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    Clinical Trial Results:
    Zoledronic Acid to Maintain Bone Mass After Denosumab Discontinuation: AfterDmab

    Summary
    EudraCT number
    		 2016-000852-91
    Trial protocol
    		 NL  
    Global end of trial date
    01 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Feb 2021
    First version publication date
    14 Feb 2021
    Other versions
    Summary report(s)
    		 summary

    Trial information

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    Trial identification
    Sponsor protocol code
    W15.032
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02499237
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    LUMC
    Sponsor organisation address
    albinusdreef 2, leiden, Netherlands,
    Public contact
    Clinical Research Internal Medicine, Leiden University Medical Center, research_interne@Lumc.nl
    Scientific contact
    Clinical Research Internal Medicine, Leiden University Medical Center, research_interne@Lumc.nl
    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
    05 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Feb 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate changes in BMD of the lumbar spine (LS) one year after treatment discontinuation in denosumab-treated women and in denosumab-treated women who received a single infusion of zoledronic acid one year before treatment discontinuation
    Protection of trial subjects
    NR
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    Greece: 60
    Worldwide total number of subjects
    75
    EEA total number of subjects
    75
    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)
    45
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 recruitment at the FLS from the Leiden University Medical Center from 25/10/2016 till 01-02-2018

    Pre-assignment
    Screening details
    		 as stated in summary

    Period 1
    Period 1 title
    25/10/2016 till 01-02-2018 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zoledronate
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    zoledronate
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg iv

    Arm title
    		 none
    Arm description
    		 no active treatment
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    		Zoledronate none
    Started
    30
    30
    Completed
    27
    30
    Not completed
    3
    0
         Consent withdrawn by subject
    3
    -
    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: query not clear

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    25/10/2016 till 01-02-2018
    Reporting group description
    		 -

    Reporting group values
    		 25/10/2016 till 01-02-2018 Total
    Number of subjects
    		 60 60
    Age categorical
    age
    Units: Subjects
        Adults (18-64 years)
    		 30 30
        From 65-84 years
    		 29 29
        85 years and over
    		 1 1
    Gender categorical
    Units: Subjects
        Female
    		 60 60
        Male
    		 0 0
    Subject analysis sets

    Subject analysis set title
    zol
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The trial required 56 patients to have a power of 95% to detect a 6% difference in LS-BMD between the two treatment groups with a two-sided error α probability of 0.05. Data for continuous variables are presented as mean ± standard error of the mean (SEM). Data for categorical variables are presented as number and/or frequencies. Kolmogorov-Smirnov test was used to test the normality of distribution of continuous variables. Within group comparisons of continuous variables were performed with repeated measures analysis of variance (ANOVA) or Friedman test. In case of statistically significant trend, multiple pairwise comparisons were performed with Bonferroni post-hoc adjustment. Independent T-test or Mann-Whitney test were used to compare continuous variables between groups. Chi-square or Fischer’s exact test were used for comparisons of categorical variables between groups. Spearman’s (rs) coefficient of correlation was used for bivariate correlations between continuous variables. A

    Subject analysis set title
    no
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    see protocol

    Subject analysis sets values
    		 zol no
    Number of subjects
    27
    30
    Age categorical
    age
    Units: Subjects
        Adults (18-64 years)
    30
        From 65-84 years
    26
        85 years and over
    1
    Age continuous
    Units: years
        median (standard deviation)
    64 ( 3 )
    ( )
    Gender categorical
    Units: Subjects
        Female
    57
        Male
    0

    End points

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    End points reporting groups
    Reporting group title
    Zoledronate
    Reporting group description
    		 -

    Reporting group title
    none
    Reporting group description
    		 no active treatment

    Subject analysis set title
    zol
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The trial required 56 patients to have a power of 95% to detect a 6% difference in LS-BMD between the two treatment groups with a two-sided error α probability of 0.05. Data for continuous variables are presented as mean ± standard error of the mean (SEM). Data for categorical variables are presented as number and/or frequencies. Kolmogorov-Smirnov test was used to test the normality of distribution of continuous variables. Within group comparisons of continuous variables were performed with repeated measures analysis of variance (ANOVA) or Friedman test. In case of statistically significant trend, multiple pairwise comparisons were performed with Bonferroni post-hoc adjustment. Independent T-test or Mann-Whitney test were used to compare continuous variables between groups. Chi-square or Fischer’s exact test were used for comparisons of categorical variables between groups. Spearman’s (rs) coefficient of correlation was used for bivariate correlations between continuous variables. A

    Subject analysis set title
    no
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    see protocol

    Primary: lumbale spine

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    End point title
    		 lumbale spine
    End point description
    see summary
    End point type
    Primary
    End point timeframe
    24 months
    End point values
    		 Zoledronate none zol no
    Number of subjects analysed
    30
    30
    27
    30
    Units: g/cm
    number (not applicable)
        BMD
    30
    30
    27
    30
    Statistical analysis title
    		 analyses
    Statistical analysis description
    see protocol
    Comparison groups
    Zoledronate v none v zol v no
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1
    Variability estimate
    Standard deviation
    Dispersion value
    2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    during the trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    2
    Reporting groups
    Reporting group title
    patients
    Reporting group description
    		 -

    Serious adverse events
    		 patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 27 (66.67%)
    General disorders and administration site conditions
    flue like reaction
    Additional description: Eighteen (66.7%) of the 27 women in the ZOL group developed symptoms compatible with a transient acute phase reaction that was treated with paracetamol. No adverse events were recorded in the Dmab group of women. No cases of osteonecrosis of the jaw
         subjects affected / exposed
    18 / 27 (66.67%)
         occurrences all number
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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