Ivacaftor Treatment in 4 Month to 2 Year Old CF Subjects

Nutritional Impact of Ivacaftor Treatment in 4 Month to 2 Year Old Children With CF Gating Mutations

The purpose of this research study is to determine the effects of clinically prescribed ivacaftor treatment on 4-24 month old children with CF and gating mutations on sleeping energy expenditure, growth status and gut health and function.

Study Overview

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

Detailed Description

Ivacaftor is a novel FDA approved therapy for patients with CF and gating mutations who are 4 months and older. This investigator-Initiated study is designed to evaluate the nutritional, growth and GI impact of ivacaftor treatment for the youngest (4-24 months) patient cohort and for whom FDA approval has recently been granted. This proposal directly extends the previous highly informative nutrition and weight gain investigation of ivacaftor treatment in the older patient cohort (1). The primary aims of the study are to evaluate the impact of 12 weeks of ivacaftor treatment in 4-24 month old subjects with CF and gating mutations on sleeping energy expenditure, growth status and gut health and function in 18 children with protocol evaluations at baseline (pre-treatment) and 6 and 12 weeks after clinically prescribed ivacaftor treatment has begun. Other outcomes of significant clinical interest in young subjects with CF will be explored. All subjects will be evaluated at the Children's Hospital of Philadelphia (CHOP) and will be recruited both regionally and nationally to ensure timely enrollment.

• Study Type: Observational
• Enrollment (Actual): 15

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: 4 months to 2 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

4-24 month old subjects with a diagnosis of cystic fibrosis with at least one CFTR gating mutation of these ten (G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1439D, or R117H) approved for treatment in a usual state of good health with a clinical decision to start ivacaftor treatment.

Description

Inclusion Criteria:

• Cystic fibrosis with at least one CFTR gating mutation (E56K, G178R, S549R, S977F, F1074L, 2789+5G→A,P67L, E193K, G551D, F1052V, D1152H, 3272-26A→G, R74W, L206W, G551S, K1060T, G1244E, 3849+10kbC→T, D110E, R347H, D579G, A1067T, S1251N, D110H, R352Q, 711+3A→G, G1069R, S1255P, R117C, A455E, E831X, R1070Q, D1270N, R117H, S549N, S945L, R1070W, G1349D) approved for treatment
• Age: 4-24 months of age
• In their usual state of good health
• A clinical decision has been made for subject to begin ivacaftor treatment
• Family committed to the 4 to 6 month study protocol with visits to CHOP that will last 2 or 3 days for the baseline visit (Visit 1) prior to ivacaftor and the 12 week visit (Visit 3) after clinically prescribed ivacaftor treatment has begun, and will last 2 days for the 6 week visit (Visit 2) after ivacaftor treatment has begun.

Exclusion Criteria:

• On parenteral nutrition
• Use of any medications which are as inhibitors or inducers of cytochrome P450 (CYP) 3A
• Liver function tests elevated above 3x the reference range for age and sex
• Other illness affecting growth or nutritional status
• Other contraindications described for ivacaftor therapy

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleeping Energy Expenditure	Investigators will examine the effects of 12 weeks of Ivacaftor treatment on subject's SEE. Using indirect calorimetry, SEE will be assessed using a computerized metabolic cart Vmax ENCORE at each protocol visit while the child is asleep. SEE 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	12 Weeks
Anthropometric Assessment	Investigators will examine the effects of 12 weeks of Ivacaftor treatment on subject's BMI. Investigators will compare the results to BMI Z scores over 12 weeks compared to baseline.	12 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fecal Elastase I/Pancreatic Function	Investigators will examine the effects of 12 weeks of Ivacaftor 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.	12 Weeks
Fecal Calprotectin/Gut Inflammation	Investigators will examine the effects of 12 weeks of Ivacaftor treatment on subject's gut health and function. Spot stool samples will be obtained to determine fecal calprotectin, a marker for gut inflammation.	12 Weeks
Plasma Total Fatty Acids:	Investigators will examine the effects of 12 weeks of Ivacaftor 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, the concentration of plasma fatty acids is indicative of dietary fat absorption.	4 to 6 months

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 12 weeks on ivacaftor treatment. The weighed food in grams will be used to determine the calories consumed, as well as calories from fat. The caloric intake will be used to determine micro and macro nutrient intake.	12 Weeks
Serum fat soluble vitamins A, D, E and K, bile acids, and serum calprotectin	Investigators will examine the changes in serum vitamin A, E, D and K concentrations after 12 weeks of Ivacaftor treatment. Additionally, investigators will examine the changes in total serum bile acids concentration and 14 bile acid species. Additionally, serum calprotectin will be obtained as a marker of lung and gut inflammation.	12 Weeks
Muscle/Fat Stores	Investigators will measure body composition to determine muscle and fat store changes over the course of 12 weeks on ivacaftor treatment compared to baseline.	12 Weeks
Growth Status/Growth Velocity	Investigators will observe the changes in growth status/growth velocity. This will be assessed amongst three different measurements- length (cm), weight (kg) and head circumference (cm). Each value will be used to calculate the growth velocity percentile of the subjects over the course of 12 weeks on ivacaftor treatment compared to baseline.	12 Weeks

Collaborators and Investigators

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

Publications and helpful links

General Publications

• 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.
• 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.
• Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordonez CL, Campbell PW, Ashlock MA, Ramsey BW. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010 Nov 18;363(21):1991-2003. doi: 10.1056/NEJMoa0909825.
• Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordonez C, Elborn JS; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011 Nov 3;365(18):1663-72. doi: 10.1056/NEJMoa1105185.
• 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.
• 7. 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.
• 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.
• 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.
• 11. 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.
• 12. 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): February 6, 2019
• Primary Completion (ACTUAL): December 30, 2021
• Study Completion (ACTUAL): December 30, 2021

Study Registration Dates

• First Submitted: December 18, 2018
• First Submitted That Met QC Criteria: December 18, 2018
• First Posted (ACTUAL): December 21, 2018

Study Record Updates

• Last Update Posted (ACTUAL): March 11, 2022
• Last Update Submitted That Met QC Criteria: March 10, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: CFTR; CF transmembrane conductance regulator; Gating Mutations
• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Chloride Channel Agonists; Ivacaftor
• Other Study ID Numbers: 18-015299

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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.: No