Study to Evaluate Efficacy, Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis Imperfecta

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 150

Inclusion Criteria

- Informed consent (to be provided by parent or legal guardian) and informed assent (to be provided by subjects when age-appropriate).
- Children aged 2 to 17 years inclusive at screening
- Clinical diagnosis of OI defined as a clinical history consistent with type I-IV OI as determined by presence of expected phenotype (examples include: facial shape, voice, blue sclera, dentinogenesis imperfecta, typical radiographic features, fracture pattern) and lack of additional features unrelated to type I-IV OI (eg, blindness, mental retardation, neuropathy, craniosynostosis; premature exfoliation of deciduous teeth)
o* If familial, also must be autosomal dominant
- Clinical severity of OI as defined by
o 2 or more prevalent vertebral compression fractures; OR
o 1 prevalent vertebral compression fracture and 1 or more nonvertebral fractures within the previous 2 years; OR
o 3 or more fractures within the previous 2 years
Are the trial subjects under 18? yes
Number of subjects for this age range: 150
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

Subjects meeting any of the following criteria at screening are not eligible for enrollment:
- 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 (see Section 2.3.2.1)
- 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 known mutation in a gene other than COL1A1/COL1A2 causing OI or metabolic bone disease
- Abnormalities of the following per central laboratory reference ranges at screening:
o Serum albumin corrected calcium < lower limit of normal (LLN)
o Serum vitamin D < 20 ng/mL; re-screening for Vitamin D level < 20 ng/mL will be allowed, after adequate supplementation
o Aspartate aminotransferase (AST), alanine aminotransferase (ALT) > 1.5 x upper limit of normal (ULN)
o Total bilirubin (TBL) > 1.5 x ULN (subjects with Gilbert syndrome are eligible)
o Serum phosphorus < LLN
o Serum alkaline phosphatase > 20% above the ULN or > 20% below the LLN
- Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (calculated by the Schwartz equation at screening)
- Evidence of any of the following:
o Current hyperthyroidism (unless well-controlled on stable antithyroid therapy)
o Current clinical hypothyroidism (unless well-controlled on stable thyroid replacement therapy)
o History of hyperparathyroidism
o Current hypoparathyroidism
o Current, uncontrolled hypercalcemia (albumin-corrected serum Ca >10% ULN)
o Current metaphyseal index Z-score > +1
o History of osteomalacia or rickets (chart review)
o Other bone diseases that affect bone metabolism (eg, osteoporosis pseudoglioma syndrome, idiopathic juvenile osteoporosis, osteopetrosis, hypophosphatasia)
o History of autoimmune disease
o History of malabsorption (in children with serum albumin < LLN, malabsorption should be clinically ruled out by the PI to confirm eligibility)
o History of rare hereditary problems of fructose intolerance
o History of long QT syndrome
o History of non-healing osteotomy
o History of malignancy
o History of alcohol or drug abuse
o History of any solid organ or bone marrow transplant
o Contraindicated or poorly tolerant of denosumab therapy
- Positive blood screen for human immunodeficiency virus -1 or -2 antibody
- Positive blood screen for hepatitis B surface antigen or hepatitis C antibody
- Currently pregnant or planning a pregnancy during the study and for an additional 5 months after the last dose of denosumab
- For sexually active girls: refusal to use highly effective methods of contraception and to continue this practice for 5 months after the last injection of denosumab

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

Study to Evaluate Efficacy, Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis Imperfecta

Recruitment & Eligibility

Study & Design

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