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    Clinical Trial Results:
    Influence of Zoledronic acid (Zometa®) on bone mineral density and bone ultrasonometry in premenopausal women with hormone receptor positive breast cancer and neoadjuvant or adjuvant chemotherapeutic treatment

    Summary
    EudraCT number
    		 2004-002832-24
    Trial protocol
    		 DE  
    Global end of trial date
    19 May 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    26 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CZOL446GDE21
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00375505
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 6132411121,
    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
    19 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    19 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate superiority of Zometa® vs. placebo in improving bone mineral density at lumbar spine (L2-L4) in premenopausal hormone receptor positive patients with breast cancer and neoadjuvant chemotherapy or adjuvant chemoendocrine or endocrine treatment.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Oct 2005
    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
    Germany: 70
    Worldwide total number of subjects
    70
    EEA total number of subjects
    70
    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)
    70
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The patients were either randomized (ratio 1:1) to the placebo or Zometa treatment group, where they received 4 mg ZOL or placebo as an infusion every 3 months (altogether 8 infusions).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo as a 15-minute infusion every 3 months for a treatment period of 24 months (total of 8 infusions).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    4 mg ZOL or placebo as an infusion every 3 months (altogether 8 infusions)

    Arm title
    		 Zoledronic Acid
    Arm description
    		 Zoledronic Acid 4mg as a 15-minute infusion every 3 months for a treatment period of 24 months (total of 8 infusions).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronic Acid
    Investigational medicinal product code
    CZOL446
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    4 mg ZOL or placebo as an infusion every 3 months (altogether 8 infusions)

    Number of subjects in period 1
    		Placebo Zoledronic Acid
    Started
    36
    34
    Completed
    35
    32
    Not completed
    1
    2
         Adverse event, non-fatal
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo as a 15-minute infusion every 3 months for a treatment period of 24 months (total of 8 infusions).

    Reporting group title
    Zoledronic Acid
    Reporting group description
    		 Zoledronic Acid 4mg as a 15-minute infusion every 3 months for a treatment period of 24 months (total of 8 infusions).

    Reporting group values
    		 Placebo Zoledronic Acid Total
    Number of subjects
    		 36 34 70
    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)
    		 36 34 70
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 42.8 ± 6.3 43.2 ± 6 -
    Gender, Male/Female
    All participants were females
    Units: participants
        Female
    		 36 34 70
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo as a 15-minute infusion every 3 months for a treatment period of 24 months (total of 8 infusions).

    Reporting group title
    Zoledronic Acid
    Reporting group description
    		 Zoledronic Acid 4mg as a 15-minute infusion every 3 months for a treatment period of 24 months (total of 8 infusions).

    Primary: Change in bone mineral density (BMD) measured by Dual (energy) x-ray absorptiometry (DXA) at lumbar spine (L2-L4) from baseline to month 24

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    End point title
    		 Change in bone mineral density (BMD) measured by Dual (energy) x-ray absorptiometry (DXA) at lumbar spine (L2-L4) from baseline to month 24
    End point description
    Bone mineral density (BMD) by DXA at lumbar spine (L2-L4); DXA assessments of the BMD at dual hips. (BMD). Two X-ray beams with different energy levels are aimed at the patient's bones. When soft tissue absorption is subtracted out, the BMD can be determined from the absorption of each beam by bone.
    End point type
    Primary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: Z-score
        arithmetic mean (standard deviation)
    -0.075 ± 0.041
    0.037 ± 0.042
    Statistical analysis title
    		 Change in BMD
    Comparison groups
    Placebo v Zoledronic Acid
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval

    Primary: Change in bone mineral density (BMD) at lumbar spine (L2-L4) from baseline to month 24 or last visit measure by T-score

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    End point title
    		 Change in bone mineral density (BMD) at lumbar spine (L2-L4) from baseline to month 24 or last visit measure by T-score
    End point description
    Bone mineral density (BMD) at lumbar spine (L2-L4) by T-score. Your T-score is the number of units that your bone density is above or below the average. -1 and above-bone density is considered normal; Between -1 and -2.5-is a sign of osteopenia, a condition in which bone density is below normal and may lead to osteoporosis. -2.5 and below-indicates that it is likely osteoporosis.
    End point type
    Primary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: T-score
        arithmetic mean (standard deviation)
    -0.622 ± 0.346
    0.309 ± 0.348
    Statistical analysis title
    		 Change in BMD for T-Score
    Comparison groups
    Placebo v Zoledronic Acid
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval

    Primary: Change in bone mineral density (BMD) at lumbar spine (L2-L4) from baseline to month 24 or last visit measure by Z-score

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    End point title
    		 Change in bone mineral density (BMD) at lumbar spine (L2-L4) from baseline to month 24 or last visit measure by Z-score
    End point description
    Bone mineral density (BMD) at lumbar spine (L2-L4) measured by Z-score. If Z-score is -2 or lower, it may suggest that something other than aging is causing abnormal bone loss.
    End point type
    Primary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: Z-score
        arithmetic mean (standard deviation)
    -0.658 ± 0.355
    0.309 ± 0.414
    Statistical analysis title
    		 Change in BMD -Z Score
    Comparison groups
    Placebo v Zoledronic Acid
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval

    Primary: Percent change in bone mineral density for L2-L4 from baseline to month 24 or last visit

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    End point title
    		 Percent change in bone mineral density for L2-L4 from baseline to month 24 or last visit
    End point description
    Bone mineral density (BMD) at lumbar spine (L2-L4) measured by using Lunar or Hologic dual-energy X-ray absorptiometry (DXA) Instruments. Measurements were done in the lumbar vertebrae (L2-L4)
    End point type
    Primary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: percentage change
        arithmetic mean (standard deviation)
    6.429 ± 3.414
    3.139 ± 3.388
    Statistical analysis title
    		 Change in BMD - Month 24
    Comparison groups
    Placebo v Zoledronic Acid
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change in bone mineral density for femoral neck (right and left side) from baseline to month 24

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    End point title
    		 Change in bone mineral density for femoral neck (right and left side) from baseline to month 24
    End point description
    Bone mineral density (BMD) for femoral neck (right and left side) is measured by using Lunar or Hologic dual-energy X-ray absorptiometry (DXA) Instruments. Measurements were done on femoral neck (right and left side)
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: change in BMD
    arithmetic mean (standard deviation)
        femoral neck (right)
    -0.023 ± 0.033
    0.011 ± 0.021
        femoral neck (left)
    -0.023 ± 0.035
    0.008 ± 0.028
    No statistical analyses for this end point

    Secondary: Change in bone mineral density for total femoral neck (right and left side) from baseline to month 24

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    End point title
    		 Change in bone mineral density for total femoral neck (right and left side) from baseline to month 24
    End point description
    Bone mineral density (BMD) for total femoral neck (right and left side) is measured by using Lunar or Hologic dual-energy X-ray absorptiometry (DXA) Instruments. Measurements were done on femoral neck (right and left side)
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: change in BMD
    arithmetic mean (standard deviation)
        femoral neck (right)
    -0.039 ± 0.028
    0.013 ± 0.018
        femoral neck (left)
    -0.036 ± 0.028
    0.014 ± 0.018
    No statistical analyses for this end point

    Secondary: Change in bone mineral density Os calcis (right and left side) from baseline to month 24 as measured by speed of sound (SOS)

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    End point title
    		 Change in bone mineral density Os calcis (right and left side) from baseline to month 24 as measured by speed of sound (SOS)
    End point description
    Bone mineral density (BMD) for Os calcis (right and left side) is measured by SOS; SOS is a Quantitative ultrasonography scanning and measures bone mass and strength and assesses bone microarchitecture by detecting the transmission of high-frequency sound waves through bone.
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: m/s
    arithmetic mean (standard deviation)
        Os calcis (right)
    -13.139 ± 23.111
    -10.853 ± 16.613
        Os calcis (left)
    -13.028 ± 19.761
    -13.485 ± 15.969
    No statistical analyses for this end point

    Secondary: Change in bone mineral density Os calcis (right and left side) from baseline to month 24 as measured by broadband ultrasound attenuation (BUA)

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    End point title
    		 Change in bone mineral density Os calcis (right and left side) from baseline to month 24 as measured by broadband ultrasound attenuation (BUA)
    End point description
    Bone mineral density (BMD) for Os calcis (right and left side) is measured by BUA; BUA is a Quantitative ultrasonography scanning and measures bone mass and strength and assesses bone microarchitecture by detecting the transmission of high-frequency sound waves through bone.
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: dB/MHz
    arithmetic mean (standard deviation)
        Os calcis (right)
    -0.306 ± 11.369
    1.824 ± 8.997
        Os calcis (left)
    -2.417 ± 12.514
    1.848 ± 9.628
    No statistical analyses for this end point

    Secondary: Change in bone mineral density Phalanges II, III, IV, and V from baseline to month 24 or last visit as measured by Amplitude-dependent speed of sound (ADSOS)

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    End point title
    		 Change in bone mineral density Phalanges II, III, IV, and V from baseline to month 24 or last visit as measured by Amplitude-dependent speed of sound (ADSOS)
    End point description
    Bone mineral density (BMD) for Phalanges II, III, IV, and V is measured by ADSOS; ADSOS is a Quantitative ultrasonography scanning and measures bone mass and strength and assesses bone microarchitecture by detecting the transmission of high-frequency sound waves through bone.
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: m/s
    arithmetic mean (standard deviation)
        Phalanges II (n=35, 33)
    -48.514 ± 50.905
    -21.485 ± 78.284
        Phalanges III (n=35, 33)
    -62.971 ± 53.76
    -19.879 ± 70.968
        Phalanges IV (n=35, 33)
    -49.086 ± 61.99
    0.455 ± 93.598
        Phalanges V (n=35, 33)
    -35 ± 38.072
    0.303 ± 79.985
    No statistical analyses for this end point

    Secondary: Change in Serum CTX-carboxy-terminal collagen crosslinks from baseline to month 24

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    End point title
    		 Change in Serum CTX-carboxy-terminal collagen crosslinks from baseline to month 24
    End point description
    CTX is a telopeptide that can be used as a biomarker in the serum to measure the rate of bone turnover. The test used to detect the CTX marker is specific to bone resorption.
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: ng/mL
        arithmetic mean (standard deviation)
    0.137 ± 0.164
    -0.118 ± 0.11
    No statistical analyses for this end point

    Secondary: Change in Aminoterminal propeptide on type I procollagen (P1NP) from baseline to month 24

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    End point title
    		 Change in Aminoterminal propeptide on type I procollagen (P1NP) from baseline to month 24
    End point description
    Change in Aminoterminal propeptide on type I procollagen (P1NP) from baseline to month 24. P1NP is a marker for bone formation. It is a specific indicator of type 1 collagen deposition. P1NP is increased in states of high bone turnover
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: ng/ml
        arithmetic mean (standard deviation)
    16.729 ± 19.346
    -21.476 ± 13.142
    No statistical analyses for this end point

    Secondary: Change in Estradiol (E2) from baseline to month 24

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    End point title
    		 Change in Estradiol (E2) from baseline to month 24
    End point description
    Change in Estradiol from baseline to month 24
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: ng/L
        arithmetic mean (standard deviation)
    -119.026 ± 213.03
    -10.421 ± 134.529
    No statistical analyses for this end point

    Secondary: Change in Follicle- Stimulating Hormone (FSH) from baseline to month 24

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    End point title
    		 Change in Follicle- Stimulating Hormone (FSH) from baseline to month 24
    End point description
    Change in Follicle- Stimulating Hormone (FSH) from baseline to month 24
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: mIU/ml
        arithmetic mean (standard deviation)
    -0.593 ± 36.851
    0.86 ± 28.444
    No statistical analyses for this end point

    Secondary: Change in Testosterone from baseline to month 24

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    End point title
    		 Change in Testosterone from baseline to month 24
    End point description
    Change in Testosterone from baseline to month 24
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: ng/ml
        arithmetic mean (standard deviation)
    0.039 ± 0.11
    0.015 ± 0.111
    No statistical analyses for this end point

    Secondary: Change in Sex Hormone binding globulin (SHGB) from baseline to month 24

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    End point title
    		 Change in Sex Hormone binding globulin (SHGB) from baseline to month 24
    End point description
    Change in Sex Hormone binding globulin (SHGB) from baseline to month 24
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: nmol/l
        arithmetic mean (standard deviation)
    5.609 ± 45.614
    12.806 ± 32.501
    No statistical analyses for this end point

    Secondary: Change in Parathyroid Hormone (PTH) from baseline to month 24

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    End point title
    		 Change in Parathyroid Hormone (PTH) from baseline to month 24
    End point description
    Change in Parathyroid Hormone (PTH) from baseline to month 24
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: pg/ml
        arithmetic mean (standard deviation)
    7.288 ± 12.838
    4.729 ± 10.401
    No statistical analyses for this end point

    Secondary: Change in Vitamine D from baseline to month 24

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    End point title
    		 Change in Vitamine D from baseline to month 24
    End point description
    Change in Vitamine D from baseline to month 24
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: ng/ml
        arithmetic mean (standard deviation)
    11.163 ± 9.234
    9.638 ± 9.242
    No statistical analyses for this end point

    Secondary: Change in anti-Mueller hormone (AMH) from baseline to month 24

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    End point title
    		 Change in anti-Mueller hormone (AMH) from baseline to month 24
    End point description
    Change in anti-Mueller hormone (AMH) from baseline to month 24
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: ng/ml
        arithmetic mean (standard deviation)
    -0.584 ± 0.962
    -0.878 ± 2.019
    No statistical analyses for this end point

    Secondary: Change in Inhibin A and Inhibin B from baseline to month 24

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    End point title
    		 Change in Inhibin A and Inhibin B from baseline to month 24
    End point description
    Change in Inhibin A and Inhibin B from baseline to month 24
    End point type
    Secondary
    End point timeframe
    baseline, month 24
    End point values
    		 Placebo Zoledronic Acid
    Number of subjects analysed
    36
    34
    Units: pg/ml
    arithmetic mean (standard deviation)
        Inhibin A (n=34,34)
    -19.079 ± 29.592
    -10.209 ± 24.125
        Inhibin B (n=34,34)
    -28.2 ± 41.545
    -39.126 ± 43.421
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14
    Reporting groups
    Reporting group title
    Zometa
    Reporting group description
    		 Zometa

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Zometa Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 34 (17.65%)
    3 / 36 (8.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BREAST CANCER
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOMA
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    ADENOIDECTOMY
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYSTERECTOMY
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    ATAXIA
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    DENTAL CARIES
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL OEDEMA
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATOCHEZIA
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    MENORRHAGIA
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    OSTEONECROSIS
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    FEBRILE INFECTION
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBCUTANEOUS ABSCESS
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Zometa Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 34 (97.06%)
    36 / 36 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BASAL CELL CARCINOMA
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Vascular disorders
    HOT FLUSH
         subjects affected / exposed
    16 / 34 (47.06%)
    20 / 36 (55.56%)
         occurrences all number
    16
    20
    HYPERTENSION
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    LYMPHOEDEMA
         subjects affected / exposed
    11 / 34 (32.35%)
    19 / 36 (52.78%)
         occurrences all number
    11
    20
    THROMBOSIS
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    General disorders and administration site conditions
    CHILLS
         subjects affected / exposed
    7 / 34 (20.59%)
    1 / 36 (2.78%)
         occurrences all number
    9
    1
    FATIGUE
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    IMPAIRED HEALING
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    11 / 34 (32.35%)
    4 / 36 (11.11%)
         occurrences all number
    11
    5
    PYREXIA
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    Reproductive system and breast disorders
    MENOPAUSAL SYMPTOMS
         subjects affected / exposed
    16 / 34 (47.06%)
    14 / 36 (38.89%)
         occurrences all number
    16
    14
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    5 / 34 (14.71%)
    1 / 36 (2.78%)
         occurrences all number
    5
    1
    SLEEP DISORDER
         subjects affected / exposed
    2 / 34 (5.88%)
    7 / 36 (19.44%)
         occurrences all number
    2
    7
    Investigations
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    Injury, poisoning and procedural complications
    RADIATION SKIN INJURY
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    6 / 34 (17.65%)
    3 / 36 (8.33%)
         occurrences all number
    8
    3
    MIGRAINE
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    MOVEMENT DISORDER
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    PARAESTHESIA
         subjects affected / exposed
    4 / 34 (11.76%)
    6 / 36 (16.67%)
         occurrences all number
    4
    6
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    3
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    LEUKOPENIA
         subjects affected / exposed
    2 / 34 (5.88%)
    4 / 36 (11.11%)
         occurrences all number
    2
    4
    Eye disorders
    VISUAL IMPAIRMENT
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    CONSTIPATION
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    GASTRITIS
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    NAUSEA
         subjects affected / exposed
    8 / 34 (23.53%)
    5 / 36 (13.89%)
         occurrences all number
    8
    6
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    HYPERHIDROSIS
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    URGE INCONTINENCE
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    16 / 34 (47.06%)
    22 / 36 (61.11%)
         occurrences all number
    16
    26
    BACK PAIN
         subjects affected / exposed
    4 / 34 (11.76%)
    4 / 36 (11.11%)
         occurrences all number
    4
    4
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    BONE PAIN
         subjects affected / exposed
    11 / 34 (32.35%)
    12 / 36 (33.33%)
         occurrences all number
    12
    16
    MUSCULOSKELETAL STIFFNESS
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    MYALGIA
         subjects affected / exposed
    5 / 34 (14.71%)
    0 / 36 (0.00%)
         occurrences all number
    7
    0
    PAIN IN EXTREMITY
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    OSTEOARTHRITIS
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    PAIN IN JAW
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 36 (2.78%)
         occurrences all number
    5
    1
    CYSTITIS
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 36 (8.33%)
         occurrences all number
    2
    4
    GASTROENTERITIS
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    MASTITIS
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    INFLUENZA
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 36 (5.56%)
         occurrences all number
    4
    2
    TOOTH ABSCESS
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    VAGINAL INFECTION
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    VULVOVAGINAL CANDIDIASIS
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2006
    Issued after the inclusion of the first patient, introduced the following changes: - Change on Inclusion criteria 2: deletion of absence of evidence of regional lymph node metastasis (N0) Patient is premenopausal at diagnosis of breast cancer (spontaneous and regular - Change on Inclusion criteria 6: correction of estradiol level unit in > 10 ng/ml - Clarification of randomization, treatment blinding and medication procedure- Patients can receive adjuvant chemotherapy but do not have to.
    11 Dec 2006
    Issued after the inclusion of the first patient, introduced the following changes: Inclusion criteria: Patients under adjuvant chemoendocrine or endocrine therapy: Node negative (pN-) and Node positive (pN+; ≤ 4 positive lymph nodes) patients - Inclusion criteria: Patients under neoadjuvant chemotherapy: no clinical evidence for nodal involvement -Inclusion criteria: Patient is premenopausal; determined by spontaneous and regular menses at diagnosis of breast cancer or by premenopausal estradiol levels (>20ng/L) at diagnosis of breast cancer - Clarification of ONJ cases
    23 Nov 2007
    Issued after the inclusion of the first patient, introduced the following changes: - Change in secondary objective: Development of metastases as assessed by X-ray, CT, bone scan or MRI during 24 months and during 60 months, if data available - Change in assessment at final visit/month 60: Tumor assessments will be performed to exclude presence of bone metastases only if clinically indicated
    28 Nov 2008
    Issued after the inclusion of the first patient, introduced the following changes: - BMD by DXA and QUS as well as Tumor Assessments do not have to be repeated at Baseline (-1 month to 0) if recent data from assessments within 12 weeks to Randomization (-3 months to 0) are available and reduction of BMD and progression of disease is not suspected
    29 Jun 2011
    Issued after the inclusion of the first patient, introduced the following changes: - Change in secondary objective/efficacy assessments: additional analysis of the following biochemical markers: CTX PTH, SHBG, Testosterone, Vitamine D, anti-Müller-Hormone (AMH), Inhibin A/B, Activin A, OPG, RANKL, BSP, Sclerostin and DKK-1. Deletion of the following markers: osteocalcin, deoxypyridinoline in serum.

    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
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