Study of Romosozumab (AMG 785) in Tibial Diaphyseal Fractures Status Post Intramedullary Nailing

Study Overview
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Brief Summary
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The primary objective of this study is to investigate the effect of romosozumab compared with placebo on time to radiographic healing of fresh tibial diaphyseal fractures (fractures in the midsection of the shinbone).

Official Title
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A Multi-center, Randomized, Double Blind, Placebo-controlled Study of AMG 785 in Skeletally Mature Adults With a Fresh Unilateral Tibial Diaphyseal Fracture Status Post Definitive Fracture Fixation With an Intramedullary Nail

Conditions
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Fracture Healing

Intervention / Treatment
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* Biological: Romosozumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Skeletally mature adults, age 18 to 85 years with radiographically closed growth plates Fresh unilateral closed or Gustilo type I or type II open tibial fracture Definitive fracture fixation with reamed (closed and open fractures) or unreamed (open fractures only) intramedullary nailing Exclusion Criteria: Major polytrauma or significant axial trauma Associated lower extremity fracture that will delay subject's ability to bear weight beyond the normal time expected for a tibial shaft fracture Use of bone grafts at the time of fracture fixation Pathological fracture or metabolic or bone disease History of symptomatic spinal stenosis or facial nerve paralysis Malignancy within the last 5 years Evidence of the following (currently or within the past 5 years): elevated transaminases, significantly impaired renal function, current hyper- or hypocalcaemia Use of agents affecting bone metabolism Subject refuses to use appropriate methods of contraception

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received subcutaneous injections of matching placebo on day 1 and at weeks 2, 6, and 12. | Drug: Placebo<br>* Administered by subcutaneous injection<br>|
| Experimental: Romosozumab 70 mg: 2 Doses<br>Participants received subcutaneous injections of 70 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12. | Biological: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: Evenity;|
| Experimental: Romosozumab 70 mg: 3 Doses<br>Participants received subcutaneous injections of 70 mg romosozumab on day 1 and weeks 2 and 6, and matching placebo at week 12. | Biological: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: Evenity;|
| Experimental: Romosozumab 70 mg: 4 Doses<br>Participants received subcutaneous injections of 70 mg romosozumab on day 1 and weeks 2, 6, and 12. | Biological: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: Evenity;|
| Experimental: Romosozumab 140 mg: 2 Doses<br>Participants received subcutaneous injections of 140 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12. | Biological: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: Evenity;|
| Experimental: Romosozumab 140 mg: 3 Doses<br>Participants received subcutaneous injections of 140 mg romosozumab on day 1 and weeks 2 and 6, and matching placebo at week 12. | Biological: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: Evenity;|
| Experimental: Romosozumab 140 mg: 4 Doses<br>Participants received subcutaneous injections of 140 mg romosozumab on day 1 and weeks 2, 6, and 12. | Biological: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: Evenity;|
| Experimental: Romosozumab 210 mg: 2 Doses<br>Participants received subcutaneous injections of 210 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12. | Biological: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: Evenity;|
| Experimental: Romosozumab 210 mg: 3 Doses<br>Participants received subcutaneous injections of 210 mg romosozumab on day 1 and weeks 2 and 6, and matching placebo at week 12. | Biological: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: Evenity;|
| Experimental: Romosozumab 210 mg: 4 Doses<br>Participants received subcutaneous injections of 210 mg romosozumab on day 1 and weeks 2, 6, and 12. | Biological: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: Evenity;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Radiographic Healing | Time to radiographic healing was defined as the time from intramedullary (IM) nailing to the first occurrence of bridging of 3 out of 4 cortices. Radiographic fracture healing was determined by a panel of independent reviewers (orthopedic/trauma surgeons and radiologists) blinded to treatment. The cumulative incidence function (CIF) method was used to estimate the median time to radiographic healing and the confidence intervals. Unplanned revision surgery to promote healing was considered a competing risk in CIF estimate. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Week 8 in Short Form (36) Health Survey Physical Functioning Domain | The Medical Outcome Study Short Form 36-Item Health Survey (SF-36), Version 2, is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical functioning domain includes 10 questions that assess limitations in physical activities because of health problems. Norm-based scores were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. The range of SF-36 physical functioning is 14.94 - 57.03. Higher scores indicate a higher level of functioning. A positive change from baseline score indicates an improvement in physical functioning. | Week 8 and weeks 12, 16, 20, 24, 36, and 52 | 
| Number of Participants With Unplanned Revision Surgeries |  | 52 weeks | 
| Time to Clinical Healing | Time to clinical healing was defined as the time from the IM nailing surgery date to the first date that both the score for ability to bear weight on the fractured limb and the score for absence of pain at the fracture site were equal to 6. The score for the ability to bear weight on the fractured limb was based on the ability to stand on affected leg without assistive device and the ability to walk without assistive device. The score ranges from 0 (unable to bear full body weight on the fractured limb) to 6 (able to bear full body weight on the fractured limb). Absence of pain at the fracture site was based on the absence of pain at the fracture site when applying direct pressure to the fracture site and applying a stress to the fracture site. The score ranges from 0 (pain without palpation at fracture site) to 6 (total absence of pain at fracture site). Time to clinical healing was estimated using CIF; unplanned revision surgery was considered a competing risk in CIF estimate. | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fracture Healing, Tibial Diaphyseal Fracture