Effect of Glycine in Cystic Fibrosis

Phase 2

Terminated

• Conditions: Cystic Fibrosis
• Interventions: Dietary Supplement: Glycine; Dietary Supplement: Placebo

• Registration Number: NCT01417481
• Lead Sponsor: Instituto Nacional de Enfermedades Respiratorias

Brief Summary

The aim of this study is to evaluate if glycine, orally administered in a daily dose of 0.5 g/kg during 8 weeks, can ameliorate the airway inflammation in children with cystic fibrosis, as compared with placebo. During all of the study children will receive their usual treatment for cystic fibrosis.

Detailed Description

Background. Cystic fibrosis (CF) is a genetic disorder caused by a mutation in a gene that codifies for a chloride channel named "cystic fibrosis transmembrane regulator" (CFTR). In the lungs this results in thick and dehydrated mucus that tends to cause obstruction of the bronchial lumen. Neutrophils and proinflammatory substances have been detected in bronchoalveolar lavage fluid of children with CF who have no bacterial infection. This inflammation conditions a vicious circle in which airways are colonized by bacteria that further increase inflammation. Persistent inflammation leads to irreversible changes in airways, which become distorted. Therefore, a key step in CF treatment is reduction of airway inflammation, for which long-term use of corticosteroids, ibuprofen or macrolides may be indicated.

Glycine and its antiinflammatory effect. Glycine is the most simple aminoacid, but it is also an agonist of the glycine receptors (GlyR) that, when activated, cause that cells such as Kupffer cells, alveolar macrophages and neutrophils decrease their sensitivity to proinflammatory agents. Orally administered glycine has been used for some illnesses, and it has been noticed that it is well tolerated. Considering that children with CF have an intense inflammatory process in the airways, here we propose to use glycine as antiinflammatory agent.

Problem statement. Can a glycine oral supplement decrease the airway inflammation in children with CF?

Hypothesis. Compared with placebo, a daily supplement of glycine administered for 8 weeks to children with CF produce a statistically significant decrease of bronchial inflammation, measured by the concentration of neutrophils and inflammatory substances in sputum and peripheral blood, as well as by respiratory symptoms and spirometry.

Main objective: To determine whether a daily supplement of 0.5 g/kg glycine for 8 weeks significantly decrease the concentration, including neutrophils, interleukin(IL)-1β, IL-6, IL-8, tumor necrosis factor alpha (TNF-α), and myeloperoxidase, in sputum and peripheral blood of children with CF.

Secondary Objectives:

1. To determine if glycine can improve respiratory symptoms, including decreased amount and better fluidity of sputum.

2. To determine if glycine can improve spirometric variables.

Study design. This will be a randomized, placebo controlled, blinded, two-arms, cross-over clinical trial. Patients will receive glycine or placebo during the initial 8 weeks (initial phase), and after a 2 weeks washout period, they will receive the alternate treatment during another 8 weeks (second phase).

Material and methods: Children with CF fulfilling the selection criteria will be studied if their parents accept their participation. They will be randomly assigned to one of two groups. The experimental group will receive glycine and the control group will receive placebo (sugar glass), both at doses of 0.5 g/kg divided in 3 doses per os dissolved in any liquid. At study entry and at weeks 4, 8, 10, 14 and 18 we will collect a 2 ml blood sample and a sputum sample, and the children will be submitted to spirometry. A daily symptom questionnaire will be filled by the parents.

Statistical analysis: Each variable will be compared between experimental and control groups using Student's t test (or Mann Whitney U test if lacking normal distribution). Sample size: There are no previous studies that allow us to calculate a sample size. For convenience, it is estimated that 30 children can be included.

Time to complete: 24 months.

Study Timeline

• Study First Submitted: 2011-08-15
• Study First Submitted QC: 2011-08-15
• Study First Posted: 2011-08-16
• Study Start: 2012-03
• Primary Completion: 2013-09
• Study Completion: 2013-09
• Results First Submitted: 2014-09-09
• Status Verified: 2014-10
• Results First Submitted QC: 2014-10-21
• Results First Posted: 2014-10-23
• Last Update Submitted: 2014-10-30
• Last Update Posted: 2014-11-05

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 13

Inclusion Criteria

• Children of either sex
• Between 5 and 15 years of age
• With CF diagnosed according to established criteria
• Without changes in the CF treatment in the last 30 days
• Without CF exacerbation in the last 30 days
• Without acute respiratory infection (e.g., common cold) in the last 15 days
• Informed consent letter signed by their parents or legal guardians

Exclusion Criteria

• Children with CF that had participated in a research protocol in the last 3 months
• Presence of serious adverse effects attributable to glycine, in which case the result will be considered as therapeutic failure in the statistical analysis
• Development of a CF exacerbation, in which case the available data so far collected will be included in the statistical analysis

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Glycine	Glycine	Patients will receive a daily oral supplement of 0.5 g/kg glycine dissolved in water.
Placebo	Placebo	Patients will receive a daily supplement of 0.5 g/kg sugar glass dissolved in water.

Primary Outcome Measures

Name	Time	Method
Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha)	8 weeks	To correct for the baseline variability, all measurements were expressed as percentage of baseline (value at week 8 with respect to baseline value \[beginning of the glycine or placebo period, respectively\]). Then, percentages were log-transformed to adjust to a normal distribution.
Changes in Serum Concentration of Inflammatory Biomarkers (TNF-alpha)	8 weeks	To correct for the baseline variability, all measurements were expressed as percentage of baseline (value at week 8 with respect to baseline value \[beginning of the glycine or placebo period, respectively\]). Then, percentages were log-transformed to adjust to a normal distribution.
Changes in Sputum Concentration of Inflammatory Biomarkers (IL-6)	8 weeks	To correct for the baseline variability, all measurements were expressed as percentage of baseline (value at week 8 with respect to baseline value \[beginning of the glycine or placebo period, respectively\]). Then, percentage change was log-transformed to adjust to a normal distribution.
Changes in Sputum Concentration of Inflammatory Biomarkers (G-CSF)	8 weeks	To correct for the baseline variability, all measurements were expressed as percentage of baseline (value at week 8 with respect to baseline value \[beginning of the glycine or placebo period, respectively\]). Then, percentage change was log-transformed to adjust to a normal distribution.
Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF)	8 weeks	To correct for the baseline variability, all measurements were expressed as percentage of baseline (value at week 8 with respect to baseline value \[beginning of the glycine or placebo period, respectively\]). Then, percentage change was log-transformed to adjust to a normal distribution.

Secondary Outcome Measures

Name	Time	Method
Changes in Score for Sputum Production, Dyspnea and Global Symptoms	8 weeks	To correct for the baseline variability, all measurements were expressed as percentage of baseline (value at week 8 with respect to baseline value \[beginning of the glycine or placebo period, respectively\]).; In the symptoms questionnaire, each respiratory symptom (Cough severity, Sputum features, Appetite, Dyspnea, and Energy perception) was evaluated in a 5-options Likert scale, ranging from 1 (better) to 5 (worse). The total score was computed by the simple sum of the five symptoms.
Changes in FEV1, FEF25, and FEFmax	8 weeks	To correct for the baseline variability, all measurements were expressed as percentage of baseline (value at week 8 with respect to baseline value \[beginning of the glycine or placebo period, respectively\]).
Changes in Other Spirometric Variables	8 weeks	To correct for the baseline variability, all measurements were expressed as percentage of baseline (value at week 8 with respect to baseline value \[beginning of the glycine or placebo period, respectively\]).
Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms)	8 weeks	To correct for the baseline variability, all measurements were expressed as percentage of baseline (value at week 8 with respect to baseline value \[beginning of the glycine or placebo period, respectively\]).; Each respiratory symptom (Cough severity, Sputum features, Appetite, Dyspnea, and Energy perception) was evaluated in a 5-options Likert scale, ranging from 1 (better) to 5 (worse). The total score was computed by the simple sum of the five symptoms.
Changes in Pulse Oximetry, FEV1/FVC, and FEF50.	8 weeks	To correct for the baseline variability, all measurements were expressed as percentage of baseline (value at week 8 with respect to baseline value \[beginning of the glycine or placebo period, respectively\]).

Trial Locations

Locations (3)

Hospital Infantil de México; 🇲🇽 Mexico DF, Mexico

Unidad de Investigación Médica en Enfermedades Respiratorias, Hospital de Pediatría, CMN SXXI, IMSS; 🇲🇽 Mexico DF, Mexico

Instituto Nacional de Enfermedades Respiratorias; 🇲🇽 Mexico DF, Mexico