Body-weight Reduction Effect on Portal Hypertension in Compensated Cirrhosis (B-REACH)
Efficacy and Safety of Mazdutide Injection for the Treatment of Overweight Patients With Compensated Cirrhosis and Clinically Significant Portal Hypertension
Obesity and metabolic abnormalities accelerate decompensation in compensated cirrhosis, driven by clinically significant portal hypertension (CSPH, HVPG≥10 mmHg). Lifestyle-induced weight loss can lower portal pressure, but pharmacological options are limited. Mazdutide, a dual GLP-1/glucagon receptor agonist, has proven weight-loss and glycaemic benefits, yet its safety and efficacy in cirrhosis with portal hypertension are unknown. This investigator-initiated, single-arm, open-label, exploratory trial evaluates whether mazdutide can safely reduce portal pressure in overweight patients with compensated cirrhosis and CSPH.
The main questions it aims to answer are:
Does 16-week mazdutide treatment reduce HVPG (percentage change from baseline)? What adverse events occur, and is the drug tolerated?
Participants will:
Receive mazdutide SC injection once weekly for 16 weeks, titrated from 2 mg to 4 mg to 6 mg (if tolerated), with dose adjustment for intolerance.
Undergo HVPG at baseline and week 16 (primary endpoint). Have FibroScan® (liver/spleen stiffness, CAP) at baseline and weeks 4, 8, 12, 16.
Provide blood samples for liver, renal, glucose, lipid, and coagulation tests at each visit.
Undergo body composition, handgrip strength, and nutritional assessments to monitor muscle mass.
Attend clinic visits every 4 weeks during treatment and one follow-up visit 4 weeks post-treatment.
Key eligibility: Adults 18-75 with compensated cirrhosis (viral, MASLD, or alcohol-related), HVPG≥10 mmHg, BMI≥28 or ≥26 with comorbidities, stable weight, and stable carvedilol/propranolol if used. Exclude prior decompensation, HCC, CTP≥B8, eGFR<60, mazdutide contraindications, active infection, uncontrolled hepatitis, portal vein thrombosis, etc.
Endpoints: Primary - % change in HVPG. Secondary - HVPG response (≥10% decrease or <10 mmHg), decompensation events, treatment discontinuation due to AEs. Exploratory - changes in stiffness, liver fat, metabolic parameters, body composition, nutrition.
Safety: AEs (CTCAE v5.0), labs, vitals, with special monitoring for GI symptoms, dehydration, renal function, hepatic encephalopathy, muscle loss, pancreatitis, and gallbladder events.
Sample size and analysis: 50 patients. Primary endpoint analysed by paired t-test or Wilcoxon (α=0.05, two-sided) in FAS and PPS. Secondary endpoints mainly descriptive; key secondary tested for support. Subgroup analyses planned if feasible.
Study duration: 20 weeks (2-week screening, 16-week treatment, 4-week follow-up). Conducted at Second Affiliated Hospital of Chongqing Medical University, China. Ethics approved, informed consent required. This study will provide first evidence on mazdutide for portal hypertension in overweight cirrhosis.
研究概览
研究类型
注册 (估计的)
阶段
- 不适用
参与标准
资格标准
适合学习的年龄
- 成人
- 年长者
接受健康志愿者
描述
Inclusion Criteria:
- Aged 18 to 75 years (inclusive), male or female.
- Documented etiology of chronic liver disease, limited to chronic hepatitis B, chronic hepatitis C, metabolic dysfunction-associated steatotic liver disease (MASLD), or alcohol-related liver disease.
- Cirrhosis confirmed by imaging (ultrasound, CT, or MRI), or pathology showing F3/F4 fibrosis, or liver stiffness measurement (LSM) ≥15 kPa by vibration-controlled transient elastography (VCTE).
- Hepatic venous pressure gradient (HVPG) ≥10 mmHg.
- Body mass index (BMI) ≥28 kg/m², or BMI ≥26 kg/m² with at least one weight-related comorbidity (e.g., hyperglycemia, hypertension, dyslipidemia, fatty liver, obstructive sleep apnea syndrome).
- Stable body weight over the past 6 months, defined as weight fluctuation <3 kg.
- For patients with gastroesophageal varices requiring carvedilol or propranolol, the dose must have been stable for at least 3 months with no planned dose adjustments during the trial.
- Voluntarily signed informed consent form.
Exclusion Criteria:
- Concurrent hepatocellular carcinoma or other malignancies (excluding cured basal cell carcinoma of the skin).
- Prior history of clinically significant decompensation events (grade 2/3 ascites, overt hepatic encephalopathy, or gastroesophageal variceal bleeding).
- Progressive jaundice during the screening period.
- Hepatic impairment defined as Child-Turcotte-Pugh (CTP) score ≥B8 at screening.
- Moderate to severe renal impairment (eGFR <60 mL/min) or current renal replacement therapy.
- Contraindications to mazdutide: known allergy, personal or family history of medullary thyroid carcinoma, or multiple endocrine neoplasia syndrome type 2.
- Previous or current use of other weight-loss interventions (e.g., bariatric surgery, endoscopic bariatric procedures, other weight-loss drugs).
- Participation in another interventional clinical trial within 3 months prior to screening, or previous treatment with mazdutide.
- Active infection at screening.
- For alcohol-related cirrhosis: alcohol abstinence <6 months or ongoing alcohol consumption. For viral cirrhosis (hepatitis B/C): failure to achieve virologic suppression (HBV-DNA <100 IU/mL for hepatitis B; for hepatitis C, HCV-RNA below the lower limit of detection after >12 weeks of antiviral therapy).
- Prior portal-systemic shunt surgery (e.g., splenectomy).
- Previous orthotopic liver transplantation.
- Known portal vein thrombosis.
- Contraindications to trial assessments, e.g., inability to undergo HVPG measurement.
- Pregnancy or breastfeeding, or unwillingness to use investigator-approved contraception during the study and for 6 months after the study end.
- Psychiatric or cognitive disorders that interfere with study compliance.
- Any other condition judged by the investigator to make the participant unsuitable for participation.
学习计划
研究是如何设计的？
设计细节
- 主要用途：治疗
- 分配：不适用
- 介入模型：单组作业
- 屏蔽：无（打开标签）
武器和干预
参与者组/臂 |
干预/治疗 |
|---|---|
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实验性的：Experimental: Mazdutide (2/4/6 mg Titration) SC QW
|
Mazdutide injection is a sterile, clear to almost colorless liquid formulated for subcutaneous administration.
It is supplied in three fixed-dose strengths for this study: 2 mg/0.5 mL, 4 mg/0.5 mL, and 6 mg/0.5 mL.
Participants assigned to this arm receive once-weekly subcutaneous injections over a 16-week active treatment period.
The regimen begins with a forced dose-titration phase: 2 mg weekly for the first 4 weeks, followed by 4 mg weekly for the next 4 weeks, and then 6 mg weekly for the final 8 weeks, provided the preceding dose is tolerated.
In cases of treatment-emergent adverse events (CTCAE grade ≥2 or intolerable grade 1), the investigator may temporarily withhold the dose, step down to the next lower dose level (6 mg→4 mg→2 mg), or permanently discontinue the drug.
After symptom resolution, gradual re-escalation (2 mg→4 mg→6 mg) may be attempted at the investigator's discretion.
|
研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Percentage Change in Hepatic Venous Pressure Gradient (HVPG) from Baseline
大体时间：Baseline (screening, Day -14 to -1) to Week 16 (End of Treatment, Day 112 ± 3 days)
|
Percentage change in HVPG (measured in mmHg) from baseline to week 16.
HVPG is calculated as the difference between wedged hepatic venous pressure (WHVP) and free hepatic venous pressure (FHVP), measured via hepatic vein catheterization under fasting conditions.
A negative percentage change indicates a reduction in portal pressure.
HVPG measurements will be performed in triplicate through the same hepatic vein, preferably in the morning, at baseline (screening period) and at week 16 (end-of-treatment visit, Day 112).
All measurements follow a standardized procedure by experienced operators (≥25 HVPG measurements annually).
|
Baseline (screening, Day -14 to -1) to Week 16 (End of Treatment, Day 112 ± 3 days)
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次要结果测量
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Proportion of Participants Achieving HVPG Response
大体时间：Baseline to Week 16 (End of Treatment, Day 112 ± 3 days)
|
Proportion of participants with a reduction in HVPG of ≥10% from baseline, or a reduction to an absolute value of <10 mmHg at week 16.
HVPG is measured via hepatic vein catheterization in triplicate under fasting conditions.
|
Baseline to Week 16 (End of Treatment, Day 112 ± 3 days)
|
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Incidence of Hepatic Decompensation Events
大体时间：Baseline up to Week 16 (End of Treatment)
|
Number of participants experiencing any first or recurrent decompensation event during the treatment period, including: overt ascites (requiring paracentesis or diuretic escalation), overt hepatic encephalopathy (West Haven grade ≥2), or gastroesophageal variceal bleeding (confirmed by endoscopy or imaging).
|
Baseline up to Week 16 (End of Treatment)
|
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Treatment Discontinuation Due to Adverse Events
大体时间：Day 1 (First dose) to Week 16 (End of Treatment)
|
Number of participants who permanently discontinue study drug due to any adverse event (AE) during the 16-week treatment period, regardless of causality.
Reasons for discontinuation will be summarized by system organ class and preferred term.
|
Day 1 (First dose) to Week 16 (End of Treatment)
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Change in Liver and Spleen Stiffness
大体时间：Baseline to Week 16 (End of Treatment, Day 112 ± 3 days)
|
Absolute change (kPa) and percentage change in liver stiffness measurement (LSM) and spleen stiffness measurement (SSM) from baseline to week 16, assessed by vibration-controlled transient elastography (VCTE™, FibroScan®) under fasting conditions.
|
Baseline to Week 16 (End of Treatment, Day 112 ± 3 days)
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其他结果措施
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Liver stiffness measured by VCTE
大体时间：Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
Change from baseline in liver stiffness assessed by Vibration-Controlled Transient Elastography (VCTE).
Unit of measure: kPa
|
Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
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|
Spleen Stiffness measured by VCTE
大体时间：Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
Change from baseline in spleen stiffness assessed by Vibration-Controlled Transient Elastography (VCTE).
Unit of measure: kPa.
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Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
|
Liver Fat Content measured by Controlled Attenuation Parameter (CAP)
大体时间：Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
Change from baseline in liver fat content assessed by CAP.
Unit of measure: dB/m.
|
Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
|
Liver Function Tests (ALT, AST, Bilirubin, Albumin)
大体时间：Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
Change from baseline in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and direct bilirubin, and albumin.
These assessments have different units (ALT/AST in U/L; bilirubin in μmol/L or mg/dL; albumin in g/L) and will be reported individually without aggregation into a composite value.
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Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
|
Coagulation Function (PT, INR, APTT)
大体时间：Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
Change from baseline in prothrombin time (PT, in seconds), international normalized ratio (INR, dimensionless ratio), and activated partial thromboplastin time (APTT, in seconds).
These assessments with different units will be reported separately.
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Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
|
Renal Function (eGFR)
大体时间：Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
Change from baseline in estimated glomerular filtration rate calculated using the CKD-EPI or MDRD formula.
Unit of measure: mL/min/1.73m².
|
Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
|
Body Composition Indices (BMI, Waist-to-Hip Ratio, Waist-to-Height Ratio)
大体时间：Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
Change from baseline in body composition indices.
Note on aggregation: Weight (kg) and height (m) will be combined to calculate BMI (kg/m²); waist circumference (cm) and hip circumference (cm) will be combined to calculate waist-to-hip ratio and waist-to-height ratio (both expressed as dimensionless ratios).
All derived indices will be reported individually.
|
Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
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Fasting Glucose and Lipid Profile
大体时间：Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
Change from baseline in fasting plasma glucose, total cholesterol, triglycerides, LDL-C, and HDL-C.
All assessments share the same unit of measure (mmol/L or mg/dL, depending on local laboratory standard) and will be reported as separate numerical values.
|
Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
|
Uric Acid
大体时间：Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
Change from baseline in serum uric acid.
Unit of measure: μmol/L or mg/dL (as per local laboratory).
|
Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
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Urine Protein
大体时间：Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
|
Change from baseline in urine protein concentration.
Unit of measure: mg/dL or g/24h (as per collection method).
|
Baseline to weeks 4, 8, 12, and 16 (Days 28, 56, 84, 112; ±3 days)
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合作者和调查者
研究记录日期
研究主要日期
学习开始 (估计的)
初级完成 (估计的)
研究完成 (估计的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (实际的)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
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