Trial Outcomes & Findings for Evaluation of New or Worsening Lens Opacifications in Men With Non-metastatic Prostate Cancer Receiving Denosumab for Bone Loss (NCT NCT00925600)

Last Updated: 2017-05-30

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

769 participants

Primary outcome timeframe

12 months

Results posted on

2017-05-30

Participant Flow

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.

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).

Participant milestones

Participant milestones
Measure	Placebo Participants randomized to receive placebo administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab Participants randomized to receive denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
Overall Study STARTED	386	383
Overall Study Received Treatment	383	382
Overall Study COMPLETED	354	355
Overall Study NOT COMPLETED	32	28

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants randomized to receive placebo administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab Participants randomized to receive denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
Overall Study Withdrawal by Subject	16	14
Overall Study Death	4	3
Overall Study Lost to Follow-up	2	2
Overall Study Disease Progression	1	3
Overall Study Administrative Decision	1	1
Overall Study Noncompliance	2	0
Overall Study Ineligibility Determined	2	0
Overall Study Protocol Deviation	0	1
Overall Study Requirement for Alternative Therapy	0	1
Overall Study Other	3	1
Overall Study Adverse Event	1	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=386 Participants Participants randomized to receive placebo administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab n=383 Participants Participants randomized to receive denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Total n=769 Participants Total of all reporting groups
Age, Continuous	71.0 years STANDARD_DEVIATION 7.0 • n=93 Participants	71.1 years STANDARD_DEVIATION 7.2 • n=4 Participants	71.0 years STANDARD_DEVIATION 7.1 • n=27 Participants
Age, Customized 18 - 64 years	73 participants n=93 Participants	66 participants n=4 Participants	139 participants n=27 Participants
Age, Customized 65 - 74 years	189 participants n=93 Participants	194 participants n=4 Participants	383 participants n=27 Participants
Age, Customized 75 - 84 years	119 participants n=93 Participants	116 participants n=4 Participants	235 participants n=27 Participants
Age, Customized ≥ 85 years	5 participants n=93 Participants	7 participants n=4 Participants	12 participants n=27 Participants
Sex: Female, Male Female	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Sex: Female, Male Male	386 Participants n=93 Participants	383 Participants n=4 Participants	769 Participants n=27 Participants
Race/Ethnicity, Customized White	359 participants n=93 Participants	346 participants n=4 Participants	705 participants n=27 Participants
Race/Ethnicity, Customized Black (or African American)	12 participants n=93 Participants	11 participants n=4 Participants	23 participants n=27 Participants
Race/Ethnicity, Customized Hispanic/Latino	1 participants n=93 Participants	9 participants n=4 Participants	10 participants n=27 Participants
Race/Ethnicity, Customized Other	7 participants n=93 Participants	8 participants n=4 Participants	15 participants n=27 Participants
Race/Ethnicity, Customized Asian	7 participants n=93 Participants	7 participants n=4 Participants	14 participants n=27 Participants
Race/Ethnicity, Customized Japanese	0 participants n=93 Participants	1 participants n=4 Participants	1 participants n=27 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 participants n=93 Participants	1 participants n=4 Participants	1 participants n=27 Participants
Presence of Cataract(s) Yes	59 participants n=93 Participants	63 participants n=4 Participants	122 participants n=27 Participants
Presence of Cataract(s) No	327 participants n=93 Participants	320 participants n=4 Participants	647 participants n=27 Participants
Presence of Diabetes Yes	70 participants n=93 Participants	61 participants n=4 Participants	131 participants n=27 Participants
Presence of Diabetes No	316 participants n=93 Participants	322 participants n=4 Participants	638 participants n=27 Participants
Received Androgen-deprivation Therapy (ADT) Yes	350 participants n=93 Participants	353 participants n=4 Participants	703 participants n=27 Participants
Received Androgen-deprivation Therapy (ADT) No	36 participants n=93 Participants	30 participants n=4 Participants	66 participants n=27 Participants
Orchiectomy (Surgical Castration) Yes	58 participants n=93 Participants	51 participants n=4 Participants	109 participants n=27 Participants
Orchiectomy (Surgical Castration) No	328 participants n=93 Participants	332 participants n=4 Participants	660 participants n=27 Participants
Screening Lens Opacities Classification System (LOCS) III Status < 3.0 at all sites [P, C, and NO]	299 participants n=93 Participants	299 participants n=4 Participants	598 participants n=27 Participants
Screening Lens Opacities Classification System (LOCS) III Status ≥ 3.0 at any of these sites	87 participants n=93 Participants	84 participants n=4 Participants	171 participants n=27 Participants
Participant-reported History of Cataract Yes	35 participants n=93 Participants	35 participants n=4 Participants	70 participants n=27 Participants
Participant-reported History of Cataract No	351 participants n=93 Participants	348 participants n=4 Participants	699 participants n=27 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=374 Participants Participants received placebo administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab n=379 Participants Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab - Right Eye Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
Percentage of Participants With Lens Opacification Event Development or Progression by Month 12	33.2 percentage of participants	33.5 percentage of participants	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=374 Participants Participants received placebo administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab n=379 Participants Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab - Right Eye Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
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	8.4 percentage of participants	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=374 Participants Participants received placebo administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab n=379 Participants Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab - Right Eye Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
Percentage of Participants With Lens Opacification Event Development or Progression by Month 6	19.3 percentage of participants	19.0 percentage of participants	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=361 Participants Participants received placebo administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab n=367 Participants Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab - Right Eye Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
Percentage of Participants With Confirmed Lens Opacification Event Development or Progression by Month 12	18.3 percentage of participants	16.1 percentage of participants	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=374 Participants Participants received placebo administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab n=379 Participants Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab - Right Eye Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
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	6.4 percentage of participants	—	—
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	6.6 percentage of participants	—	—
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	6.1 percentage of participants	—	—
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	7.3 percentage of participants	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=374 eyes Participants received placebo administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab n=374 eyes Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab n=379 eyes Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab - Right Eye n=379 eyes Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
Change From Baseline in Refraction Needed to Achieve BCVA Month 3 (n = 362, 358, 358, 359)	0.01 diopters Standard Deviation 0.60	0.01 diopters Standard Deviation 0.49	0.05 diopters Standard Deviation 0.73	0.04 diopters Standard Deviation 0.51
Change From Baseline in Refraction Needed to Achieve BCVA Month 6 (n = 347, 343, 341, 344)	-0.01 diopters Standard Deviation 0.80	0.06 diopters Standard Deviation 0.70	0.06 diopters Standard Deviation 0.90	0.04 diopters Standard Deviation 0.59
Change From Baseline in Refraction Needed to Achieve BCVA Month 9 (n = 341, 339, 332, 332)	0.00 diopters Standard Deviation 0.84	0.01 diopters Standard Deviation 0.73	0.04 diopters Standard Deviation 0.75	0.01 diopters Standard Deviation 0.62
Change From Baseline in Refraction Needed to Achieve BCVA Month 12 (n = 336, 334, 328, 329)	-0.03 diopters Standard Deviation 0.70	-0.04 diopters Standard Deviation 0.59	0.03 diopters Standard Deviation 0.77	0.00 diopters Standard Deviation 0.48

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=380 Participants Participants received placebo administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab n=385 Participants Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.	Denosumab - Right Eye Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
Number of Participants With Adverse Events Any adverse event	193 participants	191 participants	—	—
Number of Participants With Adverse Events Serious adverse events	52 participants	42 participants	—	—
Number of Participants With Adverse Events AE leading to discontinuation of study drug	5 participants	7 participants	—	—
Number of Participants With Adverse Events AE leading to discontinuation from study	2 participants	4 participants	—	—
Number of Participants With Adverse Events Fatal adverse events	4 participants	3 participants	—	—
Number of Participants With Adverse Events AE grade 3, 4, or 5	53 participants	46 participants	—	—
Number of Participants With Adverse Events Treatment-related adverse events	19 participants	21 participants	—	—
Number of Participants With Adverse Events Serious treatment-related adverse events	1 participants	2 participants	—	—
Number of Participants With Adverse Events TRAE leading to discontinuation of study drug	1 participants	3 participants	—	—
Number of Participants With Adverse Events TRAE leading to discontinuation from study	0 participants	1 participants	—	—
Number of Participants With Adverse Events Fatal treatment-related adverse events	0 participants	0 participants	—	—
Number of Participants With Adverse Events TRAE grade 3, 4, or 5	2 participants	2 participants	—	—

Adverse Events

Placebo

Serious events: 52 serious events

Other events: 107 other events

Deaths: 0 deaths

Denosumab

Serious events: 42 serious events

Other events: 121 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER