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    Clinical Trial Results:
    A PHASE 2, MULTICENTER, RANDOMIZED, ACTIVE-CONTROLLED, PARALLEL-GROUP, DOSE-FINDING AND SAFETY STUDY OF RECOMBINANT HUMAN BONE MORPHOGENETIC PROTEIN-2 (RHBMP 2)/CALCIUM PHOSPHATE MATRIX (CPM) IN SUBJECTS WITH DECREASED BONE MINERAL DENSITY

    Summary
    EudraCT number
    		 2007-007456-34
    Trial protocol
    		 ES   BE   PL   FI   NL  
    Global end of trial date
    24 Apr 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    3100N0-2213-WW
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00752557
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 East 42nd Street,, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 800 718 1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 800 718 1021, ClinicalTrials.gov_Inquiries@pfizer.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
    31 Aug 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Apr 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to show increased bone mineral density (BMD) of the proximal femur (total hip [TH] BMD) after injection of rhBMP-2/CPM (either 1 mg/mL) as an adjunct to systemic osteoporosis (OP) therapy. To assess the primary objective, BMD was measured by dual-energy x-ray absorptiometry (DXA) every 3 months from 6 to 12 months.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants.
    Background therapy
    		 Regardless of treatment group assignment, bisphosphonate, calcium, and vitamin D were provided to all study participants as background therapy to provide adequate protection against osteoporosis.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Dec 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 60 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    United States: 41
    Worldwide total number of subjects
    46
    EEA total number of subjects
    5
    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)
    0
    From 65 to 84 years
    45
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 10 centers in the United States of America, Belgium, and Poland.

    Pre-assignment
    Screening details
    		 Treatments were stratified by previous OP therapy regardless of rhBMP-2/CPM treatment assignment; bisphosphonate, calcium, vitamin D were provided to all participants as background concomitant OP therapy. Due to early termination of participant enrollment, efficacy analyses were not performed as the study never reached its intended sample size.

    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
    Blinding implementation details
    The trial was designed to allow for the Sponsor to be fully unblinded throughout the trial. To minimize the selection bias, the trial used a centralized, automated randomization procedure. Separate randomization lists were available for each randomization strata (Naïve participants and those with previous exposure to system OP therapy). To further reduce selection bias, randomization was carried out at the level of the hip, systematically and prospectively designated by the randomization schema.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard of Care Control
    Arm description
    		 Participants had received systemic osteoporosis therapy with an oral bisphosphonate plus supplemental calcium, and vitamin D as prescribed by the study physician.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oral bisphosphonate therapy, Calcium and Vitamin D
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral bisphosphonate plus supplemental calcium, and vitamin D as prescribed by the study physician.

    Arm title
    		 rhBMP-2/CPM 1.0 mg/mL
    Arm description
    		 Participants had received 1 mg/mL rhBMP 2/CPM administered via intraosseous injection administered percutaneously to the proximal femur. Participants in treatment groups additionally received SOC treatment for OP.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rhBMP-2/CPM (Dibotermin alfa)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraosseous use
    Dosage and administration details
    1 mg/mL rhBMP-2/CPM administered via intraosseous injection administered percutaneously to the proximal femur.

    Arm title
    		 rhBMP-2/CPM 2.0 mg/mL
    Arm description
    		 Participants had received 2 mg/mL rhBMP 2/CPM administered via intraosseous injection administered percutaneously to the proximal femur. Participants in both injected treatment groups additionally received SOC treatment for OP.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rhBMP-2/CPM (Dibotermin alfa)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraosseous use
    Dosage and administration details
    2 mg/mL rhBMP-2/CPM administered via intraosseous injection administered percutaneously to the proximal femur.

    Number of subjects in period 1
    		Standard of Care Control rhBMP-2/CPM 1.0 mg/mL rhBMP-2/CPM 2.0 mg/mL
    Started
    17
    15
    14
    Completed
    12
    11
    11
    Not completed
    5
    4
    3
         Consent withdrawn by subject
    4
    3
    2
         Lost to follow-up
    1
    -
    1
         Unspecified reasons
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard of Care Control
    Reporting group description
    		 Participants had received systemic osteoporosis therapy with an oral bisphosphonate plus supplemental calcium, and vitamin D as prescribed by the study physician.

    Reporting group title
    rhBMP-2/CPM 1.0 mg/mL
    Reporting group description
    		 Participants had received 1 mg/mL rhBMP 2/CPM administered via intraosseous injection administered percutaneously to the proximal femur. Participants in treatment groups additionally received SOC treatment for OP.

    Reporting group title
    rhBMP-2/CPM 2.0 mg/mL
    Reporting group description
    		 Participants had received 2 mg/mL rhBMP 2/CPM administered via intraosseous injection administered percutaneously to the proximal femur. Participants in both injected treatment groups additionally received SOC treatment for OP.

    Reporting group values
    		 Standard of Care Control rhBMP-2/CPM 1.0 mg/mL rhBMP-2/CPM 2.0 mg/mL Total
    Number of subjects
    		 17 15 14 46
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0
        From >= 65 years
    		 17 15 14 46
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 73.35 ( 5.454 ) 75.93 ( 5.271 ) 73.21 ( 5.041 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 17 15 14 46
        Male
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Standard of Care Control
    Reporting group description
    		 Participants had received systemic osteoporosis therapy with an oral bisphosphonate plus supplemental calcium, and vitamin D as prescribed by the study physician.

    Reporting group title
    rhBMP-2/CPM 1.0 mg/mL
    Reporting group description
    		 Participants had received 1 mg/mL rhBMP 2/CPM administered via intraosseous injection administered percutaneously to the proximal femur. Participants in treatment groups additionally received SOC treatment for OP.

    Reporting group title
    rhBMP-2/CPM 2.0 mg/mL
    Reporting group description
    		 Participants had received 2 mg/mL rhBMP 2/CPM administered via intraosseous injection administered percutaneously to the proximal femur. Participants in both injected treatment groups additionally received SOC treatment for OP.

    Primary: Change from Baseline in Bone Mineral Density (BMD) measured by Dual-Energy X-ray Absorptiometry (DXA)

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    End point title
    		 Change from Baseline in Bone Mineral Density (BMD) measured by Dual-Energy X-ray Absorptiometry (DXA) [1]
    End point description
    Evaluating local changes (expected increases) in BMD after administration of rhBMP-2/CPM, compared to those observed with systemic osteoporosis therapy alone. Alternatively, if changes in the total area surrounding the proximal femur are observed, bone mineral content (BMC) may instead be applied for the primary measure. BMD is defined as a derived measure of bone density, generated by dividing the bone mineral content value obtained from a bone densitometry technique (for example, DXA) by the total area of the region scanned. Due to early termination of participant enrollment, mainly descriptive statistics were provided, and no statistical tests were performed.
    End point type
    Primary
    End point timeframe
    12 months post dose
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analysis was done.
    End point values
    		 Standard of Care Control rhBMP-2/CPM 1.0 mg/mL rhBMP-2/CPM 2.0 mg/mL
    Number of subjects analysed
    14
    12
    14
    Units: g/cm2
    arithmetic mean (standard deviation)
        Total hip
    -0.0026 ( 0.018 )
    0.1299 ( 0.045 )
    0.1196 ( 0.063 )
        Intertrochanter
    -0.0029 ( 0.02 )
    0.1063 ( 0.066 )
    0.1192 ( 0.063 )
        Trochanter
    -0.0091 ( 0.023 )
    0.1197 ( 0.066 )
    0.0869 ( 0.073 )
        Femoral neck
    0.0058 ( 0.021 )
    0.2408 ( 0.111 )
    0.212 ( 0.117 )
    No statistical analyses for this end point

    Primary: Time course distribution of volumetric BMD for the Hip Under Study (HUS) for total hip

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    End point title
    		 Time course distribution of volumetric BMD for the Hip Under Study (HUS) for total hip [2]
    End point description
    Evaluating local changes (expected increases) in BMD after administration of rhBMP-2/CPM, compared to those observed with systemic osteoporosis therapy alone. Alternatively, if changes in the total area surrounding the proximal femur are observed, bone mineral content (BMC) may instead be applied for the primary measure.
    End point type
    Primary
    End point timeframe
    12 months with Follow-Up ±14 days
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analysis was done.
    End point values
    		 Standard of Care Control rhBMP-2/CPM 1.0 mg/mL rhBMP-2/CPM 2.0 mg/mL
    Number of subjects analysed
    13
    11
    14
    Units: mg/cm3
    arithmetic mean (standard deviation)
        Cortical + Sub-Cortical
    136.8 ( 16.91 )
    165.6 ( 18.37 )
    151.6 ( 26.07 )
        Peeled Trabecular
    45.1 ( 16.02 )
    77.8 ( 23.07 )
    88.4 ( 37.63 )
        Integral
    181.9 ( 20.6 )
    243.4 ( 31.04 )
    240 ( 45.31 )
    No statistical analyses for this end point

    Primary: Timecourse Distribution of Volumetric Bone Mineral Density (BMD) for the Hip Under Study (HUS). Volume of Interest: Femoral Neck

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    End point title
    		 Timecourse Distribution of Volumetric Bone Mineral Density (BMD) for the Hip Under Study (HUS). Volume of Interest: Femoral Neck [3]
    End point description
    Evaluating local changes (expected increases) in BMD after administration of rhBMP-2/CPM, compared to those observed with systemic osteoporosis therapy alone. Alternatively, if changes in the total area surrounding the proximal femur are observed, bone mineral content (BMC) may instead be applied for the primary measure.
    End point type
    Primary
    End point timeframe
    12 months with Follow-Up ±14 days
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analysis was done.
    End point values
    		 Standard of Care Control rhBMP-2/CPM 1.0 mg/mL rhBMP-2/CPM 2.0 mg/mL
    Number of subjects analysed
    13
    11
    14
    Units: mg/cm3
    arithmetic mean (standard deviation)
        Cortical +Sub Cortical
    144.3 ( 16.81 )
    166.3 ( 31.06 )
    164.4 ( 29.37 )
        Peeled Trabecular
    61.1 ( 14.39 )
    165 ( 59.13 )
    159.3 ( 38.97 )
        Integral
    205.4 ( 23.02 )
    331.3 ( 73.99 )
    323.7 ( 58.96 )
    No statistical analyses for this end point

    Secondary: Summary of Cortical Thickness and Trabecular Bone Volume Calculated by Quantitative Computed Tomography (vQTC)

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    End point title
    		 Summary of Cortical Thickness and Trabecular Bone Volume Calculated by Quantitative Computed Tomography (vQTC)
    End point description
    Measurement of cortical thickness in various regions of interest (ROIs) in the femoral neck, proximal shaft, and individual trochanters and quantification of trabecular bone volume in ROIs
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Standard of Care Control rhBMP-2/CPM 1.0 mg/mL rhBMP-2/CPM 2.0 mg/mL
    Number of subjects analysed
    5
    7
    6
    Units: mg/cm3
    arithmetic mean (standard deviation)
        Cortical Thickness
    2.5782 ( 0.16805 )
    2.4259 ( 0.24267 )
    2.5128 ( 0.17484 )
        Trabecular Bone Volume
    0 ( 0 )
    4.7073 ( 2.405 )
    4.2205 ( 1.63904 )
    No statistical analyses for this end point

    Secondary: Number participant responses to Injectability Questionnaire Injected Population

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    End point title
    		 Number participant responses to Injectability Questionnaire Injected Population [4]
    End point description
    Investigator documents preparation of the study medication evaluates injectability and product placement relative to desired location (for participants in active treatment groups). Surgeon performing the injection had to complete the questionnaire that evaluates ease of preparing the study medication, ability to administer study medication, and ability for the study medication to remain in the location it was administered.
    End point type
    Secondary
    End point timeframe
    Participants were monitored after treatment administration (dosing period)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No descriptive statistics was done for the reporting arm standard of care control.
    End point values
    		 rhBMP-2/CPM 1.0 mg/mL rhBMP-2/CPM 2.0 mg/mL
    Number of subjects analysed
    15
    14
    Units: Participants
        Ease of Preparing-satisfactory
    15
    14
        Ease of Preparing-unsatisfactory
    0
    0
        Ease of Injecting-satisfactory
    15
    11
        Ease of Injecting-unsatisfactory
    0
    3
        Ability to inject entire volume- satisfactory
    13
    12
        Ability to inject entire volume- unsatisfactory
    2
    2
        Localization within Proximal Femur-satisfactory
    15
    11
        Localization within Proximal Femur-unsatisfactory
    0
    2
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline in Serum Biomarkers of Bone Turnover

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    End point title
    		 Percentage Change from Baseline in Serum Biomarkers of Bone Turnover
    End point description
    Biomarkers of bone formation and resorption and serum biomarkers of bone turnover with percentage change from baseline are listed by participant. No significant changes in biochemical markers of bone turnover were identified. Additionally, the number of partcipants treated was too small to draw any further conclusions.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Standard of Care Control rhBMP-2/CPM 1.0 mg/mL rhBMP-2/CPM 2.0 mg/mL
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    Units: percentage of participants
    Notes
    [5] - The number of participants treated was too small to draw any conclusion.
    [6] - The number of participants treated was too small to draw any conclusion.
    [7] - The number of participants treated was too small to draw any conclusion.
    No statistical analyses for this end point

    Secondary: Timecourse Distribution of Areal Bone Mineral Density (BMD) for the contralateral: Region of Interest: for Total Hip

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    End point title
    		 Timecourse Distribution of Areal Bone Mineral Density (BMD) for the contralateral: Region of Interest: for Total Hip
    End point description
    Evaluating local changes (expected increases) in BMD after administration of rhBMP-2/CPM, compared to those observed with systemic osteoporosis therapy alone. The percentage change from baseline in BMD for total hip (assessed by DXA) is presented for the contralateral (untreated) hip below.
    End point type
    Secondary
    End point timeframe
    36 months
    End point values
    		 Standard of Care Control rhBMP-2/CPM 1.0 mg/mL rhBMP-2/CPM 2.0 mg/mL
    Number of subjects analysed
    10
    12
    12
    Units: mg/cm2
        arithmetic mean (standard deviation)
    0.73 ( 0.057 )
    0.71 ( 0.045 )
    0.71 ( 0.11 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the time of written informed consent through 3 years, month 36 (Visit 10) for SOC participants and through 5 years, month 60 for participants who either received 1.0 mg/mL or 2.0 mg/mL of rhBMP-2/CPM.
    Adverse event reporting additional description
    The as-treated population included randomly assigned participants who received at least 1 dose of rhBMP-2/CPM or comparator agent. Participants in the as-treated population are grouped according to the treatment they received (not the treatment to which they were randomly assigned).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Standard of Care Control
    Reporting group description
    		 Participants had received systemic osteoporosis therapy with an oral bisphosphonate plus supplemental calcium, and vitamin D as prescribed by the study physician.

    Reporting group title
    rhBMP-2/CPm 2.0 mg/mL
    Reporting group description
    		 Participants had received 2 mg/mL rhBMP 2/CPM administered via intraosseous injection administered percutaneously to the proximal femur. Participants in treatment groups additionally received SOC treatment for OP.

    Reporting group title
    rhBMP-2/CPM 1.0 mg/mL
    Reporting group description
    		 Participants had received 1 mg/mL rhBMP 2/CPM administered via intraosseous injection administered percutaneously to the proximal femur. Participants in treatment groups additionally received SOC treatment for OP.

    Serious adverse events
    		 Standard of Care Control rhBMP-2/CPm 2.0 mg/mL rhBMP-2/CPM 1.0 mg/mL
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 17 (17.65%)
    7 / 14 (50.00%)
    7 / 15 (46.67%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Nuclear magnetic resonance imaging abnormal
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Intracranial aneurysm
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Oesophagitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone infarction
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Standard of Care Control rhBMP-2/CPm 2.0 mg/mL rhBMP-2/CPM 1.0 mg/mL
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 17 (76.47%)
    12 / 14 (85.71%)
    15 / 15 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Benign neoplasm of skin
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Choroid melanoma
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Colon adenoma
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Dysplastic naevus
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Neoplasm
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    Skin papilloma
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Tumour ulceration
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Aortic calcification
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Hypotension
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Vascular calcification
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Breakthrough pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Chills
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Facial pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Gait deviation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Gait disturbance
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Injection site bruising
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site discharge
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Injection site erythema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Injection site mass
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Injection site pain
         subjects affected / exposed
    0 / 17 (0.00%)
    5 / 14 (35.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    8
    0
    Injection site swelling
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Malaise
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Pain
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences all number
    2
    1
    3
    Peripheral swelling
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    2
    Pyrexia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Soft tissue inflammation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Vulvovaginal discomfort
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Vulvovaginal pruritus
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    2
    Choking sensation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Cough
         subjects affected / exposed
    3 / 17 (17.65%)
    3 / 14 (21.43%)
    1 / 15 (6.67%)
         occurrences all number
    3
    3
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    Nasal congestion
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences all number
    2
    1
    2
    Productive cough
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Sinus congestion
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Chest X-ray abnormal
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Scan bone marrow abnormal
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Urine output increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Clavicle fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    1
    Epicondylitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Fall
         subjects affected / exposed
    4 / 17 (23.53%)
    3 / 14 (21.43%)
    5 / 15 (33.33%)
         occurrences all number
    5
    6
    5
    Fibula fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Hand fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Head injury
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Humerus fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Injection related reaction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Joint injury
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Laceration
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    1
    Ligament sprain
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Lower limb fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle strain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Patella fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Procedural hypotension
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    0 / 17 (0.00%)
    5 / 14 (35.71%)
    2 / 15 (13.33%)
         occurrences all number
    0
    6
    3
    Road traffic accident
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Skeletal injury
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    4
    0
    Skin abrasion
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Superficial injury of eye
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Thermal burn
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Wound
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Wrist fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Chronotropic incompetence
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 14 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Dizziness postural
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 14 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    1
    3
    4
    Hypoaesthesia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    4
    0
    Lethargy
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Loss of consciousness
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Meralgia paraesthetica
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Neuralgia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Peroneal nerve palsy
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Sciatica
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Sinus headache
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    11
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Bone marrow oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Lymph node calcification
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Lymphadenopathy
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Choroidal haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Dark circles under eyes
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Eye pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Eyelid ptosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Cataract
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Macular generation
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Retinal haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Cheilitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    1
    0
    3
    Diarrhoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Dry mouth
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Gastric ulcer
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Hiatus hernia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 17 (5.88%)
    5 / 14 (35.71%)
    6 / 15 (40.00%)
         occurrences all number
    2
    8
    6
    Oesophagitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Oral discomfort
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Pancreatic cyst
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 14 (21.43%)
    3 / 15 (20.00%)
         occurrences all number
    0
    4
    4
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Dandruff
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    Dermatitis allergic
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Erythema
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    2
    Ingrowing nail
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Rash
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Skin lesion
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Incontinence
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Renal failure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 17 (29.41%)
    9 / 14 (64.29%)
    12 / 15 (80.00%)
         occurrences all number
    9
    19
    24
    Arthritis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Back pain
         subjects affected / exposed
    2 / 17 (11.76%)
    3 / 14 (21.43%)
    4 / 15 (26.67%)
         occurrences all number
    5
    3
    23
    Bone pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Bursitis
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    2
    Exostosis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Foot deformity
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Intervertebral disc degeneration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Joint effusion
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Joint range of motion decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Joint swelling
         subjects affected / exposed
    2 / 17 (11.76%)
    4 / 14 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    2
    7
    4
    Mobility decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Limb discomfort
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences all number
    1
    4
    3
    Muscle swelling
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 14 (14.29%)
    3 / 15 (20.00%)
         occurrences all number
    2
    2
    9
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 14 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    2
    3
    1
    Myalgia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    0
    3
    Osteitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Osteoarthritis
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 14 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    1
    3
    2
    Pain in extremity
         subjects affected / exposed
    3 / 17 (17.65%)
    4 / 14 (28.57%)
    2 / 15 (13.33%)
         occurrences all number
    3
    11
    2
    Pain in jaw
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Periarthritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Plantar fasciitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    2
    Scoliosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Synovitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Tendonitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Vertebral osteophyte
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Weight bearing difficulty
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    2
    Infections and infestations
    Arthritis infective
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 14 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    3
    2
    2
    Coccidioidomycosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    4
    0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Labyrinthitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    Lung infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    0
    4
    0
    Onychomycosis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Osteomyelitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Rhinitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences all number
    2
    1
    2
    Tooth infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Iodine deficiency
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Oct 2009
    In Protocol amendment 1, the following changes were made; reduced number and type of diagnostic tests for Cohort 2, Removed mandatory postdosing hospital stay for Cohort 2, Extended VAS assessment, Revised Risk/Benefits Section, Shifted full physical examination from screening to predosing and added parameters for obtaining detailed medical history, Incorporated predefined stopping criteria specific to Cohort 2, Incorporated upper age limit of 85 years old. [Previously, participants ≥65 years were allowed to be enrolled], Revised terminology to describe SOC, Revised permitted/prohibited concomitant therapies, Expanded window between randomization and treatment from 24 hours to 1 week (7 days), Clarified eligibility criterion regarding use of anticonvulsant agents, Physically revised protocol so that sections of Synopsis and Body matched, Provided criteria for participant discharge, Added guidelines for pain management, Revised contact information to reflect changes in Wyeth study staff, Clarified dosing regimens and provide guidelines for calcium and vitamin D Revised verbiage for clarity and to better reflect original protocol intent.
    29 Sep 2010
    In protocol amendment 2, bone resorption to key safety events was added.
    19 Sep 2011
    In Protocol amendment 3, the following changes were made; MRI test was added as a mandatory procedure at the 24 month visit for Cohort 2 participants. MRI was a mandatory study procedure at the 36 month visit for all participants Volumetric QCT was not needed for safety follow-up; and therefore, was replaced with the MRI test. Cohort 1 received vQCT at the 24 month visit; Cohort 2 did not receive vQCT at 24 months, Radiation exposure was the same for Cohort 1 participants, but not for Cohort 2 participants because participants in this group did not receive vQCT at 24 months, Clarified the difference between follow-up vQCT scans for Cohort 1 and Cohort 2.
    01 Mar 2012
    In Protocol amendment 4, the following changes were made; text updated to reflect that Emergency contact, as well as SAE reporting fax, is no longer centralized in the USA. Each country has its own emergency contact phone number and SAE fax reporting number, Medication errors text moved and AE reporting text updated to comply with Pfizer language and format, Study suspension, termination and completion text removed; redundant with Section 5 Synopsis Ethical Considerations, and text added with respect to reporting of safety issues and serious breaches of the protocol or ICH GCP.
    26 Oct 2012
    In Protocol amendment 5, the following changes were made; projected duration of the study was updated from 46 months to 70 months. Taking into consideration the 2 confirmed cases of ON, which was considered as an important identified risk in participants with OP who received a percutaneous injection of rhBMP 2/CPM administered intraosseously into the proximal femur, Pfizer decided it would be necessary to continue following participants in the 1 and 2 mg/mL rhBMP 2/CPM treatment arms for a total of 5 years after TA injection, Duration of participant participation was updated from 36 months to 60 months for participants who received the TA (see above), In the follow-up period, additional annual evaluations at 48 and 60 months for participants who received (either 1 mg/mL or 2 mg/mL of rhBMP 2/CPM were added. This long-term extension was intended to provide supportive safety data for inclusion in the regulatory filing. Participants were to be followed for AEs and SAEs during this time, The protocol flowchart was updated to reflect the 2 additional safety evaluations scheduled at 48 and 60 month post TA injection for participants in the 1 and 2 mg/mL rhBMP 2/CPM treatment arms. SOC participants were planned to complete the study following the 36 month follow up visit. Because participants were to be followed for safety reasons after 36 months, text was amended to state that the investigator could decide whether or not the supplemental calcium and vitamin D as well as BP therapy was needed for each participant, Evaluations at additional follow-up visits added to the protocol text and Imaging modality section was updated in order to add Pelvic MRI as imaging procedure, and also to document there was no radiation exposure with pelvic MRI procedure.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Aug 2010
    Enrollment was terminated on 26 August 2010, due to the finding of an unexpected proximal femur fracture in a study medication-injected participant shortly after study medication injection and long-term follow-up of participants in the rhBMP-2/CPM-administered groups was extended from 36 months to 60 months.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to early termination of participant enrollment, mainly descriptive statistics were provided, and no statistical tests were performed. The study was terminated early due to safety concerns.
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