Each overweight/mildly obese but otherwise healthy male subjects and female subjects of non-childbearing potential will receive a single dose of AZD2693 dose 1 or placebo in the form of SC injection in the abdomen

Each overweight/mildly obese but otherwise healthy male subjects and female subjects of non-childbearing potential will receive a single dose of AZD2693 dose 2 or placebo in the form of SC injection in the abdomen

Each overweight/mildly obese but otherwise healthy male subjects and female subjects of non-childbearing potential will receive a single dose of AZD2693 dose 3 or placebo in the form of SC injection in the abdomen

Each overweight/mildly obese but otherwise healthy male subjects and female subjects of non-childbearing potential will receive a single dose of AZD2693 dose 4 or placebo in the form of SC injection in the abdomen

Each overweight/mildly obese but otherwise healthy male subjects and female subjects of non-childbearing potential will receive a single dose of AZD2693 dose 5 or placebo in the form of SC injection in the abdomen

Each overweight/mildly obese but otherwise healthy male subjects and female subjects of non-childbearing potential will receive a single dose of AZD2693 dose 6 or placebo in the form of SC injection in the abdomen

Each NASH patient will receive a single dose of AZD2693 dose 7 or placebo in the form of SC injection in the abdomen

Each NASH patient will receive a single dose of AZD2693 dose 8 or placebo in the form of SC injection in the abdomen

Each Japanese subject will receive a single dose of AZD2693 dose 9 or placebo in the form of SC injection in the abdomen

Each Japanese subject will receive a single dose of AZD2693 dose 10 or placebo in the form of SC injection in the abdomen

Each Chinese subject will receive a single dose of AZD2693 dose 11 or placebo in the form of SC injection in the abdomen

Metabolic Diseases

Non-alcoholic Steatohepatitis (NASH)

Within each cohort, subjects/patients will be randomized to receive AZD2693. Dosing for each ascending dose cohort in this study will start with 2 subjects/patients in 1 sentinel cohort, consisting of 1 subject/patient randomized to receive placebo and 1 subject/patient randomized to receive AZD2693.

AZD2693

Within each cohort, subjects/patients will be randomized to receive placebo. Dosing for each ascending dose cohort in this study will start with 2 subjects/patients in 1 sentinel cohort, consisting of 1 subject/patient randomized to receive placebo and 1 subject/patient randomized to receive AZD2693.

Placebo

Research Site

A Study to Understand the Safety, Tolerability of a Single Dose of AZD2693 and How the AZD2693 Behaves Inside the Body When Given to Overweight/Mildly Obese Healthy Male Subjects and Healthy Female Subjects of Non-childbearing Potential and Patients With Non-alcoholic Steatohepatitis

A Phase I, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD2693 Following Single Ascending Dose Administration in Male and Female Subjects of Non-childbearing Potential in 3 Populations: Overweight But Otherwise Healthy Subjects, Healthy Chinese and Japanese Subjects, and Patients With Non-alcoholic Steatohepatitis (NASH) Homozygous for the PNPLA3 148M Risk Allele

To investigate the safety and tolerability of SC administration of single ascending doses of AZD2693

To characterize the PK of AZD2693 following SC administration of SAD of AZD2693

To assess the effect of AZD2693 on changes in LFC using magnetic resonance imaging based proton density fat fraction (MRI-PDFF) compared to placebo

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca

Parexel

This is a randomized, single blind, placebo-controlled study.
Overweight/mildly obese, but otherwise healthy subjects:
Six cohorts of 8 subjects each are planned. Within each cohort, 6 subjects will be randomized to receive AZD2693, at 1 dose level, and 2 subjects randomized to receive placebo.
NASH patients:
Two cohorts, each consisting of 21 subjects are planned. Within each cohort, 14 subjects will be randomized to receive AZD2693 and 7 subjects randomized to receive placebo.
Japanese and Chinese subjects:
Two cohorts of Japanese and one cohort of Chinese subjects are planned. Each cohort will consist of 8 subjects. Within each cohort, 6 subjects will be randomized to receive AZD2693 and 2 subjects randomized to receive placebo.

This study is single blind (in which the study center staff including the Principal Investigator have to remain blinded during the clinical conduct of a given cohort) with regard to treatment (AZD2693 or placebo) at each dose level. The subjects will be blinded throughout the study.

NAFLD

Liver Fibroses

Cardiovascular Diseases

Cardiovascular Risk Factor

Day Service of Internal Medicine and Metabolic Disorders - Policlinico Umberto I - Sapienza University of Rome

Liver Damage and Cardiometabolic Disorders in NAFLD

Progression of LIver Damage and Cardiometabolic Disorders in Non-alcoholic Fatty Liver dIsease: an Observational Cohort STUDY. The Plinio Study

To detect non conventional factors associated with the progression of liver fibrosis in patients with NAFLD. Progression of liver fibrosis will be assessed by non invasive markers (such as FIB-4, Nafld Fibrosis Score e liver elastography). The predictive role of the following factors will be assessed: plasmatic and urinary isoprostanes, thromboxane, platelet recruitment, reactive species of oxygen, nadph oxidase (nox2). Genes of interested will be sequenced.

Non invasive score of liver fibrosis (such as NAFLD fibrosis score, AST-to-Platelets index and FIB-4) will be calculated at baseline and their predictive role on the incidence of major cardiovascular events will be tested

Data on mediterranean diet adherence and on nutrients consumption will be collected and related to NAFLD severity. Data on circulating free fatty acid will be collected.

Plasmatic and urinary thromboxane and platelet recruitment will be measured as markers of platelets activation. Differences of these markers in different degree of NAFLD severity will be investigated

Oxidative stress markers such as plasmatic and urinary isoprostanes, thromboxane, platelet recruitment, reactive species of oxygen, nadph oxidase(nox2) will be measured. The predictive role of these markers on the incidence of cardiovascular events will be tested

To investigate the prevalence of chronic renal failure in Patients with NAFLD. Moreover, genetic, pharmacological and biochemical factors associated with estimated glomerular filtration rate (eGFR) < 90 and with eGFR < 60 will be investigated.

The rate of Kidney disease progression in patients with NAFLD will be measured and will and compared to that in general populations. Predictors of kidney disease progression will be investigated.

Serum Lipopolysaccharide (LPS) and serum zonulin will be measured in NAFLD patients and the correlation between LPS and NAFLD severity will be tested

Measures of systolic and diastolic function will be collected at baseline and correlated with the severity of NAFLD, of metabolic disorders and with genetic mutations correlated with NAFLD.

Performance of classical scores of cardiovascular risk will be tested in patients of NAFLD. In particular, the 2MACE score and the Systemic Coronary Risk Estimation (SCORE) will be tested. 2MACE score will be calculated assigning 2 points for Metabolic Syndrome and Age ≥75, 1 point for MI/revascularization, Congestive heart failure (ejection fraction ≤40 %), thrombo-Embolism (stroke/transient ischemic attack. The score, ranging from 0 to 7 points, will be considered positive for values higher than 2. SCORE will be calculated using age, sex, systolic blood pressure, smoking status, total and HDL cholesterol. The SCORE system estimates the 10-year cumulative risk of a first fatal atherosclerotic event. In absence of a good performance of pre-existing scores, we'll try to assess a specific cardiovascular risk score in NAFLD patients.

The predictive role of triglycerides rich lipoproteins and cholesterol remnants will be evaluated.

Plasmatic and urinary isoprostanes will be measured as markers of systemic oxidative stress and of antioxidant status in NAFLD and NASH. Differences of these markers in different degree of NAFLD severity will be investigated

Reactive species of oxygen will be measured as markers of systemic oxidative stress and of antioxidant status in NAFLD and NASH. Differences of these markers in different degree of NAFLD severity will be investigated

Nadph oxidase (nox2) activation will be estimated as markers of systemic oxidative stress and of antioxidant status in NAFLD and NASH. Differences of these markers in different degree of NAFLD severity will be investigated

Francesco Violi

Department Head

University of Roma La Sapienza

Subjects in the control condition will be instructed to continue their medical care at the discretion of their treating medical professional. They will be informed to maintain their current physical activity level. Weekly phone calls will be performed by study personnel to ensure adherence to the protocol (no changes in activity). Subjects will report to Penn State on a monthly basis for anthropometric assessment to confirm their self-reports and study investigators will perform and interim history and physical examination at that time.

Subjects in the aerobic exercise group will be supervised to exercise 30 minutes, 5 times per week at a moderate intensity. Formal exercise instruction and supervision will be provided by ACSM certified fitness professionals at the Penn State University Fitness Center. Aerobic exercise can be completed on either the treadmill, exercise bike, rowing machine or the elliptical machine.

Liver Diseases

Blood Disorder

Digestive System Disease

Aerobic Exercise

Penn State Hershey Medical Center

NASH Fitness Intervention in Thrombosis Trial (NASHFit)

The primary outcome of interest is change in fibrinolysis as measured by PAI-1 level immediately following completion of the exercise program.

genotyping subjects (GG, GC and CC genotypes)

measured by magnetic resonance imaging proton density fat fractionation (MRI-PDFF)

Jonathan Stine

Assistant Professor Medicine

Milton S. Hershey Medical Center

Hypocaloric Mediterranean diet for a 4-month period;
Aerobic exercise training for a 4-month period;

Hypocaloric low fat diet supplemented by branched and essential amino acids considering the total protein intake for a 4- month period;
Aerobic exercise training for a 4- month period;

Non-alcoholic Fatty Liver Disease

Obesity

In the Mediterranean diet fat intake will be equal to 35% of the total energy intake minus carbohydrate and protein energy carbohydrate as 65% of total calorie intake, dietary cholesterol <300 mg/day, dietary fiber 25 g/day.

Mediterranean diet

In the hypocaloric low fat diet, fat will represent less than 25% of the total energy intake. Branched and essential amino acids will be administered taking into account the total protein intake.

Low fat diet

A personalized program of aerobic exercise will be prescribed to the participants of both arms, following the "FITT" principles (frequency, intensity, time and type).

Aerobic exercise

Stefano Ginanni Corradini

Department of Clinical Medicine, Sapienza University of Rome, Umberto I Hospital

Study on Metabolic Flexibility and Gut Microbiota Composition in Obese Subjects With NAFLD, Taking Into Account PNPLA3 and TM6SF2 Polymorphisms. Effects of Nutritional Intervention Combined to Exercise

Body Composition, Adiposity Phenotype, Metabolic Flexibility, and Gut Microbiota in PNPLA3 and TM6SF2 Gene Variant Carriers and Non-carriers With Nonalcoholic Fatty Liver Disease and Obesity. Effects of a Nutritional Intervention Combined to Exercise

patatin/obesidad

A Study to Understand the Safety, Tolerability of a Single Dose of AZD2693 and How the AZD2693 Behaves Inside the Body When Given to Overweight/Mildly Obese Healthy Male Subjects and Healthy Female Subjects of Non-childbearing Potential and Patients With Non-alcoholic Steatohepatitis

Liver Damage and Cardiometabolic Disorders in NAFLD

NASH Fitness Intervention in Thrombosis Trial (NASHFit)

Study on Metabolic Flexibility and Gut Microbiota Composition in Obese Subjects With NAFLD, Taking Into Account PNPLA3 and TM6SF2 Polymorphisms. Effects of Nutritional Intervention Combined to Exercise

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