Keiichiro Imanaka

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.

A Phase 2 Trial of Abiraterone Acetate in Japanese Men with Metastatic Castration-resistant Prostate Cancer and without Prior Chemotherapy (JPN-201 Study)

Objective Abiraterone acetate has been approved in >70 countries for chemotherapy-naïve metastatic castration-resistant prostate cancer patients. Efficacy and safety of abiraterone acetate (1000 mg/once daily) with prednisolone (5 mg/twice daily) in chemotherapy-naïve Japanese patients with metastatic castration-resistant prostate cancer was evaluated. Methods Men, ≥20 years, with prostate-specific antigen levels of ≥5 ng/ml and evidence of progression were enrolled in this Phase 2, multicenter, open-label study. Primary efficacy endpoint was proportion of patients achieving a prostate-specific antigen decline of ≥50% from baseline (prostate-specific antigen response) after 12 week of treatment. Secondary efficacy endpoints and safety were assessed. Results A confirmed prostate-specific antigen response was observed in 29/48 (60.4%) patients by week 12; lower limit of two-sided 90% confidence interval was >35% (threshold response rate), demonstrating efficacy of abiraterone acetate. Secondary efficacy endpoints: prostate-specific antigen response rate during treatment period: 62.5%; objective radiographic response, partial response: 4/18 (22.2%) patients; complete response: none; stable disease: 11/18 (61.1%) patients; median percent change in prostate-specific antigen level from baseline at Week 12: −66.62%. Median prostate-specific antigen response duration and progression-free survival were not reached, and median radiographic progression-free survival was 253 days. Of 31/48 (64.6%) patients experienced adverse events of special interest; most common was hepatic function abnormality (37.5%, Grade 3: 10.4%). One Grade 3 hypertension was the only mineralocorticoid adverse event >Grade 1/2. Conclusions Efficacy of abiraterone acetate plus prednisolone was demonstrated by decline in prostate-specific antigen levels with evidence of antitumor activity by radiography in Japanese patients with chemotherapy-naïve metastatic castration-resistant prostate cancer. Abiraterone acetate plus prednisolone had an acceptable safety profile. Clinical trial registration no NCT01756638.

A Phase 2 Study of Abiraterone Acetate in Japanese Men with Metastatic Castration-resistant Prostate Cancer Who Had Received Docetaxel-based Chemotherapy

Objective In this Phase 2 multicenter study the efficacy and safety of oral abiraterone acetate (1000 mg/once daily) plus prednisolone (5 mg/twice daily) was evaluated in metastatic castration-resistant prostate cancer patients from Japan who had previously received docetaxel-based chemotherapy. Methods Men (aged ≥20 years) with metastatic castration-resistant prostate cancer (prostate-specific antigen levels: ≥5 ng/ml), who had received 1 or 2 cytotoxic chemotherapies (with ≥1 regimen being docetaxel) for prostate cancer, were enrolled in this open-label, single-arm study. Primary efficacy endpoint was proportion of patients achieving a ≥50% prostate-specific antigen decline from baseline (prostate-specific antigen response rate) after 12-week treatment. Safety and pharmacokinetics were also assessed. Results Confirmed prostate-specific antigen response rate by Week 12 was 28.3% (90% confidence interval: 17.6%; 41.1%) or 13 out of 46 (full analysis set) treated patients. However, total prostate-specific antigen response rate including confirmed and unconfirmed responses was 34.8% (90% confidence interval: 23.2%; 47.9%). Secondary efficacy endpoints and outcomes were: improvement in Eastern Cooperative Oncology Group performance status score by ≥1 unit: 7/16 patients (43.8%); objective radiographic response: complete response, partial response and stable disease in 0, 1/22 (4.5%) and 9/22 (40.9%) patients, respectively; pain palliation response: 9/16 (56.3%) patients. The most common adverse events (>20% patients) were upper respiratory tract infection (13/47, 27.7% patients) and hepatic function abnormal (10/47, 21.3% patients, Grade 3: 8.5%). All mineralocorticoid-related toxicities were Grade 1/2. Conclusions Abiraterone acetate plus prednisolone showed favorable efficacy in metastatic castration-resistant prostate cancer Japanese patients who had received chemotherapy. Abiraterone acetate plus prednisolone had an acceptable safety profile. Clinical trial registration no NCT01795703.

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.

Burden of illness of chemotherapy in castration-resistant prostate cancer patients in Japan: a retrospective database analysis

Abstract Objective: The objective was to assess the burden of chemotherapy for castration-resistant prostate cancer (CRPC) in Japan. Methods: Utilizing a large administrative hospital database we compared a set of outcome measures 12 months before and after initiation of chemotherapy, namely total medical costs, number of outpatient visits, number of hospital admissions and number of days spent in hospital. Results: A total of 598 CRPC patients were identified in the database. Total healthcare costs increased from 143,578 Japanese Yen (JPY) per patient per month (PPPM), before chemotherapy, to 333,628 JPY after start of chemotherapy. The number of hospital admissions increased by 280%, and the number of days spent in hospital by 380%. Conclusions: The overall costs of chemotherapy for patients diagnosed with castration-resistant prostate cancer in Japan are high. Our findings can serve as a basis for health economic evaluations.

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.

Patient Preferences and Urologist Judgments on Prostate Cancer Therapy in Japan

The purpose of the present study is to investigate the concordance of treatment preferences between patients and physicians in prostate cancer (PCa) in Japan. An internet-based discrete choice experiment was conducted. Patients and physicians were asked to select their preferred treatment from a pair of hypothetical treatments consisting of four attributes: quality of life (QOL), treatment effectiveness, side effects, and accessibility of treatment. The data were analyzed using a conditional logistic regression model to calculate coefficients and the relative importance (RI) of each attribute. A total of 103 PCa patients and 127 physicians responded. The study looked at 37 patients considered as advanced PCa and 66 who were non-advanced PCa. All of the physicians were urologists. Advanced PCa patients ranked the attributes as follows: treatment effectiveness (RI: 32%), accessibility of treatment (RI: 26%), QOL (RI: 23%), and side effects (RI: 19%). For physicians, the RI ranking was the same as for advanced PCa patients; treatment effectiveness (RI: 29%), accessibility of treatment (RI: 27%), QOL (RI: 26%), and side effects (RI: 18%). For non-advanced PCa patients, accessibility of treatment ranked the highest RI (27%) and treatment effectiveness ranked as the lowest RI (14%). Our study suggests that the ranking of the attributes was consistent between advanced PCa patients and physicians. The most influential attribute was treatment effectiveness. Treatment preferences also vary by disease stage.