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Some of the researchers finished their participation in the study.
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| Name | Class |
|---|---|
| Hospital Infantil de Mexico Federico Gomez | OTHER |
| Instituto Mexicano del Seguro Social | OTHER_GOV |
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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.
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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Glycine | Active Comparator | Patients will receive a daily oral supplement of 0.5 g/kg glycine dissolved in water. |
|
| Placebo | Placebo Comparator | Patients will receive a daily supplement of 0.5 g/kg sugar glass dissolved in water. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Glycine | Dietary Supplement | Daily oral supplement of glycine at a dose of 0.5 g/kg divided in three doses during 8 weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | 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. | 8 weeks |
| Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | 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. | 8 weeks |
| Changes in Serum Concentration of Inflammatory Biomarkers (TNF-alpha) | 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. | 8 weeks |
| Changes in Sputum Concentration of Inflammatory Biomarkers (IL-6) | 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. | 8 weeks |
| Changes in Sputum Concentration of Inflammatory Biomarkers (G-CSF) | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mario H Vargas, MD, MSc | Instituto Nacional de Enfermedades Respiratorias | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Infantil de México | Mexico City | 06720 | Mexico | |||
| Unidad de Investigación Médica en Enfermedades Respiratorias, Hospital de Pediatría, CMN SXXI, IMSS |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21330455 | Background | 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. | |
| 11212343 | Background | 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. |
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Patients attending the Hospital Infantil de México and the Instituto Mexicano del Seguro Social (both in Mexico city) were recruited from March 7, 2012 to October 31, 2012. The two arms of the study were: 1) Glycine, then placebo, and 2) Placebo, then glycine.
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| ID | Title | Description |
|---|---|---|
| FG000 | Glycine, Then Placebo | First intervention (8 weeks) with Glycine (0.5 g/kg/day divided in three doses). Washout period of 2 weeks. Second intervention (8 weeks) with Placebo (sugar glass, 0.5 g/kg/day divided in three doses). |
| FG001 | Placebo, Then Glycine | First intervention (8 weeks) with Placebo (sugar glass, 0.5 g/kg/day divided in three doses). Washout period of 2 weeks. Second intervention (8 weeks) with Glycine (0.5 g/kg/day divided in three doses). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (8 Weeks) |
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| ||||||||||||||||||
| Washout (2 Weeks) |
| |||||||||||||||||||
| Second Period (8 Weeks) |
|
The total number of patiens was fewer than planned mainly because other protocols were running concurrently. The protocolo had to be concluded because some of the researchers finished their participation.
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| ID | Title | Description |
|---|---|---|
| BG000 | Glycine, Then Placebo | First intervention (8 weeks) with Glycine (0.5 g/kg/day divided in three doses). Washout period of 2 weeks. Second intervention (8 weeks) with Placebo (sugar glass, 0.5 g/kg/day divided in three doses). |
| BG001 | Placebo, Then Glycine |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | During the course of the study, inclusion criteria was expanded to include subjects older than 15 years of age. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Secondary | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | 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. | Posted | Mean | Standard Error | Percentage of baseline | 8 weeks |
|
Weeks 4 and 8 of each study arm.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Glycine | Patients received a daily oral supplement of glycine at a dose of 0.5 g/kg divided in three doses during 8 weeks, dissolved in any liquid. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Mario H. Vargas | Instituto Nacional de Enfermedades Respiratorias | (+55)54871771 | mhvargasb@yahoo.com.mx |
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| ID | Term |
|---|---|
| D003550 | Cystic Fibrosis |
| ID | Term |
|---|---|
| D010182 | Pancreatic Diseases |
| D004066 | Digestive System Diseases |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D005998 | Glycine |
| ID | Term |
|---|---|
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
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| Placebo | Dietary Supplement | Daily oral administration of placebo (sugar glass) at a dose of 0.5 g/kg divided in three doses during 8 weeks |
|
|
| 8 weeks |
| 8 weeks |
| Changes in Score for Sputum Production, Dyspnea and Global Symptoms | 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. | 8 weeks |
| Changes in Pulse Oximetry, FEV1/FVC, and FEF50. | 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]). | 8 weeks |
| Changes in FEV1, FEF25, and FEFmax | 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]). | 8 weeks |
| Changes in Other Spirometric Variables | 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]). | 8 weeks |
| Mexico City |
| 06720 |
| Mexico |
| Instituto Nacional de Enfermedades Respiratorias | Mexico City | 14080 | Mexico |
| 10926563 | Background | 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. |
| 18499099 | Background | 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. |
| 29246256 | Derived | 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. |
| NOT COMPLETED |
|
| NOT COMPLETED |
|
First intervention (8 weeks) with Placebo (sugar glass, 0.5 g/kg/day divided in three doses). Washout period of 2 weeks. Second intervention (8 weeks) with Glycine (0.5 g/kg/day divided in three doses). |
| BG002 | Total | Total of all reporting groups |
| Count of Participants |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
All study participants receiving a daily oral supplement of 0.5 g/kg placebo (sugar glass) dissolved in water during 8 weeks. |
|
|
|
| Primary | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | 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. | From the 13 patients who initiated the study, some parents did not give consent for blood sampling, and some children refused the venous puncture at some visits. Thus, only a non-paired population of 9 children per group could be analyzed. | Posted | Mean | Standard Error | log (percent change) | 8 weeks |
|
|
|
|
| Primary | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | 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. | From the 13 patients who initiated the study, some children at some visits could not give an appropriate sputum sample. Thus, only a non-paired population of 9 (glycine group) and 11 (placebo group) children could be analyzed. | Posted | Mean | Standard Error | log (percent change) | 8 weeks |
|
|
|
|
| Primary | Changes in Serum Concentration of Inflammatory Biomarkers (TNF-alpha) | 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. | From the 13 patients who initiated the study, some parents did not give consent for blood sampling, and some children refused the venous puncture at some visits. Thus, only a non-paired population of 9 children per group could be analyzed. | Posted | Mean | Standard Error | log (percent change) | 8 weeks |
|
|
|
|
| Primary | Changes in Sputum Concentration of Inflammatory Biomarkers (IL-6) | 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. | From the 13 patients who initiated the study, some children did not expectorate at some visits. Thus, only a non-paired population of 9 children under glycine and 11 under placebo could be analyzed. | Posted | Mean | Standard Error | log (percent change) | 8 weeks |
|
|
|
|
| Primary | Changes in Sputum Concentration of Inflammatory Biomarkers (G-CSF) | 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. | Posted | Mean | Standard Error | log (percent change) | 8 weeks |
|
|
|
|
| Secondary | Changes in Score for Sputum Production, Dyspnea and Global Symptoms | 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. | Posted | Mean | Standard Error | Percentage of baseline | 8 weeks |
|
|
|
|
| Secondary | Changes in Pulse Oximetry, FEV1/FVC, and FEF50. | 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]). | Posted | Mean | Standard Error | Percentage of baseline | 8 weeks |
|
|
|
|
| Secondary | Changes in FEV1, FEF25, and FEFmax | 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]). | Posted | Mean | Standard Error | Percentage of baseline | 8 weeks |
|
|
|
|
| Secondary | Changes in Other Spirometric Variables | 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]). | Posted | Mean | Standard Error | Percentage of baseline | 8 weeks |
|
|
|
|
| 0 |
| 13 |
| 0 |
| 13 |
| EG001 | Placebo | Patients received a daily oral supplement of sugar glass at a dose of 0.5 g/kg divided in three doses during 8 weeks, dissolved in any liquid. | 0 | 13 | 0 | 13 |
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| D030342 |
| Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D007232 | Infant, Newborn, Diseases |
| IL-4 |
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| IL-6 |
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| IL-7 |
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| IL-8 |
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| IL-12 |
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| IL-13 |
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| G-CSF |
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| IFN-gamma |
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| MCP-1 |
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| MIP-1beta |
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| IL-2 |
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| IL-4 |
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| IL-5 |
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| IL-7 |
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| IL-8 |
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| IL-10 |
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| IL-12 |
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| IL-13 |
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| IL-17 |
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| IFN-gamma |
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| MCP-1 |
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| MIP-1beta |
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| TNF-alpha |
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| GM-CSF |
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| Total questionnaire score |
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| Forced expiratory flow at 50%FVC (FEF50) |
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| Maximal forced expiratory flow (FEFmax, PEFR) |
|