| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with chronic hepatitis C |
| Patienter med kronisk hepatitis C |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with a chronic liver diasease caused by a virus called hepatitis C virus. |
Patienter med kronisk leverbetændelse type C.
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10074391 |
| E.1.2 | Term | Chronic hepatitis C virus genotype 1 |
| E.1.2 | System Organ Class | 100000004862 |
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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 study the rate of adverse events and sustanied viral response in a randomized study of patients with chronic hepatitis C, genotype 1 patients, treated for 12 weeks with Viekira PAK® and ribavirin versus Harvoni® and ribavirin. Compare the adverse events- and sustanied viral response rates between the two groups of patients in each treatment arm in relation to demographic, biological and genetic factors.
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Del 1
Vi ønsker at undersøge hyppigheden af bivirkninger af patienter med kronisk hepatitis C, genotype 1, randomiseret til behandling i 12 uger med Viekira PAK® og ribavirin versus Harvoni® og ribavirin.
Vi ønsker at sammenligne hyppigheden af bivirkninger og helbredelses raten mellem de to grupper af patienter i hver behandlingsarm i forhold til demografisk data samt biologiske og genetiske faktorer.
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| E.2.2 | Secondary objectives of the trial |
To investigate, by population sequencing for resistance associated varients, hepatitis C virus isolated from all patients who fail treatment in the randomised study described above both at baseline and post-treatment failure.
Examine the effect of sofosbuvir/daclatasvir/ribavirin or sofosbuvir/velpatasvir with and without ribavirin for 12 weeks on the hepatic venous pressure gradient, systemic blood pressure, metabolic function of the liver and inflammatory cells in patients with chronic hepatitis C, genotype 3 and liver cirrhosis.
To study if there is a change in perfusion of the heart and calcium score analyzed by heart - rubidium PET/CT scan, after treatment with direct acting antivirals for 8, 12 or 24 weeks in patients with chronic hepatitis C, genotype 1 or 3.
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Undersøgelse for viral resistens evalueret ved hjælp af populations sekventering af hepatitis C virus genomet hos patienter i forsøg 1 del 1 med behandlingssvigt.
Vi ønsker at undersøge effekten af behandling med sofosbuvir /daclatasvir / ribavirin eller sofosbuvir/velpatasvir med og yden ribavirin i 12 uger på betændelsesceller (sCD163), blodtrykket i leveren, det systemiske blodtryk og leverfunktionen hos patienter med kronisk hepatitis C, genotype 3 og levercirrose.
Vi ønsker at undersøge med hjerte-rubidium-PET, om der ses en ændring i hjertets perfusion og ved hjerte-CT om calciumscore ændres efter behandling med direkte virkende antivirale præparater i 8, 12 eller 24 uger hos patienter med kronisk hepatitis C, genotype 1 eller 3.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients of both sexes between 18-70 years
• Patients are followed at one of the 18 departments affiliated with DANHEP, diagnosed with chronic HCV infection (verified by real-time PCR as the presence of HCV RNA in two blood samples taken 6 months apart).
• Treatment-naïve or previous treatment with pegylated interferon / ribavirin or discontinuing treatment with pegylated interferon / ribavirin / telaprevir / boceprevir due to side effects.
• Treatment demanding chronic hepatitis C virus infection.
• Liver biopsy or Fibroscanning showing moderate to severe fibrosis (Metavir ≥F2 score) or cirrhosis. Liver fibrosis or cirrhosis examined by liver biopsy ranked by the Danish scoring system based on the Metavir scoring system, where stage F2 indicate moderate fibrosis stage F3; severe fibrosis and stage F4; cirrhosis. If the diagnosis is made with Fibroscanning; values> 7 kPa and <17kPa indicate moderate to severe fibrosis and values ≥17 kPa indicate cirrhosis.
- Clinically diagnosed cirrhosis in the absence of liver biopsy or Fibroscanning, defined as overt cirrhosis at ultrasound (+/- spleen enlargement), low platelet count ≤110 * 109 cells / L, PT≤75 / INR> 1.7 (increased clotting of the blood) , serum albumin <6g / L or the presence of complications: ascites confirmed by ultrasound, esophageal varices diagnosed by gastroscopy or hepatic encephalopathy.
• Infected with genotype 1 or genotype 3.
• Women of childbearing potential must use effective contraception defined as copper or progesten spiral and condom must be used by partner throughout the treatment period.
• Men who are treated in the trial must use condoms throughout treatment and for at least 7 months after completion of treatment.
• Must be able to read and understand Danish.
• Must be able to sign informed consent.
• patients co-infected with HIV must be in anti-viral therapy. |
• Patienter af begge køn mellem 18-70 år
• Patienter som følges på en af de 18 afdelinger der er tilknyttet DANHEP, diagnosticeret med kronisk HCV infektion (verificeret ved real-time PCR som tilstedeværelsen af HCV-RNA i 2 blodprøver taget med 6 måneders mellemrum).
• Behandlings-naive eller tidligere behandling med PEGINF/RBV eller afbrudt behandling med pegyleret interferon/ribavirin/telaprevir/boceprevir pga. bivirkninger.
• Behandlingskrævende kronisk hepatitis C virus infektion.
• Lever biopsi eller Fibroscanning visende moderate til svær fibrose (Metavir ≥F2 score) eller cirrose. Lever fibrose eller cirrose undersøgt ved lever biopsi klassificeret efter det Danske score system baseret på Metavir scoring systemet, hvor stadie F2 indikere moderat fibrose, stadie F3; svær fibrose og stadie F4; cirrose. Hvis diagnosen er stillet med Fibroscanning; værdier >7 kPa og < 17kPa indikere moderat til svær fibrose og værdier ≥17 kPa indikere cirrose.
• Klinisk diagnosticeret cirrose hvis der ikke foreligger leverbiopsi eller Fibroscanning, defineret som åbenlys cirrose ved ultralydsscanning (+/- milt forstørrelse), nedsat antal blodplader ≤110*109 celler/L, PT≤75/ INR>1.7 (forøget størkningstid af blodet), serum albumin < 6g/L eller tilstedeværelse af komplikationer: ascites konfirmeret ved ultralydsscanning, øsofagus varicer diagnosticeret ved gastroskopi eller hepatisk encephalopati.
• Inficeret med genotype 1 eller genotype 3.
• Kvinder i den fødedygtige alder skal benytte sikker prævention defineret som kobber eller gestagen spiral og kondom skal benyttes af partner i hele behandlingsperioden.
• Mænd der behandles i forsøget skal anvende kondom under hele behandlingsforløbet samt i minimum 7 måneder efter afsluttet behandling.
• Skal kunne læse og forstå dansk.
• Skal kunne underskrive informeret samtykke.
• Patienter co-inficeret med HIV skal være i anti-viral behandling.
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| E.4 | Principal exclusion criteria |
Hypersensitivity to any of the ingredients in the medicine.
• Severe untreated psychiatric illness which the investigator believe may affect treatment.
• Severe mental illness; schizophrenia, psychosis, bipolar disorder, post-traumatic stress disorder, mania.
• Current alcohol (> 25 objects weekly), intravenous drug or other drug abuse.
• Decompensated cirrhosis.
• Diagnosed with hepatocellular carcinoma or are being investigated for this.
• Severe heart failure NYHA class III and IV
• Previous stroke, TIA or AMI.
• Severe angina pectoris, cardiomyopathy, pulmonary hypertension, uncontrolled hypertension or significant arrhythmia diagnosed by ECG.
• Severe chronic lung disease; COPD, pulmonary fibrosis or sarcoidosis defined as; GOLD stage 3: FEV1 / FVC <0.7 and FEV1 between 30-50% predicted and GOLD stage 4: FEV1 / FVC <0.7 and FEV1 between the 30% predicted.
• Myelodysplastic diseases.
• Organ transplantation (except from hair or cornea)
• Active cancer or diagnosed with cancer (other than basal cell skin cancer) within the past 5 years.
• Autoimmune liver disease.
• Haemoglobinopathies; sickle cell anemia and thalassemia.
• Neutropenia <1.5 x 103 l
• Thrombocytopenia <50 x 103 ul
• Renal impairment (GFR <50 ml / min., Including hemodialysis)
• thyroid disease that is not controlled by conventional therapy.
• Insufficient treated epilepsy.
• Pregnancy / lactation.
• Severe untreated anemia, hemoglobin ≤ 5 mmol / l.
• Treatment with carbamazepine, phenytoin, rifabutin, rifampicin, herbal preparations containing St. John's wort and modafinil.
• Insufficient treated severe diabetes, HbA1c> 8.5%.
• Severe hepatic impairment (Child-Pugh C).
• The use of contraceptives with ethinylestradiol
• Treatment with CYP3A4 substrates; Alfuzosin, amiodarone, Atorvastatin, ergotamine, Fusidic acid, Lovastatin, Oral midazolam, pimozide, Quetiapine, Salmeterol, Sildenafil against pulmonary arterial hypertension, Simvastatin, Triazolam, Rosuvastatin.
• Treatment with potent CYP3A4 inducers or other enzyme inducers; Efavirenz, etravirine, Enzalutamid, Mitotane, Nevirapine, Phenobarbital.
• The treatment with strong CYP3A4 inhibitors; Clarithromycin, Cobicistat, itraconazole, lopinavir / ritonavir, posaconazole, voriconazole.
• Treatment with strong CYP2C8 inhibitors; Gemfibrozil. |
• Allergi overfor et af indholdsstofferne i medicinen.
• Svær ubehandlet psykiatrisk sygdom som i følge investigator kan påvirke behandlingen.
• Svær psykisk sygdom; skizofreni, psykose, bipolær sygdom, post-traumatisk stress syndrom, mani.
• Nuværende alkohol (> 25 genstande ugentligt), intravenøst stof eller narkotika misbrug.
• Dekompenseret cirrose.
• Er kendt med hepatocellulær carcinoma eller er under udredning for dette.
• Svær hjertesygdom NYHA klasse III og IV,
• Tidligere blodprop i hjernen, TCI eller AMI.
• Svær angina pectoris, kardiomyopati, pulmonal hypertension, ukontrolleret hypertension eller signifikant arythmi diagnosticeret ved EKG.
• Svær kronisk lungesygdom; KOL, pulmonal fibrose eller sarkoidose defineret som GOLD stadium 3: FEV1/FVC < 0,7 og FEV1 mellem 30-50 % af forventet værdi og GOLD stadium 4: FEV1/FVC < 0,7 og FEV1 mellemunder 30 % af forventet værdi.
• Myelodysplastiske sygdomme.
• Organtransplanteret (udover hår eller hornhinde)
• Aktiv cancer eller diagnosticeret med cancer (udover basalcelle hud cancer) indenfor de sidste 5 år.
• Autoimmun leversygdom.
• Hæmoglobinopatier; seglcelleanæmi og thalassæmi.
• Neutropeni <1.5 x 103 µL
• Trombocytopeni <50 x 103 µL
• Nedsat nyrefunktion (GFR < 50 ml/min., herunder hæmodialyse)
• Thyroideasygdom, der ikke er under kontrol med konventionel behandling.
• Insufficient behandlet epilepsi.
• Graviditet/amning.
• Svær ubehandlet anæmi (blodmangel), hæmoglobin ≤ 5 mmol/l.
• Behandling med carbamazepin, phenytoin, rifabutin, rifampicin, naturlægemidler med perikon og modafinil.
• Insufficient behandlet svær diabetes, HbA1c >8.5%.
• Stærkt nedsat leverfunktion (Child-Pugh C).
• Indtagelse af præventionsmidler med ethinylestradiol
• Behandling med CYP3A4-substrater; Alfuzosin, Amiodaron, Atorvastatin, Ergotamin, Fusidinsyre, Lovastatin, Oralt midazolam, Pimozid, Quetiapin, Salmeterol, Sildenafil mod pulmonal arteriel hypertension, Simvastatin, Triazolam, Rosuvastatin.
• Behandling med kraftige CYP3A4-induktorer eller andre enzyminduktorer; Efavirenz, Etravirin, Enzalutamid, Mitotan, Nevirapin, Phenobarbital.
• Behandling med kraftige CYP3A4-inhibitorer; Clarithromycin, Cobicistat, Itraconazol, Lopinavir/ritonavir, Posaconazol, Voriconazol.
• Behandling med kraftige CYP2C8-inhibitorer; Gemfibrozil.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The frequency of side effects seen when treated for 12 weeks with Viekira PAK + Exviera® and ribavirin versus Harvoni® and ribavirin in patients with chronic hepatitis C infected with genotype 1. |
| Hyppigheden af bivirkninger ved behandling i 12 uger med Viekira PAK®+Exviera® og ribavirin versus Harvoni® og ribavirin hos patienter med kronisk hepatitis C inficeret med genotype 1. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After end of treatment of the last included patient in the trial. |
| Når alle inkluderede patienter har færdiggjort behandlingen. |
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| E.5.2 | Secondary end point(s) |
Treatment response defined as following:
- Sustained virological response (SVR): negative HCV RNA 12 weeks after end of treatment.
- Virus breakthrough: HCV RNA decreases during treatment (undetectable levels can be seen), followed by a clinically relevant increase of HCV RNA during treatment.
- Partial response:> 2 log drop in HCV RNA, but the viral load remains above the lowest measurable level after 12 weeks of treatment.
- Relapse: negative HCV RNA during treatment but relapse of HCV RNA after treatment is completed.
- Non-response: no effect of treatment. The patient is persistent HCV RNA positive, despite treatment.
- Date of birth, sex and ethnicity
- Country of origin.
- Previous treatment and treatment response.
- Hepatitis B and / or HIV infection.
- Mode of transmission.
- IL-28B genotype and subtype.
- Liver fibrosis / cirrhosis status at baseline and liver transplantations status.
- Start and end dates of treatment, hepatitis C viral load (HCV RNA titers) and alanine transaminase (ALT) levels at baseline and during treatment at weeks 1, 2, 4, 8, 12 and at week 4, 8, 12 after end of treatment.
- Viral resistance evaluated by population sequencing of the hepatitis C virus genome in patients with treatment failure in Study I.
- The immune systems response to DAA treatment evaluated by measuring the number of T cells and the amount of antibodies produced by B cells before, during and after treatment for participants enrolled at Copenhagen University Hospital, Hvidovre.
- A reduction in the degree of inflammation in the liver and macrophage activation determined by the level of sCD163.
- Change in hepatic venous pressure determined by HVPG
- Changes in the metabolic liver function determined by GEC.
- Change in the degree of liver fibrosis measured by Fibroscan.
- Changes in MELD and Child-Pugh score
- Changes in the level of liver enzymes, albumin, INR, platelets and
alpha-fetoprotein.
- Changes in the levels of renin, aldosterone, copeptin, catecholamines,
cytokines, hsCRP, hsTNT, pro-ANP, pro-BNP, NGAL and Cystatin C.
- Changes in WWF-A, WWF-N, D-Dimer, D-fragment, FPA, FXIII, LOXL2, ELM7, LG1M.
- Change in the perfusion and calcium score assessed by cardiac
rubidium PET/CT scan. |
Behandlingsrespons defineret som følgende:
- Vedvarende virologisk respons (SVR): Negativ HCV-RNA 12 uger efter endt behandling.
- Virus-gennembrud: HCV-RNA falder under behandlingen (umålelige niveauer kan ses), hvorefter der ses en klinisk relevant stigning af HCV-RNA under behandling.
- Partiel respons: >2 log fald i HCV-RNA, men virus mængde over laveste målelige niveau efter 12 ugers behandling.
- Relaps: Negativ HCV RNA under behandlingen, men recidiv (forekomst på ny) af HCV RNA efter behandlingen er afsluttet.
- Non-respons: ingen effekt af behandlingen. Patienten er vedvarende HCV RNA positiv, trods behandling.
- Fødselsdag, køn og etnicitet.
- Oprindelsesland.
- Tidligere behandling og behandlingsrespons.
- Hepatitis B og/eller HIV infektion.
- Smittemåde.
- IL-28B genotype samt subtype.
- Lever fibrose/cirrose status ved behandlingsstart samt levertransplantations status.
- Start- samt slut dato for behandling, hepatitis C virus mængde (HCV-RNA titer) og alanintransaminase (ALT) niveau ved behandlingsstart og under behandlingen ved uge 1, 2, 4, 8, 12 samt ved uge 4, 8, 12 efter endt behandling.
- Viral resistens evalueret ved hjælp af populations sekventering af hepatitis C virus genomet hos patienter i forsøg I med behandlingssvigt.
- Immunsystemets respons på DAA behandling evalueret ved hjælp af måling af antallet af T-celler samt mængden af antistoffer produceret af B-celler før, under og efter behandlingen hos forsøgsdeltagere inkluderet på Hvidovre Hospital.
- Ændring i graden af inflammation i leveren og makrofag aktivering bestemt ved niveauet af sCD163.
- Ændring i portal trykket bestemt ved HVPG
- Ændring i den metaboliske leverfunktion bestemt ved GEC test.
- Ændring i graden af lever fibrose målt ved Fibroscanning.
- Ændringer i MELD og Child-Pugh score
- Ændringer i niveauet af leverenzymer, albumin, INR, trombocytter og alpha-føtoprotein.
- Ændringer i niveauet af renin, aldosteron, copeptin, catecholaminer, cytokiner, hsCRP, hsTNT, pro-ANP, pro-BNP, NGAL og Cystatin C
- Ændringer i niveauet af WWF-A, WWF-N, D-Dimer, D-fragment, FPA, FXIII, LOXL2, ELM7, LG1M.
- Ændring i perfusion og calciumscore vurderet ved hjælp af hjerte-rubidium PET/CT scanning.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After the last enrolled patient has completed treatment. |
| Når alle patienter har afsluttet 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 | 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 6 |
| 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
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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 | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
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