Bernd Lange

Efficacy and Safety of Tapentadol Extended Release Compared with Oxycodone Controlled Release for the Management of Moderate to Severe Chronic Pain Related to Osteoarthritis of the Knee: A Randomized, Double-Blind, Placebo- and Active-Controlled Phase III Study

AbstractBackground: Tapentadol is a novel, centrally acting analgesic with μ-opioid receptor agonist and norepinephrine reuptake inhibitor activity. Objective: To evaluate the efficacy and safety of tapentadol extended release (ER) compared with oxycodone controlled release (CR) for management of moderate to severe chronic osteoarthritis-related knee pain. Methods: This was a randomized, double-blind, active- and placebo-controlled, parallel-arm, multicentre, phase III study during which patients received tapentadol ER, oxycodone CR or placebo for a 3-week titration period followed by a 12-week maintenance period. The study was carried out at sites in Australia, Canada, New Zealand and the US. A total of 1030 patients with chronic osteoarthritis-related knee pain were randomized to receive tapentadol ER 100–250 mg twice daily, oxycodone HCl CR 20–50 mg twice daily or placebo. Primary endpoints (as determined prior to initiation of the study) were the changes from baseline in average daily pain intensity (rated by patients on an 11-point numerical rating scale) over the last week of maintenance and over the entire 12-week maintenance period; last observation carried forward was used to impute missing values after early treatment discontinuation. Results: Efficacy and safety were evaluated for 1023 patients. Tapentadol ER significantly reduced average pain intensity from baseline to week 12 of the maintenance period versus placebo (least squares mean [LSM] difference [95% CI], −0.7 [−1.04, −0.33]), and throughout the maintenance period (−0.7 [−1.00, −0.33]). Oxycodone CR significantly reduced average pain intensity from baseline throughout the maintenance period versus placebo (LSM difference [95% CI], −0.3 [−0.67, −0.00]) but not at week 12 (−0.3 [−0.68, 0.02]). A significantly higher percentage of patients achieved ≥50% improvement in pain intensity in the tapentadol ER group (32.0% [110/344]) compared with the placebo group (24.3% [82/337]; p = 0.027), indicating a clinically significant improvement in pain intensity, while a significantly lower percentage of patients achieved ≥50% improvement in pain intensity in the oxycodone CR group (17.3% [59/342]; p = 0.023 vs placebo). In the placebo, tapentadol ER and oxycodone CR groups, respectively, 61.1% (206/337), 75.9% (261/344) and 87.4% (299/342) of patients reported at least one treatment-emergent adverse event (TEAE); incidences of gastrointestinal-related TEAEs were 26.1% (88/337), 43.0% (148/344) and 67.3% (230/342). Conclusion: Treatment with tapentadol ER 100–250 mg twice daily or oxycodone HCl CR 20–50 mg twice daily was effective for the management of moderate to severe chronic osteoarthritis-related knee pain, with substantially lower incidences of gastrointestinal-related TEAEs associated with treatment with tapentadol ER than with oxycodone CR. [Trial registration number: NCT00421928 (ClinicalTrials.gov Identifier)]

A Randomized Withdrawal, Placebo-Controlled Study Evaluating the Efficacy and Tolerability of Tapentadol Extended Release in Patients With Chronic Painful Diabetic Peripheral Neuropathy

OBJECTIVE This study evaluated the efficacy and tolerability of tapentadol extended release (ER) for the management of chronic pain associated with diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS Adults with moderate to severe DPN pain were titrated to tapentadol ER 100–250 mg bid during a 3-week open-label period; patients with ≥1-point reduction in pain intensity (11-point numerical rating scale) at end of titration were randomized to receive placebo or tapentadol ER (optimal dose from titration) for 12 weeks (double-blind, fixed-dose maintenance phase). The primary end point was mean change in average pain intensity from the start to week 12 (last observation carried forward [LOCF]) of the double-blind maintenance phase. RESULTS A total of 358 patients completed the titration period; 318 patients (placebo, n = 152; tapentadol ER, n = 166) were randomized and received one or more doses of double-blind study medication. Mean (SD) pain intensity (observed case) was 7.33 (1.30) at the start and 4.16 (2.12) at week 3 of the open-label titration period (mean [SD] change, –3.22 [1.97]). The mean (SD) change in pain intensity (LOCF) from start of double-blind treatment to week 12 was as follows: placebo, 1.30 (2.43); tapentadol ER, 0.28 (2.04; least squares mean difference, –0.95 [95% CI –1.42 to –0.49]; P < 0.001). Treatment-emergent adverse events (≥10%) in the tapentadol ER group during the double-blind maintenance phase were nausea (21.1%) and vomiting (12.7%). CONCLUSIONS Tapentadol ER (100–250 mg bid) was effective and well tolerated for the management of moderate to severe chronic pain associated with DPN.

Tapentadol prolonged-release for moderate-to-severe chronic osteoarthritis knee pain: a double-blind, randomized, placebo- and oxycodone controlled release-controlled study

Abstract Objective: To assess efficacy and safety of tapentadol prolonged release (PR) for moderate-to-severe chronic osteoarthritis knee pain. Methods: Patients (n = 990) were randomized (1:1:1) to tapentadol PR, oxycodone controlled release (CR; reference compound for assay sensitivity), or placebo for a double-blind 3-week titration and 12-week maintenance period. Primary efficacy end-points were change from baseline in average pain intensity at week 12 of maintenance (US end-point) and over the entire maintenance period (non-US end-point) with “last observation carried forward” as imputation method for missing scores. Results: Both primary end-points were not significantly different for tapentadol PR nor for oxycodone CR vs placebo at week 12 (least squares [LS] mean difference = –0.3 [95% CI = –0.61–0.09]; p = 0.152 and 0.2 [95% CI = –0.16–0.54]; p = 0.279, respectively) and over the maintenance period (LS mean difference = –0.2 [95% CI = –0.55–0.07]; p = 0.135 and 0.1 [95% CI = –0.18–0.44]; p = 0.421, respectively). Considerably more patients receiving tapentadol PR than oxycodone CR completed the trial (58.3% vs 36.6%). This is consistent with better results with tapentadol PR on the overall health status (PGIC) compared to oxycodone CR. Indeed, respectively, 56% and 42.5% rated at least “much improved” at the end of treatment. Incidences of gastrointestinal adverse events were higher for both active treatments compared to placebo. Tapentadol PR was associated with a better gastrointestinal tolerability profile with incidences of constipation (17.9% vs 35%) and of the composite of nausea and/or vomiting (23.8% vs 46.8%) significantly lower vs oxycodone CR (p < 0.001). Conclusions: The study did not demonstrate assay sensitivity. The finding that both primary end-points for tapentadol PR were not met can, thus, not be interpreted. Tapentadol PR was better tolerated than oxycodone CR, largely due to fewer gastrointestinal side-effects.

708 RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO- AND ACTIVE-CONTROLLED TRIAL OF TAPENTADOL EXTENDED RELEASE FOR CHRONIC LOW BACK PAIN

oxycodone CR (opioid-naive, 7.4 to 4.6; opioid-experienced, 7.7 to 4.7). Overall incidences of treatment-emergent adverse events (TEAEs) were 80.0% and 71.9%, respectively, for opioid-naive and opioid-experienced patients treated with tapentadol ER, and 84.0% and 85.5%, respectively, for opioid-naive and opioid-experienced patients treated with oxycodone CR. Incidences of gastrointestinalrelated TEAEs for opioid-naive and opioid-experienced patients, respectively, were as follows: tapentadol ER, 49.8% and 39.3%; oxycodone CR, 59.5% and 64.2%. TEAE-related discontinuation rates were lower for tapentadol ER than for oxycodone CR for both opioid-naive (13.6% vs 33.7% [20.1% reduction]) and opioidexperienced (19.1% vs 30.9% [11.8% reduction]) patients. Conclusions: Regardless of previous opioid treatment, tapentadol ER provides effective analgesia for moderate-to-severe chronic low back pain, with lower incidences of gastrointestinal-related TEAEs and discontinuations related to TEAEs compared with oxycodone CR. MSE, DYS, AO, IVH, and JH are Johnson & Johnson employees and shareholders. CL is a former employee of Grünenthal GmbH.

Efficacy and safety of tapentadol prolonged release for moderate-to-severe chronic osteoarthritis knee pain: a pooled analysis of two double-blind, randomized, placebo- and oxycodone controlled release-controlled studies

Abstract Objective: To compare efficacy and safety of tapentadol prolonged-release (PR) and oxycodone-controlled release (CR) in moderate-to-severe chronic osteoarthritis knee pain. Methods: Data from two double-blind, randomized, placebo- and oxycodone CR-controlled phase 3 studies with a 3-week titration period and 12-week controlled dose adjustment maintenance period were pooled. Primary efficacy end-points were change from baseline in average pain intensity at week 12 (US end-point) and over the entire maintenance period (non-US end-point). Results: A total of 2,010 patients were assessed. For both primary end-points, tapentadol PR was significantly more effective than oxycodone CR (LS mean difference of –0.41 [95% CI = –0.65, –0.16; p = 0.001] at week 12 and –0.35 [95% CI = –0.58, –0.12; p = 0.003] over 12 weeks of maintenance [last observation carried forward]). Significantly better outcomes than for oxycodone CR were also observed for patient global impression of change, both Short Form-36 component scores, and EuroQoL-5Dimensions health status index (all p < 0.001). Relative risk for vomiting, constipation, nausea, somnolence, and pruritus was lower for tapentadol PR than for oxycodone CR. A higher proportion of oxycodone CR patients discontinued treatment (64% vs 42.2% for tapentadol PR); time to treatment discontinuation due to an adverse event was significantly shorter for oxycodone CR (p < 0.001). Conclusions: The analyses suggest that tapentadol PR provided superior pain relief and a more improved overall health status than oxycodone CR in a large patient population with moderate-to-severe chronic osteoarthritis pain. Compared to oxycodone CR, tapentadol PR showed a more favorable tolerability profile with better gastrointestinal tolerability.

Health status (EuroQol-5 Dimension [EQ-5D]) in patients with painful diabetic peripheral neuropathy (DPN) treated with tapentadol extended release (ER): results of a randomized-withdrawal phase 3 study

| 245 -0.6), WOCF (-1.1), PMI (-0.6), modified BOCF (-0.8), and OC for patients who completed treatment (-1.0). The most frequently reported treatment-emergent adverse events were nausea, dizziness, and somnolence in the OL phase, and nausea, anxiety, and diarrhea in the tapentadol ER group in the DB phase. conclusion: Significant improvement in the primary endpoint was demonstrated with all imputation methods used, indicating that the efficacy of tapentadol ER was robust in this study of patients with moderate to severe chronic pain related to DPN. Complications nerve Conflict of interest Employee: ME, DYS, AO, and JH are employees of Johnson & Johnson. AS is an employee of Grunenthal GmbH.

Efficacy and safety of tapentadol prolonged release formulation in the treatment of elderly patients with moderate-to-severe chronic osteoarthritis knee pain: a pooled analysis of two double-blind, randomized, placebo-, and active-controlled trials

Abstract Objective: To compare efficacy and safety of tapentadol prolonged release (PR) vs oxycodone controlled release (CR) in younger patients (<65 years of age) and in elderly patients (≥65 and ≥75 years of age) in the treatment of moderate-to-severe chronic osteoarthritis (OA) knee pain. Methods: Data from two double-blind, randomized, placebo-, and oxycodone CR-controlled phase 3 trials were pooled and stratified by age. Primary efficacy end-points were change from baseline in average pain intensity at week 12 (US end-point) and over the entire maintenance period (non-US end-point). Results: A total of 1357 patients <65 years, 653 patients ≥65 years, and 176 patients ≥75 years of age were assessed. The comparison between tapentadol PR and oxycodone CR showed numerically better pain relief under tapentadol PR for both primary end-points in all three age groups. More favorable improvements were also observed for patient global impression of change, the Short Form-36 physical component score, and EuroQoL-5Dimensions health status index. In the elderly, incidences of dizziness and somnolence were comparable between active treatments, but incidences of nausea, vomiting, and constipation were considerably lower under tapentadol PR. Treatment completion rates were lowest under oxycodone CR; > 50% of elderly oxycodone CR patients named side-effects as the main reason for discontinuation. Conclusions: Tapentadol PR was effective in the treatment of moderate-to-severe chronic OA pain in elderly and younger patients. Compared to oxycodone CR, the overall and the gastrointestinal tolerability profile in particular were better in all tapentadol PR groups, regardless of age.