Cystic Fibrosis
Conditions
Keywords
Growth Parameters, Cystic Fibrosis
Brief summary
The purpose of this randomized, placebo-controlled (Phase II) study will be to further evaluate the effects of oral glutathione on growth in children with CF.
Detailed description
a prospective, multi-center, randomized, placebocontrolled, double-blind, Phase II clinical trial. Approximately sixty pancreatic insufficient (PI) subjects with CF who are ≥ 2 and \< 11 years of age, will be enrolled to receive either L-Glutathione Reduced (GSH) or placebo given orally (tid) for 24 weeks. Each subject will be seen for four study visits: Visit 1 (Screening), Visit 2 (Baseline/Randomization, Day 0), Visit 3 (Week 12) and Visit 4 (Week 24). At Visit 2, subjects will be randomized to receive either active treatment or placebo. Visit 1 and 2 may be combined if subject meets eligibility requirements and a fecal specimen is collected prior to dosing. Safety and clinical outcomes will be assessed throughout the study. Assessment of inflammatory and other bio-markers in blood and fecal specimens will be performed at Visits 2 and 4
Interventions
DRUGOral Glutathione
Oral Glutathione oral powder
DRUGPlacebo
Placebo oral powder
Sponsors
Cystic Fibrosis Foundation
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female ≥ 2 and \< 11 years of age at Visit 1 2. Documentation of a CF diagnosis as evidenced by the following criteria: Sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis test (QPIT) AND Two well-characterized mutations in the cystic fibrosis transmembrane conductive regulator (CFTR) gene 3. Weight-for-age between the 10th and 50th percentiles at Screening (Visit 1) (using the Center for Disease Control (CDC) reference equations) 4. Current chronic use, greater than 8 weeks before Day 0, of pancreatic enzyme replacement therapy (PERT) for management of pancreatic insufficiency 5. Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability to comply with the requirements of the study 6. Clinically stable with no significant changes in health status within 2 weeks prior to Day 0
Exclusion criteria
* 1\. Intestinal obstruction or gastrointestinal surgery within the 6 months prior to Day 0 2. History of diabetes, Crohn's disease, celiac disease, or bowel resection 3. Use of either oral or inhaled GSH or N-acetyl cysteine within the 4 months prior to Screening (Visit 1) 4. Known hypersensitivity to oral glutathione or lactose 5. Initiation of any new chronic therapy (e.g., ibuprofen, hypertonic saline, azithromycin, Pulmozyme, Cayston TOBI Kalydeco,Orkambi, Proton Pump Inhibitor, Histamine H-2 Blocker \[PPI/H2-blocker\], Miralax® , PERT, dietary supplementation, probiotics) within the 4 weeks prior to Day 0 6. Changes in the amount of proprietary dietary supplement formulas (e.g., Scandishakes, Boost, Pediasure, or homemade formula) given (oral or gastrostomy tube) within the 4 weeks prior to Day 0 7. Use of antibiotics (oral, IV, or inhaled) for acute symptoms within the 2 weeks prior to Day 0 8. Use of oral steroids within the 4 weeks prior to Day 0 9. Active treatment for nontuberculous mycobacteria (NTM) at Day 0 10. Active treatment for allergic bronchopulmonary aspergillosis (ABPA) at Day 0 11. Administration of any investigational drug within the 30 days prior to Day 0 12. Sibling who received study drug as part of this study 13. Presence of a condition or abnormality that in the opinion of the investigator would compromise the safety of the patient or the quality of the data
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Weight-for-age Z-score | Baseline to 24 weeks | Difference between the oral glutathione and placebo groups in the 24-week change from baseline in weight-for-age Z-score. Weight-for-age Z-scores are derived from the 2000 Centers for Disease Control and Prevention growth charts for U.S. children. The reference population in these growth charts is children surveyed by the National Center for Health Statistics from 1963-65 to 1988-94. The Z-score indicates the number of standard deviations away from the mean of the reference population. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in BMI-for-age Z-score | Baseline to 24 weeks | Difference between the oral glutathione and placebo groups in the 24-week change from baseline in BMI-for-age Z-score. BMI-for-age Z-scores are derived from the 2000 Centers for Disease Control and Prevention growth charts for U.S. children. The reference population in these growth charts is children surveyed by the National Center for Health Statistics from 1963-65 to 1988-94. The Z-score indicates the number of standard deviations away from the mean of the reference population. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean. |
| Change in Fecal Calprotectin | Baseline to 24 weeks | Difference between the oral glutathione and placebo groups in the 24-week change from baseline in fecal calprotectin. |
| Change in Height-for-age Z-score | Baseline to 24 weeks | Difference between the oral glutathione and placebo groups in the 24-week change from baseline in height-for-age Z-score. Height-for-age Z-scores are derived from the 2000 Centers for Disease Control and Prevention growth charts for U.S. children. The reference population in these growth charts is children surveyed by the National Center for Health Statistics from 1963-65 to 1988-94. The Z-score indicates the number of standard deviations away from the mean of the reference population. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean. |
| Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline to 24 weeks | The number and percentage of participants with at least one event over the 24 week follow-up period. |
| Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline to 24 weeks | Rate is defined as the number of events per participant follow-up month. |
| Change in High-sensitivity C-reactive Protein (Hs-CRP) | Baseline to 24 weeks | Difference between the oral glutathione and placebo groups in the 24-week change from baseline in hs-CRP. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Oral Glutathione Oral Glutathione oral powder at 65mg/kg/day
Oral Glutathione: Oral Glutathione oral powder | 30 |
| Placebo Placebo oral powder at 65mg/kg/day
Placebo: Placebo oral powder | 30 |
| Total | 60 |
Baseline characteristics
| Characteristic | Oral Glutathione | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 6.1 years STANDARD_DEVIATION 2.43 | 6 years STANDARD_DEVIATION 2.87 | 6.1 years STANDARD_DEVIATION 2.64 |
| Age, Customized Age Distribution < 6 years | 16 Participants | 15 Participants | 31 Participants |
| Age, Customized Age Distribution ≥ 6 years | 14 Participants | 15 Participants | 29 Participants |
| Cystic Fibrosis (CF) Genotype Delta F508 Heterozygous | 9 Participants | 13 Participants | 22 Participants |
| Cystic Fibrosis (CF) Genotype Delta F508 Homozygous | 18 Participants | 14 Participants | 32 Participants |
| Cystic Fibrosis (CF) Genotype Not Available | 0 Participants | 0 Participants | 0 Participants |
| Cystic Fibrosis (CF) Genotype Other | 3 Participants | 3 Participants | 6 Participants |
| Cystic Fibrosis (CF) Genotype Unidentified | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 27 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Fecal Elastase < 200 mg/g | 30 Participants | 30 Participants | 60 Participants |
| Fecal Elastase ≥ 200 mg/g | 0 Participants | 0 Participants | 0 Participants |
| Fecal Elastase Not Available | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 29 Participants | 30 Participants | 59 Participants |
| Region of Enrollment United States | 30 participants | 30 participants | 60 participants |
| Sex: Female, Male Female | 18 Participants | 17 Participants | 35 Participants |
| Sex: Female, Male Male | 12 Participants | 13 Participants | 25 Participants |
| Weight-for-age Z-score Distribution < -0.52 (equiv. to < 30th percentile) | 13 Participants | 13 Participants | 26 Participants |
| Weight-for-age Z-score Distribution ≥ -0.52 (equiv. to ≥ 30th percentile) | 17 Participants | 17 Participants | 34 Participants |
| Weight (Z-score) | -0.57 z-score STANDARD_DEVIATION 0.33 | -0.53 z-score STANDARD_DEVIATION 0.35 | -0.55 z-score STANDARD_DEVIATION 0.34 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 30 |
| other Total, other adverse events | 29 / 30 | 29 / 30 |
| serious Total, serious adverse events | 1 / 30 | 5 / 30 |
Outcome results
Primary
Change in Weight-for-age Z-score
Difference between the oral glutathione and placebo groups in the 24-week change from baseline in weight-for-age Z-score. Weight-for-age Z-scores are derived from the 2000 Centers for Disease Control and Prevention growth charts for U.S. children. The reference population in these growth charts is children surveyed by the National Center for Health Statistics from 1963-65 to 1988-94. The Z-score indicates the number of standard deviations away from the mean of the reference population. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean.
Time frame: Baseline to 24 weeks
Population: Include participants with weight-for-age Z-score measurements at Baseline, Week 12 and Week 24
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Oral Glutathione | Change in Weight-for-age Z-score | -0.018 Z-score |
| Placebo | Change in Weight-for-age Z-score | 0.045 Z-score |
p-value: 0.252195% CI: [-0.221, 0.059]Mixed Models Analysis
Secondary
Adverse Events (AEs) and Serious Adverse Events (SAEs)
The number and percentage of participants with at least one event over the 24 week follow-up period.
Time frame: Baseline to 24 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Oral Glutathione | Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse Events | 29 Participants |
| Oral Glutathione | Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious Adverse Events | 1 Participants |
| Placebo | Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse Events | 29 Participants |
| Placebo | Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious Adverse Events | 5 Participants |
p-value: 195% CI: [-13.6, 13.6]Fisher Exact
p-value: 0.194595% CI: [-30.5, 2.9]Fisher Exact
Secondary
Change in BMI-for-age Z-score
Difference between the oral glutathione and placebo groups in the 24-week change from baseline in BMI-for-age Z-score. BMI-for-age Z-scores are derived from the 2000 Centers for Disease Control and Prevention growth charts for U.S. children. The reference population in these growth charts is children surveyed by the National Center for Health Statistics from 1963-65 to 1988-94. The Z-score indicates the number of standard deviations away from the mean of the reference population. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean.
Time frame: Baseline to 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Glutathione | Change in BMI-for-age Z-score | -0.01 Z-score | Standard Deviation 0.48 |
| Placebo | Change in BMI-for-age Z-score | 0.04 Z-score | Standard Deviation 0.44 |
p-value: 0.57395% CI: [-0.28, 0.15]Mixed Models Analysis
Secondary
Change in Fecal Calprotectin
Difference between the oral glutathione and placebo groups in the 24-week change from baseline in fecal calprotectin.
Time frame: Baseline to 24 weeks
Population: Include participants with fecal calprotectin measurements at Baseline and Week 24.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Glutathione | Change in Fecal Calprotectin | 0.05 log base 10 transformation of ug/g | Standard Deviation 0.55 |
| Placebo | Change in Fecal Calprotectin | -0.05 log base 10 transformation of ug/g | Standard Deviation 0.53 |
p-value: 0.425995% CI: [-0.17, 0.4]Mixed Models Analysis
Secondary
Change in Height-for-age Z-score
Difference between the oral glutathione and placebo groups in the 24-week change from baseline in height-for-age Z-score. Height-for-age Z-scores are derived from the 2000 Centers for Disease Control and Prevention growth charts for U.S. children. The reference population in these growth charts is children surveyed by the National Center for Health Statistics from 1963-65 to 1988-94. The Z-score indicates the number of standard deviations away from the mean of the reference population. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean.
Time frame: Baseline to 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Glutathione | Change in Height-for-age Z-score | -0.04 Z-score | Standard Deviation 0.21 |
| Placebo | Change in Height-for-age Z-score | 0.03 Z-score | Standard Deviation 0.16 |
p-value: 0.08995% CI: [-0.18, 0.01]Mixed Models Analysis
Secondary
Change in High-sensitivity C-reactive Protein (Hs-CRP)
Difference between the oral glutathione and placebo groups in the 24-week change from baseline in hs-CRP.
Time frame: Baseline to 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Glutathione | Change in High-sensitivity C-reactive Protein (Hs-CRP) | -0.45 mg/L | Standard Deviation 3.4 |
| Placebo | Change in High-sensitivity C-reactive Protein (Hs-CRP) | -0.04 mg/L | Standard Deviation 1.6 |
p-value: 0.466695% CI: [-2.06, 0.96]ANCOVA
Secondary
Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Rate is defined as the number of events per participant follow-up month.
Time frame: Baseline to 24 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oral Glutathione | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse Events | 0.89 number of events/total follow-up months |
| Oral Glutathione | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious Adverse Events | 0.01 number of events/total follow-up months |
| Placebo | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse Events | 0.74 number of events/total follow-up months |
| Placebo | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious Adverse Events | 0.05 number of events/total follow-up months |
Comparison: Rate Ratio for Adverse Events calculated using Poisson Regression with an offset for the log of follow-up time in months. The total number of follow-up months of all participants (not per participant) in the trial was as follows: in the GSH group was 179.22 and in the Placebo group was 177.19.p-value: 0.108795% CI: [0.96, 1.52]Poisson Regression
Comparison: Rate Ratio for Serious Adverse Events calculated using Poisson Regression with an offset for the log of follow-up time in months. The total number of follow-up months of all participants (not per participant) in the trial was as follows: in the GSH group was 179.22 and in the Placebo group was 177.19.p-value: 0.012295% CI: [0.01, 0.67]Poisson Regression