Orkambi Treatment in 2 to 5 Year Old Children With CF

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Orkambi


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Orkambi|Orkambi is a novel approved therapy for use in people homozygous for the F508del mutation in the CFTR gene. It is a combination of lumacaftor (VX-809) and ivacaftor( VX-770) that addresses both the processing and gating defects of the F508del mutation. The small-molecule corrector lumacaftor corrects the F508del processing defect and increases epithelial delivery of CFTR protein1. Ivacaftor is a CFTR potentiator that increases the channel open probability in F508del-mutant CFTRs that undergo epithelial delivery in vitro and has an additive effect with lumacaftor on chloride transport (2,3,4,5).|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CF, CFTR, Cystic Fibrosis