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

• Register: EUCTR
• Last refreshed on: 19 April 2022
• Main ID: EUCTR2014-000184-40-HU
• Date of registration: 29/08/2014
• Prospective Registration: Yes
• Primary sponsor: Amgen, Inc.
• Public title: Study to Evaluate Efficacy, Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis Imperfecta
• Scientific title: Prospective, Multicenter, Single-arm Study to Evaluate Efficacy, Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis Imperfecta
• Date of first enrolment: 18/10/2014
• Target sample size: 150
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-000184-40
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Bulgaria, Canada, Czech Republic, France, Germany, Hungary, Italy, Poland, Spain, United Kingdom, United States

Contacts

• Name: IHQ-Medical Info - Clinical Trials
• Affiliation: Amgen (Europe) GmbH

• Name: IHQ-Medical Info - Clinical Trials
• Affiliation: Amgen (Europe) GmbH

Key inclusion & exclusion criteria

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)
?* 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 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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Osteogenesis Imperfecta
MedDRA version: 19.0 Level: PT Classification code 10031243 Term: Osteogenesis imperfecta System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Trade Name: XGEVA
Product Name: Denosumab
Product Code: AMG 162
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Denosumab
CAS Number: 615258-40-7
Current Sponsor code: AMG 162
Other descriptive name: Denosumab - Immunoglobulin G2 Human Monoclonal Antibody to RANK Ligand
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 70-

Primary Outcome(s)

Main Objective: To evaluate the effect of denosumab on 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 with osteogenesis imperfecta (OI).

Secondary Objective: To evaluate denosumab in children 2 to 17 years of age with OI with respect to:
- Change in lumbar spine BMD Z-score, as assessed by DXA, at 6, 18, 24, and 36 months
- Change in proximal femur BMD Z-score, as assessed by DXA, at 6, 12, 18, 24, and 36 months (in subjects 5 years of age and older)
- Incidence of x-ray confirmed long bone and new and worsening vertebral fractures from pre-treatment to post-treatment at 12, 24, and 36 months
- Incidence of improving vertebral fractures from pre-treatment to post-treatment at 12, 24, and 36 months (overall, among subjects with clinical fracture reduction, and among subjects with clinical fracture increase)
- Incidence of pre-treatment compared with post-treatment vertebral and nonvertebral fractures at 12, 24, and 36 months
+ Exploratory and Safety objectives
For complete list, please refer to the protocol

Primary end point(s): Change from baseline in lumbar spine BMD Z-score, as assessed by DXA, at 12 months.

Timepoint(s) of evaluation of this end point: at 12 months

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: see list above

Secondary end point(s): - Change from baseline in lumbar spine BMD Z-score, as assessed by DXA, at 6, 18, 24, and 36 months
- Change from baseline in proximal femur BMD Z-score, as assessed by DXA, at 6, 12, 18, 24, and 36 months (in subjects 5 years of age and older)
- Subject incidence of x-ray confirmed long bone and new and worsening vertebral fractures at 12, 24, and 36 months compared to pre-treatment
- Subject incidence of improved vertebral fractures at 12, 24, and 36 months compared to pre-treatment (overall, among subjects with clinical fracture reduction and among subjects with clinical fracture increase)
- Subject incidence of vertebral and nonvertebral fractures at 12, 24, and 36 months compared to pre-treatment
- Change from baseline in CHQ-PF-50 Physical Summary score at 12, 24, and 36 months
- Change from baseline in CHQ-PF-50 Psychological Summary score at 12, 24, and 36 months
- Change from baseline in CHAQ Disability Index score at 12, 24, and 36 months
- Change from baseline in WBFPRS at 12, 24, and 36 months
- Change from baseline in growth velocity (determined by calculating age-adjusted Z-scores for height, weight and BMI) at 36 months
- Serum concentration of denosumab at 1 and 10 days, and 6, 12, 18, 24, 30, and 36 months
- Serum concentration of denosumab at 1, 10, and 30 days, and 3, 6, 12, 18, 24, 30, and 36 months (PK/BTM substudy only)

Secondary ID(s)

20130173

2014-000184-40-CZ

Source(s) of Monetary Support

Amgen Inc

Ethics review

Status: Approved
Approval date: 14/10/2014
Contact: