Gastrointestinal Outcome Measures Before and After Orkambi Therapy in Cystic Fibrosis (CF) Patients Carrying the F508del Mutation on Both Alleles
Conditions: Cystic Fibrosis
Sponsor: Karolinska University Hospital

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TITLE PAGE 
 
Official English title: 
 
Gastrointestinal outcome measures before and after 
Orkambi therapy in Cystic Fibrosis (CF) Patients 
carrying the F508del mutation on both alleles 
 
or 
Official Swedish title: 
Gastrointestinal studie vid Orkambi-behandling hos 
cystisk fibros-patienter 
 
Isabelle de Monestrol, MD, PhD 
Director, Stockholm CF Center, 
Karolinska University Hospital 
Stockholm, Sweden, 
 
 
Miroslav Vujasinovic, MD 
Karolinska University Hospital 
Stockholm, Sweden 
 
& 
 
Michael Wilschanski, Professor 
Pediatric Gastroenterology, CF Center,  
Hadassah Hebrew University Medical Center,  
Jerusalem, Israel 
 
 
Date of the document: 2018-06-27 
 
NCT number, not available 
 
 

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Synopsis 
Ivacaftor caused a significance increase in weight in patients carrying the G551D mutation and the 
etiology of this has largely remained unknown but may be due to improved function of the 
gastrointestinal tract. The combination therapy of Orkambi has been recently approved for subjects 
with Cystic Fibrosis homozygous for F508del mutation. This provides an opportunity to examine if 
there are any improvements in gastrointestinal function. We aim to investigate various aspects of 
gastrointestinal and pancreatic function before and 6 months after the commencement of Orkambi 
therapy. 
 
Objective  
To examine the entire intestinal mucosa via capsule endoscopy before and 6 months after Orkambi 
therapy to ascertain if the inflammatory changes in the intestine have improved. A marker of intestinal 
inflammation measured in the stool, Calprotectin, will be examined before and 6 months after 
Orkambi treatment. We hypothesize that the result will be reduced on therapy. 
A marker of pancreatic exocrine function, pancreatic elastase, will be examined before and 6 months 
after therapy to examine if the result has increased indicating improvement of exocrine pancreatic 
function 
 
Study Population 
All subjects with CF homozygous for the F508del mutation in Sweden. There is a total of 145 patients 
with this mutation in Sweden and 60 at Stockholm CF Center; we aim to examine 20 patients.  
 
Study Duration 
The duration will be 6 months.  
 
Introduction 
In recent years, great progress has been achieved in therapeutic Cystic Fibrosis Transmembrane 
Corrector (CFTR) protein modulation.  Current CFTR modulation treatment is based on the use of 
small molecules, that either improve gating of ions (“CFTR potentiators”) or restore folding (“CFTR 
correctors”) of the CFTR protein to improve its function.  
The CFTR modulator Ivacaftor already has proven to improve clinical status in children and adults 
with the G551D CFTR gating mutation. Clinical trials have shown significant clinical improvement, 
including sustained improvement in lung function as measured by forced expiratory volume in 1 
second (FEV1), and an increase in body mass index (BMI) and other parameters including intestinal 
pH and insulin secretion (1,2,3,). 
In a recent study of 213 patients with the G551D mutation there was a significant improvement in 
nutritional status after 48 weeks of treatment with Ivacaftor in children and adults (4).  This is a most 

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relevant finding considering that decreased mortality has been associated with greater body weight 
and BMI in patients with CF (5) This observation opens the window of opportunity to investigate how 
the improvement in CFTR function affects the function of the gastrointestinal tract in CF. 
Less emphasis has been given to the development of gastrointestinal outcome measures for 
therapeutic trials in cystic fibrosis than for pulmonary outcome measures. This was partially due to 
the presumed irreversible character of CF gastrointestinal manifestations, for example exocrine 
pancreatic insufficiency. Different from pulmonary disease, some GI manifestations of CF do not 
present with clinically recognizable and relevant disease. Ivacaftor has been shown in a few studies to 
have systemic benefit on the gastrointestinal tract (2,4). 
The current studies with CFTR modulators offer new and promising opportunities to implement GI 
outcome measures for cystic fibrosis, and the use of GI outcome measures can provide evidence of the 
systemic action of these medications. In fact, we do not have a good explanation as to why the BMI 
increases after Ivacaftor treatment. This may be due to rectification of gastrointestinal pathology 
caused by CFTR dysfunction (2,4). As these drugs are systemically absorbed, it is reasonable to 
assume they will have a systemic benefit. 
 
An exciting new development has been that the combination therapy of Ivacaftor and Lumacaftor 
(Orkambi) has been recently approved for CF patients homozygous for  F508del (6). 
 
To date the major accepted and established clinical outcome measures for CF are FEV1, weight and 
body mass index (BMI). However, unlike previous symptomatic treatment approaches for cystic 
fibrosis, therapeutic CFTR modulation offers the prospect of early intervention and possible 
preemptive treatment. Therefore, clinical trials to prove efficacy will be performed in increasingly 
younger cystic fibrosis patients (7)  
 
The gastrointestinal tract offers opportunities to measure CFTR protein function and systematically 
evaluate CF related clinical outcomes for clinical trials. Clinical signs of CFTR dysfunction in the 
gastrointestinal tract often occur earlier in disease development than in the respiratory tract.  
Meconium ileus is almost pathognomonic for CF. Meconium ileus can be symptomatic before 
neonatal screening results are available. Exocrine pancreatic insufficiency can present at birth or 
develop in weeks to months during the first year of life (8). Additionally, the same pathophysiologic 
triad of obstruction, infection, and inflammation that causes disease in the airways also causes disease 
in the intestine (9)  
 
In this protocol, we systematically examine gastrointestinal outcome measurements for cystic fibrosis 
that are available to date. We describe clinically measurable outcome parameters and methods to 
directly measure CFTR protein function in gastrointestinal tissues. The aim of the protocol is to draw 

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attention to the need and the ample opportunities for the development and validation of relevant 
clinical endpoints for scientific evaluation of Orkambi modulation treatment.  
 
In this study, we propose that patients who are eligible to receive Orkambi will provide a stool sample 
for Calprotectin and fecal elastase 1 and undergo a capsule endoscopy intestinal examination before 
and 6 months after commencing treatment. 
 
 

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Materials and Methods 
 
 
Measurements of clinical gastrointestinal manifestations of cystic fibrosis 
 
Intestinal inflammation 
Several studies have shown evidence of intestinal inflammation in cystic fibrosis, particularly in 
patients with pancreatic insufficiency. The underlying pathophysiology of intestinal inflammation is 
not completely understood. Data from cystic fibrosis mouse models suggest that the intestinal 
inflammation is related to CFTR dysfunction in the intestinal tissues, which leads to mucus 
accumulation, disturbed motility, small bowel bacterial overgrowth and inflammation with altered 
innate immune responses. It is to be expected that these different factors interact with one another (10)  
 
I) 
Fecal calprotectin  
To date several fecal biomarkers are available of which fecal calprotectin is the most studied and used 
in the clinical practice (11, 12). Calprotectin is a very stable protein originating from inflammatory 
neutrophils.  Several studies have demonstrated significantly increased fecal calprotectin levels in 
cystic fibrosis patients compared to healthy controls. The fecal calprotectin levels do not seem to be 
related to the presence of small intestinal bacterial overgrowth frequently observed in cystic fibrosis 
patients (13). Clinical trials using probiotics to treat intestinal inflammation in cystic fibrosis patients 
have shown a therapeutic responsiveness of fecal calprotectin indicating the potential of this marker 
as a clinical endpoint (14)  
  
 
II) 
Fecal elastase-1 
Fecal elastase-1 is one of the proteolytic pancreatic enzymes. In the intestine elastase-1 is not subject 
to degradation. It is pH and temperature stabile and is excreted via the feces. A small fecal sample can 
easily be obtained and stored. Elastase-1 has no cross reactions with chymotrypsin of animal sources 
that is present in exogenous submitted pancreatic enzymes (PERT). For this reason, elastase-1 can 
still be used a marker of exocrine pancreatic function during PERT use. In the case of exocrine 
pancreatic insufficiency fecal elastase-1 is decreased. Reference values of fecal elastase-1 have been 
established (16). There have been reports of Ivacaftor improving exocrine pancreatic insufficiency in 
patients with G551D mutation (personal communication -Prof Kevin Gaskin, Sydney, Australia). We 
hypothesize that there may be improvement in patients with delF508 after Orkambi treatment.  
 
 
 

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III) 
Small bowel capsule endoscopy  
A relatively new option for making the diagnosis of intestinal inflammation is small bowel capsule 
endoscopy (SBCE). The primary indication of SBCE is to examine areas of the small intestine that 
cannot be inspected by other types of endoscopy. SBCE has been performed in CF patients. One study 
from Israel reported SBCE results in CF patients (15). The study showed that most cystic fibrosis 
patients had varying degrees of diffuse areas of inflammatory findings in the small bowel including 
edema, erythema, mucosal breaks, and frank ulcerations. The method of SBCE has been well 
established as a descriptive diagnostic tool for intestinal inflammation. However, systematic 
quantitative evaluation of SBCE is not easy and not yet well established. SBCE has been used as an 
outcome measure in clinical trial but not yet in therapeutic trails for cystic fibrosis. Due to the size of 
the video capsule SBCE cannot be applied in young children and infants.  
 
 
Blood tests 
Inflammatory markers in blood, such as CRP, sedimentation rate and serum electrophoresis, as well as 
liver function tests will be taken in this study. 
 
 
Inclusion Criteria 
1. Patients with CF with F508del homozygote eligible for Orkambi therapy 
2. Males and females 
3. >12 years of age  
 
Exclusion Criteria 
1. Patients who the patency capsule does not pass within 48 hours 
2. FEV1 <30% 
3. Pregnancy and breastfeeding women 
4. Liver function blood tests > 3 times the normal value 
5. Bilirubin > 2 times normal value 
6. AST or ALT alone more than 5 times normal value 
7. Patients who have had a lung transplant 
 
 
 
 
 
 

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Dosing of Orkambi 
 
This study is being carried out in patients who are receiving Orkambi for clinical and non-research 
indications. Orkambi will be administered according to the approved label in Sweden. There will be 
no changes in dosing because of this study.  
 
 
Dosage Adjustment for Patients with Hepatic Impairment. 
 
No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A 
dose reduction to 2 tablets in the morning and 1 tablet in the evening (lumacaftor 600 mg/ivacaftor 
375 mg total daily dose) is recommended for patients with moderate hepatic impairment (Child-Pugh 
Class B). 
Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but 
exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use 
with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening (lumacaftor 400 
mg/ivacaftor 250 mg total daily dose), or less, in patients with severe hepatic impairment after 
weighing the risks and benefits of treatment  
 
Safety Monitoring 
 
Monitoring will be carried out in accordance with GCP regulations and according to the general 
protocol for patients receiving Orkambi as per label. This includes monitoring liver function blood 
tests after 3 months. Ophthalmological assessment will be performed to rule out cataracts and liver 
function tests will be performed at the start of the study and at the end. 
Adverse events will be recorded and following local laws and regulations reported 
to GlobalPatientSafety@vrtx.com 
 
Statistical Analysis 
This study is a prospective observation on the gastrointestinal tract before and after Orkambi 
treatment. Each patient will act as his or her own control and changes will be compared from baseline. 
Lesions which will be seen on the capsule endoscopy will be assessed according to the Maiden 
criteria (erythema, petechiae, mucosal erosions, ulcerations) (15) before commencement of Orkambi 
and at the second capsule endoscopy examination.  
 
 

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Study in Detail 
 
After informed consent the subject will undergo physical examination and females will provide a 
urine sample for a pregnancy test. The subjects will provide a stool sample for: 
1- Calprotectin and fecal elastase – the stool will be placed in a freezer at -4degrees. 
2- The patients will perform liver function tests. 
3- The first phase of the capsule endoscopy is the patency capsule to ensure that there is no 
obstruction in the intestine. The patency capsule is the same size as the "real" capsule but is made of a 
biodegradable lactose polymer. If it is not seen in the intestine after 48 hours the subject is able to 
ingest the capsule. The preparation for the patency capsule is a liquid only diet from midday on the 
day prior to the test and fasting from 12 midnight before the test. 
The subject will then swallow the patency capsule which is a placebo SBCE. The subject will notice 
the capsule in the stool. If not the subject reports back to the study nurse who will examine the 
abdomen with a non-radiation emitting scanner.  
If the capsule is not present the subject will proceed to the next stage -swallowing the capsule 
(SBCE).  
4-The preparation is somewhat different as the mucosa needs to be as clean as possible. Once again 
the subject takes a liquid diet the day before the capsule but in the evening before the subject with 
ingest one sachet of laxative (picosalax). This will cause the subject to have increased bowel 
movements. 
The following morning the subject with ingest the capsule endoscopy which will take pictures for 8-
10 hours. The readings are collected on a belt worn by the subject for this entire time. 
5-The subject will return the belt to the study nurse within 2 to 3 days at their convenience. 
The data will be read by a gastroenterologist trained in reading the capsule endoscopy by Rapid 
Software (Medtronic).  
The subject will receive Orkambi. 
6 months after commencing Orkambi the subject will perform the following tests: 
Stool sample for calprotectin and elastase to be stored at -4 degrees and liver function tests. 
The subject will have Picosalax preparation the evening before the capsule endoscopy 
The subject will swallow the capsule wearing the belt as before 
 
Study Endpoints 
The results of SBCE, stool calprotectin and pancreatic elastase 6 months after commencement of 
Orkambi therapy will be compared to baseline. Findings at capsule endoscopy including mucosal 
erythema, petechiae, erosions and ulcerations will be recorded before and after 6 months of treatment. 
 

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