Ascites, Cirrhosis
Conditions
Keywords
albumin, ascites, paracentesis
Brief summary
This clinical trial compares a combination of two drugs that constrict blood vessels (Octreotide LAR and Midodrine) to albumin after large volume paracentesis. Subjects have cirrhosis and ascites.
Detailed description
This prospective, placebo-controlled, randomized, clinical trial compares the effect of a combination of vasoconstrictors (octreotide plus midodrine) to albumin on the time to recurrence of ascites in patients with refractory ascites treated with large volume paracentesis. The treatment allocation ratio for the two treatment arms is 1:1 using a stratified random permuted block design. Subjects are patients 18-80 years old with cirrhosis and ascites who are stratified according to the presence or absence of renal dysfunction at the time of randomization. Measurements include blood pressure, weight, girth, abdominal ultrasound, forearm blood flow, plasma renin activity, angiotensin, and aldosterone, repeated during a 6 month period.
Interventions
DRUGAlbumin
Intravenous Albumin at a dose of 8g/liter of ascitic fluid removed
DRUGIntravenous Saline Infusion (Albumin placebo)
Intravenous saline Infusion (Albumin placebo)
DRUGMidodrine
Midodrine oral tablet at 10 mg three times a day.
DRUGOral tablet (Midodrine placebo)
Oral tablet (Midodrine placebo) three times a day
DRUGOctreotide LAR
Octreotide LAR 20 mg intramuscular injection every 30 days
Saline intramuscular injection 5 cc every 30 days.
PROCEDURELarge Volume Paracentesis
Procedure to remove large amounts (more than 5 liter) of ascitic fluid via a catheter.
Sponsors
US Department of Veterans Affairs
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Cirrhosis of any etiology * Age 18-80 years * Moderate to severe ascites
Exclusion criteria
* No or small ascites * Severe hepatic hydrothorax * Recent GI (gastrointestinal) hemorrhage * Active bacterial infection * Cardiac failure * Organic renal disease * Hepatocellular carcinoma * Severe comorbidity (advanced neoplasia) * Serum creatinine \> 3 mg/dl * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Recurrence of Ascites. | Variable depending on the patient, average 10 days | Comparison between Albumin (Control group) and Vasoconstrictor (Treatment group) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Development of Post-paracentesis Circulatory Dysfunction (PCD) | 6 days after paracentesis | Defined as an increase in Plasma Renin Activity (PRA) by \>50% from baseline to a level \> 4 ng/mL/h at post-paracentesis day |
Countries
United States
Participant flow
Recruitment details
Between October 2003 and June 2010, about 200 patients with cirrhosis and ascites were screened, of which, only 29 met inclusion criteria. Twenty five patients (13 control, 12 study group) were included in the analysis.
Participants by arm
| Arm | Count |
|---|---|
| Albumin (Control Group) After LVP, patients in this group received:
Intravenous albumin (25%) at 8 g/liter of ascitic fluid removed, one time dose; Intramuscular injection of 5 cc saline (Octreotide LAR placebo), every 30 days ; Oral tablet 3 times a day (Midodrine placebo) | 13 |
| Vasoconstrictor (Treatment Group) After LVP, patients in this group received:
Octreotide LAR intramuscular injection 20 mg, every 30 days; Midodrine tablet, 10 mg three times a day; Intravenous saline infusion (Albumin placebo), one time dose | 12 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Loculated ascites, limiting paracentesis | 1 | 1 |
| Overall Study | Peritonitis at index paracentesis | 1 | 1 |
Baseline characteristics
| Characteristic | Vasoconstrictor (Treatment Group) | Albumin (Control Group) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 11 Participants | 21 Participants |
| Age, Continuous age median | 60 years INTER_QUARTILE_RANGE 8.4 | 55 years INTER_QUARTILE_RANGE 7.5 | 58 years INTER_QUARTILE_RANGE 8 |
| Region of Enrollment United States | 12 participants | 13 participants | 25 participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 12 Participants | 10 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 13 | 4 / 12 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 |
Outcome results
Primary
Time to Recurrence of Ascites.
Comparison between Albumin (Control group) and Vasoconstrictor (Treatment group)
Time frame: Variable depending on the patient, average 10 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Albumin (Control Group) | Time to Recurrence of Ascites. | 10 days |
| Vasoconstrictor (Treatment Group) | Time to Recurrence of Ascites. | 8 days |
Comparison: Initial estimation: median time to recurrence of ascites of 38 days in the study group and 20 days in the control group in a fixed duration of 6 months (5% type-I error (2 sided) and an 80% power). However, due to low accrual and based on randomized trials using vasoconstrictors in the prevention of PCD and a study that showed that midodrine leads to a significant improvement in effective arterial blood volume, each of which had sample sizes of 24-25 patients,we decided on a sample size of 30.p-value: <0.05Log Rank
Secondary
Development of Post-paracentesis Circulatory Dysfunction (PCD)
Defined as an increase in Plasma Renin Activity (PRA) by \>50% from baseline to a level \> 4 ng/mL/h at post-paracentesis day
Time frame: 6 days after paracentesis
Population: Plasma Renin Activity (lab value to measure PCD) was not available for 6 patients leaving 11 patients in Albumin (control group) and 8 patients in Vasoconstrictor (Treatment group) for this outcome analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Albumin (Control Group) | Development of Post-paracentesis Circulatory Dysfunction (PCD) | 2 participants |
| Vasoconstrictor (Treatment Group) | Development of Post-paracentesis Circulatory Dysfunction (PCD) | 2 participants |