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    Clinical Trial Results:
    A Multicenter, Double-blind, Randomized Study to Assess the Efficacy and Safety of Denosumab Produced by Two Different Processes in Postmenopausal Women With Osteoporosis

    Summary
    EudraCT number
    		 2013-001279-19
    Trial protocol
    		 CZ   PL   DK  
    Global end of trial date
    09 Jul 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    20120187
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02157948
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ-Medical Info - Clinical Trials, Amgen (Europe) GmbH, MedinfoInternational@amgen.com
    Scientific contact
    IHQ-Medical Info - Clinical Trials, Amgen (Europe) GmbH, MedinfoInternational@amgen.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
    09 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study are to evaluate 1. whether the efficacy of denosumab (60 mg subcutaneously every 6 months) manufactured by the proposed process referred to as CP4 is not inferior to that of denosumab manufactured by the currently approved commercial process referred to as CP2 based on the change in lumbar spine bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) at 12 months in postmenopausal women with osteoporosis; 2. whether the efficacy of denosumab CP4 (60 mg subcutaneously every 6 months) is equivalent to that of denosumab CP2 based on the change in lumbar spine BMD by DXA at 12 months in postmenopausal women with osteoporosis.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. The study protocol and the informed consent form were reviewed by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) and written approval was received by Amgen before recruitment of subjects and shipment of Amgen investigational product (IP). All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 May 2014
    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
    Poland: 167
    Country: Number of subjects enrolled
    Denmark: 142
    Country: Number of subjects enrolled
    United States: 52
    Country: Number of subjects enrolled
    Canada: 33
    Worldwide total number of subjects
    394
    EEA total number of subjects
    309
    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)
    135
    From 65 to 84 years
    257
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 21 centers in Poland, Denmark, United States (US), and Canada. The first subject enrolled on 05 May 2014 and the last subject enrolled on 03 July 2014.

    Pre-assignment
    Screening details
    		 Ambulatory postmenopausal women 55 years or older with a BMD value equivalent to a T-score of ≤ 2.5 at lumbar spine, total hip, or femoral neck were eligible to enroll. Five hundred and forty-seven subjects were screened; 394 were enrolled and 153 did not meet eligibility criteria.

    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
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Denosumab CP2
    Arm description
    		 Participants received denosumab CP2 60 mg subcutaneously once every 6 months for 1 year.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Denosumab CP2
    Investigational medicinal product code
    Other name
    Prolia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once every 6 months

    Arm title
    		 Denosumab CP4
    Arm description
    		 Participants received denosumab CP4 60 mg subcutaneously once every 6 months for 1 year.
    Arm type
    		 Experimental

    Investigational medicinal product name
    denosumab CP4
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once every 6 months

    Number of subjects in period 1
    		Denosumab CP2 Denosumab CP4
    Started
    197
    197
    Received Treatment
    196
    196
    Completed
    188
    188
    Not completed
    9
    9
         Consent withdrawn by subject
    4
    5
         Protocol specified criteria
    2
    1
         Lost to follow-up
    3
    2
         Decision by sponsor
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Denosumab CP2
    Reporting group description
    		 Participants received denosumab CP2 60 mg subcutaneously once every 6 months for 1 year.

    Reporting group title
    Denosumab CP4
    Reporting group description
    		 Participants received denosumab CP4 60 mg subcutaneously once every 6 months for 1 year.

    Reporting group values
    		 Denosumab CP2 Denosumab CP4 Total
    Number of subjects
    		 197 197 394
    Age categorical
    Units: Subjects
        < 65 years
    		 65 70 135
        ≥ 65 years
    		 132 127 259
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68 ( 6.8 ) 68.3 ( 7.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 197 197 394
        Male
    		 0 0 0
    Race
    Units: Subjects
        White
    		 190 195 385
        Asian
    		 4 1 5
        Native Hawaiian or Other Pacific Islander
    		 2 1 3
        Other
    		 1 0 1
    Lumbar Spine Bone Mineral Density (BMD) T-score
    The T-score is the bone mineral density (BMD) at the site when compared to that of a healthy thirty-year-old. Normal is a T-score of −1.0 or higher; Osteopenia is defined as between −1.0 and −2.5; Osteoporosis is defined as −2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a thirty-year-old man/woman.
    Units: T-score
        arithmetic mean (standard deviation)
    		 -2.75 ( 0.91 ) -2.75 ( 0.75 ) -
    Serum Type I collagen C-telopeptide (CTX-1)
    Units: ng/mL
        arithmetic mean (standard deviation)
    		 0.48 ( 0.333 ) 0.501 ( 0.269 ) -
    Serum Procollagen type 1 N-terminal (P1NP)
    Units: µg/L
        arithmetic mean (standard deviation)
    		 62 ( 31.7 ) 64.5 ( 32.8 ) -

    End points

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    End points reporting groups
    Reporting group title
    Denosumab CP2
    Reporting group description
    		 Participants received denosumab CP2 60 mg subcutaneously once every 6 months for 1 year.

    Reporting group title
    Denosumab CP4
    Reporting group description
    		 Participants received denosumab CP4 60 mg subcutaneously once every 6 months for 1 year.

    Primary: Percent Change from Baseline in Lumbar Spine BMD

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    End point title
    		 Percent Change from Baseline in Lumbar Spine BMD
    End point description
    Lumbar spine bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. The primary efficacy analysis subset included all randomized subjects who had a baseline lumbar spine DXA BMD measurement and at least 1 postbaseline lumbar spine DXA BMD measurement. Postbaseline BMD values obtained at the early termination visit were carried forward as the month-12 value.
    End point type
    Primary
    End point timeframe
    Baseline and Month 12
    End point values
    		 Denosumab CP2 Denosumab CP4
    Number of subjects analysed
    187 [1]
    188 [2]
    Units: percent change
        arithmetic mean (standard deviation)
    5.78 ( 3.44 )
    5.73 ( 3.08 )
    Notes
    [1] - Subjects with a non-missing baseline and at least 1 non-missing postbaseline measurement
    [2] - Subjects with a non-missing baseline and at least 1 non-missing postbaseline measurement
    Statistical analysis title
    		 Non-inferiority Testing
    Statistical analysis description
    The treatment comparison was analyzed using the analysis of covariance (ANCOVA) model including treatment, baseline BMD value, machine type, and machine type-by-baseline BMD value interaction. The effect of denosumab CP4 on lumbar spine BMD at 12 months relative to the effect of denosumab CP2 was estimated by the least-squares mean of the treatment difference (denosumab CP4 – denosumab CP2) and the corresponding 2-sided 95% confidence interval (CI).
    Comparison groups
    Denosumab CP2 v Denosumab CP4
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.001 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Difference from CP2
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.72
         upper limit
    		 0.57
    Notes
    [3] - The lower bound of the 2-sided 95% CI of the between-group difference (denosumab CP4 – denosumab CP2) in percent change from baseline in lumbar spine BMD at 12 months was compared with the non-inferiority margin of -1.44% for assessing non-inferiority.
    [4] - One-sided p-value based on the prespecified non-inferiority margin of -1.44% for lumbar spine
    Statistical analysis title
    		 Equivalence Testing
    Statistical analysis description
    The treatment comparison was analyzed using the analysis of covariance (ANCOVA) model including treatment, baseline BMD value, machine type, and machine type-by-baseline BMD value interaction. The effect of denosumab CP4 on lumbar spine BMD at 12 months relative to the effect of denosumab CP2 was estimated by the least-squares mean of the treatment difference (denosumab CP4 – denosumab CP2) and the corresponding 2-sided 95% confidence interval (CI).
    Comparison groups
    Denosumab CP2 v Denosumab CP4
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    P-value
    		 < 0.001 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Difference from CP2
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.72
         upper limit
    		 0.57
    Notes
    [5] - The lower and upper bounds of the same 2-sided 95% CI of the between-group difference were compared with the equivalence margin of ±1.44% for assessing equivalence.
    [6] - Two-sided p-value based on the prespecified equivalence margin of ±1.44% for lumbar spine.

    Secondary: Percent Change from Baseline in Serum Type I Collagen C-telopeptide (sCTX)

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    End point title
    		 Percent Change from Baseline in Serum Type I Collagen C-telopeptide (sCTX)
    End point description
    The bone turnover marker (BTM) efficacy analysis subset includes all randomized subjects who had a baseline measurement and at least one post baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline, month 1, month 6 and month 12
    End point values
    		 Denosumab CP2 Denosumab CP4
    Number of subjects analysed
    197
    197
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Month 1 (n = 195, 193)
    -86.39 (-90.65 to -78.45)
    -88.05 (-91.12 to -80.79)
        Month 6 (n = 191, 189)
    -76.46 (-85.58 to -60.58)
    -79.48 (-87.06 to -66.86)
        Month 12 (n = 187, 188)
    -71.34 (-83.33 to -47.13)
    -75.44 (-85.88 to -61.9)
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Serum Procollagen Type 1 N-terminal Propeptide (P1NP)

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    End point title
    		 Percent Change from Baseline in Serum Procollagen Type 1 N-terminal Propeptide (P1NP)
    End point description
    The bone turnover marker (BTM) efficacy analysis subset includes all randomized subjects who had a baseline measurement and at least one post baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and month 1, month 6 and month 12
    End point values
    		 Denosumab CP2 Denosumab CP4
    Number of subjects analysed
    197
    197
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Month 1 (N = 195, 193)
    -29.59 (-38.06 to -20.02)
    -29.86 (-38.8 to -20.9)
        Month 6 (n = 192, 190)
    -76.63 (-82.9 to -66.69)
    -77.74 (-85.02 to -70.31)
        Month 12 (n = 186, 188)
    -71.44 (-77.64 to -57.35)
    -72.08 (-80.24 to -62.4)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 Months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Denosumab CP4
    Reporting group description
    		 Participants received denosumab CP4 60 mg subcutaneously once every 6 months for 1 year.

    Reporting group title
    Denosumab CP2
    Reporting group description
    		 Participants received denosumab CP2 60 mg subcutaneously once every 6 months for 1 year.

    Serious adverse events
    		 Denosumab CP4 Denosumab CP2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 196 (3.06%)
    13 / 196 (6.63%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign ovarian tumour
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site haematoma
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary contusion
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 196 (0.51%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 196 (0.00%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 196 (0.00%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 196 (0.51%)
         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
    0 / 196 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 196 (0.51%)
         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
    Dyspnoea
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 196 (0.51%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 Denosumab CP4 Denosumab CP2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 196 (18.37%)
    25 / 196 (12.76%)
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 196 (7.65%)
    11 / 196 (5.61%)
         occurrences all number
    21
    11
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    21 / 196 (10.71%)
    15 / 196 (7.65%)
         occurrences all number
    24
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 May 2014
    - Reference was removed for the possibility of informed consent for eligible subjects being provided by a legally acceptable representative. - The protocol was updated to state that the comparison between denosumab CP2 and CP4, in terms of the change from baseline in lumbar spine BMD, was being performed using noninferiority testing in addition to equivalence testing to conform to guidance received from the US FDA. - Minor clarifications were made to the exclusion criteria, and other administrative changes were made where necessary. Typographic and formatting errors were corrected throughout the protocol.

    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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