Clinical Trial Results:
A randomized, double-blind trial investigating the efficacy and safety of intravenous neridronic acid in subjects with complex regional pain syndrome type I (CRPS-I)
Summary
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EudraCT number |
2014-001915-37 |
Trial protocol |
GB DE |
Global end of trial date |
02 Nov 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Nov 2017
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First version publication date |
12 Nov 2017
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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 |
KF7013-01
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02402530 | ||
WHO universal trial number (UTN) |
U1111-1151-2181 | ||
Sponsors
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Sponsor organisation name |
Grünenthal GmbH
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Sponsor organisation address |
Zieglerstr. 6, Aachen, Germany, 52099
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Public contact |
Grünenthal Trial Information Desk, Grünenthal GmbH, 49 2415693223, Clinical-Trials@grunenthal.com
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Scientific contact |
Grünenthal Trial Information Desk, Grünenthal GmbH, 49 2415693223, Clinical-Trials@grunenthal.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 |
23 Feb 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Nov 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Nov 2016
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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 demonstrate the efficacy of neridronic acid, versus placebo, in treatment of pain associated with CRPS-I.
Cumulative doses of neridronic acid 125 mg and 250 mg were investigated in this trial to characterize a dose response and find a minimally effective dose in CRPS. Other phase 3 trials will confirm the efficacy and safety of neridronic acid 400 mg previously established.
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Protection of trial subjects |
The trial was conducted according to ICH-GCP guidelines, the applicable local laws, and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Regulatory and competent authorities were notified of the trial as required by national regulations, and, where necessary, relevant authorization was obtained. The 12-week trial period was followed by an extended follow-up period with visits at Month 6, Month 9, and Month 12. The extended follow-up period was terminated for all subjects according to protocol after the last subject allocated to treatment completed their Month 6 visit.
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Background therapy |
No rescue medication was planned for this trial. Subjects were to remain on stable doses of concomitant analgesic medications, including opioids, during the 12-week trial period. Other stable therapies for CRPS, including physical therapy and use of spinal cord stimulators, were permitted during the trial. In the event of a severe pain flare, a short-acting opioid could be added to the stable analgesic regimen for up to 7 days. | ||
Evidence for comparator |
There was no activ comparator in this trial. Use of a placebo control was considered justified as there are no established effective treatments for CRPS. | ||
Actual start date of recruitment |
01 Apr 2015
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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: 2
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Country: Number of subjects enrolled |
Germany: 11
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Country: Number of subjects enrolled |
United States: 217
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Worldwide total number of subjects |
230
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EEA total number of subjects |
13
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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) |
221
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From 65 to 84 years |
9
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85 years and over |
0
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Recruitment
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Recruitment details |
First subject was enrolled on the 01 Apr 2015 and the last subject completed the trial on the 02 Nov 2016. 459 Subjects signed an Informed consent form (ICF), 229 Subjects not allocated to Investigational medicinal product (IMP). | ||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Subjects had to have a confirmed diagnosis of Complex regional pain syndrome type I (CRPS-I) according to the clinical diagnostic criteria recommended by the International Association for the Study of Pain and a Baseline Pain Intensity Score of at least 4 using an 11-point numerical rating scale. | ||||||||||||||||||||||||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
459 [1] | ||||||||||||||||||||||||||||||||||||||||
Number of subjects completed |
230 | ||||||||||||||||||||||||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Adverse event, non-fatal: 1 | ||||||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Consent withdrawn by subject: 18 | ||||||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
No reason given: 15 | ||||||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Inclusion Criteria Not Met/Exclusion Criteria Met: 195 | ||||||||||||||||||||||||||||||||||||||||
Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 459 Subjects signed an Informed consent form (ICF), 229 Subjects not allocated to Investigational medicinal product (IMP). 230 Subjects allocated to IMP. |
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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, Carer, Assessor | ||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
Subjects and investigators were blinded to the subject’s treatment for the duration of the trial, including the extended follow-up period.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Neridronic acid 125 mg | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received infusions of IMP during visits on Day 1, Day 4, Day 7, and Day 10 and returned for follow-up visits on Day 14 and at Week 6 and Week 12. The 12-week trial period (milestone defined as trial completers) was followed by an extended follow-up period with visits at Month 6, Month 9, and Month 12. The extended follow-up period was terminated for all subjects according to protocol after the last subject allocated to treatment completed their Month 6 visit. One subject in the placebo arm received medication from a 125 mg kit and was included in the 125 mg arm. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Sodium neridronate hemi hydrate for intravenous infusion
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Investigational medicinal product code |
GRT7013
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Other name |
Neridronic acid
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Five milliliters of IMP (equivalent to 62.5 mg neridronic acid) diluted in 500 mL normal saline and administered by intravenous infusion on Day 1 and Day 4; and 5 mL of IMP (matching placebo) diluted in 500 mL normal saline and administered by intravenous infusion on Day 7 and Day 10, resulting in a total dose of 125 mg neridronic acid.
Cumulative doses of neridronic acid 125 mg and 250 mg were investigated in this trial to characterize a dose response and find a minimally effective dose in CRPS. Other phase 3 trials will confirm the efficacy and safety of neridronic acid 400 mg previously established.
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Arm title
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Neridronic acid 250 mg | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received infusions of IMP during visits on Day 1, Day 4, Day 7, and Day 10 and returned for follow-up visits on Day 14 and at Week 6 and Week 12. The 12-week trial period (milestone defined as trial completers) was followed by an extended follow-up period with visits at Month 6, Month 9, and Month 12. The extended follow-up period was terminated for all subjects according to protocol after the last subject allocated to treatment completed their Month 6 visit. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Sodium neridronate hemi hydrate for intravenous infusion
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Investigational medicinal product code |
GRT7013
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Other name |
Neridronic acid
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Five milliliters of IMP (equivalent to 62.5 mg neridronic acid) diluted in 500 mL normal saline and administered by intravenous infusion on Day 1 and Day 4; and 5 mL of IMP diluted in 500 mL normal saline and administered by intravenous infusion on Day 7 and Day 10, resulting in a total dose of 250 mg neridronic acid.
Cumulative doses of neridronic acid 125 mg and 250 mg were investigated in this trial to characterize a dose response and find a minimally effective dose in CRPS. Other phase 3 trials will confirm the efficacy and safety of neridronic acid 400 mg previously established.
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received infusions of IMP during visits on Day 1, Day 4, Day 7, and Day 10 and returned for follow-up visits on Day 14 and at Week 6 and Week 12. The 12-week trial period (milestone defined as trial completers) was followed by an extended follow-up period with visits at Month 6, Month 9, and Month 12. The extended follow-up period was terminated for all subjects according to protocol after the last subject allocated to treatment completed their Month 6 visit. One subject in the placebo arm received medication from a 125 mg kit and was included in the 125 mg arm. | ||||||||||||||||||||||||||||||||||||||||
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 |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Five milliliters of IMP (matching placebo) diluted in 500 mL normal saline and administered by intravenous infusion on Day 1, Day 4, Day 7, and Day 10.
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Baseline characteristics reporting groups
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Reporting group title |
Neridronic acid 125 mg
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Reporting group description |
Subjects received infusions of IMP during visits on Day 1, Day 4, Day 7, and Day 10 and returned for follow-up visits on Day 14 and at Week 6 and Week 12. The 12-week trial period (milestone defined as trial completers) was followed by an extended follow-up period with visits at Month 6, Month 9, and Month 12. The extended follow-up period was terminated for all subjects according to protocol after the last subject allocated to treatment completed their Month 6 visit. One subject in the placebo arm received medication from a 125 mg kit and was included in the 125 mg arm. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Neridronic acid 250 mg
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Reporting group description |
Subjects received infusions of IMP during visits on Day 1, Day 4, Day 7, and Day 10 and returned for follow-up visits on Day 14 and at Week 6 and Week 12. The 12-week trial period (milestone defined as trial completers) was followed by an extended follow-up period with visits at Month 6, Month 9, and Month 12. The extended follow-up period was terminated for all subjects according to protocol after the last subject allocated to treatment completed their Month 6 visit. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects received infusions of IMP during visits on Day 1, Day 4, Day 7, and Day 10 and returned for follow-up visits on Day 14 and at Week 6 and Week 12. The 12-week trial period (milestone defined as trial completers) was followed by an extended follow-up period with visits at Month 6, Month 9, and Month 12. The extended follow-up period was terminated for all subjects according to protocol after the last subject allocated to treatment completed their Month 6 visit. One subject in the placebo arm received medication from a 125 mg kit and was included in the 125 mg arm. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Neridronic acid 125 mg
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Reporting group description |
Subjects received infusions of IMP during visits on Day 1, Day 4, Day 7, and Day 10 and returned for follow-up visits on Day 14 and at Week 6 and Week 12. The 12-week trial period (milestone defined as trial completers) was followed by an extended follow-up period with visits at Month 6, Month 9, and Month 12. The extended follow-up period was terminated for all subjects according to protocol after the last subject allocated to treatment completed their Month 6 visit. One subject in the placebo arm received medication from a 125 mg kit and was included in the 125 mg arm. | ||
Reporting group title |
Neridronic acid 250 mg
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Reporting group description |
Subjects received infusions of IMP during visits on Day 1, Day 4, Day 7, and Day 10 and returned for follow-up visits on Day 14 and at Week 6 and Week 12. The 12-week trial period (milestone defined as trial completers) was followed by an extended follow-up period with visits at Month 6, Month 9, and Month 12. The extended follow-up period was terminated for all subjects according to protocol after the last subject allocated to treatment completed their Month 6 visit. | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects received infusions of IMP during visits on Day 1, Day 4, Day 7, and Day 10 and returned for follow-up visits on Day 14 and at Week 6 and Week 12. The 12-week trial period (milestone defined as trial completers) was followed by an extended follow-up period with visits at Month 6, Month 9, and Month 12. The extended follow-up period was terminated for all subjects according to protocol after the last subject allocated to treatment completed their Month 6 visit. One subject in the placebo arm received medication from a 125 mg kit and was included in the 125 mg arm. |
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End point title |
Change in the Pain Intensity Score from baseline to Week 12 | ||||||||||||||||
End point description |
The Pain Intensity Score, related to the CRPS-affected limb, was determined from current pain intensity ratings, captured in an electronic diary, using an 11-point numerical rating scale (NRS). Subjects were asked to rate their current CRPS-related pain intensity twice daily, once in the morning and once in the evening. Subjects rated their pain on this scale from 0 = “no pain” to 10 = “pain as bad as you can imagine”.
Pain Intensity Scores are weekly averages calculated as the average of 14 current pain intensity ratings obtained over the 7 days of each week. A reduction in pain intensity results in negative values.
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End point type |
Primary
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End point timeframe |
Baseline to Week 12.
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Notes [1] - Full Analysis Set [2] - Full Analysis Set [3] - Full Analysis Set |
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Statistical analysis title |
Primary efficacy analysis | ||||||||||||||||
Statistical analysis description |
A mixed effects model for repeated measures (MMRM) was used, including pooled site, disease duration, baseline pain intensity, week, treatment, and treatment-by-week interaction as fixed effects and subject as random effect covariates.
LSmeans, standard errors, and 95% CIs for the interaction term treatment-by-week of the MMRM model representing the weekly averages of change from baseline in each week for each treatment arm were calculated.
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Comparison groups |
Neridronic acid 125 mg v Placebo v Neridronic acid 250 mg
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Number of subjects included in analysis |
230
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.1812 [4] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Confidence interval |
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Notes [4] - Dunnett test for comparison of two active arms to placebo at Week 12. |
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End point title |
Response to treatment, defined as 30 percent reduction | ||||||||||||
End point description |
The response to treatment based on a reduction of 30% in the current pain intensity score from baseline to Week 12 was evaluated.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 12.
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Notes [5] - Full Analysis Set [6] - Full Analysis Set [7] - Full Analysis Set |
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Statistical analysis title |
Response to treatment | ||||||||||||
Statistical analysis description |
A logistic regression model with covariates baseline and CRPS-I duration (time in years), and factors pooled site and treatment was fitted using the responder status as response variable.
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Comparison groups |
Neridronic acid 125 mg v Placebo
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Number of subjects included in analysis |
153
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Analysis specification |
Pre-specified
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Analysis type |
superiority [8] | ||||||||||||
P-value |
= 0.4025 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.41
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.63 | ||||||||||||
upper limit |
3.13 | ||||||||||||
Notes [8] - The statistical tests is not part of the overarching global null hypothesis and was not adjusted for multiplicity and is exploratory in nature. |
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Statistical analysis title |
Response to treatment | ||||||||||||
Statistical analysis description |
A logistic regression model with covariates baseline and CRPS-I duration (time in years), and factors pooled site and treatment was fitted using the responder status as response variable.
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Comparison groups |
Neridronic acid 250 mg v Placebo
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Number of subjects included in analysis |
153
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.9201 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
0.96
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.42 | ||||||||||||
upper limit |
2.18 |
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End point title |
Response to treatment, defined as 50 percent reduction | ||||||||||||
End point description |
The response to treatment based on a reduction of 50% in the current pain intensity score from baseline to Week 12 was evaluated.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 12.
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Notes [9] - Full Analysis Set [10] - Full Analysis Set [11] - Full Analysis Set |
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Statistical analysis title |
Response to treatment | ||||||||||||
Statistical analysis description |
A logistic regression model with covariates baseline and CRPS-I duration (time in years), and factors pooled site and treatment was fitted using the responder status as response variable.
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Comparison groups |
Placebo v Neridronic acid 250 mg
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Number of subjects included in analysis |
153
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.8125 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.13
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.41 | ||||||||||||
upper limit |
3.08 | ||||||||||||
Statistical analysis title |
Response to treatment | ||||||||||||
Statistical analysis description |
A logistic regression model with covariates baseline and CRPS-I duration (time in years), and factors pooled site and treatment was fitted using the responder status as response variable.
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Comparison groups |
Neridronic acid 125 mg v Placebo
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Number of subjects included in analysis |
153
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.9612 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
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 |
0.36 | ||||||||||||
upper limit |
2.97 |
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End point title |
Change in the Brief Pain Inventory (BPI) interference scale | ||||||||||||||||
End point description |
The BPI interference scale is a multi-item scale measuring the impact of pain on functioning and well-being. The 7 pain interference items: general activity, walking, work, mood, enjoyment of life, relations with others, and sleep, are each rated on a 0 to 10 scale using a 24-hour recall period, with 0 indicating “does not interfere” and 10 indicating “completely interferes”. The total Pain Interference Score is calculated by adding the scores for the 7 questions and dividing by 7. This gives an interference score with a range from 0 to 10.
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End point type |
Secondary
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End point timeframe |
Change from baseline to Week 12.
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Notes [12] - Full Analysis Set [13] - Full Analysis Set [14] - Full Analysis Set |
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Statistical analysis title |
Comparison Neridronic acid 125 mg to placebo | ||||||||||||||||
Statistical analysis description |
An ANCOVA of the change from baseline to Week 12 with covariates baseline and CRPS-I duration (time in years), and factors pooled site and treatment was performed.
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Comparison groups |
Neridronic acid 125 mg v Placebo
|
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Number of subjects included in analysis |
153
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.4329 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
-0.33
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-1.16 | ||||||||||||||||
upper limit |
0.5 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.42
|
||||||||||||||||
Statistical analysis title |
Comparison Neridronic acid 250 mg to placebo | ||||||||||||||||
Statistical analysis description |
An ANCOVA of the change from baseline to Week 12 with covariates baseline and CRPS-I duration (time in years), and factors pooled site and treatment was performed.
|
||||||||||||||||
Comparison groups |
Neridronic acid 250 mg v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
153
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.7202 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.15
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.65 | ||||||||||||||||
upper limit |
0.94 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.4
|
|
|||||||||||||
End point title |
Responder status based on PGIC questionnaire score | ||||||||||||
End point description |
The Patient Global Impression of Change (PGIC) is a self-reported measure of perceived change in overall condition since the start of the study. The 7-point PGIC is a complementary assessment of analgesic efficacy. Subjects respond to the question “Since the start of the trial, my overall status is:” with 1 of 7 possible responses (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse. The response to treatment based on the PGIC was derived by classifying subjects with outcome “very much improved” or “much improved” as responders.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to Week 12.
|
||||||||||||
|
|||||||||||||
Notes [15] - Full Analysis Set [16] - Full Analysis Set [17] - Full Analysis Set |
|||||||||||||
Statistical analysis title |
Comparison Neridronic acid 125 mg to placebo | ||||||||||||
Statistical analysis description |
A logistic regression model with covariates current baseline pain intensity score and CRPS-I duration (time in years), and factors pooled site and treatment was fitted using the responder status as response variable.
|
||||||||||||
Comparison groups |
Neridronic acid 125 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
153
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.5203 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.29
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.59 | ||||||||||||
upper limit |
2.81 | ||||||||||||
Statistical analysis title |
Comparison Neridronic acid 250 mg to placebo | ||||||||||||
Statistical analysis description |
A logistic regression model with covariates current baseline pain intensity score and CRPS-I duration (time in years), and factors pooled site and treatment was fitted using the responder status as response variable.
|
||||||||||||
Comparison groups |
Neridronic acid 250 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
153
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.9406 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.03
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.47 | ||||||||||||
upper limit |
2.25 |
|
|||||||||||||||||
End point title |
Change in the EuroQol 5-dimension 5-level index score | ||||||||||||||||
End point description |
The EuroQol 5-dimension 5-level (EQ-5D-5L) questionnaire assesses the level of current health for 5 dimensions: mobility, selfcare, usual activities, pain and discomfort, and anxiety and depression. For each dimension, subjects selected a statement at one of 5 levels, with level 1 indicating better health state (no problems) and level 5 indicating worst health state (e.g., unable to walk about). The scoring formula developed by EuroQol Group assigns an index score for each domain in the profile.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Change from baseline at week 12.
|
||||||||||||||||
|
|||||||||||||||||
Notes [18] - Full Analysis Set [19] - Full Analysis Set [20] - Full Analysis Set |
|||||||||||||||||
Statistical analysis title |
Comparison Neridronic acid 125 mg to placebo | ||||||||||||||||
Statistical analysis description |
An ANCOVA of the change from baseline to Week 12 with covariates baseline and CRPS-I duration (time in years), and factors pooled site and treatment was performed.
|
||||||||||||||||
Comparison groups |
Neridronic acid 125 mg v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
153
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.2149 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.03
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.02 | ||||||||||||||||
upper limit |
0.09 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.03
|
||||||||||||||||
Statistical analysis title |
Comparison Neridronic acid 250 mg to placebo | ||||||||||||||||
Statistical analysis description |
An ANCOVA of the change from baseline to Week 12 with covariates baseline and CRPS-I duration (time in years), and factors pooled site and treatment was performed.
|
||||||||||||||||
Comparison groups |
Neridronic acid 250 mg v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
153
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.6386 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
-0.01
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.06 | ||||||||||||||||
upper limit |
0.04 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.03
|
|
|||||||||||||||||
End point title |
Change in the EuroQol health-related visual analogue scale | ||||||||||||||||
End point description |
EuroQol health-related visual analogue scale (EQ-5D-5L-VAS). The EQ VAS is a self-reported measure of the subjects overall health "today". Subjects placed a mark on a 20 cm vertical scale numbered from 0 to 100, with 0 labeled as "the worst health you can imagine" and 100 labeled as "the best health you can imagine". The EQ VAS ranges from 0 to 100, with higher scores representing better overall health.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Change from baseline at week 12.
|
||||||||||||||||
|
|||||||||||||||||
Notes [21] - Full Analysis Set [22] - Full Analysis Set [23] - Full Analysis Set |
|||||||||||||||||
Statistical analysis title |
Comparison Neridronic acid 125 mg to placebo | ||||||||||||||||
Statistical analysis description |
An ANCOVA of the change from baseline to Week 12 with covariates baseline and CRPS-I duration (time in years), and factors pooled site and treatment was performed.
|
||||||||||||||||
Comparison groups |
Neridronic acid 125 mg v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
153
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.586 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
-2.01
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-9.3 | ||||||||||||||||
upper limit |
5.27 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
3.69
|
||||||||||||||||
Statistical analysis title |
Comparison Neridronic acid 250 mg to placebo | ||||||||||||||||
Statistical analysis description |
An ANCOVA of the change from baseline to Week 12 with covariates baseline and CRPS-I duration (time in years), and factors pooled site and treatment was performed.
|
||||||||||||||||
Comparison groups |
Neridronic acid 250 mg v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
153
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0784 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
-6.28
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-13.28 | ||||||||||||||||
upper limit |
0.72 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
3.55
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Baseline to end of trial. Up to 12 month.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Adverse events are reported for the Safety Set, this included all subjects with at least 1 IMP administration (i.e. all subjects who were administered at least 1 infusion of Investigational medicinal product (full or partial dose) of Neridronic acid and matching placebo) as per randomization schedule.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Neridronic acid 125 mg
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Neridronic acid 250 mg
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
03 Jun 2015 |
Amendment 01:
The principal change in this protocol amendment was a reduction in cumulative dose levels from neridronic acid 400 mg and 200 mg to neridronic acid 250 mg and 125 mg, respectively. Due to the reduction in cumulative dose levels, the amount of drug infused during each infusion (of active study medication) was reduced from 100 mg to 62.5 mg. To preserve the use of the packaged clinical trial supplies consisting of ampules containing neridronic acid 100 mg in 8 mL volume, the volume transferred from the ampule to the infusion bag containing normal saline was reduced to 5 mL. A witness was required for the transfer procedure to ensure the correct dose was given. Consistent with the lower dose per infusion, the infusion time was reduced from 3 hours to 2 hours. |
||
25 Aug 2015 |
Amendment 02:
• The requirements for discontinuation of IMP were modified to allow for resumption of treatment upon further assessment of laboratory changes or other findings within 7 days, if changes were transient and/or considered to be not clinically significant. This included modification of the procedure to prevent discontinuation of treatment due to spurious changes in eGFR determined from the local laboratory creatinine values or due to clinically insignificant variations in serum calcium values. The changes were implemented to improve the benefit/risk for subjects who would otherwise be discontinued due to transient, variable, or arbitrary findings. In situations where treatment was temporarily discontinued, the final IMP infusion had to be completed by 21 days after the first infusion.
• Trial termination following last subject allocated was changed from 3 months to 6 months to provide a minimum of 6 months follow-up for all subjects. This provided additional long-term follow-up data to support evaluation of safety and the duration of effect of neridronic acid.
• The enrollment period was extended from 28 days to 60 days (up to 90 days with approval of the sponsor) to provide sufficient time to meet requirements for repletion of vitamin D levels and to add flexibility due to issues in visit scheduling.
• In consideration of the fact that CRPS is a rare disease, re-enrollment was permitted for subjects who previously failed enrollment due to reasons that were no longer included under protocol amendment 02, provided the subject met all current inclusion/exclusion criteria. Other re-enrollment was permitted (e.g., due to an erroneous enrollment failure), upon sponsor approval, provided the subject met all inclusion/exclusion criteria.
• The enrollment cap for the subgroup of patients with CRPS duration ≥1 year was changed to 85% due to difficulty in enrolling subjects with duration of disease <1 year. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
For dose finding purposes, cumulative doses (125 and 250 mg) used in this trial were lower than that (400 mg) previously shown to be clearly effective (Varenna et al. 2013). |