To Assess the Effectiveness, Safety, and Tolerability of Oral Docarpamine in Patients with Refractory Ascites due to Liver Cirrhosis
A Phase 2a Open-Label Study Assessing the Effectiveness, Safety, and Tolerability of Oral Docarpamine in Patients with Refractory Ascites due to Liver Cirrhosis
Martin Pharmaceuticals Australia Pty Ltd.
20 participants
May 12, 2020
Interventional
Conditions
Summary
This study is an open-label, single-arm study in which each subject will serve as his/her own control. The study will assess the effect of DCP treatment on ascites formation in cirrhotic subjects with RA, by examining the frequency of LVP and the volume of ascitic fluid drained. All subjects will participate in a Dose exposure assessment visit, followed by a 90 day open label treatment period, followed by a 90-day follow-up period of additional data collection from medical records. Ascites history (relevant medications, LVP dates, and volume of drained fluid) for the 90 days prior to treatment and the 90 days after treatment will be collected and used for comparison with on-treatment frequency and volume. The study will be conducted in two parts. At the start of the study, subjects will be enrolled into Part A. When a sufficient number of subjects have been enrolled into Part A to provide information about preliminary efficacy, safety, and exposure, additional subjects will then be enrolled into Part B.
Eligibility
Inclusion Criteria9
- For Part A and Part B:
- Patients 18 years to 70 years of age.
- Documented cirrhosis of the liver.
- Refractory ascites, defined as ascites not manageable with diuretics and diet restriction, managed with periodic large volume therapeutic paracentesis.
- Patients must have a documented minimum of 2 therapeutic paracenteses in the 60 days prior to enrollment (V0), with an anticipated minimum of 3 paracentesis in the 90 days prior to the start of study treatment on Day 1 (V1) (Part A)
- OR
- Patients must have had regular paracentesis over the previous 9 weeks prior to study entry, with a documented minimum of 2 therapeutic paracenteses in the 9 weeks prior to the start of study (Part B)
- Outpatient, with expected survival of at least 6 months.
- Willing and able to complete an informed consent form.
Exclusion Criteria25
- For Part A and Part B:
- Ascites due to any cause other than cirrhosis such as malignant ascites.
- Existing or planned placement of transjugular intrahepatic portosystemic shunt (TIPS) or other surgical shunts.
- Active bacterial infection.
- Scheduled organ transplantation within the next 6 months.
- Anticipated change in diuretics schedule within 30 days prior to V1.
- Model for End-Stage Liver Disease-Sodium (MELD-Na) Score of > 25 (based on the most recent bloodwork per medical records and within 30 days of V0).
- Serum creatinine > 2 mg/dL (based on the most recent bloodwork per medical records).
- Serum bilirubin > 5 mg/dL (based on the most recent bloodwork per medical records)
- International normalized ratio (INR) > 2.0 (based on the most recent bloodwork per medical records).
- Hepatocellular Carcinoma Barcelona Clinic Liver Cancer (BCLC) stage C or above.
- Current or recent (within 3 months of consent) renal dialysis.
- Hepatic encephalopathy grade 3 or 4.
- Pheochromocytoma or hypertrophic obstructive cardiomyopathy.
- Current or recent treatment (within 7 days of V0 dosing) with octreotide, midodrine, vasopressin, dopamine or other vasopressors.
- Current or recent treatment (within 21 days of V0 dosing) with monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, phenytoin, haloperidol or haloperidol-like drugs, or phenothiazines such as prochlorperazine.
- Episode of spontaneous bacterial peritonitis or gastrointestinal hemorrhage, or any acute decompensation within 30 days of enrollment (V0).
- Severe cardiovascular disease such as Congestive Heart Failure (CHF), advanced arteriosclerosis, coronary insufficiency, tachyarrhythmia, or uncontrolled hypertension above 160/100.
- Known or suspected extra-hepatic malignancy (other than skin cancer and in-situ cancers), unless adequately treated or in complete remission for at least 3 years.
- Pregnant females, females anticipating pregnancy during study period, or breastfeeding.
- Known allergy or hypersensitivity to dopamine or docarpamine (DCP).
- Any severe comorbidity that in the opinion of the Investigator would disallow safe participation in the trial.
- Participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 90 days of consent.
- Type 1 hepatorenal syndrome (Part B)
- Untreated or uncontrolled large (F3) esophageal varices that in the opinion of the Investigator would disallow safe participation in the trial (Part B).
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Interventions
Docarpamine (DCP), an orally available dopamine prodrug. Docarpamine contains reversible chemical modifications of the catechol and amino groups of dopamine. The study will assess the effect of Docarpamine (DCP) treatment on ascites formation in cirrhotic subjects with Refractory Ascites (RA), by examining the frequency of large volume paracentesis (LVP) and the volume of ascitic fluid drained. All subjects will participate in a 90-day open-label treatment period, followed by a 90-day follow-up period of additional data collection from medical records. Ascites history (relevant medications, large volume paracentesis (LVP) dates, and volume of drained fluid) for the 90 days prior to treatment and the 90 days after treatment will be collected and used for comparison with on-treatment frequency and volume. The study will be conducted in two parts. At the start of the study, subjects will be enrolled into Part A. When a sufficient number of subjects have been enrolled into Part A to provide information about preliminary efficacy, safety, and exposure, additional subjects will then be enrolled into Part B. The study consists of two parts: Part A: Subjects enrolled into Part A will participate in a 90-day open-label treatment period, followed by a 90-day follow-up period of additional data collection from medical records. Ascites history (relevant medications, large volume paracentesis (LVP) dates, and volume of drained fluid) for the 90 days prior to treatment and the 90 days after treatment will be collected and used for comparison with on-treatment frequency and volume. After screening and enrolment, subjects under Amendment 2 will begin V0 (Exposure Assessment Visit). At this visit, each subject will be administered one single dose of 750 mg Docarpamine (DCP) orally. Pharmacokinetic assessments will be performed to evaluate each subjects optimal dose for the study duration. Following V0, Dosing in Part A will be either 750 mg or 1500 mg three times a day (TID) daily for 90 days, depending on V0 PK assessment result. Part B: Subjects enrolled into Part B will participate in a 63 day (9 week) open-label treatment period: 7 days on Docarpamine (DCP) 750 mg three times a day (TID), followed by 56 days (8 weeks) on Docarpamine (DCP) 1500 mg TID. Ascites history (medication, large volume paracentesis (LVP) dates, and volume of drained fluid) for the 63 days prior to treatment will be collected and used for comparison with on-treatment large volume paracentesis (LVP) frequency and volume. Subjects assessed as showing a response to treatment (either a reduction in large volume paracentesis (LVP) volume, and/or a decrease in the frequency of large volume paracentesis (LVP) compared to prior history) will also be observed post-treatment for 63 days. Subjects who do not show a response during the treatment period will not be followed for the post-treatment period. In Part B, dosing for all subjects will be 750 three times a day (TID) for the first 7 days, and 1500 three times a day (TID) for the remainder of the treatment period
Locations(8)
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ACTRN12620000211965