TY - JOUR
T1 - A randomized study to evaluate the analgesic efficacy of a single dose of the TRPV1 antagonist mavatrep in patients with osteoarthritis
AU - Mayorga, Arthur J.
AU - Flores, Christopher M.
AU - Trudeau, Jeremiah J.
AU - Moyer, John A.
AU - Shalayda, Kevin
AU - Dale, Mark
AU - Frustaci, Mary Ellen
AU - Katz, Nathaniel
AU - Manitpisitkul, Prasarn
AU - Treister, Roi
AU - Ratcliffe, Stuart
AU - Romano, Gary
N1 - Funding Information: This study was funded by Janssen Research & Development, LLC, New Jersey, USA. Drs. Arthur J. Mayorga, Prasarn Manitpisitkul, Gary Romano, Christopher M. Flores, Kevin Shalayda, Mary Ellen Frustaci and John A. Moyer are employed by Janssen Research & Development. All authors meet ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data and made the final decision about where to publish these data. Publisher Copyright: © 2017 Scandinavian Association for the Study of Pain
PY - 2017/10
Y1 - 2017/10
N2 - 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 50 mg mavatrep, 500 mg 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).
AB - 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 50 mg mavatrep, 500 mg 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).
KW - Efficacy
KW - Knee osteoarthritis
KW - Mavatrep
KW - Pain
KW - Randomized study
KW - Safety
UR - http://www.scopus.com/inward/record.url?scp=85028023414&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.sjpain.2017.07.021
DO - https://doi.org/10.1016/j.sjpain.2017.07.021
M3 - Article
C2 - 28850367
SN - 1877-8860
VL - 17
SP - 134
EP - 143
JO - Scandinavian Journal of Pain
JF - Scandinavian Journal of Pain
ER -