Clinical Trial Results:
A phase II, randomised, double blind, placebo controlled, three way crossover study to assess the bronchodilator effect of RPL554 administered in addition to open label tiotropium in patients with COPD.
Summary
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EudraCT number |
2016-004450-15 |
Trial protocol |
GB |
Global end of trial date |
24 Jul 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Aug 2018
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First version publication date |
09 Aug 2018
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Other versions |
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 |
RPL554-CO-202
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Verona Pharma Plc
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Sponsor organisation address |
3 More London Riverside, London, United Kingdom, SE1 2RE
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Public contact |
Brian Maurer, Verona Pharma plc, +44 203 283 4200, brian.maurer@veronapharma.com
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Scientific contact |
Brian Maurer, Verona Pharma plc, +44 203 283 4200, brian.maurer@veronapharma.com
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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 |
25 Sep 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
24 Jul 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
24 Jul 2017
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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 investigate the bronchodilator effect on peak FEV1 measured in first 4 hours after dosing and average FEV1 over 12 hours of nebulised RPL554, dosed twice daily for 3 days (five total doses), as compared to placebo when administered in addition to once daily tiotropium.
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Protection of trial subjects |
Standard procedures for emergency care were followed for any individual adverse events if clinically needed. Short acting bronchodilators could be used as rescue medication.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Jan 2017
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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 |
United Kingdom: 30
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Worldwide total number of subjects |
30
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EEA total number of subjects |
30
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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) |
15
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From 65 to 84 years |
15
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85 years and over |
0
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Recruitment
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Recruitment details |
The first patient was consented on 27 January 2017. Overall, 74 patients were screened for the study and 30 were treated. Patients received study treatment between 14 February 2017 and 07 July 2017. A total of 26 patients completed the study and 4 were withdrawn. | ||||||||||||
Pre-assignment
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Screening details |
74 were screened. The main reasons for screen failure were reversibility test criteria not met (21 patients), withdrew consent (5 patients) and unsuitable COPD history (4 patients). Patients had to discontinue long acting bronchodilators on the day prior to screening and short acting bronchodilators for 8 hours before all spirometry assessments | ||||||||||||
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, Assessor | ||||||||||||
Arms
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Are arms mutually exclusive |
No
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Arm title
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Tiotropium+1.5 mg RPL554 | ||||||||||||
Arm description |
18 mcg tiotropium once daily and 1.5 mg RPL554 twice daily | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Tiotropium
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder, hard capsule
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Routes of administration |
Inhalation use
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Dosage and administration details |
18 mcg tiotropium administered by dry powder inhaler
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Investigational medicinal product name |
1.5 mg RPL554
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Nebuliser suspension
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Routes of administration |
Inhalation use
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Dosage and administration details |
1.5 mg RPL554 administered using a nebuliser
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Arm title
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Tiotropium+6 mg RPL554 | ||||||||||||
Arm description |
18 mcg tiotropium once daily and 6 mg RPL554 twice daily | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Tiotropium
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder, hard capsule
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Routes of administration |
Inhalation use
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Dosage and administration details |
18 mcg tiotropium administered by dry powder inhaler
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Investigational medicinal product name |
6 mg RPL554
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Nebuliser suspension
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Routes of administration |
Inhalation use
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Dosage and administration details |
6 mg RPL554 administered using a nebuliser
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Arm title
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Tiotropium+placebo | ||||||||||||
Arm description |
18 mcg tiotropium once daily and placebo twice daily | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Tiotropium
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder, hard capsule
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Routes of administration |
Inhalation use
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Dosage and administration details |
18 mcg tiotropium administered by dry powder inhaler
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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 |
Nebuliser solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
Placebo administered using a nebuliser
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Tiotropium+1.5 mg RPL554
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Reporting group description |
18 mcg tiotropium once daily and 1.5 mg RPL554 twice daily | ||
Reporting group title |
Tiotropium+6 mg RPL554
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Reporting group description |
18 mcg tiotropium once daily and 6 mg RPL554 twice daily | ||
Reporting group title |
Tiotropium+placebo
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Reporting group description |
18 mcg tiotropium once daily and placebo twice daily |
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End point title |
Peak FEV1 on Day 3 | ||||||||||||||||
End point description |
Change from baseline in peak FEV1
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End point type |
Primary
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End point timeframe |
Over 4 hours after morning dosing on Day 3
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Statistical analysis title |
Tiotropium+1.5 mg RPL554 versus tiotropium+placebo | ||||||||||||||||
Comparison groups |
Tiotropium+1.5 mg RPL554 v Tiotropium+placebo
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Number of subjects included in analysis |
55
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.0022 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS Mean Ratio | ||||||||||||||||
Point estimate |
1.05
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
1.02 | ||||||||||||||||
upper limit |
1.09 | ||||||||||||||||
Statistical analysis title |
Tiotropium+6 mg RPL554 versus tiotropium+placebo | ||||||||||||||||
Comparison groups |
Tiotropium+placebo v Tiotropium+6 mg RPL554
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Number of subjects included in analysis |
54
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
< 0.0001 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS Means Ratio | ||||||||||||||||
Point estimate |
1.09
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
1.05 | ||||||||||||||||
upper limit |
1.12 |
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End point title |
Area under the curve over 12 hours for FEV1 on Day 3 | ||||||||||||||||
End point description |
Change from baseline in area under the curve for FEV1 over 12 hours
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End point type |
Primary
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End point timeframe |
Over 12 hours after morning dosing on Day 3
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Statistical analysis title |
Tiotropium+1.5 mg RPL554 versus tiotropium+placebo | ||||||||||||||||
Comparison groups |
Tiotropium+1.5 mg RPL554 v Tiotropium+placebo
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Number of subjects included in analysis |
55
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.0988 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS Means Ratio | ||||||||||||||||
Point estimate |
1.03
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.99 | ||||||||||||||||
upper limit |
1.06 | ||||||||||||||||
Statistical analysis title |
Tiotropium+6 mg RPL554 versus tiotropium+placebo | ||||||||||||||||
Comparison groups |
Tiotropium+6 mg RPL554 v Tiotropium+placebo
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Number of subjects included in analysis |
54
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.0009 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS Mean Ratio | ||||||||||||||||
Point estimate |
1.06
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
1.02 | ||||||||||||||||
upper limit |
1.09 |
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End point title |
Peak FEV1 on Day 1 | ||||||||||||||||
End point description |
Change from baseline in peak FEV1
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End point type |
Secondary
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End point timeframe |
Over 4 hours after morning dosing on Day 1
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Statistical analysis title |
Tiotropium+1.5 mg RPL554 versus tiotropium+placebo | ||||||||||||||||
Comparison groups |
Tiotropium+placebo v Tiotropium+1.5 mg RPL554
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Number of subjects included in analysis |
55
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.2496 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS Mean Ratio | ||||||||||||||||
Point estimate |
1.02
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.98 | ||||||||||||||||
upper limit |
1.06 | ||||||||||||||||
Statistical analysis title |
Tiotropium+6 mg RPL554 versus tiotropium+placebo | ||||||||||||||||
Comparison groups |
Tiotropium+6 mg RPL554 v Tiotropium+placebo
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Number of subjects included in analysis |
54
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.0039 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS Mean Ratio | ||||||||||||||||
Point estimate |
1.06
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
1.02 | ||||||||||||||||
upper limit |
1.1 |
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End point title |
Area under the curve over 12 hours for FEV1 on Day 1 | ||||||||||||||||
End point description |
Change from baseline in area under the curve for FEV1 over 12 hours
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End point type |
Secondary
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End point timeframe |
Over 12 hours after morning dosing on Day 1
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Statistical analysis title |
Tiotropium+1.5 mg RPL554 versus tiotropium+placebo | ||||||||||||||||
Comparison groups |
Tiotropium+1.5 mg RPL554 v Tiotropium+placebo
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Number of subjects included in analysis |
55
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.1404 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS Mean Ratio | ||||||||||||||||
Point estimate |
1.03
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.99 | ||||||||||||||||
upper limit |
1.06 | ||||||||||||||||
Statistical analysis title |
Tiotropium+6 mg RPL554 versus tiotropium+placebo | ||||||||||||||||
Comparison groups |
Tiotropium+6 mg RPL554 v Tiotropium+placebo
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Number of subjects included in analysis |
54
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.0228 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS Mean Ratio | ||||||||||||||||
Point estimate |
1.04
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
1.01 | ||||||||||||||||
upper limit |
1.08 |
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End point title |
Area under the curve over 4 hours on Day 1 | ||||||||||||||||
End point description |
Change from baseline in area under the curve for FEV1 over 4 hours
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End point type |
Secondary
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End point timeframe |
Over 4 hours after morning dosing on Day 1
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Statistical analysis title |
Tiotropium+1.5 mg RPL554 versus tiotropium+placebo | ||||||||||||||||
Comparison groups |
Tiotropium+1.5 mg RPL554 v Tiotropium+placebo
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Number of subjects included in analysis |
55
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.0073 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS Mean Ratio | ||||||||||||||||
Point estimate |
1.05
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
1.01 | ||||||||||||||||
upper limit |
1.08 | ||||||||||||||||
Statistical analysis title |
Tiotropium+6 mg RPL554 versus tiotropium+placebo | ||||||||||||||||
Comparison groups |
Tiotropium+6 mg RPL554 v Tiotropium+placebo
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Number of subjects included in analysis |
54
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.0001 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS Mean Ratio | ||||||||||||||||
Point estimate |
1.08
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
1.05 | ||||||||||||||||
upper limit |
1.12 |
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Adverse events information
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Timeframe for reporting adverse events |
From informed consent until the end of the study
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.1
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Reporting groups
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Reporting group title |
Tiotropium+1.5 mg RPL554
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tiotropium+6 mg RPL554
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tiotropium+placebo
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 3% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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26 Apr 2017 |
The exclusion criteria were amended to remove the prohibition against prior exposure to RPL554. |
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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 |