Idiopathic Pulmonary Fibrosis
Conditions
Keywords
idiopathic pulmonary fibrosis, IPF, pulmonary fibrosis, carbon monoxide
Brief summary
The purpose of this study is to determine whether low concentration inhaled carbon monoxide is effective in treating idiopathic pulmonary fibrosis.
Detailed description
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by destruction of normal epithelial structure, proliferation of fibroblasts, and deposition of connective-tissue matrix proteins. There are currently no effective therapies for IPF. Over the past two decades, preclinical studies of inhaled low dose carbon monoxide (CO) have shown that this biologically active diatomic gas possesses properties that would make it a viable novel therapy for IPF. CO therapy has been well tolerated in Phase I and Phase II human trials to date. This phase II study is designed to investigate whether IPF patients show evidence of decreased peripheral blood levels of matrix metalloproteinase-7 (MMP7) and stability of secondary indicators of disease progression after 3 months of inhaled therapy.
Interventions
The intervention will be inhaled CO at 100-200 ppm administered two times weekly for two hours per dose to complete 12 weeks of treatment.
OTHEROxygen
Room air oxygen concentrations will be administered as placebo
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of California, San Francisco
University of Chicago
University of Illinois at Chicago
University of Michigan
Columbia University
Tulane University
University of Washington
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Adults above the age of 18 and equal to or below the age of 85 * Diagnosis of IPF by biopsy or * American Thoracic Society (ATS)/European Respiratory Society (ERS)/ Latin American Thoracic Association (ALAT) Guidelines (Am J Respir Crit Care Med Vol 183. pp 788-824,2011) * Forced vital capacity (FVC) greater than or equal to 50% predicted, greater than or equal to one month off all medications prescribed for IPF
Exclusion criteria
* Evidence of active infection within the last month * Significant obstructive respiratory defect * Supplemental oxygen required to maintain an oxygen saturation over 88% at rest * History of myocardial infarction within the last year, heart failure within the last 3 years or cardiac arrhythmia requiring drug therapy * History of smoking within 4 weeks of screening * Pregnancy or lactation * Participation in another therapeutic clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum MMP7 Level | Baseline to Week 12 | The primary study endpoint was the change in MMP7 serum concentration (ng/ml) from baseline to 12 weeks. Serum MMP7 concentrations in peripheral blood are easily measureable and reflect changes in the alveolar microenvironment. Thus, we have chosen to study mean serum MMP7 concentrations after three months of CO treatment as a surrogate biomarker of the effect of inhaled CO administration on disease progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Lung Capacity % Predicted Values (TLC) | Baseline to Week 12 | Total lung capacity % predicted values (TLC) is a major clinical determinant of restrictive lung disease in practice, with TLC measurement below the 5th percentile of the predicted value indicative of a restrictive ventilatory defect |
| Diffusing Capacity for Carbon Monoxide (DLCO) % Predicted Values | Baseline to Week 12 | Interstitial changes associated with IPF can worsen diffusing capabilities across the alveolar-capillary membrane. As a result, diffusing capacity of carbon monoxide is an important outcome to assess architectural distortion and resultant decrements in diffusing capabilities |
| Six Minute Walk Distance | Baseline to Week 12 | The six minute walk distance is commonly used both in research studies and in clinical practice as a measure of functional capabilities, and changes in six minute walk distance and oxygen use during testing over time often reflect clinically relevant disease progression. We will measure the distance travelled during six minutes (meters) in accordance with published guidelines |
| St George's Respiratory Questionnaire | Baseline to Week 12 | St. George's Respiratory Questionnaire (SGRQ) is a validated self-reported instrument. In this instrument, scores range from 0 to 100, with higher scores reflective of worse quality of life. |
Countries
United States
Participant flow
Recruitment details
The enrollment period opened on 11/29/2011 and was closed on 1/10/2014 when the study reached its enrollment target of 58 subjects. Subjects were enrolled at 8 participating academic medical centers.
Pre-assignment details
Sixty-five subjects were screened, of which 7 subjects were screen failures. Reasons for screen failure included subjects who completed screening changed their mind about participation before visit 2, FEV1/FVC less than 70% predicted, and infection within 1 month before screening. The screening period up to 28 days from date of consent to Visit 2.
Participants by arm
| Arm | Count |
|---|---|
| Carbon Monoxide Inhalation The primary intervention will be inhaled CO at 100-200 ppm administered two times weekly for two hours per dose to complete 12 weeks of treatment.
inhaled carbon monoxide: The intervention will be inhaled CO at 100-200 ppm administered two times weekly for two hours per dose to complete 12 weeks of treatment. | 29 |
| Oxygen 21% Oxygen: Room air oxygen concentrations will be administered as placebo | 29 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 2 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | Carbon Monoxide Inhalation | Total | Oxygen 21% |
|---|---|---|---|
| Age, Continuous | 66.6 years STANDARD_DEVIATION 6.1 | 68 years STANDARD_DEVIATION 7 | 68.6 years STANDARD_DEVIATION 8.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 55 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 29 participants | 58 participants | 29 participants |
| Sex: Female, Male Female | 4 Participants | 11 Participants | 7 Participants |
| Sex: Female, Male Male | 25 Participants | 47 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 28 / 29 | 19 / 29 |
| serious Total, serious adverse events | 3 / 29 | 7 / 29 |
Outcome results
Primary
Serum MMP7 Level
The primary study endpoint was the change in MMP7 serum concentration (ng/ml) from baseline to 12 weeks. Serum MMP7 concentrations in peripheral blood are easily measureable and reflect changes in the alveolar microenvironment. Thus, we have chosen to study mean serum MMP7 concentrations after three months of CO treatment as a surrogate biomarker of the effect of inhaled CO administration on disease progression.
Time frame: Baseline to Week 12
Population: One subject randomized to placebo withdrew consent prior to the MMP7 blood draw at visit 2. This is missing data and the reason why we have n=28 for placebo group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Carbon Monoxide Inhalation | Serum MMP7 Level | -0.15 ng/ml | Standard Error 0.58 |
| Oxygen 21% | Serum MMP7 Level | 0.88 ng/ml | Standard Error 0.57 |
p-value: 0.2072ANOVA
Secondary
Diffusing Capacity for Carbon Monoxide (DLCO) % Predicted Values
Interstitial changes associated with IPF can worsen diffusing capabilities across the alveolar-capillary membrane. As a result, diffusing capacity of carbon monoxide is an important outcome to assess architectural distortion and resultant decrements in diffusing capabilities
Time frame: Baseline to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Carbon Monoxide Inhalation | Diffusing Capacity for Carbon Monoxide (DLCO) % Predicted Values | 1.10 % predicted | Standard Error 1.41 |
| Oxygen 21% | Diffusing Capacity for Carbon Monoxide (DLCO) % Predicted Values | 0.46 % predicted | Standard Error 1.32 |
p-value: 0.7401ANOVA
Secondary
Six Minute Walk Distance
The six minute walk distance is commonly used both in research studies and in clinical practice as a measure of functional capabilities, and changes in six minute walk distance and oxygen use during testing over time often reflect clinically relevant disease progression. We will measure the distance travelled during six minutes (meters) in accordance with published guidelines
Time frame: Baseline to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Carbon Monoxide Inhalation | Six Minute Walk Distance | -35.54 meters | Standard Error 12.83 |
| Oxygen 21% | Six Minute Walk Distance | 12.92 meters | Standard Error 12.83 |
p-value: 0.0099ANOVA
Secondary
St George's Respiratory Questionnaire
St. George's Respiratory Questionnaire (SGRQ) is a validated self-reported instrument. In this instrument, scores range from 0 to 100, with higher scores reflective of worse quality of life.
Time frame: Baseline to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Carbon Monoxide Inhalation | St George's Respiratory Questionnaire | -2.12 Total Score | Standard Error 1.7 |
| Oxygen 21% | St George's Respiratory Questionnaire | -1.55 Total Score | Standard Error 1.72 |
p-value: 0.8124ANOVA
Secondary
Total Lung Capacity % Predicted Values (TLC)
Total lung capacity % predicted values (TLC) is a major clinical determinant of restrictive lung disease in practice, with TLC measurement below the 5th percentile of the predicted value indicative of a restrictive ventilatory defect
Time frame: Baseline to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Carbon Monoxide Inhalation | Total Lung Capacity % Predicted Values (TLC) | -2.29 % Predicted | Standard Error 1.12 |
| Oxygen 21% | Total Lung Capacity % Predicted Values (TLC) | -1.44 % Predicted | Standard Error 1.1 |
p-value: 0.5882ANOVA