E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
critically-ill patients with pneumonia from COVID-19 infection |
Pazienti critici ventilati per polmonite e severa insufficienza respiratoria da SARS-CoV-2 |
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E.1.1.1 | Medical condition in easily understood language |
critically-ill patients with pneumonia from COVID-19 infection |
Pazienti critici ventilati per polmonite e severa insufficienza respiratoria da SARS-CoV-2 |
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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 | 10053983 |
E.1.2 | Term | Corona virus infection |
E.1.2 | System Organ Class | 100000004862 |
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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 |
The primary objective is to assess the hypothesis that an adjunctive therapy with steroids and unfractionated heparin or with steroids and molecular weight heparin (LMWH) are more effective in reducing any-cause mortality in critically-ill patients with pneumonia from COVID- 19 infection compared to low molecular weight heparin (LMWH) alone. Mortality will be measured at 28 days. The confirmation of the efficacy of this composite treatment in reducing the mortality rate among critically ill patients with pneumonia from COVID-19 infection will lead to a revision of the current clinical approach to this disease. |
L'obiettivo primario è verificare l'ipotesi che una terapia aggiuntiva con steroidi ed eparina non frazionata o con steroidi e eparina a basso peso molecolare sia più efficace nel ridurre la mortalità per qualsiasi causa in pazienti in condizioni critiche con polmonite da infezione da COVID-19 rispetto all'eparina a basso peso molecolare (LMWH) da sola La mortalità sarà misurata a 28 giorni. La conferma dell'efficacia di questo trattamento composito nel ridurre il tasso di mortalità tra i pazienti critici con polmonite da infezione da COVID-19 porterà a una revisione dell'attuale approccio clinico a questa patologia. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material) - Positive pressure ventilation (either non-invasive or invasive) from > 24 hours - Invasive mechanical ventilation from < 96 hours - P/F ratio < 150 - D-dimer level > 6 x upper limit of local reference range - PCR > 6 fold upper limit of local reference range |
- DIagnostica per infezione da SARS-CoV-2 positiva (su tampone faringeo o material respiratorio profondo) - Ventilazione a pressione positive (sia non invasiva che invasiva) da > 24 ore - Ventilazione meccanica invasive da < 96 ore - Rapporto P/F < 150 - D-dimero > 6 x il limite superiore del range di normalità del laboratorio locale - PCR > 6 il limite superiore del range di normalità del laboratorio locale |
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E.4 | Principal exclusion criteria |
- Age <18 years - On-going treatment with anticoagulant drugs - Platelet count < 100.000/mmc - History of heparin-induced thrombocytopenia - Allergy to sodium enoxaparine or other LMWH, unfractionated heparin or metylprednisolone; - Active bleeding or on-going clinical condition deemed at high risk of bleeding contraindicating anticoagulant treatment - Recent (in the last 1 month prior to randomization) brain, spinal or ophthalmic surgery - Chronic assumption or oral corticosteroids - Pregnancy or breastfeeding or positive pregnancy test. In childbearing age women, before inclusion, a pregnancy test will be performed if not available; - Clinical decision to withhold life-sustaining treatment or “too sick to benefit”; - Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition); - Lack or withdrawal of informed consent. |
- Età < 18 anni - Trattamenti in corso con farmaci anti-coagulanti o anti-aggreganti - Conta piastrinica < 100.000/mmc - Storia di trombocitopenia indotta da eparina - Allergia all’enoxaparina sodica o ad alter eparine a basso peso molecolare, all’eparina non frazionata o al metilprednisolone. - Sanguinamento attivo o condizioni cliniche intercorrenti per cui il paziente ha un elevato rischio di sanguinamento che controindica in trattamento anti-coagulante. - Recente (nell’ultimo mese prima della randomizzazione) - Recent chirurgia all’encefalo, Colonna vertebrale o oftalmica nell’ultimo mese prima della randomizzazione - Assunzione cronica di corticosteroidi - Gravidanza o allattamento al seno o test di gravidanza positivo. Nelle donne in età fertile verrà effettuato un test di gravidanza prima dell’inclusione dello studio; - Decisione clinica di interrompere I trattamenti di support o pazienti troppo gravi per beneficiare delle cure. - Presenza di altre malattie gravi in grado di ridurre l’aspettativa di vita (es. pazienti per i quali non ci si aspetta una sopravvivenza a 28 giorni a causa della loro condizione medica preesistente non correggibile); - Mancanza o ritiro del consenso informato |
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E.5 End points |
E.5.1 | Primary end point(s) |
All-cause mortality at day 28 |
Mortalità per qualsiasi causa al giorno 28. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Ventilation free days (VFDs) at day 28, defined as the total number of days that patient is alive and free of ventilation between randomisation and day 28 (censored at hospital discharge). Ventilation is considered as positive pressure ventilation, either invasive or non-invasive. Periods of assisted breathing lasting less than 24 hours for surgical procedures will not count against the ventilation free days calculation; - Need of rescue administration of high-dose steroids or immune-modulatory drugs; - Occurrence of switch from non-invasive to invasive mechanical ventilation during ICU-stay; - Delay from start of non-invasive ventilation to switch to invasive ventilation; - All-cause mortality at ICU discharge and hospital discharge; - ICU free days (IFDs) at day 28, defined as the total number of days between ICU discharge and day 28. If death occurs during the ICU stay before day 28 the ICU free days calculation will be 0. The ICU readmission before day 28 after randomization will be considered; - Occurrence of new infections from randomization to day 28,including infections by Candida, Aspergillus, Adenovirus, Herpes Virus e Citomegalovirus; - Occurrence of new organ dysfunction and grade of dysfunction during ICU stay. Organ dysfunction is defined as a Sequential Organ Failure Assessment (SOFA) score28 =3 occurring after randomization, grade of dysfunction is measured with SOFA score (see SOFA score in APPENDIX 4) daily from randomization to ICU discharge (censored at day 28); - Objectively confirmed venous thromboembolism, stroke or myocardial infarction; - Occurrence of protocol related adverse events (see chapter 5.2) at day 28 (safety endpoint). Physiological and Processes of care outcomes - Vital signs such as mean arterial pressure (MAP), hearth rate (HR), respiratory rate (RR), diuresis and systemic body temperature and fluid balance will be recorded daily from inclusion until ICU discharge (censored day 28); - Routine laboratory test parameters for organ function assessment: haemoglobin, platelets count, white blood cells count, troponin, coagulative parameters (INR, PT, aPTT), parameters for liver (AST, ALT, bilirubin) and renal function (creatinine) will be recorded daily from inclusion to ICU discharge (censored at day 28); - Blood cells count, C-reactive protein (CRP), procalcitonin (PCT) and interleukin 6 (IL-6) will be recorded daily from inclusion to ICU discharge (censored at day 28); - Ventilation mode, inspired oxygen fraction and arterial blood gas analysis parameters will be recorded daily from inclusion to ICU discharge from (censored at day 28); - Adjunctive treatment such as pronation cycles, Nitric Oxide or ECMO will be recorded daily from inclusion to ICU discharge from (censored at day 28); - Newblood, respiratory and urinary-tract infections will be recorded from randomization to day 28; - Viral reactivation measured by CMV DNA titres will be recorded from randomization to day 28; - Need of new renal replacement therapy (intermittent haemodialysis or continuous veno-venous hemofiltration) from randomization to 28 days.; Endpoint primario saranno valutati mediante: - Mortalità per ogni causa a 28 giorni. Endpoint secondari: - Giorni liberi da ventilazione (VFD) al giorno 28, definito come il numero totale di giorni in cui il paziente è vivo e privo di ventilazione tra la randomizzazione e il giorno 28 (censurato alla dimissione dall'ospedale). La ventilazione è considerata come ventilazione a pressione positiva, invasiva o non invasiva. I periodi di respirazione assistita di durata inferiore a 24 ore per le procedure chirurgiche non verranno conteggiati nel calcolo dei giorni senza ventilazione; - Necessità di somministrazione di salvataggio di steroidi ad alto dosaggio o di farmaci immunomodulatori; - Passaggio dalla ventilazione meccanica non invasiva a quella meccanica invasiva durante la permanenza in terapia intensiva; - Ritardo dall'inizio della ventilazione non invasiva alla ventilazione invasiva; - Mortalità per qualsiasi causa alla dimissione dalla terapia intensiva e alla dimissione ospedaliera; - Giorni liberi dalla terapia intensiva (IFD) al giorno 28, definito come il numero totale di giorni tra la dimissione dalla terapia intensiva e il giorno 28. Se il decesso si verifica durante la permanenza in terapia intensiva prima del giorno 28, il calcolo dei giorni liberi in terapia intensiva sarà 0. La riammissione in terapia intensiva prima del giorno 28 dopo la randomizzazione sarà presa in considerazione; - Comparsa di nuove infezioni dalla randomizzazione al giorno 28,incluse infezioni da Candida, Aspergillus, Adenovirus, Herpes Virus e Citomegaloviru; - Comparsa di nuove disfunzioni d'organo e grado di disfunzione durante la degenza in terapia intensiva. La disfunzione d'organo è definita come un punteggio di SOFA score =3 che si verifica dopo la randomizzazione, il grado di disfunzione viene misurato con il punteggio SOFA dalla randomizzazione alla dimiss |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.5 | Efficacy | No |
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 | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 9 |
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 | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
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 | 1 |
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 |