E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Liver cirrhosis with refractory ascites. |
Levercirrose med behandlingsrefraktær ascites. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with liver cirrhosis and abdominal fluid which cannot be treated with diuretics. |
Skrumpeleverpatienter med væske i bugen (ascites), som ikke lader sig behandle med vanddrivende lægemidler. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024667 |
E.1.2 | Term | Liver cirrhosis |
E.1.2 | System Organ Class | 100000004871 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003445 |
E.1.2 | Term | Ascites |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal 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 investigate the safety, tolerability and efficacy of ularitide on the renal response in patients with liver cirrhosis and refractory ascites (as defined in this protocol) for a maximum exposure duration of 48 hours, through a randomized, placebo-controlled, double-blind, single-center clinical trial. |
Vi ønsker med dette kliniske studie, at undersøge sikkerheden, tolerancen og effekten af det salt- og vandudskillende peptid ularitide hos patienter med skrumpelever og refraktær ascites. Vi har derfor i sinde at behandle cirrosepatienter med refraktær ascites med op til 48 timers kontinuerlig ularitide-infusion. |
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E.2.2 | Secondary objectives of the trial |
Not applicable |
Ikke relevant |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age > 18 years - Liver cirrhosis confirmed by fibroscan (>20 kPa), or by imaging with signs of an irregular liver surface with collaterals, or clinically by cirrhosis stigmata - Refractory ascites: Definition: failure to respond to or intolerance to high dose diuretics (spironolactone up to 400mg/day and furosemide up to 160mg/day) and/or early ascites recurrence (reappearance of grade 2 or 3 ascites within 4 weeks of initial mobilization or ≥2 paracentesis within last 3 months) - Urine sodium excretion <60 mmol/24 hour - Serum creatinine <150 µmol/L - Child-Turcotte-Pugh score of B or C (<13) - Bilirubin <150 µmol/L - Systolic blood pressure ≥95 mmHg - Written informed consent to participate in the clinical trial |
- Alder over 18 år - Bekræftet cirrose (radiologisk eller klinisk) - Refraktær ascites - Natriumudskillelse <60mmol/døgn - Serum-kreatinin <150μmolL - Child-Turcotte-Pugh-score B7-C12 - Serum-bilirubin <150μmol/L - Systolisk blodtryk ≥95mmHg - Skriftligt informeret samtykke til deltagelse |
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E.4 | Principal exclusion criteria |
- Gastrointestinal bleeding within 2 weeks prior to inclusion - Proteinuria >500 mg/day - Hemoglobin <5.5 mmol/L - Spontaneous bacterial peritonitis within 2 weeks prior to inclusion - Loculated ascites - Hepatic encephalopathy grade 2-4 (West-Haven classification) - Obstructive uropathy - Primary kidney disease - Known diagnosis of congestive heart failure - Known diagnosis of acute-on-chronic liver failure - Known diagnosis of systemic inflammatory response syndrome - Acute infections by known diagnosis and/or antibiotic treatment - Known HIV infection - Known allergy to the investigational drug or other natriuretic peptides - Treatment with dobutamine, levosimendan, milrinone, any phosphodiesterase inhibitor, octreotide, midodrine, vasopressin, dopamine or other vasopressors within 2 weeks prior to inclusion - Nephrotoxic drugs within 1 month prior to inclusion - Fertile women not using contraception, either an intrauterine device or hormonal contraception (tablets, implants, transdermal patches, vaginal rings and injections) - Positive pregnancy test in pre-menopausal women or in breast-feeding women. Menopause is defined as no menses since ≥12 months prior to screening - Participation in an interventional clinical drug trial within 1 month prior to inclusion - Legal incapacity or limited legal capacity - Patients who are employees or relatives of the investigator |
- Blødning i mavetarmkanalen op til 2 uger inden forsøgsinklusion - Bakteriel bughindeinfektion (spontan bakteriel peritonitis) op til 2 uger inden forsøgsinklusion - Proteinuri >500mg/døgn - Hæmoglobin <5,5mmol/L - Lommedannende ascites - Hepatisk encefalopati grad 2-4 - Obstruktioner af urinvejene - Pågående akut infektion - Systemisk inflammatorisk respons syndrom - Akut i kronisk leversvigt - Primær nyresygdom - Hjertesvigt - HIV-infektion - Allergi overfor saltudskillende peptider - Deltagelse i kliniske medicinske forsøg indenfor den seneste måned - Inhabilitet - Kollega eller familiemedlem til forsøgsansvarlige - Behandling med nyreskadelige lægemidler op til 1 måned forinden inklusion - Behandling med dobutamin, levosimendan, milrinon, fosfodiesterasehæmmere, ocreotid, midodrin, vasopressin, dopamin, eller andre vasopresserstoffer 2 uger inden inklusion - Fertile kvinder, der ikke benytter hormonel prævention - Kvinder med positiv graviditetstest |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change (absolute and relative) in sodium excretion rate at 24 hours post infusion start and at the end of treatment versus baseline. Change (absolute and relative) in urine volume at 24 hours post infusion start and at the end of treatment versus baseline. Change of absolute body weight at the end of treatment versus baseline. |
Absolut og relativ ændring i natriumudskillelse efter 24 timers infusion og ved afslutning af behandlingen sammenlignet med baseline. Absolut og relativ ændring i urinvolumen efter 24 timers infusion og ved afslutning af behandlingen sammenlignet med baseline. Absolut ændring i kropsvægt ved afslutning af behandlingen sammenlignet med baseline. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
To evaluate the parameters above: Urine samples are collected at baseline, after 24 hours of infusion and at the end of treatment. Body weight is measured at baseline and at the end of treatment. |
For at bestemme primære endepunkter udføres: Urinprøver ved baseline, efter 24 timers infusion og ved afslutningen af behandlingen. Bestemmelse af kropsvægt ved baseline og ved afslutning af behandlingen. |
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E.5.2 | Secondary end point(s) |
- Number of responders in the ularitide group versus the placebo group at the end of treatment as defined by: urine volume increase of ≥100 % versus baseline at 2 hours post treatment start or, urine volume increase of ≥50 % versus baseline at 24 hours post treatment start or, natriuresis increase at the end of treatment by 100 % versus baseline and/or bodyweight reduction by ≥2 kg at the end of treatment versus baseline. - Change (absolute and relative) in sodium excretion rate at 2 and 4 hours post infusion start and at 4 hours after the end of treatment. - Change (absolute and relative) in urine volume at 2 and 4 hours post infusion start and at 4 hours after the end of treatment versus baseline. - Change (absolute and relative) in serum creatinine at 24 hours post infusion start and at the end of treatment versus baseline. - Change (absolute and relative) in waist circumference at 24 hours post infusion start and at the end of treatment versus baseline. - Change (absolute and relative) in urine osmolality at 24 hours post infusion start, at the end of treatment and at 4 hours after the end of treatment versus baseline. - Change (absolute and relative) in plasma osmolality at 24 hours post infusion start, at the end of treatment and at 4 hours after the end of treatment versus baseline. - Change (absolute and relative) in plasma copeptin concentration at 2, 24 hours post infusion start, at the end of treatment and at 4 hours after the end of treatment versus baseline. - Change (absolute and relative) in hematocrit at 24 hours post infusion start, at the end of treatment and at 4 hours after the end of treatment versus baseline. - Change (absolute and relative) in plasma cGMP concentration at 2, 24 hours post infusion start, at the end of treatment and at 4 hours after the end of treatment versus baseline. - Change (absolute and relative) in plasma aquaporin concentration at 2, 24 hours post infusion start, at the end of treatment and at 4 hours after the end of treatment versus baseline. - Change (absolute and relative) in eGFR (Cockroft) at 24 hours post infusion start and at the end of treatment versus baseline. - Change (absolute and relative) in GFR-24h-Crea at 24 hours post infusion start and at the end of treatment versus the baseline value measured at inclusion. - Change (absolute and relative) in plasma renin concentration at 2, 24 hours post infusion start, at the end of treatment and at 4 hours after the end of treatment versus baseline. - Change (absolute and relative) in plasma angiotensin concentration at 2, 24 hours post infusion start, at the end of treatment and at 4 hours after the end of treatment versus baseline. - Change (absolute and relative) in plasma aldosterone concentration at 2, 24 hours post infusion start, at the end of treatment and at 4 hours after the end of treatment versus baseline. |
- Antal respondenter i ularitide-gruppen sammenlignet med placebo-gruppen ved afslutning af behandlingen med øget urinvolumen, øget natriumudskillelse og/eller reduceret kropsvægt. - Absolut og relativ ændring i natriumudskillelse efter 2 og 4 timers infusion og 4 timer efter endt infusion sammenlignet med baseline. - Absolut og relativ ændring i urinvolumen efter 2 og 4 timers infusion og 4 timer efter endt infusion sammenlignet med baseline. - Absolut og relativ ændring i serum-kreatinin efter 24 timers infusion og ved afslutning af behandlingen sammenlignet med baseline. - Absolut og relativ ændring i livvidde efter 24 timers infusion og ved afslutning af behandlingen sammenlignet med baseline. - Absolut og relativ ændring i urinosmolalitet efter 24 timers infusion, ved afslutning af behandlingen og 4 timer efter endt infusion sammenlignet med baseline. - Absolut og relativ ændring i plasmaosmolalitet efter 24 timers infusion, ved afslutning af behandlingen og 4 timer efter endt infusion sammenlignet med baseline. - Absolut og relativ ændring i plasma copeptin koncentration efter 2 og 24 timers infusion, ved afslutning af behandlingen og 4 timer efter endt infusion sammenlignet med baseline. - Absolut og relativ ændring i hæmatokrit efter 24 timers infusion, ved afslutning af behandlingen og 4 timer efter endt infusion sammenlignet med baseline. - Absolut og relativ ændring i plasma cGMP koncentration efter 2 og 24 timers infusion, ved afslutning af behandlingen og 4 timer efter endt infusion sammenlignet med baseline. - Absolut og relativ ændring i plasma aquaporin koncentration efter 2 og 24 timers infusion, ved afslutning af behandlingen og 4 timer efter endt infusion sammenlignet med baseline. - Absolut og relativ ændring i eGFR efter 24 timers infusion og ved afslutning af behandlingen sammenlignet med baseline. - Absolut og relativ ændring i GFR-24h-Crea efter 24 timers infusion og ved afslutning af behandlingen sammenlignet med baselineværdien bestemt ved inklusion. - Absolut og relativ ændring i plasma renin koncentration efter 2 og 24 timers infusion, ved afslutning af behandlingen og 4 timer efter endt infusion sammenlignet med baseline. - Absolut og relativ ændring i plasma angiotensin koncentration efter 2 og 24 timers infusion, ved afslutning af behandlingen og 4 timer efter endt infusion sammenlignet med baseline. - Absolut og relativ ændring i plasma aldosteron koncentration efter 2 og 24 timers infusion, ved afslutning af behandlingen og 4 timer efter endt infusion sammenlignet med baseline. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
To evaluate the parameters above: Blood samples are collected at baseline, after 2 and 24 hours of infusion, at the end of treatment and 4 hours post infusion. Urine samples are collected at baseline, after 2, 4 and 24 hours of infusion, at the end of treatment and 4 hours post infusion. Waist circumference is measured at baseline, after 24 hours of infusion and at the end of treatment. |
For at bestemme sekundære endepunkter udføres: Blodprøver ved baseline, efter 2 og 24 timers infusion, ved afslutning af behandlingen og 4 timer efter endt infusion. Urinprøver ved baseline, efter 2, 4 og 24 timers infusion, ved afslutningen af behandlingen og 4 timer efter endt infusion. Bestemmelse af livvidde ved baseline, efter 24 timers infusion og ved afslutning af behandlingen. |
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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 | Yes |
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.8.5 | 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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LVLS |
Sidste deltagers sidste besøg |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |