Clinical Trial Results:
A randomized double-blind multiple-dose placebo controlled
trial to establish the efficacy of QBX258
(combination of VAK694 and QAX576) in asthma that is
inadequately controlled with inhaled corticosteroids and
long acting beta agonists
Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
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Summary
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EudraCT number |
2011-003066-32 |
Trial protocol |
GB DE |
Global end of trial date |
27 Feb 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Jun 2016
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First version publication date |
01 Jun 2016
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CQBX258X2201
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01479595 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Novartis Pharma AG
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Sponsor organisation address |
CH-4002, Basel, Switzerland,
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Public contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
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Scientific contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Feb 2015
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Feb 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess whether treatment with QBX258 versus placebo over a 12–week period, in
individuals with moderate to severe asthma that is inadequately controlled, leads to significant
improvement in the severity of asthma as measured by change in the asthma control
questionnaire (ACQ) score at Day 85.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Feb 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 14
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Country: Number of subjects enrolled |
United States: 48
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Country: Number of subjects enrolled |
United Kingdom: 3
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Worldwide total number of subjects |
65
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EEA total number of subjects |
17
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
64
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Participants were assigned to either QBX258 or placebo in a 2:1 ratio. Randomization was done by stratification of Q576R. | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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QBX258 | ||||||||||||||||||||||||
Arm description |
Participants received QBX258 intravenous (iv) infusion every 4 weeks for up to 4 doses total. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
QBX258
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Investigational medicinal product code |
QBX258
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Other name |
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Pharmaceutical forms |
Powder for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Participants received QBX258 (combination of VAK696, 3mg/kg, and QAX576, 6mg/kg) intravenous (iv) infusion every 4 weeks for up to 4 doses.
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Arm title
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Placebo | ||||||||||||||||||||||||
Arm description |
Participants received placebo to QBX258 iv infusion every 4 weeks for up to 4 doses total. | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Participants received placebo (equal volume of 5% dextrose to QBX258) iv infusion every 4 weeks for up to 4 doses total.
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| Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: The number of subjects for the PK analysis set and Per Protocol analysis set is correct. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: The number of subjects for the PK analysis set and Per Protocol analysis set is correct. |
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Baseline characteristics reporting groups
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Reporting group title |
QBX258
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Reporting group description |
Participants received QBX258 intravenous (iv) infusion every 4 weeks for up to 4 doses total. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received placebo to QBX258 iv infusion every 4 weeks for up to 4 doses total. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
QBX258
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Reporting group description |
Participants received QBX258 intravenous (iv) infusion every 4 weeks for up to 4 doses total. | ||
Reporting group title |
Placebo
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Reporting group description |
Participants received placebo to QBX258 iv infusion every 4 weeks for up to 4 doses total. | ||
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End point title |
Change from baseline in Asthma Control Questionnaire (ACQ) score | ||||||||||||
End point description |
The ACQ consists of 7 questions assessing symptoms, rescue medication use and lung function. Except for lung function (FEV1), each question was scored on a 7-point scale where 0 = no impairment and 6 = maximum impairment. Scores ranged between 0 totally controlled to 6 (severely uncontrolled). Participants with a score below 1.0 are considered to have adequately controlled asthma. Participants with a score above 1.0 were considered not to be well controlled. A negative change from baseline indicates improvement.
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End point type |
Primary
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End point timeframe |
Baseline and 12 weeks
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Statistical analysis title |
Change from baseline in ACQ score | ||||||||||||
Comparison groups |
QBX258 v Placebo
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.005 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-0.514
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Confidence interval |
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90% | ||||||||||||
sides |
2-sided
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lower limit |
-0.811 | ||||||||||||
upper limit |
-0.217 | ||||||||||||
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End point title |
Change in Forced Expiratory Volume in one second (FEV1) | ||||||||||||
End point description |
FEV1 was assessed using central spirometry according to the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines.
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End point type |
Secondary
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End point timeframe |
Baseline and 12 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in Asthma Quality of Life Questionnaire (AQLQ) score | ||||||||||||
End point description |
The AQLQ is a 32-item disease specific questionnaire designed to measure functional impairments that are most important to patients with asthma. It consists of 4 domains: symptoms, emotions., exposure to environmental stimuli and activity limitation. Patients were asked to recall their experiences during the previous 2 weeks and to score each item on a 7-point scale. The scale ranges from 1 to 7. The overall AQLQ score was the mean response to all 32 questions. Higher scores represent better outcomes.
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End point type |
Secondary
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End point timeframe |
Baseline and 12 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Morning and evening peak expiratory flow (PEF) rate | |||||||||
End point description |
Morning and evening PEFs were recorded on an electronic diary (e-diary). PEF was assessed twice daily approximately 12 hours apart and the measurements were recorded in the e-diary.
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End point type |
Secondary
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End point timeframe |
Baseline and 12 weeks
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| Notes [1] - This outcome was not analyzed due to high variability in the data. [2] - This outcome was not analyzed due to high variability in the data. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change from baseline in maximum expiratory flow | ||||||||||||
End point description |
Maximum expiratory flow was assessed using central spirometry according to the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines.
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End point type |
Secondary
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End point timeframe |
Baseline and 12 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of participants with anti-QAX576 antibodies or anti-VAK694 antibodies | |||||||||
End point description |
Anti-QAX576 and anti-VAK694 antibodies in serum were analyzed.
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End point type |
Secondary
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End point timeframe |
12 weeks
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| No statistical analyses for this end point | ||||||||||
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End point title |
Observed maximum plasma concentration following drug administration at steady state (Cmax,ss) of the QAX576 analyte [3] | ||||||||||||||
End point description |
Blood samples were obtained to measure Cmax,ss.
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End point type |
Secondary
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End point timeframe |
days 1 (pre-dose and 2 hours post-dose), 15, 29 (pre-dose and 2 hours post-dose), 43, 57 (pre-dose and 2 hours post-dose), 71, 85 (pre-dose and 2 hours post-dose), 99, 113, 141, 183
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| Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the 3 arms presented are applicable to this end point. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Observed maximum plasma concentration following drug administration at steady state (Cmax,ss) of the VAK694 analyte [4] | ||||||||||||||
End point description |
Blood samples were obtained to measure Cmax,ss.
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End point type |
Secondary
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End point timeframe |
days 1 (pre-dose and 2 hours post-dose), 15, 29 (pre-dose and 2 hours post-dose), 43, 57 (pre-dose and 2 hours post-dose), 71, 85 (pre-dose and 2 hours post-dose), 99, 113, 141, 183
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| Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the 3 arms presented are applicable to this end point. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Lowest plasma concentration observed during a dosing interval at steady state (Cmin,ss) of the QAX576 analyte [5] | ||||||||||||||
End point description |
Blood samples were obtained to measure Cmin,ss.
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End point type |
Secondary
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End point timeframe |
days 1 (pre-dose and 2 hours post-dose), 15, 29 (pre-dose and 2 hours post-dose), 43, 57 (pre-dose and 2 hours post-dose), 71, 85 (pre-dose and 2 hours post-dose), 99, 113, 141, 183
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| Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the 3 arms presented are applicable to this end point. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Lowest plasma concentration observed during a dosing interval at steady state (Cmin,ss) of the VAK694 analyte [6] | ||||||||||||||
End point description |
Blood samples were obtained to measure Cmin,ss.
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End point type |
Secondary
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End point timeframe |
days 1 (pre-dose and 2 hours post-dose), 15, 29 (pre-dose and 2 hours post-dose), 43, 57 (pre-dose and 2 hours post-dose), 71, 85 (pre-dose and 2 hours post-dose), 99, 113, 141, 183
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| Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the 3 arms presented are applicable to this end point. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change from baseline in fractional exhaled nitric oxide (FeNO) | ||||||||||||
End point description |
FeNO was assessed as a measure of airway inflammation. An FeNO machine was used to obtain the FeNO measurements. FeNO measurements were obtained prior to the spirometry assessments.
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End point type |
Secondary
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End point timeframe |
baseline, 12 weeks
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
QBX258
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Reporting group description |
QBX258 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Placebo | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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04 Nov 2011 |
Amendment 1 introduced the following changes as requested from the health authority: clarified the period of time following dosing during which women of child-bearing potential were to use highly effective contraception; and introduced a requirement for males to use contraception to minimize potential risk of exposure to the fetus. |
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16 Nov 2011 |
Amendment 2 introduced the following changes: revised the blood volumes to reflect accurate volumes for the central laboratory. The overall blood volume taken during the study was reduced from 559.4 mL to 523.4 mL; and revised inclusion criterion 6 to require a peripheral blood eosinophil count > 140/μL combined with serum IgE > 100 IU/mL. |
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16 Jan 2012 |
Amendment 3 introduced the following changes: included a blood sample for Serum IgE to be taken at Screening in order for patients to be eligible as per Inclusion Criterion 6 (introduced at Amendment 2 but requirement for sample to be taken was missed); added a requirement for women of child bearing potential to have a negative pregnancy test result up to 14 days prior to the methacholine challenge (as per the package insert for methacholine); and revised inclusion criterion 7 to note that patients taking antihistamine therapy should withhold their medication prior to skin prick testing. |
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15 Feb 2013 |
Amendment 4 introduced the following changes: revised inclusion criterion 6 to require peripheral blood eosinophil count ≥ 140/μL and serum IgE ≥ 100 IU/mL at Screening, or IgE ≥ 400 IU/mL at Screening regardless of eosinophil count (change made to enrich the study population with individuals whose asthma was more likely to be characterized by Th2-type inflammation and therefore were more likely to respond to therapy targeting IL-4 and IL-13); clarified ACQ measurements were to be performed at Visit 3 and added a spirometry measurement (integral to measurement of ACQ) at Visit 3; added body weight measurement to Visit 4 (prior to dosing); revised the first Baseline visit from Days -14 to -4 to Days -14 to -3, to allow all Baseline assessments to be performed on Day -3, where logistically possible; revised dispensing of the eDiary to allow the eDiary to be dispensed at the Screening visit while screening results were obtained; revised exclusion criterion 17 to clarify that travel was restricted not to all of Southeast and Southwest Asia, South America, and Africa, but only to those parts that were endemic for schistosomiasis; revised the study stopping rules for clarification that “study-related SAE” referred to a study drug-related or study procedure-related SAE; added windows for early collection of PK assessment and performance of other study procedures; added more details for the withholding of asthma medications prior to spirometry, FeNOand the methacholine challenge; clarified that local spirometers, as opposed to central spirometry, may have been used for safety monitoring of lung function during induced sputum procedures; and added restriction of nitrate-rich foods and allowed for the consumption of water prior to measurements of FeNO. |
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19 Jun 2013 |
Amendment 5 introduced the following changes: removed the requirement for the methacholine challenge, sputum collection for biomarker assessments, and Elispot PBMC biomarker collection; shortened the Screening period and Run-in period to minimize study durations; clarified the definition of positive stool sample for ova and parasites; revised exclusion criterion 14 to include a more specific value of ≤ 12mg/dL; clarified the early withdrawal assessments and procedures for individual patient withdrawal; and revised the analysis of placebo treated patients in the additional explorative analysis onthe impact of the Q576R SNP on the QBX258 treatment. Placebo treated patients were not to be pooled but analyzed by their Q576R SNP status. |
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11 Dec 2013 |
Amendment 6 introduced the following changes as requested by the Paul- Ehrlich Institute: included a specific futility analysis in the planned interim analysis, and the definition of change from baseline was updated to the current reporting standard; and added Germany-specific requirements for contraception, to recommend against the use of spermicidals and condoms in this country. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
