Clinical Trial Results:
A Phase 2a Enriched Enrollment Randomized Withdrawal Study to Assess Analgesic Efficacy and Safety of ASP8477 in Subjects with Peripheral Neuropathic Pain (MOBILE)
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Summary
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EudraCT number |
2013-002521-27 |
Trial protocol |
DE CZ GB |
Global end of trial date |
13 Feb 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
14 Jul 2016
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First version publication date |
14 Jul 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 |
8477-CL-0020
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02065349 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Astellas Code: ASP8477 | ||
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Sponsors
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Sponsor organisation name |
APGD EU, Astellas Pharma B.V.
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Sponsor organisation address |
Sylviusweg 62, Leiden, Netherlands, 2333 BE
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Public contact |
Senior Medical Director, APGD US, Astellas.resultsdisclosure@astellas.com
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Scientific contact |
Senior Medical Director, Global Medical Science, Astellas Pharma B.V., Astellas.resultsdisclosure@astellas.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 |
13 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 |
13 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 |
The main objective of the trial was to assess analgesic efficacy of ASP8477 relative to placebo in participants with peripheral neuropathic pain (PNP) as determined by the change in the average daily pain intensity in responders. The key secondary objective was to assess analgesic efficacy of ASP8477 relative to placebo in participants with peripheral neuropathic pain (PNP), as determined by the time to efficacy failure in responders.
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Protection of trial subjects |
This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
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Background therapy |
. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 Feb 2014
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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 |
Czech Republic: 73
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Country: Number of subjects enrolled |
Poland: 53
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Country: Number of subjects enrolled |
United Kingdom: 6
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Worldwide total number of subjects |
132
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EEA total number of subjects |
132
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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) |
74
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From 65 to 84 years |
57
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85 years and over |
1
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Recruitment
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Recruitment details |
In total 12 centers enrolled participants from 3 different countries. Eligible participants were male or female, ≥ 18 years of age with peripheral neuropathic pain (PNP) resulting from painful diabetic peripheral neuropathy (PDPN) or postherpetic neuralgia (PHN). | |||||||||||||||||||||
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Pre-assignment
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Screening details |
The study consisted of a 4-week Screening Period including a 1-week Single-blind Placebo Run-in Period. Subjects with an average Numeric Pain Rating Scale score of 4-8 on the last 3 days of the Run-in entered a 4-week Single-blind Treatment Period. Responders in the Single-blind Period entered a 3-week Double-blind Randomized Withdrawal Period. | |||||||||||||||||||||
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Period 1
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Period 1 title |
Placebo Run-in Period
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Single blind | |||||||||||||||||||||
Roles blinded |
Subject | |||||||||||||||||||||
Blinding implementation details |
During the placebo run-in period investigators and study staff instructed participants that they might or might not be receiving active study drug.
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Arms
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Arm title
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Placebo | |||||||||||||||||||||
Arm description |
Participants received 3 placebo tablets twice-daily from Day -7 to Day -1. | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo to Match ASP8477
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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 |
Placebo matched the tablet strength of 10 mg of ASP8477.
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Period 2
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Period 2 title |
Single-blind Treatment Period
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Is this the baseline period? |
No | |||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Single blind | |||||||||||||||||||||
Roles blinded |
Subject | |||||||||||||||||||||
Blinding implementation details |
During the single blind period investigators and study staff instructed the participants that they might or might not be receiving active study drug.
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Arms
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Arm title
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ASP8477 20/40/60 mg | |||||||||||||||||||||
Arm description |
Participants received starting dose of ASP8477 10 mg twice-daily for 3 days (Days 1, 2 and 3). If tolerated, the dose was escalated to 20 mg twice-daily administered on Days 4, 5 and 6. Participants entered the maintenance phase at 30 mg dose twice-daily on Day 7 and if the dose was well tolerated continued at that dose for 21 days. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
ASP8477
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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 |
ASP8477 immediate-release tablets in the strength of 10 mg of active substance.
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Period 3
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Period 3 title |
Double-blind Withdrawal Period
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Is this the baseline period? |
No | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor | |||||||||||||||||||||
Blinding implementation details |
During the double-blind withdrawal period participants were randomized to receive ASP8477 or placebo in a double-blind fashion such that neither the investigator, Sponsor’s study management team, clinical staff, nor the patient knew which agent was being administered.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||||||||
Arm description |
Participants were randomly assigned on Day 28 (Visit 8) to receive placebo for 3 weeks. | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo to Match ASP8477
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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 |
Placebo matched the tablet strength of 10 mg of ASP8477.
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Arm title
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ASP8477 40/60 mg | |||||||||||||||||||||
Arm description |
Participants were randomly assigned on Day 28 (Visit 8) to receive ASP8477 at the same dose continued from the Single-blind Maintenance Period (i.e., 20 mg or 30 mg twice daily) | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
ASP8477
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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 |
ASP8477 immediate-release tablets in the strength of 10 mg of active substance.
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| Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Only participants identified as the responders (individuals who had a ≥ 30% decrease in mean average daily pain intensity) were moved to Double-blind Period. |
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Baseline characteristics reporting groups
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Reporting group title |
Placebo Run-in Period
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Reporting group description |
Baseline characteristics reflect data collected for the SAF1 population, all participants who took at least one dose of study medication during the placebo run-in period. | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants received 3 placebo tablets twice-daily from Day -7 to Day -1. | ||
Reporting group title |
ASP8477 20/40/60 mg
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Reporting group description |
Participants received starting dose of ASP8477 10 mg twice-daily for 3 days (Days 1, 2 and 3). If tolerated, the dose was escalated to 20 mg twice-daily administered on Days 4, 5 and 6. Participants entered the maintenance phase at 30 mg dose twice-daily on Day 7 and if the dose was well tolerated continued at that dose for 21 days. | ||
Reporting group title |
Placebo
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Reporting group description |
Participants were randomly assigned on Day 28 (Visit 8) to receive placebo for 3 weeks. | ||
Reporting group title |
ASP8477 40/60 mg
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Reporting group description |
Participants were randomly assigned on Day 28 (Visit 8) to receive ASP8477 at the same dose continued from the Single-blind Maintenance Period (i.e., 20 mg or 30 mg twice daily) | ||
Subject analysis set title |
ASP8477 40 mg
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Participants who received ASP8477 20 mg twice daily on day 14 of the single-blind treatment period.
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Subject analysis set title |
ASP8477 60 mg
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Participants who received ASP8477 30 mg twice daily on day 14 of the single-blind treatment period.
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End point title |
Change from Double-blind Baseline in Mean of 24-Hour Average NPRS Score to End of Double-blind Period | ||||||||||||
End point description |
The e-diary was used daily to capture the average pain in the past 24 hours using the NPRS scale (an 11-point scale 0 to 10, where “0” anchored “no pain” and “10” meant “pain as bad as you can imagine”). Assessment was based on the question 5 of the Brief Pain Inventory – Diabetic Neuropathy. The scores of the 24-hour average pain intensity (NPRS) assessments from the last 3 days of the double-blind randomized withdrawal period were determined for each participant and compared to the double-blind baseline score. Double-blind baseline NPRS score was defined as the mean of 24-hour average pain intensity for the last 3 days of the single-blind period. The end of double-blind period NPRS score was defined as the mean of 24-hour average pain intensity for the last 3 days of the double-blind period. A negative change from baseline represented a reduction in pain, and a positive change represented an increase in pain.
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End point type |
Primary
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End point timeframe |
Last 3 days of single-blind period (study days 25-27) and last 3 days of double-blind withdrawal period (study days 27-49).
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Statistical analysis title |
Treatment Difference Between ASP8477 and Placebo | ||||||||||||
Statistical analysis description |
Analysis of covariance model (ANCOVA) was used with treatment group and pooled sites as fixed factors and baseline as a covariate. For the treatment difference (ASP8477 versus placebo), a negative difference shows a benefit for ASP8477 over placebo, and a positive difference shows a benefit of placebo over ASP8477.
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Comparison groups |
Placebo v ASP8477 40/60 mg
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Number of subjects included in analysis |
66
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.644 [1] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS Mean difference | ||||||||||||
Point estimate |
0.11
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Confidence interval |
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level |
95% | ||||||||||||
sides |
1-sided
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lower limit |
- | ||||||||||||
upper limit |
0.59 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.29
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| Notes [1] - 1-sided |
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End point title |
Time to Treatment Failure in the Double-blind Randomized Withdrawal Period | |||||||||||||||
End point description |
Endpoint reports number of participants with treatment failure in the Double-blind Randomized Withdrawal period. Treatment failure is defined as 3 consecutive days in which mean 24-hour pain intensity was >=4, and with at least a 30% increase in pain intensity (on each day) relative to baseline of the Double-Blind Period.
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End point type |
Secondary
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End point timeframe |
Day 28 (Visit 8) - Day 49 (Visit 10)
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Statistical analysis title |
Treatment Failure for Placebo v ASP8477 | |||||||||||||||
Statistical analysis description |
Cox proportional hazards model with covariates for treatment, pooled sites and double-blind baseline mean of 24-hour average pain intensity as covariates. One-sided 95% CI (upper limit) shown for treatment comparison.
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Comparison groups |
Placebo v ASP8477 40/60 mg
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Number of subjects included in analysis |
67
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||
P-value |
= 0.485 [2] | |||||||||||||||
Method |
Cox proportional hazards model | |||||||||||||||
Parameter type |
Hazard ratio (HR) | |||||||||||||||
Point estimate |
0.97
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
1-sided
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lower limit |
- | |||||||||||||||
upper limit |
3.733 | |||||||||||||||
| Notes [2] - 1-sided P value for treatment comparisons |
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End point title |
Percentage of Participants who Responded in the Single-blind Period to ASP8477 Treatment | ||||||||||
End point description |
Single-blind baseline NPRS score was defined as the mean of 24-hour average pain intensity for the last 3 days of the placebo run-in period. Response to ASP8477 treatment was defined as a ≥ 30% decrease in mean average daily pain intensity (NPRS score) during the last 3 days of the single-blind maintenance period versus the last three days of the placebo run-in period (baseline of single-blind period).
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End point type |
Secondary
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End point timeframe |
Last 3 days of of the placebo run-in period (study days -3 to -1) and last 3 days of the single-blind maintenance period (study days 25-27)
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Participants with a Patient Global Impression of Change (PGIC) Response for Overall Patient Status | |||||||||||||||
End point description |
The PGIC queried participant: “As compared to when you started the treatment on visit 2, how would you rate your overall symptoms now?” The 7 PGIC grades were “very much worse”, “much worse”, “minimally worse”, “no change”, “minimally improved”, “much improved” or “very much improved”. A responder on the PGIC was defined as someone who scored “much improved” or “very much improved” on the scale.
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End point type |
Secondary
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End point timeframe |
Day 28 (Visit 8) and Day 49 (EOT) (Visit 10)
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Number of Participants with Adverse Events During the Single-blind and Double-blind Period | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
A treatment-related AE was defined as any AE whose relationship to study drug was assessed as “possible” or “probable” by the investigator, or where the relationship to study drug was missing.
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End point type |
Secondary
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End point timeframe |
Day 1- Day 49 (EOT)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Assessment of Pharmacokinetic Plasma Concentration of ASP8477 | |||||||||||||||||||||||||||
End point description |
Summary of plasma concentrations for ASP8477 collected for each treatment dose (40 mg and 60 mg daily).Four participants discontinued prior to Day 14 and were therefore not assigned to any ASP8477 dose for this summary. In addition one participant was excluded from analysis due to undetectable levels.
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End point type |
Secondary
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End point timeframe |
Predose and 1, 2, 4, 6 hour postdose on Day 14 (Visit 7)
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
Day 1- Day 49 (EOT)
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Adverse event reporting additional description |
Treatment-emergent adverse events (TEAE) include all participants who received at least one dose of study drug.
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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 |
14.0
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Reporting groups
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Reporting group title |
ASP8477 20/40/60 mg [FAS1]
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Reporting group description |
Participants received starting dose of ASP8477 10 mg twice-daily for 3 days (Days 1, 2 and 3). If tolerated, the dose was escalated to 20 mg twice-daily administered on Days 4, 5 and 6. Participants entered the maintenance phase at 30 mg dose twice-daily on Day 7 and if the dose was well tolerated continued at that dose for 21 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ASP8477 40/60 mg [SAF2]
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Reporting group description |
Participants received 20 mg of ASP8477 twice-daily administered on Days 4, 5 and 6. Participants entered the maintenance phase at 30 mg dose twice-daily on Day 7 and if the dose was well tolerated continued at that dose for 21 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo [SAF2]
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Reporting group description |
Placebo to match ASP8477 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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: Overall, there were no adverse events of marked frequency or severity observed in this study. Non-serious adverse events table was based on the frequency threshold of 5% |
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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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25 Feb 2014 |
Amendment 2 was a substantial amendment issued after the first participant visit. Changes to the protocol included the following; Revised the definition of screen failure to reflect participants who were screened but not enrolled; Clarified that participants who discontinued from the study during the Titration Period should return to the clinic for the ED and EOS visits; Changed the use of concomitant medications; Modified the criterion regarding alcohol use during the study to specify that no more than moderate alcohol consumption by participants was allowed; Modified rescue medication (ketoprofen) dosing from four times daily to PRN; Modified the pharmacokinetic endpoint to base the analysis on individual participant concentrations rather than on Ctrough, Cmax, and AUC0-6, which were not calculated; Added menstrual diary collection to visits 4 and 6 in the Schedule of Assessments; Clarified the timing of pharmacodynamic lab sample collection, so that on day 1, blood samples for hormones that regulate satiety and hunger (leptin, ghrelin, glucagon-like peptide, peptide YY, and cholecystokinin [CCK]) were taken prior to dosing, and that all pharmacodynamic lab samples (for hormones that regulate satiety and hunger and FAAH-substrates) were taken at the same time; Corrected duration of double-blind period to 3 weeks; Clarified that after a participant’s dose had been reduced from 30 mg twice-daily to 20 mg twice-daily during the Single-blind Maintenance Phase the dose could not be changed again; a participant requiring further dose modification was to be discontinued from the study; Added instructions to site personnel to counsel the participants on the need to meet compliance with daily diary entries; were not eligible for randomization into the Double-blind Treatment Period; Added criteria for participant discontinuation; the participant experienced an AE and intense pain that required additional medical treatment. |
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03 Mar 2014 |
Amendment 3 was a substantial amendment requested by the Czech authorities and specific for the Czech Republic, it was issued prior to enrollment of the first Czech participants. Changes to the protocol included the following: Pharmacokinetic laboratory samples were not to be taken when the participant’s pain score had a value of 7 to 10 on the NPRS scale on that visit. Added a criterion for discontinuation, i.e., if the participant recorded a pain score of 7 to 10 on the NPRS scale for a period of 3 consecutive days during the double-blind Period. |
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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. | |||
| A futility analysis of the responder rate, based on the FAS1, was performed by Astellas after first 75 participants completed or discontinued from the single-blind period. Test results confirmed study did not meet futility criterion. | |||
