A Phase 2, Prospective, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Saroglitazar Magnesium 2 mg and 4 mg in Patients With Non-alcoholic Steatohepatitis (NASH)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 16
- 试验地点
- 6
- 主要终点
- NAS Score (Nonalcoholic Fatty Liver Disease [NAFLD] Activity Score)
研究概览
简要总结
This is a randomized, double-blind, placebo-controlled study to evaluate safety and efficacy of Saroglitazar Magnesium 2 mg and 4 mg in patients with NASH. This study will be initiated after obtaining the approvals of Institutional Ethics Committee/Institutional Review Board (IEC/IRB) and the local regulatory authority.
详细描述
Patients clinically suspected of NASH will be invited for a screening programme for inclusion in the study. Patients will be screened according to the inclusion and exclusion criteria. Clinical evaluation will be conducted for baseline characteristics and anthropometry measurements such as body weight and height.
After clinical evaluations, all baseline safety and efficacy parameters will be recorded as per Visit Schedule. All laboratory collections will be performed following overnight fasting (at least 8 hrs).
Following confirmation of all clinical and laboratory inclusion and exclusion criteria, patients will continue into the screening period. During the screening period liver biopsy will be performed. However, if a biopsy was performed within 6 months the slides and biopsy material, or block, must be made available for baseline documentation. Such Patients, whose historical biopsy report is available, should not use medication suspected of having an effect on NASH from the 3 months prior to the screening.
Liver biopsy will be performed to confirm the diagnosis of NASH and record a baseline Non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS). The histological evidence of NASH is defined as NAS ≥ 4 with a minimum score of 1 for all of its three components [steatosis, hepatocyte ballooning and lobular inflammation].
Following confirmation of inclusion/exclusion criteria and upon histological confirmation of NASH by liver biopsy, patients will be enrolled into the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients able to provide written informed consent for participation in this trial.
- •Males or females, 18 to 75 years of age, both inclusive.
- •Female must be either of non-child bearing potential (surgically sterilized at least 6 months prior to screening or postmenopausal) or using one or more methods of contraception.
- •Histologic confirmation of NASH without cirrhosis (fibrosis stage 0, 1, 2, or 3) from liver biopsy performed either during the screening period or no more than 6 months prior to the first visit, with a NAS of ≥4 and a score of at least 1 in each (steatosis scored 0-3, ballooning scored 0-2, and lobular inflammation scored 0-3). If biopsy was performed within 6 months of screening, the slides, biopsy material or block should be available for baseline documentation. Such patients, whose historical biopsy report is available, should not use medications suspected of having an effect on NASH for at least 3 months prior to the screening.
- •BMI ≥25 kg/m^
- •For hypertensive patients, blood pressure must be controlled by a stable dose of antihypertensive medications for at least 3 months prior to screening (and the stable dose can be maintained throughout the study)
- •Patients with type 2 diabetes mellitus may be included if they fulfil the following criteria;
- •Stable therapeutic regimen as defined by no changes in oral agents or dose for at least 3 months before screening and the stable dose can be maintained throughout the study.
- •HbA1c ≤ 9.5%
- •Patients agree to comply with the study procedure.
排除标准
- •Pregnant and lactating female.
- •Positive pregnancy test.
- •Patients with history of myopathies or evidence of active muscle diseases.
- •Patients with history of alcohol consumption of >30 gm/day for men, >20 gm/day for women for consecutive previous 2 years and/or drug abuse.
- •Known allergy, sensitivity or intolerance to the study drug or formulation ingredients.
- •Participation in an interventional clinical study and/or receipt of any investigational medication within 3 months prior to screening.
- •History of malignancy in the past 5 years and/or active neoplasm with the exception of superficial, non-melanoma, skin cancer.
- •Any of the following laboratory values at screening:
- •Direct bilirubin >1.5 mg/dL,
- •Serum albumin <2.5 g/dL.
- •Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m
- •Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >200 IU/L.
- •Patient with international normalized ratio (INR) >1.
- •Creatinine kinase ≥ 1.5 upper limit of normal (ULN).
- •Lipase ≥ULN.
- •Amylase ≥ ULN.
- •Unstable cardiovascular disease, including:
- •unstable angina, (i.e., new or worsening symptoms of coronary heart disease within the 3 months preceding screening), acute coronary syndrome within the 6 months preceding Screening, acute myocardial infarction within the 3 months preceding screening or heart failure of New York Heart Association class (III - IV) or worsening congestive heart failure, or coronary artery intervention, within the 6 months preceding screening
- •history of (within 3 months preceding Screening) or current unstable cardiac dysrhythmias
- •uncontrolled hypertension (systolic blood pressure [BP] > 155 mmHg and/or diastolic BP > 95 mmHg)
- •Stroke or transient ischemic attack within the 6 months preceding screening.
- •Previous history of bladder disease and/or hematuria.
- •Previous liver biopsy that demonstrated presence of cirrhosis or radiologic imaging consistent with cirrhosis or portal hypertension.
- •Type 1 diabetes mellitus.
- •Use of drugs that are known Cytochrome P4502C8 (CYP2C8) inhibitors/substrate.
- •Use of drugs associated with a clinical or histological picture consistent with fatty liver disease or NASH for more than 12 consecutive weeks in the 1 year prior to start of the study; (these include amiodarone, tamoxifen, methotrexate, glucocorticoids, anabolic steroids, tetracyclines, estrogens, valproate/valproic acid, chloroquine, anti-HIV drugs).
- •History of thyroid disease (hypothyroid patients who are euthyroid on thyroid hormone replacement can be included).
- •History of, or current, cardiac dysrhythmias.
- •History of bariatric surgery, or undergoing evaluation for bariatric surgery.
- •Patients with a >10% weight loss in the 3 months prior to screening.
- •History or other evidence of severe illness or any other conditions that would make the patient, in the opinion of the Investigator, unsuitable for the study (such as poorly controlled psychiatric disease, coronary artery disease, HIV or active gastrointestinal conditions that might interfere with drug absorption).
- •Patients on any treatment with other drugs used for treatment of NASH [pentoxyphyllin, ursodeoxycholic acid, antioxidants such as vitamin E (>800 IU/day), glutathione, orlistat, betaine, incretin mimetics or non-prescribed complementary alternative medications (including dietary supplements, megadose vitamins, herbal preparations and special teas)] or any medicine in clinical trials for NASH. (However, patients who are taking stable dose of vitamin E for at least 3 months prior to screening will be enrolled in the study).
- •History of other causes of chronic liver disease [autoimmune, primary biliary cirrhosis, hepatitis B virus (HBV) and hepatitis C virus (HCV), Wilson disease, alpha-1-antitrypsin deficiency, hemochromatosis etc.
研究组 & 干预措施
Saroglitazar Magnesium 2 mg
Saroglitazar Magnesium 2 mg tablet orally once daily in the morning before breakfast for 24 weeks.
干预措施: Saroglitazar Magnesium 2mg (Drug)
Saroglitazar Magnesium 4 mg
Saroglitazar Magnesium 4 mg tablet orally once daily in the morning before breakfast for 24 weeks.
干预措施: Saroglitazar Magnesium 4mg (Drug)
Placebo
Placebo tablet orally once daily in the morning before breakfast for 24 weeks.
干预措施: Placebos (Drug)
结局指标
主要结局
NAS Score (Nonalcoholic Fatty Liver Disease [NAFLD] Activity Score)
时间窗: Baseline to Week 24
The primary endpoint is to assess the changes in NAFLD Activity Score (NAS) at week 24 from baseline and with no worsening of fibrosis in NASH patients. NAFLD Activity Score Steatosis \<5% - 0 5% -33% - 1 \>33% -66% - 2 \>66% - 3 Lobular Inflammation No foci - 0 \<2 foci per 200 X field -1 2-4 foci per 200 X field - 2 \>4 foci per 200 X field - 3 Ballooning None - 0 Few balloon cells -1 Many cells/prominent ballooning - 2 Final NAFLD Activity Score = Steatosis Score + Lobular Inflammation Score + Ballooning Score Minimum score for NAS is 0 Maximum score for NAS is 8 Higher score represents the worse disease activity
次要结局
- To Evaluate the Percentage of Responders in the Treatment Groups.(Baseline to Week 24)
- Percentage of Responders Defined by the Disappearance of Steatohepatitis.(Baseline to Week 24)
- Changes in the Stage of Steatosis, Lobular Inflammation and Ballooning.(Baseline to Week 24)
- Changes in the Stage of Fibrosis.(Baseline to Week 24)
- Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]).(Baseline to Week 24)
- Changes in the Liver Function Tests; Albumin and Total Protein(Baseline to Week 24)
- Changes in the Liver Function Tests; Direct Bilirubin(Baseline to Week 24)
- Changes in the Lipid Profile.(Baseline to Week 24)
- Number of Participants Experiencing Adverse Events After Consuming Saroglitazar Magnesium 2 mg and 4 mg(Baseline to Week 24)
- Changes in the Glycemic Control and Insulin Resistance; Fasting Plasma Glucose(Baseline to Week 24)
- Changes in the Glycemic Control and Insulin Resistance; Hemoglobin A1c(Baseline to Week 24)
- Changes in the Glycemic Control and Insulin Resistance; Insulin(Baseline to Week 24)
- Changes in the Glycemic Control and Insulin Resistance: C-peptide(Baseline to Week 24)
- Changes in the Glycemic Control and Insulin Resistance: Homeostasis Model Assessment of Beta Cell Function (HOMA -β)(Baseline to Week 24)
- Changes in the Glycemic Control and Insulin Resistance: HOMA of Insulin Resistance(Baseline to Week 24)
- Changes in the Glycemic Control and Insulin Resistance: Total Adiponectin(Baseline to Week 24)