Clinical Trial Results:
An Evaluation of Losmapimod in patients with Chronic Obstructive Pulmonary Disease (COPD) with systemic inflammation stratified using fibrinogen (EVOLUTION)
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Summary
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EudraCT number |
2011-004936-75 |
Trial protocol |
GB |
Global end of trial date |
06 Aug 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Mar 2016
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First version publication date |
02 Mar 2016
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Other versions |
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Summary report(s) |
EVOLUTION SAE Listing |
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 |
EVOLUTION
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01541852 | ||
WHO universal trial number (UTN) |
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Other trial identifiers |
R&D Number: A092519 | ||
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Sponsors
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Sponsor organisation name |
Cambridge University Hospitals NHS Foundation Trust & the University of Cambridge
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Sponsor organisation address |
Addenbrookes Hospital, Hills Road, Cambridge , United Kingdom, CB2 0QQ
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Public contact |
Dr Katan Patel
, "Cambridge Clinical Trials Unit (Box 111), Addenbrookes Hospital, Hills Road
Cambridge"
, 01223 349243, katan.patel@addenbrookes.nhs.uk
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Scientific contact |
Professor Ian Wilkinson
, Experimental Medicine & Immunotherapeutics (EMIT)
, 01223 296006, ibw20@cam.ac.uk
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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 Jul 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
06 Aug 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Aug 2014
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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 |
"The primary research question is to determine the effect of losmapimod in COPD patients on vascular structure and function as assessed by
1. Vascular inflammation
2. Endothelial function
3. Arterial structure and plaque characteristics"
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Protection of trial subjects |
"During participant recruitment, any medical history or clinically relevant abnormality that is deemed by the principal investigator and/or medical monitor to be a safety concern, will make the patient ineligible for inclusion .The safety and tolerability of protocol-specified treatments will be assessed by physical exam findings, 12-lead ECGs recordings, vital signs (blood pressure and heart rate) measurements, clinical laboratory tests (including liver function tests, LFTs), clinical monitoring /observation and spontaneous and elicited adverse event reporting. Methodology for safety assessments will be on file at the clinical research unit.
There will also be overall supervision for the trial provided by the Trial Steering Committee (TSC), to ensure that it is conducted in accordance with the protocol and GCP and to provide advice through its independent chairman.
Participants will be withdrawn from the trial if they experience a SUSAR. At the discretion of the PI/CI, participants will be withdrawn if they experience a SAE, which would affect their ability to participate in the trial. "
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Background therapy |
Losmapimod 7.5mg BD (twice daily): 1 x 7.5mg tablet each morning and each evening for 16 weeks. Placebo: one Placebo tablet to match Losmapimod each morning and each evening, for 16 weeks | ||
Evidence for comparator |
The placebo product visually matches the GW856553(Losmapimod) Tablets 7.5 mg and all placebo batches have been formulated to comply with the test for absence of GW856553X (active ingredient) if tested. The film coat used for the placebo product, Opadry white OY-S-28876, is identical to that used for the active tablets. The placebo product is manufactured using commonly used and recognised tablet excipients that are also employed in the active tablets and are packed into high-density polyethylene (HDPE) bottles. | ||
Actual start date of recruitment |
01 Apr 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
United Kingdom: 73
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Worldwide total number of subjects |
73
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EEA total number of subjects |
73
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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) |
21
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From 65 to 84 years |
52
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85 years and over |
0
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Recruitment
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Recruitment details |
There were 2 sites taking part namely Cambridge University Hospitals NHS Foundation Trust and Royal Brompton & Harefield Foundation NHS Trust. A sufficient number of participants were recruited to complete approximately 60 participant data sets suitable for the primary statistical analysis (approximately 30 per arm). | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
"There is a screening visit within 45 days prior to administration of the first dose of trial medication (V3). Written informed consent must be obtained prior to performance of any protocol specific procedures. The following procedures will be performed: • Medical history including smoking history. • Current medication history prior to the screen | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
overall trial (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 | ||||||||||||||||||||||||
Blinding implementation details |
The placebo tablets will be manufactured to appear identical to the Losmapimod tablets. Packaging and labelling at point of supply to the patient will be blinded against the active preparation. The site pharmacy will be unblinded.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Experimental | ||||||||||||||||||||||||
Arm description |
Experimental Arm who receive Losmapimod | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Losmapimod
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Investigational medicinal product code |
GW856553
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Losmapimod 7.5mg BD (twice daily): 1 x 7.5mg tablet each morning and each evening for 16 weeks.Placebo: one Placebo tablet to match Losmapimod each morning and each evening, for 16 weeks. Dispensing of IMP will be on Visits 3, 5, 6 and 7. At the point of initial dispensation, the bottles will contain 70 tablets. Participants will be expected to bring their trial medication in with them every visit. Participants will be required to swallow each tablet with approximately 240mL of water.
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Arm title
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Control | ||||||||||||||||||||||||
Arm description |
Control arm who receive placebo | ||||||||||||||||||||||||
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 |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Losmapimod 7.5mg BD (twice daily): 1 x 7.5mg tablet each morning and each evening for 16 weeks.Placebo: one Placebo tablet to match Losmapimod each morning and each evening, for 16 weeks. Dispensing of IMP will be on Visits 3, 5, 6 and 7. At the point of initial dispensation, the bottles will contain 70 tablets. Participants will be expected to bring their trial medication in with them every visit. Participants will be required to swallow each tablet with approximately 240mL of water.
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Baseline characteristics reporting groups
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Reporting group title |
Experimental
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Reporting group description |
Experimental Arm who receive Losmapimod | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control
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Reporting group description |
Control arm who receive placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Experimental
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Reporting group description |
Experimental Arm who receive Losmapimod | ||
Reporting group title |
Control
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Reporting group description |
Control arm who receive placebo | ||
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End point title |
Vascular inflammation as measured by FDG/PET scan | ||||||||||||
End point description |
Change in mean TBR-max in the index vessel. (The index vessel is the vessel segment with highest mean TBR-max at baseline, excluding the aortic arch. TBR is the tissue to blood ratio; the ratio of FDG uptake in the tissue to the background blood.)
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End point type |
Primary
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End point timeframe |
Visit 3 scan and Visit 9 scan
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Statistical analysis title |
Change in mean TBR-max in the index vessel | ||||||||||||
Statistical analysis description |
Linear regression analysis with the change from baseline as the dependent variable, the treatment as the independent variable, and the baseline value, and treatment site as covariates
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Comparison groups |
Control v Experimental
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Number of subjects included in analysis |
56
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.525 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-0.0462
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.191 | ||||||||||||
upper limit |
0.0968 | ||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
AEs will be recorded from the start of IMP dosing V3 (Day1), V4, V5, V6, V7 (Days 14/28/56/84 (All 96h)), V8 (Days 105-111), V9 (Days 109-112) and until the follow-up V10 (Days 120-126).
SAEs will be collected over the same time period as stated above fo
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Assessment type |
Non-systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
None | ||
Dictionary version |
1
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| Frequency threshold for reporting non-serious adverse events: 0% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: A listing of serious adverse events has been uploaded. |
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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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19 Jul 2012 |
Minor amendment. Reason for amendment: A registration form was created for IMANOVA (non-NHS site 12-EE-0135/0180 SSA) involved in the EVOLUTION clinical trial.
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10 Aug 2012 |
"1) The telephone number (for information on the product, trial and emergency unblinding) on the Annex 13 dispensing label originally submitted to the MHRA as part of CTA is that of the CI’s secretary and not, therefore, available 24-hours. This telephone number is not the label on the unblinded/QP’d product.
Since CTA submission, a 24-hour emergency contact number has been put into place for each site (different numbers for each site). This telephone number will appear on a patient card which trial subjects will be provided with at the point of enrolment into the trial (informed consent) and instructed to keep in their possession at all times.
To avoid confusion, the telephone number will be removed from the Annex 13 dispensing label.
2) The original Annex 13 label submission to the MHRA listed ‘Batch No:’ on the label. Now the exact process has been clarified, the label of the final dispensed product will have the addition of ‘Bottle No:’. Therefore the Annex 13 label has been clarified by changing ‘Batch No:’ to ‘Batch/Bottle No:’. Please note that the ‘Batch No’ is exactly the same number as the ‘Bottle No:’, therefore there is no reconciliation required.
The amended Annex 13 label (v2 - ‘Batch/Bottle No:’) has been further clarified by changing ‘Batch/Bottle No:’ to ‘Bottle No:’. The reason for the change is to avoid any pharmacy staff potentially using the source (original IMP/Placebo) product batch number on the label which could inadvertently unblind the study. This change should minimize any confusion (v2.1).
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01 Jun 2014 |
"1) The MRI primary endpoint, which is an optional assessment, requires further clarification (as below from the protocol). Wording has now been added to explain that the MRI primary endpoint analysis will be dependent on a sufficient number of MRI datasets otherwise the endpoint will not be analysed.
Page 19 - Change in atheromatous plaque and vessel wall characterisation using MRI and/or FDG-PET/CT, following 16 weeks of treatment. MRI Analysis will be dependent on a sufficient number of datasets. In the case of insufficient datasets the MRI primary endpoint will not be analysed and reported.
Page 45 - Change in atheromatous plaque and vessel wall characteristic using MRI and/or FDG-PET/CT, following 16 weeks of treatment. MRI Analysis will be dependent on a sufficient number of datasets. In the case of insufficient datasets the MRI primary endpoint will not be analysed and reported.
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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 | |||
