| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult patients with decompensated cirrhosis |
| PAZIENTI ADULTI CON CIRROSI SCOMPENSATA |
|
| E.1.1.1 | Medical condition in easily understood language |
| Adult patients with decompensated cirrhosis |
| PAZIENTI ADULTI CON CIRROSI SCOMPENSATA |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009209 |
| E.1.2 | Term | Cirrhosis bilary |
| E.1.2 | System Organ Class | 100000004871 |
|
| 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 |
To evaluate the efficacy of oral administration of simvastatin plus
rifaximin in halting the progression of decompensated cirrhosis as
assessed by the time to first incidence of ACLF during treatment
period. |
| Valutare l'efficacia della somministrazione orale di simvastatina più rifaximina nell'arrestare la progressione della cirrosi scompensata valutato nel tempo dalla prima incidenza di ACLF durante il periodo di trattamento |
|
| E.2.2 | Secondary objectives of the trial |
Time to transplant-free survival, and incidence
Severity of ACLF as assessed by number and types of organ failures.
Frequency of hospital admissions due to complications of cirrhosis.
Development/worsening of complications of cirrhosis
Systemic inflammatory response
Plasma and urine levels of biomarkers
Vasoactive hormones
Blood levels of bacterial DNA
Changes in fecal microbiome composition
Liver function, evaluated by MELD, CLIF-C AD and Child-Pugh Score
Quality of life, functional assessment and minimal hepatic
encephalopathy as assessed by CLDQ, Liver Frailty score, and PHES questionnaires
Stigmatization in patients with decompensated cirrhosis
Appearance of muscle toxicity assessed
To evaluate genetic polymorphisms of statins membrane
transporter OATP1B1
Muscle or liver toxicity
Type and severity of treatment-related adverse events
Annualized incidence of ACLF
Time to overall and time to disease related survival |
Tempo di sopravvivenza libera da trapianto e incidenza
Gravità delle ACLF valutata in base al numero e al tipo di guasti agli organi.
Frequenza dei ricoveri ospedalieri a causa di complicanze della cirrosi.
Sviluppo/peggioramento delle complicanze della cirrosi.
Risposta infiammatoria sistemica
Livelli di plasma e urine dei biomarcatori
Ormoni vasoattivi
Livelli ematici del DNA batterico
Cambiamenti nella composizione del microbioma fecale
Funzione del fegato, valutata da MELD, CLIF-C AD e Child-Pugh Score.
Qualità della vita, valutazione funzionale e epatica minima
encefalopatiavalutata da CLDQ, Liver Frailty score, e questionari PHES
Stigmatizzazione in pazienti con cirrosi scompensata
Valutazione dell'aspetto della tossicità muscolare
Valutare i polimorfismi genetici della membrana delle statine
trasportatore OATP1B1B1
Tossicità muscolare o epatica
Tipo e gravità degli eventi avversi legati al trattamento
Incidenza annualizzata di ACLF
Tempo di sopravvivenza globale |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age = 18 years old.
2. Cirrhosis defined by standard clinical criteria, ultrasonographic
findings and/or histology. Cirrhosis of any aetiology may be included.
However, patients with cirrhosis due to autoimmune hepatitis must be
on stable corticosteroid dose for =3-month period before study
inclusion.
3. Child-Pugh B patients or Child-Pugh C patients (up to 12 points).
4. Women of child-bearing potential* must have a negative pregnancy
test in serum normal at study inclusion. |
1. Età = 18 anni.
2. Cirrosi definita da criteri clinici standard, ultrasonografia
risultati e/o istologia. Può essere inclusa la cirrosi di qualsiasi eziologia.
Tuttavia, i pazienti con cirrosi dovuta ad epatite autoimmune devono essere
su una dose stabile di corticosteroidi per un periodo =3 mesi prima dello studio
3. Pazienti Child-Pugh B o Child-Pugh C (fino a 12 punti).
4. Le donne con potenziale fertile* devono avere una gravidanza negativa. |
|
| E.4 | Principal exclusion criteria |
1. Patients on treatment with statins or rifaximin up to one month
before study inclusion.
2. Patients with contraindications for statins or rifaximin therapy.
3. Known hypersensitivity to simvastatin or rifaximin (or rifamycin
derivatives).
4. Patients with CK elevation of 50% or more above the upper limit of
5. Patients on treatment with potent inhibitors of CYP3A4 enzyme (See
section 5.2: Concomitant, nonpermitted and permitted medication).
6. Patients on treatment with drugs with potential interactions with
simvastatin (see section 5.2: Concomitant, nonpermitted and
permitted medication).
7. Patients with previous history of myopathy.
8. Patients with previous history of intestinal obstruction or those who
are at increased risk of this complication.
9. Patients with ACLF according to the criteria published by Moreau et
al. (see appendix 2).
10. Serum creatinine =2 mg/dL (176.8 µmol/L).
11. Serum bilirubin>5 mg/dL (85.5 µmol/L).
12. INR =2.5.
13. Bacterial infection within 10 days before study inclusion.
14. Gastrointestinal bleeding within 10 days before study inclusion.
15. Current overt hepatic encephalopathy, defined as grade II-IV
hepatic encephalopathy according to the New-Haven classification.
16. Patients with active hepatocellular carcinoma or history of
hepatocellular carcinoma that is in remission for less than six months
for uninodular HCC or for less than 12 months for multinodular HCC
within Milan criteria.
17. Patients on antiviral therapy for HCV or those who have received it
within the last 6 months.
18. Severe alcoholic hepatitis requiring corticosteroid therapy
(Maddrey’s Discriminant function = 32 and/or ABIC score > 6.7).
19. Patients with active alcohol consumption of more than 21 units per
week.
20. HIV infection.
21. Patients with a history of significant extra hepatic disease with
impaired short-term prognosis, including congestive heart failure New
York Heart Association Grade III/IV, COPD GOLD >2, chronic kidney
disease with serum creatinine >2mg/dL or under renal replacement
therapy.
22. Patients with current extra hepatic malignancies including solid
tumours and hematologic disorders.
23. Pregnancy or breastfeeding.
24. Patients included in other clinical trials in the month before
inclusion.
25. Patients with mental incapacity, language barrier, bad social
support or any other reason considered by the investigator precluding
adequate understanding, cooperation or compliance in the study.
26. Refusal to give informed consent |
1. Pazienti in trattamento con statine o rifaximina fino a un mese
prima dell'inclusione nello studio.
2. Pazienti con controindicazioni per la terapia con statine o rifaximina.
3. Ipersensibilità nota alla simvastatina o rifaximina (o rifamicina)
4. Pazienti con CK pari o superiore al 50% al di sopra del limite superiore di
5. Pazienti in trattamento con potenti inibitori dell'enzima CYP3A4
6. Pazienti in trattamento con farmaci con potenziali interazioni con
simvastatina
7. Pazienti con storia precedente di miopatia.
8. Pazienti con precedenti anamnesi di ostruzione intestinale o che
sono a maggior rischio di questa complicazione.
9. Pazienti con ACLF secondo i criteri pubblicati da Moreau et
al
10. Creatinina sierica =2 mg/dL (176,8 µmol/L).11. Bilirubina sierica >5 mg/dL (85,5 µmol/L).
12. INR =2.5.
13. Infezione batterica entro 10 giorni prima dell'inclusione nello studio.
14. Sanguinamento gastrointestinale entro 10 giorni prima dell'inclusione nello studio.
15. Encefalopatia epatica palese corrente, definita di grado II-IV.
encefalopatia epatica secondo la classificazione New-Haven.
16. Pazienti con carcinoma epatocellulare attivo o storia di
carcinoma epatocellulare in remissione da meno di sei mesi
per gli HCC uninodulari o per meno di 12 mesi per gli HCC multinodulari
all'interno dei criteri di Milano.
17. Pazienti in terapia antivirale per l'HCV o che l'hanno ricevuto
negli ultimi sei mesi.
18. Epatite alcolica grave che richiede una terapia con corticosteroidi
(Funzione discriminante di Maddrey = 32 e/o punteggio ABIC > 6.7).
19. Pazienti con un consumo attivo di alcool superiore a 21 unità per
settimana.
20. Infezione da HIV.
21. Pazienti con una storia di malattia epatica extra significativa con
prognosi a breve termine compromessa, compresa l'insufficienza cardiaca congestizia Nuovo
York Heart Association Grado III/IV, COPD GOLD >2, rene cronico
malattia con creatinina sierica >2mg/dL o sotto sostituzione renale
terapia.
22. Pazienti con attuali neoplasie epatiche extra epatiche tra cui
tumori e disturbi ematologici.
23. Gravidanza o allattamento al seno.
24. Pazienti incluse in altri studi clinici nel mese precedente
inclusione.
25. Pazienti con incapacità mentale, barriere linguistiche, cattive condizioni sociali
il sostegno o qualsiasi altra ragione considerata dall'investigatore, che precluda
un'adeguata comprensione, cooperazione o conformità allo studio.
26. Rifiuto di dare il consenso informato |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy of treatment in halting the progression of decompensated cirrhosis as assessed by
time to first ACLF during the treatment period, defined according to criteria by Moreau et al.,
Gastroenterology 2013. |
Efficacia del trattamento nell'arrestare la progressione della cirrosi scompensata dalla prima ACLF durante il periodo di trattamento, definito secondo i criteri di Moreau et al,
Gastroenterologia 2013. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| during the treatment period |
| Durante il periodo di trattamento |
|
| E.5.2 | Secondary end point(s) |
1. Time to transplant-free survival. Incidences at 1 month, 3 months, 6 months, 9 months and 12 months.
2. Severity of ACLF assessed by number and types of organ failures at baseline, 1 month, 3 months, 6 months, 9 months and 12 months.
3. Frequency of hospital admissions due to complications of cirrhosis assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months.
4. Development/worsening of individual complications of cirrhosis (ascites, acute kidney injury, gastrointestinal bleeding, hepatic encephalopathy (HE), bacterial infections) assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months, defined as:
4.1. ASCITES:
1A. Development of new-onset ascites or worsening of preexisting ascites as estimated by:
• Percentage of patients with new-onset ascites.
• Percentage of patients presenting worsening of ascites, defined as:
o Increased diuretic dosage, as indicated by a double of the diuretic dose received at entry into the study, to a dose of at least spironolactone 200 mg/day (or its equivalent dose in other aldosterone antagonists) and furosemide 20 mg/day (or its equivalent dose in other loop diuretics).
o Need for large-volume paracentesis in patients who had never been treated with this procedure.
1B. Number of episodes of ascites per patient requiring large volume paracentesis during the treatment period.
4.2. ACUTE KIDNEY INJURY:
• Percentage of patients developing episodes of renal function impairment defined by AKI criteria, following criteria of the “EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis”.
• Percentage of patients developing episodes of renal function impairment defined by AKI criteria as AKI IB or higher.
• Number of episodes of AKI1B or higher per patient.
• Number of patients developing severe AKI requiring RRT.
• Number of patients developing AKI-HRS syndrome (following the criteria established by the “EASL Clinical Practice Guidelines for the management of patients withdecompensated cirrhosis”).
4.3. GASTROINTESTINAL BLEEDING:
• Percentage of patients developing the first episode of bleeding by esophageal or gastric varices and number of bleeding episodes per patient during the treatment period.
• Percentage of patients developing recurrent variceal bleeding, defined as a second episode of variceal bleeding.
• Complications of variceal bleeding, defined as the percentage of patients requiring:
o blood transfusion during an episode of variceal bleeding.
o alternative treatment to variceal bleeding (transjugular intrahepatic portosystemic shunt).
4.4. HEPATIC ENCEPHALOPATHY
• Percentage of patients developing the first episode of HE, grade II or greater, and number of episodes of HE (grade II or greater) per patient during the follow-up period.
• Percentage of patients developing recurrent HE, defined as two episodes of HE grade II or greater within a period of 6 months during the study period.
• Percentage of patients developing severe HE, defined of grade III or IV HE.
• Percentage of patients without minimal HE, as estimated by PHES questionnaire, at entry into the study, who developed minimal HE at some point during follow-up.
4.5. BACTERIAL INFECTIONS
• Percentage of patients developing bacterial infections during the study follow up period, defined by one of the following:
oPresence of infection confirmed by positive cultures and need for antibiotic treatment.
oClinical suspicion of infection based on clinical and analytical data requiring empirical antibiotic therapy.
• Number of infections per patient during the study period requiring hospital admission.
• Percentage of patients developing septic shock. |
1. Time to transplant-free survival. Incidences at 1 month, 3 months, 6 months, 9 months and
12 months.
2. Severity of ACLF assessed by number and types of organ failures at baseline, 1 month, 3
months, 6 months, 9 months and 12 months.
3. Frequency of hospital admissions due to complications of cirrhosis assessed at baseline, 1
month, 3 months, 6 months, 9 months and 12 months.
4. Development/worsening of individual complications of cirrhosis (ascites, acute kidney injury,
gastrointestinal bleeding, hepatic encephalopathy (HE), bacterial infections) assessed at
baseline, 1 month, 3 months, 6 months, 9 months and 12 months
5. Changes from baseline in systemic inflammatory response, evaluated by measurement in a
large array of plasma cytokine levels including, but not limited to TNFa, IL-6, IL8, IL-10, IL-1ß,
IFN-¿, G-CSF, VCAM, VEGF, as well as an oxidized form of albumin, human
nonmercaptalbumin-2 (HNA2), dimethylarginine (ADMA and SDMA) at 3 months, 6 months
and 12 months.
6. Changes from baseline in plasma biomarkers (FABP4, sCD-163), von Willebrand factor (vWF)
and urine biomarkers (NGAL, MCP-1, and albumin) at 3 months, 6 months, and 12 months.
7. Changes from baseline in vasoactive hormones: plasma renin concentration, plasma
norepinephrine and plasma copeptin at 3 months, 6 months and 12 months.
8. Changes from baseline in blood levels of bacterial DNA or bacterial products at 3 months, 6
months and 12 months.
9. To evaluate changes in microbiome composition by analysis of microbial genes and
signature in patients included in the study at baseline, 3 months, 6 months and 12 months.
10. Changes from baseline in liver function, evaluated by MELD score, CLIF-AD score and Child
Pugh Score (see Appendix 4) at 1 month, 3 months, 6 months, 9 months and 12 months.
11. Quality of life, functional assessment and in Minimal Hepatic Encephalopathy during
treatment period, as assessed by CLDQ (Chronic Liver Disease Questionnaire), Liver Frailty
Index and PHES (Psychometric Hepatic Encephalopathy Score) questionnaires at baseline, 1
month, 3 months, 6 months, 9 months and 12 months (see appendix 5, 6 and 7).
12. Changes from baseline in stigmatization in patients with decompensated cirrhosis as
assessed by a previously validated specific questionnaire (see appendix 8) at 3 months, 6
months and 12 months.
13. Appearance of muscle toxicity at baseline, 1 month, 3 months, 6 months, 9 months and 12
months as defined using a specific statin-associated myopathy questionnaire (see appendix 3).
14. Assessment of genetic polymorphisms of statins membrane transporter OATP1B1 in all the
patients included in the study.
15. To evaluate liver or muscle toxicity as defined by analytical changes from baseline in liver
or muscle enzymes (transaminases, alkaline phosphatase and creatine kinase) at 1 month, 3
months, 6 months, 9 months and 12 months.
16. Proportion of patients and severity of treatment-related adverse events during the study
period.
17. Annualized incidence of ACLF.
18. Time to overall and time to disease related survival.; 1. Tempo di sopravvivere senza trapianti. Incidenze a 1 mese, 3 mesi, 6 mesi, 9 mesi e 12mesi.
2. Gravità dell'ACLF valutata in base al numero e ai tipi di guasti agli organi alla baseline, 1 mese, 3
mesi, 6 mesi, 9 mesi e 12 mesi.
3. 3. Frequenza dei ricoveri ospedalieri a causa di complicanze della cirrosi valutata alla baseline, 1
mesi, 3 mesi, 6 mesi, 9 mesi e 12 mesi.
4. 4. Sviluppo/peggioramento delle complicanze individuali della cirrosi (ascite, lesioni renali acute,
sanguinamento gastrointestinale, encefalopatia epatica (HE), infezioni batteriche) valutata alla
baseline, 1 mese, 3 mesi, 6 mesi, 9 mesi e 12 mesi
5. Cambiamenti rispetto alla linea di base della risposta infiammatoria sistemica, valutata mediante misurazione in un
ampia livelli di citochine nel plasma
6. Cambiamenti rispetto alla baseline nei biomarcatori plasmatici (FABP4, sCD-163), fattore von Willebrand (vWF)
e biomarcatori delle urine (NGAL, MCP-1 e albumina) a 3 mesi, 6 mesi e 12 mesi.
7. Cambiamenti rispetto alla linea di base degli ormoni vasoattivi: concentrazione di renina nel plasma, plasma
norepinefrina e copeptina plasmatica a 3 mesi, 6 mesi e 12 mesi.
8. Cambiamenti rispetto alla linea di base nei livelli ematici di DNA batterico o prodotti batterici a 3 mesi, 6
mesi e 12 mesi.
9. Valutare i cambiamenti nella composizione del microbioma attraverso l'analisi dei geni microbici e
firma in pazienti inclusi nello studio alla baseline, 3 mesi, 6 mesi e 12 mesi.
10. Cambiamenti rispetto alla baseline della funzione epatica, valutati in base al punteggio MELD, CLIF-AD score e Child
a 1 mese, 3 mesi, 6 mesi, 9 mesi e 12 mesi.
11. Qualità della vita, valutazione funzionale e nell'encefalopatia epatica minima nel corso di
periodo di trattamento, valutato da CLDQ (Chronic Liver Disease Questionnaire), Liver Frailty
Indice e questionari PHES (Psychometric Hepatic Encephalopathy Score) al baseline, 1
mese, 3 mesi, 6 mesi, |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 12 months from baseline; during the treatment period |
| 12 mesi dalla baseline; Durante il periodo di trattamento |
|
| 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 | No |
| 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 | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 | 32 |
| 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 | 32 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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