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Trial registered on ANZCTR


Registration number
ACTRN12619000891123
Ethics application status
Approved
Date submitted
11/06/2019
Date registered
26/06/2019
Date last updated
1/08/2019
Date data sharing statement initially provided
26/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The impact of continuous terlipressin infusion on complications of end-stage liver disease
Scientific title
The impact of continuous terlipressin infusion on muscle, nutrition, ascites and inflammation in end-stage liver disease
Secondary ID [1] 298463 0
Nil known
Universal Trial Number (UTN)
U1111-1235-1089
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cirrhosis 313222 0
Sarcopaenia 313223 0
Inflammation 313224 0
Malnutrition 313225 0
Ascites 313226 0
Infection 313456 0
Immune function 313457 0
Hepatic encephalopathy 313458 0
Condition category
Condition code
Oral and Gastrointestinal 311670 311670 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Musculoskeletal 311671 311671 0 0
Other muscular and skeletal disorders
Diet and Nutrition 311672 311672 0 0
Other diet and nutrition disorders
Inflammatory and Immune System 311889 311889 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Thirty patients with cirrhosis, clinically significant ascites despite diuretic use or requiring large volume paracentesis, and lower than average handgrip strength will be invited to participate in the study.
Participants will be enrolled in a prospective cross-over study comprised of 2 12-week study periods: an observation period and a treatment period. There will be no washout period between each study period. All participants will undergo both the treatment and the observation periods, but will be randomly allocated by drawing a counter out of a box to begin in either the treatment period or the observation period before crossing over to the other period.
During the treatment period, patients will receive a continuous infusion of terlipressin, administered as 3.4mg daily intravenously via a peripherally inserted central catheter (PICC) line. Compliance with the terlipressin treatment will be monitored by the Hospital in the Home nurses who will attend the patients home daily to change their terlipressin infusion pump. Any non-compliance (eg intentional disconnection of the pump) will be reported to the study investigators.
Intervention code [1] 314705 0
Treatment: Drugs
Comparator / control treatment
Participants will act as their own controls during this study. During the 12 week observation period, they will undergo the same tests and assessments, and at the same time points, as they do during the treatment period, only they will not receive the terlipressin infusion during this period.
Control group
Active

Outcomes
Primary outcome [1] 320372 0
Change in muscle strength as measured by handgrip strength. This will be assessed using handgrip dynamometry.
Timepoint [1] 320372 0
Assessed at baseline, and 12-weeks of each arm of the cross-over.
Primary outcome [2] 320373 0
Effect on ascites, as measured by frequency and volume of paracentesis. This will be assessed via accessing medical records to record the number of attendances for paracentesis and the volumes drained each time.
Timepoint [2] 320373 0
This will be evaluated at baseline and at 12-weeks for each arm of the crossover.
Secondary outcome [1] 371382 0
Effect on muscle mass as measured by serial Dual energy X-ray Absorptiometry (DEXA) body composition scan
Timepoint [1] 371382 0
At baseline, at the end of the treatment period and at the end of the observation period
Secondary outcome [2] 371383 0
Effect on muscle function and frailty, as assessed by the Liver Frailty Index
Timepoint [2] 371383 0
Monthly throughout the course of the study
Secondary outcome [3] 371384 0
Effect on nutrition and energy expenditure, as assessed by the Subjective Global Assessment (SGA) and indirect calorimetry
Timepoint [3] 371384 0
SGA: monthly
Indirect calorimetry: at every clinical visit (weekly for 4 weeks then monthly) during both treatment and observation periods
Secondary outcome [4] 371385 0
Effect of terlipressin on number, cause and length of hospital admissions. This data will be obtained by accessing medical records for each participant.
Timepoint [4] 371385 0
At baseline, and at the end of the treatment and observation periods
Secondary outcome [5] 371386 0
Effect on quality of life, as assessed by the Chronic Liver Disease Questionnaire (CLDQ)
Timepoint [5] 371386 0
Monthly during the course of the study
Secondary outcome [6] 371387 0
Effect on overall healthcare costs, estimated utilising information from hospital admissions, outpatient visits and medications. This data will be obtained by accessing medical records to determine number and length of hospital admissions, outpatient attendances and medication and resource usage.
Timepoint [6] 371387 0
At baseline and at the end of the treatment and observation periods
Secondary outcome [7] 371388 0
A composite secondary outcome will be to examine the impact of continuous terlipressin infusion on markers of systemic inflammation, as assessed by serum CRP, interleukin (IL)- 1, IL-2, IL-6, IL-12, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, toll-like receptor (TLR)-4, and procalcitonin.
Timepoint [7] 371388 0
Monthly during the treatment and observation periods
Secondary outcome [8] 371389 0
A composite secondary outcome will be to examine the impact of continuous terlipressin infusion on markers of bacterial translocation, as assessed by serum endotoxin and bacterial DNA, lipopolysaccharide (LPS) and LPS-binding protein, soluble CD14 and faecal calprotectin
Timepoint [8] 371389 0
At baseline and then monthly during the treatment and observation periods
Secondary outcome [9] 371390 0
Impact on immune function as assessed via serum QuantiFERON Monitor
Timepoint [9] 371390 0
Monthly during the treatment and observation periods
Secondary outcome [10] 371391 0
A composite secondary outcome will be to examine the impact of continuous terlipressin infusion on biomarkers of liver disease as assessed by serum FBE, UEC, LFT, coagulation profile, MELD score, ammonia and urinary sodium
Timepoint [10] 371391 0
Monthly during the treatment and observation periods
Secondary outcome [11] 371392 0
Effect on cardiac output as assessed by dobutamine stress echo
Timepoint [11] 371392 0
At the start and end of the 12-week terlipressin infusion
Secondary outcome [12] 371584 0
A composite secondary outcome will be the impact of continuous terlipressin infusion on renin, angiotensin and aldosterone as measured via serum assays.
Timepoint [12] 371584 0
At baseline and at the end of the treatment and observation periods
Secondary outcome [13] 371742 0
Effect of terlipressin on serum myostatin.
Timepoint [13] 371742 0
Monthly during the course of the study
Secondary outcome [14] 371745 0
Effect of terlipressin on the number and severity of episodes of hepatic encephalopathy. This data will be obtained by accessing medical records for each participant.
Timepoint [14] 371745 0
At baseline, and at the end of the treatment and observation periods
Secondary outcome [15] 371746 0
Effect of terlipressin on the number of clinically significant infections. This data will be obtained by accessing medical records for each participant.
Timepoint [15] 371746 0
At baseline, and at the end of the treatment and observation periods
Secondary outcome [16] 371749 0
Effect on muscle mass as measured by serial skeletal muscle index calculated via single Slice CT scan at 3rd Lumbar vertebrae
Timepoint [16] 371749 0
At baseline, at the end of the treatment period and at the end of the observation period
Secondary outcome [17] 371750 0
Effect on muscle mass and anthropometry as measured by serial triceps skinfold measured by skinfold calipers, and mid-upper arm circumference measured with tape measure
Timepoint [17] 371750 0
Monthly during the course of the study

Eligibility
Key inclusion criteria
Patients able to give informed consent
Age > 18 years
Patients with cirrhosis
Clinically significant ascites despite diuretic use or those requiring large volume paracentesis
Handgrip strength below average for age and gender
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients who have not seen a dietician for counselling and education on the recommended high protein high energy diet, and salt restriction at least 3 months prior to the commencement of the study
Past history of vascular disease (coronary artery disease or significant other vascular disease)
Past intolerance of terlipressin
Other contraindications to terlipressin including severe congestive cardiac failure (NYHA class III or IV) and poorly controlled hypertension
Patient deemed unsuitable for the Hospital in the Home (HITH) program

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be concealed at the time of entry to the study. Participants will be allocated to begin with either the treatment or observation period by an independent person drawing a counter out of a box once they have been enrolled into the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
All participants will undergo both the treatment and the observation periods, but will be randomly allocated by drawing a counter out of a box to begin in either the treatment period or the observation period before crossing over to the other period, such that half the participants will begin in the observation period before crossing over to the treatment period, and the other half of the participants will start in the treatment period before crossing over to the observation period.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Patients with cirrhosis tend to develop sarcopenia which deteriorates further as their cirrhosis progresses. However, a recent pilot study in our unit looking at dietary intake in patients on continuous terlipressin infusion found that handgrip strength increased from 25.36±8.13kg to 28.49±7.63kg (p=0.001) over a median of 51 days of terlipressin therapy.
Our primary endpoint is an increase in handgrip strength of 6kg after 12 weeks of terlipressin, which has been guided by the median increase in handgrip strength in patients in our pilot study receiving > 2 months of terlipressin. To detect a 6kg in handgrip strength with the terlipressin intervention, with a p-value set at 0.05 and a power of 80%, we would need 42 patients for a parallel randomized double-blinded placebo-controlled trial. We however plan to use a cross-over study to increase the power of this study in the context of a rare condition (being diuretic-resistant ascites) and plan to recruit 30 patients (15 receiving terlipressin for the first 3 months of the study, and 15 patients receiving terlipressin for the second 6 months of the study).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 13970 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 26743 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 303006 0
Commercial sector/Industry
Name [1] 303006 0
Mallinckrodt Pharmaceuticals
Address [1] 303006 0
1425 Route 206
Bedminster
NJ 07921
Country [1] 303006 0
United States of America
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Road
Heidelberg
Victoria
3084
Country
Australia
Secondary sponsor category [1] 302977 0
None
Name [1] 302977 0
Address [1] 302977 0
Country [1] 302977 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303557 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 303557 0
145 Studley Road
Heidelberg, Victoria
3084
Ethics committee country [1] 303557 0
Australia
Date submitted for ethics approval [1] 303557 0
Approval date [1] 303557 0
07/06/2019
Ethics approval number [1] 303557 0
HREC/48098/ Austin-2018

Summary
Brief summary
End-stage liver disease, known as cirrhosis, is a common condition in Western society, and is associated with poor prognosis. Cirrhosis can lead to many complications, including fluid retention, kidney impairment and increased risk of infection. Many patients with cirrhosis are malnourished and also develop muscle wasting.
Terlipressin is a medication used in the management of severe bleeding and some forms of kidney impairment associated with liver disease, but little is known about its impact on other complications of liver disease such as muscle wasting, fluid retention or infection. Early data from our centre suggests that terlipressin can also improve nutrition in this population.
This study will attempt to confirm that long-term terlipressin can improve nutrition and muscle mass in patients with end-stage liver disease as well as understanding the mechanisms by which this occurs. It will also look at whether it improves other complications such as ascites (fluid retention in the abdominal cavity), infection, hospital admissions and healthcare costs.
Participants will undertake 2 study periods: an observation period and a treatment period, where they will receive a continuous infusion of terlipressin for 12 weeks which will be administered via the Hospital-in-the-Home program. They will undergo assessment of muscle strength and function using radiology scans and bedside tests, as well as monthly blood tests during both study periods. Hospital records will be accessed to identify causes of hospital admission and estimates of infection rates and to calculate direct healthcare costs. Quality of life will be assessed using validated questionnaires. In total, the participants will be involved in the study for a period of 6 months.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 94074 0
Dr Marie Sinclair
Address 94074 0
Austin Health
145 Studley Road
Heidelberg, Victoria
3084
Country 94074 0
Australia
Phone 94074 0
+61 3 9496 5353
Fax 94074 0
Email 94074 0
marie.sinclair@austin.org.au
Contact person for public queries
Name 94075 0
Dr Ryma Terbah
Address 94075 0
Austin Health
145 Studley Road
Heidelberg, Victoria
3084
Country 94075 0
Australia
Phone 94075 0
+61 3 9496 5353
Fax 94075 0
Email 94075 0
ryma.terbah@austin.org.au
Contact person for scientific queries
Name 94076 0
Dr Ryma Terbah
Address 94076 0
Austin Health
145 Studley Road
Heidelberg, Victoria
3084
Country 94076 0
Australia
Phone 94076 0
+61 3 9496 5353
Fax 94076 0
Email 94076 0
ryma.terbah@austin.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Patients are not being consented for release of their individual information and results to anyone other than the study investigators.
A summary table of all the results will be provided in any study-related publications.
What supporting documents are/will be available?
No other documents available
Summary results
No Results