The course of Cystic fibrosis cirrhosis in homozygotes f508del patients after initiation of Orkambi therapy in the Netherlands

liver fibrosis cystic fibrosis farmacology

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

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
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.


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.
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
Biopsy proven cirrhosis
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:
-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
JKZ/HAGA ziekenhuis Den Haag

Potential international expansion to centers in Europe
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