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Jonathan Fallowfield
The University of Edinburgh
Corresponding Author
ORCiD: https://orcid.org/0000-0002-5741-1471
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Background: In preclinical models recombinant human relaxin-2 (serelaxin) had anti-fibrotic effects and ameliorated portal hypertension (PH). A small exploratory study in patients with cirrhosis also suggested that serelaxin could reduce portal pressure.
Methods: In a phase 2 double-blind randomised controlled study conducted in a single centre (Royal Infirmary of Edinburgh, UK), male and female adult participants with cirrhosis and clinically-significant PH (CSPH; hepatic venous pressure gradient (HVPG) >10 mmHg) were enrolled. Participants were allocated to serelaxin or placebo in a 3:1 ratio. The placebo control group was used to maintain the blind. The primary endpoint was the change from baseline in fasting HVPG after 2 h peripheral i.v. serelaxin infusion (80 μg/kg/day for 60 min followed by 30 μg/kg/day for at least 60 min). Secondary endpoints included the change from baseline in hepatic blood flow and systemic haemodynamics (cardiac index, systemic vascular resistance index and aortic pulse wave velocity). Short-term safety and tolerability of serelaxin was also assessed.
Results: A total of 17 participants were screened, 15 were randomised and 11 completed the study (n=9 serelaxin, n=2 placebo). Reasons for withdrawal were baseline HVPG <10 mmHg (n=2) and technical failure (n=2). Median age was 56 (range 43-69) and 73% of participants were male. Cirrhosis aetiologies were alcohol (n=10), non-alcoholic fatty liver disease (n=2), hepatitis C (n=2) and hepatitis B (n=1). Participants were Child-Pugh class A (60%) and B (40%) with a median Model for End-Stage Liver Disease score of 10 (range 6-14). Mean baseline HVPG was 16.3 mmHg (range 10.3-21.7). Individual responses were variable, but overall there was no statistically significant change in HVPG after 2 h i.v. serelaxin (arithmetic mean of difference ±SD was 0.4 ±3.5 mmHg (95% CI -2.3, 3.1; p=0.76)). There were also no substantial changes from baseline in hepatic blood flow or systemic haemodynamic measures following serelaxin. We recorded 12 adverse events in 7 participants treated with serelaxin; none were significant, and most were unrelated to the investigational medicinal product. There were no serious adverse events.
Conclusion: In a small randomised phase 2 proof-of-concept study in patients with cirrhosis and CSPH, serelaxin infusion was safe and well-tolerated but had a neutral effect on HVPG.
Keywords
Cirrhosis, portal hypertension, serelaxin
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CURRENT STATUS: Published
View the published article at Trials.
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Editorial decision: Accept
On 24 Feb, 2020
Reviewer #1 agreed
On 22 Feb, 2020
Review #1 received
Received 22 Feb, 2020
Editor assigned
On 21 Feb, 2020
Reviewers invited
Invitations sent on 21 Feb, 2020
Submission checks complete
On 20 Feb, 2020
Version 2
Posted 30 Jan, 2020
No comments provided
Editorial decision: Minor revision
On 19 Feb, 2020
Review #3 received
Received 18 Feb, 2020
Reviewer #3 agreed
On 06 Feb, 2020
Review #2 received
Received 03 Feb, 2020
Review #1 received
Received 02 Feb, 2020
Editor assigned
On 30 Jan, 2020
Reviewers invited
Invitations sent on 30 Jan, 2020
Reviewer #1 agreed
On 30 Jan, 2020
Reviewer #2 agreed
On 30 Jan, 2020
Submission checks complete
On 29 Jan, 2020
No comments provided
Review #2 received
Received 03 Jan, 2020
Editorial decision: Major revision
On 03 Jan, 2020
Reviewer #2 agreed
On 15 Dec, 2019
Review #1 received
Received 09 Dec, 2019
Reviewers invited
Invitations sent on 03 Dec, 2019
Reviewer #1 agreed
On 03 Dec, 2019
Editor assigned
On 10 Oct, 2019
Submission checks complete
On 25 Aug, 2019
First submitted
On 21 Aug, 2019
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A new preprint design is coming!
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See the published version of this preprint at Trials.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Jonathan Fallowfield
The University of Edinburgh
Corresponding Author
ORCiD: https://orcid.org/0000-0002-5741-1471
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Trials.
No community comments so far
Editorial decision: Accept
On 24 Feb, 2020
Reviewer #1 agreed
On 22 Feb, 2020
Review #1 received
Received 22 Feb, 2020
Editor assigned
On 21 Feb, 2020
Reviewers invited
Invitations sent on 21 Feb, 2020
Submission checks complete
On 20 Feb, 2020
Version 2
Posted 30 Jan, 2020
No comments provided
Editorial decision: Minor revision
On 19 Feb, 2020
Review #3 received
Received 18 Feb, 2020
Reviewer #3 agreed
On 06 Feb, 2020
Review #2 received
Received 03 Feb, 2020
Review #1 received
Received 02 Feb, 2020
Editor assigned
On 30 Jan, 2020
Reviewers invited
Invitations sent on 30 Jan, 2020
Reviewer #1 agreed
On 30 Jan, 2020
Reviewer #2 agreed
On 30 Jan, 2020
Submission checks complete
On 29 Jan, 2020
No comments provided
Review #2 received
Received 03 Jan, 2020
Editorial decision: Major revision
On 03 Jan, 2020
Reviewer #2 agreed
On 15 Dec, 2019
Review #1 received
Received 09 Dec, 2019
Reviewers invited
Invitations sent on 03 Dec, 2019
Reviewer #1 agreed
On 03 Dec, 2019
Editor assigned
On 10 Oct, 2019
Submission checks complete
On 25 Aug, 2019
First submitted
On 21 Aug, 2019
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Trials.
Background: In preclinical models recombinant human relaxin-2 (serelaxin) had anti-fibrotic effects and ameliorated portal hypertension (PH). A small exploratory study in patients with cirrhosis also suggested that serelaxin could reduce portal pressure.
Methods: In a phase 2 double-blind randomised controlled study conducted in a single centre (Royal Infirmary of Edinburgh, UK), male and female adult participants with cirrhosis and clinically-significant PH (CSPH; hepatic venous pressure gradient (HVPG) >10 mmHg) were enrolled. Participants were allocated to serelaxin or placebo in a 3:1 ratio. The placebo control group was used to maintain the blind. The primary endpoint was the change from baseline in fasting HVPG after 2 h peripheral i.v. serelaxin infusion (80 μg/kg/day for 60 min followed by 30 μg/kg/day for at least 60 min). Secondary endpoints included the change from baseline in hepatic blood flow and systemic haemodynamics (cardiac index, systemic vascular resistance index and aortic pulse wave velocity). Short-term safety and tolerability of serelaxin was also assessed.
Results: A total of 17 participants were screened, 15 were randomised and 11 completed the study (n=9 serelaxin, n=2 placebo). Reasons for withdrawal were baseline HVPG <10 mmHg (n=2) and technical failure (n=2). Median age was 56 (range 43-69) and 73% of participants were male. Cirrhosis aetiologies were alcohol (n=10), non-alcoholic fatty liver disease (n=2), hepatitis C (n=2) and hepatitis B (n=1). Participants were Child-Pugh class A (60%) and B (40%) with a median Model for End-Stage Liver Disease score of 10 (range 6-14). Mean baseline HVPG was 16.3 mmHg (range 10.3-21.7). Individual responses were variable, but overall there was no statistically significant change in HVPG after 2 h i.v. serelaxin (arithmetic mean of difference ±SD was 0.4 ±3.5 mmHg (95% CI -2.3, 3.1; p=0.76)). There were also no substantial changes from baseline in hepatic blood flow or systemic haemodynamic measures following serelaxin. We recorded 12 adverse events in 7 participants treated with serelaxin; none were significant, and most were unrelated to the investigational medicinal product. There were no serious adverse events.
Conclusion: In a small randomised phase 2 proof-of-concept study in patients with cirrhosis and CSPH, serelaxin infusion was safe and well-tolerated but had a neutral effect on HVPG.
Figure 1
Figure 2
This is a list of supplementary files associated with this preprint. Click to download.
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