Hepatopulmonary SyndromeNCT05373134
Efficacy and Safety of Pentoxifylline in Improving Oxygenation in Hepatopulmonary Syndrome
A study testing Pentoxifylline in people with Hepatopulmonary Syndrome, run by Institute of Liver and Biliary Sciences, India at 1 site in India.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Hepatopulmonary Syndrome
- What is being tested?
- Pentoxifylline
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteIndia
- Study dates
- 5 May 2022to 30 Apr 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 17Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
India1 site
Institute of Liver & Biliary Sciences
New Delhi, National Capital Territory of Delhi, 110070
Dr Vishnu Girish, MD, 01146300000, vishnugirish@gmail.com
About this study
Official title: Efficacy and Safety of Pentoxifylline in Improving Oxygenation in Hepatopulmonary Syndrome: A Randomized Double-blind Placebo-controlled Trial
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.
Read more
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
Read the detailed description
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.
DLCO and exhaled NO will be measured at the baseline and at the end of 3 and 6 months Blinding The study drug and placebo will be administered in identical packaging and labelling to ensure that investigators and participants are blinded to study treatment. The study drug and placebo will be labelled with a unique label letter that will be used to allocate treatment to the patient, but the allocation will not be indicated to the investigators or participants. Except for the trial pharmacists and biostatistician, no member of the study team or their extended personnel will have access to the randomization method during the study's execution. The investigator will get the treatment assignment from trial pharmacists in the case of a medical emergency in which breaking the blind is necessary to give medical care to the participant.
DEFINITION - Hepatopulmonary syndrome will be defined by
- Presence of liver disease and / or portal hypertension AND
- Partial pressure of oxygen <80mm Hg or Alveolar-arterial oxygen gradient [P (A-a)O2 gradient ≥ 15mmHg (0r 20 mmHg for patients >65 years] AND
- Documented Intrapulmonary Vascular Dilatation by saline contrast echocardiogram
Sample size: Assuming that the improvement in oxygenation in the pentoxifylline group is 50% and that in the control group it would be 1%, with an alpha error of 5% and power of 90% investigator need to enroll 38 cases in the study.
Further assuming a dropout rate of 5% investigator need to enroll 40 cases randomized into two groups, 20 each, by block randomization method taking a block size of 4.
STATISTICAL ANALYSIS: Continuous data- Student's t test
- Nonparametric analysis- Mann Whitney test
- Survival outcome By Kaplan-Meier method curve.
- For all tests, p≤ 0.05 will be considered statistically significant.
- Analysis will be performed using SPSS.
- The analysis will be done with intention to treat and per protocol analysis if applicable.
Stopping rule:
Development of serious adverse effects leading to withdrawal of the drug or death from any cause Adverse events It is defined as the new onset event that is considered as a part of intervention which otherwise may be absent in absence of such intervention or therapy. All adverse events will be recorded.
- Conditions
- Hepatopulmonary Syndrome
- Being tested
- Pentoxifylline, Placebo
- Medical subject headings
- Hepatopulmonary Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PentoxifyllineDrug
400mg OD x 1 week, 400mg BD x 1 week then increased to 400mg TDS and continued
PlaceboOther
Placebo
| Study group | Role | What they receive |
|---|---|---|
| Pentoxifylline | Experimental | 400mg OD x 1 week, 400mg BD x 1 week then increased to 400mg TDS and continued Receives: Drug: Pentoxifylline |
| Placebo | Placebo comparator | Placebo will be given in a same manner as experimental drug Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in AaPO2 gradient by at least 5mmHg or to a value less than 15mm Hg at the end of 6 months from baseline
Measured: 6 months
Secondary outcomes (22)
Change in grading of intrapulmonary shunting at the end of 3 month, from baseline as assessed by saline contrast echocardiography
Measured: 3 months
Change in grading of intrapulmonary shunting at the end of 6 month, from baseline as assessed by saline contrast echocardiography
Measured: 6 months
Change in DLCO (Diffusing Capacity of the lungs for Carbon Monoxide) at the end of 3 month from baseline
Measured: 3 month
Change in Forced expiratory volume 1 (FEV1) at the end of 3 month from baseline
Measured: 3 month
Change in FVC (Forced Vital Capacity) at the end of 3 month from baseline
Measured: 3 month
Change in FEV1/FVC ratio at the end of 3 month from baseline
Measured: 3 month
Change in 6-minute walk test at the end of 3 month from baseline
Measured: 3 month
Change in DLCO (Diffusing Capacity of the lungs for Carbon Monoxide) at the end of 6 month from baseline
Measured: 6 month
Change in Forced expiratory volume 1 (FEV1) at the end of 6 month from baseline
Measured: 6 month
Change in FVC (Forced Vital Capacity) at the end of 6 month from baseline
Measured: 6 month
Change in FEV1/FVC ratio at the end of 6 month from baseline
Measured: 6 month
Change in 6-minute walk test at the end of 6 month from baseline
Measured: 6 month
Change in seated oxygen saturation at 3 month from baseline
Measured: 3 month
Change in PaO2 at 3 month from baseline
Measured: 3 month
Change in seated oxygen saturation at 6 month from baseline
Measured: 6 month
Change in PaO2 at 6 month from baseline
Measured: 6 month
Change in inflammatory markers at the end of 3 month from baseline
TNF alpha levels, vWF, ET-1, IL-6, S-1-P levels
Measured: 3 month
Change in inflammatory markers at the end of 6 month from baseline
TNF alpha levels, vWF, ET-1, IL-6, S-1-P levels at the end of 6 month from baseline
Measured: 6 month
Change in inflammatory markers at the end of 3 month from baseline in a subset of patients wherever feasible
VEGFR-3, iNOS, eNOS and IL-1 β
Measured: 3 month
Change in inflammatory markers at the end of 6 month from baseline in a subset of patients wherever feasible
VEGFR-3, iNOS, eNOS and IL-1 β
Measured: 6 month
Change in DLCO fraction of exhaled NO after 3 month from baseline
Measured: 3 month
Change in DLCO fraction of exhaled NO after 6 month from baseline
Measured: 6 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 May 2022
- Study start5 May 2022 (estimated)
- Primary completion30 Apr 2023 (estimated)
- Study completion30 Apr 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hepatopulmonary SyndromeStudies of the same condition, open and under way.
- More trials run by Institute of Liver and Biliary Sciences, IndiaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Institute of Liver and Biliary Sciences, India
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05373134
- Sponsor's protocol ID
- ILBS-HPS-02
- Status last verified
- Apr 2022
- First submitted
- 13 Apr 2022
- Last updated
- 13 May 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 13 May 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy and Safety of Pentoxifylline in Improving Oxygenation in Hepatopulmonary Syndrome: A Randomized Double-blind Placebo-controlled Trial
- ClinicalTrials.gov ID
- NCT05373134
- Acronym / sponsor ID
- ILBS-HPS-02
- Conditions
- Hepatopulmonary Syndrome
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Institute of Liver and Biliary Sciences, IndiaUniversity, hospital or other
- Study start
- 5 May 2022 (estimated)
- Primary completion
- 30 Apr 2023 (estimated)
- Study completion
- 30 Apr 2023 (estimated)
- First posted
- 13 May 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Detailed description
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.
DLCO and exhaled NO will be measured at the baseline and at the end of 3 and 6 months Blinding The study drug and placebo will be administered in identical packaging and labelling to ensure that investigators and participants are blinded to study treatment. The study drug and placebo will be labelled with a unique label letter that will be used to allocate treatment to the patient, but the allocation will not be indicated to the investigators or participants. Except for the trial pharmacists and biostatistician, no member of the study team or their extended personnel will have access to the randomization method during the study's execution. The investigator will get the treatment assignment from trial pharmacists in the case of a medical emergency in which breaking the blind is necessary to give medical care to the participant.
DEFINITION - Hepatopulmonary syndrome will be defined by
- Presence of liver disease and / or portal hypertension AND
- Partial pressure of oxygen <80mm Hg or Alveolar-arterial oxygen gradient [P (A-a)O2 gradient ≥ 15mmHg (0r 20 mmHg for patients >65 years] AND
- Documented Intrapulmonary Vascular Dilatation by saline contrast echocardiogram
Sample size: Assuming that the improvement in oxygenation in the pentoxifylline group is 50% and that in the control group it would be 1%, with an alpha error of 5% and power of 90% investigator need to enroll 38 cases in the study.
Further assuming a dropout rate of 5% investigator need to enroll 40 cases randomized into two groups, 20 each, by block randomization method taking a block size of 4.
STATISTICAL ANALYSIS: Continuous data- Student's t test
- Nonparametric analysis- Mann Whitney test
- Survival outcome By Kaplan-Meier method curve.
- For all tests, p≤ 0.05 will be considered statistically significant.
- Analysis will be performed using SPSS.
- The analysis will be done with intention to treat and per protocol analysis if applicable.
Stopping rule:
Development of serious adverse effects leading to withdrawal of the drug or death from any cause Adverse events It is defined as the new onset event that is considered as a part of intervention which otherwise may be absent in absence of such intervention or therapy. All adverse events will be recorded.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Pentoxifylline | Experimental | Drug: Pentoxifylline400mg OD x 1 week, 400mg BD x 1 week then increased to 400mg TDS and continued |
| Placebo | Placebo comparator | Other: PlaceboPlacebo will be given in a same manner as experimental drug |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (17 listed)
- Child C cirrhosis with CTP > 10 or with refractory ascites
- Intrinsic significant cardiopulmonary disease
- Current use of exogenous nitrates
- Patients already on pentoxifylline
- Prior intolerance to pentoxifylline
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Pentoxifylline400mg OD x 1 week, 400mg BD x 1 week then increased to 400mg TDS and continued | Drug | Pentoxifylline |
| PlaceboPlacebo | Other | Placebo |
Primary outcome
Change in AaPO2 gradient by at least 5mmHg or to a value less than 15mm Hg at the end of 6 months from baseline
Time frame: 6 months
22 secondary outcomes
Change in grading of intrapulmonary shunting at the end of 3 month, from baseline as assessed by saline contrast echocardiography
Time frame: 3 months
Change in grading of intrapulmonary shunting at the end of 6 month, from baseline as assessed by saline contrast echocardiography
Time frame: 6 months
Change in DLCO (Diffusing Capacity of the lungs for Carbon Monoxide) at the end of 3 month from baseline
Time frame: 3 month
Change in Forced expiratory volume 1 (FEV1) at the end of 3 month from baseline
Time frame: 3 month
Change in FVC (Forced Vital Capacity) at the end of 3 month from baseline
Time frame: 3 month
Change in FEV1/FVC ratio at the end of 3 month from baseline
Time frame: 3 month
Change in 6-minute walk test at the end of 3 month from baseline
Time frame: 3 month
Change in DLCO (Diffusing Capacity of the lungs for Carbon Monoxide) at the end of 6 month from baseline
Time frame: 6 month
Change in Forced expiratory volume 1 (FEV1) at the end of 6 month from baseline
Time frame: 6 month
Change in FVC (Forced Vital Capacity) at the end of 6 month from baseline
Time frame: 6 month
Change in FEV1/FVC ratio at the end of 6 month from baseline
Time frame: 6 month
Change in 6-minute walk test at the end of 6 month from baseline
Time frame: 6 month
Change in seated oxygen saturation at 3 month from baseline
Time frame: 3 month
Change in PaO2 at 3 month from baseline
Time frame: 3 month
Change in seated oxygen saturation at 6 month from baseline
Time frame: 6 month
Change in PaO2 at 6 month from baseline
Time frame: 6 month
Change in inflammatory markers at the end of 3 month from baseline
Time frame: 3 month
Change in inflammatory markers at the end of 6 month from baseline
Time frame: 6 month
Change in inflammatory markers at the end of 3 month from baseline in a subset of patients wherever feasible
Time frame: 3 month
Change in inflammatory markers at the end of 6 month from baseline in a subset of patients wherever feasible
Time frame: 6 month
Change in DLCO fraction of exhaled NO after 3 month from baseline
Time frame: 3 month
Change in DLCO fraction of exhaled NO after 6 month from baseline
Time frame: 6 month
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 May 2022.
- Individual participant dataSharing planned: Undecided
Related trials for Hepatopulmonary Syndrome
Enrolling by invitationObservational study
International Registry of Congenital Portosystemic Shunt (IRCPSS)
Congenital Portosystemic Shunt, CPSS (Congenital Portosystemic Shunt)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Pentoxifylline in people with Hepatopulmonary Syndrome, run by Institute of Liver and Biliary Sciences, India at 1 site in India.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 13 May 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in India. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Dr Vishnu Girish, MD (01146300000, vishnugirish@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in AaPO2 gradient by at least 5mmHg or to a value less than 15mm Hg at the end of 6 months from baseline (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 May 2022.