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Project properties

Title	The course of Cystic fibrosis cirrhosis in homozygotes f508del patients after initiation of Orkambi therapy in the Netherlands
Keywords	liver fibrosis cystic fibrosis farmacology
Researchers	dr. F.A.J.A. Bodewes
Nature of the research	medical chart review in CF centers in the Netherlands
Fields of study	pediatrics pulmonology gastroenterology

Background / introduction

Introduction Cystic fibrosis (CF) is a severe congenital multiorgan disease. CF is caused by a mutation in the CFTR gene. f508del is the most frequent disease causing mutation in the CFTR gene in the Caucasian population. In the Netherlands, ~60% of CF patients are homozygous for the CFTR f508del mutation. Cystic fibrosis related cirrhosis (CFRC) is the most severe hepatic complication of CF. In the Netherlands, around 10% of homozygous f508del patients have developed cirrhosis. Almost all CFRC patients present with cirrhosis in childhood with a peak prevalence around the age of 10 years. Although cirrhosis is irreversible, clinical symptoms are variable. CFRC patient frequently present with signs and symptoms of portal hypertension like splenomegaly, hypersplenism, and intestinal variceal bleeding. The liver protein synthesis and detoxification functions are often spared. However, liver failure may occur. CFRC patients have increased risk to develop CF related diabetes at a younger age. Although end stage liver failure is not frequent, CFRC is an independent risk factor for a decreased survival of CF patients. CFRC patients are at risk for acute on chronic liver failure due to liver decompensation in episodes of pulmonary disease of surgical procedures. In a recent survey in all CF Centers in the Netherlands, we found that in a case of mortality, the average age at death of CFRC patients was significantly lower compared to non-CFRC deceased CF patients (28 vs. 37 years). Orkambi® (Lumacaftor/Ivacaftor) is a new, FDA approved, combination therapy, for CF patients, age 6 and older, with homozygous for the f508del mutation. This new drug is currently introduced in several countries in Europe for this patient group. In the clinical trials reported for Orkambi CFRC patient were not included. Therefore, to date, no data are reported on the effect of Orkambi on the liver functional hepatic complication and development of cirrhosis in CFRD patients. Elevation of liver enzymes was reported in studies including the Orkambi Lumacaftor-ivacaftor combination therapy and Ivacaftor monotherapy. In a pediatric clinical phase 2 trial for children 2-5 year of age, significant, reversible, elevation of liver enzymes was reported. These hepatic side effects might indicate that Orkambi treatment may affect the liver at the parenchymal level.

Research question / problem definition

Aim In this study, we have two goals. The first aim is to evaluate prospectively if Orkambi is well tolerated and can be safely provided to homozygous f508del CF cirrhotic patients without worsening liver test or liver function test. The secondary aim is to evaluate is Orkambi therapy influences the evolution of CFRC like changes in the progression of fibrosis, the prevalence of complication of portal hypertension, or need for liver transplantation or premature death. These finding may provide evidence for an additional hepatic efficacy of Orkambi therapy in CF patients. Additionally, the result may provide information on risks and subsequent user advice and medical precautions that might have to be specifically considered during initiation of Orkambi therapy in CFRC patients. Hypothesis Orkambi therapy can be safely initiated in homozygous f508del CF cirrhotic patients without increased risk of liver test disturbances and/or short term or long term liver function decompensation. Orkambi therapy improves clinical and biochemical marker of liver function and cirrhosis in established homozygous f508del CF cirrhotic patients.

Workplan

Study methodology Multicenter long term phase IV follow up study. Duration 12 months after start Orkambi therapy Inclusion criteria: -Homozygous f508del CF cirrhotic patients -Established CFRC -Patiënt considered for starting Orkambi therapy Definition of CFRC All three of following symptoms: inhomogeneous, multinodular liver on ultrasound Splenomegaly on physical examination or ultrasound Repeated platelet count below 200 * 109/l Or Biopsy proven cirrhosis Or History of endoscopically proven gastrointestinal variceal bleeding Evaluation at inclusion: Medical history: GI variceal bleeding/therapy Use of ursodeoxycholic acid therapy Liver transplantation Physical examination: -Length -Weight -BMI -MUAC -Ultra sound spleen span -Forced expiratory volume in 1 second -Oxygen saturation (standing up and laying down) -(Measurement of body composition; eg DEXA) Blood test panel Standard analysis (local measurement) -Full blood cell count, AST, ALT, GGT, Total bilirubin, Direct bilirubin INR, APTT, Albumin, Ammonia, Alpha foeto-protein, glucose, HbA1C, Advised Follow up protocol (after start Orkambi therapy) Standard evaluation at 1 week, 2 weeks, 1-3-6-12-24 months History of variceal GI bleeding Body weight, length, BMI, oxygen saturation Blood sampling standard analysis (local measurement) -Full blood cell count, AST, ALT, GGT, Total bilirubin, Direct bilirubin INR, APTT, Albumin, Ammonia, Alpha foeto-protein, glucose, HbA1C Based on mutation frequency and CFRC we would theoretically expect to be able to include between 50-60 patient in this protocol. UMC Utrecht UMC Rotterdam UMC Groningen UMC Nijmegen UMC Maastricht UMC AMC/VU JKZ/HAGA ziekenhuis Den Haag Potential international expansion to centers in Europe

References

Pals, F. H., et al. "Cirrhosis associated with decreased survival and a 10-year lower median age at death of cystic fibrosis patients in the Netherlands." Journal of Cystic Fibrosis 18.3 (2019): 385-389. Debray, Dominique, et al. "Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease." Journal of Cystic Fibrosis 10 (2011): S29-S36. Rowland, Marion, et al. "Outcome in cystic fibrosis liver disease." The American journal of gastroenterology 106.1 (2011): 104-109. Wainwright, Claire E., et al. "Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR." New England Journal of Medicine 373.3 (2015): 220-231. Milla, Carlos E., et al. "Lumacaftor/Ivacaftor in Patients Aged 6-11 Years With Cystic Fibrosis Homozygous for F508del-CFTR." American Journal of Respiratory And Critical Care Medicine ja (2016). Davies, Jane C., et al. "Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study." The Lancet Respiratory Medicine 4.2 (2016): 107-115. van der Feen, Cathelijne, et al. "Ursodeoxycholic acid treatment is associated with improvement of liver stiffness in cystic fibrosis patients." Journal of Cystic Fibrosis 15.6 (2016): 834-838. Aqul, Amal, et al. "Correlation of Transient Elastography With Severity of Cystic Fibrosis–related Liver Disease." Journal of pediatric gastroenterology and nutrition 64.4 (2017): 505-511. Stonebraker, Jaclyn R., et al. "Features of severe liver disease with portal hypertension in patients with cystic fibrosis." Clinical Gastroenterology and Hepatology 14.8 (2016): 1207-1215. Flass, Thomas, et al. "Intestinal lesions are associated with altered intestinal microbiome and are more frequent in children and young adults with cystic fibrosis and cirrhosis." PloS one 10.2 (2015): e0116967.