Cystic Fibrosis
Conditions
Keywords
cystic fibrosis, glycine, airway inflammation
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.
Interventions
DIETARY_SUPPLEMENTGlycine
Daily oral supplement of glycine at a dose of 0.5 g/kg divided in three doses during 8 weeks
DIETARY_SUPPLEMENTPlacebo
Daily oral administration of placebo (sugar glass) at a dose of 0.5 g/kg divided in three doses during 8 weeks
Sponsors
Hospital Infantil de Mexico Federico Gomez
Instituto Mexicano del Seguro Social
Instituto Nacional de Enfermedades Respiratorias
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
5 Years to 15 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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 \[beginning of the glycine or placebo period, respectively\]). |
| 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 \[beginning of the glycine or placebo period, respectively\]). |
Countries
Mexico
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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). | 8 |
| 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). | 7 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (8 Weeks) | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo, Then Glycine | Glycine, Then Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 6 Participants | 13 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Continuous | 11.00 years STANDARD_DEVIATION 4.01 | 14.39 years STANDARD_DEVIATION 5.82 | 12.81 years STANDARD_DEVIATION 5.19 |
| Region of Enrollment Mexico | 7 participants | 8 participants | 15 participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 9 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 13 | 0 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 |
Outcome results
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.
Time frame: 8 weeks
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glycine | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | Myeloperoxidase | -0.4361 log (percent change) | Standard Error 0.2184 |
| Glycine | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IL-1 | -0.1635 log (percent change) | Standard Error 0.1467 |
| Glycine | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IL-4 | 0.2964 log (percent change) | Standard Error 0.142 |
| Glycine | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IL-6 | 0.0085 log (percent change) | Standard Error 0.2064 |
| Glycine | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IL-7 | 0.0356 log (percent change) | Standard Error 0.0613 |
| Glycine | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IL-8 | -0.1466 log (percent change) | Standard Error 0.2981 |
| Glycine | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IL-12 | 0.3203 log (percent change) | Standard Error 0.1449 |
| Glycine | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IL-13 | -0.0561 log (percent change) | Standard Error 0.1684 |
| Glycine | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | G-CSF | -0.0776 log (percent change) | Standard Error 0.1554 |
| Glycine | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IFN-gamma | 0.3272 log (percent change) | Standard Error 0.1761 |
| Glycine | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | MCP-1 | -0.0836 log (percent change) | Standard Error 0.1041 |
| Glycine | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | MIP-1beta | 0.0330 log (percent change) | Standard Error 0.1426 |
| Placebo | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | MCP-1 | 0.0472 log (percent change) | Standard Error 0.0894 |
| Placebo | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | Myeloperoxidase | -0.2906 log (percent change) | Standard Error 0.2877 |
| Placebo | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IL-12 | 0.2603 log (percent change) | Standard Error 0.2117 |
| Placebo | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IL-1 | -0.0352 log (percent change) | Standard Error 0.1294 |
| Placebo | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IFN-gamma | 0.3639 log (percent change) | Standard Error 0.2505 |
| Placebo | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IL-4 | 0.1470 log (percent change) | Standard Error 0.2223 |
| Placebo | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IL-13 | 0.1953 log (percent change) | Standard Error 0.1849 |
| Placebo | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IL-6 | 0.2255 log (percent change) | Standard Error 0.1865 |
| Placebo | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | MIP-1beta | -0.0608 log (percent change) | Standard Error 0.0963 |
| Placebo | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IL-7 | 0.0819 log (percent change) | Standard Error 0.0986 |
| Placebo | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | G-CSF | 0.2272 log (percent change) | Standard Error 0.1983 |
| Placebo | Changes in Serum Concentration of Inflammatory Biomarkers (Other Than TNF-alpha) | IL-8 | -0.2364 log (percent change) | Standard Error 0.1761 |
p-value: >0.05t-test, 1 sided
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.
Time frame: 8 weeks
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glycine | Changes in Serum Concentration of Inflammatory Biomarkers (TNF-alpha) | -0.3908 log (percent change) | Standard Error 0.2744 |
| Placebo | Changes in Serum Concentration of Inflammatory Biomarkers (TNF-alpha) | 0.2035 log (percent change) | Standard Error 0.2384 |
p-value: =0.061t-test, 1 sided
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.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (G-CSF) | -0.0819 log (percent change) | Standard Error 0.079 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (G-CSF) | 0.1668 log (percent change) | Standard Error 0.1022 |
p-value: =0.04t-test, 1 sided
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.
Time frame: 8 weeks
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (IL-6) | -0.00007 log (percent change) | Standard Error 0.0677 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (IL-6) | 0.1739 log (percent change) | Standard Error 0.0838 |
p-value: =0.068t-test, 1 sided
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.
Time frame: 8 weeks
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | Myeloperoxidase | 0.1294 log (percent change) | Standard Error 0.2204 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-1 | -0.0918 log (percent change) | Standard Error 0.1552 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-10 | 0.0549 log (percent change) | Standard Error 0.0847 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-12 | 0.1675 log (percent change) | Standard Error 0.1443 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-13 | 0.1630 log (percent change) | Standard Error 0.1379 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-17 | 0.0680 log (percent change) | Standard Error 0.0411 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IFN-gamma | 0.0248 log (percent change) | Standard Error 0.0652 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | MCP-1 | 0.0042 log (percent change) | Standard Error 0.0694 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | MIP-1beta | -0.0303 log (percent change) | Standard Error 0.1234 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | TNF-alpha | 0.0412 log (percent change) | Standard Error 0.1091 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | GM-CSF | -0.0538 log (percent change) | Standard Error 0.0338 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-2 | 0.0233 log (percent change) | Standard Error 0.0828 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-4 | -0.0161 log (percent change) | Standard Error 0.0482 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-5 | 0.2498 log (percent change) | Standard Error 0.1855 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-7 | 0.0611 log (percent change) | Standard Error 0.0852 |
| Glycine | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-8 | -0.0824 log (percent change) | Standard Error 0.2311 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | MCP-1 | 0.2608 log (percent change) | Standard Error 0.2025 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | Myeloperoxidase | 0.0669 log (percent change) | Standard Error 0.1725 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-2 | -0.0274 log (percent change) | Standard Error 0.1243 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-1 | -0.0102 log (percent change) | Standard Error 0.1329 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-8 | 0.0542 log (percent change) | Standard Error 0.0934 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | MIP-1beta | 0.0977 log (percent change) | Standard Error 0.1207 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-10 | 0.0074 log (percent change) | Standard Error 0.0849 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-5 | 0.1304 log (percent change) | Standard Error 0.1864 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-12 | 0.0677 log (percent change) | Standard Error 0.125 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | TNF-alpha | 0.1568 log (percent change) | Standard Error 0.1393 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-13 | 0.0953 log (percent change) | Standard Error 0.1049 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-4 | 0.0522 log (percent change) | Standard Error 0.0671 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-17 | 0.1140 log (percent change) | Standard Error 0.0823 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | GM-CSF | -0.0822 log (percent change) | Standard Error 0.0468 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IFN-gamma | 0.0649 log (percent change) | Standard Error 0.073 |
| Placebo | Changes in Sputum Concentration of Inflammatory Biomarkers (Other Than IL-6 and G-CSF) | IL-7 | 0.1387 log (percent change) | Standard Error 0.1028 |
p-value: >0.05t-test, 1 sided
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.
Time frame: 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glycine | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Cough questionnaire score | 81.1 Percentage of baseline | Standard Error 12.6 |
| Glycine | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Appetite questionnaire score | 89.1 Percentage of baseline | Standard Error 11 |
| Glycine | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Energy questionnaire score | 84.6 Percentage of baseline | Standard Error 7.4 |
| Glycine | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Body weight | 101.6 Percentage of baseline | Standard Error 1.1 |
| Glycine | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Height | 100.5 Percentage of baseline | Standard Error 0.2 |
| Glycine | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Heart rate | 103.5 Percentage of baseline | Standard Error 6 |
| Glycine | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Respiratory rate | 94.8 Percentage of baseline | Standard Error 5.5 |
| Glycine | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Temperature | 100.0 Percentage of baseline | Standard Error 0.3 |
| Placebo | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Temperature | 100.1 Percentage of baseline | Standard Error 0.5 |
| Placebo | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Cough questionnaire score | 89.1 Percentage of baseline | Standard Error 4.9 |
| Placebo | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Height | 100.5 Percentage of baseline | Standard Error 0.2 |
| Placebo | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Appetite questionnaire score | 132.1 Percentage of baseline | Standard Error 25.4 |
| Placebo | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Respiratory rate | 109.0 Percentage of baseline | Standard Error 6.4 |
| Placebo | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Energy questionnaire score | 111.5 Percentage of baseline | Standard Error 16.2 |
| Placebo | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Heart rate | 98.1 Percentage of baseline | Standard Error 3 |
| Placebo | Changes in Clinical Data Scores (Other Than Sputum Production, Dyspnea and Global Symptoms) | Body weight | 103.6 Percentage of baseline | Standard Error 1 |
p-value: >0.05t-test, 1 sided
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 \[beginning of the glycine or placebo period, respectively\]).
Time frame: 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glycine | Changes in FEV1, FEF25, and FEFmax | Forced expiratory volume at first second (FEV1) | 109.7 Percentage of baseline | Standard Error 6.4 |
| Glycine | Changes in FEV1, FEF25, and FEFmax | Forced expiratory flow at 25%FVC (FEF25) | 133.9 Percentage of baseline | Standard Error 13.6 |
| Glycine | Changes in FEV1, FEF25, and FEFmax | Maximal forced expiratory flow (FEFmax, PEFR) | 115.3 Percentage of baseline | Standard Error 6.1 |
| Placebo | Changes in FEV1, FEF25, and FEFmax | Forced expiratory volume at first second (FEV1) | 91.4 Percentage of baseline | Standard Error 4.1 |
| Placebo | Changes in FEV1, FEF25, and FEFmax | Forced expiratory flow at 25%FVC (FEF25) | 83.3 Percentage of baseline | Standard Error 7.7 |
| Placebo | Changes in FEV1, FEF25, and FEFmax | Maximal forced expiratory flow (FEFmax, PEFR) | 91.2 Percentage of baseline | Standard Error 4.6 |
p-value: <0.01t-test, 1 sided
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 \[beginning of the glycine or placebo period, respectively\]).
Time frame: 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glycine | Changes in Other Spirometric Variables | Forced vital capacity (FVC) | 104.1 Percentage of baseline | Standard Error 4.1 |
| Glycine | Changes in Other Spirometric Variables | Forced expiratory flow at 75%FVC (FEF75) | 111.8 Percentage of baseline | Standard Error 11.7 |
| Placebo | Changes in Other Spirometric Variables | Forced vital capacity (FVC) | 100.6 Percentage of baseline | Standard Error 9.8 |
| Placebo | Changes in Other Spirometric Variables | Forced expiratory flow at 75%FVC (FEF75) | 108.9 Percentage of baseline | Standard Error 15.8 |
p-value: >0.05t-test, 1 sided
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 \[beginning of the glycine or placebo period, respectively\]).
Time frame: 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glycine | Changes in Pulse Oximetry, FEV1/FVC, and FEF50. | FEV1/FVC | 105.2 Percentage of baseline | Standard Error 2.9 |
| Glycine | Changes in Pulse Oximetry, FEV1/FVC, and FEF50. | Peripheral oxygen saturation (SpO2) | 105.2 Percentage of baseline | Standard Error 2.5 |
| Glycine | Changes in Pulse Oximetry, FEV1/FVC, and FEF50. | Forced expiratory flow at 50%FVC (FEF50) | 115.5 Percentage of baseline | Standard Error 10.4 |
| Placebo | Changes in Pulse Oximetry, FEV1/FVC, and FEF50. | Peripheral oxygen saturation (SpO2) | 98.9 Percentage of baseline | Standard Error 1.4 |
| Placebo | Changes in Pulse Oximetry, FEV1/FVC, and FEF50. | FEV1/FVC | 94.9 Percentage of baseline | Standard Error 4.2 |
| Placebo | Changes in Pulse Oximetry, FEV1/FVC, and FEF50. | Forced expiratory flow at 50%FVC (FEF50) | 93.1 Percentage of baseline | Standard Error 7.8 |
p-value: <0.05t-test, 1 sided
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.
Time frame: 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glycine | Changes in Score for Sputum Production, Dyspnea and Global Symptoms | Sputum questionnaire score | 82.0 Percentage of baseline | Standard Error 7 |
| Glycine | Changes in Score for Sputum Production, Dyspnea and Global Symptoms | Dyspnea questionnaire score | 75.6 Percentage of baseline | Standard Error 7.5 |
| Glycine | Changes in Score for Sputum Production, Dyspnea and Global Symptoms | Total questionnaire score | 77.7 Percentage of baseline | Standard Error 5.2 |
| Placebo | Changes in Score for Sputum Production, Dyspnea and Global Symptoms | Sputum questionnaire score | 102.6 Percentage of baseline | Standard Error 10.1 |
| Placebo | Changes in Score for Sputum Production, Dyspnea and Global Symptoms | Dyspnea questionnaire score | 103.8 Percentage of baseline | Standard Error 10.7 |
| Placebo | Changes in Score for Sputum Production, Dyspnea and Global Symptoms | Total questionnaire score | 98.7 Percentage of baseline | Standard Error 8.4 |
p-value: <0.05t-test, 1 sided