Safety and Tolerability of Yaq-001 in Patients With Non-Alcoholic Steatohepatitis ("NASH-Safety")
试验速览
- 阶段
- 不适用
- 状态
- 撤回
- 发起方
- Yaqrit Ltd
- 试验地点
- 18
- 主要终点
- Assessment of treatment-related Serious Adverse Events
研究概览
简要总结
Gut-derived endotoxaemia, microbial imbalance and bacterial translocation play an increasingly recognized role in the progression from non-alcoholic fatty liver disease (NAFLD) to its more advanced state, NASH (non-alcoholic steatohepatitis). Animal model studies confirmed that Yaq-001 reduces liver injury and prevents steatosis in these models which leads to the theoretical potential of Yaq-001 altering the microbiome and gut permeability in patients with NASH.
The purpose of this clinical trial is to study the safety and tolerability of Yaq-001 in patients with NASH. Results from this study will lead to the design of future pivotal performance and safety trials for registration purposes.
Candidate patients must be between 18-70 years old and have a clinical diagnosis of NASH, determined histologically or phenotypically, as well as meeting other clinical inclusion/exclusion criteria.
Eligible patients will be randomly assigned to receive standard of care treatment plus Yaq-001, or standard of care treatment plus placebo).
The treatment lasts for 48 weeks. During treatment, the patient will have 6 study visits. At all the visits, the patients will undergo a routine physical examination, electrocardiogram, collection of blood and urine samples. On three occasions the patients will be asked to provide additional samples of blood, urine and stool for analysis outside the hospital. On two occasions the patient will have a liver Multiscan and on three occasions the patient will have a liver Fibroscan.
70 patients from 9 hospitals in UK, France, Italy, Portugal, Spain and Switzerland will participate in this study.
详细描述
This is a multicentre, randomized, double blinded, placebo controlled trial to intended to evaluate safety and tolerability of oral administration of Yaq-001 therapy.
70 Non-Alcoholic Steatohepatitis patients will be randomized (1:1) to:
- Standard medical treatment + Yaq-001 (8 g/ day) - n= 35
- Standard medical treatment + placebo-control (placebo for 8 g of Yaq-001/ day) - n= 35
Study patients will be dosed daily with Yaq-001 (or an equivalent quantity of placebo) for 48 weeks.
Assessment of DSMB will take place when 15 Yaq-001- and 15 placebo-treated patients have completed 12 weeks of dosing.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Placebo
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 <70 years at screening
- •HbA1C < 10.5%
- •BMI >25kg/m2
- •ALT <250IU/L
- •Ability to provide informed consent
- •Agree to the use of effective contraceptive measures if either male or female of child bearing potential.
排除标准
- •History of metabolic acidosis or ketoacidosis
- •Presence of vascular liver disease
- •Cirrhosis diagnosed either histologically, by laboratory or clinically;
- •Presence of liver disease of other aetiology (autoimmune, metabolic, medication induced);
- •HIV antibody positive, hepatitis B surface antigen positive (HBsAg) or Hepatitis C virus (HCV)-RNA positive;
- •Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening (significant alcohol consumption is defined as more than 20 grams per day in females and more than 30 grams per day in males, on average)
- •Type 1 diabetes;
- •History of bariatric intervention (surgical or endoscopic) performed 6 months or more prior to screening;
- •Weight loss or gain of 5kg or more in the past 3 months or >10% change in bodyweight in the past 3 months;
- •Inadequate venous access;
- •Lactating/breastfeeding/pregnant at Screening or Baseline;
- •Receiving an elemental diet or parenteral nutrition;
- •Medical conditions, such as:
- •Inflammatory bowel disease;
- •Unstable angina, myocardial infarction, transient ischemic events, or stroke within 24 weeks of Screening;
- •Active infection
- •Active autoimmune disease
- •Malignant disease at any time
- •Severe congestive heart failure (current medical therapy or current clinical evidence of congestive heart failure NHYA class III/IV) Persistent, uncontrolled hypertension despite optimal medical treatment (for example: Systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure (DBP) >100 mmHg (average of 2 readings) measured in the sitting position at Visit 1, after at least 5 minutes seated rest at screening).
- •Any other medical condition which, in the opinion of the investigator, could impact adversely on the subject participating or on the interpretation of the study data
- •Presence of clinically relevant cardiovascular, pulmonary, gastrointestinal, renal, hepatic, metabolic, haematological, neurological, psychiatric, systemic, ocular, gynaecologic or any acute infectious disease or signs of acute illness that, in the opinion of the investigator, might compromise the patient's safe participation in the trial
- •Concurrent medications including:
- •Anti-NASH therapy(s) taken for more than 10 continuous days in the last 3 months. These include S-adenosyl methionine (SAM-e), betaine, milk thistle, probiotic supplements (other than yoghurt), vitamin E and gemfibrozil.
- •Wash out for any of the anti-NASH therapies is as follows: under 10 days no washout required, more than 10 days and up to 3 months treatment requires 6 weeks washout.
- •Use of drugs historically associated with non-alcoholic fatty liver disease (NAFLD) (amiodarone, methotrexate, systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone replacement, anabolic steroids, valproic acid, and other known hepatotoxins) during the previous year prior to randomization
- •Thiazolidinediones (glitazones), or glucagon-like peptide-1 analogues in the last 90 days.
- •NOTE: Allowable anti-diabetic treatment includes metformin and/or sulfonylureas and/or dipeptidyl peptidase 4 inhibitors (gliptins) administered at constant dose for at least 2 months prior to study entry
- •NOTE: Subjects treated with Insulin are eligible if clinically stable on insulin treatment (i.e. no recurrent acute hypo-/hyperglycaemic episodes diagnosed clinically and by Glucose serum levels of <50 mg/dL and >200 mg/dL respectively) for at least 2 months prior to study entry
- •immune modulatory agents including: systemic steroids for more than 7 days; daily treatment with multiple non-steroidal anti-inflammatory drugs (such as aspirin (>100mg/day), ibuprofen, naproxen, meloxicam, celecoxib) for more than 1 month
- •Use of ursodeoxycholic acid (Ursodiol, Urso) or obeticholic acid (Ocaliva) within 90 days prior to enrolment
- •In the last 6 months:
- •azathioprine, 6-mercaptopurine, methotrexate, cyclosporin, anti-TNFα therapies (infliximab, adalimumab, etanercept) or anti-integrin therapies (namixilab)
- •More than 10 consecutive days oral or parenteral antibiotics within 4 weeks prior to study entry. NOTE: subjects administered with antibiotics for more the 5 days prior to study entry would not be included in the stool and PBMC analysis
- •Within the preceding 4 weeks before treatment:
- •immunosuppression, long acting benzodiazepine or barbiturates and antiviral medication
- •The following laboratory abnormalities:
- •Neutrophil count ≤1.0 x 109/L; Platelets <100 x 109/L
- •Haemoglobin <10g/dL; Albumin <3.5g/dL
- •International Normalized Ratio (INR) >1.5
- •Total bilirubin >1.5 x upper limit of reference range (unless Gilbert's syndrome or extrahepatic source as denoted by increased indirect bilirubin fraction)
- •Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 at Screening or Baseline using the Modification of Diet in Renal Disease (MDRD) equation.
- •Creatine Phosphokinase >5x ULN
- •Past history of acute pancreatitis with current triglycerides 400 mg/dL at Visit
- •Any planned major surgery to be performed during the study (e.g., coronary artery bypass surgery, abdominal aortic aneurysm repair, etc.).
- •Clinical evidence of hepatic decompensation as defined by the presence of any of the following abnormalities:
- •Serum albumin less than 3.4 grams/deciliter (g/dL)
- •International Normalized Ratio (INR) greater than 1.3
- •Total bilirubin greater than 1.5 milligrams per deciliter (mg/dL)
- •Direct bilirubin greater than 0.4 milligrams per deciliter (mg/dL)
- •History of esophageal varices, ascites or hepatic encephalopathy
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结局指标
主要结局
Assessment of treatment-related Serious Adverse Events
时间窗: Week 48
The percentage of patients experiencing device-related SAEs will be tabulated by arm.
Assessment of withdrawals due to Adverse Events
时间窗: Week 48
The percentage of patients who withdraw due to an AE will be tabulated by arm.
Assessment of reported and observed Serious Adverse Events
时间窗: Week 48
The percentage of patients experiencing SAEs will be tabulated by arm.
次要结局
- Determine potential of Yaq-001 for the treatment of NASH(From Baseline at 1, 12, 24, 36 and 48 weeks)
- Assessment of changes in nutritional status(Baseline, Weeks 24 and 48)