E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acceleration of fracture healing |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the effect of AMG 785 compared to placebo on time to radiographic healing of fresh tibial diaphyseal fractures. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of AMG 785 compared to placebo on • Physical functioning as measured by Short Form (36) Health Survey Physical Functioning subscale (SF-36 PF) • Incidence of revision surgery • Time to clinical healing as determined by the ability to bear weight on the fractured limb and the absence of pain at the fracture site |
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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 |
Study Title:
Dual energy X-ray Absorptiometry (DXA) sub-study,
Date, Version:
25 March 2009, Amendment 1
Related Objectives:
To investigate the percent change from baseline in lumbar spine BMD at Week 52.
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E.3 | Principal inclusion criteria |
Skeletally mature adults, age ≥ 18 to ≤ 85 years at randomization, with radiographically closed growth plates.
Fresh unilateral closed or Gustilo type I or type II open tibial fracture as the primary injury.
For closed fractures: Definitive fracture fixation with reamed IM nailing (modern, statically, interlocking nail) performed no later than 14 days after injury.
For Gustilo type I/II open fractures: Definitive fracture fixation with reamed or unreamed IM nailing (modern, statically, interlocking nail) performed no later than 24 hours after injury. |
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E.4 | Principal exclusion criteria |
Major polytrauma or significant axial trauma, with injury severity score >16
Head-injury, as defined by Glasgow Coma Scale <13 at time of randomization
Associated fracture of the lower extremity that, in the opinion of the surgeon, will delay the subject’s ability to bear weight beyond the normal time expected for a tibial shaft fracture
Use of bone grafts at the time of definitive fracture fixation
History of pathological fracture or metabolic or bone disease that may interfere with the interpretation of the results, such as Paget’s disease, rheumatoid arthritis, osteomalacia, osteogenesis imperfecta, osteopetrosis, ankylosing spondylitis, Cushing’s disease, hyperprolactinemia
History of spinal stenosis
History of facial nerve paralysis
Malignancy (except fully resected cutaneous basal cell or squamous cell carcinoma, cervical carcinoma in situ) within the last 5 years
History of solid organ or bone marrow transplants
Evidence of any of the following per subject report, chart review or local laboratory result (currently or within the past 5 years):
• Elevated transaminases (a) Serum aspartate aminotransferase (AST; serum glutamate-oxaloacetic transaminase [SGOT]) ≥ 2.0 x upper limits of normal; (b) Serum alanine aminotransferase (ALT; serum glutamate-pyruvate transaminase [SGPT]) ≥ 2.0 x upper limits of normal • Significantly impaired renal function as determined by a derived creatinine clearance of ≤ 30 mL/min using the Modification of Diet in Renal Disease equation (Levey et al, 1999). The estimated glomerular filtration rate is calculated as follows: estimated glomerular filtration rate (mL/min/1.73m2) = 186 x [Serum creatinine (mg/dL)]-1.154 x [Age]-0.203 x [0.742 if subject is female] x [1.210 if subject is black]. • Current hypercalcemia or hypocalcaemia (outside the normal range set by the local lab) • Hypoalbuminemia (below lower limit of normal as set by the local lab)
Known to have tested positive for human immunodeficiency virus, hepatitis C virus, or hepatitis B surface antigen
Use of the following agents affecting bone metabolism: • Intravenous bisphosphonates at any time • Denosumab at any time • Fluoride (for osteoporosis) within the past 24 months • Oral bisphosphonates, parathyroid hormone or strontium within the past 12 months • Calcitonin, selective estrogen receptor modulators, systemic oral or transdermal estrogen within the past three months (estrogen-containing contraceptive therapy is permitted) • Systemic glucocorticosteroids (≥ 5 mg prednisone equivalent per day for more than 10 days) within the past three months • Tibolone within the past three months • BMP-2 or BMP-7 at the time of definitive fracture fixation
Current use of anticoagulants (doses for deep vein thrombosis prophylaxis are permitted)
General • Subject is currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s), or subject is receiving other investigational agent(s) • Previous enrollment in an AMG 785 clinical study • Subject of child-bearing potential who is pregnant (eg, positive human chorionic gonadotropin test) or is breast-feeding • Females of childbearing potential: Subject refuses to use 2 different forms of effective contraception in order to achieve a highly effective contraception result during treatment with study drug and for an additional 5 months after the end of treatment with study drug (5 months after the week 12 study visit) • Sexually active males with a female partner of childbearing potential: Subject in combination with his partner refuses to use 2 different forms of effective contraception in order to achieve a highly effective contraception result during treatment with study drug and for an additional 7 months after the end of treatment with study drug (7 months after the week 12 study visit) • Males with a partner who is pregnant: Subject refuses to use a condom during treatment with study drug and for an additional 7 months after the end of treatment with study drug (7 months after the week 12 study visit) • Known intolerance to calcium supplements or vitamin D products • Known sensitivity to mammalian cell derived drug products • Any kind of disorder that, in the opinion of the investigator, − compromises the ability of the subject (or legally acceptable representative) to give written informed consent − prevents the subject from complying with study procedures − prevents the subject from completing the study − interferes with the interpretation of the study results |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the time to radiographic healing for the AMG 785 and placebo groups, defined as bridging of three out of four cortices. Radiographic fracture healing will be determined by a panel of independent reviewers (orthopaedic/trauma surgeons and radiologists) blinded to treatment. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
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 | Information not present in EudraCT |
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 |
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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
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End of study (EOS) is defined as the date the last eligible subject completes the final study visit at Week 52. |
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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 | 1 |
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 | 1 |
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 |