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    Clinical Trial Results:
    Randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of intravenous neridronic acid in subjects with complex regional pain syndrome (CRPS)

    Summary
    EudraCT number
    2016-003833-91
    Trial protocol
    ES  
    Global end of trial date
    31 Jul 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Jul 2020
    First version publication date
    25 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KF7013-02
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03530345
    WHO universal trial number (UTN)
    U1111-1187-8036
    Sponsors
    Sponsor organisation name
    Grünenthal GmbH
    Sponsor organisation address
    Zieglerstraße 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
    11 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jul 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate the superior efficacy of a cumulative dose of 400 mg intravenous neridronic acid versus placebo for the treatment of CRPS-related pain.
    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
    30 May 2018
    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
    Spain: 20
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    United States: 141
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 7
    Worldwide total number of subjects
    182
    EEA total number of subjects
    24
    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)
    170
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The first subject was enrolled on 30 May 2018, the last subject's last assessment was on 31 July 2019. After a pooled interim analysis of primary endpoint data of trials KF7013-02 and KF7013-04, recruitment was stopped as interim results indicated futility (neridronic acid unlikely to be statistically significantly superior to placebo).

    Pre-assignment
    Screening details
    182 subjects were enrolled (signed consent), 57 were allocated to treatment and received neridronate or placebo. Of 125 subjects not allocated, 95 did not meet inclusion/met exclusion criteria, 1 was lost to follow-up, 9 withdrew consent, 1 had technical problems, and 19 were not allocated for other reasons (mainly trial termination).

    Period 1
    Period 1 title
    Treatment Period A/Follow-up Period 1
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Data analyst, Assessor, Subject
    Blinding implementation details
    Blinded treatment with neridronic acid or placebo in Treatment Period A.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Baseline to Week 26: Neridronic Acid TPA
    Arm description
    Neridronic acid 400 mg administered in Treatment Period A (TPA) by 4 intravenous infusions within 10 Days; Follow-up Period 1 until 26 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Neridronate acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Neridronic acid 400 mg administered by 4 intravenous infusions within 10 Days.

    Arm title
    Baseline to Week 26: Placebo TPA
    Arm description
    Matching placebo was administered in Treatment Period A (TPA) by 4 intravenous infusions within 10 Days; Follow-up Period 1 until 26 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Matching placebo was administered by 4 intravenous infusions within 10 Days.

    Number of subjects in period 1 [1]
    Baseline to Week 26: Neridronic Acid TPA Baseline to Week 26: Placebo TPA
    Started
    28
    29
    Treatment Period A completers
    26
    27
    Follow-up Period 1 completers
    7
    7
    Completed
    7
    7
    Not completed
    21
    22
         Various reasons (mainly trial termination)
    21
    22
    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: 182 subjects were enrolled (signed consent), 57 were allocated to treatment and received trial medication. Baseline characteristics are reported for subjects who received trial medication.
    Period 2
    Period 2 title
    Treatment Period B/Follow-up Period 2
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Week 26-52: Neridronic acid TPA, Neridronic acid TPB
    Arm description
    Subjects with neridronic acid treatment in Treatment Period A (TPA) who received neridronic acid 100 mg - 4 intravenous infusions within 10 days also in Treatment Period B (TPB) with a Follow-up Period 2 until 52 weeks. Infusions in Treament Period B were not blinded.
    Arm type
    Experimental

    Investigational medicinal product name
    Neridronate acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Neridronic acid 400 mg administered by 4 intravenous infusions within 10 Days (open-label infusions)

    Arm title
    Week 26-52: Placebo TPA, Neridronic acid TPB
    Arm description
    Subjects with placebo treatment in Treatment Period A (TPA) who received neridronic acid 100 mg - 4 intravenous infusions within 10 days in Treatment Period B (TPB) with a Follow-up Period 2 until 52 weeks. Infusions in Treament Period B were not blinded.
    Arm type
    Experimental

    Investigational medicinal product name
    Neridronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Neridronic acid 400 mg administered by 4 intravenous infusions within 10 Days.

    Arm title
    Week 26 to Week 52: Neridronic Acid TPA
    Arm description
    Subjects who had completed treatment with neridronic acid treatment in Treatment Period A/Follow-up Period 1 were followed up without administration of trial medication until 52 weeks in Follow-up Period 2.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Week 26-52: Neridronic acid TPA, Neridronic acid TPB Week 26-52: Placebo TPA, Neridronic acid TPB Week 26 to Week 52: Neridronic Acid TPA
    Started
    5
    7
    2
    Treatment Period B completers
    4
    6
    0
    Follow-up Period 2 completers
    0
    0
    0
    Completed
    0
    0
    0
    Not completed
    5
    7
    2
         Various reasons (mainly trial termination)
    -
    -
    2
         Discontinued before end of Follow-up Period 2
    5
    7
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline to Week 26: Neridronic Acid TPA
    Reporting group description
    Neridronic acid 400 mg administered in Treatment Period A (TPA) by 4 intravenous infusions within 10 Days; Follow-up Period 1 until 26 weeks.

    Reporting group title
    Baseline to Week 26: Placebo TPA
    Reporting group description
    Matching placebo was administered in Treatment Period A (TPA) by 4 intravenous infusions within 10 Days; Follow-up Period 1 until 26 weeks.

    Reporting group values
    Baseline to Week 26: Neridronic Acid TPA Baseline to Week 26: Placebo TPA Total
    Number of subjects
    28 29 57
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    28 25 53
        From 65-84 years
    0 4 4
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    46.1 ± 11.0 49.4 ± 12.1 -
    Gender categorical
    Units: Subjects
        Female
    22 22 44
        Male
    6 7 13
    Race
    Units: Subjects
        American Indian or Alska Native
    0 0 0
        Asian
    2 0 2
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    2 1 3
        White
    24 28 52
        More than one race
    0 0 0
        Unknown or Not Reported
    0 0 0
    CRPS type
    CRPS Type I: Occurs after a minor or major tissue injury without clinical signs of major peripheral nerve injury. CRPS Type II: Occurs after an injury with clinical signs of major peripheral nerve injury.
    Units: Subjects
        Type I
    25 21 46
        Type II
    3 8 11
        Unknown
    0 0 0
    Time since onset of CRPS symptoms
    Units: months
        median (inter-quartile range (Q1-Q3))
    17.72 (7.60 to 22.02) 13.47 (8.20 to 18.87) -
    Time since diagnosis of CRPS
    Units: months
        median (inter-quartile range (Q1-Q3))
    9.15 (4.82 to 16.07) 11.37 (3.30 to 17.87) -

    End points

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    End points reporting groups
    Reporting group title
    Baseline to Week 26: Neridronic Acid TPA
    Reporting group description
    Neridronic acid 400 mg administered in Treatment Period A (TPA) by 4 intravenous infusions within 10 Days; Follow-up Period 1 until 26 weeks.

    Reporting group title
    Baseline to Week 26: Placebo TPA
    Reporting group description
    Matching placebo was administered in Treatment Period A (TPA) by 4 intravenous infusions within 10 Days; Follow-up Period 1 until 26 weeks.
    Reporting group title
    Week 26-52: Neridronic acid TPA, Neridronic acid TPB
    Reporting group description
    Subjects with neridronic acid treatment in Treatment Period A (TPA) who received neridronic acid 100 mg - 4 intravenous infusions within 10 days also in Treatment Period B (TPB) with a Follow-up Period 2 until 52 weeks. Infusions in Treament Period B were not blinded.

    Reporting group title
    Week 26-52: Placebo TPA, Neridronic acid TPB
    Reporting group description
    Subjects with placebo treatment in Treatment Period A (TPA) who received neridronic acid 100 mg - 4 intravenous infusions within 10 days in Treatment Period B (TPB) with a Follow-up Period 2 until 52 weeks. Infusions in Treament Period B were not blinded.

    Reporting group title
    Week 26 to Week 52: Neridronic Acid TPA
    Reporting group description
    Subjects who had completed treatment with neridronic acid treatment in Treatment Period A/Follow-up Period 1 were followed up without administration of trial medication until 52 weeks in Follow-up Period 2.

    Primary: Change From Baseline to Week 12 in the Average Pain Intensity Score (Weekly Average of Pain Values Recorded Daily in the Electronic Diary)

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    End point title
    Change From Baseline to Week 12 in the Average Pain Intensity Score (Weekly Average of Pain Values Recorded Daily in the Electronic Diary)
    End point description
    In the Baseline Phase and in Treatment Period A/Follow-up Period 1, subjects were asked to assessed their average CRPS-related pain on an 11-point numerical rating scale (NRS) - from 0 = “no pain” to 10 = “pain as bad as you can imagine” and report it once daily (in the evening, 24-hour recall) in an electronic diary. Changes from baseline (average for the Baseline Phase) to the weekly average for Week 12 were calculated for the Full Analysis Set, i.e., all subjects treated in Treatment Period A with all data available at the time of last subject out following premature trial termination.
    End point type
    Primary
    End point timeframe
    From the Baseline Phase (Day -7 to Day -1) to Week 12
    End point values
    Baseline to Week 26: Neridronic Acid TPA Baseline to Week 26: Placebo TPA
    Number of subjects analysed
    28
    29
    Units: Units on a scale
        least squares mean (standard error)
    -1.23 ± 0.310
    -0.16 ± 0.305
    Statistical analysis title
    Superiority testing
    Statistical analysis description
    Mixed-effects model for repeated measures (MMRM) defined with baseline pain intensity as covariate, the factors geographic region, week, treatment and treatment-by-week as fixed effects, and an unstructured covariance matrix to model the covariance structure of the repeated measurements.
    Comparison groups
    Baseline to Week 26: Placebo TPA v Baseline to Week 26: Neridronic Acid TPA
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0111 [1]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.89
         upper limit
    -0.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.404
    Notes
    [1] - Two-sided p-value for testing superiority of neridronic acid 400 mg compared to placebo.

    Secondary: Change From Baseline to Week 26 in the Average Pain Intensity Recorded on the Tablet Computer

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    End point title
    Change From Baseline to Week 26 in the Average Pain Intensity Recorded on the Tablet Computer
    End point description
    11-point NRS - from 0 = “no pain” to 10 = “pain as bad as you can imagine” - reported at the visits on a tablet computer (24-hour recall). Changes from baseline to Week 26 were planned to be analyzed. Secondary endpoints were not analyzed because the trial was terminated prematurely following a pooled interim analysis of primary endpoint data of trials KF7013-02 and KF7013-04 (EudraCT 2017-004244-37).
    End point type
    Secondary
    End point timeframe
    From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26).
    End point values
    Baseline to Week 26: Neridronic Acid TPA Baseline to Week 26: Placebo TPA
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Units on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [2] - No analysis performed
    [3] - No analysis performed
    No statistical analyses for this end point

    Secondary: Pain Response to Treatment, Defined as at Least 30% Decrease from Baseline in the Average Pain Intensity at Week 12, Recorded on the Tablet Computer

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    End point title
    Pain Response to Treatment, Defined as at Least 30% Decrease from Baseline in the Average Pain Intensity at Week 12, Recorded on the Tablet Computer
    End point description
    11-point NRS - from 0 = “no pain” to 10 = “pain as bad as you can imagine” - reported at the visits on a tablet computer (24-hour recall). The number of subjects with response at Week 12 was planned to be determined. Secondary endpoints were not analyzed because the trial was terminated prematurely following a pooled interim analysis of primary endpoint data of trials KF7013-02 and KF7013-04 (EudraCT 2017-004244-37).
    End point type
    Secondary
    End point timeframe
    From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
    End point values
    Baseline to Week 26: Neridronic Acid TPA Baseline to Week 26: Placebo TPA
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Number of subjects
    Notes
    [4] - No analysis performed.
    [5] - No analysis performed.
    No statistical analyses for this end point

    Secondary: Pain Response to Treatment, Defined as at Least 30% Decrease from Baseline in the Average Pain Intensity at Week 26, Recorded on the Tablet Computer

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    End point title
    Pain Response to Treatment, Defined as at Least 30% Decrease from Baseline in the Average Pain Intensity at Week 26, Recorded on the Tablet Computer
    End point description
    11-point NRS - from 0 = “no pain” to 10 = “pain as bad as you can imagine” - reported at the visits on a tablet computer (24-hour recall). The number of subjects with response at Week 26 was planned to be determined. Secondary endpoints were not analyzed because the trial was terminated prematurely following a pooled interim analysis of primary endpoint data of trials KF7013-02 and KF7013-04 (EudraCT 2017-004244-37).
    End point type
    Secondary
    End point timeframe
    From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)
    End point values
    Baseline to Week 26: Neridronic Acid TPA Baseline to Week 26: Placebo TPA
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: Number of subjects
    Notes
    [6] - No analysis performed.
    [7] - No analysis performed.
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 12 in the Pain Intensity Level of Dynamic Mechanical Allodynia (DMA)

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    End point title
    Change From Baseline to Week 12 in the Pain Intensity Level of Dynamic Mechanical Allodynia (DMA)
    End point description
    Dynamic Mechanical Allodynia: a Tactile Stimulus is Applied in a Single Sweeping Motion (1 cm to 2 cm Length) on the Skin on the Affected Limb. The subjects were asked to judge the stimulus intensity by means of an NRS (0 to 10). “0” in this case means “no pain”. Each “pricking”, “stinging” or “burning” sensation is defined as a painful sensation, which should always be evaluated by giving a value greater than “0”. “10” corresponds to the individual maximum pain imaginable. Changes from baseline to Week 12 were planned to be analyzed. Secondary endpoints were not analyzed because the trial was terminated prematurely following a pooled interim analysis of primary endpoint data of trials KF7013-02 and KF7013-04 (EudraCT 2017-004244-37).
    End point type
    Secondary
    End point timeframe
    From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
    End point values
    Baseline to Week 26: Neridronic Acid TPA Baseline to Week 26: Placebo TPA
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: Units on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [8] - No analysis performed.
    [9] - No analysis performed.
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 12 in the Pressure Pain Threshold (PPT) Ratio for the Thenar Muscle/Abductor Hallucis Muscle

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    End point title
    Change From Baseline to Week 12 in the Pressure Pain Threshold (PPT) Ratio for the Thenar Muscle/Abductor Hallucis Muscle
    End point description
    Pressure pain threshold: using a pressure algometer (contact area 1 cm2), the threshold for pressure- induced pain is measured on the thenar muscle/abductor hallucis muscle in 3 series of slowly increasing stimulus intensities (at a rate of about 50 kPa/s). The threshold is then determined as the arithmetic mean of the 3 series (in kPa). The ratio of the thresholds of the affected limb versus the unaffected limb was planned to be calculated and used for the determination of the change from baseline. Secondary endpoints were not analyzed because the trial was terminated prematurely following a pooled interim analysis of primary endpoint data of trials KF7013-02 and KF7013-04 (EudraCT 2017-004244-37).
    End point type
    Secondary
    End point timeframe
    From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
    End point values
    Baseline to Week 26: Neridronic Acid TPA Baseline to Week 26: Placebo TPA
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: Ratio
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [10] - No analysis performed.
    [11] - No analysis performed.
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 12 in the Ratio of the Figure of Eight Measurements of the Affected Limb Versus the Unaffected Limb

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    End point title
    Change From Baseline to Week 12 in the Ratio of the Figure of Eight Measurements of the Affected Limb Versus the Unaffected Limb
    End point description
    In subjects with the CRPS sign of edema on the CRPS severity score at baseline, circumference of the hand or foot will be measured by the investigator with measurement tape using the figure-of-eight method at both the affected limb and the contralateral unaffected limb. Each measurement will be performed 3 times. The average of the 3 measurements will be used for further analysis. The ratio of the averages of the affected limb versus the unaffected limb was planned to be calculated and used for the determination of the change from baseline. Secondary endpoints were not analyzed because the trial was terminated prematurely following a pooled interim analysis of primary endpoint data of trials KF7013-02 and KF7013-04 (EudraCT 2017-004244-37).
    End point type
    Secondary
    End point timeframe
    From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
    End point values
    Baseline to Week 26: Neridronic Acid TPA Baseline to Week 26: Placebo TPA
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: Ratio
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [12] - No analysis performed.
    [13] - No analysis performed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were documented from the time of enrollment (i.e., the time the informed consent form was signed) up to the time of the last protocol scheduled contact, i.e., date of last visit/contact (could be a phone call, e.g., in case of withdrawal).
    Adverse event reporting additional description
    Only treatment emergent adverse events (TEAEs) reported after first administration of trial medication are reported. Subjects with TEAEs may be presented in 2 of 6 reporting groups depending on the time the TEAEs were reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Baseline to Week 26: Neridronic Acid TPA
    Reporting group description
    In Treatment Period A (TPA), subjects received neridronic acid 100 mg - 4 intravenous infusions within 10 Days; Follow-up Period 1 until 26 weeks.

    Reporting group title
    Baseline to Week 26: Placebo TPA
    Reporting group description
    In Treatment Period A (TPA), subjects received matching placebo - 4 intravenous infusions within 10 days; Follow-up Period 1 until 26 weeks.

    Reporting group title
    Week 26 to Week 52: Placebo TPA
    Reporting group description
    Subjects with placebo treatment in Treatment Period A/Follow-up Period 1 were followed up without administration of trial medication until 52 weeks in Follow-up Period 2.

    Reporting group title
    Week 26 to Week 52: Placebo TPA, Neridronic Acid TPB
    Reporting group description
    Subjects who had completed treatment with placebo in Treatment Period A/Follow-up Period 1 received neridronic acid treatment (100 mg - 4 intravenous infusions within 10 days) in Treatment Period B (TPB) with a Follow-up Period 2 until 52 weeks.

    Reporting group title
    Week 26 to Week 52: Neridronic Acid TPA
    Reporting group description
    Subjects who had completed treatment with neridronic acid treatment in Treatment Period A/Follow-up Period 1 were followed up without administration of trial medication until 52 weeks in Follow-up Period 2.

    Reporting group title
    Week 26 to Week 52: Neridronic Acid TPA, Neridronic Acid TPB
    Reporting group description
    Subjects who had completed treatment with neridronic acid in Treatment Period A/Follow-up Period 1 received re-treatment with neridronic acid 100 mg - 4 intravenous infusions within 10 days in Treatment Period B (TPB) with a Follow-up Period 2 until 52 weeks.

    Serious adverse events
    Baseline to Week 26: Neridronic Acid TPA Baseline to Week 26: Placebo TPA Week 26 to Week 52: Placebo TPA Week 26 to Week 52: Placebo TPA, Neridronic Acid TPB Week 26 to Week 52: Neridronic Acid TPA Week 26 to Week 52: Neridronic Acid TPA, Neridronic Acid TPB
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Baseline to Week 26: Neridronic Acid TPA Baseline to Week 26: Placebo TPA Week 26 to Week 52: Placebo TPA Week 26 to Week 52: Placebo TPA, Neridronic Acid TPB Week 26 to Week 52: Neridronic Acid TPA Week 26 to Week 52: Neridronic Acid TPA, Neridronic Acid TPB
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 28 (57.14%)
    15 / 29 (51.72%)
    0 / 22 (0.00%)
    3 / 7 (42.86%)
    1 / 23 (4.35%)
    0 / 5 (0.00%)
    Surgical and medical procedures
    Foot operation
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Medical device removal
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Medical device implantation
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Acute phase reaction
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    3 / 7 (42.86%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    7
    0
    0
    6
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 29 (6.90%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    5
    0
    0
    0
    0
    Feeling cold
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 29 (6.90%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    5
    0
    0
    1
    0
    0
    Pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Epicondylitis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Skin laceration
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    2 / 28 (7.14%)
    3 / 29 (10.34%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    6
    0
    0
    0
    0
    Migraine
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Occipital neuralgia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Burning mouth syndrome
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dental paraesthesia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    Gastritis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gingival discomfort
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    2 / 28 (7.14%)
    4 / 29 (13.79%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    4
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    Joint instability
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 29 (6.90%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Periarthritis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Synovitis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Nov 2018
    The principal changes in this amendment are based on FDA feedback received in September 2018 as well as feedback from ECs, IRBs, and other regulatory authorities. The following changes were implemented: • Addition of weekly pain intensity assessments after Week 12 using an electronic diary. • Clarification of concomitant analgesic medication use as a (non-objective related) outcome. • Simplification of the description of “other data to be collected that are not directly attributed to or considered as an endpoint” (there was no change to the planned assessments or evaluations). • Removal of specification of male contraception in inclusion criterion 6. • Clarification in exclusion criterion 1 that the quoted eGFR and ACR thresholds refer to severe renal impairment. refer to severe renal impairment.

    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.
    A protocol specified interim analysis was conducted on pooled primary endpoint data of trials KF7013-02 and KF7013-04. The interim analysis indicated futility and both trials were stopped.
    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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