Post Marketing Clinical Follow up Study to Evaluate the Performance and Safety of ORTHIX PLUS

Design:

Open, non-randomised, non-comparative, single group assignment, multicentre study.

Chronogram of visits:

The study foresees the following visits per patient:

Visit 1 day -3 to day -1: Screening. Visit 2 day 0: Baseline visit (1st injection). Visit 3 day 7 (± 1 day): Follow up visit and, 2nd injection. Visit 4 day 14 (± 2 days): Follow up visit and, 3rd injection. Visit 5 day 21 (± 2 days): Follow up visit. Visit 6 day 56 (± 2 days): Follow up visit. Visit 7 day 98 (± 2 days): Follow up visit. Visit 8 day 194 (± 4 days): Final visit.

Patient enrollment and allocation:

After informed consent signature, the patient is considered enrolled. Once the eligibility is established according to inclusion/exclusion criteria the patient will receive a unique patient code and will be allocated to ORTHIX PLUS® (the tested medical device). The Investigator must also complete a patient screening log, which reports on all patients who were seen to determine eligibility for inclusion in the study.

Statistical Analysis:

The protocol outlines that a two-sided p-value of 0.05 or less will be used to declare statistical significance for all analyses. Similarly, all confidence intervals will be calculated at the 95% level.

No adjustment for multiplicity will be made to adjust type 1 error rate for secondary endpoints. If necessary, relevant results from other studies already reported in the literature will be considered in the interpretation of results.

The final analysis will be completed after all patients have been exited the study, all queries resolved, and the database have been locked.

If a patient is missing information for one or more variables, the missing data will not be replaced. Quantitative variables (i.e., demographic) if normally distributed will be described through media, standard deviation (SD); variables non-normally distributed will be described using median and range of interquartile.

Considering this clinical trial's design as a longitudinal cohort study, the focus of the performed statistical assessments will be the longitudinal (statistical) analysis.

Primary endpoint, change in Knee injury and Osteoarthritis Outcome Score(KOOS) pain sub-scale score from baseline to 14 weeks visit, will be analysed by performing a Student's t-test for paired data, or a Wilcoxon signed rank test if major deviations from former's test assumptions are recorded. As no missing data imputation on the primary outcome is planned, if such cases arise, a Linear Mixed Model analysis will be performed, to make use of the complete ITT(Intention to treat) population.

Secondary endpoints, all continuous variables in nature, will be assessed by performing ANOVA for repeated measures tests, or ANCOVA for repeated measures tests (if considering covariates like age, sex, BMI, etc.), assuming completeness of data (no missing data). If missingness of data drastically reduces the sample size (e.g., > 5% of patients will be eliminated), a robust statistical analysis method will be employed instead. Such a method, Linear Mixed Models analysis, has the main advantage of making use of the complete ITT population.

The safety analysis will be done on the ITT population.