E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cirrhosis of the liver |
Lever cirrose og komplikationer |
|
E.1.1.1 | Medical condition in easily understood language |
Cirrhosis of the liver |
Lever cirrose og komplikationer |
|
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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024667 |
E.1.2 | Term | Liver cirrhosis |
E.1.2 | System Organ Class | 100000004871 |
|
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 |
Add on treatment with atorvastatin 10-20 mg to standard treatment improves survival in patients with cirrhosis of any etiology. |
|
E.2.2 | Secondary objectives of the trial |
Add on treatment with atorvastatin 10-20 mg to standard treatment delays onset of systemic inflammation and decompensation in cirrhosis of any etiology. Atorvastatin alters macrophage activation and immune response to inflammation in the hepatic stellate cell, by altered expression in the inflammation cascade. Atorvastatin alters protein expression in the hepatic stellate cell and in Kupffer cells. Atorvastatin prevents micro-thrombosis in the small vasculature of the liver.
|
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Study Part One, July 2020: After enrolment of the first 48 participants an evaluation of the trial feasibility will performed on the following parameters: i) recruitment rates, ii) allocation of adequate resources to the trial, iii) safety for the participants. The project steering committee will conduct the feasibility evaluation.
Study Part one will deliver data to conduct a pilot study on the exploratory and secondary endpoints: - Degree of inflammation by: immunohistochemistry of the stellate cell in combination with PCR analysis for specific markers of inflammation in blood serum. - Degree of inflammation in the hepatic stellate cell by: gene activation by transcriptomics of mRNA in the hepatic stellate cell, combined with protein activity by mass spectrometry proteomics - Effect of atorvastatin of hepatic stellate cell and hepatocyte liver proteome will be investigated by mass spectrometry-based proteomics. - By high-sensitivity Mass spectrometry-based proteomics, we will perform proteomics analysis of hepatic stellate cells and Kupffer cells under atorvastatin influence. - By host genetics and metagenomics assess disease progression under atorvastatin influence. - The impact of atorvastatin on the human microbiome in combination with systemic inflammation. |
|
E.3 | Principal inclusion criteria |
- Patients in the age of 18 to 80 years are eligible for inclusion. - Patients with liver cirrhosis, diagnosed by liver biopsy, ultrasound or CT scan of the liver and / or clinical biochemistry compatible with cirrhosis are eligible for inclusion. - Both patients with compensated and decompensated liver disease are eligible for inclusion - In women, documented absence of pregnancy and unless in menopause commitment to use adequate contraception. - Clinically significant portal hypertension with a hepatic venous pressure gradient measured by liver vein catheterization >10 mmHg. - Ability to read and understand project information and give written, informed consent. |
|
E.4 | Principal exclusion criteria |
- People treated with statins within the last year. - People with liver cirrhosis, with a clinically verified infection (standard biochemistry, culture) within the last four weeks. - Pregnancy or lactation. - Hepatocellular carcinoma - HIV infection and treatment with protease inhibitors - People in whom the clinician and investigators may have reason to doubt compliance to trial medication - Clinical and biochemical signs of hepato-renal syndrome defined by current guidelines within the last 14 days - A MELD score above 23, or Child-Pugh score higher than 13. - Hepatic encephalopathy grade 2 or higher |
|
E.5 End points |
E.5.1 | Primary end point(s) |
- Composite endpoint of death or liver transplantation after 1.5 and 5 years. - Hospitalization with liver related complications after 1.5 and 5 years. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
- Survival within 1.5 years. - Survival within five years. - Decompensation of liver cirrhosis - Adverse events - Time to first hospital admission due to decompensation or complications of liver cirrhosis - Numbers of episodes of decompensation - Inflammation and macrophage activation (biomarkers specified in appendix 4) - Decrease in MELD score after one year - Decrease in Child-Pugh score after one year - Frailty Index evaluated by the Life Space Assessment questionnaire (validated in Danish) and the Short Physical Performance Battery (SPPB) - Degree of inflammation by: immunohistochemistry of the stellate cell in combination with PCR analysis for specific markers of inflammation in blood serum. - Degree of inflammation in the hepatic stellate cell by: gene activation by transcriptomics of mRNA in the hepatic stellate cell, combined with protein activity by mass spectrometry proteomics - Effect of atorvastatin of hepatic stellate cell and hepatocyte liver proteome will be investigated by mass spectrometry-based proteomics. - By high-sensitivity Mass spectrometry-based proteomics, we will perform proteomics analysis of hepatic stellate cells and Kupffer cells under atorvastatin influence. - By host genetics and metagenomics assess disease progression under atorvastatin influence. - The impact of atorvastatin on the human microbiome in combination with systemic inflammation. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Pathophysiological mechanisms. Metagenomics, transcriptomics and proteomics approach |
Patofysiologiske mekanismer, metagenomics, transcriptomics og proteomics tilgang |
|
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
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 | Yes |
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
|
Inclusion will be stopped when: - The reached sample size is met. That is, when 140 participants have at least 18 months of treatment with trial medication. The trial will end if: - The investigators or sponsor finds evidence to suggest that atorvastatin is harmful or ineffective in patients with liver cirrhosis. - Conditions arise in which the trial cannot be completed with adherence to the guidelines of Good Clinical Practice and the ethical guidelines of Helsinki Declaration. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |