Background/Purpose:

Fasitibant (FAS) is a competitive, potent and selective antagonist of the bradykinin B2 receptor administered IA for SOAK. In response to positive outcomes in a previous exploratory RCT, a phase 2 double blind RCT to evaluate FAS, given as single IA injection at three different doses versus placebo, was conducted at 25 clinical sites in Europe and US.

Methods:

Patients with moderate to severe symptomatic knee OA were randomized (1:1:1:1) to single IA injections of either FAS (1 mg, 2.5 mg or 5 mg) or Placebo (saline) given as 1 ml solution. IA administration was performed by clinical investigators experienced with the use of the IA injection route.

The efficacy variable of primary interest was the change in pain intensity evaluated as change of WOMAC VA 3.1 A (total pain) subscore (A1-5, VAS 0-500 mm) from baseline over 2 weeks post treatment. Secondary measures included WOMAC Index, WOMAC stiffness (B) and functional impairment (C) subscores, pain at rest, pain after 15 meters walk (100 mm VAS) and patient global assessment (PGA) scores.

Safety was assessed by monitoring of lab tests, vital signs, ECG, physical examinations including the target knee, adverse events and concomitant medications.

Results:

All randomized patients (Intention-to-Treat-ITT, n=431) were allocated to the study treatment; with FAS 1mg (n=108), FAS 2.5 mg (n=108), FAS 5mg (n=107) and Placebo (n=108), with balanced demographic and baseline characteristics across treatment arms. Single IA injections of fasitibant did not significantly discriminate for WOMAC A pain over Placebo, with all treatments showing a decrease at week 1 and at week 2 post administration (Table 1). The time to first use of rescue medication (secondary endpoint) discriminated significant from placebo in the fasitibant 5 mg dose group (Kaplan-Meyer analysis; p< 0.0154). Fasitibant was well tolerated. There were no related SAEs. The majority of TESSs were mild or moderate. Severe TESSs occurred only in 12 patients (2.8%). Only 29 TESSs were considered related, most of them in placebo group (n=13). Lab tests, ECGs and vital signs were in general unremarkable and similar between treatments.

Conclusion:

The primary efficacy analysis has not shown any statistical significant evidence of superiority of fasitibant at any dose overPlacebo on pain reduction from baseline over 2 weeks after randomisation; however fasitibant 5 mg treated patients used statistically significant less rescue medication, which might be considered as an indirect evidence of its efficacy. The very high placebo response as well as the long duration of OA-symptoms (8.5±7.06 years) in all treatment groups may have contributed to the lack of efficacy as reported for other RCT in patients with symptomatic knee OA. Fasitibant was in general safe and local tolerability at the target knee was good.

Table 1: Change versus baseline for WOMAC pain over two weeks (ITT Population)

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-double-blind-randomized-controlled-four-parallel-arm-dose-finding-study-to-evaluate-the-efficacy-safety-tolerability-and-pharmacokinetics-of-single-intra-articular-ia-injections-of-fas/