Liver Cirrhosis Network Efficacia e sicurezza della rosuvastatina per la cirrosi negli Stati Uniti (LCN RESCU)
Liver Cirrhosis Network (LCN) Efficacia e sicurezza della rosuvastatina per la cirrosi negli Stati Uniti (RESCU): uno studio di fase 2 randomizzato in doppio cieco, controllato con placebo
This is a double-blind, phase 2 study to evaluate safety and efficacy of rosuvastatin in comparison to placebo after 2 years in patients with compensated cirrhosis.
Panoramica dello studio
Stato
Stato
Condizioni
Condizioni
Intervento / Trattamento
Intervento / Trattamento
Descrizione dettagliata
This study is a randomized, double-blind, placebo-controlled Phase 2 clinical trial, of 20mg of rosuvastatin by mouth, once daily. Participants will be randomized (1:1) to either once daily placebo or once daily rosuvastatin.
Patients meeting all eligibility criteria will be assigned to a randomization arm prior to initiation of a 4-week lead-in phase of the study. All participants will undergo a 4-week, open-label active run-in phase to evaluate initial safety and adherence to rosuvastatin. During this active run-phase, all participants will receive target dose rosuvastatin-- 20 mg daily. After the active run-in phase, all participants will continue with their pre-assigned randomization (1:1) treatment of rosuvastatin 20 mg daily or matching placebo.
The total duration of the study will be 96 weeks in the assigned treatment arm plus the 4-week lead-in period. The primary outcome will be the mean change in liver stiffness from the baseline measurement to the end of study liver stiffness, as measured by ultrasound-based vibration-controlled transient elastography (VCTE).
There are 10 participating clinical centers, and we anticipate a total of 260 patients will be recruited for the initial lead-in as we estimate 20% of participants may dropout after the lead-in (260 x 0.8 = 208 for randomization into the study drug treatment phase).
Tipo di studio
Tipo di studio
Iscrizione (Stimato)
Iscrizione
Fase
Fase
- Fase 2
Contatti e Sedi
Contatto studio
Contatto studio
- Nome: Crystal Santillanes, MS
- Numero di telefono: 312-503-5536
- Email: lcn@northwestern.edu
Backup dei contatti dello studio
- Nome: Mary Beth Tull, MBA, CCRP
- Numero di telefono: 312-503-4746
- Email: mary.tull@northwestern.edu
Luoghi di studio
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California
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La Jolla, California, Stati Uniti, 92035
- Reclutamento
- University of California San Diego NAFLD Research Center
-
Contatto:
- Rohit Loomba
- Email: roloomba@health.ucsd.edu
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Los Angeles, California, Stati Uniti, 90033
- Reclutamento
- Keck Medical Center of USC
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Contatto:
- Norah Terrault
- Email: norah.terrault@med.usc.edu
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Los Angeles, California, Stati Uniti, 90033
- Reclutamento
- LAC + USC Medical Center
-
Contatto:
- Norah Terrault
- Email: norah.terrault@med.usc.edu
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San Francisco, California, Stati Uniti, 94143
- Reclutamento
- UCSF Medical Center
-
Contatto:
- Bilal Hameed
- Email: bilal.hameed@ucsf.edu
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San Francisco, California, Stati Uniti, 94110
- Reclutamento
- UCSF/Zuckerberg San Francisco General Hospital and Trauma Center
-
Contatto:
- Mandana Khalili
- Email: Mandana.Khalili@ucsf.edu
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-
Florida
-
Miami, Florida, Stati Uniti, 33122
- Reclutamento
- University of Miami Health System
-
Contatto:
- David Goldberg
- Email: dsgoldberg@med.miami.edu
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-
Michigan
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Ann Arbor, Michigan, Stati Uniti, 48109
- Reclutamento
- University of Michigan
-
Contatto:
- Elliot Tapper
- Email: etapper@med.umich.edu
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-
Minnesota
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Rochester, Minnesota, Stati Uniti, 55901
- Reclutamento
- Mayo Clinic
-
Contatto:
- Doug A. Simonetto, MD
- Numero di telefono: (507) 284-2511
- Email: simonetto.douglas@mayo.edu
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-
New York
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New York, New York, Stati Uniti, 10021
- Reclutamento
- New York Presbyterian/Weill Cornell
-
Contatto:
- Robert Brown
- Email: rsb2005@med.cornell.edu
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New York, New York, Stati Uniti, 10031
- Reclutamento
- Columbia University Iriving School of Medicine
-
Contatto:
- Elizabeth Verna
- Email: ev77@cumc.columbia.edu
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-
North Carolina
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Durham, North Carolina, Stati Uniti, 27710
- Reclutamento
- Duke Liver Center
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Contatto:
- Cynthia Ann Moylan, MD, MHS, MS
- Numero di telefono: 919-681-4044
- Email: cynthia.moylan@duke.edu
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Contatto:
- Mariko Kopping
- Email: mariko.kopping@duke.edu
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Ohio
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Cleveland, Ohio, Stati Uniti, 44192
- Reclutamento
- Cleveland Clinic
-
Contatto:
- Srinivasan Dasarathy
- Email: DASARAS@ccf.org
-
-
Virginia
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Richmond, Virginia, Stati Uniti, 23298
- Reclutamento
- Virginia Commonwealth University
-
Contatto:
- Arun Sanyal
- Email: arun.sanyal@vcuhealth.org
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-
Criteri di partecipazione
Criteri di ammissibilità
Criteri di ammissibilità
Età idonea allo studio
Accetta volontari sani
Sessi ammissibili allo studio
Descrizione
Inclusion Criteria
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Age 18-75 years
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Cirrhosis due to NAFLD, ALD, or chronic viral hepatitis (treated HBV or HCV)
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Clinical diagnosis of cirrhosis as defined by investigator confirmation and the following:
a. At least one liver biopsy within 5 years prior to consent showing either: Metavir stage 4 fibrosis; Ishak Stage 5-6 fibrosis, OR b. At least 2 of the following: i. Evidence on imaging: Nodular liver with either splenomegaly or recanalized umbilical vein within the past 48 weeks ii. Liver stiffness: VCTE within 48 weeks prior to consent or during Screening ≥15.0 kPa or MRE within 48 weeks prior to consent or during Screening ≥5 kPa iii. Evidence of varices demonstrated on imaging or endoscopy within 3 years prior to consent or during Screening iv. Either: FIB-4>2.67 or platelets <150/mL within 6 months prior to consent or during Screening
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Two measures of VCTE: one at screening and one at the open-label dispense study visit, meeting the following criteria:
- The first measure must be ≥ 15.0 kPa.
- The two measures must be at least 2 hours apart and no more than 60 days apart from one another.
- The mean of two measurements must be ≥ 15.0 kPa.
- Additionally, both screening and open-label dispense liver stiffness measures must be ≤50 kPa
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Compensated defined by:
- Absence of ascites/hydrothorax, hepatic encephalopathy or variceal bleeding currently or in the last 48 weeks, as determined clinically by investigator.
- If prior history of decompensation, must be without current symptoms of decompensation and no longer requiring treatment of complications for the last 48 weeks, including the use of diuretics for the treatment of ascites, and/or rifaximin or lactulose for the treatment of hepatic encephalopathy. Use of non-selective beta blockers will be allowed.
- Child-Pugh score <8
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Provision of written informed consent. Exclusion Criteria
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Currently on a statin or any statin exposure within 24 weeks prior to consent.
-
Known indication for statin therapy, defined as:
- Prior peripheral vascular, cardiovascular or cerebrovascular event for which statins are indicated for secondary prevention, OR
- Documented familial hypercholesterolemia, heterozygous familial hypercholesterolemia, OR
- Fasting LDL-C ≥ 190 mg/dL
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Myocardial infarction, Unstable angina, transient ischemic events, or stroke within 24 weeks of screening.
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Alcohol Use Disorder Identification Test (AUDIT) total score of ≥8 at screening.
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Patients with limitations in attending study visits.
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Prisoners.
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Known prior or current hepatocellular carcinoma (HCC) or cholangiocarcinoma.
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Known transjugular intrahepatic portosystemic shunt (TIPS), balloon retrograde transvenous obliteration (BRTO) or porto-systemic shunt surgery regardless of time of occurrence.
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Current (in past 24 weeks prior to consenting) use of medications known to cause hepatic fibrogenesis or confound endpoint assessment, defined as:
- amiodarone
- methotrexate
- warfarin
-
Current (in past 24 weeks prior to consenting) use of medications which may increase risk for rosuvastatin-related myositis or DILI, defined as:
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fenofibrate
-
erythromycin
-
gemfibrozil
-
niacin (500 mg or more)
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HIV protease inhibitors (darunivar, indinavir, nelfinavir, amprenavir)
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colchicine
-
cyclosporin
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Additional medications that will be excluded:
atazanavir/ritonavir capmatinib darolutamide dasabuvir/ombitasvir/paritaprevir/ritonavir ledipasvir/sofosbuvir elbasvir/grazoprevir erythromycin lopinavir/ritonavir regorafenib ritonavir, in any combination simeprevir sofbuvir/velpatasvir/voxilaprevir sofosbuvir/velpatasvir tafamidis tamoxifen teriflunomide
*If exposure was for 7 or less days for one of these medications can consider enrollment after 28 days from final dose.
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Presence of portal or hepatic vein thrombosis
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Diagnosis of untreated hypothyroidism or on unstable treatment regimen for hypothyroidism
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Receiving an elemental diet or parenteral nutrition
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Chronic pancreatitis or pancreatic insufficiency
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Etiology of cirrhosis other than ALD, NAFLD, or viral hepatitis (excluded diagnoses include cryptogenic immune-mediated such as AIH, PSC and PBC, cardiac cirrhosis or Fontan-associated liver disease, A1AT, Wilson's disease, etc.)
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Conditions which may confound study outcome:
a. Unstable or active inflammatory bowel disease b. Active infection c. Any malignant disease (other than squamous or basal cell carcinoma of the skin) within previous 3 years d. Prior solid organ or hematopoietic cell transplant e. Bariatric surgery in the last 24 weeks prior to consent or planned bariatric surgery within the next 96 weeks f. Current liver-unrelated end-stage organ failures such as end-stage renal disease on dialysis, stage 3-4 congestive heart failure (CHF), current chronic obstructive pulmonary disease (COPD) on home oxygen.
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Known current medical or psychiatric conditions which, in the opinion of the investigator, would make the participant unsuitable for the study for safety reasons or interfere with or prevent adherence to the protocol.
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The following laboratory abnormalities within 90 days of screening:
a. Hemoglobin <10 g/dL b. Albumin <3.0 g/dL c. Prolonged international normalized ratio (INR) >1.5 d. Total bilirubin ≥ 2.0 mg/dl (unless due to Gilbert's syndrome or hemolysis as denoted by normal direct bilirubin fraction) e. Direct bilirubin ≥ 0.9 f. Uncontrolled diabetes (HbA1c ≥ 9.5%) within past 90 days.
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Kidney function abnormalities including:
- Dialysis
- Baseline eGFR < 30 cc/min with CKD-Epi equation
- Known nephrotic proteinuria, defined as 3g or greater of protein in 24-hour urine collection
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Recent (within 48 weeks) or present hepatic decompensation with ascites/hydrothorax, hepatic encephalopathy or variceal bleeding
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Untreated chronic hepatitis B or C infection
- HCV eligible for enrollment if HCV RNA negative at baseline or documentation of prior SVR12
- HBV eligible if an HBV DNA <100 IU/mL within the last 48 weeks and on treatment
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Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 200 U/L within the past 24 weeks or alkaline phosphatase (ALP) ≥ 300.
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Documented history of intolerance to statins
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Serious comorbid medical disease which in the investigator's opinion renders a life-expectancy less than 96 weeks
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Active illicit substance use (other than THC), including inhaled or injected drugs, in the 24 weeks prior to screening
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Pregnancy, planned pregnancy or breastfeeding
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Current participation in active medication treatment trials (within 24 weeks prior to randomization) or planned participation in active medication treatment trials simultaneous to participation in present trial.
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Significant existing muscle pain or tenderness or prior history of myasthenia gravis as determined by a site physician.
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Failure or inability to provide informed consent.
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East Asian Descent within one degree of relatedness (e.g., if the participant's parents are of East Asian descent)
Piano di studio
Come è strutturato lo studio?
Dettagli di progettazione
- Scopo principale: Trattamento
- Assegnazione: Randomizzato
- Modello interventistico: Assegnazione parallela
- Mascheramento: Quadruplicare
Numero di armi
Armi e interventi
Gruppo di partecipanti / ArmGruppo di partecipanti / Arm |
Intervento / TrattamentoIntervento / Trattamento |
|---|---|
|
Sperimentale: Active
Open-label lead-in period of 4 weeks on 20 mg rosuvastatin by mouth once daily, followed by a period of 96 weeks rosuvastatin 20 mg daily. |
Patients meeting all eligibility criteria will be assigned to a randomization arm prior to initiation of a 4-week lead-in phase of the study. All participants will undergo a 4-week, open-label active run-in phase to evaluate initial safety and adherence to rosuvastatin. During this active run-phase, all participants will receive target dose rosuvastatin-- 20 mg daily . After the active run-in phase, all participants will continue with their pre-assigned randomization (1:1) treatment of rosuvastatin 20 mg daily or matching placebo.
Altri nomi:
|
|
Comparatore placebo: Placebo
Open-label lead-in period of 4 weeks on 20 mg rosuvastatin by mouth once daily, followed by a period of 96 weeks placebo. |
Patients meeting all eligibility criteria will be assigned to a randomization arm prior to initiation of a 4-week lead-in phase of the study. All participants will undergo a 4-week, open-label active run-in phase to evaluate initial safety and adherence to rosuvastatin. During this active run-phase, all participants will receive target dose rosuvastatin-- 20 mg daily . After the active run-in phase, all participants will continue with their pre-assigned randomization (1:1) treatment of rosuvastatin 20 mg daily or matching placebo.
Altri nomi:
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Cosa sta misurando lo studio?
Misure di risultato primarie
Misure di risultato primarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
|
Mean change in liver stiffness
Lasso di tempo: 96 weeks
|
Mean change in liver stiffness as measured in kilopascal with Vibration-Controlled Transient Elastography between study entry and week 96. Range: 2 to 75 kilopascal. Higher stiffness indicates increased disease progression |
96 weeks
|
Misure di risultato secondarie
Misure di risultato secondarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
|
Time to disease progression
Lasso di tempo: 96 weeks
|
Time to disease progression defined as time to development of decompensation event (ascites, hepatic encephalopathy, variceal bleed) or hepatocellular carcinoma. Analyzed as time-to-event; binary if low counts. |
96 weeks
|
|
All-cause mortality
Lasso di tempo: 96 weeks
|
All-cause mortality: time-to-event, binary if low counts |
96 weeks
|
|
Time to development of ascites
Lasso di tempo: 96 weeks
|
Ascites: time-to-event, binary if low counts |
96 weeks
|
|
Time to development of overt hepatic encephalopathy
Lasso di tempo: 96 weeks
|
Time to development of overt hepatic encephalopathy: time-to-event, binary if low counts |
96 weeks
|
|
Time to development of variceal bleed
Lasso di tempo: 96 weeks
|
Variceal bleed: time-to-event, binary if low counts |
96 weeks
|
|
Time to development of hepatocellular carcinoma
Lasso di tempo: 96 weeks
|
Hepatocellular carcinoma: time-to-event, binary if low counts |
96 weeks
|
|
Change in spleen stiffness as measured by Vibration-Controlled Transient Elastography (VCTE)
Lasso di tempo: 96 weeks
|
Units: kilopascal; Range: 5 to 100 kilopascal; higher stiffness indicates increased disease progression |
96 weeks
|
|
Change in Child-Turcotte-Pugh score
Lasso di tempo: 96 weeks
|
Ordinal score from 5 to 15; higher score indicates further disease progression |
96 weeks
|
|
Change in Model for End Stage Liver Disease - Sodium (MELD-Na)
Lasso di tempo: 96 weeks
|
Unitless; Range: 6-40; higher score indicates further disease progression |
96 weeks
|
|
Change in liver stiffness via Magnetic Resonance Elastography
Lasso di tempo: 96 weeks
|
Units: kilopascal; Range: 0 to 20; higher stiffness indicates increased disease progression |
96 weeks
|
|
Change in Enhanced Liver Fibrosis test
Lasso di tempo: 96 weeks
|
Unitless; Range: 5 to 11; Higher score is worse |
96 weeks
|
|
Change in Fibrosis-4
Lasso di tempo: 96 weeks
|
Unitless; Range: 0 to 10; higher score indicates more stiffness |
96 weeks
|
|
Change in patient-reported quality of life scores
Lasso di tempo: 96 weeks
|
Patient Reported Outcomes Measurement Information System (29-item version) Global Health T-Score: Population centered at 50 points, standard deviation of 10 (higher score signifies "better" health) |
96 weeks
|
|
Rate of adverse events
Lasso di tempo: 96 weeks
|
Count |
96 weeks
|
|
Rate of serious adverse events
Lasso di tempo: 96 weeks
|
Count |
96 weeks
|
|
Rate of adverse events of special interest
Lasso di tempo: 96 weeks
|
Rate of adverse events of special interest (myopathy, drug-induced liver injury, cardiovascular events, cancer other than hepatocellular carcinoma, new onset diabetes as separate outcomes): Count |
96 weeks
|
|
Time to cardiovascular events
Lasso di tempo: 96 weeks
|
Cardiovascular events: time-to-event, binary if low counts |
96 weeks
|
|
Time to new onset diabetes
Lasso di tempo: 96 weeks
|
New onset diabetes: time-to-event, binary if low counts |
96 weeks
|
Collaboratori e investigatori
Sponsor
Sponsor
Collaboratori
Collaboratori
Investigatori
Investigatori
- Investigatore principale: Abigail Smith, PhD, Northwestern University
Pubblicazioni e link utili
Collegamenti utili
Studiare le date dei record
Studia le date principali
Inizio studio (Effettivo)
Inizio studio
Completamento primario (Stimato)
Completamento primario
Completamento dello studio (Stimato)
Completamento dello studio
Date di iscrizione allo studio
Primo inviato
Primo inviato
Primo inviato che soddisfa i criteri di controllo qualità
Primo inviato che soddisfa i criteri di controllo qualità
Primo Inserito (Effettivo)
Primo Inserito
Aggiornamenti dei record di studio
Ultimo aggiornamento pubblicato (Effettivo)
Ultimo aggiornamento pubblicato
Ultimo aggiornamento inviato che soddisfa i criteri QC
Ultimo aggiornamento inviato che soddisfa i criteri QC
Ultimo verificato
Ultimo verificato
Maggiori informazioni
Termini relativi a questo studio
Parole chiave
Termini MeSH pertinenti aggiuntivi
- Processi patologici
- Malattie dell'apparato digerente
- Malattie del fegato
- Disturbi Correlati a Sostanze
- Disturbi indotti chimicamente
- Disturbi correlati all'alcol
- Fegato grasso
- Malattie del fegato, alcoliche
- Disturbi indotti dall'alcol
- Condizioni patologiche, segni e sintomi
- Fibrosi
- Malattia del fegato grasso non alcolica
- Cirrosi epatica
- Cirrosi epatica, alcolica
- Composti di zolfo
- Prodotti chimici organici
- Composti eterociclici, 1-anello
- Composti eterociclici
- Idrocarburi
- Amides
- Pirimidine
- Idrocarburi, alogenati
- Sulfonamidi
- Solfoni
- Fluorobenzenes
- Idrocarburi, fluorurati
- Rosuvastatina Calcio
Altri numeri di identificazione dello studio
Altri numeri di identificazione dello studio
- Pro00070580
- 5U24DK130164-04 (Sovvenzione/contratto NIH degli Stati Uniti)
Piano per i dati dei singoli partecipanti (IPD)
Hai intenzione di condividere i dati dei singoli partecipanti (IPD)?
Descrizione del piano IPD
Dataset with National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Repository.
Tipo di informazioni di supporto alla condivisione IPD
- STUDIO_PROTOCOLLO
- ICF
Informazioni su farmaci e dispositivi, documenti di studio
Studia un prodotto farmaceutico regolamentato dalla FDA degli Stati Uniti
Studia un dispositivo regolamentato dalla FDA degli Stati Uniti
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