Compensated Cirrhosis and Portal Hypertension
Conditions
Keywords
Portal hypertension, cirrhosis, TIPSS, MRI, MRA, portal pressure, portal pressure gradient
Brief summary
The main purpose of this exploratory study was to investigate the effect of serelaxin (RLX030) infusion on the hepatic and renal circulation in patients with compensated cirrhosis and portal hypertension. Measurements were acquired non-invasively using magnetic resonance angiography (MRA) (study part A) and more directly via cannulation of the hepatic portal vein during a routine transjugular intrahepatic portosystemic shunt (TIPSS) check procedure (study part B), to determine the acute haemodynamic response to serelaxin (RLX030).
Interventions
IV bolus injection
DRUGSerelaxin (RLX030)
Part A2: IV infusion for 2-3 hours; duration of infusion depends on time required for completion of MRA data acquisition; Part B: IV infusion for approximately 2 hours
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Study Parts A and B: -Cirrhosis of alcohol aetiology according to physician's assessment prior to screening. Part A: -Cirrhosis with clinical and/or endoscopic evidence of portal hypertension (e.g. oesophageal varices). Part B: * Cirrhosis with TIPSS in situ and PPG\>5mmHg. * Fully functioning TIPSS without variceal filling as confirmed by portography.
Exclusion criteria
Study Parts A and B: * Use of any drug to treat portal hypertension (e.g. vasodilators such as non-selective beta blockers or nitrates) within 1 month prior to screening. * Decompensated cirrhosis (Child-Pugh score \>9 points, and/or ascites requiring diuretics, and/or hepatic encephalopathy) at visit 1. * Presence of any non-controlled and clinically significant disease that could affect the study outcome or that would place the patient at undue risk. Part A: * BMI (weight\[kg\] / height\[m\^2\]) \> 40 kg/m\^2. * Any contraindication to having an MRI scan Part B: -Contraindication to catheterization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of the Blood Flow for the Total Renal Arteries (Study Part A (Serelaxin Treatment Group Only)) | Baseline, 120 min post serelaxin infusion | The flow is the average flow over the cardiac cycle. Total renal artery flow = left renal artery flow + right renal artery flow. These measurements were collected through magnetic resonance angiography (MRA) scans. Baseline blood flow for total renal artery is measured at pre-dose (Day 1, 0 min post-treatment) |
| Change From Baseline of the Portal Pressure Gradient (PPG) (Study Part B) | Baseline, 120 min post-infusion start | Direct venous pressure was measured by portal pressure gradient (PPG). PPG = portal vein pressure (PVP) - inferior vena cava pressure (IVCP). Baseline blood flow for PPG was measured at pre-dose (Day 1, 0 min post-treatment). PVP was measured at 15 min intervals (i.e. prior to and at 15, 30, 45, 60, 75, 90, 105, and 120 min of serelaxin infusion). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of the Blood Flow for the Superior Mesenteric Artery (Study Part A (Serelaxin Treatment Group Only)) | Baseline, 120 min post-infusion | A non-contrast magnetic resonance angiography (MRA) sequence was performed to acquire phase contrast blood flow measurements from vessels of interest such as superior mesenteric artery. The flow is the average flow over the cardiac cycle. Baseline blood flow measurements are measured at pre-dose (Day 1, 0 min post-treatment). |
| Change From Baseline of the Blood Flow for the Descending Thoracic Aorta (Study Part A (Serelaxin Treatment Group Only)) | Baseline, 120 min post-infusion | A non-contrast magnetic resonance angiography (MRA) sequence was performed to acquire phase contrast blood flow measurements from vessels of interest such as descending thoracic aorta. The flow is the average flow over the cardiac cycle. Baseline blood flow measurements are measured at pre-dose (Day 1, 0 min post-treatment). |
| Change From Baseline of the Blood Flow for the Total Renal Arteries (Study Part A (Terlipressin Acetate Group Only)) | Baseline, 120 min post infusion | The flow is the average flow over the cardiac cycle. Total renal artery flow = left renal artery flow + right renal artery flow. These measurements were collected through magnetic resonance angiography (MRA) scans. Baseline blood flow for total renal artery is measured at pre-dose (Day 1, 0 min post-treatment) |
| Change From Baseline of the Portal Vein Pressure (PVP) (Study Part B) | Baseline, 120 min post infusion | Portal vein pressure was measured at 15 min intervals (i.e. prior to and at 15, 30, 45, 60, 75, 90, 105, and 120 min of serelaxin infusion). |
| Number of Patients With Total Adverse Events, Serious Adverse and Death as Assessment of Safety and Tolerability of Serelaxin | 4 weeks | This endpoint reports patients with any adverse event, serious adverse event and death for the serelaxin group of Part A and Part B of the study. |
| Change From Baseline of the Blood Flow for the Portal Vein (Study Part A (Serelaxin Treatment Group Only)) | Baseline, 120 min post-infusion | A non-contrast magnetic resonance angiography (MRA) sequence was performed to acquire phase contrast blood flow measurements from vessels of interest such as the portal vein. The flow is the average flow over the cardiac cycle. Baseline blood flow measurements are measured at pre-dose (Day 1, 0 min post-treatment). |
| Change From Baseline of the Blood Flow for the Hepatic Artery (Study Part A (Serelaxin Treatment Group Only)) | Baseline, 120 min post-infusion | A non-contrast magnetic resonance angiography (MRA) sequence was performed to acquire phase contrast blood flow measurements from vessels of interest such as hepatic artery. The flow is the average flow over the cardiac cycle. Baseline blood flow measurements are measured at pre-dose (Day 1, 0 min post-treatment). |
Countries
United Kingdom
Participant flow
Recruitment details
Out of 47 enrolled patients, 1 patient did not get randomized to Part A serelaxin arm ; patient withdrew consent due to failure of meeting an exclusion criterion for Part A prior to receiving the dose of study medication.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Terlipressin Acetate Patients received terlipressin acetate 2 mg intravenous (IV) bolus injection. | 20 |
| Part A: Serelaxin (RLX030) Randomized patients received an intravenous serelaxin infusion at two different infusion rates: 80 μg/kg/day for 60 min followed by 30 μg/kg/day for at least 60 min.; duration of infusion depends on time required for completion of magnetic resonance angiography (MRA) data acquisition | 20 |
| Part B: Serelaxin (RLX030) The patients enrolled in this part of the study received an intravenous (iv) serelaxin infusion at two different infusion rates: 80 μg/kg/day for 60 min followed by 30 μg/kg/day for at least 60 min; duration of infusion depends on time required for completion of the Portal pressure gradient (PPG) data acquisition. | 6 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Protocol Deviation | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | Part A: Terlipressin Acetate | Part A: Serelaxin (RLX030) | Part B: Serelaxin (RLX030) | Total |
|---|---|---|---|---|
| Age, Customized < 65 years | 17 Patients | 15 Patients | 6 Patients | 38 Patients |
| Age, Customized >= 65 years | 3 Patients | 5 Patients | 0 Patients | 8 Patients |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Male | 16 Participants | 16 Participants | 3 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 20 | 11 / 20 | 2 / 6 |
| serious Total, serious adverse events | 1 / 20 | 1 / 20 | 2 / 6 |
Outcome results
Primary
Change From Baseline of the Blood Flow for the Total Renal Arteries (Study Part A (Serelaxin Treatment Group Only))
The flow is the average flow over the cardiac cycle. Total renal artery flow = left renal artery flow + right renal artery flow. These measurements were collected through magnetic resonance angiography (MRA) scans. Baseline blood flow for total renal artery is measured at pre-dose (Day 1, 0 min post-treatment)
Time frame: Baseline, 120 min post serelaxin infusion
Population: Full analysis set (FAS) included all patients who received any amount of study treatment during the treatment period and had at least one post-Baseline assessment during that period.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Serelaxin (RLX030) | Change From Baseline of the Blood Flow for the Total Renal Arteries (Study Part A (Serelaxin Treatment Group Only)) | 0.438 L/min |
Primary
Change From Baseline of the Portal Pressure Gradient (PPG) (Study Part B)
Direct venous pressure was measured by portal pressure gradient (PPG). PPG = portal vein pressure (PVP) - inferior vena cava pressure (IVCP). Baseline blood flow for PPG was measured at pre-dose (Day 1, 0 min post-treatment). PVP was measured at 15 min intervals (i.e. prior to and at 15, 30, 45, 60, 75, 90, 105, and 120 min of serelaxin infusion).
Time frame: Baseline, 120 min post-infusion start
Population: For Part B of the study, full analysis set included all patients who received any amount of study treatment during the treatment period and had at least one post-baseline assessment during that period.Only patients with a value at both baseline and this time point are included.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Serelaxin (RLX030) | Change From Baseline of the Portal Pressure Gradient (PPG) (Study Part B) | -1.2 mmHg |
Secondary
Change From Baseline of the Blood Flow for the Descending Thoracic Aorta (Study Part A (Serelaxin Treatment Group Only))
A non-contrast magnetic resonance angiography (MRA) sequence was performed to acquire phase contrast blood flow measurements from vessels of interest such as descending thoracic aorta. The flow is the average flow over the cardiac cycle. Baseline blood flow measurements are measured at pre-dose (Day 1, 0 min post-treatment).
Time frame: Baseline, 120 min post-infusion
Population: For the part A of the study, full analysis set included all patients who received any amount of study treatment during the treatment period and had at least one post-baseline assessment during that period. Only patients with a value at both baseline and at the time point are included
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Serelaxin (RLX030) | Change From Baseline of the Blood Flow for the Descending Thoracic Aorta (Study Part A (Serelaxin Treatment Group Only)) | 0.293 L/min |
Secondary
Change From Baseline of the Blood Flow for the Hepatic Artery (Study Part A (Serelaxin Treatment Group Only))
A non-contrast magnetic resonance angiography (MRA) sequence was performed to acquire phase contrast blood flow measurements from vessels of interest such as hepatic artery. The flow is the average flow over the cardiac cycle. Baseline blood flow measurements are measured at pre-dose (Day 1, 0 min post-treatment).
Time frame: Baseline, 120 min post-infusion
Population: For the part A of the study, full analysis set included all patients who received any amount of study treatment during the treatment period and had at least one post-baseline assessment during that period. Only patients with a value at both baseline and at the time point are included
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Serelaxin (RLX030) | Change From Baseline of the Blood Flow for the Hepatic Artery (Study Part A (Serelaxin Treatment Group Only)) | 0.084 L/min |
Secondary
Change From Baseline of the Blood Flow for the Portal Vein (Study Part A (Serelaxin Treatment Group Only))
A non-contrast magnetic resonance angiography (MRA) sequence was performed to acquire phase contrast blood flow measurements from vessels of interest such as the portal vein. The flow is the average flow over the cardiac cycle. Baseline blood flow measurements are measured at pre-dose (Day 1, 0 min post-treatment).
Time frame: Baseline, 120 min post-infusion
Population: For the part A of the study, full analysis set included all patients who received any amount of study treatment during the treatment period and had at least one post-baseline assessment during that period. Only patients with a value at both baseline and at the time point are included
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Serelaxin (RLX030) | Change From Baseline of the Blood Flow for the Portal Vein (Study Part A (Serelaxin Treatment Group Only)) | -0.091 L/min |
Secondary
Change From Baseline of the Blood Flow for the Superior Mesenteric Artery (Study Part A (Serelaxin Treatment Group Only))
A non-contrast magnetic resonance angiography (MRA) sequence was performed to acquire phase contrast blood flow measurements from vessels of interest such as superior mesenteric artery. The flow is the average flow over the cardiac cycle. Baseline blood flow measurements are measured at pre-dose (Day 1, 0 min post-treatment).
Time frame: Baseline, 120 min post-infusion
Population: For the part A of the study, full analysis set included all patients who received any amount of study treatment during the treatment period and had at least one post-baseline assessment during that period. Only patients with a value at both baseline and at the time point are included
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Serelaxin (RLX030) | Change From Baseline of the Blood Flow for the Superior Mesenteric Artery (Study Part A (Serelaxin Treatment Group Only)) | 0.002 L/min |
Secondary
Change From Baseline of the Blood Flow for the Total Renal Arteries (Study Part A (Terlipressin Acetate Group Only))
The flow is the average flow over the cardiac cycle. Total renal artery flow = left renal artery flow + right renal artery flow. These measurements were collected through magnetic resonance angiography (MRA) scans. Baseline blood flow for total renal artery is measured at pre-dose (Day 1, 0 min post-treatment)
Time frame: Baseline, 120 min post infusion
Population: Full analysis set (FAS) included all patients who received any amount of study treatment during the treatment period and had at least one post-Baseline assessment during that period.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Serelaxin (RLX030) | Change From Baseline of the Blood Flow for the Total Renal Arteries (Study Part A (Terlipressin Acetate Group Only)) | 0.059 L/min |
Secondary
Change From Baseline of the Portal Vein Pressure (PVP) (Study Part B)
Portal vein pressure was measured at 15 min intervals (i.e. prior to and at 15, 30, 45, 60, 75, 90, 105, and 120 min of serelaxin infusion).
Time frame: Baseline, 120 min post infusion
Population: For Part B of the study, full analysis set included all patients who received any amount of study treatment during the treatment period and had at least one post-baseline assessment during that period. Only patients with a value at both baseline and this time point are included.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Serelaxin (RLX030) | Change From Baseline of the Portal Vein Pressure (PVP) (Study Part B) | -3.7 mmHg |
Secondary
Number of Patients With Total Adverse Events, Serious Adverse and Death as Assessment of Safety and Tolerability of Serelaxin
This endpoint reports patients with any adverse event, serious adverse event and death for the serelaxin group of Part A and Part B of the study.
Time frame: 4 weeks
Population: Safety assessment happened on full analysis set which included all patients who received any amount of study treatment during the treatment period and had at least one post-Baseline assessment during that period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Serelaxin (RLX030) | Number of Patients With Total Adverse Events, Serious Adverse and Death as Assessment of Safety and Tolerability of Serelaxin | Any adverse event | 3 Patients |
| Part A: Serelaxin (RLX030) | Number of Patients With Total Adverse Events, Serious Adverse and Death as Assessment of Safety and Tolerability of Serelaxin | Serious Adverse Events | 1 Patients |
| Part A: Serelaxin (RLX030) | Number of Patients With Total Adverse Events, Serious Adverse and Death as Assessment of Safety and Tolerability of Serelaxin | Death | 0 Patients |
| Part B: Serelaxin (RLX030) | Number of Patients With Total Adverse Events, Serious Adverse and Death as Assessment of Safety and Tolerability of Serelaxin | Any adverse event | 3 Patients |
| Part B: Serelaxin (RLX030) | Number of Patients With Total Adverse Events, Serious Adverse and Death as Assessment of Safety and Tolerability of Serelaxin | Serious Adverse Events | 2 Patients |
| Part B: Serelaxin (RLX030) | Number of Patients With Total Adverse Events, Serious Adverse and Death as Assessment of Safety and Tolerability of Serelaxin | Death | 0 Patients |