Clinical Trial Results:
Open-label safety trial of intravenous neridronic acid in subjects with complex regional pain syndrome (CRPS)
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Summary
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EudraCT number |
2016-001164-11 |
Trial protocol |
DE PL |
Global end of trial date |
09 Jan 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
21 Dec 2019
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First version publication date |
21 Dec 2019
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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 |
KF7013-03
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02972359 | ||
WHO universal trial number (UTN) |
U1111-1180-8099 | ||
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Sponsors
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Sponsor organisation name |
Grünenthal GmbH
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Sponsor organisation address |
Zieglerstr. 6, Aachen, Germany, 52078
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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 |
08 Jul 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
09 Jan 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Jan 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the safety and tolerability of neridronic acid in subjects with complex regional pain syndrome.
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Protection of trial subjects |
The trial was conducted according to ICH-GCP guidelines, the applicable local laws and regulations, and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Regulatory authorities were notified of the trial as required by national regulations, and where necessary relevant authorization was obtained.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
20 Dec 2016
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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 |
Germany: 13
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Country: Number of subjects enrolled |
United States: 567
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Worldwide total number of subjects |
580
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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) |
531
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From 65 to 84 years |
49
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85 years and over |
0
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Recruitment
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Recruitment details |
The trial started on 20 December 2016 with the enrollment of the first subject and was completed on 09 January 2019 when the last subject completed the last final examination according to the protocol. | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
- | ||||||||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
580 | ||||||||||||||||||||||||
Number of subjects completed |
316 | ||||||||||||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Consent withdrawn by subject: 11 | ||||||||||||||||||||||||
Reason: Number of subjects |
Lost to follow-up: 3 | ||||||||||||||||||||||||
Reason: Number of subjects |
Other reason: 9 | ||||||||||||||||||||||||
Reason: Number of subjects |
Inclusion criteria not met/exclusion criteria met: 241 | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
Neridronic Acid 400 mg (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||
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Arms
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Arm title
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Neridronic acid 400 mg | ||||||||||||||||||||||||
Arm description |
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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 |
108 mg sodium neridronate hemi hydrate (equivalent to 100 mg neridronic acid) in a total volume of 8 mL was diluted in 500 mL normal saline and administered by slow intravenous infusion (240 minutes [maximum 260 minutes]) on Day 1, Day 4, Day 7, and Day 10, resulting in a total dose of 400 mg neridronic acid.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 580 subjects were enrolled (signed an informed consent form), 318 subjects were allocated, but only 316 subjects were treated (2 did not meet inclusion/met exclusion criteria). Baseline characteristics are presented for all treated subjects (Safety Set). |
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Baseline characteristics reporting groups
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Reporting group title |
Neridronic Acid 400 mg
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Reporting group description |
Safety Set: 316 subjects with at least 1 administration of investigational medicinal product (IM), including any partial infusion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Neridronic acid 400 mg
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Reporting group description |
- | ||
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End point title |
Number of Subjects with Occurrence of Any Treatment Emergent Adverse Event (TEAE) [1] | ||||||||||||||||||||||||
End point description |
The primary endpoint of this trial was a binary endpoint assessing whether or not a subject experienced any TEAE.
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End point type |
Primary
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End point timeframe |
Day 1 to Week 52
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Safety data were summarized descriptively only for the single treatment group neridronic acid 400 mg. |
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| Notes [2] - Safety Set: 316 subjects with at least 1 administration of IMP, including any partial infusion. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Number of Subjects with Occurrence of Permanent Discontinuation From Treatment Due to an Adverse Event | ||||||
End point description |
The investigator could choose to permanently discontinue a subject from treatment if continued exposure of the subject to neridronic acid could have posed an undue risk to the subject.
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End point type |
Secondary
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End point timeframe |
Day 1 to Day 10
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| Notes [3] - Safety Set: 316 subjects with at least 1 administration of IMP, including any partial infusion. |
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| No statistical analyses for this end point | |||||||
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End point title |
Change From Baseline in the Current Pain Intensity Score | ||||||||||||
End point description |
The current Complex Regional Pain Syndrome (CRPS)-related pain intensity score was captured at each visit using an 11-point numerical rating scale where 0 = “no pain” and 10 = “pain as bad as you can imagine”, a higher score indicates more pain.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 12 and Week 26
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| Notes [4] - Full Analysis Set (coincided with Safety Set) |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Subjects with Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Current Pain Intensity Score | ||||||||||
End point description |
Subjects with at least a 30 percent decrease in the current pain intensity score were considered to have responded to treatment.
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End point type |
Secondary
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End point timeframe |
Baseline, at Week 12 and Week 26
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| Notes [5] - Full Analysis Set (coincided with Safety Set) |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Subjects with Response to Treatment, Defined as at Least 50% Decrease From Baseline in the Current Pain Intensity Score | ||||||||||
End point description |
Subjects with at least a 50 percent decrease in the current pain intensity score were considered to have responded to treatment.
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End point type |
Secondary
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End point timeframe |
Baseline, at Week 12 and Week 26
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| Notes [6] - Full Analysis Set (coincided with Safety Set) |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Patient Global Impression of Change (PGIC) at Week 12 | ||||||||||||||||||||||
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. Subjects selected one of seven responses ranging from "very much improved" to "very much worse". A response of "very much improved" or "much improved" is generally regarded as a clinically important improvement.
Overall, 286 out of 316 subjects attended the visit at Week 12 and were asked to complete the PGIC questionnaire.
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End point type |
Secondary
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End point timeframe |
at Week 12
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| Notes [7] - Full Analysis Set (coincided with Safety Set) |
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Patient Global Impression of Change (PGIC) at Week 26 | ||||||||||||||||||||||
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. Subjects selected one of seven responses ranging from "very much improved" to "very much worse". A response of "very much improved" or "much improved" is generally regarded as a clinically important improvement.
Overall, 273 out of 316 subjects attended the visit at Week 26 and were asked to complete the PGIC questionnaire.
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End point type |
Secondary
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End point timeframe |
at Week 26
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| Notes [8] - Full Analysis Set (coincided with Safety Set) |
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Change in the Pain Interference Score of the Brief Pain Inventory (BPI) | ||||||||||||
End point description |
The Brief Pain Inventory (BPI) Interference Score is the mean value of 7 self-reported items in question 9 of the BPI Short Form Questionnaire. Subjects rated their interference of pain with general activity, walking, work, sleep and other activities in the past 24 hours, with possible ratings from 0 (does not interfere) to 10 (completely interferes). The BPI interference Score ranges from 0 to 10, with higher values indicating greater pain interference of daily activities.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 12 and Week 26
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| Notes [9] - Full Analysis Set |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Day 1 to Week 52
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Adverse event reporting additional description |
Subjects were questioned about possible adverse events (AEs) with non-leading questions before administration of IMP and at regular intervals thereafter. All AEs reported spontaneously by subjects at any time point were also documented.
Overall, 316 of 318 allocated subjects were treated (Safety Set). Treatment emergent AEs are tabulated.
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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 |
21.1
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Reporting groups
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Reporting group title |
Neridronic acid 400 mg
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Reporting group description |
Safety Set: 316 subjects with at least 1 administration of investigational medicinal product (IMP), including any partial infusion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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21 Oct 2016 |
Amendment 01
This amendment was implemented to:
• Remove the requirement for blood sampling for a population pharmacokinetic analysis. A population pharmacokinetic analysis of the cumulative dose of 400 mg was not required because sufficient data had been collected in a previous trial.
• Follow-up all subjects for up to 52 weeks.
• Add continuous real-time ECG monitoring covering the period of infusions.
• Modify the allowance of medications known to prolong the QT interval. |
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20 Mar 2017 |
Amendment 02 (valid for Germany)
This amendment was implemented to:
• Exclude subjects who were taking forbidden concomitant medications/therapies or were not able to follow the rules for use of concomitant medications/treatments.
• Revise the dose rationale to include additional information from a previous pilot study.
• State that treatment discontinuation was to be permanent if eye symptoms reoccurred.
• Clarify the distribution of ampules and vials during the trial. |
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19 Apr 2017 |
Amendment 03 (valid for all countries)
This amendment was implemented to:
• Apply all changes introduced in protocol amendment 02 to all countries.
• Clarify that Visit 1 did not need to be performed in a fasted state.
• Adjust the duration of stable contraceptive use from 2 months to 1 month prior to allocation.
• Allow repeat testing of estimated glomerular filtration rate (eGFR), albumine creatinine ratio (ACR), serum calcium or magnesium, and vitamin D level.
• Clarify that the combination of opioids and benzodiazepines was forbidden only if the combination was felt to jeopardize subject safety, in the opinion of the investigator.
• Introduce re-enrollment of suitably qualified subjects who failed allocation due to technical reasons.
• Clarify that drugs of abuse testing was to be performed at the site and that the investigator should judge whether subjects who were receiving stable doses of prescribed medications containing amphetamines, benzodiazepines, or opioids could participate (together with approval by the sponsor).
• Exclude subjects incapable of signing the informed consent.
• Only include subjects who had failed at least 2 available treatments for CRPS, 1 of which had to be a pharmacologic treatment.
• Adjust exclusion criterion for urinary ACR from <30 mg/g to <150 mg/g, due to impact on enrollment of subjects with moderate levels of urinary albumin and based on lack of evidence for changes in urinary ACR in a previous trial.
• Adjust temporary IMP discontinuation criteria to allow resumption of treatment if urinary ACR was <150 mg/g, and remove temporary discontinuation criterion for eGFR <50 mL/min/1.73 m2 and urinary ACR >150 mg/g. A persistent change of this magnitude remained a criterion for permanent discontinuation.
• Adapt time period for collection of dental history.
• Clarify that the Pharmacodynamics Set included only subjects who had been treated.
• Clarify requirements for documentation of abnormal laboratory values |
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17 Nov 2017 |
Amendment 04 (valid for United States)
This amendment was implemented to:
• Increase the size of the target population.
• Clarify the planned number of bone biopsies and bone densitometry and MRI assessments. |
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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. | |||
| Due to the open-label, uncontrolled nature of the trial and the concomitant use of pain medication, the effect of neridronic acid on pain intensity and the side effect profile of neridronic acid have to be interpreted with care. | |||
