Cancer, Cataract, Low Bone Mineral Density, Osteopenia, Osteoporosis, Prostate Cancer
Conditions
Keywords
Lens Opacification, Bone Loss, Androgen Deprivation Therapy, Non-metastatic prostate cancer
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.
Interventions
BIOLOGICALDenosumab
Prefilled syringe for subcutaneous (SC) injection administered at a dose of 60 mg
BIOLOGICALPlacebo
Prefilled syringe for subcutaneous (SC) injection
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
30 Years to 120 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Australia, Bulgaria, Canada, Czechia, France, Greece, Hungary, India, Latvia, Mexico, New Zealand, Poland, Russia, Slovakia, Slovenia, South Africa, Ukraine, United States
Participant flow
Recruitment details
This 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 details
Participants 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).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants randomized to receive placebo administered by subcutaneous injection on Day 1 and at Month 6. | 386 |
| Denosumab Participants randomized to receive denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6. | 383 |
| Total | 769 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative Decision | 1 | 1 |
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Death | 4 | 3 |
| Overall Study | Disease Progression | 1 | 3 |
| Overall Study | Ineligibility Determined | 2 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Noncompliance | 2 | 0 |
| Overall Study | Other | 3 | 1 |
| Overall Study | Protocol Deviation | 0 | 1 |
| Overall Study | Requirement for Alternative Therapy | 0 | 1 |
| Overall Study | Withdrawal by Subject | 16 | 14 |
Baseline characteristics
| Characteristic | Denosumab | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 71.1 years STANDARD_DEVIATION 7.2 | 71.0 years STANDARD_DEVIATION 7 | 71.0 years STANDARD_DEVIATION 7.1 |
| Age, Customized 18 - 64 years | 66 participants | 73 participants | 139 participants |
| Age, Customized 65 - 74 years | 194 participants | 189 participants | 383 participants |
| Age, Customized 75 - 84 years | 116 participants | 119 participants | 235 participants |
| Age, Customized ≥ 85 years | 7 participants | 5 participants | 12 participants |
| Orchiectomy (Surgical Castration) No | 332 participants | 328 participants | 660 participants |
| Orchiectomy (Surgical Castration) Yes | 51 participants | 58 participants | 109 participants |
| Participant-reported History of Cataract No | 348 participants | 351 participants | 699 participants |
| Participant-reported History of Cataract Yes | 35 participants | 35 participants | 70 participants |
| Presence of Cataract(s) No | 320 participants | 327 participants | 647 participants |
| Presence of Cataract(s) Yes | 63 participants | 59 participants | 122 participants |
| Presence of Diabetes No | 322 participants | 316 participants | 638 participants |
| Presence of Diabetes Yes | 61 participants | 70 participants | 131 participants |
| Race/Ethnicity, Customized Asian | 7 participants | 7 participants | 14 participants |
| Race/Ethnicity, Customized Black (or African American) | 11 participants | 12 participants | 23 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 9 participants | 1 participants | 10 participants |
| Race/Ethnicity, Customized Japanese | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 8 participants | 7 participants | 15 participants |
| Race/Ethnicity, Customized White | 346 participants | 359 participants | 705 participants |
| Received Androgen-deprivation Therapy (ADT) No | 30 participants | 36 participants | 66 participants |
| Received Androgen-deprivation Therapy (ADT) Yes | 353 participants | 350 participants | 703 participants |
| Screening Lens Opacities Classification System (LOCS) III Status < 3.0 at all sites [P, C, and NO] | 299 participants | 299 participants | 598 participants |
| Screening Lens Opacities Classification System (LOCS) III Status ≥ 3.0 at any of these sites | 84 participants | 87 participants | 171 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 383 Participants | 386 Participants | 769 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 107 / 380 | 121 / 385 |
| serious Total, serious adverse events | 52 / 380 | 42 / 385 |
Outcome results
Primary
Percentage of Participants With Lens Opacification Event Development or Progression by Month 12
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.
Time frame: 12 months
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Lens Opacification Event Development or Progression by Month 12 | 33.2 percentage of participants |
| Denosumab | Percentage of Participants With Lens Opacification Event Development or Progression by Month 12 | 33.5 percentage of participants |
Comparison: 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).p-value: 0.002695% CI: [-6.3, 7.2]Mantel Haenszel
Other Pre-specified
Change From Baseline in Refraction Needed to Achieve BCVA
Refraction error was measured using a phoropter. The change from baseline in spherical refraction error needed to achieve BCVA is reported.
Time frame: Baseline and months 3, 6, 9, and 12
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Refraction Needed to Achieve BCVA | Month 3 (n = 362, 358, 358, 359) | 0.01 diopters | Standard Deviation 0.6 |
| Placebo | Change From Baseline in Refraction Needed to Achieve BCVA | Month 6 (n = 347, 343, 341, 344) | -0.01 diopters | Standard Deviation 0.8 |
| Placebo | Change From Baseline in Refraction Needed to Achieve BCVA | Month 9 (n = 341, 339, 332, 332) | 0.00 diopters | Standard Deviation 0.84 |
| Placebo | Change From Baseline in Refraction Needed to Achieve BCVA | Month 12 (n = 336, 334, 328, 329) | -0.03 diopters | Standard Deviation 0.7 |
| Denosumab | Change From Baseline in Refraction Needed to Achieve BCVA | Month 12 (n = 336, 334, 328, 329) | -0.04 diopters | Standard Deviation 0.59 |
| Denosumab | Change From Baseline in Refraction Needed to Achieve BCVA | Month 9 (n = 341, 339, 332, 332) | 0.01 diopters | Standard Deviation 0.73 |
| Denosumab | Change From Baseline in Refraction Needed to Achieve BCVA | Month 6 (n = 347, 343, 341, 344) | 0.06 diopters | Standard Deviation 0.7 |
| Denosumab | Change From Baseline in Refraction Needed to Achieve BCVA | Month 3 (n = 362, 358, 358, 359) | 0.01 diopters | Standard Deviation 0.49 |
| Denosumab | Change From Baseline in Refraction Needed to Achieve BCVA | Month 9 (n = 341, 339, 332, 332) | 0.04 diopters | Standard Deviation 0.75 |
| Denosumab | Change From Baseline in Refraction Needed to Achieve BCVA | Month 12 (n = 336, 334, 328, 329) | 0.03 diopters | Standard Deviation 0.77 |
| Denosumab | Change From Baseline in Refraction Needed to Achieve BCVA | Month 6 (n = 347, 343, 341, 344) | 0.06 diopters | Standard Deviation 0.9 |
| Denosumab | Change From Baseline in Refraction Needed to Achieve BCVA | Month 3 (n = 362, 358, 358, 359) | 0.05 diopters | Standard Deviation 0.73 |
| Denosumab - Right Eye | Change From Baseline in Refraction Needed to Achieve BCVA | Month 12 (n = 336, 334, 328, 329) | 0.00 diopters | Standard Deviation 0.48 |
| Denosumab - Right Eye | Change From Baseline in Refraction Needed to Achieve BCVA | Month 3 (n = 362, 358, 358, 359) | 0.04 diopters | Standard Deviation 0.51 |
| Denosumab - Right Eye | Change From Baseline in Refraction Needed to Achieve BCVA | Month 6 (n = 347, 343, 341, 344) | 0.04 diopters | Standard Deviation 0.59 |
| Denosumab - Right Eye | Change From Baseline in Refraction Needed to Achieve BCVA | Month 9 (n = 341, 339, 332, 332) | 0.01 diopters | Standard Deviation 0.62 |
Other Pre-specified
Number of Participants With Adverse Events
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.
Time frame: 12 months
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events | Any adverse event | 193 participants |
| Placebo | Number of Participants With Adverse Events | Serious adverse events | 52 participants |
| Placebo | Number of Participants With Adverse Events | AE leading to discontinuation of study drug | 5 participants |
| Placebo | Number of Participants With Adverse Events | AE leading to discontinuation from study | 2 participants |
| Placebo | Number of Participants With Adverse Events | Fatal adverse events | 4 participants |
| Placebo | Number of Participants With Adverse Events | AE grade 3, 4, or 5 | 53 participants |
| Placebo | Number of Participants With Adverse Events | Treatment-related adverse events | 19 participants |
| Placebo | Number of Participants With Adverse Events | Serious treatment-related adverse events | 1 participants |
| Placebo | Number of Participants With Adverse Events | TRAE leading to discontinuation of study drug | 1 participants |
| Placebo | Number of Participants With Adverse Events | TRAE leading to discontinuation from study | 0 participants |
| Placebo | Number of Participants With Adverse Events | Fatal treatment-related adverse events | 0 participants |
| Placebo | Number of Participants With Adverse Events | TRAE grade 3, 4, or 5 | 2 participants |
| Denosumab | Number of Participants With Adverse Events | Fatal treatment-related adverse events | 0 participants |
| Denosumab | Number of Participants With Adverse Events | Any adverse event | 191 participants |
| Denosumab | Number of Participants With Adverse Events | Treatment-related adverse events | 21 participants |
| Denosumab | Number of Participants With Adverse Events | Serious adverse events | 42 participants |
| Denosumab | Number of Participants With Adverse Events | TRAE leading to discontinuation from study | 1 participants |
| Denosumab | Number of Participants With Adverse Events | AE leading to discontinuation of study drug | 7 participants |
| Denosumab | Number of Participants With Adverse Events | Serious treatment-related adverse events | 2 participants |
| Denosumab | Number of Participants With Adverse Events | AE leading to discontinuation from study | 4 participants |
| Denosumab | Number of Participants With Adverse Events | TRAE grade 3, 4, or 5 | 2 participants |
| Denosumab | Number of Participants With Adverse Events | Fatal adverse events | 3 participants |
| Denosumab | Number of Participants With Adverse Events | TRAE leading to discontinuation of study drug | 3 participants |
| Denosumab | Number of Participants With Adverse Events | AE grade 3, 4, or 5 | 46 participants |
Other Pre-specified
Percentage of Participants With a Decrease From Baseline in Best Corrected Visual Acuity (BCVA) of ≥ 10 Letters
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.
Time frame: Baseline and Months 3, 6, 9 and 12
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With a Decrease From Baseline in Best Corrected Visual Acuity (BCVA) of ≥ 10 Letters | Month 3 (n = 372, 375) | 5.4 percentage of participants |
| Placebo | Percentage of Participants With a Decrease From Baseline in Best Corrected Visual Acuity (BCVA) of ≥ 10 Letters | Month 6 (n = 355, 357) | 4.2 percentage of participants |
| Placebo | Percentage of Participants With a Decrease From Baseline in Best Corrected Visual Acuity (BCVA) of ≥ 10 Letters | Month 9 (n = 350, 346) | 4.6 percentage of participants |
| Placebo | Percentage of Participants With a Decrease From Baseline in Best Corrected Visual Acuity (BCVA) of ≥ 10 Letters | Month 12 (n = 343, 342) | 5.2 percentage of participants |
| Denosumab | Percentage of Participants With a Decrease From Baseline in Best Corrected Visual Acuity (BCVA) of ≥ 10 Letters | Month 12 (n = 343, 342) | 7.3 percentage of participants |
| Denosumab | Percentage of Participants With a Decrease From Baseline in Best Corrected Visual Acuity (BCVA) of ≥ 10 Letters | Month 3 (n = 372, 375) | 6.1 percentage of participants |
| Denosumab | Percentage of Participants With a Decrease From Baseline in Best Corrected Visual Acuity (BCVA) of ≥ 10 Letters | Month 9 (n = 350, 346) | 6.6 percentage of participants |
| Denosumab | Percentage of Participants With a Decrease From Baseline in Best Corrected Visual Acuity (BCVA) of ≥ 10 Letters | Month 6 (n = 355, 357) | 6.4 percentage of participants |
Other Pre-specified
Percentage of Participants With Confirmed Lens Opacification Event Development or Progression by Month 12
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.
Time frame: 12 months
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Confirmed Lens Opacification Event Development or Progression by Month 12 | 18.3 percentage of participants |
| Denosumab | Percentage of Participants With Confirmed Lens Opacification Event Development or Progression by Month 12 | 16.1 percentage of participants |
Comparison: 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).95% CI: [-7.6, 3.3]
Other Pre-specified
Percentage of Participants With Lens Opacification Event Development or Progression by Month 6
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.
Time frame: 6 months
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Lens Opacification Event Development or Progression by Month 6 | 19.3 percentage of participants |
| Denosumab | Percentage of Participants With Lens Opacification Event Development or Progression by Month 6 | 19.0 percentage of participants |
Comparison: 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).95% CI: [-5.9, 5.3]
Other Pre-specified
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
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.
Time frame: 12 months
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | 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 | 10.7 percentage of participants |
| Denosumab | 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 | 8.4 percentage of participants |
Comparison: 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).95% CI: [-6.4, 2]