Gastrointestinal Study at Orkambi Therapy in CF Patients

Gastrointestinal Outcome Measures Before and After Orkambi Therapy in Cystic Fibrosis (CF) Patients Carrying the F508del Mutation on Both Alleles

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. The investigators aim to investigate various aspects of gastrointestinal and pancreatic function before and 6 months after the commencement of Orkambi therapy.

Study Overview

• Status: Unknown
• Conditions: Cystic Fibrosis

Detailed Description

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. The investigators 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 eligible for Orkambi therapy, i.e. above 12 years of age, in total 145 patients in Sweden of which 60 are taken care of at Stockholm CF Center; the investigators aim to examine 20 patients.

Study Duration The duration will be 6 months for each patient.

• Study Type: Observational
• Enrollment (Anticipated): 20

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden, 14186
    • Recruiting
    • Stockholm CF center
    • Contact: Isabelle de Monestrol, MD PhD; Phone Number: +468 58580000; Email: isabelle.demonestrol@ki.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

CF patients, F508del homozygote, >12 years of age, eligible and planned for Orkambi therapy in Clinical routine.

Description

Inclusion Criteria:

• CF patients F508del homozygote
• >12 years of age
• eligible for Orkambi therapy.

Exclusion Criteria:

• Patients who the patency capsule does not pass within 48 hrs
• FEV1<30%
• Pregnancy and breastfeeding women
• Liver function blood tests (AST, ALT, Gamma-GT, ALP) >3 xULN
• Bilirubin >2 xULN
• AST or ALT alone >5 xULN
• Previous lung transplant

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
CF patients planned to receive Orkambi; CF patients carrying the F508del mutation on both alleles planned to receive Orkambi therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of fecal calprotectin	Is a marker of intestinal inflammation measured in the stool	Change from baseline at 6 months after commencing treatment with Orkambi
Concentration of fecal elastase-1	Is a test of pancreatic function measured in the stool.	Change from baseline at 6 months after commencing treatment with Orkambi
Change in small bowel capsule endoscopy (SBCE)	The method of SBCE has been well established as a descriptive diagnostic tool for intestinal inflammation and has been used as an outcome measure in clinical trials. Erythema, petechiae, mucosal erosions and ulcerations will be assessed according to the Maiden criteria	Change from baseline at 6 months after commencing treatment with Orkambi

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in CRP	Inflammatory marker, unit mg/L.	Change from baseline at 6 months after commencing treatment with Orkambi
Change in sedimentation rate	Inflammatory marker, unit mm.	Change from baseline at 6 months after commencing treatment with Orkambi
Concentration of serum electrophoresis.	Inflammatory markers: alpha-1-antitrypsin, haptoglobin, orosomucoid, immunoglobulin A, M and G.	Change from baseline, 6 months after commencing treatment with Orkambi
Change in liver function tests	ALT, AST, ALP, gamma-GT. Unit: mikrokat/L	Change from baseline at 6 months after commencing treatment with Orkambi
Change in bilirubin	Bilirubin. Unit: mikromol/L	Change from baseline at 6 months after commencing treatment with Orkambi

Collaborators and Investigators

• Sponsor: Karolinska University Hospital
• Collaborators: Hadassah Medical Organization; Vertex Pharmaceuticals Incorporated
• Investigators: Principal Investigator: Isabelle de Monestrol, MD PhD, Stockholm CF center

Publications and helpful links

General Publications

• Wainwright CE, Elborn JS, Ramsey BW. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015 Oct 29;373(18):1783-4. doi: 10.1056/NEJMc1510466. No abstract available.
• Borowitz D, Lubarsky B, Wilschanski M, Munck A, Gelfond D, Bodewes F, Schwarzenberg SJ. Nutritional Status Improved in Cystic Fibrosis Patients with the G551D Mutation After Treatment with Ivacaftor. Dig Dis Sci. 2016 Jan;61(1):198-207. doi: 10.1007/s10620-015-3834-2. Epub 2015 Aug 7.
• Werlin SL, Benuri-Silbiger I, Kerem E, Adler SN, Goldin E, Zimmerman J, Malka N, Cohen L, Armoni S, Yatzkan-Israelit Y, Bergwerk A, Aviram M, Bentur L, Mussaffi H, Bjarnasson I, Wilschanski M. Evidence of intestinal inflammation in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2010 Sep;51(3):304-8. doi: 10.1097/MPG.0b013e3181d1b013.

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2019
• Primary Completion (Anticipated): June 30, 2020
• Study Completion (Anticipated): June 30, 2020

Study Registration Dates

• First Submitted: February 26, 2019
• First Submitted That Met QC Criteria: February 27, 2019
• First Posted (Actual): March 1, 2019

Study Record Updates

• Last Update Posted (Actual): March 4, 2019
• Last Update Submitted That Met QC Criteria: February 28, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: CF-GI-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Because this would expose the patients too much

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No