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    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
    EudraCT number
    2014-001915-37
    Trial protocol
    GB   DE  
    Global end of trial date
    02 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Nov 2017
    First version publication date
    12 Nov 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KF7013-01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02402530
    WHO universal trial number (UTN)
    U1111-1151-2181
    Sponsors
    Sponsor organisation name
    Grünenthal GmbH
    Sponsor organisation address
    Zieglerstr. 6, Aachen, Germany, 52099
    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
    23 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    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.
    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.
    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
    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
    United Kingdom: 2
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    United States: 217
    Worldwide total number of subjects
    230
    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)
    221
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    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
    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
    Number of subjects started
    459 [1]
    Number of subjects completed
    230

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    No reason given: 15
    Reason: Number of subjects
    Adverse event, non-fatal: 1
    Reason: Number of subjects
    Consent withdrawn by subject: 18
    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.
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    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.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    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
    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
    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.

    Arm title
    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
    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
    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.

    Arm title
    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
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    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.

    Number of subjects in period 1
    Neridronic acid 125 mg Neridronic acid 250 mg Placebo
    Started
    77
    77
    76
    12 Weeks - treatment completers
    64
    73
    69
    Completed
    24
    21
    23
    Not completed
    53
    56
    53
         Lack of efficacy
    1
    4
    3
         Adverse event, non-fatal
    -
    -
    1
         Other reasons incl. planned termination after V9
    38
    40
    35
         Consent withdrawn by subject
    7
    7
    8
         Lost to follow-up
    7
    5
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Neridronic acid 125 mg
    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
    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
    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 values
    Neridronic acid 125 mg Neridronic acid 250 mg Placebo Total
    Number of subjects
    77 77 76 230
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    74 73 74 221
        From 65-84 years
    3 4 2 9
        85 years and over
    0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    45.2 ± 11.8 46.1 ± 13.1 43.9 ± 12.8 -
    Gender categorical
    Units: Subjects
        Female
    54 58 64 176
        Male
    23 19 12 54
    Race
    Units: Subjects
        American Indian Or Alaska Native
    1 0 1 2
        Black Or African American
    4 3 2 9
        White
    69 74 70 213
        More than one race
    0 0 2 2
        Other
    3 0 1 4
    Ethnicity
    Units: Subjects
        Hispanic Or Latino
    4 1 5 10
        Not Hispanic Or Latino
    73 76 71 220

    End points

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    End points reporting groups
    Reporting group title
    Neridronic acid 125 mg
    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
    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
    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.

    Primary: Change in the Pain Intensity Score from baseline to Week 12

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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.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12.
    End point values
    Neridronic acid 125 mg Neridronic acid 250 mg Placebo
    Number of subjects analysed
    77 [1]
    77 [2]
    76 [3]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -1.38 (-1.83 to -0.94)
    -1.07 (-1.51 to -0.63)
    -1.01 (-1.46 to -0.55)
    Notes
    [1] - Full Analysis Set
    [2] - Full Analysis Set
    [3] - Full Analysis Set
    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.
    Comparison groups
    Neridronic acid 125 mg v Placebo v Neridronic acid 250 mg
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1812 [4]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [4] - Dunnett test for comparison of two active arms to placebo at Week 12.

    Secondary: Response to treatment, defined as 30 percent reduction

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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.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12.
    End point values
    Neridronic acid 125 mg Neridronic acid 250 mg Placebo
    Number of subjects analysed
    77 [5]
    77 [6]
    76 [7]
    Units: Subjects
    20
    16
    16
    Notes
    [5] - Full Analysis Set
    [6] - Full Analysis Set
    [7] - Full Analysis Set
    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.
    Comparison groups
    Neridronic acid 125 mg v Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    = 0.4025
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.41
    Confidence interval
         level
    95%
         sides
    2-sided
         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.
    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.
    Comparison groups
    Neridronic acid 250 mg v Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9201
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.42
         upper limit
    2.18

    Secondary: Response to treatment, defined as 50 percent reduction

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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.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12.
    End point values
    Neridronic acid 125 mg Neridronic acid 250 mg Placebo
    Number of subjects analysed
    77 [9]
    77 [10]
    76 [11]
    Units: Subjects
    8
    10
    9
    Notes
    [9] - Full Analysis Set
    [10] - Full Analysis Set
    [11] - Full Analysis Set
    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.
    Comparison groups
    Placebo v Neridronic acid 250 mg
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8125
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.13
    Confidence interval
         level
    95%
         sides
    2-sided
         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.
    Comparison groups
    Neridronic acid 125 mg v Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9612
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.36
         upper limit
    2.97

    Secondary: Change in the Brief Pain Inventory (BPI) interference scale

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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.
    End point type
    Secondary
    End point timeframe
    Change from baseline to Week 12.
    End point values
    Neridronic acid 125 mg Neridronic acid 250 mg Placebo
    Number of subjects analysed
    77 [12]
    77 [13]
    76 [14]
    Units: units on a scale
        least squares mean (standard error)
    -1.55 ± 0.31
    -1.08 ± 0.3
    -1.22 ± 0.32
    Notes
    [12] - Full Analysis Set
    [13] - Full Analysis Set
    [14] - 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
    = 0.4329
    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

    Secondary: Responder status based on PGIC questionnaire score

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    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.
    End point values
    Neridronic acid 125 mg Neridronic acid 250 mg Placebo
    Number of subjects analysed
    77 [15]
    77 [16]
    76 [17]
    Units: Subjects
    19
    18
    17
    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

    Secondary: Change in the EuroQol 5-dimension 5-level index score

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    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.
    End point values
    Neridronic acid 125 mg Neridronic acid 250 mg Placebo
    Number of subjects analysed
    77 [18]
    77 [19]
    76 [20]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    0.06 (0.02 to 0.1)
    0.02 (-0.02 to 0.06)
    0.03 (-0.01 to 0.07)
    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

    Secondary: Change in the EuroQol health-related visual analogue scale

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    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.
    End point values
    Neridronic acid 125 mg Neridronic acid 250 mg Placebo
    Number of subjects analysed
    77 [21]
    77 [22]
    76 [23]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    2.15 (-3.23 to 7.52)
    -2.12 (-7.32 to 3.09)
    4.16 (-1.27 to 9.59)
    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

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    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.
    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
    -

    Serious adverse events
    Neridronic acid 125 mg Neridronic acid 250 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 77 (2.60%)
    5 / 75 (6.67%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Complex regional pain syndrome
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 77 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Staphylococcal infection
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Neridronic acid 125 mg Neridronic acid 250 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 78 (71.79%)
    61 / 77 (79.22%)
    56 / 75 (74.67%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 78 (3.85%)
    4 / 77 (5.19%)
    7 / 75 (9.33%)
         occurrences all number
    4
    7
    8
    Headache
         subjects affected / exposed
    19 / 78 (24.36%)
    15 / 77 (19.48%)
    18 / 75 (24.00%)
         occurrences all number
    23
    24
    21
    Paraesthesia
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    4 / 75 (5.33%)
         occurrences all number
    0
    0
    4
    Eye disorders
    Vision blurred
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 77 (1.30%)
    1 / 75 (1.33%)
         occurrences all number
    4
    1
    1
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    1 / 78 (1.28%)
    3 / 77 (3.90%)
    4 / 75 (5.33%)
         occurrences all number
    1
    4
    5
    Fatigue
         subjects affected / exposed
    11 / 78 (14.10%)
    8 / 77 (10.39%)
    5 / 75 (6.67%)
         occurrences all number
    12
    14
    7
    Influenza like illness
         subjects affected / exposed
    3 / 78 (3.85%)
    5 / 77 (6.49%)
    3 / 75 (4.00%)
         occurrences all number
    5
    5
    5
    Pain
         subjects affected / exposed
    9 / 78 (11.54%)
    13 / 77 (16.88%)
    13 / 75 (17.33%)
         occurrences all number
    11
    14
    15
    Pyrexia
         subjects affected / exposed
    6 / 78 (7.69%)
    4 / 77 (5.19%)
    6 / 75 (8.00%)
         occurrences all number
    6
    5
    8
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 78 (3.85%)
    4 / 77 (5.19%)
    2 / 75 (2.67%)
         occurrences all number
    3
    4
    2
    Diarrhoea
         subjects affected / exposed
    5 / 78 (6.41%)
    9 / 77 (11.69%)
    6 / 75 (8.00%)
         occurrences all number
    5
    10
    7
    Nausea
         subjects affected / exposed
    7 / 78 (8.97%)
    10 / 77 (12.99%)
    21 / 75 (28.00%)
         occurrences all number
    9
    16
    29
    Vomiting
         subjects affected / exposed
    2 / 78 (2.56%)
    4 / 77 (5.19%)
    4 / 75 (5.33%)
         occurrences all number
    2
    5
    5
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 78 (0.00%)
    4 / 77 (5.19%)
    0 / 75 (0.00%)
         occurrences all number
    0
    4
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 78 (6.41%)
    9 / 77 (11.69%)
    4 / 75 (5.33%)
         occurrences all number
    6
    12
    4
    Back pain
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 77 (2.60%)
    4 / 75 (5.33%)
         occurrences all number
    6
    2
    6
    Muscle spasms
         subjects affected / exposed
    2 / 78 (2.56%)
    4 / 77 (5.19%)
    3 / 75 (4.00%)
         occurrences all number
    2
    4
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 77 (2.60%)
    1 / 75 (1.33%)
         occurrences all number
    4
    2
    1
    Myalgia
         subjects affected / exposed
    10 / 78 (12.82%)
    9 / 77 (11.69%)
    3 / 75 (4.00%)
         occurrences all number
    11
    13
    5
    Pain in extremity
         subjects affected / exposed
    7 / 78 (8.97%)
    7 / 77 (9.09%)
    5 / 75 (6.67%)
         occurrences all number
    12
    8
    6
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    2 / 78 (2.56%)
    6 / 77 (7.79%)
    1 / 75 (1.33%)
         occurrences all number
    2
    6
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 78 (0.00%)
    4 / 77 (5.19%)
    5 / 75 (6.67%)
         occurrences all number
    0
    4
    7
    Urinary tract infection
         subjects affected / exposed
    5 / 78 (6.41%)
    4 / 77 (5.19%)
    6 / 75 (8.00%)
         occurrences all number
    5
    4
    7

    More information

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    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).
    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
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