E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10031243 |
E.1.2 | Term | Osteogenesis imperfecta |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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). |
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E.2.2 | Secondary objectives of the trial |
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 |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PK/bone turnover markers (BTM) substudy of approximately 50 subjects to
- determine serum concentration of denosumab at 1 and 10 days and 6, 12, 18, 24, 30, and 36 months in all subjects
- evaluate changes observed in bone turnover markers (bone-specific alkaline phosphatase [BSAP], serum type I collagen C-telopeptide [sCTX]) |
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E.3 | Principal 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 |
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E.4 | Principal 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 antobody
- Positive blood screen for hepatitis B surface antigen or hepatitis C antibody
- Known to have tested positive for human immunodeficiency virus
- Known hepatic disease or evidence of acute or chronic hepatitis B or hepatitis C
- 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in lumbar spine BMD Z-score, as assessed by DXA, at 12 months. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | 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 fractures 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) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Bulgaria |
Canada |
Czech Republic |
Finland |
France |
Germany |
Hungary |
Poland |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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the end of the trial is defined as the date when the last subject is last assessed for evaluation in the study, which corresponds to the month 36 visit |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |