con infezioni diagnosticate come descritto nella sezione 11.9 del protocollo di studio;
11. Diagnosi di lesione per inalazione di fumo;
12. Donne incinte (test di gravidanza positivo) o in allattamento;
13. Diabete mellito scarsamente controllato (HbA1c> 11%) in pazienti affetti da diabete noto presente nell'anamnesi;
14. IMC maggiore di 39,0 kg/m2 in pazienti con aree ustionate fino al 15% della TBSA o IMC maggiore di 34,0 kg/m2 in pazienti con aree ustionate superiori al 15% della TBSA;
15. L'ASA superiore a 2 (vedi Appendice 13 nel protocollo dello studio)
16. Malattie cardio-polmonari (MI nei 6 mesi precedenti al trauma, grave ipertensione polmonare, BPCO grave o malattie polmonari ossigeno-dipendenti preesistenti, grave broncopolmonite entro 1 mese prima del trauma, steroidi asma dipendente o asma non controllata),
17. Le condizioni note che interferiscono con la circolazione (la malattia vascolare periferica, l'edema, la linfedema, la chirurgia ai
linfonodi regionali e significative vene varicose),
18. Le eventuali condizioni note che potrebbero precludere la partecipazione sicura allo studio o aggiungere l'ulteriore rischio alla
base del trauma dell'ustione acuta (così come le malattie immuno-compromesse, i traumi in pericolo di vita, i disturbi della
coagulazione pre-esistente grave, pulmono-cardiovascolare, la malattia del fegato o neoplastica),
19. L'assunzione cronica di steroidi sistemici,
20. Storia di allergia e/o sensibilità nota all'ananas, alla papaia, alla Bromelina o alla papaina,
21.Tentativo di suicidio corrente (entro 12 mesi prima dello screening),
22. adulti mentalmente incapaci che non sono in grado di dare il consenso legale,
23. L'arruolamento in qualsiasi sperimentazione di farmaco in studio/sperimentale entro 4 settimanw prima dello screening,
24. Attuale abuso (entro 12 mesi prima dello screening) di alcolo abuso di droghe (definizione nella sezione 1.1) ,
25. Prigionieri e incarcerati,
26. Pazienti che potrebbero dipendere dal luogo dello studio clinico o dallo sperimentatore. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint will be investigated at a "per patient" level:
Incidence of complete eschar removal: Demonstrate superiority over Gel Vehicle for eschar removal as measured by incidence of complete eschar removal assessed by the blinded assessor at the end of the topical agent soaking period (6 hours after start of the 1st topical application).
Or, in cases where 2 applications are performed, complete ER is assessed 6 hours after start of the 2nd Treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of the topical agent soaking period.
|
|
| E.5.2 | Secondary end point(s) |
The following secondary endpoints will be evaluated in this study and compared between NexoBrid and SOC.
1. Reduction in surgical need- Demonstrate superiority of NexoBrid over SOC in reduction of surgical need for excisional eschar removal as measured by an analysis of incidence of surgical eschar removal (tangential/ minor/ avulsion/ Versajet and/or dermabrasion excision).
2. Earlier eschar removal- Demonstrate superiority of NexoBrid over SOC in reduction of the time to achieve complete eschar removal.
3. Blood loss- Demonstrate superiority of NexoBrid over SOC with regard to the blood loss incurred during the eschar removal procedures
Safety Endpoints
The following group of safety endpoints will be evaluated in this study and compared between NexoBrid and SOC. These endpoints are used to ensure that NexoBrid does not cause an unacceptable level of harm.
1. Time to reach complete wound closure assessed in days, starting from randomization date. Demonstrate that NexoBrid does not cause any clinically meaningful harm to the patients with respect to the wound healing process by comparing NexoBrid mean time to wound closure with SOC mean time to wound closure, where a difference of not more than 7 days difference will be interpreted as clinically not relevant.
2. Cosmesis and function at 12 months from wound closure - A measure of cosmesis, using MVSS, will be used to demonstrate - that treatment with NexoBrid does not cause any clinically meaningful deleterious effect on scars quality as compared to scars quality of burns treated with SOC, measured at 12 months from wound closure date, by a blinded assessor. Clinically meaningful deleterious effect will be defined as a NexoBrid group mean MVSS score higher by 1.9 or more units than the SOC group mean MVSS score.
3. Cosmesis and function at 24 months from wound closure - A measure of cosmesis, using MVSS, will be used to demonstrate that Treatment with NexoBrid does not cause any clinically meaningful deleterious effect on scars quality as compared to scars quality of burns treated with SOC, measured at 24 months from wound closure date, by a blinded assessor. Clinically meaningful deleterious effect will be defined as a NexoBrid group mean MVSS score higher by 1.9 or more units than the SOC group mean MVSS score. |
The following secondary endpoints will be evaluated in this study and compared between NexoBrid and SOC.
1. Reduction in surgical need- Demonstrate superiority of NexoBrid over SOC in reduction of surgical need for excisional eschar removal as measured by an analysis of incidence of surgical eschar removal (tangential/ minor/ avulsion/ Versajet and/or dermabrasion excision).
2. Earlier eschar removal- Demonstrate superiority of NexoBrid over SOC in reduction of the time to achieve complete eschar removal.
3. Blood loss- Demonstrate superiority of NexoBrid over SOC with regard to the blood loss incurred during the eschar removal procedures
Safety Endpoints
The following group of safety endpoints will be evaluated in this study and compared between NexoBrid and SOC. These endpoints are used to ensure that NexoBrid does not cause an unacceptable level of harm.
1. Time to reach complete wound closure assessed in days, starting from randomization date. Demonstrate that NexoBrid does not cause any clinically meaningful harm to the patients with respect to the wound healing process by comparing NexoBrid mean time to wound closure with SOC mean time to wound closure, where a difference of not more than 7 days difference will be interpreted as clinically not relevant.
2. Cosmesis and function at 12 months from wound closure - A measure of cosmesis, using MVSS, will be used to demonstrate - that treatment with NexoBrid does not cause any clinically meaningful deleterious effect on scars quality as compared to scars quality of burns treated with SOC, measured at 12 months from wound closure date, by a blinded assessor. Clinically meaningful deleterious effect will be defined as a NexoBrid group mean MVSS score higher by 1.9 or more units than the SOC group mean MVSS score.
3. Cosmesis and function at 24 months from wound closure - A measure of cosmesis, using MVSS, will be used to demonstrate that Treatment with NexoBrid does not cause any clinically meaningful deleterious effect on scars quality as compared to scars quality of burns treated with SOC, measured at 24 months from wound closure date, by a blinded assessor. Clinically meaningful deleterious effect will be defined as a NexoBrid group mean MVSS score higher by 1.9 or more units than the SOC group mean MVSS score.; I seguenti endpoint secondari saranno valutati in questo studio e confrontati tra NexoBrid e SOC.
1. Riduzione della chirurgia -dimostrare la superiorit¿ di NexoBrid rispetto al SOC nella riduzione della necessit¿ chirurgica per la rimozione dell'escara come misurato da un'analisi di incidenza della rimozione chirurgica dell'escara (tangenziale / minore / avulsione / Versajet e / o la dermoabrasione escissione).
2. prematura eliminazione dell'escara- dimostrare la superiorit¿ di NexoBrid rispetto al SOC nella riduzione del tempo necessario ad ottenere la rimozione completa dell'escara.
3. Perdita di sangue: dimostrare la superiorit¿ di NexoBrid rispetto al trattamento SOC per quanto riguarda la perdita di sangue subita durante le procedure di rimozione dell'escara.
Endpoint di sicurezza
In questo studio sar¿ valutato confrontato tra NexoBrid e il SOC il seguente gruppo di endpoint di sicurezza. Questi endpoint vengono utilizzati per confermare che NexoBrid ha un effetto deleterio inferiore.
1. Tempo richiesto per raggiungere la completa cicatrizzazione delle ferite, valutato in giorni a partire dalla randomizzazione.
2. Estetica e funzionalit¿: saranno misurate utilizzando la scala MVSS per dimostrare che il trattamento con NexoBrid non ha alcun effetto deleterio clinicamente significativo sulla qualit¿ delle cicatrici di ustioni rispetto alla qualit¿ delle cicatrici di ustioni trattate con il SOC. L'endpoint sar¿ valutato mediante misurazioni a 12 mesi dalla data di cicatrizzazione della ferita da un valutatore in cieco;
3. Estetica e funzionalit¿: saranno misurate utilizzando la scala MVSS per dimostrare che il trattamento con NexoBrid non ha alcun effetto deleterio clinicamente significativo sulla qualit¿ delle cicatrici di ustioni rispetto alla qualit¿ delle cicatrici di ustioni trattate con il SOC. L'endpoint sar¿ valutato mediante misurazioni a 24 mesi dalla data di cicatrizzazione della ferita da un valutatore in cieco.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-time when complete eschar removal has been achieved.
- time when complete wound closure has been achieved
-12 and 24 months following to the confirmatory wound closure visit |
-time when complete eschar removal has been achieved.
- time when complete wound closure has been achieved
-12 and 24 months following to the confirmatory wound closure visit; -Momento in cui la completa rimozione dell'escara ¿ stata raggiunta.
- Momento in cui la completa chiusura della ferita ¿ stata raggiunta
-12 e 24 mesi dopo la visita di conferma di chiusura della ferita |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 |
| Immunogenicity |
| Immunogenicit¿ |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.3 | Single blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Standard di cura |
| Standard of Care |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 | Information not present in EudraCT |
| 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 |
| Canada |
| Israel |
| United States |
| Belgium |
| Czechia |
| Germany |
| Italy |
| Romania |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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