IntroductionFibromyalgia is a chronic disorder characterized by widespread pain and tenderness. Prior trials have demonstrated the efficacy of pregabalin for the relief of fibromyalgia symptoms, and it is approved for the treatment of fibromyalgia in the United States. However, prior to this study, there has not been a large-scale efficacy trial in patients with fibromyalgia in Japan.MethodsThis randomized, double-blind, multicenter, placebo-controlled trial was conducted at 44 centers in Japan to assess the efficacy and safety of pregabalin for the symptomatic relief of pain in fibromyalgia patients. Patients aged ≥18 years who had met the criteria for fibromyalgia were randomized to receive either pregabalin, starting at 150 mg/day and increasing to a maintenance dose of 300 or 450 mg/day, or placebo, for 15 weeks. The primary efficacy endpoint was mean pain score at final assessment. Secondary endpoints included Patient Global Impression of Change (PGIC) together with measures of sleep, physical functioning and quality of life.ResultsA total of 498 patients (89% female) were randomized to receive either pregabalin (n = 250) or placebo (n = 248). Pregabalin significantly reduced mean pain score at final assessment (difference in mean change from baseline, compared with placebo -0.44; P = 0.0046) and at every week during the study (P <0.025). Key secondary endpoints were also significantly improved with pregabalin treatment compared with placebo, including PGIC (percentage reporting symptoms "very much improved" or "much improved", 38.6% vs 26.7% with placebo; P = 0.0078); pain visual analog scale (difference in mean change from baseline, compared with placebo -6.19; P = 0.0013); Fibromyalgia Impact Questionnaire total score (-3.33; P = 0.0144); and quality of sleep score (-0.73; P <0.0001). Treatment was generally well tolerated, with somnolence and dizziness the most frequently reported adverse events.ConclusionsThis trial demonstrated that pregabalin, at doses of up to 450 mg/day, was effective for the symptomatic relief of pain in Japanese patients with fibromyalgia. Pregabalin also improved measures of sleep and functioning and was well tolerated. These data indicate that pregabalin is an effective treatment option for the relief of pain and sleep problems in Japanese patients with fibromyalgia.Trial RegistrationClinicalTrials.gov: NCT00830167
AMG 531 is a novel thrombopoiesis-stimulating peptibody being investigated for the treatment of chronic immune thrombocytopenic purpura. This double-blind, phase I study evaluated the safety, pharmacodynamics, and pharmacokinetics of AMG 531 in healthy Japanese men. Thirty subjects were randomly assigned 4:1 (AMG 531/placebo) to receive 1 dose of AMG 531 (0.3, 1, or 2 microg/kg) or placebo by subcutaneous injection; subjects were evaluated for 6 weeks. AMG 531 was generally well tolerated, with adverse events similar to placebo. Treatment-related adverse events (headache, "feeling hot," malaise) were reported for 5 of 24 AMG 531-treated subjects. Platelets generated after exposure to AMG 531 functioned normally. Four of 8 subjects receiving 1 microg/kg and 7 of 8 receiving 2 microg/kg had platelet count increases > or =1.5-fold over baseline, an effect similar to that seen in non-Japanese subjects. Serum AMG 531 concentrations were below the lower limit of quantification in all but 2 subjects receiving 2 microg/kg.
Bone is a common site of metastasis in breast cancer. An estimated 75% of women with advanced breast cancer will develop bone metastases, (1)(2)(3) which are characterized by pain, fracturing, and spinal cord compression that cause morbidity for many patients. Receptor activator of nuclear factor-kappa B ligand (RANKL) is a key mediator of the 'vicious cycle' of bone destruction in metastatic cancer. RANKL is a critical mediator of osteoclast differentiation, function, and survival. (4)(5)(6) Within the bone microenvironment, tumor cells secrete factors that stimulate stromal cells and osteoblasts to express and secrete RANKL, which binds to its cognate receptor RANK on the surface of precursor and mature osteoclasts. Osteoclastmediated bone resorption releases growth factors that further stimulate tumor growth, resulting in a propagation of bone destruction and tumor cell proliferation.(7) RANKL has recently been shown to promote migration of RANK-expressing tumor cells to bone. (8) Patients with bone metastases often have increased bone turnover that can be measured using biochemical markers of bone resorption and formation, such as urinary N-telopeptide (uNTx) and bone-specific alkaline phosphatase (BSAP). Elevated levels of bone turnover markers are correlated with an increased risk of skeletal complications, disease progression, and death.(9-12) A key objective in the management of bone metastases is to minimize skeletal morbidity by re-establishing the homeostasis of bone metabolism. If excessive osteolysis is inhibited, skeletal complications caused by bone metastases may be prevented or delayed.Denosumab is a fully human monoclonal antibody that binds and inhibits RANKL, thus inhibiting osteoclast-mediated bone destruction. Results from clinical trials in non-Japanese women with breast cancer-related bone metastases showed that denosumab suppressed bone turnover, and the incidence of adverse events was similar in the denosumab and control groups. (2,13) The objectives of this trial were to evaluate the safety, pharmacokinetics, and pharmacodynamics of denosumab in Japanese women with bone metastases associated with breast cancer and to compare the results of this trial with those from a similar study in an analogous population of non-Japanese women (NCT00091832, Clinical Trials.gov). (2,13,14) Materials and MethodsThis study was conducted according to the principles of the Japanese Ministry of Health, Labour, and Welfare, and the International Conference on Harmonisation regulations and guidelines. Institutional Review Boards at each clinical site approved the protocol and all amendments. An Efficacy and Safety Evaluation Committee monitored patient safety during the study as needed. Patients provided appropriate written informed consent.Study design. In this phase 1 open-label, multicenter, doseascending single, and multiple dose study, patients were sequentially enrolled in one of three cohorts. Patients in the first cohort received a single 60-mg subcutaneous injection of denosumab. If no safety sign...
This open-label, single-arm, phase 2 study (ClinicalTrials.gov, NCT03128411) evaluated the efficacy, safety, and pharmacokinetics of bosutinib at a starting dose of 400 mg once daily (QD) in Japanese patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML).The primary endpoint was major molecular response (MMR) at Month 12 in the modified astreated population (Philadelphia chromosome-positive [Ph+] patients with e13a2/e14a2 transcripts). Sixty Japanese patients with CP CML were treated with bosutinib; median age was 55 years (range, 20-83), 60.0% were male, and all were Ph+ and had e13a2/e14a2 transcripts.After median follow-up of 16.6 months (range, 11.1-21.9), 41 (68.3%) patients remained on bosutinib. The MMR rate at Month 12 was 55.0% (2-sided 90% confidence interval: 44.4-65.6).There were no on-treatment transformations to accelerated/blast phase, and no patient died on treatment or within 28 days of the last bosutinib dose. The most common treatment-emergent adverse events were diarrhea (86.7%), increased alanine aminotransferase (55.0%), and increased aspartate aminotransferase (46.7%). The primary objective of this phase 2 study was met, and there were no new safety signals for bosutinib. These data suggest bosutinib is an effective first-line treatment option for Japanese patients with newly diagnosed CP CML. Keywords Bosutinib • Tyrosine kinase inhibitor • Chronic myeloid leukemia • JapanThis study was sponsored by Pfizer. Medical writing support was provided by Joanna Bloom, PhD, of Engage Scientific Solutions and was funded by Pfizer.
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