Trial Outcomes & Findings for Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI (NCT NCT02352753)

Last Updated: 2022-12-28

Results Overview

Lumbar spine BMD was measured by dual-energy X-ray absorptiometry (DXA) adjusted for age, sex, and race/ethnicity. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from Baseline indicated an improvement in lumbar spine BMD.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

153 participants

Primary outcome timeframe

Baseline and 12 months

Results posted on

2022-12-28

Participant Flow

The study was conducted at 32 centers in North America, Europe, and Australia from June 2015 to March 2022.

Participant milestones

Participant milestones
Measure	Denosumab Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months. Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and pharmacokinetic (PK) data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
6-Month Dosing Period STARTED	153
6-Month Dosing Period Received Investigational Product	153
6-Month Dosing Period COMPLETED	55
6-Month Dosing Period NOT COMPLETED	98
3-Month Dosing Period STARTED	60
3-Month Dosing Period Received Investigational Product	60
3-Month Dosing Period COMPLETED	40
3-Month Dosing Period NOT COMPLETED	20

Reasons for withdrawal

Reasons for withdrawal
Measure	Denosumab Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months. Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and pharmacokinetic (PK) data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
6-Month Dosing Period Decision by sponsor	2
6-Month Dosing Period Withdrawal by Subject	34
6-Month Dosing Period Lost to Follow-up	2
6-Month Dosing Period Transitioning to Q3M	60
3-Month Dosing Period Decision by sponsor	14
3-Month Dosing Period Withdrawal by Subject	6

Baseline Characteristics

Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Denosumab n=153 Participants Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months. Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Age, Continuous	9.3 Years STANDARD_DEVIATION 3.9 • n=5 Participants
Sex: Female, Male Female	73 Participants n=5 Participants
Sex: Female, Male Male	80 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	15 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	138 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race/Ethnicity, Customized Asian	4 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	2 Participants n=5 Participants
Race/Ethnicity, Customized White	135 Participants n=5 Participants
Race/Ethnicity, Customized Other	8 Participants n=5 Participants
Race/Ethnicity, Customized Multiple	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 12 months

Population: DXA Analysis Set included all participants in the FAS with Baseline and Month 12 DXA assessment on the Q3M dosing regimen for lumbar spine as provided by the central imaging vendor.

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=45 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-Score at 12 Months	1.009 Z-score Standard Error 0.119	—

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: DXA Analysis Set included all participants in the FAS with Baseline and Month 6 DXA assessment on the Q3M dosing regimen for lumbar spine as provided by the central imaging vendor.

Lumbar spine BMD was measured by DXA adjusted for age, sex, and race/ethnicity. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from Baseline indicated an improvement in lumbar spine BMD.

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=54 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Change From Baseline in Lumbar Spine BMD Z-score at 6 Months	0.925 Z-score Standard Error 0.078	—

SECONDARY outcome

Timeframe: Baseline, 6 and 12 months

Population: DXA Analysis Set included all participants in the FAS with Baseline, Month 6 and Month 12 DXA assessment on the Q3M dosing regimen for lumbar spine as provided by the central imaging vendor. Only participants 5 years of age or older are included.

Proximal femur (total hip and femoral neck) BMD Z-score was measured by DXA adjusted for age, sex, and race/ethnicity. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from Baseline indicated an improvement in lumbar spine BMD.

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=32 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Change From Baseline in Proximal Femur BMD Z-score at 6 and 12 Months Total hip BMD Z-score - 6 Months	0.799 Z score Standard Error 0.082	—
Change From Baseline in Proximal Femur BMD Z-score at 6 and 12 Months Total hip BMD Z-score - 12 Months	0.793 Z score Standard Error 0.154	—
Change From Baseline in Proximal Femur BMD Z-score at 6 and 12 Months Femoral neck BMD Z-score - 6 Months	0.769 Z score Standard Error 0.067	—
Change From Baseline in Proximal Femur BMD Z-score at 6 and 12 Months Femoral neck BMD Z-score - 12 Months	0.689 Z score Standard Error 0.131	—

SECONDARY outcome

Timeframe: Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months

Population: Q3M Dosing Regimen Safety Analysis Set: includes all participants in the FAS who received ≥ 1 dose of Q3M dosing regimen.

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=60 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen n=60 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Percentage of Participants With at Least 1 X-ray Confirmed Long Bone or New and Worsening Vertebral Fracture	28.3 Percentage of participants	26.7 Percentage of participants

SECONDARY outcome

Timeframe: Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months

Population: The Vertebral Fracture Analysis Set: includes all participants in the FAS who had a readable non-missing baseline and ≥1 non-missing postbaseline X-ray vertebral evaluation on the Q3M dosing regimen as provided by the central imaging vendor.

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=47 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen n=47 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Percentage of Participants With at Least 1 X-ray Confirmed New and Worsening Vertebral Fracture	12.8 Percentage of participants	8.5 Percentage of participants

SECONDARY outcome

Timeframe: Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=47 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen n=47 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Percentage of Participants With at Least 1 X-ray Confirmed New Vertebral Fracture	10.6 Percentage of participants	6.4 Percentage of participants

SECONDARY outcome

Timeframe: Q3M Dosing Regimen: Baseline up to 12 months

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=47 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Percentage of Participants Wth at Least 1 X-ray Confirmed Improving Vertebral Fracture	27.7 Percentage of participants	—

SECONDARY outcome

Timeframe: Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months

Population: Q3M Dosing Regimen Safety Analysis Set: includes all participants in the FAS who received ≥ 1 dose of Q3M dosing regimen. Only participants 5 years of age or older are included.

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=56 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen n=56 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Percentage of Participants With at Least 1 Vertebral and Nonvertebral Fracture	28.6 Percentage of participants	30.4 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and 12 months

Population: Patient Reported Outcomes (PRO) Analysis Set: includes all participants in the FAS who had a baseline and ≥ 1 postbaseline valid PRO response on Q3M dosing regimen for the CHQ-PF-50. The CHQ-PF-50 analysis set only includes participants 5 years of age and older at screening.

The CHQ-PF-50 was a 50-item questionnaire completed by the parents or guardians of children between 5 and 18 years of age. The 50 questions measure 14 domains which were summarized as the physical and psychological summary scores. Each summary score was transformed and could range from 0 to 100, with higher score indicating better physical and psychosocial health. A negative change from Baseline indicates decreased well-being.

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=45 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Change From Baseline in Child Health Questionnaire-Parent Form Physical Summary Score (CHQ-PF-50) at 12 Months	-0.98 Score on a scale Standard Deviation 15.41	—

SECONDARY outcome

Timeframe: Baseline and 12 months

Population: PRO Analysis Set includes all participants in the FAS who had a baseline and ≥ 1 postbaseline valid PRO response on Q3M dosing regimen for the CHQ-PF-50. The CHQ-PF-50 analysis set only includes participants 5 years of age and older at screening

The CHQ-PF-50 was a 50-item questionnaire completed by the parents or guardians of children between 5 and 18 years of age. The 50 questions measure 14 domains which were summarized as the physical and psychological summary scores. Each summary score was transformed and could range from 0 to 100, with higher score indicating better physical and psychosocial health. A positive change from Baseline indicates improved well-being.

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=45 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12 Months	0.85 Score on a scale Standard Deviation 8.57	—

SECONDARY outcome

Timeframe: Baseline and 12 months

Population: PRO Analysis Set includes all participants in the FAS who had a baseline and ≥ 1 postbaseline valid PRO response on Q3M dosing regimen for the CHAQ disability index score.

The disability domain (questions 1-54) of the CHAQ was used to measure the participant's assessment of physical functioning or the parent's assessment of the child's physical functioning. The disability index comprised of 8 categories (dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, and activities). Scoring ranged from 1 to 5; 1 was "without any difficulty," 2 was "with some difficulty," 3 was "with much difficulty," and 4 was "unable to do." An answer of "not applicable" was scored as a 5, but was not counted. If a child required assistance from another person or used an aid or other device for any of the 8 categories, the minimum score for that category was recorded as a 3. The CHAQ questions were scored and converted to a total index score ranging from 0 to 3. Negative change from Baseline indicates an improvement.

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=51 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12 Months	-0.06 Score on a scale Standard Deviation 0.46	—

SECONDARY outcome

Timeframe: Baseline and 12 months

Population: Patient Reported Outcomes (PRO) Analysis Set: includes all participants in the FAS who had a baseline and ≥ 1 postbaseline valid PRO response on Q3M dosing regimen for the WBFPRS.

Participants were asked to report their level of pain by choosing a face that best described their own pain (the corresponding number: 0, 2, 4, 6, 8, 10) were then recorded. The WBFPRS ranged from 0, "no hurt," to 10, "hurts worst". A negative change from baseline indicates an improvement.

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=49 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Change From Baseline in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12 Months	0.0 Score on a scale Standard Deviation 1.7	—

SECONDARY outcome

Timeframe: Days 1 (predose), 10, 30, and 60, & weeks 12, 24, 36, 48, 60, 72 (end of study visit), early termination visit, & follow-up visit 12 weeks after last dose (average duration of treatment: 231 days)

Population: PK Analysis Set includes all participants in the 3QM dosing regimen safety analysis set who had ≥ 1 serum denosumab reported result on 3QM dosing regimen at any 1 time point.

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=60 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Serum Concentration of Denosumab Day 1	8.1 ng/mL Standard Deviation 62.0	—
Serum Concentration of Denosumab Day 10	6685.4 ng/mL Standard Deviation 1761.8	—
Serum Concentration of Denosumab Day 30	3840.5 ng/mL Standard Deviation 1329.9	—
Serum Concentration of Denosumab Day 60	1291.4 ng/mL Standard Deviation 971.2	—
Serum Concentration of Denosumab Week 12 Day 1	406.2 ng/mL Standard Deviation 627.0	—
Serum Concentration of Denosumab Week 24 Day 1	589.8 ng/mL Standard Deviation 804.3	—
Serum Concentration of Denosumab Week 36	835.1 ng/mL Standard Deviation 983.5	—
Serum Concentration of Denosumab Week 48	647.3 ng/mL Standard Deviation 875.1	—
Serum Concentration of Denosumab Week 60	1266.7 ng/mL Standard Deviation 861.1	—
Serum Concentration of Denosumab Week 72	970.0 ng/mL Standard Deviation 1371.8	—
Serum Concentration of Denosumab Early Termination Visit	4.2 ng/mL Standard Deviation 11.8	—
Serum Concentration of Denosumab Week 12 Follow-up Visit	72.6 ng/mL Standard Deviation 103.9	—

SECONDARY outcome

Timeframe: Baseline and Days 10 and 30, and Months 3, 6, 9, 12, 15 and 18

Population: BTM Analysis Set: includes all participants in the 3QM dosing regimen safety analysis set who had baseline and ≥ 1 postbaseline assessment for the BTM endpoint of interest on Q3M dosing regimen.

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=54 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide Baseline	1136.5 ng/L Standard Deviation 569.7	—
Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide Day 10	174.4 ng/L Standard Deviation 64.7	—
Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide Day 30	176.5 ng/L Standard Deviation 87.9	—
Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide Month 3	498.4 ng/L Standard Deviation 332.0	—
Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide Month 6	537.1 ng/L Standard Deviation 427.1	—
Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide Month 9	539.0 ng/L Standard Deviation 425.0	—
Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide Month 12	681.2 ng/L Standard Deviation 563.1	—
Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide Month 15	1050.8 ng/L Standard Deviation 758.8	—
Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide Month 18	1290.0 ng/L Standard Deviation NA Evaluable samples were too low to calculated standard deviation.	—

SECONDARY outcome

Timeframe: Baseline and Days 10 and 30, and Months 3, 6, 9, 12, and 15

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=59 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
BTM - Bone-specific Alkaline Phosphatase (BSAP) Baseline	69.22 μg/L Standard Deviation 34.26	—
BTM - Bone-specific Alkaline Phosphatase (BSAP) Day 10	70.88 μg/L Standard Deviation 32.77	—
BTM - Bone-specific Alkaline Phosphatase (BSAP) Day 30	56.28 μg/L Standard Deviation 28.32	—
BTM - Bone-specific Alkaline Phosphatase (BSAP) Month 3	498.4 μg/L Standard Deviation 332.0	—
BTM - Bone-specific Alkaline Phosphatase (BSAP) Month 6	40.30 μg/L Standard Deviation 22.58	—
BTM - Bone-specific Alkaline Phosphatase (BSAP) Month 9	51.17 μg/L Standard Deviation 106.27	—
BTM - Bone-specific Alkaline Phosphatase (BSAP) Month 12	40.02 μg/L Standard Deviation 27.64	—
BTM - Bone-specific Alkaline Phosphatase (BSAP) Month 15	49.49 μg/L Standard Deviation 31.20	—

SECONDARY outcome

Timeframe: Baseline and 12 months

Population: Growth Velocity Analysis Set includes all participants in the FAS with non-missing height, weight, or BMI, as applicable, at Baseline and postbaseline on the Q3M dosing regimen. Only participants with observed data at Baseline and Month 12 are included.

Change from baseline in growth velocity was determined by calculating age-adjusted Z-scores for height, weight and body mass index (BMI). Height-for-age Z-score was defined as the difference between the participant's height and the median height for the population with the same age and gender, divided by the population standard deviation. The definitions of growth velocity based on weight and BMI were analogously calculated. To programmatically calculate the Z-scores, the National Center for Health Statistics percentiles growth charts, based on the 2000 Center for Disease Control and Prevention (CDC) (http://www.cdc.gov/growthcharts/c c\_charts.htm), and the CDC Anthropometric Software Package 3.0 Z-scores were used. During normal growth, the change in z-score for each of the three should equal 0. A positive change in any of the three indicates growth acceleration, whereas a negative change indicates deceleration.

Outcome measures

Outcome measures
Measure	Denosumab 3-Month Dosing Regimen n=48 Participants Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	Denosumab 3-Month Dosing Regimen Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Change From Baseline in Growth Velocity at 12 Months Height -for-age Z-score	-0.01 Z-score Standard Deviation 0.43	—
Change From Baseline in Growth Velocity at 12 Months Weight-for-age Z-score	0.01 Z-score Standard Deviation 0.53	—
Change From Baseline in Growth Velocity at 12 Months BMI-for-age Z-score	-0.07 Z-score Standard Deviation 0.52	—

Adverse Events

Denosumab 6-Month Dosing Regimen

Serious events: 52 serious events

Other events: 141 other events

Deaths: 0 deaths

Denosumab 3-Month Dosing Regimen

Serious events: 12 serious events

Other events: 38 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Email: [email protected]

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