Chronic Obstructive Pulmonary Disease
Conditions
Brief summary
This study will test whether daily use of azithromycin will reduce the rate of exacerbations and improve lung ventilation and perfusion assessed by XE-MRI. The sensitivity of XE-MRI to detect COPD progression will be compared with standard clinical assessment measures including standard lung function tests, 6 minute walk test, and patient reported quality of life.
Interventions
DRUGAzithromycin
Azithromycin will be administered orally.
OTHERHP xenon (¹²⁹XE)
HP xenon (¹²⁹XE) will be administered at specified timepoints and the total dose bag volume should target 20% of the patient's forced vital capacity followed by a breath hold of up to 15 seconds
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a multicenter, open-label, parallel group, randomized controlled trial (RCT).
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Current or former smokers with years ≥ 10 pack years * mMRC dyspnea score \> 1 * Post-bronchodilator FEV-1/forced vital capacity (FVC) \<0.70 at Visit 1 or Visit 2 * Cohort A: GOLD Stage 2-4 COPD with a history of ≥ 2 moderate/severe exacerbations within a 12-month period in the 24 months prior to screening * Cohort B: GOLD Stage 1 COPD with a history of ≥1 moderate/severe exacerbations within a 12-month period in the 24 months prior to screening * Receiving SOC background drug therapy as per GOLD or British Thoracic Society (BTS) guidance for COPD for 12 weeks prior to screening Visit 1 * On an eligible bronchodilator medication (LABA ± LAMA) ± ICS therapy for ≥12 weeks prior to Visit 1 * Chest X-ray or CT scan within 6 months prior to Visit 1, or during the screening period (prior to Visit 2), that confirms the absence of clinically significant lung disease besides COPD * Use of contraceptive measures
Exclusion criteria
* Diagnosis of significant respiratory disease other than COPD * Comorbid conditions that may interfere with the evaluation of an investigational medical product * Known sensitivity or allergy to azithromycin * A COPD exacerbation and or pneumonia within 4 weeks prior to Visit 1 * Use of systemic corticosteroids within 4 weeks (oral or intravenous) or within 12 weeks (intramuscular IM) prior to screening Visit 1 * MRI is contraindicated * Any known arrhythmia, bradycardia or severe cardiac insufficiency * Participant can not hold breath for 15 seconds * Participant does not fit in the ¹²⁹XE vest coil used for MRI * Pregnant, lactating, or intending to become pregnant during the study or within 4 weeks after the last dose of the investigational medical product * History or evidence of substance abuse that would pose a risk to participants safety, interfere with the conduct of the study, or have an impact on the study results * For participants in Cohort A: Known significant hearing impairment as indicated by a score of ≥ 26 on the Hearing Handicap Inventory in the Elderly-Screening Questionnaire or as determined by the investigator * History of Clostridium difficile (C. difficile) diarrhea Clinically significant ECG changes, which in the opinion of investigator warrants further investigation or with a QTc interval \> 450 ms
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in 129Xenon (129Xe) Magnetic Resonance Imaging (MRI) Ventilation Defect Percentage (VDP) From Baseline to Week 24 | Baseline up to Week 24 | Hyperpolarized 129Xe gas was administered to the participants at specified timepoints. MRI using hyperpolarized 129Xe was used for 3D mapping of ventilation and gas distribution in the alveolar space and its uptake in interstitial barrier tissues as well as its transfer to red blood cells. Positive change from baseline indicated worse outcomes. |
| Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over 48 Weeks | Baseline up to Week 48 | A moderate COPD exacerbation was defined as new or increased COPD symptoms (e.g., dyspnea, sputum volume, and sputum purulence) for at least 2 consecutive days that led to treatment with systemic corticosteroids and/or antibiotics. A severe COPD exacerbation was defined as new or increased COPD symptoms (e.g., dyspnea, sputum volume, and sputum purulence) for at least 2 consecutive days that led to hospitalization or death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AE) With Severity Determined According To The World Health Organization (WHO) Toxicity Scale | Baseline up to Week 52 | An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptoms, or disease temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. The WHO toxicity grading scale was used for assessing adverse event severity. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening; Grade 5: death. There were no participants with grade 5 AEs. Participants were counted once at their highest AE reported. |
| Change in 129Xe MRI VDP From Baseline to Week 48 | Baseline to Week 48 | Hyperpolarized 129Xe gas was administered to the participants at specified timepoints. MRI using hyperpolarized 129Xe was used for 3D mapping of ventilation and gas distribution in the alveolar space and its uptake in interstitial barrier tissues as well as its transfer to red blood cells. Positive change from baseline indicated worse outcomes. |
| Change in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1, Liters) From Baseline to Week 24 and Week 48 | Baseline to Week 24 and Week 48 | FEV1 is the volume of air (in liters) exhaled in the first second during forced exhalation after maximal inspiration. Positive change from baseline indicated better outcomes. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A Open-label: Azithromycin + SOC Therapy Participants received azithromycin and SOC therapy for 52 weeks. | 3 |
| Arm A Open-label: SOC Therapy Participants received SOC therapy for 52 weeks. | 5 |
| Arm B Observational: SOC Therapy Participants received SOC therapy for 52 weeks. | 4 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Study termination by the Sponsor | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Arm A Open-label: Azithromycin + SOC Therapy | Arm A Open-label: SOC Therapy | Arm B Observational: SOC Therapy | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 3 Participants | 2 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 5 Participants | 4 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 5 | 0 / 4 |
| other Total, other adverse events | 3 / 3 | 5 / 5 | 2 / 4 |
| serious Total, serious adverse events | 1 / 3 | 2 / 5 | 2 / 4 |
Outcome results
Primary
Change in 129Xenon (129Xe) Magnetic Resonance Imaging (MRI) Ventilation Defect Percentage (VDP) From Baseline to Week 24
Hyperpolarized 129Xe gas was administered to the participants at specified timepoints. MRI using hyperpolarized 129Xe was used for 3D mapping of ventilation and gas distribution in the alveolar space and its uptake in interstitial barrier tissues as well as its transfer to red blood cells. Positive change from baseline indicated worse outcomes.
Time frame: Baseline up to Week 24
Population: ITT population. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A Open-label: Azithromycin + SOC Therapy | Change in 129Xenon (129Xe) Magnetic Resonance Imaging (MRI) Ventilation Defect Percentage (VDP) From Baseline to Week 24 | 6.33 ventilation defect percentage | Standard Deviation 12.7 |
| Arm A Open-label: SOC Therapy | Change in 129Xenon (129Xe) Magnetic Resonance Imaging (MRI) Ventilation Defect Percentage (VDP) From Baseline to Week 24 | -1.75 ventilation defect percentage | Standard Deviation 5.12 |
| Arm B Observational : SOC Therapy | Change in 129Xenon (129Xe) Magnetic Resonance Imaging (MRI) Ventilation Defect Percentage (VDP) From Baseline to Week 24 | -1.00 ventilation defect percentage | Standard Deviation 7.07 |
Primary
Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over 48 Weeks
A moderate COPD exacerbation was defined as new or increased COPD symptoms (e.g., dyspnea, sputum volume, and sputum purulence) for at least 2 consecutive days that led to treatment with systemic corticosteroids and/or antibiotics. A severe COPD exacerbation was defined as new or increased COPD symptoms (e.g., dyspnea, sputum volume, and sputum purulence) for at least 2 consecutive days that led to hospitalization or death.
Time frame: Baseline up to Week 48
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A Open-label: Azithromycin + SOC Therapy | Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over 48 Weeks | 1.41 exacerbations per year | Standard Deviation 1.7 |
| Arm A Open-label: SOC Therapy | Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over 48 Weeks | 1.06 exacerbations per year | Standard Deviation 1.11 |
| Arm B Observational : SOC Therapy | Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over 48 Weeks | 0.23 exacerbations per year | Standard Deviation 0.47 |
Secondary
Change in 129Xe MRI VDP From Baseline to Week 48
Hyperpolarized 129Xe gas was administered to the participants at specified timepoints. MRI using hyperpolarized 129Xe was used for 3D mapping of ventilation and gas distribution in the alveolar space and its uptake in interstitial barrier tissues as well as its transfer to red blood cells. Positive change from baseline indicated worse outcomes.
Time frame: Baseline to Week 48
Population: ITT Population. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A Open-label: Azithromycin + SOC Therapy | Change in 129Xe MRI VDP From Baseline to Week 48 | 0.50 ventilation defect percentage | Standard Deviation 6.36 |
| Arm A Open-label: SOC Therapy | Change in 129Xe MRI VDP From Baseline to Week 48 | -6.00 ventilation defect percentage | Standard Deviation 9.85 |
| Arm B Observational : SOC Therapy | Change in 129Xe MRI VDP From Baseline to Week 48 | -4.67 ventilation defect percentage | Standard Deviation 7.77 |
Secondary
Change in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1, Liters) From Baseline to Week 24 and Week 48
FEV1 is the volume of air (in liters) exhaled in the first second during forced exhalation after maximal inspiration. Positive change from baseline indicated better outcomes.
Time frame: Baseline to Week 24 and Week 48
Population: ITT Population. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analyses at the specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A Open-label: Azithromycin + SOC Therapy | Change in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1, Liters) From Baseline to Week 24 and Week 48 | Change from Baseline at Week 48 | 0.19 liters | — |
| Arm A Open-label: Azithromycin + SOC Therapy | Change in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1, Liters) From Baseline to Week 24 and Week 48 | Change from Baseline at Week 24 | 0.15 liters | — |
| Arm A Open-label: SOC Therapy | Change in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1, Liters) From Baseline to Week 24 and Week 48 | Change from Baseline at Week 24 | -0.01 liters | Standard Deviation 0.21 |
| Arm A Open-label: SOC Therapy | Change in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1, Liters) From Baseline to Week 24 and Week 48 | Change from Baseline at Week 48 | -0.03 liters | Standard Deviation 0.17 |
| Arm B Observational : SOC Therapy | Change in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1, Liters) From Baseline to Week 24 and Week 48 | Change from Baseline at Week 24 | -0.12 liters | Standard Deviation 0.04 |
| Arm B Observational : SOC Therapy | Change in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1, Liters) From Baseline to Week 24 and Week 48 | Change from Baseline at Week 48 | -0.26 liters | Standard Deviation 0.14 |
Secondary
Number of Participants With Adverse Events (AE) With Severity Determined According To The World Health Organization (WHO) Toxicity Scale
An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptoms, or disease temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. The WHO toxicity grading scale was used for assessing adverse event severity. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening; Grade 5: death. There were no participants with grade 5 AEs. Participants were counted once at their highest AE reported.
Time frame: Baseline up to Week 52
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A Open-label: Azithromycin + SOC Therapy | Number of Participants With Adverse Events (AE) With Severity Determined According To The World Health Organization (WHO) Toxicity Scale | Grade 1 | 0 Number of Participants |
| Arm A Open-label: Azithromycin + SOC Therapy | Number of Participants With Adverse Events (AE) With Severity Determined According To The World Health Organization (WHO) Toxicity Scale | Grade 2 | 1 Number of Participants |
| Arm A Open-label: Azithromycin + SOC Therapy | Number of Participants With Adverse Events (AE) With Severity Determined According To The World Health Organization (WHO) Toxicity Scale | Grade 3 | 1 Number of Participants |
| Arm A Open-label: Azithromycin + SOC Therapy | Number of Participants With Adverse Events (AE) With Severity Determined According To The World Health Organization (WHO) Toxicity Scale | Grade 4 | 1 Number of Participants |
| Arm A Open-label: SOC Therapy | Number of Participants With Adverse Events (AE) With Severity Determined According To The World Health Organization (WHO) Toxicity Scale | Grade 4 | 2 Number of Participants |
| Arm A Open-label: SOC Therapy | Number of Participants With Adverse Events (AE) With Severity Determined According To The World Health Organization (WHO) Toxicity Scale | Grade 1 | 1 Number of Participants |
| Arm A Open-label: SOC Therapy | Number of Participants With Adverse Events (AE) With Severity Determined According To The World Health Organization (WHO) Toxicity Scale | Grade 3 | 1 Number of Participants |
| Arm A Open-label: SOC Therapy | Number of Participants With Adverse Events (AE) With Severity Determined According To The World Health Organization (WHO) Toxicity Scale | Grade 2 | 1 Number of Participants |
| Arm B Observational : SOC Therapy | Number of Participants With Adverse Events (AE) With Severity Determined According To The World Health Organization (WHO) Toxicity Scale | Grade 4 | 1 Number of Participants |
| Arm B Observational : SOC Therapy | Number of Participants With Adverse Events (AE) With Severity Determined According To The World Health Organization (WHO) Toxicity Scale | Grade 2 | 1 Number of Participants |
| Arm B Observational : SOC Therapy | Number of Participants With Adverse Events (AE) With Severity Determined According To The World Health Organization (WHO) Toxicity Scale | Grade 3 | 1 Number of Participants |
| Arm B Observational : SOC Therapy | Number of Participants With Adverse Events (AE) With Severity Determined According To The World Health Organization (WHO) Toxicity Scale | Grade 1 | 0 Number of Participants |