E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-alcoholic steatohepatitis |
nealkoholni steatohepatitis |
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E.1.1.1 | Medical condition in easily understood language |
Non-alcoholic steatohepatitis (NASH) |
nealkoholni steatohepatitis (NASH) |
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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 | 24.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053219 |
E.1.2 | Term | Non-alcoholic steatohepatitis |
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 |
1. Part 1: To demonstrate that treatment with semaglutide 2.4 mg administered subcutaneously (under the skin, s.c.) improves liver histology compared to placebo in subjects with NASH and fibrosis stage 2 or 3. 2. Part 2: To demonstrate that treatment with semaglutide s.c. 2.4 mg lowers the risk of liver-related clinical events compared to placebo in subjects with NASH and fibrosis stage 2 or 3. |
1.Prvi dio ispitivanja: Pokazati da subkutano uzimanje semaglutida 2,4 mg poboljšava histološku sliku jetre u odnosu na placebo kod pacijenata s NASH-om i fibrozom stupnja 2 ili 3
2.Drugi dio ispitivanja: Pokazati da subkutano uzimanje semaglutida 2,4 mg smanjuje rizik od kliničkih događaja povezanih s jetrom u odnosu na placebo kod pacijenata s NASH-om i fibrozom stupnja 2 ili 3. |
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E.2.2 | Secondary objectives of the trial |
1. To demonstrate that treatment with semaglutide s.c. 2.4 mg lowers body weight compared to placebo in subjects with NASH and fibrosis stages 2 or 3. 2. To demonstrate that treatment with semaglutide s.c. 2.4 mg improves patient-reported outcomes compared to placebo in subjects with NASH and fibrosis stages 2 or 3. 3. To compare the effects of semaglutide s.c. 2.4 mg versus placebo on cardiovascular disease and cardio-metabolic factors in subjects with NASH and fibrosis stages 2 or 3. 4. To compare the effect of semaglutide s.c. 2.4 mg versus placebo on biomarkers related to fibrosis in subjects with NASH and fibrosis stages 2 or 3. |
1.Pokazati da subkutano uzimanje semaglutida 2,4 mg smanjuje tjelesnu masu u odnosu na placebo kod pacijenata s NASH-om i fibrozom stupnja 2 ili 3. 2.Pokazati da subkutano uzimanje semaglutida 2,4 mg poboljšava ishode prijavljene od pacijenata u odnosu na placebo kod pacijenata s NASH-om i fibrozom stupnja 2 ili 3. 3.Usporediti utjecaj subkutanog uzimanja semaglutida 2,4 mg naspram placeba na kardiovaskularnu bolest i kardio – metaboličke faktore kod pacijenata s NASH-om i fibrozom stupnja 2 ili 3. 4.Usporediti utjecaj subkutanog uzimanja semaglutida 2,4 mg naspram placeba na biomarkere povezane uz fibrozu kod pacijenata s NASH-om i fibrozom stupnja 2 ili 3. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age above or equal to 18 years at the time of signing informed consent. • Histological evidence of NASH based on a central pathologist evaluation of the baseline liver biopsy. The baseline liver biopsy can be a historical biopsy obtained within 180 days prior to the screening visit (V1). • Histological evidence of fibrosis stage 2 or stage 3 according to the NASH CRN classification based on a central pathologist evaluation of the baseline liver biopsy. • A histological NAS ≥ 4 with a score of 1 or more in steatosis, lobular inflammation and hepatocyte ballooning based on a central pathologist evaluation of the baseline liver biopsy. |
- Muškarci i žene u dobi od ili iznad 18 godina u vrijeme potpisivanja Informiranog pristanka - Histološki dokaz NASH-a temeljen na evaluaciji polaznog nalaza biopsije jetre od strane patologa. Polazni nalaz biopsije jetre može biti raniji nalaz biopsije jetre dobiven unutar 180 dana do posjeta probira. - Histološki dokaz fibroze stupnja 2 ili 3 prema NASH CRN klasifikaciji temeljen na evaluaciji polaznog nalaza biopsije jetre od strane patologa. - Histološki rezultat NAS ≥ 4 s 1 ili više bodom u steatozi, lobularnoj inflamaciji i degeneraciji hepatocita napuhavanjem temeljen na evaluaciji polaznog nalaza biopsije jetre od strane patologa. |
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E.4 | Principal exclusion criteria |
• Documented causes of chronic liver disease other than non-alcoholic fatty liver disease (NAFLD) • Positive HBsAg, positive anti-HIV, positive HCV RNA at screening (V2A) or any known presence of HCV RNA or HBsAg within 2 years of screening (V2A). • Presence or history of ascites, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis or liver transplantation at randomisation. • Known or suspected excessive consumption of alcohol (greater than 20 g/day for women or greater than 30 g/day for men) or alcohol dependence (assessed by the Alcohol Use Disorders Identification Test (AUDIT questionnaire)). • Treatment with vitamin E (at doses greater than or equal to 800 IU/day) or pioglitazone or medications approved for treatment of NASH which has not been at a stable dose in the period from 90 days prior to the screening visit (V2A). In addition, for subjects with historical liver biopsies taken more than 90 days prior to screening, treatment should be at a stable dose in from time of biopsy until screening. • Treatment with GLP-1 RAs in the period from 90 days prior to the screening visit (V2A). In addition, for subjects with historical liver biopsies taken more than 90 days prior to screening, any treatment with GLP-1 RAs from time of biopsy until screening (V2A). • Treatment with glucose-lowering agent(s) (other than GLP-1 RAs), lipid-lowering medication or weight loss medication not stable in the opinion of the investigator in the period from 90 days prior to the screening visit (V2A). In addition, for subjects with historical liver biopsies taken more than 90 days prior to screening, treatment should be at a stable dose in the opinion of the investigator from time of biopsy until screening. |
- Dokumentirani uzroci kronične bolesti jetre, osim NAFLD-a - Pozitivan test na površinski antigen hepatitisa B (HBsAg), pozitivan test na antigene humanog virusa imunodeficijencije (HIV), pozitivni test na RNA virus hepatitisa C (HCV-RNA) kod probira ili bilo koja poznata prisutnost HCV RNA ili HBsAg u razdoblju od 2 godine nakon probira. - Prisutnost ili anamneza ascitesa, varičealnog krvarenja, encefalopatije jetre, spontanog bakterijskog peritonitisa ili transplantacija jetre u trenutku randomizacije. - Poznata ili sumnja na pretjeranu konzumaciju alkohola (iznad 20 g / dan za žene ili iznad 30 g / dan za muškarce) ili ovisnost o alkoholu (procjenjuje se testom za identifikaciju poremećaja u konzumaciji alkohola (AUDIT upitnik). - Liječenje vitaminom E (u dozama jednakim ili višim od 800 IU / dan) ili pioglitazonom ili lijekovima odobrenim za liječenje NASH-a kojima nije postignuta stabilna doza prema mišljenju ispitivača u razdoblju od 90 dana prije probira. Osim toga, za ispitanike s biopsijom jetre u povijesti bolesti provedene u periodu više od 90 dana prije probira, liječenje treba biti u stabilnoj dozi, prema mišljenju ispitivača, u razdoblju od trenutka biopsije do probira. - Liječenje agonistima GLP-1 receptora unutar 90 dana prije probira. Pogotovo za ispitanike s biopsijom jetre u povijesti bolesti provedene više od 90 dana prije probira, bilo koji tretman agonistima GLP-1 receptora od trenutka biopsije do probira. - Liječenje lijekovima za snižavanje glukoze (osim agonistima GLP-1 receptora), lijekovima za snižavanje lipida ili lijekovima za mršavljenje nije stabilno po mišljenju ispitivača u razdoblju od 90 dana prije probira. Pogotovo za ispitanike s biopsijama jetre u povijesti bolesti uzete više od 90 dana prije probira, liječenje treba biti u stabilnoj dozi prema mišljenje ispitivača od trenutka biopsije do probira. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1: 1. Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) 2. Improvement in liver fibrosis and no worsening of steatohepatitis (Yes/No)
Part 2: 3. Time to first liver-related clinical event (composite endpoint) |
Prvi dio (dvije zasebne krajnje točke): 1.Rješavanje steatohepatitisa te održavanje stanja fibroze jetre (Da/Ne) 2.Poboljšanje stanja fibroze jetre te održavanje steatohepatitisa (Da/Ne)
Drugi dio: 3.Vrijeme do prvog kliničkog događaja povezanog s jetrom |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1.- 2. From randomisation (week 0) to week 72 3. From randomisation (week 0) to week 240 |
1.-2. Vrijeme od randomizacije (tjedan 0) do 72. tjedna 3. Vrijeme od randomizacije (tjedan 0) do 240. tjedna |
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E.5.2 | Secondary end point(s) |
1. Progression of liver fibrosis (Yes/No) 2. Change in body weight 3. Change in Short Form 36 v2.0 acute (SF-36) Bodily Pain 4. Change in body weight 5. Improvement in steatohepatitis with at least a 2-point reduction in NAS and no worsening of fibrosis (Yes/No) 6. Change in histology-assessed liver collagen proportionate area 7. Resolution of steatohepatitis and improvement in liver fibrosis (Yes/No) 8. Worsening in steatohepatitis (Yes/No) 9. Improvement in histology-assessed ballooning (Yes/No) 10. Improvement in histology-assessed inflammation (Yes/No) 11. Improvement in histology-assessed steatosis (Yes/No) 12. Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No) 13. Improvement in liver fibrosis and no worsening of steatohepatitis (Yes/No) 14. Change in alanine aminotransferase (ALT) 15. Change in aspartate aminotransferase (AST) 16. Change in inflammation assessed by High Sensitive C-Reactive Protein (hsCRP) 17. Change in glycosylated haemoglobin (HbA1c) 18. Change in triglyceride 19. Change in free fatty acids 20. Change in low-density lipoprotein (LDL) cholesterol 21. Change in high-density lipoprotein (HDL) cholesterol 22. Changes in SF-36 Physical Component Summary 23. Changes in SF-36 Mental Component Summary 24. Changes in NASH-CHECK Pain 25. Time to first Major Adverse Cardiovascular event (MACE) (composite endpoint) 26. Time to first major cardio-hepatic event (composite endpoint) 27. Change in liver stiffness assessed by FibroScan® 28. Change in Enhanced Liver Fibrosis (ELF) score |
2. Promjena u tjelesnoj masi 3. Promjena u SF-36 tjelesnoj boli 4. Promjena u tjelesnoj masi 5. Poboljšanje steatohepatitisa s najmanje 2 boda smanjenja na NAS skali bez pogoršanja stanja fibroze (Da/Ne) 6. Promjena u histologiji – procjena je proporcionalna prisutnog kolagena u jetri 7. Rješavanje steatohepatitisa i poboljšanje vlakana jetre (Da/Ne) 8. Pogoršanje steatohepatitisa (Da/Ne) 9. Poboljšanje histološkog baloniranja (Da/Ne) 10. Poboljšanje histološki dozane upale (Da/Ne) 11. Poboljšanje histološki procijenjene steatoze (Da / Ne) 12. Rješavanje steatohepatitisa bez pogoršanja fibroze jetre (Da/Ne) 13. . Poboljšanje fibroze jetre bez pogoršanja steatohepatitisa (Da/Ne) 14. Promjena u alanin aminotransferazi (ALT) 15. Promjena u aspartat aminotransferazi (AST) 16. Promjena u upali procijenjenoj pomoću visoko osjetljivog C reaktivnog Proteina (HsCRP) 17. Promjena glikoziliranog hemoglobina (HbA1c) 18. Promjena triglicerida 19. Promjena slobodnih masnih kiselina 20. Promjena kolesterola lipoproteina male gustoće (LDL) 21. Promjena kolesterola lipoproteina visoke gustoće (HDL) 22. Promjene u upitniku SF-36 fizičke komponente 23. Promjene u upitniku SF-36 mentalne komponente 24. Promjene u upitniku NASH-CHECK boli 25. Vrijeme do prvog velikog neželjenog kardiovaskularnog događaja (MACE) (složena krajnja točka) 26. Vrijeme do prvog velikog kardio-jetrenog događaja (složena krajnja točka) 27. Promjena elastičnosti jetre procijenjena pomoću FibroScan®-na 28. Promjena u ocjeni pojačane fibroze jetre (ELF) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. - 3. From randomisation (week 0) to week 72 4. From randomisation (week 0) to week 240 5. - 11. From randomisation (week 0) to week 72 12. - 13. From randomisation (week 0) to week 240 14.- 24. From randomisation (week 0) to week 72 25. - 26. From randomisation (week 0) to week 240 27. - 28. From randomisation (week 0) to week 72 |
1. - 3. Vrijeme od randomizacije (tjedan 0) do 72. tjedna 4. Vrijeme od randomizacije (tjedan 0) do 240. tjedna 5. - 11. Vrijeme od randomizacije (tjedan 0) do 72. tjedna 12. - 13. Vrijeme od randomizacije (tjedan 0) do 240. tjedna 14.- 24. Vrijeme od randomizacije (tjedan 0) do 72. tjedna 25. - 26. Vrijeme od randomizacije (tjedan 0) do 240. tjedana 27. - 28. Vrijeme od randomizacije (tjedan 0) do 72. tjedna |
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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 | No |
E.6.4 | Safety | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 101 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Canada |
China |
India |
Israel |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
South Africa |
Taiwan |
United States |
European Union |
Switzerland |
Norway |
Russian Federation |
Serbia |
Turkey |
United Kingdom |
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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
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 25 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 25 |