Vitamin D and Prebiotics for Intestinal Health in Cystic Fibrosis

Study Overview
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Brief Summary
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The study will assess if administration of high-dose vitamin D and a commonly used prebiotic (inulin) is effective to reduce gastrointestinal dysbiosis and to improve critical intestinal functions in Cystic Fibrosis with the additive or synergistic effects of the combination of vitamin D + inulin.

Detailed Description
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Cystic fibrosis (CF) is the most common life-shortening genetic condition among Caucasians in the United States. Individuals with CF have an altered gastrointestinal (GI) microbiota, which may be a result of chronic systemic inflammation and infection, frequent use of antibiotics, and/or medically prescribed and habitual high-fat/high-calorie diets. The study will assess if administration of high-dose vitamin D and a commonly used prebiotic (inulin) is effective to reduce gastrointestinal dysbiosis and to improve critical intestinal functions in Cystic Fibrosis.

Official Title
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Vitamin D and Prebiotics for Intestinal Health in Cystic Fibrosis

Conditions
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Cystic Fibrosis, Dysbiosis

Intervention / Treatment
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* Drug: Vitamin D3
* Drug: Placebo vitamin D3
* Drug: Inulin
* Drug: Placebo Inulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: male and female patients (age > 18 years) with confirmed CF by genetic mutation and/or sweat chloride testing, not currently on oral or systemic antibiotics for pulmonary exacerbation, vitamin D deficient/insufficient (25(OH)D, 6 - 30 ng/mL) with most recent 25(OH)D in the past 12 months, use of CFTR modulator therapy is allowed Exclusion Criteria: severe vitamin D deficiency 25(OH)D ≤ 5 ng/mL or hypocalcemia or hypercalcemia, active GI disease, abdominal pain and/or diarrhea, chronic kidney disease worse than stage 3 (eGFR < ml/min per 1.73 m2), any vitamin D supplement use >2,000 IU or vitamin D analogue (patients who are taking more than 2,000 IU of vitamin D must agree to stop the vitamin D for 6 weeks and take less than 2,000 IU of vitamin D during the study), use of immunosuppressants or history of organ transplantation, current use of probiotics or prebiotics

Ages Eligible for Study
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Minimum Age: 18 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vitamin D3 and Inulin<br>Vitamin D3 50,000 IU/week and 12 g/day chicory-derived prebiotic inulin for 12 weeks | Drug: Vitamin D3<br>* High-dose vitamin D3 50,000 IU /week for 12 weeks<br>Drug: Inulin<br>* Chicory-derived prebiotic inulin 12 g/day for 12 weeks<br>|
| Active Comparator: Vitamin D3 and placebo Inulin<br>Vitamin D3 50,000 IU/week and 12 g/day corn-derived maltodextrin/day as the prebiotic placebo for 12 weeks | Drug: Vitamin D3<br>* High-dose vitamin D3 50,000 IU /week for 12 weeks<br>Drug: Placebo Inulin<br>* Corn-derived maltodextrin 12g/day as the prebiotic placebo for 12 weeks<br>|
| Active Comparator: Placebo vitamin D3 and Inulin<br>Matching to Vitamin D3 placebo capsules, and 12 g/day chicory-derived prebiotic inulin for 12 weeks | Drug: Placebo vitamin D3<br>* Matching to Vitamin D3 placebo capsules for 12 weeks<br>Drug: Inulin<br>* Chicory-derived prebiotic inulin 12 g/day for 12 weeks<br>|
| Placebo Comparator: Placebo vitamin D3 and placebo Inulin<br>Matching to Vitamin D3 placebo capsules, and 12 g/day corn-derived maltodextrin/day as the prebiotic placebo for 12 weeks | Drug: Placebo vitamin D3<br>* Matching to Vitamin D3 placebo capsules for 12 weeks<br>Drug: Placebo Inulin<br>* Corn-derived maltodextrin 12g/day as the prebiotic placebo for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in GI microbiota composition | Changes in GI microbiota composition will be determined using 16S rRNA gene sequencing and microbiome-dependent metabolites pathways in stool and plasma using high-resolution metabolomics analysis.Changes in GI microbiota composition will be reported as a percentage of bacteria. | Baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in GI microbiota diversity | Changes in GI microbiota diversity will be determined using 16S rRNA gene sequencing and microbiome-dependent metabolites pathways in stool and plasma using high-resolution metabolomics analysis.Changes in GI microbiota diversity will be reported as the Shannon Index. | Baseline, 12 weeks | 
| Change in GI microbiota richness | Changes in GI microbiota richness will be determined using 16S rRNA gene sequencing and microbiome-dependent metabolites pathways in stool and plasma using high-resolution metabolomics analysis.Changes in GI microbiota richness will be reported as a number of populations of microorganisms. | Baseline, 12 weeks | 
| Change in calprotectin level in the stool | Calprotectin is a protein released by a type of white blood cell called a neutrophil. When there is inflammation in the gastrointestinal (GI) tract, neutrophils move to the area and release calprotectin, resulting in an increased level in the stool. | Baseline, 12 weeks | 
| Change in lipocalin-2 blood level | Lipocalin-2 (LCN2), also known as oncogene 24p3 or neutrophil gelatinase-associated lipocalin (NGAL), is a protein that in humans is encoded by the LCN2 gene.NGAL is involved in innate immunity by sequestrating iron that in turn limits bacterial growth.It is expressed in neutrophils and in low levels in the kidney, prostate, and epithelia of the respiratory and alimentary tracts.NGAL is used as a biomarker of kidney injury. | Baseline, 12 weeks | 
| Change in serum C-reactive protein blood level | C-reactive protein (CRP) is a substance produced by the liver in response to inflammation. A high level of CRP in the blood is a marker of inflammation. | Baseline, 12 weeks | 
| Change in tumor necrosis factor (TNF) blood level | Tumor necrosis factor (TNF) is a multifunctional cytokine that plays important roles in diverse cellular events such as cell survival, proliferation, differentiation, and death. As a pro-inflammatory cytokine, TNF is secreted by inflammatory cells, which may be involved in inflammation-associated carcinogenesis. | Baseline, 12 weeks | 
| Change in interleukin-6 blood level | Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. | Baseline, 12 weeks | 
| Change in interleukin-8 blood level | IL-8 is a chemotactic factor that attracts neutrophils, basophils, and T-cells, but not monocytes. It is also involved in neutrophil activation. It is released from several cell types in response to an inflammatory stimulus. | Baseline, 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis, Gastrointestinal Dysbiosis, Vitamin D, Prebiotic, Inulin, Gut microbiome, Intestinal inflammation, Intestinal absorption