Item Response Analyses of the Children's Depression Rating Scale-Revised Using Data from Clinical Studies.

Objective: We aimed to identify which of the 17 items comprising the Children's Depression Rating Scale-Revised (CDRS-R) can sensitively capture changes in depression severity. Methods: We used data from four studies involving two antidepressants. For each of the 17 CDRS-R items, we conducted item response analyses to identify and evaluate those that reflect changes in depression severity. We created plots of the item characteristic curves (ICCs) estimated by the graded response model, and option characteristic curves and ICCs using nonparametric item response theory. The change from baseline in the CDRS-R subscale score with specified reflective items by item response analyses and the effect size between the treatment group and placebo group were calculated and compared with those of the CDRS-R total score. Results: CDRS-R items #2 (difficulty having fun), #3 (social withdrawal), #10 (low self-esteem), #11 (depressed feelings), and #15 (depressed facial expression) have favorable profiles that reflect disease severity. Changes from baseline in the CDRS-R total score (least square mean ± standard error) at week 8 were -22.3 ± 0.7 and -23.9 ± 0.7 in the placebo group and treatment group, respectively (difference, -1.5; estimated effect size, -0.113), changes from baseline in the CDRS-R5 (CDRS-R subscale consisting of the specified reflective items [#2, #3, #10, #11, and #15]) score at week 8 were -8.4 ± 0.3 and -9.6 ± 0.3 in each group, respectively (difference, -1.2; effect size, -0.202). Conclusions: The item response analyses clarified the properties of 17 items of the CDRS-R for major depressive disorder in children and adolescents. The CDRS-R5 might optimize the assessment of changes in overall depression severity and differentiation of treatment responses.

Effectiveness of pregabalin for treatment of chronic cervical radiculopathy with upper limb radiating pain: an 8-week, multicenter prospective observational study in Japanese primary care settings.

Background: Despite high prevalence of chronic neck pain in Japan and the negative impact pain has on patient's quality of life (QoL), the therapeutic value of pregabalin for chronic neck pain with a neuropathic pain (NeP) component has not been assessed in a typical Japanese health care setting. Methods: An 8-week, non-interventional, multicenter, observational study of Japanese adults (≥20 years) with chronic refractory cervical pain including a NeP element (for ≥12 weeks) and sleep disturbance on the Pain-Related Sleep-Interference Scale (PRSIS) ≥1 (from 0 "does not interfere with sleep" to 10 "completely interferes"). Patients received either usual care with conventional analgesics or pregabalin (150-600 mg/day) for 8 weeks. "Usual care" with analgesics or other treatment(s) was determined based on physician's best clinical judgment. Primary endpoint was change from baseline to week 8 in PRSIS. Secondary endpoints included: change from baseline to week 4 in PRSIS, and to week 4 and 8 in pain Numerical Rating Scale (NRS; from 0 "no pain" to 10 "worst possible pain"), and on the Neck Disability Index (NDI). Other assessments of QoL were undertaken. Safety was monitored. Results: Overall, 369 patients received pregabalin (n=145) or usual care (n=224). The median (range) dose of pregabalin was 49.6 (25.0-251.5) mg/day. Least-squares mean change in PRSIS from baseline to week 8 favored pregabalin (-1.167 vs -0.269; treatment difference -0.898 [95% CI -1.262, -0.535], P<0.001). Similar observations were seen at week 4 in favor of pregabalin versus usual care (P<0.001). Pregabalin significantly improved pain NRS and NDI scores at weeks 4 and 8 (all P<0.001). Improvements in QoL versus usual care were also observed. Pregabalin was generally well tolerated. Conclusion: In this open-label study, pregabalin improved PRSIS and resulted in clinically meaningful reductions in pain in Japanese patients with NeP associated with chronic cervical pain. ClinicalTrials.gov identifier: NCT02868359.

The efficacy of pregabalin for the treatment of neuropathic pain in Japanese subjects with moderate or severe baseline pain.

PURPOSE: Although analyses of pooled clinical trial data have reported how international populations respond to pregabalin by baseline neuropathic pain (NeP) severity, no studies have evaluated this specifically in patients from Japan. Thus, this post hoc pooled analysis evaluated the efficacy of pregabalin in Japanese subjects for treating moderate or severe baseline NeP. PATIENTS AND METHODS: Data were pooled from three placebo-controlled trials enrolling Japanese subjects with postherpetic neuralgia (PHN), diabetic peripheral neuropathy (DPN), and spinal cord injury (SCI). The efficacy of pregabalin was evaluated by baseline pain severity (moderate or severe NeP). The trials on PHN and DPN included a 1-week titration of pregabalin from 150 mg/day to 300 or 600 mg/day; the SCI trial included a 4-week dose optimization phase (150 mg/day, titrated up to 600 mg/day). Treatment durations were 13-16 weeks (excluding 1-week taper periods), and pregabalin was administered in two divided doses per day. RESULTS: Mean baseline pain scores and demographic characteristics were comparable between treatment cohorts. Pregabalin treatment significantly reduced pain scores from baseline to endpoint compared with placebo in subjects with both moderate (P<0.001) and severe (P<0.05) baseline pain. Significant improvements in mean sleep scores from baseline to endpoint were associated with pregabalin compared with placebo in subjects with both moderate and severe baseline pain (both P<0.0001). A greater proportion of subjects in both pain cohorts achieved a ≥30% reduction in pain from baseline with pregabalin vs placebo (P<0.05). Higher proportions of pregabalin-treated vs placebo-treated subjects shifted to a less severe pain category at endpoint. Consistent with the known safety profile of pregabalin, common adverse events included dizziness, somnolence, weight gain, and peripheral edema. CONCLUSION: Pregabalin demonstrated efficacy for pain relief and sleep improvement with a consistent safety profile in Japanese subjects with either moderate or severe baseline pain severity. CLINICALTRIALSGOV IDENTIFIERS: NCT0039490130, NCT0055347522, NCT0040774524.

Long-Term Extensions of Randomized Vaccination Trials of ACC-001 and QS-21 in Mild to Moderate Alzheimer's Disease.

OBJECTIVES: Long-term safety and tolerability of ACC-001 (vanutide cridificar), an antiamyloid- beta therapeutic vaccine, was evaluated in subjects with mild to moderate Alzheimer's disease. DESIGN: Phase 2a extension studies of randomized parent trials were conducted in the United States, European Union, and Japan. METHODS: Four immunizations of ACC-001 were administered at the same 3 dose levels (3, 10, and 30 µg) to subjects randomized in the parent studies; ACC-001 was administered with QS-21 adjuvant. Safety, tolerability, and immunogenicity were assessed during active treatment and 6-month follow-up. RESULTS: ACC-001 + QS-21 was well tolerated in the United States (N=110) and European Union (N=50), and Japan (N=53) extension studies; safety profile was similar to that observed in the parent studies, and no new safety signals were identified. Overall, injection site reactions were the most common adverse event in these studies. Anti-amyloid antibody titers were elicited in all groups, with the highest titers observed in subjects who received ACC-001 + QS-21 in both the parent and extension studies. CONCLUSIONS: Long-term exposure to ACC-001 + QS-21 was well tolerated in subjects with Alzheimer's disease, suggesting that side effects do not pose a principal limitation for anti-amyloid active immunotherapy. The highest anti-amyloid-beta IgG titers are elicited during long-term therapy with ACC-001 + QS-21 compared with other regimens.

Pregabalin for Neuropathic Pain: Why Benefits Could Be Expected for Multiple Pain Conditions.

BACKGROUND AND OBJECTIVE: Limited research exists to support the extrapolation of the analgesic efficacy of pregabalin from one neuropathic pain condition to another. This retrospective analysis evaluated similarities in the efficacy of pregabalin for treating neuropathic pain associated with post-herpetic neuralgia (PHN), diabetic peripheral neuropathy (DPN), and spinal cord injury (SCI) in a Japanese population, as a basis for considering the extrapolation of these data to other neuropathic pain conditions. METHODS: Data were analysed across pregabalin doses within each pain condition, from three comparable 13- to 16-week, randomized, double-blind, placebo-controlled trials (RCTs) and the corresponding 52-week, open-label extension trials of pregabalin in Japanese patients with PHN, DPN or SCI. Efficacy outcomes in the RCTs included endpoint and weekly mean pain and sleep interference scores; endpoint proportions of responders in pain; Patient Global Impression of Change scores; and 36-Item Short Form Health Survey (SF-36) scores or Hospital Anxiety and Depression Scale (HADS) assessments. Study discontinuation rates were compared between treatment groups. The extension trials assessed pain intensity, using the Short-Form McGill Pain Questionnaire. RESULTS: In the RCTs for all pain conditions, significant improvements in comparison with placebo in mean pain and sleep interference scores were evident after 1 week with pregabalin and were sustained throughout the treatment periods (p < 0.05). At the study endpoint, in comparison with placebo, a significantly greater percentage of pregabalin-treated patients experienced a ≥30 % reduction in pain across the RCTs (p < 0.05), and pregabalin significantly improved six of 16 SF-36 subscale scores in the PHN and DPN trials (p < 0.05). In the SCI trial, pregabalin-treated patients had numerically better outcomes of HADS scores. In the extension trials, improvements in pain intensity were maintained over a 52-week period. CONCLUSION: Similarities in the pregabalin efficacy profiles, including time to onset and magnitude of response, were confirmed regardless of the neuropathic pain condition. These data support the potential for extrapolating analgesic efficacy to other neuropathic pain conditions. CLINICALTRIALS. GOV IDENTIFIERS: NCT00394901, NCT00553475, NCT00407745, NCT00424372, NCT00553280, NCT01202227.

Effectiveness of pregabalin for the treatment of chronic low back pain with accompanying lower limb pain (neuropathic component): a non-interventional study in Japan.

OBJECTIVE: To evaluate the impact of pregabalin on sleep, pain, function, and health status in patients with chronic low back pain with accompanying neuropathic pain (CLBP-NeP) under routine clinical practice. METHODS: This prospective, non-interventional, observational study enrolled Japanese adults (≥18 years) with CLBP-NeP of duration ≥3 months and severity ≥5 on a numerical rating scale (0= no pain, 10= worst possible pain). Treatment was 8 weeks with pregabalin (n=157) or usual care alone (n=174); choice of treatment was determined by the physician. The primary efficacy outcome was change from baseline to 8 weeks in pain-related interference with sleep, assessed using the Pain-Related Sleep Interference Scale (PRSIS; 0= did not interfere with sleep, 10= completely interferes with sleep). Secondary endpoints were changes in PRSIS at week 4, and changes at weeks 4 and 8 in pain (numerical rating scale), function (Roland-Morris Disability Questionnaire), and quality of life (EuroQol 5D-5L); global assessments of change were evaluated from the clinician and patient perspectives at the final visit. RESULTS: Demographic characteristics were similar between cohorts, but clinical characteristics suggested greater disease severity in the pregabalin group including a higher mean (standard deviation) pain score, 6.3 (1.2) versus 5.8 (1.1) (P<0.001). For the primary endpoint, pregabalin resulted in significantly greater improvements in PRSIS at week 8, least-squares mean changes of -1.3 versus -0.4 for usual care (P<0.001); pregabalin also resulted in greater PRSIS improvement at week 4 (P=0.012). Relative to usual care at week 8, pregabalin improved pain and function (both P<0.001), and showed global improvements since beginning study medication (P<0.001). Pregabalin was well tolerated. CONCLUSION: In clinical practice in patients with CLBP-NeP, pregabalin showed significantly greater improvements in pain-related interference with sleep relative to usual care. In addition, pregabalin significantly improved pain, function, and health status, suggesting the benefits of pregabalin for overall health and well-being relative to usual care in these patients. (Clinicaltrials. gov identifier NCT02273908).

Vanutide cridificar and the QS-21 adjuvant in Japanese subjects with mild to moderate Alzheimer's disease: results from two phase 2 studies.

OBJECTIVE: Multiple lines of evidence indicate that pathological accumulation of amyloid beta (Aß) peptide in the brain is linked to the pathophysiology of Alzheimer's disease (AD). Removal of Aß from the brain by binding to anti-Aß specific antibodies is under active investigation. Vaccination with a full-length Aß42 peptide (AN1792) successfully elicited anti-Aß antibodies in human subjects with AD, but was associated with meningoencephalitis. To avoid this safety issue, an aminoterminal Aß1-7 peptide conjugate, vanutide cridificar (ACC-001), was designed and is currently in clinical development. This report describes two phase 2 multiple ascending-dose studies in Japanese subjects with mild to moderate AD. Safety and immunogenicity evaluation were the primary and secondary objectives, respectively. METHODS: ACC-001 was administered to three cohorts of subjects at doses of 3, 10, or 30 µg, with or without a QS-21 adjuvant in Study 1, and with a QS-21 adjuvant in Study 2; control groups consisted of QS-21 alone (both studies) and phosphate-buffered saline (Study 1 only). RESULTS: A variety of treatment-emergent adverse events (TEAEs) were reported from most subjects during the studies; most of these were mild or moderate in intensity. Three subjects withdrew from the study because of an adverse event (in Study 2). The most common treatment-associated TEAE was injection site reactions. No deaths were observed in either study. All doses of ACC-001 + QS-21 elicited high, sustained anti-Aß antibody titers; QS-21 was necessary for this effect. CONCLUSION: These data will provide valuable information on further investigation of anti-Aß vaccine therapy for AD.

An open-label, long-term study examining the safety and tolerability of pregabalin in Japanese patients with central neuropathic pain.

PURPOSE: Studies of pregabalin for the treatment of central neuropathic pain have been limited to double-blind trials of 4-17 weeks in duration. The purpose of this study was to assess the long-term safety and tolerability of pregabalin in Japanese patients with central neuropathic pain. The efficacy of pregabalin was also assessed as a secondary measure. PATIENTS AND METHODS: This was a 53-week, multicenter, open-label trial of pregabalin (150-600 mg/day) in Japanese patients with central neuropathic pain due to spinal cord injury, multiple sclerosis, or cerebral stroke. RESULTS: A total of 103 patients received pregabalin (post-stroke =60; spinal cord injury =38; and multiple sclerosis =5). A majority of patients (87.4%) experienced one or more treatment-related adverse events, most commonly somnolence, weight gain, dizziness, or peripheral edema. The adverse event profile was similar to that seen in other indications of pregabalin. Most treatment-related adverse events were mild (89.1%) or moderate (9.2%) in intensity. Pregabalin treatment improved total score, sensory pain, affective pain, visual analog scale (VAS), and present pain intensity scores on the Short-Form McGill Pain Questionnaire (SF-MPQ) and ten-item modified Brief Pain Inventory (mBPI-10) total score at endpoint compared with baseline. Improvements in SF-MPQ VAS and mBPI-10 total scores were evident in all patient subpopulations. Mean changes from baseline in SF-MPQ VAS and mBPI-10 scores at endpoint were -20.1 and -1.4, respectively. CONCLUSION: These findings demonstrate that pregabalin is generally well tolerated and provides sustained efficacy over a 53-week treatment period in patients with chronic central neuropathic pain.

Pregabalin treatment for peripheral neuropathic pain: a review of safety data from randomized controlled trials conducted in Japan and in the west.

Two well-studied conditions of peripheral neuropathic pain are postherpetic neuralgia (PHN) and painful diabetic peripheral neuropathy (DPN). Several pregabalin trials for peripheral neuropathic pain have been conducted in the West, but limited data are available for Japan. As ethnicity may influence health risks, differences may be evident in safety data from pregabalin trials in Japan and in the West. The objectives of this review were to compare large pooled safety data from randomized controlled trials evaluating pregabalin for the treatment of PHN or DPN in the West with data from two (one PHN, N = 371; one DPN, N = 314) similar trials in Japan. Longer-term safety data from Japanese open-label extension studies were also reviewed in these neuropathic pain populations. Published and unpublished Pfizer-supported pregabalin trials were identified and sourced from internal Pfizer records. A PubMed search to check for inclusiveness was conducted on 2 November 2011 using the following criteria: 'diabetic peripheral neuropathy' OR 'postherpetic neuralgia' OR 'neuropathic pain' AND 'pregabalin', with limits set for clinical and randomized controlled trials published in English. Five PHN trials (N = 1250) and nine DPN trials (N = 2554) were identified as suitable for inclusion based on methodological comparability. Descriptive safety data from the original trials were reviewed and the most commonly reported adverse events (AEs; dizziness, somnolence, peripheral oedema and weight gain) were identified to be of primary interest. The majority of AEs were of mild to moderate severity in Japanese and Western populations. The most commonly reported AE data (all-causality) with pregabalin (regardless of dose) in Japan (dizziness: PHN = 31.1%; DPN = 24.6%, and somnolence: PHN = 28.6%; DPN = 25.7%) were compared with pooled data from the Western trials (dizziness: PHN = 24.9%; DPN = 23.0%, and somnolence: PHN = 15.1%; DPN = 13.4%). Further assessment of these pooled AE (all-causality) data showed that dizziness and somnolence appeared early in the course of pregabalin treatment, but resolved before the end of the treatment in the majority of PHN and DPN patients (maximum duration of trials was 13 weeks). The slightly higher incidence of dizziness and somnolence in the two Japanese trials than that seen in the Western trials may reflect an increased exposure to pregabalin per fixed dose due to the lower mean bodyweight of the Japanese versus Western populations (on a mg/kg basis). However, of the participants who experienced these AEs (all-causality), the proportion who withdrew from the trials in Japan (dizziness: PHN = 23.5%; DPN = 18.2%, and somnolence: PHN = 10.3%; DPN = 10.9%) were comparable with the proportion who withdrew from trials in the West (dizziness: PHN = 16.0%; DPN = 29.3%, and somnolence: PHN = 19.4%; DPN = 34.2%). In Japan, 12.5% (PHN) and 15.1% (DPN) of patients experienced peripheral oedema as an AE (all-causality) compared with 8.8% (PHN) and 10.3% (DPN) in the West. Weight gain as an AE (all-causality) was experienced in 11.7% (PHN) and 13.4% (DPN) of patients in Japan compared with 3.8% (PHN) and 7.0% (DPN) in the West, but stabilized with continued treatment. Despite the lower mean bodyweight in Japanese versus Western patients, the PHN and DPN patients in Japan had stable blood glucose and HbA(1c) levels throughout the trials. The results of this review indicate safety outcomes in pregabalin trials are comparable between patients in Japan and those in the West. While managing peripheral neuropathic pain with pregabalin treatment, all patients should be observed closely for the incidence of dizziness and somnolence, especially at the beginning of treatment. These patients should also be monitored for evidence of peripheral oedema and weight gain during stable treatment, regardless of the source of neuropathic pain.

Efficacy and safety evaluation of pregabalin treatment over 52 weeks in patients with diabetic neuropathic pain extended after a double-blind placebo-controlled trial.

UNLABELLED: Aims/Introduction: Diabetic peripheral neuropathy (DPN) is often associated with pain, and thus a new treatment option is anticipated. We recently showed the efficacy of pregabalin in a randomized, double-blind, placebo-controlled, 14-week trial in Japanese patients with painful DPN. In the present study, we evaluated the long-term efficacy and safety of pregabalin for the relief of painful DPN. MATERIALS AND METHODS: A total of 123 patients were enrolled in a 52-week open-label study, from among those who participated in the preceding double-blind trial. The subjects received pregabalin 150-600 mg/day. Pain intensity was measured using the short-form McGill pain questionnaire (SF-MPQ: total score, visual analog scale and present pain intensity). RESULTS: The efficacy parameter SF-MPQ showed a decrease over the treatment period. The changes in visual analog scale and present pain intensity at the final evaluation were -25.4 mm and -0.7, respectively, suggesting an analgesic effect of pregabalin. Commonly reported adverse events were somnolence, weight gain, dizziness and peripheral edema, but most of them were mild to moderate in intensity. No new concerns about safety as a result of long-term administration of pregabalin were identified. CONCLUSIONS: The findings from this trial suggest that long-term treatment with pregabalin is beneficial for pain relief in patients with DPN. This trial was registered with ClinicalTrials.gov (no. NCT00553280). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00122.x, 2011).

[Long-term efficacy and safety of pregabalin in patients with postherpetic neuralgia: results of a 52-week, open-label, flexible-dose study].

BACKGROUND: The efficacy of pregabalin was demonstrated in a randomized double-blind placebo-controlled 13-week trial in 371 Japanese patients with postherpetic neuralgia (PHN). In this study, we evaluated the long-term efficacy and safety of pregabalin for relief of PHN. METHODS: 126 patients were enrolled from the preceding double-blind study into the 52-week open-label study. Patients were given pregabalin 150 to 600 mg x day(-1). Pain intensity was measured using the Short-Form McGill Pain Questionnaire (SF-MPQ: total score, visual analogue scale and present pain intensity). RESULTS: The efficacy parameter SF-MPQ showed a decrease over the treatment-term. The changes of visual analogue scale and present pain intensity at the endpoint were -28.3 mm and -1.1 score, respectively. The commonly reported adverse events were dizziness, somnolence, peripheral edema and weight gain, and most of them were mild to moderate in intensity. No new adverse events were observed due to long-term pregabalin administration. CONCLUSIONS: These results suggest that long-term treatment of pregabalin may be beneficial in patients with PHN.

Analysis of factors interfering with the acceptance of interferon therapy by HCV-infected patients.

BACKGROUND: Interferon (IFN) therapy, an antiviral agent, contributes to the prevention of occurrence of hepatocellular carcinoma (HCC) and to improvement in long-term prognosis. However, IFN therapy is not well-implemented in Japan. The present study was conducted to analyze factors preventing the implementation of IFN therapy. MATERIAL/METHODS: Questionnaires were sent to patients with hepatitis C virus (HCV)-related liver disease who were treated at 7 clinics (by non liver-specialists) and 1 hospital (by liver specialists) and by their attending physicians. RESULTS: Of 139 patients for whom attending physicians recommended IFN therapy, 92 (66.2%) agreed to receive the treatment. The proportions of patients who agreed to receive IFN therapy were 74 (86.0%) out of 86 hospital patients and 18 (34%) out of 53 clinic patients. In logistic regression analysis, the adjusted odds ratios on treatment facilities, sex and complications were 18.06, 3.65, and 3.63 respectively, indicating that there were significant differences. Female patients more than male patients declined IFN therapy because of worries over the adverse reactions of IFN therapy. CONCLUSIONS: Multivariate analysis showed that factors contributing to the risk that a patient would not consent to receive IFN therapy included a) treatment facilities, b) sex, and c) the presence or absence of complications. It is also essential to devise measures to create cooperation between hospitals and clinics, and to improve communication between physicians and patients.