E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Portal hypertension in patients with liver cirrhosis. |
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E.1.1.1 | Medical condition in easily understood language |
High blood pressure in the portal vein (which carries blood from the gut and the spleen to the liver) due to extensive scar tissue in the liver (cirrhosis). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036200 |
E.1.2 | Term | Portal hypertension |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate that 2 hours treatment with serelaxin through a drip reduces the portal pressure in patients with liver cirrhosis and high blood pressure in the portal vein. |
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E.2.2 | Secondary objectives of the trial |
To determine the effect of serelaxin treatment on liver blood flow. To determine the effect of serelaxin treatment on the general circulation. To collect further information on the safety and tolerability of serelaxin in people with liver cirrhosis.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Male or female adult subjects over 18 years of age 2) Able to provide written informed consent and able to understand and willing to comply with the requirements of the study 3) Clinical/imaging-diagnosed or biopsy-proven liver cirrhosis of any aetiology 4) Evidence of portal hypertension either on imaging or previous endoscopy 5) Patients with large/grade 3 varices as identified by endoscopy within 6 months of screening must be in an endoscopic band ligation programme at the time of study entry 6) Suspected hepatic venous pressure gradient (HVPG) ≥10 mmHg at baseline |
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E.4 | Principal exclusion criteria |
1) Pregnancy or nursing (lactating) women 2) Women of child-bearing potential not using highly effective methods of contraception.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during the entire period of the study – until 4 weeks following Visit 2.
• Further details are found at the following web address: (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01- About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf
• In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking the investigational drug.
• Contraception must be continued for up to the end of study – 4 weeks following Visit 2.
3) Severe liver failure defined by one of the following: Prothrombin activity < 40%, Bilirubin > 5 mg/dL (85umol/L), hepatic encephalopathy > grade I 4) Presence of any non-controlled and clinically significant disease that could affect the study outcome or that would place the patient at undue risk 5) A history of variceal bleed within 1 month prior to visit 1 6) Hepatocellular carcinoma or history of malignancy of any organ system (other than localized basal cell carcinoma of the skin) treated or untreated. 7) Portal vein thrombosis 8) Previous surgical shunt or TIPSS 9) Current use of beta-blockers or nitrates, any other drug therapy known to have an influence on portal pressure (diuretics permitted provided patients have been on a stable dose for at least 30 days) 10) History of drug or alcohol abuse within 1 month of enrolment 11) Sitting Systolic Blood Pressure <110 mmHg at screening visit or within 10 minutes prior to starting study drug infusion 12) Use of other investigational drugs within 5 half-lives of enrolment, or within 30 days/until the expected pharmacodynamic effect has returned to baseline, whichever is longer 13) Significant arrhythmias, which include any of the following: sustained ventricular tachycardia, bradycardia with sustained ventricular rate < 45 beats per minute or atrial fibrillation/flutter with sustained ventricular response of > 90 beats per minute at rest, or Long QT syndrome or QTc > 450 msec (QT correction will be performed using the Fridericia correction method: QTcF = QT/RR0.33) for males and > 460 msec for females at screening (visit 1) 14) Documented hypersensitivity to intravenous contrast agents and/or iodine 15) Severe renal impairment (eGFR<30mL/min /1.73m2) 16) Significant left ventricular outflow tract obstructions (e.g., severe valvular aortic stenosis, obstructive cardiomyopathy), severe mitral stenosis, restrictive amyloid myocardiopathy, acute myocarditis 17) Severe aortic insufficiency or severe mitral regurgitation for which surgical or percutaneous intervention is indicated 18) Major neurologic event including cerebrovascular events, within 30 days prior to screening 19) Clinical evidence of acute coronary syndrome currently or within 30 days prior to enrolment 20) History of hypersensitivity to study drug serelaxin or study drug ingredients 21) Inability to follow instructions or comply with follow-up procedures 22) Permanent pacemaker, cardiac resynchronisation device or implantable cardioverter-defibrillator in situ |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in fasting hepatic venous pressure gradient (HVPG) after 2 hours serelaxin infusion. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline, 1 hour and 2 hours after initiation of serelaxin infusion. |
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E.5.2 | Secondary end point(s) |
1. Change from baseline in fasting hepatic venous pressure gradient (HVPG) after 1 hour serelaxin infusion. 2. Change from baseline in fasting hepatic blood flow after 2 hours serelaxin infusion (measured from the concentration of indocyanine green (ICG) in the hepatic venous blood vs peripheral venous blood using the Fick Principle). 3. Change from baseline in inferior vena cava pressure (IVCP) after 2 hours serelaxin infusion. 4. Change from baseline in cardiac index (CI) after 2 hours serelaxin infusion. 5. Change from baseline in systemic vascular resistance index (SVRI) after 2 hours serelaxin infusion. 6. Change from baseline in aortic pulse wave velocity after 2 hours serelaxin infusion. 7. Safety and tolerability of serelaxin infusion (as assessed throughout the study by monitoring AEs, clinical laboratory blood tests, heart rate, blood pressure and ECG). 8. Change from baseline in blood biomarker measurements after 2 hours serelaxin infusion.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Baseline and 1 hour after initiation of serelaxin infusion. 2. Baseline and 2 hours after initiation of serelaxin infusion. 3. Baseline and 2 hours after initiation of serelaxin infusion. 4. Baseline and 2 hours after initiation of serelaxin infusion. 5. Baseline and 2 hours after initiation of serelaxin infusion. 6. Baseline and 2 hours after initiation of serelaxin infusion. 7. Throughout study. 8. Baseline and 2 hours after initiation of serelaxin infusion.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 3 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 3 |