Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000211965
Ethics application status
Approved
Date submitted
27/01/2020
Date registered
20/02/2020
Date last updated
1/02/2023
Date data sharing statement initially provided
20/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
To Assess the Effectiveness, Safety, and Tolerability of Oral Docarpamine in Patients with Refractory Ascites due to Liver Cirrhosis
Scientific title
A Phase 2a Open-Label Study Assessing the Effectiveness, Safety, and Tolerability of Oral
Docarpamine in Patients with Refractory Ascites due to Liver Cirrhosis
Secondary ID [1] 300146 0
MP-0128-001
Universal Trial Number (UTN)
Trial acronym
DREAM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Liver Cirrhosis 315676 0
Condition category
Condition code
Oral and Gastrointestinal 313982 313982 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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
Intervention code [1] 316431 0
Treatment: Drugs
Comparator / control treatment
None
Control group
Active

Outcomes
Primary outcome [1] 322393 0
Part 1/ Part 2: Total volume of ascetic fluid as assessed by site procedural source documentation
Timepoint [1] 322393 0
Throughout the study
Secondary outcome [1] 378318 0
Part 1/ Part 2: Safety & tolerability will be assessed by Medical History, Physical Exam, Ascites Grade, Hepatic Encephalopathy, 12-lead ECG, vital signs, hematology, blood chemistry, liver function, coagulation tests, urine test and as well as assessing AEs, and concomitant medications and procedures.
Timepoint [1] 378318 0
Part A: Performed at baseline, at each LVP visit and at day 7, day 14, day 21, day 28, day 56, day 90, and day 120.
Part B: Performed at baseline, at each LVP visit and at day 8, day 15, day 22, day 29, and day 63.
Secondary outcome [2] 379683 0
Part A/ Part B: Docarpamine pharmacokinetics. Parameters to be examined: maximum observed plasma concentration after single and repeat dosing (Cmax), Area under the curve over the dosing interval after first dose on Day 1 (AUCtau), time to maximum observed plasma concentration after single and repeat dosing (Tmax)
Timepoint [2] 379683 0
Part A: Pharmacokinetic samples will be obtained at Visit 0 (baseline), Visit 1 (Day 1: pre-dose, 1 hours ± 5 minutes, 1.5 hours ± 5 minutes, 2 hours ± 5 minutes, 2.5 hours ± 5 minutes, 3 hours ± 5 minutes, 3.5 hours ± 5 minutes and 4 hours ± 10 minutes) for those subjects who will receive the 1500mg dose. The same PK sample schedule will be collected on Visit 7 (Day 7), although this may take place as late as Visit 10 (Day 28).

Part B: Pharmacokinetic samples will be obtained on Day 8: pre-dose, 1 hours ± 5 minutes, 2 hours ± 5 minutes, 2.5 hours ± 5 minutes, 3 hours ± 5 minutes, 3.5 hours ± 5 minutes and 4 hours ± 10 minutes. The same PK sample schedule will also be collected on Day 15, although this may take place as late as Day 29 if necessary to accommodate subject and site scheduling.

Eligibility
Key inclusion criteria
For Part A and Part B:
1. Patients 18 years to 70 years of age.
2. Documented cirrhosis of the liver.
3. Refractory ascites, defined as ascites not manageable with diuretics and diet restriction, managed with periodic large volume therapeutic paracentesis.
4. 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)
5. Outpatient, with expected survival of at least 6 months.
6. Willing and able to complete an informed consent form.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
For Part A and Part B:
1. Ascites due to any cause other than cirrhosis such as malignant ascites.
2. Existing or planned placement of transjugular intrahepatic portosystemic shunt (TIPS) or other surgical shunts.
3. Active bacterial infection.
4. Scheduled organ transplantation within the next 6 months.
5. Anticipated change in diuretics schedule within 30 days prior to V1.
6. 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).
7. Serum creatinine > 2 mg/dL (based on the most recent bloodwork per medical records).
8. Serum bilirubin > 5 mg/dL (based on the most recent bloodwork per medical records)
9. International normalized ratio (INR) > 2.0 (based on the most recent bloodwork per medical records).
10. Hepatocellular Carcinoma Barcelona Clinic Liver Cancer (BCLC) stage C or above.
11. Current or recent (within 3 months of consent) renal dialysis.
12. Hepatic encephalopathy grade 3 or 4.
13. Pheochromocytoma or hypertrophic obstructive cardiomyopathy.
14. Current or recent treatment (within 7 days of V0 dosing) with octreotide, midodrine, vasopressin, dopamine or other vasopressors.
15. 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.
16. Episode of spontaneous bacterial peritonitis or gastrointestinal hemorrhage, or any acute decompensation within 30 days of enrollment (V0).
17. Severe cardiovascular disease such as Congestive Heart Failure (CHF), advanced arteriosclerosis, coronary insufficiency, tachyarrhythmia, or uncontrolled hypertension above 160/100.
18. 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.
19. Pregnant females, females anticipating pregnancy during study period, or breastfeeding.
20. Known allergy or hypersensitivity to dopamine or docarpamine (DCP).
21. Any severe comorbidity that in the opinion of the Investigator would disallow safe participation in the trial.
22. Participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 90 days of consent.
23. Type 1 hepatorenal syndrome (Part B)
24. Untreated or uncontrolled large (F3) esophageal varices that in the opinion of the Investigator would disallow safe participation in the trial (Part B).

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
12/05/2020
Actual
12/05/2020
Date of last participant enrolment
Anticipated
31/05/2023
Actual
Date of last data collection
Anticipated
30/09/2023
Actual
Sample size
Target
20
Accrual to date
12
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA
Recruitment hospital [1] 15591 0
Nepean Hospital - Kingswood
Recruitment hospital [2] 15592 0
Gold Coast Hospital - Southport
Recruitment hospital [3] 15593 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [4] 15594 0
Royal Perth Hospital - Perth
Recruitment hospital [5] 21270 0
Box Hill Hospital - Box Hill
Recruitment hospital [6] 23894 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [7] 23895 0
Concord Repatriation Hospital - Concord
Recruitment hospital [8] 23896 0
Sunshine Coast University Hospital - Birtinya
Recruitment postcode(s) [1] 28991 0
2747 - Kingswood
Recruitment postcode(s) [2] 28992 0
4215 - Southport
Recruitment postcode(s) [3] 28993 0
5000 - Adelaide
Recruitment postcode(s) [4] 28994 0
6000 - Perth
Recruitment postcode(s) [5] 36140 0
3128 - Box Hill
Recruitment postcode(s) [6] 39378 0
2050 - Camperdown
Recruitment postcode(s) [7] 39379 0
2139 - Concord
Recruitment postcode(s) [8] 39380 0
4575 - Birtinya

Funding & Sponsors
Funding source category [1] 304581 0
Commercial sector/Industry
Name [1] 304581 0
Martin Pharmaceuticals Australia Pty Ltd.
Country [1] 304581 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Martin Pharmaceuticals Australia Pty Ltd.
Address
58 Gipps Street, Collingwood, VIC 3066, Australia
Country
Australia
Secondary sponsor category [1] 304867 0
None
Name [1] 304867 0
Address [1] 304867 0
Country [1] 304867 0
Other collaborator category [1] 281130 0
Commercial sector/Industry
Name [1] 281130 0
Novotech (Australia) Pty Limited
Address [1] 281130 0
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 281130 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305007 0
St Vincent's Hospital Melbourne Human Research Ethics Committee
Ethics committee address [1] 305007 0
41 Victoria Parade, Fitzroy VIC 3065
Ethics committee country [1] 305007 0
Australia
Date submitted for ethics approval [1] 305007 0
19/11/2019
Approval date [1] 305007 0
06/12/2019
Ethics approval number [1] 305007 0

Summary
Brief 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.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98946 0
Dr Edmund Tse
Address 98946 0
Royal Adelaide Hospital, Port Rd Adelaide SA 5000
Country 98946 0
Australia
Phone 98946 0
+61 423 080 487
Fax 98946 0
Email 98946 0
[email protected]
Contact person for public queries
Name 98947 0
Ms Joanne Morgan
Address 98947 0
Royal Adelaide Hospital, Port Rd Adelaide SA 5000
Country 98947 0
Australia
Phone 98947 0
+61 87074 2190
Fax 98947 0
Email 98947 0
[email protected]
Contact person for scientific queries
Name 98948 0
Ms Ann C. Tunstall
Address 98948 0
Martin Pharmaceuticals , 233 Broadway 17th Floor, New York, NY 10279, USA
Country 98948 0
United States of America
Phone 98948 0
+1 7039818338
Fax 98948 0
Email 98948 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
None


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.