Pivotal clinical trial //
To determine the safety and effectiveness of a single injection regimen of ORTOBRAND in the reduction of the pain score in osteoarthritis of the knee, a prospective, randomized, double-blind, 2-arm (parallel group) clinical trial in 21 centers in six European countries was conducted. A total of 253 patients were randomly assigned to study treatment; 123 received 6 mL of ORTOBRAND and 130 received 6 mL of Phosphate-Buffered Saline. Neither the patients nor the clinical observers knew the patients' treatment allocations. The outcome measures collected included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; Likert 3.1 A version); patient global assessment (PTGA); clinical observer global assessment (COGA); and use of rescue analgesic (see Treatment and Evaluation Schedule). The intent-to-treat (ITT) population (all patients randomized) was used for the primary analysis. The primary efficacy analysis was a comparison over 26 weeks between the two treatment groups of change from baseline in the WOMAC A (Pain) Subscale (see Patient Population and Demographics), performed by analysis of covariance (ANCOVA)
Treatment and Evaluation Schedule
Initial Treatment Phase
Patients were followed for 26 weeks. Study visits were scheduled for screening, baseline, and weeks 1, 4, 8, 12, 18 and 26. Injections were performed aseptically at the baseline visit after arthrocentesis to withdraw any effusion or synovial fluid present. Patients were not permitted to take long-acting NSAIDs (including cyclo-oxygenase II inhibitors), opioid analgesics or corticosteroids (by any route) during the study, but were permitted to take up to 4 g per day of acetaminophen as needed for "rescue" of injected knee pain. "Rescue" medication was not permitted within 48 hours of any study visit. Injected knee assessment, patient and clinician global assessments (PTGA & COGA), WOMAC and safety evaluations were performed at each study visit.
Repeat Treatment Phase
If patients in either blinded treatment group had at least mild pain in the injected knee at the week 26 visit (and did not experience any significant clinical concerns after the first treatment administration), they were offered an injection of (open-label) ORTOBRAND. Those who chose to receive the second injection were followed for 4 weeks for safety only.
Overall Injected Knee Safety Summary
The safety profile of ORTOBRAND is similar to the Clinical and Post-marketing experience seen with ORTHOFLEX (3 injection regimen) where pain, swelling and effusion were the most frequently occurring AEs in the injected knee.
Cases of acute inflammation, characterized by joint pain, swelling, effusion and sometimes joint warmth and/or stiffness, have been reported following an intra-articular injection of ORTOBRAND. Analysis of synovial fluid reveals aseptic fluid with no crystals. This reaction often responds within a few days to treatment with Non Steroidal Anti Inflammatory Drugs (NSAIDs), intra-articular steroids and/or arthrocentesis.
Clinical benefit from the treatment may still be apparent after such reactions.
Primary Efficacy Endpoint
The primary endpoint for the study, the difference between the treatment groups in change from baseline over 26 Weeks in the WOMAC A Pain Score (Table 4) was met.
ORTOBRAND also demonstrated superiority to saline control in multiple pre-defined secondary outcome measures, which included PTGA over and at 26 weeks, COGA over and at 26 weeks, and pain while walking on a flat surface (WOMAC A1) over and at 26 weeks.
The WOMAC A1 responder rate (where response was defined as a 1-or-more category improvement from baseline and the patient did not withdraw from the study) was significantly higher in the ORTOBRAND group than in the saline control group. Seventy-one percent (71%) of the patients were responders at week 18 in the ORTOBRAND group (versus 54% in the saline control group). At week 26, 64% of patients in the ORTOBRAND group were responders, while only 50% of patients in the saline control group were responders.
Patient Population and Demographics
Study patients had primary osteoarthritis of the knee per American College of Rheumatology criteria and were at least 40 years old. The diagnosis was confirmed via recent radiograph showing at least one osteophyte in the target knee. Study patients had continued target knee pain despite use of conservative treatment and analgesics/non-steroidal anti-inflammatory drugs (NSAIDs). Patients with severe disease (Grade IV) per Kellgren-Lawrence criteria, or who had prior arthroplasty in the target knee, were excluded. At the beginning of the study, subjects had moderate or severe target knee pain when walking on a flat surface (on a 5-point Likert scale where 0 = none, 1 = mild, 2 = moderate, 3 = severe 4 = extreme), and an average score of 1.5 to 3.5 on the five questions of the WOMAC A (Pain) Subscale. The WOMAC A Subscale asks study subjects to rate their degree of pain when:
Walking on a flat surface
Going up and down stairs
Resting during the night
Sitting or lying
Adverse Event Summary
The frequency and type of adverse events (AEs) were similar between the group of patients that received ORTOBRAND and the group that received saline control.
Initial Treatment Phase:
The overall proportions of patients with Treatment-Emergent AEs regardless of device relatedness (ORTOBRAND: n=70, 56.9%; Saline Control: n=79, 60.8%) and with injected knee AEs regardless of device relatedness (ORTOBRAND: n=44, 35.8 %; Saline Control: n=44, 33.8 %) were comparable between the two treatment groups (See Table 2). Table 3 lists the incidences of AEs in the injected knee that were assessed by the investigator to be device-related, defined as related to either the study injection or the study treatment.
Device-related AEs involving the injected knee were mild or moderate in nature and were treated symptomatically. There were no serious AEs in the injected knee in either the ORTOBRAND or the saline control group.
Repeat Treatment Phase:
The repeat treatment phase evaluated the safety profile of the initial phase of patients receiving a second injection of ORTOBRAND. One hundred and sixty patients were treated during this phase of the study, of which 77 patients received a second injection of ORTOBRAND. Of these 77 patients, 4 (5.2%) experienced five device related AEs in the injected knee. All such events were mild to moderate and were treated symptomatically. These events were arthralgia (n=2), arthritis (n=1), injection hematoma (n=1) and injection site pain (n=1). Patients who developed injected knee AEs during the initial phase of the study, and who subsequently received repeat treatment, did not experience injected knee AEs upon repeat exposure to ORTOBRAND.
Adverse Events Outside of the Injected Knee
Overall 101 patients (ORTOBRAND: n=47, 38.2%; Saline Control: n=54, 41.5%) experienced at least one AE outside the injected knee regardless of device relatedness. The most commonly occurring (5 % or greater in either group) AEs outside the injected knee were headache, back pain, nasopharyngitis and influenza. In the ORTOBRAND group there was one AE of syncope considered device-related.
No new systemic AEs were identified during this study as compared to ORTHOFLEX.