Background/Purpose: CR845 is a selective kappa opioid receptor agonist with a peripheral mechanism of action. Here we report preliminary results from a Phase 2b study designed to characterize the analgesic efficacy of orally administered CR845 in patients with osteoarthritis (OA) of the hip or knee (ClinicalTrials.gov NCT02944448).

Methods: 476 male and female patients (ages ≥25 years) with moderate to severe pain (numeric rating scale [NRS] ≥5) associated with hip or knee OA were enrolled at 33 sites in the US. Following a 14-day screening period, patients were randomized 2:1 to CR845 or placebo, respectively. CR845 (1.0, 2.5, or 5.0 mg) or placebo were administered BID for a total of 8 weeks, with doses administered at least 2 hours before or after a meal. Patients started on 1.0 mg or placebo, then during the 4-week post-randomization period, titrated upward to 2.5 or 5.0 mg to effect in a double-blind fashion and maintained for 4 weeks on the final individualized effective dose. The primary outcome measure was change from baseline in the weekly mean pain intensity score (0-10, NRS) at the index joint with CR845 compared to placebo at Week 8/Day 57. Secondary outcome measures included differences between CR845 and placebo in the Western Ontario and McMaster Osteoarthritis Index (WOMAC) total and sub-scores and in the Patient Global Impression of Change (PGIC) scale. Safety and tolerability measures were also captured over the 8-week treatment period.

Results: Efficacy was assessed in 118 hip OA patients (CR845, n=78; placebo, n=40) and 358 patients with knee OA (CR845, n=238; placebo, n=120). The primary efficacy results comparing CR845 (all doses) vs placebo were not statistically significant. However, patients with hip OA maintained on 5.0 mg (n=66) exhibited a statistically significant 69% reduction in mean joint pain score over placebo (p=0.043) accompanied by a 41% reduction over placebo in use of rescue medication at Week 8. The proportion of patients who titrated to the 5.0 mg dose and reported a PGIC score of “very much improved” or “much improved” was statistically higher in patients with knee OA (p<0.005 vs placebo) and hip OA (p<0.006 vs placebo). Patients maintained on the 1.0 and 2.5 mg doses did not exhibit statistically significant reductions in mean joint pain scores compared to placebo nor did patients with knee OA at any dose. Doses were generally well tolerated with no drug-related serious AEs. The most common AEs with ≥5% incidence were constipation (13%), dizziness (8%), and dry mouth (6%). There were no clinically significant changes in serum sodium levels during the 8-week treatment period for any dose group.

Conclusion: Post-hoc analyses demonstrated that hip OA patients receiving CR845 5.0 mg had significant pain reduction compared to placebo patients. The PGIC measure of pain in hip and knee patients combined also showed significant benefit of 5.0 mg CR845 while other pain measures showed improvement but not statistical significance. These beneficial effects and a positive safety profile warrant further clinical study.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-phase-2-randomized-double-blind-placebo-controlled-titration-to-effect-study-of-orally-administered-cr845-in-patients-with-osteoarthritis-of-the-hip-or-knee/