Patient population
The trial population comprised of male or female patients of at least 50 years of age. In total, 50 patients with fractures of the vertebral body (TH7-L4) due to osteoporosis [
14] or a trauma scheduled for one-staged kyphoplasty were consecutively screened and enrolled, and 49 were included in the safety population (SAF population). Exclusion criteria were known hypersensibility against ingredients of the tested bone cement, concomitant systemic gentamicin treatment, any concomitant disease (excluding a minimally invasive kyphoplasty of the vertebral body), presence of spondylitis or infection, renal impairment, sensorineural hearing loss, and hemorrhagic diathesis.
All patients who fulfilled the inclusion and exclusion criteria gave their written consent to participate. The trial duration per patient consisted of a screening period up to 7 days before the surgery, a hospitalisation period of 1 week including final examination, and a follow-up period of 12 months. The trial comprised ten clinical visits.
Study intervention
The investigational medical product (IMD) was administered to patients during the surgery according to the standard procedure established on site for one-staged kyphoplasty [
15]. The antibiotic-loaded bone cement consists of two components—a powder and a fluid—and was mixed directly before use (Osteopal G, Heraeus Medical GmbH, Wehrheim, Germany) [
16,
17]. The powder contained 0.325 g gentamicin per 26.5 g pouch of bone cement, and the fluid consisted of methyl methacrylate, dimethyl-p-toluidine, hydroquinone, and colorant E 141 in an ampoule of 10 ml. It was applied intra-operatively for minimal invasive kyphoplasty. The right time for the application was governed through the cement polymerization status. Depending on the need for kyphoplasty bone void filling of the vertebral body after fractures, the dosage was selected with usually 3 ml bone cement per level. It was administered as a single intra-operative injection.
Radiomorphometric evaluations of native two-level X-ray images were performed by two independent clinicians using six landmarks to determine the following medical parameters: the angle of kyphosis—the angle between two tangents attached to the ground and endplate of the radiological sagittal parameters of the spine—and the vertebral body index—the quotient of height of leading and rear edge and the pre- and post-operative height of the centre of the vertebral body (in %). As a reference (100%), the median height of an adjacent non-fractured vertebral body was used.
Study measures
The primary endpoints were the evaluation of the function by pain scores such as the visual analogue scale (VAS) vertebral spine score [
18], the Oswestry-Low-Back-Pain-Disability (ODI) score [
19], and the Short Form (SF)-36 Health Status Query [
20]. They were measured at up to 7 days before the surgery, during the final examination on day 6, and at 6 and 12 months after the surgery. The radiological examination comprised two-level X-ray-radiographs before the surgery, on the day of the surgery, and during the final examination as well as during the follow-ups at 6 and 12 months and magnetic resonance imaging radiomorphometry [
21] of the augmented region preoperatively. All radiological examinations were carried out in lying positions. Furthermore, the cement leakage and the corresponding location were evaluated. Secondary outcomes included the intra- and post-operative assessment of the cement properties such as end of adhesiveness, working time, curing time at the time of and after the application, and the assessment of the amount of injected cement as well as its overall tolerability [
22]. In this context, other investigation criteria included the amount of injected cement, imaging and visibility of the cement, the optimal injection pressure, and the complete duration of the surgical procedure.
The overall efficacy was assessed by the clinical investigator and the patients by evidences for a kyphoplasty related infection and a revision of the relevant spine level. The safety of the IMD was evaluated regarding its overall tolerability, the registration of events, and the X-ray diagnosis. Fracture characteristics, vertebral body status, and clinical examinations have been performed.
Statistics
Only descriptive statistical methods were used in the present trial as there was no control group. Continuous parameters are presented with their means, standard deviations (SDs), medians, first and third quartiles, and minimum and maximum values. Frequencies were calculated for categorical variables. The descriptive summary statistics are presented for continuous baseline data (e.g. age, height) at screening as well as for categorical data (e.g. gender, ethnic origin, nicotine consumption, alcohol consumption, special diet, and reason of fracture). In addition, fracture characteristics and vertebral body status were investigated.
Since no specific hypothesis was tested, no formal calculation of sample size was performed.
The descriptive summary statistics at screening, day 6 post-op, month 6 post-op, and month 12 post-op are presented for the overall VAS vertebral spine score, the ODI score, and for the 8 dimensions of the SF-36 Health Status Query. Additionally, pre- and post-differences (value at post-op visit—screening value) were investigated. The parameters assessed by a radiomorphometric evaluation and two-level X-ray images (angle of kyphosis and vertebral body index) at surgery, day 6 post-op, month 6 post-op, and month 12 post-op were summarised in the scope of descriptive statistics. Mean values of the clinical and radiological parameters during the follow-up were compared to the screening (t test); p values and 95% confidence intervals (CI) are given.
A shift analysis was performed on the cement leakage at surgery and day 6 post-op and to evaluate the overall tolerability at day 6, month 6, and month 12 post-op. The number and percentage of patients are given for the cement properties. All of the summary statistics are presented in order to assess the cement application procedure by evaluating the needle depth, needle volume, duration of intervention, and time frames of cement application. The number and percentage of patients are reported for the detectability of applied cement via X-ray at surgery, at month 6, and at month 12 post-op.
The overall efficacy was evaluated by the variables ‘any evidence for a kyphoplasty related infection’ and ‘had a revision of the relevant spinal level to be performed’ was assessed by means of shift tables for each of these two parameters at visits day 6, month 6, and month 12 post-op. For the additional secondary efficacy variable ‘BOS’, the number and percentage of patients are presented at the screening, at day 6, month 6, and month 12 post-op.
The AEs were reported by the investigators and provided in summary incidence tables for all reported AEs. The different proportions of the patients reporting the different AEs and SUEs, and treatment-related AEs were tabulated.
Summary statistics for vital signs and changes from the hospitalisation visit is displayed for all visits. The ECG results at screening and day 6 post-op (final examination) and the results of the physical examination as judged by the investigator were analysed using a shift table. Specifications of clinically relevant results by patient are given in an individual patient data listing. The number and percentage of patients who were still in hospital after the operation are reported by visit (day 4, day 5, and day 6).
Other analysis included previous and concomitant medications, anaesthetic and post-operative medications, number and percentage of patients who experienced any disease and underwent any previous surgery of the vertebral spine, and any complication in a previous vertebral spine intervention are shown.
All evaluations are provided for the SAF population.