COPD
Conditions
Keywords
Exacerbation of COPD, Unstable COPD
Brief summary
The primary objective of this study is to evaluate the effect of 12 weeks of treatment with once daily administration of AQX-1125 compared to placebo in subjects following exacerbations of Chronic Obstructive Pulmonary Disease (COPD) by targeting the SHIP1 (Src Homology 2-containing Inositol-5'-Phosphatase 1) pathway.
Detailed description
Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of morbidity and mortality worldwide. Acute exacerbations of COPD are usually treated with steroids and/or antibiotics. Currently this conventional therapy has significant side effects including osteoporosis, cataracts and suppression of the immune system (from the steroids) and increasing bacterial resistance and other side effects from the use of antibiotics. During an acute exacerbation of COPD, the inflammation in the airways increases. AQX-1125 represents a new type drug that based current data is thought decrease the inflammatory process and therefore may provide a therapeutic benefit in the treatment of COPD.
Interventions
DRUGAQX-1125
Synthetic SHIP1 activator
DRUGPlacebo
Placebo control
Sponsors
Aquinox Pharmaceuticals (Canada) Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female aged ≥40 years at screening 2. History of COPD for at least 18 months prior to screening, characterised by excessive sputum production 3. Chronic productive cough for at least 3 months in each of the 2 years prior to screening (if other causes of productive cough have been excluded) and/or an exacerbation of COPD with predominantly bronchitic symptoms at enrolment 4. At least 2 documented exacerbations during the last 18 months prior to screening. 5. Presentation of a diagnosed acute exacerbation of COPD, or have recently (within 3 days) been discharged from hospital due to an acute exacerbation of COPD 6. Ability to perform pulmonary function testing and with documented fixed airway obstruction determined by an FEV1 /FVC \[forced vital capacity\] ratio (post-bronchodilator) of \<0.70 and a predicted FEV1 value of 30%-80% of normal within the 6 months prior to Visit 1. 7. Former smoker or current smoker, both with a smoking history of at least 10 pack years
Exclusion criteria
1. Diagnosis of other relevant lung disease (e.g. asthma, cystic fibrosis \[CF\] or significant non-CF bronchiectasis) 2. Known alpha-1-antitrypsin deficiency 3. Treatment with roflumilast or theophylline within 1 month prior to screening 4. Lobar pneumonia, with current positive chest X-ray (CXR) or within the 3 months prior to screening including the presence of any new radiological infiltrate on CXR within the previous two weeks 5. Hospitalisation for more than 7 days for current acute exacerbation, or the requirement for intubation during hospitalisation 6. For outpatients, prior medical history indicating that previous exacerbations required \>3 weeks to stabilise
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Efficacy Variable Was the AAC for Daily EXACT Scores During the 12-week Treatment Period. | 12 weeks | The primary variable (endpoint) of this study is the difference in the Area Above the Curve (AAC) for the daily EXACT score from baseline to Week 12 between subjects treated with AQX-1125 and placebo.The EXACT questionnaire is a patient reported outcome (PRO) measure designed to standardise the method for evaluating the frequency, severity and duration of acute exacerbations of COPD. The EXACT is a 14-item daily questionnaire where each item is assessed on a 5 or 6 point ordinal scale. Participants completed the EXACT questionnaire on a daily basis via an electronic diary from Day 1 (pre-dose) to Day 84 (week 12). Higher scores on the daily EXACT questionnaire indicate a more severe health state. When the post-treatment EXACT scores are lower (i.e. improved symptoms) than baseline EXACT, the AACs are positive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Analysis of the Number of COPD Exacerbations (Medically Treated Event (MTE)) | 12 weeks | The secondary objective is to evaluate the treatment effect of once daily administrations of AQX-1125 compared to placebo over 12 weeks on the number of COPD exacerbations (MTE). COPD exacerbations were referred to as Medically Treated Exacerbations (MTEs) and identified as a change in symptoms and/or signs of COPD requiring prescription of one or both of: (1) Course of oral corticosteroids or (2) Antibiotic(s). |
| Time to First COPD Exacerbation | 12 weeks | The secondary objective is to evaluate the treatment effect of once daily administrations of AQX-1125 compared to placebo over 12 weeks on the time to first exacerbation requiring medical intervention of oral corticosteroids and/or antibiotics. |
| Change From Baseline in COPD Assessment Tool (CAT) Score | 12 weeks | The secondary objective is to evaluate the treatment effect of once daily administrations of AQX-1125 compared to placebo over 12 weeks on the COPD Assessment Tool (CAT) score.The CAT questionnaire measures the impact of COPD on wellbeing and daily life. Participants answer 8 questions on a scale from 0 (best) to 5 (worst). The total score ranges from 0 to 40 with higher scores indicating more impact. A negative change from baseline indicates improvement. The change in total CAT score from Day 1, before taking study drug (baseline), to end of the 12 week treatment period was compared between the two treatments using an ANOVA model adjusting for treatment and region and including the baseline score as a covariate. |
| Change From Baseline in FEV1 | 12 weeks | The secondary objective is to evaluate the treatment effect of once daily administrations of AQX-1125 compared to placebo over 12 weeks on forced expiratory volume in 1 second \[FEV1\]. FEV1 was determined from post-bronchodilator spirometry testing done at clinic visits. |
| AQX-1125 Concentrations in Plasma (Trough Values) | 12 weeks | The secondary objectives are to evaluate the pharmacokinetics (PK) of AQX-1125 in plasma. |
| The Number of Subjects With at Least One COPD Exacerbation. | 12 weeks | The number of subjects that presented with a COPD exacerbation during the 12 week treatment period. |
Countries
Australia, Denmark, Finland, Hungary, New Zealand, Poland, Sweden, United States
Participant flow
Recruitment details
The study was conducted in 8 countries: Australia, Denmark, Finland, Hungary, New Zealand, Poland, Sweden and US. US subjects participating in 6 month safety follow-up continued in the study until November 2015.
Pre-assignment details
Four hundred subjects were randomized into two subsets: (1) Subjects suitable for outpatient treatment of a current exacerbation of COPD (within 3 days of diagnosis) & (2) Subjects who had been hospitalized in order to treat their exacerbation for not more than 7 days & were ready to be discharged or had been discharged within the last 3 days.
Participants by arm
| Arm | Count |
|---|---|
| AQX-1125 (200 mg) 1 x AQX-1125 capsule daily
AQX-1125: Synthetic SHIP1 activator | 200 |
| Placebo 1 x Placebo capsule daily
Placebo: Placebo control | 200 |
| Total | 400 |
Baseline characteristics
| Characteristic | Total | Placebo | AQX-1125 (200 mg) |
|---|---|---|---|
| Age, Continuous | 65.1 years STANDARD_DEVIATION 8.4 | 64.4 years STANDARD_DEVIATION 8.5 | 65.8 years STANDARD_DEVIATION 8.2 |
| Body Mass Index | 27.6 kg/m2 STANDARD_DEVIATION 6.3 | 27.2 kg/m2 STANDARD_DEVIATION 6.1 | 28.1 kg/m2 STANDARD_DEVIATION 6.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 386 Participants | 193 Participants | 193 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 4 Participants | 3 Participants |
| Nicotine Replacement Therapy Use No | 9 participants | 5 participants | 4 participants |
| Nicotine Replacement Therapy Use Yes | 391 participants | 195 participants | 196 participants |
| Number of COPD Exacerbations in Last 18 months | 3.1 number of exacerbations/18 months STANDARD_DEVIATION 1.5 | 3.0 number of exacerbations/18 months STANDARD_DEVIATION 1.4 | 3.1 number of exacerbations/18 months STANDARD_DEVIATION 1.7 |
| Number of Previous Hospitalizations for COPD | 1.0 number of previous hospitlizations STANDARD_DEVIATION 2.4 | 0.9 number of previous hospitlizations STANDARD_DEVIATION 1.6 | 1.1 number of previous hospitlizations STANDARD_DEVIATION 3 |
| Post-bronchodilator FEV1/FVC Ratio | 0.52 ratio STANDARD_DEVIATION 0.11 | 0.52 ratio STANDARD_DEVIATION 0.11 | 0.51 ratio STANDARD_DEVIATION 0.11 |
| Post-bronchodilator FEV1% of Predicted | 50.6 percent predicted STANDARD_DEVIATION 13.5 | 50.9 percent predicted STANDARD_DEVIATION 13.2 | 50.2 percent predicted STANDARD_DEVIATION 13.9 |
| 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 | 20 Participants | 9 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 2 Participants | 1 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 | 377 Participants | 189 Participants | 188 Participants |
| Region of Enrollment Australia | 16 participants | 9 participants | 7 participants |
| Region of Enrollment Denmark | 26 participants | 13 participants | 13 participants |
| Region of Enrollment Finland | 8 participants | 3 participants | 5 participants |
| Region of Enrollment Hungary | 83 participants | 43 participants | 40 participants |
| Region of Enrollment New Zealand | 6 participants | 3 participants | 3 participants |
| Region of Enrollment Poland | 156 participants | 75 participants | 81 participants |
| Region of Enrollment Sweden | 1 participants | 1 participants | 0 participants |
| Region of Enrollment United States | 104 participants | 53 participants | 51 participants |
| Sex: Female, Male Female | 190 Participants | 91 Participants | 99 Participants |
| Sex: Female, Male Male | 210 Participants | 109 Participants | 101 Participants |
| Smoking Pack Years | 40.7 pYears STANDARD_DEVIATION 21.4 | 41.2 pYears STANDARD_DEVIATION 20.9 | 40.2 pYears STANDARD_DEVIATION 22 |
| Smoking Status Current Smokers | 172 participants | 103 participants | 69 participants |
| Smoking Status Former Smoker | 228 participants | 97 participants | 131 participants |
| Years Since COPD Diagnosis | 8.0 years STANDARD_DEVIATION 5.8 | 7.8 years STANDARD_DEVIATION 5.9 | 8.2 years STANDARD_DEVIATION 5.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 200 | 1 / 200 |
| other Total, other adverse events | 21 / 200 | 21 / 200 |
| serious Total, serious adverse events | 6 / 200 | 12 / 200 |
Outcome results
Primary
The Primary Efficacy Variable Was the AAC for Daily EXACT Scores During the 12-week Treatment Period.
The primary variable (endpoint) of this study is the difference in the Area Above the Curve (AAC) for the daily EXACT score from baseline to Week 12 between subjects treated with AQX-1125 and placebo.The EXACT questionnaire is a patient reported outcome (PRO) measure designed to standardise the method for evaluating the frequency, severity and duration of acute exacerbations of COPD. The EXACT is a 14-item daily questionnaire where each item is assessed on a 5 or 6 point ordinal scale. Participants completed the EXACT questionnaire on a daily basis via an electronic diary from Day 1 (pre-dose) to Day 84 (week 12). Higher scores on the daily EXACT questionnaire indicate a more severe health state. When the post-treatment EXACT scores are lower (i.e. improved symptoms) than baseline EXACT, the AACs are positive.
Time frame: 12 weeks
Population: Full Analysis Set (FAS). The FAS was all randomized subjects who have received at least one dose of the study drug and had at least one efficacy assessment (valid diary entries) post-baseline. Imputation, the mean of the last 5 days, counted backwards from day of last recording, in the treatment period will be used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AQX-1125 (200mg) | The Primary Efficacy Variable Was the AAC for Daily EXACT Scores During the 12-week Treatment Period. | 415.4 Area Above Curve on Daily Exact Score |
| Placebo | The Primary Efficacy Variable Was the AAC for Daily EXACT Scores During the 12-week Treatment Period. | 391.7 Area Above Curve on Daily Exact Score |
Comparison: Sample size based on area above the daily EXACT score curve (AAC) from Day 1 to Day 29 from subjects with an acute COPD exacerbation, collected over 28 days. Assuming a residual SD of 500 points, a sample size of 200 subjects per arm would be expected to have an 80% power to detect a true treatment difference in the AAC of 140 points over 12-weeks treatment, using a 2-sided test; alpha-level of 0.05.This difference corresponds to a mean daily improvement of 1.67 points on the EXACT symptom scorep-value: 0.75995% CI: [-128.3, 175.7]ANOVA
Secondary
Analysis of the Number of COPD Exacerbations (Medically Treated Event (MTE))
The secondary objective is to evaluate the treatment effect of once daily administrations of AQX-1125 compared to placebo over 12 weeks on the number of COPD exacerbations (MTE). COPD exacerbations were referred to as Medically Treated Exacerbations (MTEs) and identified as a change in symptoms and/or signs of COPD requiring prescription of one or both of: (1) Course of oral corticosteroids or (2) Antibiotic(s).
Time frame: 12 weeks
Population: Full analysis set was used and analyzed using the negative binomial regression model with fixed factors treatment, region and time in study as offset. Adjusted means for treatment group shows number of exacerbations/year.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AQX-1125 (200mg) | Analysis of the Number of COPD Exacerbations (Medically Treated Event (MTE)) | 1.776 Number of exacerbations/year |
| Placebo | Analysis of the Number of COPD Exacerbations (Medically Treated Event (MTE)) | 1.641 Number of exacerbations/year |
Comparison: The number of subjects with at least one COPD exacerbation were summarised by treatment group.p-value: 0.64695% CI: [0.771, 1.52]Negative binomial regression model
Secondary
AQX-1125 Concentrations in Plasma (Trough Values)
The secondary objectives are to evaluate the pharmacokinetics (PK) of AQX-1125 in plasma.
Time frame: 12 weeks
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AQX-1125 (200mg) | AQX-1125 Concentrations in Plasma (Trough Values) | 170.1 micrograms per Liter | Geometric Coefficient of Variation 70.5 |
| Placebo | AQX-1125 Concentrations in Plasma (Trough Values) | 163.9 micrograms per Liter | Geometric Coefficient of Variation 74.5 |
| AQX-1125 Week 12 | AQX-1125 Concentrations in Plasma (Trough Values) | 120.5 micrograms per Liter | Geometric Coefficient of Variation 80 |
Secondary
Change From Baseline in COPD Assessment Tool (CAT) Score
The secondary objective is to evaluate the treatment effect of once daily administrations of AQX-1125 compared to placebo over 12 weeks on the COPD Assessment Tool (CAT) score.The CAT questionnaire measures the impact of COPD on wellbeing and daily life. Participants answer 8 questions on a scale from 0 (best) to 5 (worst). The total score ranges from 0 to 40 with higher scores indicating more impact. A negative change from baseline indicates improvement. The change in total CAT score from Day 1, before taking study drug (baseline), to end of the 12 week treatment period was compared between the two treatments using an ANOVA model adjusting for treatment and region and including the baseline score as a covariate.
Time frame: 12 weeks
Population: Full analysis set. Missing post-treatment data imputed using the last observation carried forward principle.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AQX-1125 (200mg) | Change From Baseline in COPD Assessment Tool (CAT) Score | -4.05 COPD Assessment Tool Score |
| Placebo | Change From Baseline in COPD Assessment Tool (CAT) Score | -3.71 COPD Assessment Tool Score |
Comparison: ANOVA model with fixed factors treatment, region and baseline total CAT score as covariate were used. Missing post-treatment data were imputed using the Last Observation Carried Forward principle.p-value: 0.58895% CI: [-1.57, 0.89]ANOVA
Secondary
Change From Baseline in FEV1
The secondary objective is to evaluate the treatment effect of once daily administrations of AQX-1125 compared to placebo over 12 weeks on forced expiratory volume in 1 second \[FEV1\]. FEV1 was determined from post-bronchodilator spirometry testing done at clinic visits.
Time frame: 12 weeks
Population: Full analysis set. Missing post-treatment data imputed using the last observation carried forward principle.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AQX-1125 (200mg) | Change From Baseline in FEV1 | -0.02 Liter |
| Placebo | Change From Baseline in FEV1 | 0.01 Liter |
Comparison: Missing post-treatment data was imputed using the Last Observation Carried Forward principle.p-value: 0.226ANOVA
Secondary
The Number of Subjects With at Least One COPD Exacerbation.
The number of subjects that presented with a COPD exacerbation during the 12 week treatment period.
Time frame: 12 weeks
Population: Full analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AQX-1125 (200mg) | The Number of Subjects With at Least One COPD Exacerbation. | 48 participants |
| Placebo | The Number of Subjects With at Least One COPD Exacerbation. | 51 participants |
Secondary
Time to First COPD Exacerbation
The secondary objective is to evaluate the treatment effect of once daily administrations of AQX-1125 compared to placebo over 12 weeks on the time to first exacerbation requiring medical intervention of oral corticosteroids and/or antibiotics.
Time frame: 12 weeks
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AQX-1125 (200mg) | Time to First COPD Exacerbation | 38.1 day(s) | Standard Deviation 21.3 |
| Placebo | Time to First COPD Exacerbation | 43.9 day(s) | Standard Deviation 24.1 |