Safety and Efficiency of Denosumab in Pediatric Subjects With Glucocorticoid-induced Osteoporosis

Title: A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Study to
Evaluate the Safety and Efficacy of Denosumab in Pediatric Subjects With
Glucocorticoid-induced Osteoporosis

Study Phase: 3 Indication: Glucocorticoid-induced Osteoporosis

Primary Objective: To evaluate the effect of denosumab on lumbar spine bone mineral density
(BMD) Z-score as assessed by dual-energy X-ray absorptiometry (DXA) at 12 months in children
5 to 17 years of age with Glucocorticoid (GC)-induced osteoporosis (GiOP).

Secondary Objective(s): To evaluate the effect of denosumab in children 5 to 17 years of age
with GiOP with respect to:

- Change in lumbar spine BMD Z-score as assessed by DXA from baseline to 6, 18, 24, and 36
months

- Change in proximal femur BMD Z-score as assessed by DXA from baseline to 6, 12, 18, 24,
and 36 months

- Incidence of X-ray confirmed long-bone fractures and new and worsening vertebral
fractures from pretreatment to posttreatment at 12, 24, and 36 months

- Incidence of improving vertebral fractures from pretreatment to posttreatment at 12, 24,
and 36 months (overall, among subjects with clinical fracture reduction, and among
subjects with clinical fracture increase)

- Incidence of pretreatment compared with posttreatment vertebral and nonvertebral
fractures at 12, 24, and 36 months

- Change in Childhood Health Questionnaire - Parent Form-50 (CHQ-PF-50) Physical Summary
Score at 12, 24, and 36 months

- Change in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 months

- Change in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12,
24, and 36 months

- Change in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12, 24, and 36 months

- Change in growth velocity, determined by calculating age-adjusted Z-scores for height,
weight, and body mass index (BMI), at 24 and 36 months

- Serum concentration of denosumab at 1 and 10 days, and 6, 12, and 18 months (additional
serum denosumab pharmacokinetics [PK] samples to be collected at day 30 and month 3 in a
PK/bone turnover marker [BTM] substudy of up to 100 subjects) Hypotheses: The hypothesis
of this study is that the change from baseline in lumbar spine BMD Z-score following 12
months of denosumab treatment in children 5 to 17 years of age with GiOP will be greater
than placebo.

Inclusion Criteria:

- Male or female subjects, age 5 to 17 years, inclusive, at the time of informed
consent.

- Clinical diagnosis of GiOP as defined by the following (and consistent with the
International Society for Clinical Densitometry definition of osteoporosis in children
and adolescents [Bishop et al, 2014])

- A confirmed diagnosis of non-malignant condition(s) requiring treatment with systemic
GC (including, but not limited to, chronic rheumatologic, gastrointestinal,
neurologic, respiratory, and/or nephrological conditions)

- Subjects who are on systemic GC only as replacement therapy for adrenal insufficiency
are not eligible for the study - Treatment with systemic GC (intravenous or oral) of
any duration for the underlying non-malignant condition(s) within the 12 months prior
to screening

- Evidence of at least 1 vertebral compression fracture of Genant Grade 1 or higher, as
assessed by the central imaging vendor on lateral spine X-rays performed at screening
or within 2 months prior to screening; OR, in the absence of vertebral compression
fractures, presence of both clinically significant fracture history (ie, ≥ 2 long-bone
fractures by age 10 years or ≥ 3 long-bone fractures at any age up to 17 years) and
lumbar spine BMD Z-score ≤ -2.0, as assessed by the central imaging vendor.

- Subject's legally acceptable representative has provided informed consent when
the subject is legally too young to provide informed consent and the subject has
provided assent based on local regulations and/or guidelines prior to any
study-specific activities/procedures being initiated

- Male or female subjects, age 5 to 17 years, inclusive, at the time of informed
consent.

- Clinical diagnosis of GiOP as defined by the following (and consistent with the
International Society for Clinical Densitometry definition of osteoporosis in
children and adolescents [Bishop et al, 2014])

- A confirmed diagnosis of non-malignant condition(s) requiring treatment with systemic
GC (including, but not limited to, chronic rheumatologic, gastrointestinal,
neurologic, respiratory, and/or nephrological conditions)

- Subjects who are on systemic GC only as replacement therapy for adrenal insufficiency
are not eligible for the study

- Treatment with systemic GC (intravenous or oral) of any duration for the underlying
non malignant condition(s) within the 12 months prior to screening

- Prepubertal children should be expected to require significant GC use during the
study, per investigator opinion

Exclusion criteria will include the following:

- Current hyperthyroidism (unless well controlled on stable antithyroid therapy)

- Current clinical hypothyroidism (unless well controlled on stable thyroid replacement
therapy)

- History of hyperparathyroidism

- Current hypoparathyroidism

- Duchenne muscular dystrophy with symptomatic cardiac abnormality

- Current malabsorption

- Active infection or history of infections

- History of malignancy

- Current hyperthyroidism (unless well controlled on stable antithyroid therapy)

- Current clinical hypothyroidism (unless well controlled on stable thyroid
replacement therapy)

- History of hyperparathyroidism

- Current hypoparathyroidism

- Any causes of primary or secondary osteoporosis (other than GC use), or previous
exposure to non-GC medications, which the investigator considers to have been a
major factor contributing to the patient's fracture(s)

- Current adrenal insufficiency as the sole indication for GC therapy

- Duchenne muscular dystrophy with symptomatic cardiac abnormality

- Current malabsorption (in children with serum albumin -lower limit of normal
[LLN], malabsorption should be clinically ruled out by the investigator to
confirm eligibility)

- Known intolerance to calcium or vitamin D supplements

- Active infection or history of infections, defined as follows:

- Any active infection for which systemic anti-infectives were used within 4 weeks prior
to screening

- Serious infection, defined as requiring hospitalization or intravenous anti infectives
within 8 weeks prior to screening

- Recurrent or chronic infection or other active infection that, in the opinion of the
investigator, might compromise the safety of the subject