A Clinical Trial Investigating Iloprost as Medication to Improve Bone Healing in Patients With Proximal Humeral Fracture

Study Overview
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Brief Summary
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The main objective of this study is to establish the safety as well as the efficacy of local insertion of Iloprost at the fracture site for bone healing of the proximal humeral fracture. The study will have two treatment groups and one control group. All patients will receive the standard of care procedure (reduction and angular stable (PHILOS) plate fixation). The two treatment groups will additionally be treated with two different Iloprost doses. Subjects will be assessed for study eligibility within 24h after admission (screening period). Eligible subjects will be assessed for baseline parameters on day 0. Within 96 hours of the study, subjects will undergo surgery, reduction, and angular stable (PHILOS) plate fixation. During the procedure, a catheter will be inserted in the fracture site of the treatment groups in order to deliver the Iloprost locally in the fracture site. The expected total duration of study participation for each subject comprises 52 weeks, among which 26 weeks include active study participation. At the study end, a telephone call with the subjects will be performed for safety assessment. Recruitment will be completed in approximately 18 months. Follow up visits following the surgical operation shall take place during weeks 3, 6, 12, and 26. The last follow-up will be a phone call during week 52 for the purpose of safety assessment.

Official Title
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A Phase I/IIa, Prospective, Mono-center, Randomized, Open Labeled, Controlled Study to Assess the Safety and Efficacy of Applying Iloprost Locally in the Fracture Site to Promote Bone Healing in Patients With Proximal Humeral Fracture

Conditions
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Proximal Humeral Fracture

Intervention / Treatment
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* Drug: 0.125 ng/kg/min Iloprost
* Drug: 0.25 ng/kg/min Iloprost
* Procedure: open reduction and internal fixation with an angular stable plate (PHILOS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent. Adult male or female subjects between 60 to 80 years old at the time of screening visit. Scheduled Proximal Humerus Internal Locking System (PHILOS) with 3 holes plate length for proximal humerus fracture type 3 or 4 according to Neer classification. Patient with American Society of Anesthesiologists (ASA) score of ≤ 2. Single, low energy fracture. Absence of neurovascular complications at the time of trauma. Surgery done within the first 96 hours from injury. Exclusion Criteria: Subjects unable to freely give their informed consent (e.g. individuals under legal guardianship). Immunosuppression due to illness or medication. Subject with malignancy and undergoing treatment including chemotherapy, radiotherapy or immunotherapy. Known allergies to Iloprost. Conditions where the effects of Iloprost on platelets might increase the risk of haemorrhage (e.g.active peptic ulcers, or intracranial hemorrhage). Severe coronary heart disease or unstable angina; myocardial infarction within the last six months; decompensated cardiac failure if not under close medical supervision; severe arrhythmias; suspected pulmonary congestion; cerebrovascular events (e.g., transient ischaemic attack, stroke) within the last 3 months. Acute or chronic congestive heart failure (NYHA II-IV) Pulmonary hypertension due to venous occlusive disease. Congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension. Subject who is currently enrolled in or has not yet completed a period of at least ( a period of time equal to 5 times as the half-life time of the drug used in the previous trial) since ending other investigational device or drug trial(s). Patients who are dependent on the sponsor, investigator or study site. History of previous proximal humerus surgery on the same side. History of proximal humerus deformity on the same side. Pathological or open fracture. Polytrauma patient. Pregnant or breast-feeding women or women of childbearing potential not protected by an effective contraceptive method of birth control (defined as pearl index < 1). Any form of substance abuse, psychiatric disorder, or other condition that, in the opinion of the Investigator, may invalidate communication with the Investigator and/or designated study personnel. Patients who are committed to an institution by virtue of an order issued by either the judicial or the administrative authorities. Patients with a history of cerebral circulatory disorders. Patients with any symptomatic or treatable heart disease (including stenting), hypertension treated with a β-receptor blocker, calcium agonists, vasodilator or ACE (Angiotensin-converting-enzyme) inhibitor at more than moderate doses.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 80 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
Interventional Model Description: A randomized interventional study with parallel groups. Open labeled, add-on controlled study. In this study, patients will be randomized on a 1:1:1 basis to one of the three arms (two treatment arms and one control arm).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: First intervention group (0.125 ng/kg/min Iloprost)<br>The first intervention group will receive open reduction and internal fixation with an angular stable plate (PHILOS™ - Depuy Synthes) + Iloprost treatment. Patients will locally receive a dose of 0.125 ng/kg/min of Iloprost over 24 hours via a catheter and an electronic pump system. The catheter will be inserted during the surgical procedure. Infusion of Iloprost will start 24hrs post-operatively and the dose will be delivered over 24h. | Drug: 0.125 ng/kg/min Iloprost<br>* Drug administration through a catheter (inserted at the end of the surgical procedure) begins 24±2 hours after surgery: 0.125 ng/kg/min Iloprost for a duration of 24 hours<br>* Other names: CAS (Chemical Abstracts Service) number 78919-13-8;Procedure: open reduction and internal fixation with an angular stable plate (PHILOS)<br>* open reduction and internal fixation with an angular stable plate (PHILOS)<br>* Other names: PHILOS Plating;|
| Experimental: Second intervention group (0.25 ng/kg/min Iloprost)<br>The second intervention group will also receive open reduction and internal fixation with an angular stable plate (PHILOS™ - Depuy Synthes) + Iloprost treatment. Patients will locally receive a dose of 0.25 ng/kg/min of Iloprost over 24 hours via a catheter and an electronic pump system. Infusion will start 24hrs post-operatively and the dose will be delivered over 24h. | Drug: 0.25 ng/kg/min Iloprost<br>* Drug administration through a catheter (inserted at the end of the surgical procedure) begins 24±2 hours after surgery: 0.25 ng/kg/min Iloprost for a duration of 24 hours<br>* Other names: CAS number 78919-13-8;Procedure: open reduction and internal fixation with an angular stable plate (PHILOS)<br>* open reduction and internal fixation with an angular stable plate (PHILOS)<br>* Other names: PHILOS Plating;|
| Other: Control intervention group<br>Control intervention: Patients will receive the standard of care procedure for such fractures, i.e. standard of care open reduction and internal fixation with an angular stable plate (PHILOS™ - Depuy Synthes). | Procedure: open reduction and internal fixation with an angular stable plate (PHILOS)<br>* open reduction and internal fixation with an angular stable plate (PHILOS)<br>* Other names: PHILOS Plating;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity grading in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Toxicity grading in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) | 12 months | 
| Efficacy analysis using the Tip Apex Distance (TAD) readout | TAD is an indicator of the progress of fracture healing and the probability of potential complications. Thus, it reflects both the safety and efficacy of the investigational treatment. To evaluate the treatment success rate, we will calculate the percentage loss of the summation of TADs of all locking screws. The value will be classified into one of five ranks as measured after 12 weeks of postoperative follow-up compared to the baseline measurement. For the percentage of original Tip Apex Distance, the sum of the Tip Apex Distance of the humeral head screws will be used: Grade 1: 76%-100% preservation of the original distance (representing the best possible result), Grade 2: 51%-75% preservation of the original distance, Grade 3: 26%-50% preservation of the original distance, Grade 4: 0%-25% preservation of the original distance, and Grade 5: if the patient shows signs of screw protrusion (cut out). Grade 1 will be considered as treatment success, grades 2-5 as treatment failure. | 12 weeks after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of humeral head necrosis | Osteonecrosis of the humeral head is a common complication in proximal humerus fracture. (1) The occurrence of osteonecrosis varies significantly according to the grading of the fracture in addition to the initial displacement (valgus or varus), Soft tissue handling during surgical fixation can influence the rate of osteonecrosis (2,3). Both a radiologist and an orthopedic surgeon will confirm the diagnosis of osteonecrosis of the humeral head radiologically at 12th-week and 26th-week visits. | 12 weeks and 26 weeks after surgery | 
| Humeral head shaft angle | Humeral head shaft angle is used to plan corrective osteotomies and shoulder arthroplasties as well as to evaluate the postoperative x-ray outcome, as a varus displacement of more than 10 degrees in the X-ray view is considered as loss of fixation (4). | before discharge, 3 weeks, 6 weeks, 12 weeks and 26 weeks after surgery | 
| Pain assessment using the Visual Analogue Scale (VAS) | The VAS instrument consists of a 10 cm long straight line with defined endpoints, ranging from 'no pain' to 'pain as bad as it could be.' The patient will be asked to mark the respective pain level on the line that is felt subjectively. The distance between 'no pain' and the marked pain level determines the patient's pain. Scores are given in mm, ranging from 0-100 (5). | 24 hours after surgery, before discharge, 3 weeks, 6 weeks, 12 weeks and 26 weeks after surgery | 
| Quality-of-Life (QoL) by applying EQ-5D | Patients will be asked to answer the questionnaire EuroQol-5 Dimension (EQ-5D), which is a validated instrument determining the quality of life as a health outcome. Developed in Europe, it is widely applied. The tool offers 5 dimensions including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression (6). The questionnaire includes a visual analog scale where patients can give information on their health state. | 3 weeks, 6 weeks, 12 weeks and 26 weeks after surgery | 
| Constant-Murley Score (CMS): | The Constant-Murley Score (CMS) is a 100-points scale composed of different parameters to define the level of pain and the ability of the patient to perform normal daily activities. It is used to determine the functional outcome after treatment of shoulder injuries. The higher the score, the better the function of the shoulder is. CMS is divided into four main subscales: pain (max. 15 points), strength (max. 25 points), daily activity (max. 20 points) and range of motion (40 points). The European Society of Shoulder and Elbow Surgery (ESSE) has promoted the Constant- Murley Score as a gold standard for the assessment of shoulder function (7-9). The Constant-Murley Score takes patient sex and age into consideration. The score can be used relative to age and sex (10). | 12 weeks and 26 weeks after surgery | 
| Disabilities of the Arm, Shoulder and Hand score (DASH) | DASH is a 30-item questionnaire that determines the ability of a patient to perform certain upper extremity activities. DASH questionnaire is self-reported, where patients can rate the difficulty and interference with daily life (1 = no difficulty or no symptom, 5 = unable to perform or very severe symptom). Subsequently, a score is calculated using a formula. A DASH score of 0 corresponds to no disability and 100 to extreme disability. | 12 weeks and 26 weeks after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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proximal humeral fracture, proximale Humerusfraktur, Ilomedin, Iloprost