Cystic Fibrosis
Conditions
Brief summary
This Phase IIB proof-of-concept study would examine the effects of an investigational product called N-acetylcysteine (NAC) on the basic processes that cause inflammation in CF lung disease. We hope to learn more about the causes of lung disease in cystic fibrosis by studying the characteristics of the inflammation in the lungs of patients who have CF.
Interventions
DRUGN-acetylcysteine (NAC)
DRUGPlacebo
Sponsors
Cystic Fibrosis Foundation
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
7 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female 7 years of age or older 2. Diagnosis of CF based upon the following criteria: 1. One or more clinical features characteristic of CF AND (b or c) 2. Positive sweat test \> 60 mEq/L by quantitative pilocarpine iontophoresis 3. A genotype with two identifiable mutations consistent with CF 3. Written informed consent (and assent when applicable) obtained from subject or subject's legal representative 4. Clinically stable with no evidence of acute upper or lower respiratory tract infection within 4 weeks prior to enrollment 5. Stable mild or moderately severe lung disease defined by an FEV1 \> or = 40% and \< or = 85% predicted for age based on the Wang (males \< 18 years, females \< 16 years) or Hankinson (males \> or = 18 years, females \> or = 16 years) standardized equations 6. Able to tolerate sputum induction with 3% hypertonic saline and to expectorate 7. Able to perform repeatable, consistent efforts in pulmonary function testing 8. Weight \> or = 25 kg at time of enrollment 9. Females of child bearing potential must be willing to use birth control (IUD, oral, transdermal, or parenteral contraceptives; abstinence)
Exclusion criteria
1. Clinically significant liver enzymes (AST, ALT or GGT) \> 2.5 times the upper limit of normal at screening 2. History of ABPA, unless have evidence of a stable IgE (\< 5% increase compared to previous test) for 6 months prior to enrollment 3. Current or history of rheumatic or collagen vascular disorders 4. Use of NSAIDS other than for chronic therapy within 1 week prior to enrollment 5. Initiation of chronic therapy with ibuprofen, azithromycin, TOBI® or Aztreonam within 6 weeks prior to enrollment 6. Consumption or inhalation of antioxidants (including NAC, GSH, Immunocal, Nacystelyn, pentoxyfilline) within 6 weeks prior to enrollment 7. Use of oral or IV corticosteroids within 4 weeks prior to enrollment 8. Use of acetaminophen within 3 days prior to enrollment 9. Unable to forego during the study: * Vitamin E: more than 400 IU/day for subjects \< or = 12 years of age and 800 IU/day for subjects \> 12 years of age * Vitamin C: more than 0.5 gm/day * More than two alcoholic drinks per day 10. Known hypersensitivity to oral PharmaNAC® 11. Current cigarette consumption 12. Pregnant or breastfeeding 13. Subject unlikely to complete the study as determined by the Investigator 14. Any condition that the Investigator believes would interfere with the intent of this study or would make participation not in the best interest of the subject 15. Participation in trials for other anti-inflammatory or therapeutic investigational drugs within 6 weeks prior to enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Logarithm of the Level of Human Neutrophil Elastase (HNE) Activity Measured in Sputum | From enrollment to end of the 24-week trial | (change in log10 HNE in the active treatment group) - (change in log10 HNE in the placebo group) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in FEV1 (Percent of Predicted for Age) | From enrollment to the end of the 24-week trial | Change in forced expiratory volume in 1 second as compared to normals for age (percent of predicted) |
| FEF 25-75% (L/Sec) | Baseline to end of study (24 weeks) | Difference in mid-expiratory flow rates between 25 to 75% of the vital capacity, in L/sec measured at the beginning of the study to the end of the study. |
| FEF 25-75% (Percent of Predicted) | Baseline to 24 weeks | Difference in the forced expiratory flow rate in mid-exhalation as a percent of predicted to standard values measured from baseline to the end of study (24 weeks). |
| FEV1 (L) | Baseline to end of study (24 weeks) | Forced expiratory volume in 1 second (Liters) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in ECHO Tricuspid Regurgitation (mm Hg) Over Time by Treatment Group | Baseline to 24 weeks | Change in measure of estimated right ventricular pressure over the 24-week study period |
| Change in DLCO (ml/Min/mmHg) Over Time by Treatment Group | Baseline to 24 weeks | Change in the diffusing capacity of carbon monoxide across the lung measured from baseline to end of 24-week study. |
Countries
United States
Participant flow
Recruitment details
Recruitment began 11/4/2008. Recruitment process was staggered: Stanford cohort first to focus on safety data related to potential pulmonary hypertension. After half of the Stanford cohort reached the 8-week time point, the DSMC evaluated PH safety data. The other sites then began enrollment. Final subject enrolled on 2/2011.
Participants by arm
| Arm | Count |
|---|---|
| Study Drug N-acetylcysteine (NAC) :PharmaNAC® 900 mg effervescent tablets in blister packs were supplied by BioAdvantex Pharma, Inc. (Mississauga, ON, Canada). | 36 |
| Placebo Identically packaged effervescent tablets that contained only the carrier were provided in blister packs by BioAdvantex Pharma, Inc. (Mississauga, ON, Canada) | 34 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Study Drug | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 9 Participants | 10 Participants | 19 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 24 Participants | 51 Participants |
| Sex: Female, Male Female | 16 Participants | 19 Participants | 35 Participants |
| Sex: Female, Male Male | 20 Participants | 15 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 33 / 36 | 30 / 34 |
| serious Total, serious adverse events | 15 / 36 | 17 / 34 |
Outcome results
Primary
Change in the Logarithm of the Level of Human Neutrophil Elastase (HNE) Activity Measured in Sputum
(change in log10 HNE in the active treatment group) - (change in log10 HNE in the placebo group)
Time frame: From enrollment to end of the 24-week trial
Population: The primary endpoint analyses described uses the subset of the ITT population with complete case data. 70 subjects randomized, 65 completed the Week 12 visit and 62 completed the study. There were 6 withdrawals in the NAC group and 2 in Placebo. Five out of 6 subjects in the NAC group withdrew due to subject decision. Missing data was not imputed.
| Arm | Measure | Value (LOG_MEAN) |
|---|---|---|
| Study Drug | Change in the Logarithm of the Level of Human Neutrophil Elastase (HNE) Activity Measured in Sputum | 0.03 log10 mcg/mL |
| Placebo | Change in the Logarithm of the Level of Human Neutrophil Elastase (HNE) Activity Measured in Sputum | -0.17 log10 mcg/mL |
Comparison: Null hypothesis: there will be no difference in the change in human neutrophil activity measured from baseline to end of the study (24 weeks)p-value: 0.1495% CI: [-0.07, 0.48]t-test, 2 sided
Secondary
Change in FEV1 (Percent of Predicted for Age)
Change in forced expiratory volume in 1 second as compared to normals for age (percent of predicted)
Time frame: From enrollment to the end of the 24-week trial
Population: Out of 70 subjects randomized, 65 completed the Week 12 visit and 62 completed the study. There were 6 withdrawals in the NAC group and 2 in Placebo. Five out of 6 subjects in the NAC group withdrew due to subject decision. Missing data was not imputed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Drug | Change in FEV1 (Percent of Predicted for Age) | 1.055 percent of predicted vlaues |
| Placebo | Change in FEV1 (Percent of Predicted for Age) | -5.62 percent of predicted vlaues |
Secondary
FEF 25-75% (L/Sec)
Difference in mid-expiratory flow rates between 25 to 75% of the vital capacity, in L/sec measured at the beginning of the study to the end of the study.
Time frame: Baseline to end of study (24 weeks)
Population: Out of 70 subjects randomized, 65 completed the Week 12 visit and 62 completed the study. There were 6 withdrawals in the NAC group and 2 in Placebo. Five out of 6 subjects in the NAC group withdrew due to subject decision. Missing data was not imputed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug | FEF 25-75% (L/Sec) | 0.08 L/sec |
| Placebo | FEF 25-75% (L/Sec) | -0.13 L/sec |
Secondary
FEF 25-75% (Percent of Predicted)
Difference in the forced expiratory flow rate in mid-exhalation as a percent of predicted to standard values measured from baseline to the end of study (24 weeks).
Time frame: Baseline to 24 weeks
Population: Out of 70 subjects randomized, 65 completed the Week 12 visit and 62 completed the study. There were 6 withdrawals in the NAC group and 2 in Placebo. Five out of 6 subjects in the NAC group withdrew due to subject decision. Missing data was not imputed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug | FEF 25-75% (Percent of Predicted) | 1.33 percent of predicted |
| Placebo | FEF 25-75% (Percent of Predicted) | -3.81 percent of predicted |
Secondary
FEV1 (L)
Forced expiratory volume in 1 second (Liters)
Time frame: Baseline to end of study (24 weeks)
Population: Out of 70 subjects randomized, 65 completed the Week 12 visit and 62 completed the study. There were 6 withdrawals in the NAC group and 2 in Placebo. Five out of 6 subjects in the NAC group withdrew due to subject decision. Missing data was not imputed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Drug | FEV1 (L) | 2.5 Liter |
| Placebo | FEV1 (L) | -4.35 Liter |
Other Pre-specified
Change in DLCO (ml/Min/mmHg) Over Time by Treatment Group
Change in the diffusing capacity of carbon monoxide across the lung measured from baseline to end of 24-week study.
Time frame: Baseline to 24 weeks
Population: Sixteen subjects at Stanford University were enrolled as an initial safety cohort, and their data was used to evaluate the potential for NAC to cause PH in CF subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Drug | Change in DLCO (ml/Min/mmHg) Over Time by Treatment Group | -0.32 ml/min/mm Hg | Standard Deviation 2.86 |
| Placebo | Change in DLCO (ml/Min/mmHg) Over Time by Treatment Group | -1.39 ml/min/mm Hg | Standard Deviation 3.93 |
Other Pre-specified
Change in ECHO Tricuspid Regurgitation (mm Hg) Over Time by Treatment Group
Change in measure of estimated right ventricular pressure over the 24-week study period
Time frame: Baseline to 24 weeks
Population: Sixteen subjects at Stanford University were enrolled as an initial safety cohort, and their data was used to evaluate the potential for NAC to cause PH in CF subjects. 1 subject in NAC cohort has missing data. It was not imputed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Drug | Change in ECHO Tricuspid Regurgitation (mm Hg) Over Time by Treatment Group | 31.5 mm Hg | Standard Deviation 6.02 |
| Placebo | Change in ECHO Tricuspid Regurgitation (mm Hg) Over Time by Treatment Group | 31.75 mm Hg | Standard Deviation 5.84 |