Evaluation of New or Worsening Lens Opacifications in Men With Non-metastatic Prostate Cancer Receiving Denosumab for Bone Loss

Sponsor
Amgen (Industry)
Overall Status
Completed
CT.gov ID
NCT00925600
Collaborator
(none)
769
Enrollment
172
Locations
2
Arms
77.4
Actual Duration (Months)
4.5
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a phase 3, randomized, double-blind, placebo-controlled study to evaluate new or worsening lens opacifications in men with non-metastatic prostate cancer receiving denosumab for bone loss due to androgen deprivation therapy.

Condition or DiseaseIntervention/TreatmentPhase
  • Biological: Denosumab
  • Biological: Placebo
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
769 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Supportive Care
Official Title:
A Double-blind, Placebo-controlled Study to Evaluate New or Worsening Lens Opacifications in Subjects With Non-metastatic Prostate Cancer Receiving Denosumab for Bone Loss Due to Androgen-Deprivation Therapy
Actual Study Start Date :
Nov 30, 2009
Actual Primary Completion Date :
May 12, 2016
Actual Study Completion Date :
May 12, 2016

Arms and Interventions

ArmIntervention/Treatment
Placebo Comparator: Placebo

Participants received placebo administered by subcutaneous injection on Day 1 and at Month 6.

Biological: Placebo
Prefilled syringe for subcutaneous (SC) injection

Experimental: Denosumab

Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.

Biological: Denosumab
Prefilled syringe for subcutaneous (SC) injection administered at a dose of 60 mg
Other Names:
  • Prolia®
  • Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants With Lens Opacification Event Development or Progression by Month 12 [12 months]

      The Lens Opacities Classification System III (LOCS III) is a slit lamp based opacification grading method. Photographs of slit lamp cross-sections of the lens are used as references for grading nuclear opalescence (NO) and nuclear color (NC), and photographs of the lens seen by retroillumination are used as references for grading cortical (C) and posterior subcapsular (P) cataract. Opacification severity is graded on a decimal scale, scores can range from 0.1 to 6.9 for NO and NC and from 0.1 to 5.9 for C and P. For each opacification type the higher grading scores indicate greater severity. Lens opacification event development or progression by month 12 was based on a change of ≥ 1.0 in P, ≥ 1.0 in C, or ≥ 0.7 in NO in the LOCS III score from baseline.

    Other Outcome Measures

    1. Percentage of Participant With Lens Opacification Event Development or Progression by Month 12 Based on a Change of ≥ 1.5 in P, ≥ 1.5 in C, or ≥ 1.5 in NO in the LOCS III Score [12 months]

      The Lens Opacities Classification System III (LOCS III) is a slit lamp based opacification grading method. Photographs of slit lamp cross-sections of the lens are used as references for grading nuclear opalescence (NO) and nuclear color (NC), and photographs of the lens seen by retroillumination are used as references for grading cortical (C) and posterior subcapsular (P) cataract. Opacification severity is graded on a decimal scale, scores can range from 0.1 to 6.9 for NO and NC and from 0.1 to 5.9 for C and P. For each opacification type the higher grading scores indicate greater severity. Lens opacification event development or progression by month 12 was based on a change ≥ 1.5 in P, ≥ 1.5 in C, or ≥ 1.5 in NO in the LOCS III score from baseline.

    2. Percentage of Participants With Lens Opacification Event Development or Progression by Month 6 [6 months]

      The Lens Opacities Classification System III (LOCS III) is a slit lamp based opacification grading method. Photographs of slit lamp cross-sections of the lens are used as references for grading nuclear opalescence (NO) and nuclear color (NC), and photographs of the lens seen by retroillumination are used as references for grading cortical (C) and posterior subcapsular (P) cataract. Opacification severity is graded on a decimal scale, scores can range from 0.1 to 6.9 for NO and NC and from 0.1 to 5.9 for C and P. For each opacification type the higher grading scores indicate greater severity. Lens opacification event development or progression by month 6 was based on a change of ≥ 1.0 in P, ≥ 1.0 in C, or ≥ 0.7 in NO in the LOCS III score from baseline.

    3. Percentage of Participants With Confirmed Lens Opacification Event Development or Progression by Month 12 [12 months]

      The Lens Opacities Classification System III (LOCS III) is a slit lamp based opacification grading method. Photographs of slit lamp cross-sections of the lens are used as references for grading nuclear opalescence (NO) and nuclear color (NC), and photographs of the lens seen by retroillumination are used as references for grading cortical (C) and posterior subcapsular (P) cataract. Opacification severity is graded on a decimal scale, scores can range from 0.1 to 6.9 for NO and NC and from 0.1 to 5.9 for C and P. For each opacification type the higher grading scores indicate greater severity. Lens opacification event development or progression by month 12 was based on a change of ≥ 1.0 in P, ≥ 1.0 in C, or ≥ 0.7 in NO in the LOCS III score from baseline. A confirmed lens opacification event development or progression was defined as 2 directly subsequent events per protocol assessments at the same location (P, C, NO) using LOCS III as above.

    4. Percentage of Participants With a Decrease From Baseline in Best Corrected Visual Acuity (BCVA) of ≥ 10 Letters [Baseline and Months 3, 6, 9 and 12]

      The best corrected visual acuity (BCVA) is the best vision one can achieve with correction (such as eye glasses) as measured on an eye chart. BCVA was assessed by a trained ophthalmologist using the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart at 4 meters. The modified University of Crete ETDRS chart was used in Ukraine, Greece, Russia and Bulgaria, which do not use the Roman alphabet. The 2000 series revised ETDRS chart was used to assess the change in all other countries. The letter score was calculated based on the number of letters that were correctly identified; higher letter scores correspond to better visual acuity.

    5. Change From Baseline in Refraction Needed to Achieve BCVA [Baseline and months 3, 6, 9, and 12]

      Refraction error was measured using a phoropter. The change from baseline in spherical refraction error needed to achieve BCVA is reported.

    6. Number of Participants With Adverse Events [12 months]

      Adverse events (AEs) were assessed for severity by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) severity grading scale, version 3.0, where Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe AE, Grade 4 =Life-threatening AE and Grade 5 = Death due to AE. Treatment-related AEs (TRAEs) include only events for which the investigator indicated there was a reasonable possibility they may have been caused by the study drug.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    30 Years to 120 Years
    Sexes Eligible for Study:
    Male
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Men ≥ 30 years of age with non-metastatic prostate cancer, having undergone bilateral orchiectomy or initiated androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists and is expected to continue on ADT for at least 12 months

    • Adequate visual accuracy allowing eye testing

    • Bone Mineral Density (BMD) requirements: Osteopenia if under 70 years of age; Osteopenia or normal BMD if over 70 years of age

    • Signed informed consent

    Exclusion Criteria:
    • Previous surgery for cataracts in both eyes, current diagnosis of cataracts, cataracts surgery foreseen in the near future, or ocular disease leading to visual loss

    • Diagnosis of osteoporosis

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Research SiteAnaheimCaliforniaUnited States92801
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    152Research SiteBratislavaSlovakia851 05
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    157Research SiteNitraSlovakia949 01
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    Sponsors and Collaborators

    • Amgen

    Investigators

    • Study Director: MD, Amgen

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT00925600
    Other Study ID Numbers:
    • 20080560
    • 2009-012076-26
    First Posted:
    Jun 22, 2009
    Last Update Posted:
    May 30, 2017
    Last Verified:
    Apr 1, 2017

    Study Results

    Participant Flow

    Recruitment DetailsThis study was conducted at 125 centers in 18 countries: Australia, Bulgaria, Canada, the Czech Republic, France, Greece, Hungary, India, Latvia, Mexico, New Zealand, Poland, Russia, Slovakia, Slovenia, South Africa, Ukraine, and the United States. The first participant enrolled on 30 November 2009 and the last participant enrolled on 04 May 2015.
    Pre-assignment DetailParticipants were randomly assigned to receive denosumab or placebo in a 1:1 allocation ratio. Randomization was stratified on the basis of screening Lens Opacities Classification System (LOCS) III status (< 3.0 at all sites versus ≥ 3.0 at any site); age group (< 75, ≥ 75 years), and patient-reported history of cataract (yes/no).
    Arm/Group TitlePlaceboDenosumab
    Arm/Group DescriptionParticipants randomized to receive placebo administered by subcutaneous injection on Day 1 and at Month 6.Participants randomized to receive denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
    Period Title: Overall Study
    STARTED386383
    Received Treatment383382
    COMPLETED354355
    NOT COMPLETED3228

    Baseline Characteristics

    Arm/Group TitlePlaceboDenosumabTotal
    Arm/Group DescriptionParticipants randomized to receive placebo administered by subcutaneous injection on Day 1 and at Month 6.Participants randomized to receive denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.Total of all reporting groups
    Overall Participants386383769
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    71.0
    (7.0)
    71.1
    (7.2)
    71.0
    (7.1)
    Age, Customized (participants) [Number]
    18 - 64 years
    73
    18.9%
    66
    17.2%
    139
    18.1%
    65 - 74 years
    189
    49%
    194
    50.7%
    383
    49.8%
    75 - 84 years
    119
    30.8%
    116
    30.3%
    235
    30.6%
    ≥ 85 years
    5
    1.3%
    7
    1.8%
    12
    1.6%
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    0
    0%
    0
    0%
    Male
    386
    100%
    383
    100%
    769
    100%
    Race/Ethnicity, Customized (participants) [Number]
    White
    359
    93%
    346
    90.3%
    705
    91.7%
    Black (or African American)
    12
    3.1%
    11
    2.9%
    23
    3%
    Hispanic/Latino
    1
    0.3%
    9
    2.3%
    10
    1.3%
    Other
    7
    1.8%
    8
    2.1%
    15
    2%
    Asian
    7
    1.8%
    7
    1.8%
    14
    1.8%
    Japanese
    0
    0%
    1
    0.3%
    1
    0.1%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    1
    0.3%
    1
    0.1%
    Presence of Cataract(s) (participants) [Number]
    Yes
    59
    15.3%
    63
    16.4%
    122
    15.9%
    No
    327
    84.7%
    320
    83.6%
    647
    84.1%
    Presence of Diabetes (participants) [Number]
    Yes
    70
    18.1%
    61
    15.9%
    131
    17%
    No
    316
    81.9%
    322
    84.1%
    638
    83%
    Received Androgen-deprivation Therapy (ADT) (participants) [Number]
    Yes
    350
    90.7%
    353
    92.2%
    703
    91.4%
    No
    36
    9.3%
    30
    7.8%
    66
    8.6%
    Orchiectomy (Surgical Castration) (participants) [Number]
    Yes
    58
    15%
    51
    13.3%
    109
    14.2%
    No
    328
    85%
    332
    86.7%
    660
    85.8%
    Screening Lens Opacities Classification System (LOCS) III Status (participants) [Number]
    < 3.0 at all sites [P, C, and NO]
    299
    77.5%
    299
    78.1%
    598
    77.8%
    ≥ 3.0 at any of these sites
    87
    22.5%
    84
    21.9%
    171
    22.2%
    Participant-reported History of Cataract (participants) [Number]
    Yes
    35
    9.1%
    35
    9.1%
    70
    9.1%
    No
    351
    90.9%
    348
    90.9%
    699
    90.9%

    Outcome Measures

    1. Primary Outcome
    TitlePercentage of Participants With Lens Opacification Event Development or Progression by Month 12
    DescriptionThe Lens Opacities Classification System III (LOCS III) is a slit lamp based opacification grading method. Photographs of slit lamp cross-sections of the lens are used as references for grading nuclear opalescence (NO) and nuclear color (NC), and photographs of the lens seen by retroillumination are used as references for grading cortical (C) and posterior subcapsular (P) cataract. Opacification severity is graded on a decimal scale, scores can range from 0.1 to 6.9 for NO and NC and from 0.1 to 5.9 for C and P. For each opacification type the higher grading scores indicate greater severity. Lens opacification event development or progression by month 12 was based on a change of ≥ 1.0 in P, ≥ 1.0 in C, or ≥ 0.7 in NO in the LOCS III score from baseline.
    Time Frame12 months

    Outcome Measure Data

    Analysis Population Description
    The lens opacification analysis set includes randomized participants who received ≥1 dose of study drug, had an evaluable baseline and at least 1 evaluable post-baseline LOCS III assessment at the corresponding lens site. Three participants randomized to placebo who received ≥ 1 dose of denosumab in error are analyzed in the denosumab group.
    Arm/Group TitlePlaceboDenosumab
    Arm/Group DescriptionParticipants received placebo administered by subcutaneous injection on Day 1 and at Month 6.Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
    Measure Participants374379
    Number [percentage of participants]
    33.2
    8.6%
    33.5
    8.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Denosumab
    Comments The primary endpoint was summarized with the point estimate of absolute risk difference (difference in incidence rates, denosumab minus placebo) and the corresponding 95% confidence interval using the Mantel-Haenszel method adjusting for the stratification factors: baseline LOCS III status (< 3.0 at all sites [P, C, and NO] vs. ≥ 3.0 at any of these sites), age group (< 75, ≥ 75 years), and patient-reported history of cataract (yes/no).
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments Non-inferiority was demonstrated if the upper bound of the 97.5% one-sided confidence interval, or equivalently upper bound of two-sided 95% confidence interval was less than the pre-specified non-inferiority bound of 10%.
    Statistical Test of Hypothesisp-Value0.0026
    Comments
    MethodMantel Haenszel
    Comments
    Method of EstimationEstimation ParameterRisk Difference (RD)
    Estimated Value0.4
    Confidence Interval (2-Sided) 95%
    -6.3 to 7.2
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.4
    Estimation Comments
    2. Other Pre-specified Outcome
    TitlePercentage of Participant With Lens Opacification Event Development or Progression by Month 12 Based on a Change of ≥ 1.5 in P, ≥ 1.5 in C, or ≥ 1.5 in NO in the LOCS III Score
    DescriptionThe Lens Opacities Classification System III (LOCS III) is a slit lamp based opacification grading method. Photographs of slit lamp cross-sections of the lens are used as references for grading nuclear opalescence (NO) and nuclear color (NC), and photographs of the lens seen by retroillumination are used as references for grading cortical (C) and posterior subcapsular (P) cataract. Opacification severity is graded on a decimal scale, scores can range from 0.1 to 6.9 for NO and NC and from 0.1 to 5.9 for C and P. For each opacification type the higher grading scores indicate greater severity. Lens opacification event development or progression by month 12 was based on a change ≥ 1.5 in P, ≥ 1.5 in C, or ≥ 1.5 in NO in the LOCS III score from baseline.
    Time Frame12 months

    Outcome Measure Data

    Analysis Population Description
    The lens opacification analysis set includes randomized participants who received ≥1 dose of study drug, had an evaluable baseline and at least 1 evaluable post-baseline LOCS III assessment at the corresponding lens site. Three participants randomized to placebo who eceived ≥ 1 dose of denosumab in error are analyzed in the denosumab group.
    Arm/Group TitlePlaceboDenosumab
    Arm/Group DescriptionParticipants received placebo administered by subcutaneous injection on Day 1 and at Month 6.Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
    Measure Participants374379
    Number [percentage of participants]
    10.7
    2.8%
    8.4
    2.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Denosumab
    Comments The point estimate of absolute risk difference (difference in incidence rates, denosumab minus placebo) and the corresponding 95% confidence interval was constructed using the Mantel-Haenszel method adjusting for the stratification factors: baseline LOCS III status (< 3.0 at all sites [P, C, and NO] vs. ≥ 3.0 at any of these sites), age group (< 75, ≥ 75 years), and patient-reported history of cataract (yes/no).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterRisk Difference (RD)
    Estimated Value-2.2
    Confidence Interval (2-Sided) 95%
    -6.4 to 2.0
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.1
    Estimation Comments
    3. Other Pre-specified Outcome
    TitlePercentage of Participants With Lens Opacification Event Development or Progression by Month 6
    DescriptionThe Lens Opacities Classification System III (LOCS III) is a slit lamp based opacification grading method. Photographs of slit lamp cross-sections of the lens are used as references for grading nuclear opalescence (NO) and nuclear color (NC), and photographs of the lens seen by retroillumination are used as references for grading cortical (C) and posterior subcapsular (P) cataract. Opacification severity is graded on a decimal scale, scores can range from 0.1 to 6.9 for NO and NC and from 0.1 to 5.9 for C and P. For each opacification type the higher grading scores indicate greater severity. Lens opacification event development or progression by month 6 was based on a change of ≥ 1.0 in P, ≥ 1.0 in C, or ≥ 0.7 in NO in the LOCS III score from baseline.
    Time Frame6 months

    Outcome Measure Data

    Analysis Population Description
    Lens opacification analysis set includes randomized participants who received ≥1 dose of study drug, had an evaluable baseline and at least 1 evaluable post-baseline LOCS III assessment at the corresponding lens site at or before month 6. Three participants randomized to placebo who received denosumab in error are analyzed in the denosumab group.
    Arm/Group TitlePlaceboDenosumab
    Arm/Group DescriptionParticipants received placebo administered by subcutaneous injection on Day 1 and at Month 6.Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
    Measure Participants374379
    Number [percentage of participants]
    19.3
    5%
    19.0
    5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Denosumab
    Comments The point estimate of absolute risk difference (difference in incidence rates, denosumab minus placebo) and the corresponding 95% confidence interval was constructed using the Mantel-Haenszel method adjusting for the stratification factors: baseline LOCS III status (< 3.0 at all sites [P, C, and NO] vs. ≥ 3.0 at any of these sites), age group (< 75, ≥ 75 years), and patient-reported history of cataract (yes/no).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterRisk Difference (RD)
    Estimated Value-0.3
    Confidence Interval (2-Sided) 95%
    -5.9 to 5.3
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.9
    Estimation Comments
    4. Other Pre-specified Outcome
    TitlePercentage of Participants With Confirmed Lens Opacification Event Development or Progression by Month 12
    DescriptionThe Lens Opacities Classification System III (LOCS III) is a slit lamp based opacification grading method. Photographs of slit lamp cross-sections of the lens are used as references for grading nuclear opalescence (NO) and nuclear color (NC), and photographs of the lens seen by retroillumination are used as references for grading cortical (C) and posterior subcapsular (P) cataract. Opacification severity is graded on a decimal scale, scores can range from 0.1 to 6.9 for NO and NC and from 0.1 to 5.9 for C and P. For each opacification type the higher grading scores indicate greater severity. Lens opacification event development or progression by month 12 was based on a change of ≥ 1.0 in P, ≥ 1.0 in C, or ≥ 0.7 in NO in the LOCS III score from baseline. A confirmed lens opacification event development or progression was defined as 2 directly subsequent events per protocol assessments at the same location (P, C, NO) using LOCS III as above.
    Time Frame12 months

    Outcome Measure Data

    Analysis Population Description
    Lens opacification analysis set with at least two post-baseline LOCS III measurements by month 12. Three participants randomized to placebo who received at least 1 dose of denosumab in error are analyzed in the denosumab group.
    Arm/Group TitlePlaceboDenosumab
    Arm/Group DescriptionParticipants received placebo administered by subcutaneous injection on Day 1 and at Month 6.Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
    Measure Participants361367
    Number [percentage of participants]
    18.3
    4.7%
    16.1
    4.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Denosumab
    Comments The point estimate of absolute risk difference (difference in incidence rates, denosumab minus placebo) and the corresponding 95% confidence interval was constructed using the Mantel-Haenszel method adjusting for the stratification factors: baseline LOCS III status (< 3.0 at all sites [P, C, and NO] vs. ≥ 3.0 at any of these sites), age group (< 75, ≥ 75 years), and patient-reported history of cataract (yes/no).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterRisk Difference (RD)
    Estimated Value-2.2
    Confidence Interval (2-Sided) 95%
    -7.6 to 3.3
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.8
    Estimation Comments
    5. Other Pre-specified Outcome
    TitlePercentage of Participants With a Decrease From Baseline in Best Corrected Visual Acuity (BCVA) of ≥ 10 Letters
    DescriptionThe best corrected visual acuity (BCVA) is the best vision one can achieve with correction (such as eye glasses) as measured on an eye chart. BCVA was assessed by a trained ophthalmologist using the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart at 4 meters. The modified University of Crete ETDRS chart was used in Ukraine, Greece, Russia and Bulgaria, which do not use the Roman alphabet. The 2000 series revised ETDRS chart was used to assess the change in all other countries. The letter score was calculated based on the number of letters that were correctly identified; higher letter scores correspond to better visual acuity.
    Time FrameBaseline and Months 3, 6, 9 and 12

    Outcome Measure Data

    Analysis Population Description
    Lens opacification analysis set with evaluable assessments at both baseline and the time point of interest in the same eye (as indicated by "n"). Three participants randomized to placebo who received at least 1 dose of denosumab in error are analyzed in the denosumab group.
    Arm/Group TitlePlaceboDenosumab
    Arm/Group DescriptionParticipants received placebo administered by subcutaneous injection on Day 1 and at Month 6.Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
    Measure Participants374379
    Month 3 (n = 372, 375)
    5.4
    1.4%
    6.1
    1.6%
    Month 6 (n = 355, 357)
    4.2
    1.1%
    6.4
    1.7%
    Month 9 (n = 350, 346)
    4.6
    1.2%
    6.6
    1.7%
    Month 12 (n = 343, 342)
    5.2
    1.3%
    7.3
    1.9%
    6. Other Pre-specified Outcome
    TitleChange From Baseline in Refraction Needed to Achieve BCVA
    DescriptionRefraction error was measured using a phoropter. The change from baseline in spherical refraction error needed to achieve BCVA is reported.
    Time FrameBaseline and months 3, 6, 9, and 12

    Outcome Measure Data

    Analysis Population Description
    Lens opacification analysis set with evaluable assessments at both baseline and each time point in the same eye. n=the number of evaluable eyes in the lens opacification analysis set at the corresponding time point; 3 participants randomized to placebo who received denosumab in error are analyzed in the denosumab group.
    Arm/Group TitlePlacebo - Left EyePlacebo - Right EyeDenosumabDenosumab - Right Eye
    Arm/Group DescriptionParticipants received placebo subcutaneous injection on Day 1 and at Month 6.Participants received placebo subcutaneous injection on Day 1 and at Month 6.Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
    Measure Participants374374379379
    Measure eyes374374379379
    Month 3 (n = 362, 358, 358, 359)
    0.01
    (0.60)
    0.01
    (0.49)
    0.05
    (0.73)
    0.04
    (0.51)
    Month 6 (n = 347, 343, 341, 344)
    -0.01
    (0.80)
    0.06
    (0.70)
    0.06
    (0.90)
    0.04
    (0.59)
    Month 9 (n = 341, 339, 332, 332)
    0.00
    (0.84)
    0.01
    (0.73)
    0.04
    (0.75)
    0.01
    (0.62)
    Month 12 (n = 336, 334, 328, 329)
    -0.03
    (0.70)
    -0.04
    (0.59)
    0.03
    (0.77)
    0.00
    (0.48)
    7. Other Pre-specified Outcome
    TitleNumber of Participants With Adverse Events
    DescriptionAdverse events (AEs) were assessed for severity by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) severity grading scale, version 3.0, where Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe AE, Grade 4 =Life-threatening AE and Grade 5 = Death due to AE. Treatment-related AEs (TRAEs) include only events for which the investigator indicated there was a reasonable possibility they may have been caused by the study drug.
    Time Frame12 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received at least one dose of study drug. Three participants randomized to the placebo group who received at least 1 dose of denosumab in error are analyzed in the denosumab group for safety.
    Arm/Group TitlePlaceboDenosumab
    Arm/Group DescriptionParticipants received placebo administered by subcutaneous injection on Day 1 and at Month 6.Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
    Measure Participants380385
    Any adverse event
    193
    50%
    191
    49.9%
    Serious adverse events
    52
    13.5%
    42
    11%
    AE leading to discontinuation of study drug
    5
    1.3%
    7
    1.8%
    AE leading to discontinuation from study
    2
    0.5%
    4
    1%
    Fatal adverse events
    4
    1%
    3
    0.8%
    AE grade 3, 4, or 5
    53
    13.7%
    46
    12%
    Treatment-related adverse events
    19
    4.9%
    21
    5.5%
    Serious treatment-related adverse events
    1
    0.3%
    2
    0.5%
    TRAE leading to discontinuation of study drug
    1
    0.3%
    3
    0.8%
    TRAE leading to discontinuation from study
    0
    0%
    1
    0.3%
    Fatal treatment-related adverse events
    0
    0%
    0
    0%
    TRAE grade 3, 4, or 5
    2
    0.5%
    2
    0.5%

    Adverse Events

    Time Frame12 months
    Adverse Event Reporting Description All enrolled participants who received at least one dose of study drug. Three participants randomized to the placebo group received at least 1 dose of denosumab in error, and are included in the denosumab group for safety. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
    Arm/Group TitlePlaceboDenosumab
    Arm/Group DescriptionParticipants received placebo administered by subcutaneous injection on Day 1 and at Month 6.Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
    All Cause Mortality
    PlaceboDenosumab
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total/ (NaN) / (NaN)
    Serious Adverse Events
    PlaceboDenosumab
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total52/380 (13.7%) 42/385 (10.9%)
    Blood and lymphatic system disorders
    Anaemia megaloblastic1/380 (0.3%) 0/385 (0%)
    Cardiac disorders
    Angina pectoris0/380 (0%) 2/385 (0.5%)
    Atrial fibrillation1/380 (0.3%) 1/385 (0.3%)
    Cardiac failure0/380 (0%) 1/385 (0.3%)
    Cardiac failure congestive1/380 (0.3%) 0/385 (0%)
    Cardiac fibrillation1/380 (0.3%) 0/385 (0%)
    Cardio-respiratory arrest0/380 (0%) 1/385 (0.3%)
    Cardiogenic shock1/380 (0.3%) 0/385 (0%)
    Coronary artery disease2/380 (0.5%) 1/385 (0.3%)
    Coronary artery insufficiency1/380 (0.3%) 0/385 (0%)
    Coronary artery stenosis1/380 (0.3%) 0/385 (0%)
    Ischaemic cardiomyopathy0/380 (0%) 1/385 (0.3%)
    Myocardial infarction2/380 (0.5%) 1/385 (0.3%)
    Myocardial ischaemia1/380 (0.3%) 3/385 (0.8%)
    Tachycardia paroxysmal0/380 (0%) 1/385 (0.3%)
    Ventricular tachycardia0/380 (0%) 1/385 (0.3%)
    Ear and labyrinth disorders
    Tinnitus0/380 (0%) 1/385 (0.3%)
    Eye disorders
    Optic nerve disorder0/380 (0%) 1/385 (0.3%)
    Uveitis0/380 (0%) 1/385 (0.3%)
    Gastrointestinal disorders
    Abdominal pain1/380 (0.3%) 0/385 (0%)
    Colitis ulcerative0/380 (0%) 1/385 (0.3%)
    Diarrhoea2/380 (0.5%) 0/385 (0%)
    Gastrointestinal haemorrhage0/380 (0%) 1/385 (0.3%)
    Ileus1/380 (0.3%) 0/385 (0%)
    Inguinal hernia1/380 (0.3%) 1/385 (0.3%)
    Mechanical ileus1/380 (0.3%) 0/385 (0%)
    Rectal haemorrhage1/380 (0.3%) 1/385 (0.3%)
    Small intestinal stenosis0/380 (0%) 1/385 (0.3%)
    General disorders
    Asthenia1/380 (0.3%) 0/385 (0%)
    Cyst1/380 (0.3%) 0/385 (0%)
    Peripheral swelling1/380 (0.3%) 0/385 (0%)
    Pseudoangina1/380 (0.3%) 0/385 (0%)
    Pyrexia0/380 (0%) 1/385 (0.3%)
    Hepatobiliary disorders
    Bile duct stone0/380 (0%) 1/385 (0.3%)
    Cholecystitis acute1/380 (0.3%) 1/385 (0.3%)
    Cholelithiasis1/380 (0.3%) 0/385 (0%)
    Infections and infestations
    Appendicitis perforated1/380 (0.3%) 0/385 (0%)
    Arthritis bacterial1/380 (0.3%) 0/385 (0%)
    Atypical pneumonia1/380 (0.3%) 0/385 (0%)
    Diverticulitis2/380 (0.5%) 0/385 (0%)
    Herpes zoster1/380 (0.3%) 0/385 (0%)
    Kidney infection0/380 (0%) 1/385 (0.3%)
    Liver abscess0/380 (0%) 1/385 (0.3%)
    Pneumonia2/380 (0.5%) 0/385 (0%)
    Pyelonephritis acute1/380 (0.3%) 1/385 (0.3%)
    Injury, poisoning and procedural complications
    Cystitis radiation0/380 (0%) 1/385 (0.3%)
    Foot fracture1/380 (0.3%) 0/385 (0%)
    Fracture0/380 (0%) 1/385 (0.3%)
    Hip fracture1/380 (0.3%) 0/385 (0%)
    Lumbar vertebral fracture1/380 (0.3%) 1/385 (0.3%)
    Multiple injuries0/380 (0%) 1/385 (0.3%)
    Patella fracture1/380 (0.3%) 0/385 (0%)
    Radiation proctitis0/380 (0%) 1/385 (0.3%)
    Urethral stricture postoperative1/380 (0.3%) 1/385 (0.3%)
    Metabolism and nutrition disorders
    Dehydration0/380 (0%) 1/385 (0.3%)
    Diabetes mellitus inadequate control0/380 (0%) 1/385 (0.3%)
    Hyponatraemia1/380 (0.3%) 0/385 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia0/380 (0%) 1/385 (0.3%)
    Back pain1/380 (0.3%) 0/385 (0%)
    Connective tissue inflammation1/380 (0.3%) 0/385 (0%)
    Intervertebral disc compression0/380 (0%) 1/385 (0.3%)
    Osteoarthritis0/380 (0%) 2/385 (0.5%)
    Spinal osteoarthritis0/380 (0%) 1/385 (0.3%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer0/380 (0%) 1/385 (0.3%)
    Metastases to central nervous system1/380 (0.3%) 0/385 (0%)
    Plasma cell myeloma0/380 (0%) 1/385 (0.3%)
    Prostate cancer0/380 (0%) 1/385 (0.3%)
    Squamous cell carcinoma of skin1/380 (0.3%) 0/385 (0%)
    Nervous system disorders
    Aphasia1/380 (0.3%) 0/385 (0%)
    Cerebrovascular accident4/380 (1.1%) 1/385 (0.3%)
    Dementia1/380 (0.3%) 0/385 (0%)
    Dizziness2/380 (0.5%) 0/385 (0%)
    Encephalomalacia1/380 (0.3%) 0/385 (0%)
    Epilepsy1/380 (0.3%) 0/385 (0%)
    Haemorrhagic stroke1/380 (0.3%) 0/385 (0%)
    Normal pressure hydrocephalus0/380 (0%) 1/385 (0.3%)
    Syncope1/380 (0.3%) 1/385 (0.3%)
    Transient ischaemic attack1/380 (0.3%) 0/385 (0%)
    Product Issues
    Device dislocation0/380 (0%) 1/385 (0.3%)
    Device malfunction0/380 (0%) 1/385 (0.3%)
    Psychiatric disorders
    Depression1/380 (0.3%) 0/385 (0%)
    Renal and urinary disorders
    Acute kidney injury2/380 (0.5%) 0/385 (0%)
    Haematuria1/380 (0.3%) 1/385 (0.3%)
    Pelvi-ureteric obstruction1/380 (0.3%) 0/385 (0%)
    Stress urinary incontinence1/380 (0.3%) 0/385 (0%)
    Urethral stenosis1/380 (0.3%) 1/385 (0.3%)
    Urinary retention2/380 (0.5%) 0/385 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure1/380 (0.3%) 0/385 (0%)
    Chronic obstructive pulmonary disease1/380 (0.3%) 0/385 (0%)
    Chronic respiratory failure1/380 (0.3%) 0/385 (0%)
    Epistaxis0/380 (0%) 1/385 (0.3%)
    Pulmonary embolism2/380 (0.5%) 2/385 (0.5%)
    Pulmonary fibrosis1/380 (0.3%) 0/385 (0%)
    Skin and subcutaneous tissue disorders
    Diabetic foot1/380 (0.3%) 0/385 (0%)
    Rash generalised1/380 (0.3%) 0/385 (0%)
    Vascular disorders
    Deep vein thrombosis1/380 (0.3%) 0/385 (0%)
    Peripheral ischaemia1/380 (0.3%) 0/385 (0%)
    Other (Not Including Serious) Adverse Events
    PlaceboDenosumab
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total107/380 (28.2%) 121/385 (31.4%)
    Blood and lymphatic system disorders
    Anaemia4/380 (1.1%) 2/385 (0.5%)
    Cardiac disorders
    Atrial fibrillation3/380 (0.8%) 4/385 (1%)
    Ear and labyrinth disorders
    Vertigo0/380 (0%) 6/385 (1.6%)
    Eye disorders
    Vision blurred2/380 (0.5%) 5/385 (1.3%)
    Gastrointestinal disorders
    Constipation16/380 (4.2%) 8/385 (2.1%)
    Diarrhoea6/380 (1.6%) 2/385 (0.5%)
    General disorders
    Fatigue2/380 (0.5%) 6/385 (1.6%)
    Oedema peripheral1/380 (0.3%) 7/385 (1.8%)
    Infections and infestations
    Bronchitis4/380 (1.1%) 6/385 (1.6%)
    Nasopharyngitis7/380 (1.8%) 10/385 (2.6%)
    Sinusitis3/380 (0.8%) 4/385 (1%)
    Upper respiratory tract infection6/380 (1.6%) 5/385 (1.3%)
    Urinary tract infection5/380 (1.3%) 5/385 (1.3%)
    Injury, poisoning and procedural complications
    Chest injury4/380 (1.1%) 0/385 (0%)
    Investigations
    Prostatic specific antigen increased0/380 (0%) 4/385 (1%)
    Metabolism and nutrition disorders
    Diabetes mellitus5/380 (1.3%) 5/385 (1.3%)
    Type 2 diabetes mellitus4/380 (1.1%) 1/385 (0.3%)
    Musculoskeletal and connective tissue disorders
    Arthralgia10/380 (2.6%) 12/385 (3.1%)
    Back pain10/380 (2.6%) 11/385 (2.9%)
    Musculoskeletal pain5/380 (1.3%) 3/385 (0.8%)
    Myalgia2/380 (0.5%) 5/385 (1.3%)
    Osteoarthritis2/380 (0.5%) 7/385 (1.8%)
    Pain in extremity10/380 (2.6%) 6/385 (1.6%)
    Nervous system disorders
    Dizziness4/380 (1.1%) 6/385 (1.6%)
    Headache3/380 (0.8%) 6/385 (1.6%)
    Psychiatric disorders
    Insomnia3/380 (0.8%) 6/385 (1.6%)
    Renal and urinary disorders
    Dysuria4/380 (1.1%) 5/385 (1.3%)
    Haematuria4/380 (1.1%) 3/385 (0.8%)
    Pollakiuria6/380 (1.6%) 7/385 (1.8%)
    Urinary incontinence4/380 (1.1%) 1/385 (0.3%)
    Urinary retention4/380 (1.1%) 2/385 (0.5%)
    Respiratory, thoracic and mediastinal disorders
    Cough6/380 (1.6%) 4/385 (1%)
    Dyspnoea3/380 (0.8%) 4/385 (1%)
    Vascular disorders
    Hot flush7/380 (1.8%) 7/385 (1.8%)
    Hypertension16/380 (4.2%) 8/385 (2.1%)
    Hypotension5/380 (1.3%) 1/385 (0.3%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.

    Results Point of Contact

    Name/TitleStudy Director
    OrganizationAmgen Inc.
    Phone866-572-6436
    Email
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT00925600
    Other Study ID Numbers:
    • 20080560
    • 2009-012076-26
    First Posted:
    Jun 22, 2009
    Last Update Posted:
    May 30, 2017
    Last Verified:
    Apr 1, 2017