Yushin Tominaga

Efficacy and safety of oral tapentadol extended release in Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain

Abstract Objective: This phase 3 study evaluated the efficacy and safety of tapentadol extended release (ER) compared with oxycodone controlled release (CR) for the management of moderate to severe, chronic malignant tumor-related cancer pain. Research design and methods: This randomized, double-blind, active-controlled study included Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain. Patients were randomized (1:1) to receive oral tapentadol ER (25–200 mg bid) or oral oxycodone HCl CR (5–40 mg bid) for 4 weeks of double-blind treatment. ClinicalTrials.gov identifier: ClinicalTrials.gov identifier: NCT01165281. Main outcome measures: This study was designed to evaluate the non-inferiority of the efficacy provided by tapentadol ER versus oxycodone CR, based on the mean change in average pain intensity (11 point numerical rating scale) from baseline to the last 3 days of study drug administration. Treatment-emergent adverse events (TEAEs) were recorded throughout the study. Results: Of the 374 patients who were screened, 343 were randomized and 236 completed treatment. The least-squares mean difference in the change in pain intensity from baseline to the last 3 days of study treatment between tapentadol ER and oxycodone CR was −0.06 (95% confidence interval [CI], −0.506 to 0.383). The upper limit of the 95% CI was <1 (the predefined threshold value for non-inferiority), indicating that tapentadol ER provided analgesic efficacy that was non-inferior to that of oxycodone CR. The percentage of patients reporting at least one TEAE was similar in the tapentadol ER (87.5% [147/168]) and oxycodone CR (90.1% [155/172]) treatment groups, but the incidence of gastrointestinal TEAEs was lower in the tapentadol ER group (55.4% [93/168]) than in the oxycodone CR group (67.4% [116/172]). Conclusions: Tapentadol ER (25–200 mg bid) provides analgesic efficacy that is non-inferior to that provided by oxycodone HCl CR (5–40 mg bid) for the management of moderate to severe, chronic malignant tumor-related pain, and is well tolerated overall, with a better gastrointestinal tolerability profile than oxycodone CR.

Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.

Abstract Objective: To evaluate the efficacy and safety of fentanyl 1 day patch in opioid-naïve patients with non-cancer chronic pain insufficiently relieved by non-opioid analgesics. Research design and methods: Two phase III placebo-controlled, double-blind, group-comparison, randomized withdrawal studies were conducted in patients with osteoarthritis and/or low back pain (N01 study) and post-herpetic neuralgia, complex regional pain syndrome, or chronic postoperative pain (N02) in Japan. Both studies consisted of period I (10–29 days of titration, fentanyl 12.5–50.0 µg/h) and period II (12 weeks double-blind). Clinical trial registration: N01, NCT01008618; N02, NCT01008553 Main outcome measures: The primary endpoint was the number of days until study discontinuation due to insufficient pain relief in period II, and secondary endpoints included pain scored on visual analog scale (VAS), subject’s overall assessment, the number of rescue dose, brief pain inventory short form score, score on short-form 36-item health survey version 2.0, physician’s overall assessment, and assessment of adverse events. Results: Of the 218 (N01) and 258 (N02) subjects who entered period I, 150 and 163 subjects entered period II, respectively. In the N01 study, the between-group difference was significant in the VAS score (95% CI: 7.3 [1.1, 13.5] mm, P = 0.0215) but not in the primary endpoint (P = 0.0846, log-rank test). In the N02 study, both primary efficacy (P = 0.0003) and VAS (8.7 [2.4, 15.0] mm, P = 0.0071) results showed that fentanyl was more effective than placebo. The major adverse events were nervous system and gastrointestinal disorders typically associated with opioid analgesic use. The incidence of adverse events in the fentanyl group was 68.5% to 85.7%. Conclusions: Although the primary efficacy results showed significant effects of fentanyl in the N02 but not the N01 study, overall results showed that fentanyl 1 day patch is effective and well tolerated.

A randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of osmotic-controlled release oral delivery system methylphenidate HCl in adults with attention-deficit/hyperactivity disorder in Japan

Abstract Objectives. To evaluate the safety and efficacy of osmotic-controlled release oral delivery system (OROS) methylphenidate (MPH) HCl in adults with attention-deficit/hyperactivity disorder (ADHD). Methods. In this study, 284 adults with ADHD were randomized to OROS MPH or placebo. During the 4-week titration period, patients were titrated from a starting dose of 18 mg once daily to an individually-optimized dose of up to 72 mg once daily in weekly 18-mg increments. Patients continued on their individualized dose during the 4-week efficacy assessment period. The primary efficacy endpoint was change in DSM-IV Total ADHD Symptoms subscale score of Conners’ Adult ADHD Rating Scale-Observer: Screening Version (CAARS-O:SV) from baseline to endpoint. Results. The mean change in DSM-IV Total ADHD Symptoms subscale score of CAARS-O:SV was significantly larger with OROS MPH compared with placebo (P < 0.0001, ANCOVA). Similar results were observed for the majority of secondary endpoints, including CAARS-O:SV total score and other subscale scores. Although treatment-emergent adverse events were reported more frequently in the OROS MPH group (81.8%) versus the placebo group (53.9%), OROS-MPH showed a well-tolerated safety profile overall. Conclusions. OROS MPH in a dose range of 18–72 mg once daily was effective and well-tolerated in adult patients with ADHD.

Adverse event reporting in the recent study by Imanaka et al. describing the efficacy and safety of tapentadol extended release for tumor-related pain

This letter is intended to provide additional clarification for your readers regarding the potentially confusing issue of adverse event vs serious adverse event reporting in a recently published phase 3 study of tapentadol extended release (ER) for malignant tumor-related pain. The results of a randomized, double-blind, phase 3 study evaluating the efficacy and safety of tapentadol ER for the management of moderate-tosevere, chronic malignant tumor-related pain were published in this journal in October 2013 in our article entitled, ‘Efficacy and safety of oral tapentadol extended release in Japanese and Korean patients with moderate-to-severe, chronic malignant tumor-related pain’. According to our company’s policy and in accordance with guidance from the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, all treatment-emergent adverse events (TEAEs) were recorded throughout the double-blind treatment and for 3 days after the last dose of the study drug (based on the half-life of tapentadol ER), while any spontaneously reported serious AEs were recorded for up to 30 days after the last dose of the study drug. This difference in the time periods for collecting and reporting of TEAEs vs serious AEs resulted in an apparent discrepancy in the percentage of patients experiencing disease progression. The incidence of disease progression reported in Table 4 (which lists the most common [incidence 5%] TEAEs overall) was 21.4% (36/168) with tapentadol ER and 19.2% (33/172) with oxycodone controlled release (CR), while the incidence of disease progression given in the first full paragraph beneath Table 4, which was based on serious AE reporting (which included an additional 30 day reporting period after the last dose of study drug), was 23.8% (40/168) with tapentadol ER and 20.9% (36/172) with oxycodone CR.

Methodological Issues in Conducting Pilot Trials in Chronic Pain as Randomized, Double-blind, Placebo-controlled Studies

BACKGROUND The efficacy of tapentadol extended release (ER) for managing chronic pain has been demonstrated in large-scale, randomized, controlled, phase 3 studies (N=318-1,030) in patients with chronic osteoarthritis (OA) pain, low back pain (LBP), and pain related to diabetic peripheral neuropathy (DPN), which led to registration in many regions, including the United States and Europe. 2 pilot 12-week, randomized, double-blind, placebo-controlled phase 2 studies of tapentadol ER for chronic pain (OA knee pain or LBP, n=91; DPN or peripheral herpetic neuralgia [PHN] pain; n=91) were conducted in Japan. These small exploratory studies were substantially underpowered compared with the registration trials. METHODS Patients in both studies were randomized (2:1) to tapentadol ER (25-250 mg) or placebo for 12 weeks (≤6-week titration plus maintenance periods). RESULTS For the primary efficacy endpoint (change in pain intensity from baseline to last week of treatment; last observation carried forward), both studies failed to differentiate between tapentadol ER and placebo; least-squares mean differences (95% confidence intervals) for tapentadol ER vs. placebo were -0.1 (-1.04, 0.80) in the OA/LBP study and -0.1 (-1.10, 0.99) in the DPN/PHN study. More than 80% of patients took concomitant analgesics during these studies. Tapentadol was well tolerated. CONCLUSIONS Both studies were associated with methodological issues, including populations with different disease entities, small sample sizes, use of concomitant analgesics, and possible placebo effect that may have led to the failure to differentiate between tapentadol ER and placebo.

PHARMACOCOKINETIC AND PHARMACODYNAMIC STUDY (54861911ALZ1006) WITH A BACE INHIBITOR, JNJ-54861911, IN HEALTHY ELDERLY JAPANESE SUBJECTS

for pharmacokinetic and Abeta (x-40, x-42 and total) biomarker analysis. Results: No clinical abnormalities were identified and no significant changes on safety ECG, telemetry, vital signs, or labs were observed up to 360 mg single dose. Doses were escalated up to the pre-defined exposure limit and maximum tolerated dose has not been established. Following single doses under fasted condition, PF-06648671 was absorbed rapidly with median tmax of 1 to 1.5 hours. The mean terminal t1/2 was 13.9 to 23.1 hours. The Cmax and AUCinf increased by approximately 88and 140-fold over the dose range of 2 to 360 mg. With high-fat meal, a delayed median tmax of 4 hours was observed. AUCinf slightly increased by 23% while Cmaxdecreased by 24% compared to the fasted state. Significant, dose-dependent reductions in plasma Abeta42, 40 and total were observed. The placebo-adjusted maximal change from baseline was -56.9% and -68.8% for plasma Abeta42 and 40, respectively, after a single dose of 360 mg. As expected, the reduction in Abeta total was substantially less than in Abeta40 and 42. Conclusions: PF-06648671 was generally safe and well tolerated in healthy subjects after single oral doses up to 360 mg. Robust and dose-dependent reductions in plasma Ab40 and Ab42 were observed following single dose administrations. A multiple ascending dose study in healthy adult and elderly is ongoing with CSF Ab effect evaluated at steady state.

A PHARMACODYNAMIC STUDY (54861911ALZ1008) WITH A BACE INHIBITOR, JNJ-54861911 IN JAPANESE ASYMPTOMATIC SUBJECTS AT RISK FOR ALZHEIMER'S DEMENTIA

POSTER PRESENTATIONS P2 P2-001 A PHARMACODYNAMIC STUDY (54861911ALZ1008)WITHABACE INHIBITOR, JNJ54861911 IN JAPANESE ASYMPTOMATIC SUBJECTS AT RISK FOR ALZHEIMER’S DEMENTIA Masayoshi Takahashi, Luc Tritsmans, Hiroko Shimizu, Tomoko Santoh, Ayako Shiraishi, Yushin Tominaga, Johannes Streffer, 1 Janssen Pharm KK Japan, Tokyo, Japan; 2 Janssen Research & Development, Beerse, Belgium. Contact e-mail: MTAKAHA4@its.jnj.com