Supplementation of Oral Reduced Glutathione in Pediatric Cystic Fibrosis Patients

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

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Dietary supplement: Oral reduced l-glutathione; Dietary supplement: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Turin, Italy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 10 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Oral reduced l-glutathione; The treatment was pharmaceutical-grade Reduced L-Glutathione (GSH) with a daily dose of 65 mg/kg.	Dietary supplement: Oral reduced l-glutathione; 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.
PLACEBO_COMPARATOR: Placebo Calcium Citrate; 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; calcium citrate with a daily dose of 65 mg/kg. The daily dose of each substance was divided into three doses given at mealtime.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Clark Bishop
• Investigators: Study Director: Clark T Bishop, MD, Intermountain Health Care

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (ACTUAL): March 1, 2012
• Study Completion (ACTUAL): July 1, 2012

Study Registration Dates

• First Submitted: December 30, 2013
• First Submitted That Met QC Criteria: January 6, 2014
• First Posted (ESTIMATE): January 8, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): February 8, 2016
• Last Update Submitted That Met QC Criteria: January 16, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: cystic fibrosis; glutathione; growth Failure
• 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: FIMP/clin.stud/2010/1.