A randomized study to evaluate the analgesic efficacy of a single dose of the TRPV1 antagonist mavatrep in patients with osteoarthritis

Abstract

Background/aims: Transient receptor potential vanilloid type 1 (TRPV1) receptor antagonists have been evaluated in clinical studies for their analgesic effects. Mavatrep, a potent, selective, competitive TRPV1 receptor antagonist has demonstrated pharmacodynamic effects consistent with target engagement at the TRPV1 receptor in a previous single-dose clinical study. The current study was conducted to evaluate the analgesic effects of a single dose of mavatrep.

Methods: In this randomized, placebo- and active-controlled, 3-way crossover, phase 1b study, patients with painful knee osteoarthritis were treated with a single-dose of 50mg mavatrep, 500mg naproxen twice-daily, and placebo. Patients were randomized to 1 of 6 treatment sequences. Each treatment sequence included three treatment periods of 7 days duration with a 7 day washout between each treatment period. The primary efficacy evaluation was pain reduction measured by the 4-h postdose sum of pain intensity difference (SPID) based on the 11-point (0-10) Numerical Rating Scale (NRS) for pain after stair-climbing (PASC). The secondary efficacy evaluations included 11-point (0-10) NRS pain scores entered into the Actiwatch between clinic visits, the Western Ontario and McMaster Universities Arthritis Index subscales (WOMAC) questionnaire, and use of rescue medication. Safety and tolerability of single oral dose mavatrep were also assessed.

Results: Of 33 patients randomized, 32 completed the study. A statistically significantly (p<0.1) greater reduction in PASC was observed for mavatrep versus placebo (4-h SPID least square mean [LSM] [SE] difference: 1.5 [0.53]; p=0.005 and 2-h LSM [SE] difference of PID: 0.7 [0.30]; p=0.029). The mean average daily current pain NRS scores were lower in the mavatrep and naproxen treatment arm than in the placebo arm (mavatrep: 7 day mean [SD], 3.72 [1.851]; naproxen: 7 day mean [SD], 3.49 [1.544]; placebo: 7 day mean [SD], 4.9 [1.413]). Mavatrep showed statistically significant improvements as compared with placebo on the WOMAC subscales (pain on days 2 [p=0.049] and 7 [p=0.041], stiffness on day 7 [p=0.075]), and function on day 7 [p=0.077]). The same pattern of improvement was evident for naproxen versus placebo. The mean (SD) number of rescue medication tablets taken during the 7-day treatment period was 4.2 (6.49) for mavatrep treatment, 2.8 (5.42) for naproxen, and 6.3 (8.25) for placebo treatment. All patients that received mavatrep reported at least 1 treatment emergent adverse event (TEAE). Feeling cold (79%), thermohypoesthesia (61%), dysgeusia (58%), paraesthesia (36%), and feeling hot (15%) were the most common TEAEs in the mavatrep group. Total 9% patients receiving mavatrep experienced minor thermal burns. No deaths or serious AEs or discontinuations due to AEs occurred.

Conclusion: Overall, mavatrep was associated with a significant reduction in pain, stiffness, and physical function when compared with placebo in patients with knee osteoarthritis. Mavatrep's safety profile was consistent with its mechanism of action as a TRPV1 antagonist.

Implications: Further studies are required to evaluate whether lower multiple doses of mavatrep can produce analgesic efficacy while minimizing adverse events, as well as the potential for improved patient counselling techniques to reduce the minor thermal burns related to decreased heat perception.

Trial registration: 2009-010961-21 (EudraCT Number).

Keywords: Efficacy; Knee osteoarthritis; Mavatrep; Pain; Randomized study; Safety.