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Trial record 1 of 1 for:    01954628
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Efficacy and Safety of AQX-1125 in Unstable COPD (FLAGSHIP)

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ClinicalTrials.gov Identifier: NCT01954628
Recruitment Status : Completed
First Posted : October 7, 2013
Results First Posted : June 12, 2017
Last Update Posted : June 12, 2017
Sponsor:
Information provided by (Responsible Party):
Aquinox Pharmaceuticals (Canada) Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition COPD
Interventions Drug: AQX-1125
Drug: Placebo
Enrollment 400
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.
Arm/Group Title AQX-1125 (200 mg) Placebo
Hide Arm/Group Description AQX-1125 (200 mg capsule), oral once daily for 12 weeks. All standard of care treatments for COPD were permitted throughout the study with the exception of Roflumilast and Theophylline. Placebo (matching AQX-1125 capsule), oral, once daily for 12 weeks. Placebo control. All standard of care treatments for COPD were permitted throughout the study with the exception of Roflumilast and Theophylline.
Period Title: Overall Study
Started 200 200
Full Analysis Set (FAS) 200 198
Safety Set 200 200
Pharmacokinetic Population 181 0
US 6 Month Ophthalmology Safety Visit 37 32
Completed 169 173
Not Completed 31 27
Arm/Group Title AQX-1125 (200 mg) Placebo Total
Hide Arm/Group Description

1 x AQX-1125 capsule daily

AQX-1125: Synthetic SHIP1 activator

1 x Placebo capsule daily

Placebo: Placebo control

Total of all reporting groups
Overall Number of Baseline Participants 200 200 400
Hide Baseline Analysis Population Description
Safety set.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 200 participants 200 participants 400 participants
65.8  (8.2) 64.4  (8.5) 65.1  (8.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 200 participants 200 participants 400 participants
Female
99
  49.5%
91
  45.5%
190
  47.5%
Male
101
  50.5%
109
  54.5%
210
  52.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 200 participants 200 participants 400 participants
Hispanic or Latino
4
   2.0%
3
   1.5%
7
   1.8%
Not Hispanic or Latino
193
  96.5%
193
  96.5%
386
  96.5%
Unknown or Not Reported
3
   1.5%
4
   2.0%
7
   1.8%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 200 participants 200 participants 400 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
11
   5.5%
9
   4.5%
20
   5.0%
White
188
  94.0%
189
  94.5%
377
  94.3%
More than one race
1
   0.5%
2
   1.0%
3
   0.8%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 200 participants 200 participants 400 participants
New Zealand 3 3 6
Sweden 0 1 1
Hungary 40 43 83
United States 51 53 104
Finland 5 3 8
Denmark 13 13 26
Poland 81 75 156
Australia 7 9 16
Body Mass Index  
Mean (Standard Deviation)
Unit of measure:  Kg/m2
Number Analyzed 200 participants 200 participants 400 participants
28.1  (6.6) 27.2  (6.1) 27.6  (6.3)
Number of COPD Exacerbations in Last 18 months  
Mean (Standard Deviation)
Unit of measure:  Number of exacerbations/18 months
Number Analyzed 200 participants 200 participants 400 participants
3.1  (1.7) 3.0  (1.4) 3.1  (1.5)
Number of Previous Hospitalizations for COPD  
Mean (Standard Deviation)
Unit of measure:  Number of previous hospitlizations
Number Analyzed 200 participants 200 participants 400 participants
1.1  (3.0) 0.9  (1.6) 1.0  (2.4)
Years Since COPD Diagnosis  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 200 participants 200 participants 400 participants
8.2  (5.7) 7.8  (5.9) 8.0  (5.8)
Smoking Status  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 200 participants 200 participants 400 participants
Current Smokers 69 103 172
Former Smoker 131 97 228
Smoking Pack Years  
Mean (Standard Deviation)
Unit of measure:  pYears
Number Analyzed 200 participants 200 participants 400 participants
40.2  (22.0) 41.2  (20.9) 40.7  (21.4)
Nicotine Replacement Therapy Use  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 200 participants 200 participants 400 participants
Yes 196 195 391
No 4 5 9
Post-bronchodilator FEV1/FVC Ratio  
Mean (Standard Deviation)
Unit of measure:  Ratio
Number Analyzed 200 participants 200 participants 400 participants
0.51  (0.11) 0.52  (0.11) 0.52  (0.11)
Post-bronchodilator FEV1% of Predicted  
Mean (Standard Deviation)
Unit of measure:  Percent predicted
Number Analyzed 200 participants 200 participants 400 participants
50.2  (13.9) 50.9  (13.2) 50.6  (13.5)
1.Primary Outcome
Title The Primary Efficacy Variable Was the AAC for Daily EXACT Scores During the 12-week Treatment Period.
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title AQX-1125 (200mg) Placebo
Hide Arm/Group Description:
1 x AQX-1125 capsule daily
1 x Placebo capsule daily
Overall Number of Participants Analyzed 179 183
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Area Above Curve on Daily Exact Score
415.4
(290.7 to 540.1)
391.7
(268.2 to 515.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AQX-1125 (200mg), Placebo
Comments 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 score
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.759
Comments AAC were compared between treatments using an analysis of variance model adjusting for treatment and region as factors and including the baseline score as a covariate.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least sqaure mean difference
Estimated Value 23.7
Confidence Interval (2-Sided) 95%
-128.3 to 175.7
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline in COPD Assessment Tool (CAT) Score
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. Missing post-treatment data imputed using the last observation carried forward principle.
Arm/Group Title AQX-1125 (200 mg) Placebo
Hide Arm/Group Description:
1 x AQX-1125 capsule daily
1 x Placebo capsule daily
Overall Number of Participants Analyzed 179 182
Least Squares Mean (95% Confidence Interval)
Unit of Measure: COPD Assessment Tool Score
-4.05
(-5.06 to -3.04)
-3.71
(-4.71 to -2.71)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AQX-1125 (200 mg), Placebo
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.588
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least sqaure mean difference
Estimated Value -0.34
Confidence Interval (2-Sided) 95%
-1.57 to 0.89
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Analysis of the Number of COPD Exacerbations (Medically Treated Event (MTE))
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title AQX-1125 (200 mg) Placebo
Hide Arm/Group Description:
1 x AQX-1125 capsule daily
1 x Placebo capsule daily
Overall Number of Participants Analyzed 200 198
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Number of exacerbations/year
1.776
(1.374 to 2.297)
1.641
(1.261 to 2.135)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AQX-1125 (200 mg), Placebo
Comments The number of subjects with at least one COPD exacerbation were summarised by treatment group.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.646
Comments [Not Specified]
Method Negative binomial regression model
Comments Negative binomial regression model with fixed factors treatment, region and time in study as offset.
Method of Estimation Estimation Parameter Least sqaure mean difference
Estimated Value 1.083
Confidence Interval (2-Sided) 95%
0.771 to 1.520
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Time to First COPD Exacerbation
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title AQX-1125 (200 mg) Placebo
Hide Arm/Group Description:
1 x AQX-1125 capsule daily
1 x Placebo capsule daily
Overall Number of Participants Analyzed 200 198
Mean (Standard Deviation)
Unit of Measure: day(s)
38.1  (21.3) 43.9  (24.1)
5.Secondary Outcome
Title The Number of Subjects With at Least One COPD Exacerbation.
Hide Description The number of subjects that presented with a COPD exacerbation during the 12 week treatment period.
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set.
Arm/Group Title AQX-1125 (200 mg) Placebo
Hide Arm/Group Description:
1 x AQX-1125 capsule daily
1 x Placebo capsule daily
Overall Number of Participants Analyzed 200 198
Measure Type: Number
Unit of Measure: participants
48 51
6.Secondary Outcome
Title Change From Baseline in FEV1
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. Missing post-treatment data imputed using the last observation carried forward principle.
Arm/Group Title AQX-1125 (200mg) Placebo
Hide Arm/Group Description:
1 x AQX-1125 capsule daily
1 x Placebo capsule daily
Overall Number of Participants Analyzed 184 185
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Liter
-0.02
(-0.06 to 0.02)
0.01
(-0.03 to 0.06)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AQX-1125 (200mg), Placebo
Comments Missing post-treatment data was imputed using the Last Observation Carried Forward principle.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.226
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
7.Secondary Outcome
Title AQX-1125 Concentrations in Plasma (Trough Values)
Hide Description The secondary objectives are to evaluate the pharmacokinetics (PK) of AQX-1125 in plasma.
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
PK Population
Arm/Group Title AQX-1125 Week 2 AQX-1125 Week 4 AQX-1125 Week 12
Hide Arm/Group Description:
AQX-1125 Week 2 PK
AQX-1125 Week 4 PK
Week 12 PK Week 12 PK
Overall Number of Participants Analyzed 168 163 145
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: micrograms per Liter
170.1
(70.5%)
163.9
(74.5%)
120.5
(80.0%)
Time Frame 12 weeks treatment; up to 6 months safety follow-up.
Adverse Event Reporting Description SAEs listed occurred in >1 subjects per treatment arm.
 
Arm/Group Title AQX-1125 Placebo
Hide Arm/Group Description

1 x AQX-1125 capsule daily

AQX-1125: Synthetic SHIP1 activator

1 x Placebo capsule daily

Placebo: Placebo control

All-Cause Mortality
AQX-1125 Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   1/200 (0.50%)      1/200 (0.50%)    
Hide Serious Adverse Events
AQX-1125 Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/200 (3.00%)      12/200 (6.00%)    
Infections and infestations     
Pneumonia  1  3/200 (1.50%)  3 2/200 (1.00%)  2
Respiratory, thoracic and mediastinal disorders     
Chronic Obstructive Pulmonary Disease  1 [1]  1/200 (0.50%)  1 8/200 (4.00%)  9
Acute Respiratory Failure  1  2/200 (1.00%)  2 2/200 (1.00%)  2
1
Term from vocabulary, MedDRA (16.0)
Indicates events were collected by systematic assessment
[1]
COPD exacerbations occurring during the study should not have been reported as SAEs (as per protocol). However, 10 events were reported (1 in AQX-1125 group and 9 in placebo).
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
AQX-1125 Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   21/200 (10.50%)      21/200 (10.50%)    
Gastrointestinal disorders     
Diarrhoea  1  11/200 (5.50%)  13 9/200 (4.50%)  9
Nervous system disorders     
Headache  1  12/200 (6.00%)  12 13/200 (6.50%)  14
1
Term from vocabulary, MedDRA (16.0)
Indicates events were collected by systematic assessment
Secondary objective of "The frequency and severity of AEs and changes in physical exam, vital signs, ophthalmic exam, laboratory tests, weight, ECG, and con meds" was monitored throughout the study, clinically significant events were reported as AEs.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Investigators shall not publish any articles or make any presentations or communications (including any written, oral or electronic manuscript, abstract, presentation or other publication) relating to the Services, Sponsor Information, Study Drug or other Material, Deliverables or other Developments, in whole or part, without the prior written consent of the Sponsor.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Clinical
Organization: Aquinox Pharmaceuticals (Canada) Inc.
Phone: +1 (604) 629-9223
EMail: clinical@aqxpharma.com
Layout table for additonal information
Responsible Party: Aquinox Pharmaceuticals (Canada) Inc.
ClinicalTrials.gov Identifier: NCT01954628    
Other Study ID Numbers: AQX-1125-202
First Submitted: September 21, 2013
First Posted: October 7, 2013
Results First Submitted: May 8, 2017
Results First Posted: June 12, 2017
Last Update Posted: June 12, 2017