L C Rovati1, N Brambilla2, T Blicharski3, J Connell4, C Vitalini5, A Bonazzi6, G Giacovelli7, F Girolami8, M D'Amato9. 1. Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy. Electronic address: lucio.rovati@rottapharmbiotech.com. 2. Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy. Electronic address: nadia.brambilla@rottapharmbiotech.com. 3. Uniwersytet Medyczny w Lublinie, Poland. Electronic address: blicharski@vp.pl. 4. MAC Clinical Research, Manchester, UK. Electronic address: johnconnell@macplc.com. 5. Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy. Electronic address: cristina.vitalini@rottapharmbiotech.com. 6. Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy. Electronic address: albino.bonazzi@rottapharmbiotech.com. 7. Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy. Electronic address: giampaolo.giacovelli@rottapharmbiotech.com. 8. Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy. Electronic address: federica.girolami@rottapharmbiotech.com. 9. Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy. Electronic address: massimo.damato@rottapharmbiotech.com.
Abstract
OBJECTIVE:CR4056 is a selective imidazoline-2 (I2) receptor ligand with potent analgesic activity in animal pain models. This proof-of-concept study tested CR4056 efficacy and safety in patients with knee osteoarthritis (OA) and different phenotypes. DESIGN: This is a multicenter, randomized, double-blind, placebo-controlled trial. Knee OA patients with moderate to severe pain receivedCR4056 (women 100 mg bid; men 200 mg bid) or placebo (both genders) for 14 days. The primary outcome was the change in WOMAC pain score (0-100 scale) compared to placebo, analyzed in the intention-to-treat population and pre-defined OA phenotypes. RESULTS:213 patients were treated with CR4056 (92 women; 52 men) orplacebo (69 overall). After 14 days, median WOMAC pain improvements were 10 points on placebo and 14, 20 and 16 in women, men, and pooled CR4056 groups (P = 0.184, 0.030 and 0.070 vs placebo, respectively). Pre-specified subgroup analysis in the metabolic OA phenotype (BMI ≥ 27.5 kg/m2, N = 156) showed statistically significant differences in all CR4056-treated groups vs placebo of 12-18 points. Conversely, there were too few patients with a neuropathic or inflammatory phenotype for a meaningful analysis. CR4056 was well tolerated; the most common adverse event was mild headache. CONCLUSIONS: Although the primary endpoint was met in males only, this exploratory phase 2 trial shows that CR4056 might be an effective analgesic against knee OA pain, especially in overweight patients representing the metabolic OA phenotype. These findings, along with the broad-spectrum analgesic activity of CR4056 in animal models, warrant further clinical investigation in OA and other pain conditions. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2015-001136-37.
RCT Entities:
OBJECTIVE:CR4056 is a selective imidazoline-2 (I2) receptor ligand with potent analgesic activity in animal pain models. This proof-of-concept study tested CR4056 efficacy and safety in patients with knee osteoarthritis (OA) and different phenotypes. DESIGN: This is a multicenter, randomized, double-blind, placebo-controlled trial. Knee OA patients with moderate to severe pain received CR4056 (women 100 mg bid; men 200 mg bid) or placebo (both genders) for 14 days. The primary outcome was the change in WOMAC pain score (0-100 scale) compared to placebo, analyzed in the intention-to-treat population and pre-defined OA phenotypes. RESULTS: 213 patients were treated with CR4056 (92 women; 52 men) or placebo (69 overall). After 14 days, median WOMAC pain improvements were 10 points on placebo and 14, 20 and 16 in women, men, and pooled CR4056 groups (P = 0.184, 0.030 and 0.070 vs placebo, respectively). Pre-specified subgroup analysis in the metabolic OA phenotype (BMI ≥ 27.5 kg/m2, N = 156) showed statistically significant differences in all CR4056-treated groups vs placebo of 12-18 points. Conversely, there were too few patients with a neuropathic or inflammatory phenotype for a meaningful analysis. CR4056 was well tolerated; the most common adverse event was mild headache. CONCLUSIONS: Although the primary endpoint was met in males only, this exploratory phase 2 trial shows that CR4056 might be an effective analgesic against knee OA pain, especially in overweight patients representing the metabolic OA phenotype. These findings, along with the broad-spectrum analgesic activity of CR4056 in animal models, warrant further clinical investigation in OA and other pain conditions. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2015-001136-37.
Authors: Andrea Bagán; José A Morales-García; Christian Griñán-Ferré; Caridad Díaz; José Pérez Del Palacio; Maria C Ramos; Francisca Vicente; Belén Pérez; José Brea; María Isabel Loza; Mercè Pallàs; Carmen Escolano Journal: Int J Mol Sci Date: 2022-05-12 Impact factor: 6.208