Efficacy and Safety of Pentoxifylline in Improving Oxygenation in Hepatopulmonary Syndrome: A Randomized Double-blind Placebo-controlled Trial
试验速览
- 阶段
- 不适用
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Change in AaPO2 gradient by at least 5mmHg or to a value less than 15mm Hg at the end of 6 months from baseline
研究概览
简要总结
The triad of liver disease, arterial hypoxia, and extensive pulmonary vascular dilatation is known as the hepatopulmonary syndrome (HPS). The prevalence of this syndrome ranges from 10% to 30% in people with chronic liver disease.
The exact cause of HPS is unknown. Previous research has shown that eicosanoids function as vasoconstrictors and cause an increase in the number of intravascular macrophage-like cells. Cirrhosis has been linked to increased NO generation in the lungs, which has been linked to intrapulmonary venous dilation. Increased pulmonary NO production is attributed to increased expression of pulmonary vascular endothelial NO synthase (eNOS) and inducible NO synthase.
Increased hepatic synthesis and release of low levels of endothelin 1 (ET-1) has been established in recent investigations to function as a trigger for increasing eNO levels. TNF (tumor necrosis factor) and ET-1 have both been linked to the onset of experimental HPS. Increased CO generation and heme oxygenase expression have been linked to the progression of HPS in recent investigations. HPS increases mortality in cirrhotic patients and may affect the frequency and severity of portal hypertension consequences.
To the best of our knowledge there have been only three pilot studies in humans which checked the effect of pentoxifylline in hepatopulmonary syndrome and they showed highly contrasting results. The outcome was also measured in a short interval. Investigator hypothesize that pentoxifylline would improve the oxygenation in patients with hepatopulmonary syndrome
详细描述
Hypothesis Investigator hypothesize that pentoxifylline in hepatopulmonary syndrome would improve oxygenation by inhibiting TNF alpha and thereby reducing macrophage, endothelium induced NO production compared to placebo
Aim To study efficacy of pentoxifylline in reducing AaPO2 in hepatopulmonary syndrome when compared to placebo
Methodology:
Study design: Prospective double-blind randomized placebo-controlled trial DATA and SPECIMEN collection Patient data, demographics, etiology of liver disease, PFT, abdominal radiological studies will be collected 6-minute walk test will be done at the baseline, 3 months, and 6 months Sampling for ABG will be performed with the subject seated while breathing room air at baseline and at the end of 3 and 6 months and A-aPO2 values will be calculated using Alveolar gas equation.
TNF alpha levels, vWF, ET-1, VEGFR-3, iNOS, eNOS and IL-1 β levels will be measured at baseline and after 3 and 6 months.
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
- Double (Participant, Investigator)
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
- •Evidence of portal hypertension
- •Intrapulmonary vascular dilatation in the form of shunting diagnosed on contrast echocardiogram
- •AaPO2 > 15mmHg on seated room air (ABG) if age <65years and >20mmHg if Age≥ 70 years
排除标准
- •Child C cirrhosis with CTP > 10 or with refractory ascites
- •Intrinsic significant cardiopulmonary disease
- •PFT indicating severe obstructive ventilatory defect (FEV1/FVC < 70)
- •Hepatic hydrothorax, Portopulmonary hypertension
- •Moderate and severe left ventricular systolic dysfunction
- •Inability to perform Pulmonary function test
- •Intracardiac shunting
- •Current use of exogenous nitrates
- •Patients already on pentoxifylline
- •Prior intolerance to pentoxifylline
- •Very severe cases of HPS (A-aO2 gradient ≥ 15mm Hg, PO2 <50 mmHg)
- •Active bacterial infections, active hepatic encephalopathy
- •Known malignancy including HCC
- •SBP on secondary prophylaxis
- •CKD with creatinine clearance < 30
- •Enrolled in other trials
- •Has a liver transplant option
研究组 & 干预措施
Pentoxifylline
400mg OD x 1 week, 400mg BD x 1 week then increased to 400mg TDS and continued
干预措施: Pentoxifylline (Drug)
Placebo
Placebo will be given in a same manner as experimental drug
干预措施: Placebo (Other)
结局指标
主要结局
Change in AaPO2 gradient by at least 5mmHg or to a value less than 15mm Hg at the end of 6 months from baseline
时间窗: 6 months
次要结局
- Change in Forced expiratory volume 1 (FEV1) at the end of 6 month from baseline(6 month)
- Change in grading of intrapulmonary shunting at the end of 3 month, from baseline as assessed by saline contrast echocardiography(3 months)
- Change in FVC (Forced Vital Capacity) at the end of 3 month from baseline(3 month)
- Change in grading of intrapulmonary shunting at the end of 6 month, from baseline as assessed by saline contrast echocardiography(6 months)
- Change in DLCO (Diffusing Capacity of the lungs for Carbon Monoxide) at the end of 3 month from baseline(3 month)
- Change in Forced expiratory volume 1 (FEV1) at the end of 3 month from baseline(3 month)
- Change in FEV1/FVC ratio at the end of 3 month from baseline(3 month)
- Change in 6-minute walk test at the end of 3 month from baseline(3 month)
- Change in DLCO (Diffusing Capacity of the lungs for Carbon Monoxide) at the end of 6 month from baseline(6 month)
- Change in FVC (Forced Vital Capacity) at the end of 6 month from baseline(6 month)
- Change in FEV1/FVC ratio at the end of 6 month from baseline(6 month)
- Change in 6-minute walk test at the end of 6 month from baseline(6 month)
- Change in seated oxygen saturation at 3 month from baseline(3 month)
- Change in PaO2 at 3 month from baseline(3 month)
- Change in seated oxygen saturation at 6 month from baseline(6 month)
- Change in PaO2 at 6 month from baseline(6 month)
- Change in inflammatory markers at the end of 3 month from baseline(3 month)
- Change in inflammatory markers at the end of 6 month from baseline(6 month)
- Change in inflammatory markers at the end of 3 month from baseline in a subset of patients wherever feasible(3 month)
- Change in inflammatory markers at the end of 6 month from baseline in a subset of patients wherever feasible(6 month)
- Change in DLCO fraction of exhaled NO after 3 month from baseline(3 month)
- Change in DLCO fraction of exhaled NO after 6 month from baseline(6 month)