Pre-market Study to Evaluate Safety and Performance of GreenBone Implant (Long Bone Study)

Study Overview
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Brief Summary
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Multi-center, international, prospective, open-label, single-arm, first-in-human clinical investigation. The Patients enrolled in this clinical investigation will undergo a scheduled surgery for the treatment of long bone defects up to 6 cm using GreenBone Implant. After the surgery, the Patients will be monitored at pre-scheduled visits up to 12 months. Adverse events, pain, quality of life and functional parameters, as well as X-ray and CT scan, will be evaluated at scheduled follow-up visits. An independent Data Safety Monitoring Board (DSMB) will review the safety reports at regular intervals and Serious Adverse Events (SAE) as soon as reported, to protect Patients participating in the study. The initial phase of the study contemplates the treatment of bone defects up to 3 cm. An adaptive interim analysis will be performed when the first 7 Patients will have completed the 6-month follow-up visit. The DSMB will review the results of the interim analysis with respect to the primary endpoint (safety), and provide one of the following recommendations to the Sponsor: a) to stop the study for unacceptable frequency and severity of adverse events or b) to continue the study up to 25 Patients recruited and to include at least 5 Patients with a longer bone defect (> 3 cm up to 6 cm).

Detailed Description
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This is a pre-market multi-centre, international, open label, single-arm, study to evaluate the safety and performance of a Class III medical device (GreenBone Implant) for the treatment of long bone defect. Bone defects can result from malformation, high-energy traumatic events, bone resection due to different pathologies such as tumors or infections, or from the treatment of complex non-unions. Current treatment of bone defects usually implies the use of bone grafts and/or biocompatible materials, to create a scaffold that bridges the defect. Autograft and Allograft are the treatments most currently used for large bone loss, but both treatments have significant disadvantages. These types of treatment carry the risk of transferring disease from animals and/or humans to the patient; there is also a risk of host local allergic reaction. Bone substitutes are devoid of the above risks and therefore they could be used alternatively to xenografts and allografts. GreenBone is a ceramic resorbable bone scaffold that has very similar structure to bone. It can be produced in large quantities, shaped easily and sterilised without losing its properties. Consequently, it is an ideal substitute that could be used to fill bone defects. This study will assess the safety of using GreenBone treatment of long bone defects up to 6 cm. Moreover it will assess its capacity of promoting new bone formation. The investigators will recruit 25 patients with long bone defect and instead of bovine xenograft we will use the GreenBone implant for the long bone reconstruction. Patients will be followed up for 12 months in total.

Official Title
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A Pre-market, Multi-center, International, Open-label, Single-arm Study to Evaluate the Safety and Performance of a Class III Medical Device (GreenBone Implant) for Surgical Repair of Long Bone Defects

Conditions
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Bone Substitutes, Bone Defect

Intervention / Treatment
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* Device: surgical repair of long bone defects


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female Patients. Patients aged ≥ 18 and ≤ 65 years old. Patients requiring long bone defect reconstructions up to 3 cm, resulting from high-energy traumatic events, or from the treatment of complex bone non-unions in the extremities (arms and legs), or patients undergoing the second stage of the Masquelet technique. Patients understanding the nature of the study and providing their informed consent to participation. Patients willing and able to attend the follow-up visits and procedures foreseen by study protocol. Please note: after interim analysis review by the DSMB, inclusion criteria n. 3 will be modified as follows (all Investigators will be notified by the Sponsor, and adequate training by Clinical Research Associate-CRA will be conducted): Change of inclusion criteria n. 3: Patients requiring long bone defect reconstructions longer than 3 cm and up to 6 cm, resulting from high-energy traumatic events, or from the treatment of complex bone non-unions in the extremities (arms and legs), or patients undergoing the second stage of the Masquelet technique. Exclusion Criteria: Patients with bone infection at the time of enrolment. Patients with bone malignant tumor(s) at the time of enrolment. Patients who have been treated with chemotherapy or radiotherapy within 12 months before the enrolment. Patients with concomitant infectious systemic diseases at the time of enrolment. Patients with known inflammatory systemic diseases at the time of enrolment. Patients with concomitant myeloproliferative disorders at the time of enrolment. Patients currently treated with systemic immunosuppressive agents, excluding steroids. Patients with active autoimmune disease. Patients with a pre-existing calcium metabolism disorder (i.e. hypercalcemia). Known hyperthyroidism or autonomous thyroid adenoma. Patients with coagulopathy or bleeding disorders. Patients who are not allowed to undergo the study procedures involving imaging (X-rays, CT scan) based on Investigator's judgement. Patients with known or suspected allergy or hypersensitivity to the GreenBone Implant components. Patients who are participating or have participated in other clinical studies within the 30 days before the study enrolment. Patients identified by the Investigator to have intra-operative findings that may preclude conduct of study procedure. Patients with occurrence of major intra-operative complications that require resuscitation or deviation from the planned surgical procedure. Women who are pregnant or breast-feeding or who wish to become pregnant during the period of the clinical investigation and for three months later. Female Patients of childbearing age (less than 24 months after the last menstrual cycle) who do not use adequate contraception.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Surgical repair of long bone defects<br>The Patients in the study group will be surgically treated and the GreenBone Bone Substitute will be implanted | Device: surgical repair of long bone defects<br>* Current treatment of bone defects usually implies the use of bone grafts and/or biocompatible materials, to create a scaffold that bridges the defect, favoring the migration of cells from the neighboring tissues to fill the gap. Autograft and Allograft are the treatments most currently used for large bone loss, but both treatments have significant disadvantages. Different types of synthetic materials have been tested for repair of long bone gaps. However, at the moment, there is not any bone substitute with the ideal/desirable osteoinductive, osteoconductive and mechanical properties. GreenBone Implant is a synthetic, acellular, reabsorbable, new generation bone graft, being suitable for surgical reconstruction of bone defects.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Evaluation assessed by Evaluation of adverse events rate | Evaluation of adverse events rate during the study period. All adverse occurrences (serious/non-serious or device-related/non device-related) will be recorded prospectively, categorized and evaluated for causality using defined criteria. | Overall study period up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Technical Success of surgical procedure | Evaluation of technical success, defined as successful delivery of the GreenBone Implant in the target defect bone evaluated at V2 (during surgical procedure). Technical success regards the surgical procedure and evaluates the performance of medical device. | During of surgical procedure (visit 2, 1 day) | 
| Bone regeneration evaluation through modified Lane and Sandhu Radiological Scoring System (bone formation, union and remodeling) | Evaluation of the bone regeneration in the area of intervention in comparison to baseline (V1), by means of X-ray and/or CT scan examination, on visits V3, V4, V5, V6, V7 and V8. X-ray scoring systems have been implemented according to the criteria proposed by modified Lane and Sandhu Radiological Scoring System (Lane 1987). This scoring system evaluates bone formation, union and remodeling. To evaluate the bone formation, there is a scale with 5 points, from 0 to 4 (0=No evidence of bone formation-4=Bone formation occupying 100% of defect). To evaluate bone union and remodelling, there is a scale with 3 points, from 0 to 2 (0=Non-union-2=Radiographic union). | At the end of visits 1,3,4,5,6,7,8 (respectively performed at screening and 1,2,3,6,9,12 months after the surgery, each visit is 1 day) | 
| Functional assessment | Functional Assessment: evaluation of functional recovery of Patient, by means of a standardized questionnaire (36-Item Short Form Survey - SF-36), on visits V1, V3, V4, V5, V6, V7 and V8. The questionnaire is Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36). The SF-36 has eight scaled scores; the scores are weighted sums of the questions in each section. Scores range from 0-100. Lower score=more disability, higher scores=less disability. Sections: Vitality Physical functioning Bodily pain General health perceptions Physical role functioning Emotional role functioning Social role functioning Mental health | At the end of visits 1,3,4,5,6,7,8 (respectively performed at screening and 1,2,3,6,9,12 months after the surgery, each visit is 1 day) | 
| Evaluation of pain | Evaluation of degree of pain perceived by the Patient, by means of a Visual Analogue Score (VAS/0-10 point scale), on visits V1, V3, V4, V5, V6, V7 and V8. The Visual Analogue Score (VAS) that a scale with 10 points, from 0 to 10, 0 indicates no pain at all and 10 the worst pain ever. | At the end of visits 1,3,4,5,6,7,8 (respectively performed at screening and 1,2,3,6,9,12 months after the surgery, each visit is 1 day) | 
| Evaluation of Quality-of-Life | Evaluation of Quality-of-Life by means of EuroQoL EQ-5D-5L Validated Questionnaire, on visits V1, V3, V4, V5, V6, V7 and V8. The EQ-5D-5L is a descriptive system. This system comprises the same 5 dimensions (mobility, self care, usual activities, pain/discomfort, anxiety/depression). Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. | At the end of visits 1,3,4,5,6,7,8 (respectively performed at screening and 1,2,3,6,9,12 months after the surgery, each visit is 1 day) | 
| Global Tolerability of patient to treatment | Evaluation of global tolerability to treatment of Patient (by the Investigator), through a standardized questionnaire, on visits V3, V4, V5, V6, V7 and V8. Global Tolerability Questionnaire is a questionnaire with 6 questions that are completed by the investigator in order to evaluate the operated site. | At the end of visits 3,4,5,6,7,8 (respectively performed 1,2,3,6,9,12 months after the surgery, each visit is 1 day) | 
| Reinterventions number | Evaluation of the number of re-interventions occurring for the Patient throughout the 12-month observation period. | between 1 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bone substitute, Bone regeneration