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    Clinical Trial Results:
    Open-label safety trial of intravenous neridronic acid in subjects with complex regional pain syndrome (CRPS)

    Summary
    EudraCT number
    2016-001164-11
    Trial protocol
    DE   PL  
    Global end of trial date
    09 Jan 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Dec 2019
    First version publication date
    21 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KF7013-03
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02972359
    WHO universal trial number (UTN)
    U1111-1180-8099
    Sponsors
    Sponsor organisation name
    Grünenthal GmbH
    Sponsor organisation address
    Zieglerstr. 6, Aachen, Germany, 52078
    Public contact
    Grünenthal Trial Information Desk, Grünenthal GmbH, 49 2415693223, Clinical-Trials@grunenthal.com
    Scientific contact
    Grünenthal Trial Information Desk, Grünenthal GmbH, 49 2415693223, Clinical-Trials@grunenthal.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of neridronic acid in subjects with complex regional pain syndrome.
    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.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Dec 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    United States: 567
    Worldwide total number of subjects
    580
    EEA total number of subjects
    13
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    531
    From 65 to 84 years
    49
    85 years and over
    0

    Subject disposition

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    Recruitment
    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.

    Pre-assignment
    Screening details
    -

    Pre-assignment period milestones
    Number of subjects started
    580
    Number of subjects completed
    316

    Pre-assignment subject non-completion reasons
    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
    Period 1
    Period 1 title
    Neridronic Acid 400 mg (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Neridronic acid 400 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Sodium neridronate hemi hydrate for intravenous infusion
    Investigational medicinal product code
    GRT7013
    Other name
    Neridronic acid
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    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.

    Number of subjects in period 1 [1]
    Neridronic acid 400 mg
    Started
    316
    Completed
    247
    Not completed
    69
         Protocol deviation
    1
         Reason missing
    1
         Lack of efficacy
    1
         Adverse event, serious fatal
    1
         Adverse event, non-fatal
    4
         Other reasons
    5
         Consent withdrawn by subject
    30
         Lost to follow-up
    26
    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).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Neridronic Acid 400 mg
    Reporting group description
    Safety Set: 316 subjects with at least 1 administration of investigational medicinal product (IM), including any partial infusion.

    Reporting group values
    Neridronic Acid 400 mg Total
    Number of subjects
    316 316
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    290 290
        From 65-84 years
    26 26
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    47.4 ± 13.2 -
    Gender categorical
    Units: Subjects
        Female
    237 237
        Male
    79 79
    Race
    Units: Subjects
        White
    297 297
        American Indian or Alaska Native
    3 3
        Asian
    4 4
        Black or African American
    8 8
        Native Hawaiian or other Pacific Islander
    0 0
        Other
    1 1
        Multiple
    3 3
    Ethnicity
    Units: Subjects
        Ethnicity Hispanic or Latino
    16 16
        Not Hispanic or Latino
    300 300
    Body mass index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    28.3 ± 7.4 -
    Baseline current pain intensity 11-point NRS
    Measured using an 11-point Numerical rating scale (NRS) by answering the following question: “Please rate your pain by selecting the one number that best describes how much pain you have right now.” Scores ranged from 0 (no pain) to 10 (pain as bad as you can imagine), a higher score indicates more pain. Baseline was the score assessed before the first dose of investigational medicinal product (IMP). Measure Analysis Population Description: Full Analysis Set; 1 subject's baseline pain assessment was missing (N=315).
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.59 ± 1.58 -
    Baseline Pain Interference score of the Brief Pain Inventory (BPI)
    Subjects completed the BPI scale questionnaire, which measures 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. For 20 subjects, baseline pain assessments were missing . Full Analysis Set (N=296)
    Units: units on a scale
        arithmetic mean (standard deviation)
    7.3 ± 1.75 -

    End points

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    End points reporting groups
    Reporting group title
    Neridronic acid 400 mg
    Reporting group description
    -

    Primary: Number of Subjects with Occurrence of Any Treatment Emergent Adverse Event (TEAE)

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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.
    End point type
    Primary
    End point timeframe
    Day 1 to Week 52
    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.
    End point values
    Neridronic acid 400 mg
    Number of subjects analysed
    316 [2]
    Units: Subjects
        Subjects with TEAE
    277
        Subjects with serious TEAE
    27
        Subjects with non-serious TEAE
    275
        Subjects with unexpected TEAE
    267
        Subjects with related TEAE
    190
        Subjects with related serious TEAE
    3
        Subjects with TEAE leading to IMP discont.
    12
        Subjects with TEAE leading to trial discont.
    6
        Subjects with fatal TEAE
    1
    Notes
    [2] - Safety Set: 316 subjects with at least 1 administration of IMP, including any partial infusion.
    No statistical analyses for this end point

    Secondary: Number of Subjects with Occurrence of Permanent Discontinuation From Treatment Due to an Adverse Event

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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.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 10
    End point values
    Neridronic acid 400 mg
    Number of subjects analysed
    316 [3]
    Units: Subjects
    12
    Notes
    [3] - Safety Set: 316 subjects with at least 1 administration of IMP, including any partial infusion.
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Current Pain Intensity Score

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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.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 and Week 26
    End point values
    Neridronic acid 400 mg
    Number of subjects analysed
    316 [4]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline to Week 12 (N=283)
    -1.54 ± 2.27
        Baseline to Week 26 (N=269)
    -1.57 ± 2.45
    Notes
    [4] - Full Analysis Set (coincided with Safety Set)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Current Pain Intensity Score

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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.
    End point type
    Secondary
    End point timeframe
    Baseline, at Week 12 and Week 26
    End point values
    Neridronic acid 400 mg
    Number of subjects analysed
    316 [5]
    Units: Subjects
        At least 30% pain reduction - Week 12
    105
        At least 30% pain reduction - Week 26
    110
    Notes
    [5] - Full Analysis Set (coincided with Safety Set)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Response to Treatment, Defined as at Least 50% Decrease From Baseline in the Current Pain Intensity Score

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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.
    End point type
    Secondary
    End point timeframe
    Baseline, at Week 12 and Week 26
    End point values
    Neridronic acid 400 mg
    Number of subjects analysed
    316 [6]
    Units: Subjects
        At least 50% pain reduction - Week 12
    75
        At least 50% pain reduction - Week 26
    74
    Notes
    [6] - Full Analysis Set (coincided with Safety Set)
    No statistical analyses for this end point

    Secondary: Patient Global Impression of Change (PGIC) at Week 12

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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.
    End point type
    Secondary
    End point timeframe
    at Week 12
    End point values
    Neridronic acid 400 mg
    Number of subjects analysed
    286 [7]
    Units: Subjects
        Very Much Improved
    31
        Much Improved
    71
        Minimally Improved
    98
        No Change
    45
        Minimally Worse
    23
        Much Worse
    12
        Very Much Worse
    3
        Missing
    3
    Notes
    [7] - Full Analysis Set (coincided with Safety Set)
    No statistical analyses for this end point

    Secondary: Patient Global Impression of Change (PGIC) at Week 26

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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.
    End point type
    Secondary
    End point timeframe
    at Week 26
    End point values
    Neridronic acid 400 mg
    Number of subjects analysed
    273 [8]
    Units: Subjects
        Very Much Improved
    38
        Much Improved
    58
        Minimally Improved
    84
        No Change
    52
        Minimally Worse
    25
        Much Worse
    10
        Very Much Worse
    2
        Missing
    4
    Notes
    [8] - Full Analysis Set (coincided with Safety Set)
    No statistical analyses for this end point

    Secondary: Change in the Pain Interference Score of the Brief Pain Inventory (BPI)

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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.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 and Week 26
    End point values
    Neridronic acid 400 mg
    Number of subjects analysed
    316 [9]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline to Week 12 (N=264)
    -2.2 ± 2.49
        Baseline to Week 26 (N=251)
    -2.1 ± 2.64
    Notes
    [9] - Full Analysis Set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Week 52
    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.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Neridronic acid 400 mg
    Reporting group description
    Safety Set: 316 subjects with at least 1 administration of investigational medicinal product (IMP), including any partial infusion.

    Serious adverse events
    Neridronic acid 400 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 316 (8.54%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 316 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Leg amputation
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 316 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 316 (0.63%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Condition aggravated
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicide attempt
         subjects affected / exposed
    2 / 316 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Cystocele
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 316 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 316 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 316 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Neridronic acid 400 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    275 / 316 (87.03%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    65 / 316 (20.57%)
         occurrences all number
    96
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    30 / 316 (9.49%)
         occurrences all number
    44
    Fatigue
         subjects affected / exposed
    32 / 316 (10.13%)
         occurrences all number
    39
    Pain
         subjects affected / exposed
    28 / 316 (8.86%)
         occurrences all number
    37
    Pyrexia
         subjects affected / exposed
    18 / 316 (5.70%)
         occurrences all number
    19
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    34 / 316 (10.76%)
         occurrences all number
    46
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    27 / 316 (8.54%)
         occurrences all number
    31
    Back pain
         subjects affected / exposed
    25 / 316 (7.91%)
         occurrences all number
    30
    Bone pain
         subjects affected / exposed
    17 / 316 (5.38%)
         occurrences all number
    20
    Myalgia
         subjects affected / exposed
    52 / 316 (16.46%)
         occurrences all number
    70
    Pain in extremity
         subjects affected / exposed
    25 / 316 (7.91%)
         occurrences all number
    30

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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.
    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.
    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
    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.

    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.
    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.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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