E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Osteogenesis imperfecta (OI) is a group of genetic skeletal disorders
characterized by increased bone fragility, low bone mass , and increased
bone turnover contributing to osteoporosis, fractures, and other
conditions. OI is the most common form of primary osteoporosis in
children with an estimated incidence of 1 per 25,000 live births. |
|
E.1.1.1 | Medical condition in easily understood language |
Osteogenesis Imperfecta (Brittle bone disease) |
|
E.1.1.2 | Therapeutic area | Body processes [G] - Bones and nerves physological processes [G11] |
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 |
|
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 pharmacokinetics (PK) profile following multiple SC doses of romosozumab in children and adolescents with OI |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the safety, tolerability, and immunogenicity profile
following multiple SC doses of romosozumab in children and adolescents
with OI
To evaluate the pharmacodynamic (PD) profile following multiple SC doses of romosozumab in children and adolescents with OI |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subject's legally acceptable representative has provided informed
consent and the subject has provided written assent based on local
regulations and/or guidelines prior to initiation of any study-specific
activities/procedures
Ambulatory male or female children 5 to less than 12 years of age
(cohorts 2,4, and 6) or adolescents 12 to less than 18 years of age
(cohorts 1, 3 and 5) upon entry into screening
Clinical diagnosis of OI defined as a clinical history consistent with type
I-IV OI as determined by presence of expected phenotype (eg, 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 |
|
E.4 | Principal exclusion criteria |
History of an electrophoresis pattern inconsistent with type I to type IV
OI
History of known mutation in a gene other than collagen type I
alpha/collagen type I alpha 2 (COL1AI/COL1A2) causing OI or other
metabolic bone disease
History of congenital dislocation of the radial head, interosseous
membrane calcification, or exuberant callus formation
History of osteomalacia or rickets
Body weight less than 10 kg or greater than 90 kg
History of other bone diseases that affect bone metabolism (eg,
osteoporosis pseudoglioma syndrome, idiopathic juvenile osteoporosis,
osteopetrosis, hypophosphatasia)
History of Kawasaki disease, rheumatic myocarditis, ischemic
cardiomyopathy, inherited cardiomyopathies, valvular heart disease,
nephrotic syndrome, familial hypercholesterolemia, stroke, or any
thromboembolic disorder
Evidence of untreated or unhealed oral cavities or oral infections
Unhealed or planned invasive dental or tooth procedure; removal of baby
teeth is acceptable and not considered an invasive dental procedure
Unhealed fracture as defined by orthopedic opinion
Osteotomy, rodding surgery or spinal fusion surgery within 5 months
prior to screening, or not yet healed per orthopedic surgeon
Any planned major surgery, including skeletal surgery (eg, rodding
surgery, spinal surgery) within the next 6 months from Day 1 that would
interfere with study procedures or would require missing of any IP
Symptoms associated with skull abnormalities such as basilar
invagination, basilar impression or Chiari malformation (headache
induced by coughing or straining for stool, or parasthesia or weakness)
History of malabsorption (in children with serum albumin < lower limit
normal [LLN]), malabsorption should be clinically ruled out by the
investigator to confirm eligibility)
History of long QT syndrome
History of malignancy
History of any solid organ or bone marrow transplant
Positive blood screen for hepatitis B surface antigen (HbsAg), hepatitis B
core antibody (HBcAb), or hepatitis C antibody (HepCAb), human
immunodeficiency virus (HIV) -1 or -2 antibody
History of hyper- or hypothyroidism, unless subject is on stable therapy
> 6 months and has supporting laboratory documentation within 6
months prior to or at screening indicating normal serum thyroidstimulating
hormone [TSH] value
Evidence of any of the following:
Current hyper- or hypoparathyroidism (parathyroid hormone outside the
normal range)
Renal disease: Estimated glomerular filtration rate (eGFR) < 60
mL/min/1.73 m2 (calculated by the bedside Schwartz equation at
screening)
eGFR (mL/min/1.73 m2)= 0.413 X (height/serum creatinine)
(Height is in centimeters, and serum creatinine is in mg/dL)
Current hypocalcemia (albumin-adjusted serum calcium < LLN of the
laboratory's reference range) or hypercalcemia (albumin-adjusted serum
calcium > ULN of the laboratory's reference range) at the time of
screening. Serum calcium levels may be retested once in case of an
elevated serum calcium level within 1.1 x ULN of the laboratory's
reference range.
Serum phosphorous < LLN
Vitamin D insufficiency, defined as 25OHD levels < 20 ng/mL; vitamin D repletion will be allowed and subjects may be retested.
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)
Prior treatment with:
romosozumab or other anti-sclerostin antibody
fluoride or strontium for bone disease
parathyroid hormone (PTH) or PTH derivatives within 12 months prior to
screening
Denosumab within 12 months prior to first dose of romosozumab
zoledronic acid within 6 months prior to first dose of romosozumab
oral bisphosphonates or intravenous bisphosphonates other than
zoledronic acid if the first dose of romosozumab would be before their
next scheduled bisphosphonate dose would have been given
Subject unwilling to stop IV or oral bisphosphonate prior to the first
dose of IP
Administration of any of the following treatment within 3 months prior
to screening:
Systemic glucocorticoids (≥ 5.0 mg prednisone equivalent/day for more
than 10 days) within 3 months prior to screening. Topical and inhaled
glucocorticoids will be allowed
Growth hormone (subjects on stable dose of growth hormone for at least
3 months prior to screening will be allowed)
Calcitonin
Other bone active drugs including anticonvulsants (except gabapentin
and benzodiazepines) and heparin
Chronic systemic ketoconazole, androgens (except subjects who have
received testosterone therapy for physiologic replacement in the setting
of documented hormonal deficiency), adrenocorticotropic hormone
(ACTH), cinacalcet, aluminum, lithium, protease inhibitors,
gonadotropin-releasing hormone agonists |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Romosozumab serum PK parameters: maximum-observed concentration
(Cmax), time to Cmax (tmax), area under the curve (AUC) and terminal
half life (t1/2) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Investigational product will be dosed on study days 1, 29 and 57 after completion of all pre-dose procedures. Safety assessments, including blood samples for anti-romosozumab antibodies, PK
and PD measurements and time points are defined in the Schedule of Assessments as per the Protocol. |
|
E.5.2 | Secondary end point(s) |
• Treatment-emergent adverse events, including events of injection
site reactions and changes in cranial nerve function.Vital signs,
electrocardiograms, physical examinations, and safety laboratory tests,
including serum calcium
• Incidence of anti-romosozumab antibodies
• Bone turnover markers including serum P1NP and serum CTX
measurements.
• Lumbar spine BMD, bone mineral content (BMC), bone area, and BMD
Z-score as assessed by dual-energy X-ray absorptiometry (DXA) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Investigational product will be dosed on study days 1, 29 and 57 after completion of all pre-dose procedures. Safety assessments, including blood samples for anti-romosozumab antibodies, PK
and PD measurements and time points are defined in the Schedule of Assessments as per the Protocol. |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | Yes |
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) | No |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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 |
France |
Germany |
Greece |
Hungary |
Italy |
Spain |
Turkey |
|
E.8.7 | Trial has a data monitoring committee | No |
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
|
Defined as the date when the last subject is assessed or receives an intervention for evaluation in the study (ie, last subject last visit), following any additional parts in the study (eg, long-term follow-up), as applicable |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |