Clinical trial NCT01417481: Effect of Glycine in Cystic Fibrosis
Official title: Evaluation of the Capability of a Glycine Oral Supplement for Diminishing Bronchial Inflammation in Children With Cystic Fibrosis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Cystic Fibrosis
Keywords: cystic fibrosis
glycine
airway inflammation
Lead sponsor: Instituto Nacional de Enfermedades Respiratorias
Sponsor class: OTHER_GOV
Collaborators: name: Hospital Infantil de Mexico Federico Gomez
name: Instituto Mexicano del Seguro Social
First posted: 2011-08-16
Enrollment: 13
Sex: ALL
Minimum age (years): 5
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha)
timeFrame: 8 weeks
measure: Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF)
timeFrame: 8 weeks
measure: Changes in Serum Concentration of Inflammatory Biomarkers (TNF-alpha)
timeFrame: 8 weeks
measure: Changes in Sputum Concentration of Inflammatory Biomarkers (IL-6)
timeFrame: 8 weeks
measure: Changes in Sputum Concentration of Inflammatory Biomarkers (G-CSF)
timeFrame: 8 weeks
Secondary outcomes:
measure: Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms)
timeFrame: 8 weeks
measure: Changes in Score for Sputum Production, Dyspnea and Global Symptoms
timeFrame: 8 weeks
measure: Changes in Pulse Oximetry, FEV1/FVC, and FEF50.
timeFrame: 8 weeks
measure: Changes in FEV1, FEF25, and FEFmax
timeFrame: 8 weeks
measure: Changes in Other Spirometric Variables
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Mexico DF
country: Mexico
facility: Hospital Infantil de México
city: Mexico DF
country: Mexico
facility: Unidad de Investigación Médica en Enfermedades Respiratorias, Hospital de Pediatría, CMN SXXI, IMSS
city: Mexico DF
country: Mexico
facility: Instituto Nacional de Enfermedades Respiratorias
Study officials:
affiliation: Instituto Nacional de Enfermedades Respiratorias
name: Mario H Vargas, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cohen-Cymberknoh M, Shoseyov D, Kerem E. Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life. Am J Respir Crit Care Med. 2011 Jun 1;183(11):1463-71. doi: 10.1164/rccm.201009-1478CI. Epub 2011 Feb 17.
citation: Wheeler MD, Ikejema K, Enomoto N, Stacklewitz RF, Seabra V, Zhong Z, Yin M, Schemmer P, Rose ML, Rusyn I, Bradford B, Thurman RG. Glycine: a new anti-inflammatory immunonutrient. Cell Mol Life Sci. 1999 Nov 30;56(9-10):843-56. doi: 10.1007/s000180050030.
citation: Wheeler MD, Rose ML, Yamashima S, Enomoto N, Seabra V, Madren J, Thurman RG. Dietary glycine blunts lung inflammatory cell influx following acute endotoxin. Am J Physiol Lung Cell Mol Physiol. 2000 Aug;279(2):L390-8. doi: 10.1152/ajplung.2000.279.2.L390.
citation: Garcia-Macedo R, Sanchez-Munoz F, Almanza-Perez JC, Duran-Reyes G, Alarcon-Aguilar F, Cruz M. Glycine increases mRNA adiponectin and diminishes pro-inflammatory adipokines expression in 3T3-L1 cells. Eur J Pharmacol. 2008 Jun 10;587(1-3):317-21. doi: 10.1016/j.ejphar.2008.03.051. Epub 2008 Apr 8.
citation: Vargas MH, Del-Razo-Rodriguez R, Lopez-Garcia A, Lezana-Fernandez JL, Chavez J, Furuya MEY, Marin-Santana JC. Effect of oral glycine on the clinical, spirometric and inflammatory status in subjects with cystic fibrosis: a pilot randomized trial. BMC Pulm Med. 2017 Dec 15;17(1):206. doi: 10.1186/s12890-017-0528-x.