Supplementation of Oral Reduced Glutathione in Pediatric Cystic Fibrosis Patients

Study Overview
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Brief Summary
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Many individuals with cystic fibrosis experience growth failure. The reasons are not clear, but inflammation of the gut in these patients seems to be one important reason. Glutathione is important to normal function of the intestine and lungs. Glutathione functions to decrease inflammation and to thin mucus. However, in cystic fibrosis, glutathione gets trapped inside of cells, so it cannot travel to the surface of the cells and perform its proper function. Moreover, glutathione has been shown to improve nutritional status in patients with AIDS and cancer. Investigators hypothesize that supplementation of oral glutathione to pediatric individuals with cystic fibrosis could improve growth failure.

Detailed Description
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Cystic fibrosis (CF) is known principally for its pulmonary consequences. However, for most individuals with CF, the earliest manifestations are not pulmonary, but gastro-intestinal. Many children experience growth failure. Chronic gut inflammation also develops. Research has also established that lung function scores are significantly correlated with Body Mass Index (BMI) and weight percentile in CF. Therefore, interventions to improve the gastro-intestinal dimension of CF in early childhood have the potential to ameliorate the course of the disease over the life span of the patient. Both Cochrane Database reviews and a recent review commissioned by the Cystic Fibrosis Foundation found only fair evidence for current nutritional guidelines.Therefore, there is a pressing need for a treatment for CF growth failure that is more effective and less invasive than current treatments. The discovery that CF is associated with significantly diminished efflux of reduced glutathione (GSH) from most cells in the body offers a new perspective on the pathophysiology of this disease. GSH plays several important roles; among the most important are the following: 1) primary water-soluble antioxidant; 2) mucolytic capable of cleaving disulfide bonds; and 3) regulator of immune system function. The relationship between redox ratio (GSH:GSSG) and total glutathione (GSH+GSSG) and the initiation of inflammation is well established in the research literature. GSH is also an important component of the epithelial lining fluid of the intestines, helping to keep intestinal mucus thin, serving to defend the intestinal system against reactive oxygen species, and keeping inflammation in check under normal circumstances. GSH is an FDA-approved treatment for AIDS-related cachexia. The growing recognition of GSH system dysfunction in CF, coupled with an established research literature on the role of GSH in gastro-intestinal function and weight gain in non-CF contexts, suggest a new intervention for growth failure in early childhood in CF patients. Specifically, investigators hypothesized that oral glutathione could effectively treat CF growth failure in pediatric patients.

Official Title
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Supplementation of Oral Reduced Glutathione in Pediatric Cystic Fibrosis for Growth Failure

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Dietary Supplement: Oral reduced l-glutathione
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -Diagnosis of Cystic Fibrosis by either of the following criteria: >60 sweat chloride test or paired deleterious DNA cystic fibrosis transmembrane conductance regulator (CFTR) mutations (Ambry genetics, Genetech or ARUP); -Pancreatic insufficient as defined by doctor's prescription of pancreatic enzymes. Exclusion Criteria: Hospitalized for bowel obstruction or surgery in the six months prior to enrollment; had had a pulmonary exacerbation or oral steroid use or IV antibiotics within one month of enrollment, who had been taking either GSH or N-acetyl cysteine (NAC) within the 12 month period immediately prior to the trial, chronically infected with Burkholderia cepacia.

Ages Eligible for Study
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Minimum Age: 18 Months
Maximum Age: 10 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral reduced l-glutathione<br>The treatment was pharmaceutical-grade Reduced L-Glutathione (GSH) with a daily dose of 65 mg/kg. | Dietary Supplement: Oral reduced l-glutathione<br>* The treatment was pharmaceutical-grade Reduced L-Glutathione (GSH) with a daily dose of 65 mg/kg. The placebo was calcium citrate with a daily dose of 65 mg/kg. The daily dose of each substance was divided into three doses given at mealtime.<br>|
| Placebo Comparator: Placebo Calcium Citrate<br>The placebo was calcium citrate with a daily dose of 65 mg/kg. The daily dose of each substance was divided into three doses given at mealtime. | Dietary Supplement: Placebo<br>* calcium citrate with a daily dose of 65 mg/kg. The daily dose of each substance was divided into three doses given at mealtime.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight Percentile at 3 Months | Weight Percentile at 3 months adjusted for sex and age | 3 months | 
| Height Percentile | Height Percentile adjusted for sex and age | 3 months | 
| BMI Percentile | Body Mass Index percentile adjusted for sex and age. Standard BMI are not available for participants under 2 years of age | 3 months | 
| BMI Percentile | Body Mass Index percentile adjusted for sex and age. Not available for participants under 2 years of age. | 6 months | 
| Weight Percentile | Weight percentile, adjusted for sex and age | 6 months | 
| Height Percentile | The subjects were measured over the course of the study to determine if treatment improved height percentile. | 6 Months | 
| Fecal Calprotectin | Fecal Calprotectin, a measure of gut inflammation, was measured to see if the treatment decreased this outcome. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Vital Capacity | Forced vital capacity percent predicted | 3 months | 
| FEV1 | Forced expiratory volume at one second, percent predicted | 3 months | 
| Bacteriology | Expectorated sputum or throat swab | 3 months | 
| Forced Vital Capacity | Percent predicted of forced vital capacity. | 6 months | 
| FEV1 | Forced expiratory volume at one second, percent predicted. | 6 months | 
| C-Reactive Protein (CRP) | CRP was measured to determine if this test fell during the course of treatment. | 6 months | 
| White Blood Cell Count | White blood cell count was measure at the beginning and end of the study to determine if treatment affected this test. | 6 months | 
| Vitamin E | Serum Vitamin E levels were measured to determine if treatment affected this test. | 6 months | 
| Alanine Aminotransferase (ALT) | ALT was measured to determine if liver function was affected by treatment over the course of the study. | 6 Months | 
| Bacteriology | Expectorated sputum or throat swab | 6 Months | 
| Frequency of Abdominal Pain | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent | 6 months | 
| Severity of Abdominal Pain | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe | 6 months | 
| Frequency of Belching | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent | 6 months | 
| Severity of Belching | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe | 6 months | 
| Frequency of Flatulence | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent | 6 months | 
| Severity of Flatulence | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe | 6 months | 
| Frequency of Lack of Appetite | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent | 6 months | 
| Severity of Lack of Appetite | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe | 6 months | 
| Frequency of Bloating | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent | 6 months | 
| Severity of Bloating | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe | 6 months | 
| Frequency of Nausea | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent | 6 months | 
| Severity of Nausea | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe | 6 months | 
| Frequency of Vomiting | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent | 6 months | 
| Severity of Vomiting | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe | 6 months | 
| Frequency of Heart Burn | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent | 6 months | 
| Severity of Heart Burn | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe | 6 months | 
| Frequency of Diarrhea | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent | 6 months | 
| Severity of Diarrhea | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe | 6 months | 
| Frequency of More Than 2 Bowel Movements Per Day | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent | 6 months | 
| Severity of More Than 2 Bowel Movements Per Day | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe | 6 months | 
| Frequency of Less Than 2 Bowel Movements Per Week | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent | 6 months | 
| Severity of Less Than 2 Bowel Movements Per Week | Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glutathione, cystic fibrosis, growth Failure