Orkambi Treatment in 2 to 5 Year Old Children With CF

Nutritional Impact of Orkambi Treatment in 2 to 5 Year Old Children Homozygous for F508del Mutations

The purpose of this observational research study is to determine the effects of clinically prescribed Orkambi treatment on 2 to 5 year old children homozygous for the F508del Mutations in the Cystic fibrosis transmembrane conductance regulator (CFTR) gene on sleeping energy expenditure, growth status and gut health and function.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Orkambi

Detailed Description

Orkambi is a novel FDA approved (August, 2018) therapy for use in patients with cystic fibrosis (CF) who are 2 to 5 years of age and homozygous for F508del mutations in the CFTR gene. It is a combination of lumacaftor and ivacaftor that addresses both the processing and gating defects of the F508del mutation. This investigator-initiated study is designed to evaluate the nutritional, growth and GI impact of Orkambi treatment for this unique younger (2 to 5 years) patient cohort. This proposal extends previous highly informative nutrition and weight gain investigation of ivacaftor treatment in people with CF gating mutations to another CFTR modulator treatment (Orkambi) in people homozygous for F508del mutations. The primary aims of the study are to evaluate the impact of 24 weeks of Orkambi treatment in 2 to 5 year old subjects with CF homozygous for F508del mutations on sleeping or resting energy expenditure, growth status and gut health and function in n=32 children ages 2.0 to 5.9 years of age. Protocol evaluations will occur at baseline (pre-treatment) and 12 and 24 weeks after clinically prescribed Orkambi treatment has begun. Other outcomes of significant clinical interest in young subjects with CF will be explored. All subjects will be evaluated as outpatient at The Children's Hospital of Philadelphia, and will be recruited both regionally and nationally to ensure timely enrollment.

• Study Type: Observational
• Enrollment (Actual): 28

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19146
      • Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

2 to 5 year old subjects with a diagnosis of cystic fibrosis and homozygous for F508del mutations and who are in a usual state of good health with a clinical decision to start orkambi treatment.

Description

Inclusion Criteria:

• Cystic fibrosis and homozygous for F508del mutations, approved for treatment
• Age: 2.0 to 5.9 years
• In usual state of good health
• A clinical decision has been made for subject to begin Orkambi treatment
• Family committed to the 6 to 8 month study protocol with visits to the Children's Hospital of Philadelphia (CHOP) that will last 2-3 days for the baseline visit (Visit 1) prior to Orkambi and the 24 week visit (Visit 3) after clinically prescribed Orkambi treatment has begun, and will last up to 2 days for the 12 week visit (Visit 2) after Orkambi treatment has begun.

Exclusion Criteria:

• On parenteral nutrition
• Use of any medications that inhibit or induce cytochrome P450 (CYP) 3A
• Liver function tests elevated above 3x the reference range for age and sex
• Lung disease considered severe based on clinical impression by home CF center.
• Other illness affecting growth or nutritional status
• Other contraindications described for Orkambi therapy

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleeping or Resting Energy Expenditure	Investigators will examine the effects of 24 weeks of orkambi treatment on subject's SEE (sleeping energy expenditure) or REE (resting energy expenditure). Using indirect calorimetry, SEE/REE will be assessed using a computerized metabolic cart Vmax ENCORE at each protocol visit while the child is asleep or resting quietly. SEE/REE will be assessed in the morning if possible and careful note of previous feeding of the child, including the time of day, amount of food, and feeding interval prior to test. It will depend on the age of the subject, and if the subject still takes daily naps and is able to rest quietly without moving, if they will perform sleeping energy expenditure or resting energy expenditure. This will be one outcome measure for each subject, and it will depend on if the subject can nap (SEE) or rest quietly without moving (REE).	24 Weeks
Anthropometric Assessment	Investigators will examine the effects of 24 weeks of orkambi treatment on subject's body mass index (BMI). Investigators will compare the results to BMI Z scores over 24 weeks compared to baseline.	24 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fecal Elastase I/Pancreatic Function	Investigators will examine the effects of 24 weeks of orkambi treatment on subject's pancreatic function. Pancreatic function will be assessed at two visits by obtaining spot stool samples with fecal elastase 1. The concentration of fecal elastase I is indicative of pancreatic function.	24 Weeks
Fecal Calprotectin/Gut Inflammation	Investigators will examine the effects of 24 weeks of orkambi treatment on subject's fecal calprotectin concentration. Spot stool samples will be obtained to determine fecal calprotectin concentration, which is a marker for gut inflammation.	24 Weeks
Plasma Total Fatty Acids	Investigators will examine the effects of 24 weeks of orkambi treatment on subject's dietary fat absorption. A total plasma fatty acid panel will be assessed to measure the change in status of 22 fatty acids.	24 Weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dietary Intake	Three day weighed food record will be obtained and to determine changes in dietary caloric intake and micro and macronutrient intake over the course of 24 weeks on orkambi treatment.	24 Weeks
Serum fat soluble vitamin levels	Investigators will examine the changes in serum fat soluble vitamin A, E, D and K concentration levels after 24 weeks of orkambi treatment.	24 Weeks
Changes in bile acid concentration levels	Investigators will examine changes in the concentration levels of 14 bile acid species in subjects over the course of 24 weeks on orkambi treatment.	24 Weeks
Changes in concentration levels of serum calprotectin	Investigators will examine changes in the concentration levels of serum calprotectin in subjects over the course of 24 weeks on orkambi treatment.	24 Weeks
Muscle-Fat Stores	Investigators will measure body composition to determine muscle and fat store changes over the course of 24 weeks on orkambi treatment compared to baseline.	24 Weeks
Growth status changes	Investigators will observe the changes in growth status over time. Growth status will be measured by determining the changes in three different measurements- length (cm), weight (kg) and head circumference (cm). Each value will be used to calculate BMI (kg/cm^2), which will be used in accordance with age to determine the growth velocity percentile of the subjects over the course of 24 weeks on orkambi treatment. The growth velocity percentile will be indicative of changes in growth status over time.	24 Weeks

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: Vertex Pharmaceuticals Incorporated

Publications and helpful links

General Publications

• Borowitz D, Baker SS, Duffy L, Baker RD, Fitzpatrick L, Gyamfi J, Jarembek K. Use of fecal elastase-1 to classify pancreatic status in patients with cystic fibrosis. J Pediatr. 2004 Sep;145(3):322-6. doi: 10.1016/j.jpeds.2004.04.049.
• Borowitz D, Lin R, Baker SS. Comparison of monoclonal and polyclonal ELISAs for fecal elastase in patients with cystic fibrosis and pancreatic insufficiency. J Pediatr Gastroenterol Nutr. 2007 Feb;44(2):219-23. doi: 10.1097/MPG.0b013e31802c41de.
• Stallings VA, Sainath N, Oberle M, Bertolaso C, Schall JI. Energy Balance and Mechanisms of Weight Gain with Ivacaftor Treatment of Cystic Fibrosis Gating Mutations. J Pediatr. 2018 Oct;201:229-237.e4. doi: 10.1016/j.jpeds.2018.05.018. Epub 2018 Jul 18.
• Flume PA, Liou TG, Borowitz DS, Li H, Yen K, Ordonez CL, Geller DE; VX 08-770-104 Study Group. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest. 2012 Sep;142(3):718-724. doi: 10.1378/chest.11-2672.
• Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, Zhou J, McCartney J, Arumugam V, Decker C, Yang J, Young C, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu P. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18825-30. doi: 10.1073/pnas.0904709106. Epub 2009 Oct 21.
• Milla CE, Ratjen F, Marigowda G, Liu F, Waltz D, Rosenfeld M; VX13-809-011 Part B Investigator Group *. Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2017 Apr 1;195(7):912-920. doi: 10.1164/rccm.201608-1754OC.
• 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.
• Energy and protein requirements. Report of a joint FAO/WHO/UNU Expert Consultation. World Health Organ Tech Rep Ser. 1985;724:1-206. No abstract available.
• Schofield WN. Predicting basal metabolic rate, new standards and review of previous work. Hum Nutr Clin Nutr. 1985;39 Suppl 1:5-41.
• World Health Organization. WHO Child Growth Standards: Length/height-for-age, weight-for-age, weight-for-length, weight-for-height, and body mass index-for-age. Geneva, Switzerland: WHO Press, World Health Organization; 2006.
• O'Connor MG, Seegmiller A. The effects of ivacaftor on CF fatty acid metabolism: An analysis from the GOAL study. J Cyst Fibros. 2017 Jan;16(1):132-138. doi: 10.1016/j.jcf.2016.07.006. Epub 2016 Jul 26.
• World Health Organization. WHO Child Growth Standards: Head circumference-for-age, arm circumference-for-age, triceps skinfold-for-age, and subscapular skinfold-for-age. Geneva, Switzerland: WHO Press, World Health Organization; 2007.
• WHO Multicenter Growth Reference Study Group. WHO Child Growth Standards: Growth Velocity Based on Weight, Length and Head Circumference: Methods and Development. Geneva, Switzerland: WHO Press: World Health Organization; 2009.

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2019
• Primary Completion (Actual): June 16, 2021
• Study Completion (Actual): June 16, 2021

Study Registration Dates

• First Submitted: December 28, 2018
• First Submitted That Met QC Criteria: January 4, 2019
• First Posted (Actual): January 7, 2019

Study Record Updates

• Last Update Posted (Actual): December 2, 2021
• Last Update Submitted That Met QC Criteria: December 1, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Cystic Fibrosis; CFTR; CF
• 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: 18-015669

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes