Midodrine in Hepatopulmonary Syndrome

Study Overview
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Brief Summary
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This proof-of-concept clinical trial will determine the safety and tolerability of midodrine in patients with hepatopulmonary syndrome (HPS). Exploratory endpoints will assess the effect of midodrine on oxygenation, intrapulmonary shunting and symptoms.

Official Title
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A Phase 1 Proof-of-concept Clinical Trial Evaluating the Safety and Tolerability of Midodrine in Hepatopulmonary Syndrome

Conditions
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Hepatopulmonary Syndrome (HPS)

Intervention / Treatment
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* Drug: Midodrine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Moderate to very severe hepatopulmonary syndrome, defined as the presence of all of the following: Liver disease or portal hypertension Intrapulmonary shunting on contrast-enhanced echocardiogram Hypoxemia [A-a gradient ≥15mmHg (or ≥20mmHg if age >64) and PaO2<80mmHg on arterial blood gas testing] Ability to provide informed consent Ability to comply with study medication use and testing, in the opinion of the principal investigator or co-investigator Exclusion Criteria: Vulnerable study population, including imprisoned individuals, non-English speaking patients Participation in other investigational drug studies Any of the following conditions: Systolic blood pressure>160mmHg or diastolic blood pressure >100mmHg Heart rate <50bpm Urinary retention at baseline Left ventricular ejection fraction <50% Women who are pregnant, nursing, or who plan to become pregnant while in the trial Women of child-bearing potential not willing or able to use highly effective methods of birth control

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open Label<br>All subjects enrolled will be assigned to receive midodrine. The initial starting dose will be midodrine 5mg orally three times a day. After 7-10 days, patients will increase the dose to 10mg three times a day as tolerated if no adverse effects occur. Treatment duration will be 6 months. | Drug: Midodrine<br>* Midodrine is an oral alpha-1 agonist that increases vascular tone. It is administered orally. The initial starting dose will be midodrine 5mg orally three times a day. After 7-10 days, patients will increase the dose to 10mg three times a day as tolerated if no adverse effects occur. Treatment duration will be 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability (adverse events (AEs)) | Outcome will be defined by the incidence of adverse events (AEs) that occur during the study period. An adverse event is defined as any symptom, sign, illness or experience that develops or worsens in severity during the course of the study. Abnormal results of diagnostic procedures are considered to be AEs if the abnormality results in study withdrawal, is associated with a serious AE, is associated with clinical signs or symptoms, leads to additional treatment or further diagnostic tests or is considered by the investigator to be of clinical significance. Each adverse event will be further characterized by severity and relationship to the study drug. Adverse event are classified as serious if they are: fatal, life-threatening, require or prolongs hospital stay, lead to persistent or significant disability or incapacity or a congenital anomaly or birth defect. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arterial Oxygenation | Describe the effect of midodrine on: • arterial oxygenation (PaO2 and A-a gradient )(mmHg) | 3 months and 6 months | 
| Diffusion capacity | Describe the effect of midodrine on: • percent predicted diffusion capacity for carbon monoxide (Range 0-100%) | 3 months and 6 months | 
| Cardiac output | Describe the effect of midodrine on cardiac output (L/min) as estimated by echocardiogram in patients with HPS. | 3 months and 6 months | 
| Intrapulmonary shunting | Describe the effect of midodrine on severity (mild, moderate or severe) of intrapulmonary shunting (as assessed by echocardiogram shunt study) in patients with HPS. | 3 months and 6 months | 
| Intrapulmonary shunting | Describe the effect of midodrine on severity of intrapulmonary shunting (as assessed by percent shunt index (0-100%) on technetium macroaggregated albumin scan) in patients with HPS. | 6 months | 
| Symptoms as assessed by Modified Medical Research Council (MMRC)dyspnea scale | Describe the effect of midodrine on MMRC dyspnea scale (0-4). Higher numbers indicate more severe dyspnea. | 3 months and 6 months | 
| 6 minute walk distance | Describe the effect of midodrine on 6 minute walk distance, in meters. | 3 months and 6 months |