Supplementation of Oral Reduced Glutathione in Pediatric Cystic Fibrosis Patients

• ClinicalTrials.gov Identifier: NCT02029521
• Recruitment Status: Completed
• First Posted: January 8, 2014
• Results First Posted: August 21, 2014
• Last Update Posted: February 8, 2016
• Sponsor: Clark Bishop
• Information provided by (Responsible Party): Clark Bishop, Brigham Young University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis	Dietary Supplement: Oral reduced l-glutathione; Dietary Supplement: Placebo	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 47 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Supplementation of Oral Reduced Glutathione in Pediatric Cystic Fibrosis for Growth Failure
• Study Start Date: March 2011
• Actual Primary Completion Date: March 2012
• Actual Study Completion Date: July 2012

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Forced Vital Capacity [ Time Frame: 3 months ]
   Forced vital capacity percent predicted
2. FEV1 [ Time Frame: 3 months ]
   Forced expiratory volume at one second, percent predicted
3. Bacteriology [ Time Frame: 3 months ]
   Expectorated sputum or throat swab
4. Forced Vital Capacity [ Time Frame: 6 months ]
   Percent predicted of forced vital capacity.
5. FEV1 [ Time Frame: 6 months ]
   Forced expiratory volume at one second, percent predicted.
6. C-Reactive Protein (CRP) [ Time Frame: 6 months ]
   CRP was measured to determine if this test fell during the course of treatment.
7. White Blood Cell Count [ Time Frame: 6 months ]
   White blood cell count was measure at the beginning and end of the study to determine if treatment affected this test.
8. Vitamin E [ Time Frame: 6 months ]
   Serum Vitamin E levels were measured to determine if treatment affected this test.
9. Alanine Aminotransferase (ALT) [ Time Frame: 6 Months ]
   ALT was measured to determine if liver function was affected by treatment over the course of the study.
10. Bacteriology [ Time Frame: 6 Months ]
    Expectorated sputum or throat swab
11. Frequency of Abdominal Pain [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent
12. Severity of Abdominal Pain [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe
13. Frequency of Belching [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent
14. Severity of Belching [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe
15. Frequency of Flatulence [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent
16. Severity of Flatulence [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe
17. Frequency of Lack of Appetite [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent
18. Severity of Lack of Appetite [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe
19. Frequency of Bloating [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent
20. Severity of Bloating [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe
21. Frequency of Nausea [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent
22. Severity of Nausea [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe
23. Frequency of Vomiting [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent
24. Severity of Vomiting [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe
25. Frequency of Heart Burn [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent
26. Severity of Heart Burn [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe
27. Frequency of Diarrhea [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent
28. Severity of Diarrhea [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe
29. Frequency of More Than 2 Bowel Movements Per Day [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent
30. Severity of More Than 2 Bowel Movements Per Day [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe
31. Frequency of Less Than 2 Bowel Movements Per Week [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most frequent
32. Severity of Less Than 2 Bowel Movements Per Week [ Time Frame: 6 months ]
    Part of the Qualitative Symptom Assessment; scaled from 1-4 with 4 being the most severe

Eligibility Criteria

• Ages Eligible for Study: 18 Months to 10 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Italy

Turin, Italy

Sponsors and Collaborators

Clark Bishop

Investigators

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

More Information

• Responsible Party: Clark Bishop, Co investigator, Brigham Young University
• ClinicalTrials.gov Identifier: NCT02029521
• Other Study ID Numbers: FIMP/clin.stud/2010/1.
• First Posted: January 8, 2014
• Results First Posted: August 21, 2014
• Last Update Posted: February 8, 2016
• Last Verified: January 2016

Keywords provided by Clark Bishop, Brigham Young University:

cystic fibrosis; growth Failure; glutathione

Additional relevant MeSH terms:

Cystic Fibrosis; Fibrosis; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases