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

Amgen

Status and phase: Terminated; Phase 3

Conditions: Osteogenesis Imperfecta

Treatments: Drug: Denosumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT02352753

2014-000184-40 (EudraCT Number)

20130173

Details and patient eligibility

About

This is a prospective, multicenter, single-arm study in children 2 to 17 years of age with OI to evaluate efficacy and safety of denosumab.

Full description

To evaluate the effect of denosumab in lumbar spine bone mineral density (BMD) Z-score at 12 months, as assessed by dual-energy X-ray absorptiometry (DXA), in children 2 to 17 years of age (at the time of screening) on a 3-Month Dosing Regimen with osteogenesis imperfecta (OI)

Enrollment: 153 patients

Sex: All

Ages: 2 to 17 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

• Eligibility criteria relates to initial enrollment into this study (6-Month Dosing Regimen). Subjects reconsenting to a 3-Month Dosing Regimen will not repeat eligibility assessments

Inclusion Criteria:

• Clinical diagnosis of OI defined as a clinical history consistent with type I-IV OI Clinical severity of OI as defined by 2 or more prevalent vertebral compression fractures; OR1 prevalent vertebral compression fracture and 1 or more nonvertebral fractures within the previous 2 years; OR 3 or more fractures within the previous 2 years.

Exclusion Criteria:

• Inability or unwillingness to comply with the requirements for frequent calcium and phosphorus monitoring for 14 days after the first dose of denosumab (only applies to the first 5 subjects age 11 to17 enrolled in the study and the first 5 subjects of any age meeting the criteria for increased bone turnover

• Currently unhealed fracture or osteotomy as defined by orthopedic opinion

• Osteotomy within 5 months of screening

• Evidence of untreated oral cavities or oral infections

• Recent or planned invasive dental procedure

• Surgical tooth extraction which has not healed by screening

• History of an electrophoresis pattern inconsistent with type I to IV OI

• History of genetic testing results inconsistent with type I to IV OI

• Abnormalities of the following per central laboratory reference ranges at screening: Serum albumin corrected calcium < lower limit of normal (LLN) Serum vitamin D < 20 ng/mL; re-screening for Vitamin D level < 20 ng/mL will be allowed, after adequate supplementation

• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) > 1.5 x upper limit of normal (ULN)

• Total bilirubin (TBL) > 1.5 x ULN (subjects with Gilbert syndrome are eligible)

• Serum phosphorus < LLN

• Serum alkaline phosphatase > 20% above the ULN or > 20% below the LLN

• Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (calculated bythe Schwartz equation at screening) Evidence of any of 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

• Current, uncontrolled hypercalcemia (albumin-corrected serum Ca >10% ULN)

• History of osteomalacia or rickets (chart review)

• Other bone diseases that affect bone metabolism (eg, osteoporosis pseudoglioma syndrome, idiopathic juvenile osteoporosis, osteopetrosis, hypophosphatasia)

• History of autoimmune disease

• History of rare hereditary problems of fructose intolerance

• Positive blood screen for human immunodeficiency virus -1 or -2 antibody

• Positive blood screen for hepatitis B surface antigen or hepatitis C antibody

• Received other osteoporosis treatment or bone active treatment with the following guidelines:

• Prior treatment with

  • denosumab
  • fluoride or strontium for bone disease (fluoride taken for routine dental care is permitted)
  • parathyroid hormone (PTH) or PTH derivatives within 12 months prior to screening
  • zoledronic acid within 6 months prior to screening
  • oral bisphosphonates or intravenous bisphosphonates other than zoledronic acid if the first dose of denosumab would be before their next scheduled bisphosphonate dose would have been given

• Administration of systemic glucocorticoids (≥ 5.0 mg prednisone equivalents/day for more than 10 days) within 3 months of screening.

• Topical and inhaled glucocorticoids will be allowed

• Administration of any of the following treatment within 3 months of screening:

  • Growth hormone (subjects on stable dose of growth hormone for at least 3 months prior to screening will be allowed)

• Currently receiving treatment in another investigational drug study, or less than 30 days since ending treatment on another investigational drugstudy(s), or current or planned participation in a clinical trial that would preclude compliance with study requirements Other inclusion/exclusion criteria may apply.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Sequential Assignment

Masking: None (Open label)

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153 participants in 1 patient group

Denosumab

Experimental group

Description:

Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months. Early efficacy and PK data from Q6M dosing supported adjustment of the dosing regimen from Q6M to every 3 months (Q3M). 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.

Treatment:

Drug: Denosumab