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    Clinical Trial Results:
    Treatment with Zoledronate Subsequent to Denosumab in Osteoporosis: a Randomized Trial

    Summary
    EudraCT number
    		 2015-005529-37
    Trial protocol
    		 DK  
    Global end of trial date
    01 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Dec 2020
    First version publication date
    10 Dec 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    07.12.2015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03087851
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dept. of Endocrinology and Internal Medicine, Aarhus University Hospital
    Sponsor organisation address
    Pall Juul-Jensens Boulevard 99, Aarhus , Denmark, 8200
    Public contact
    Bente Lomholt Langdahl, Dept. of Endocrinology and Internal Medicine, Aarhus University Hospital, benlan@rm.dk
    Scientific contact
    Bente Lomholt Langdahl, Dept. of Endocrinology and Internal Medicine, Aarhus University Hospital, benlan@rm.dk
    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
    01 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Nov 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate if infusion of zoledronic acid can prevent increases in bone turnover and bone loss in patients previously treated with denosumab and if there is difference between infusing zoledronic acid at six or nine months after the last injection with denosumab or when bone turnover is increased.
    Protection of trial subjects
    At baseline, which was 6 months 10 days after the last denosumab (DMAB) injection, we acquired information about medical history, age at menopause, medication, calcium intake, smoking, and alcohol consumption. Treatment consisted of an intravenous infusion of 5 mg zoledronate (ZOL). We secured a daily intake of 1000 mg calcium and 38 μg vitamin D by supplementation. mx refers to month x after baseline and Mx refers to months x after the ZOL infusion. We treated the 6-month group with ZOL at baseline, which was 6 months after the last DMAB injection and the 9-month group at month three, which was 9 months after the last DMAB injection (treatment window 14 days). As a precaution, however, if p-CTX increased above 1.26 μg/L at month 1 (m1) or month 2 (m2) in the 9-month group, we administered ZOL at that time point. Also, if a patient experienced a VFx or HFx, infusion of ZOL was administered at that time point. In the OBS group we administered ZOL if p-CTX increased above 1.26 μg/L (monitored monthly), if BMD decreased more than 5% at the TH or LS at m3, or if a patient experienced a VFx or HFx. We administered ZOL no later than m6. The time point when participants randomized to the OBS group were treated with ZOL was denoted month x (Mx), thus Mx + 1 was 1 month after the initial ZOL treatment. We re-treated with ZOL if p-CTX increased above 1.26 μg/L, BMD decreased more than 5% or if a patient experienced a VFx or HFx.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 61
    Worldwide total number of subjects
    61
    EEA total number of subjects
    61
    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)
    27
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The Department of Endocrinology, Aarhus University Hospital, Denmark. Advertisements in newspapers and online. Data extractions from The Danish Health Data Authority.

    Pre-assignment
    Screening details
    		 DXA. Blood samples. Inclusion and exclusion criteria.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    2-year randomized, open label, interventional study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 6-month group
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/100 mL

    Arm title
    		 9-month group
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/100 mL

    Arm title
    		 Observation group
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/100 mL

    Number of subjects in period 1
    		6-month group 9-month group Observation group
    Started
    20
    20
    21
    Completed
    20
    19
    19
    Not completed
    0
    1
    2
         Adverse event, non-fatal
    -
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    6-month group
    Reporting group description
    		 -

    Reporting group title
    9-month group
    Reporting group description
    		 -

    Reporting group title
    Observation group
    Reporting group description
    		 -

    Reporting group values
    		 6-month group 9-month group Observation group Total
    Number of subjects
    		 20 20 21 61
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68 ( 8 ) 65 ( 7 ) 69 ( 9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 18 17 19 54
        Male
    		 2 3 2 7
    Subject analysis sets

    Subject analysis set title
    Baseline characteristics
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Baseline characteristics: analysis of variance (ANOVA), chi-square test. Changes in BMD, TBS, and BTM within groups: mixed model analysis of variance with repeated measures. Between-group differences: ANOVA. The proportion of patients who failed to maintain BMD: chi-square test. Associations: linear regression.

    Subject analysis set title
    BMD, TBS, BTM
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Baseline characteristics: analysis of variance (ANOVA), chi-square test. Changes in BMD, TBS, and BTM within groups: mixed model analysis of variance with repeated measures. Between-group differences: ANOVA. The proportion of patients who failed to maintain BMD: chi-square test. Associations: linear regression.

    Subject analysis set title
    Associations
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Baseline characteristics: analysis of variance (ANOVA), chi-square test. Changes in BMD, TBS, and BTM within groups: mixed model analysis of variance with repeated measures. Between-group differences: ANOVA. The proportion of patients who failed to maintain BMD: chi-square test. Associations: linear regression.

    Subject analysis sets values
    		 Baseline characteristics BMD, TBS, BTM Associations
    Number of subjects
    61
    61
    61
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    68 ( 8 )
    65 ( 7 )
    69 ( 9 )
    Gender categorical
    Units: Subjects
        Female
    54
    54
    54
        Male
    7
    7
    7

    End points

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    End points reporting groups
    Reporting group title
    6-month group
    Reporting group description
    		 -

    Reporting group title
    9-month group
    Reporting group description
    		 -

    Reporting group title
    Observation group
    Reporting group description
    		 -

    Subject analysis set title
    Baseline characteristics
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Baseline characteristics: analysis of variance (ANOVA), chi-square test. Changes in BMD, TBS, and BTM within groups: mixed model analysis of variance with repeated measures. Between-group differences: ANOVA. The proportion of patients who failed to maintain BMD: chi-square test. Associations: linear regression.

    Subject analysis set title
    BMD, TBS, BTM
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Baseline characteristics: analysis of variance (ANOVA), chi-square test. Changes in BMD, TBS, and BTM within groups: mixed model analysis of variance with repeated measures. Between-group differences: ANOVA. The proportion of patients who failed to maintain BMD: chi-square test. Associations: linear regression.

    Subject analysis set title
    Associations
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Baseline characteristics: analysis of variance (ANOVA), chi-square test. Changes in BMD, TBS, and BTM within groups: mixed model analysis of variance with repeated measures. Between-group differences: ANOVA. The proportion of patients who failed to maintain BMD: chi-square test. Associations: linear regression.

    Primary: Primary endpoint

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    End point title
    		 Primary endpoint
    End point description
    Our primary endpoints were change in LSBMD from baseline to six months after the initial ZOL and the proportion of patients who failed to maintain BMD, defined as ≥ 3% loss at the lumbar spine or ≥ 5% BMD loss at the femoral neck or total hip.
    End point type
    Primary
    End point timeframe
    6 months and two years
    End point values
    		 6-month group 9-month group Observation group
    Number of subjects analysed
    20
    20
    20
    Units: %
        arithmetic mean (standard error)
    2 ( 1 )
    4 ( 1 )
    3 ( 1 )
    Statistical analysis title
    		 Primary endpoint
    Statistical analysis description
    Baseline characteristics: analysis of variance (ANOVA), chi-square test. Changes in BMD, TBS, and BTM within groups: mixed model analysis of variance with repeated measures. Between-group differences: ANOVA. The proportion of patients who failed to maintain BMD: chi-square test. Associations: linear regression.
    Comparison groups
    6-month group v 9-month group v Observation group
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0 [1]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [1] - Statistical hypothesis tested p <= 0.05

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    April 12 2017 - June 30 2020
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 not specified
    Dictionary version
    x
    Reporting groups
    Reporting group title
    All participants
    Reporting group description
    		 -

    Serious adverse events
    		 All participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 61 (8.20%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Cancer
         subjects affected / exposed
    5 / 61 (8.20%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 61 (90.16%)
    Musculoskeletal and connective tissue disorders
    Fracture
         subjects affected / exposed
    6 / 61 (9.84%)
         occurrences all number
    6
    Arthralgia, osteoarthritis, back pain and unspecified
         subjects affected / exposed
    25 / 61 (40.98%)
         occurrences all number
    25
    Product issues
    Flu-like symptoms after ZOL
         subjects affected / exposed
    37 / 61 (60.66%)
         occurrences all number
    37
    Infections and infestations
    Infection (unspecified)
         subjects affected / exposed
    15 / 61 (24.59%)
         occurrences all number
    15

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32459005
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