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{"project":"2_test","denotations":[{"id":"15631624-11926722-13857383","span":{"begin":997,"end":999},"obj":"11926722"},{"id":"15631624-15232330-13857384","span":{"begin":1005,"end":1007},"obj":"15232330"},{"id":"15631624-12000204-13857385","span":{"begin":1013,"end":1015},"obj":"12000204"},{"id":"15631624-12393307-13857386","span":{"begin":1025,"end":1027},"obj":"12393307"},{"id":"15631624-9881538-13857387","span":{"begin":1797,"end":1799},"obj":"9881538"},{"id":"15631624-14399272-13857388","span":{"begin":1933,"end":1935},"obj":"14399272"},{"id":"15631624-9428860-13857389","span":{"begin":6382,"end":6384},"obj":"9428860"}],"text":"Methods\n\nStudy Design\nAll 8 studies included in these analyses were randomized, multicenter, double-blind, placebo-controlled clinical trials and represented all of the double-blind studies included in the New Drug Application reviewed by regulatory agencies for duloxetine's indication in MDD. All studies incorporated double-blind, variable-expected duration placebo lead-in periods to blind patients and investigators to the start of active therapy. Six studies also utilized an active comparator – fluoxetine (20 mg QD) in Studies 1 and 2, and paroxetine (20 mg QD) in Studies 3, 4, 7, and 8. Study protocols were reviewed and approved by the ethical review board at each center, in accordance with the principles of the Declaration of Helsinki, and all patients provided written informed consent prior to the administration of any study procedures or study drug. The numbers of patients randomized in each study are summarized in Table 1. Detailed safety and efficacy results from Studies 1 [39], 4 [40], 5 [41], and 6 [42] have been published previously.\nTable 1 Numbers of randomized patients‡ ‡ Data presented in the form T (% M), where T = total number of patients, % M = percentage of patients with melancholic features\na. SSRI in Studies 1 and 2 is fluoxetine (20 mg QD). SSRI in Studies 3, 4, 7, and 8 is paroxetine (20 mg QD).\nb. Administered 20 mg twice-daily (BID)\nc. Administered 40 mg BID\nd. Administered 60 mg BID. Studies 1 and 2 incorporated a forced titration from 20 mg BID to 60 mg BID.\n\nPatients\nIn all studies, patients were 18 years of age or older and met criteria for MDD as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4thEdition (DSM-IV) [43]. The diagnosis of MDD was confirmed by the Mini International Neuropsychiatric Interview (MINI) [44], a standardized diagnostic interview based on DSM-IV criteria. Patients had a 17-item Hamilton Rating Scale for Depression (HAMD17)[45] total score ≥ 15 and a Clinical Global Impression of Severity (CGI-S)[46] score ≥ 4 at the screening and second study visits. The presence of melancholic features (DSM-IV criteria) was determined using results from the MINI:\n\"Either feature 1 or 2 in Criteria A AND three (or more) features from Criteria B must be present to qualify for melancholic features.\nA. Either of the following, occurring during the most severe period of the current episode.\n1. Loss of pleasure in all, or almost all, activities;\n2. Lack of reactivity to usually pleasurable stimuli\nB. Three (or more) of the following:\n1. Distinct quality of depressed mood;\n2. Depression regularly worse in the morning;\n3. Early morning awakening (at least 2 hours before usual time of awakening);\n4. Marked psychomotor retardation or agitation;\n5. Significant anorexia or weight loss;\n6. Excessive or inappropriate guilt.\"\nPatients were excluded for the following reasons: a current and primary Axis I disorder, other than MDD; an Axis II disorder which could interfere with protocol compliance; lack of response of the current depressive episode to two or more adequate courses of antidepressant therapy; serious medical illness; a serious risk of suicide; a history of substance abuse or dependence within the last year, or a positive urine drug screen.\nConcomitant medications with primarily central nervous system activity were not permitted, with the exception of episodic use of chloral hydrate or zolpidem for insomnia. Chronic use of prescription analgesic medications was not allowed; episodic use was permitted at the discretion of the physician in charge of the study. Use of anti-hypertensive medications was not permitted unless the patient had been on a stable dose for at least 3 months prior to study entry.\n\nData Pooling Strategies\nEfficacy analyses were performed on three sets of data, obtained using the following pooling strategies:\n(A) \"All Studies\" – data from all 8 studies were pooled. Placebo: melancholic (n = 519; 67.0%), non-melancholic (n = 256; 33.0%). Duloxetine (40–120 mg/d): melancholic (n = 759; 66.7%), non-melancholic (n = 379; 33.3%). Duloxetine was compared with placebo in one set of analyses. In a second set of analyses using data from the 6 SSRI-controlled studies, duloxetine was compared with fluoxetine and paroxetine: Placebo: melancholic (n = 348; 67.6%), non-melancholic (n = 167; 32.4%). Duloxetine (40–120 mg/d): melancholic (n = 602; 67.8%), non-melancholic (n = 286; 32.2%). SSRI: melancholic (n = 294; 68.5%), non-melancholic (n = 135; 31.5%);\n(B) \"Positive Studies\" – data from placebo- and duloxetine-treated patients were pooled from the 6 studies (1, 4, 5, 6,7, and 8) that demonstrated a significant advantage for duloxetine over placebo on the primary efficacy measure. Placebo: melancholic (n = 415; 67.9%), non-melancholic (n = 196; 32.1%). Duloxetine (40–120 mg/d): melancholic (n = 594; 67.4%), non-melancholic (n = 287; 32.6%);\n(C) \"Focus Studies\" – data were pooled from the 2 studies (5 and 6) that compared duloxetine 60 mg once-daily with placebo. Placebo: melancholic (n = 171; 65.8%), non-melancholic (n = 89; 34.2%). Duloxetine (60 mg/d): melancholic (n = 157; 62.8%), non-melancholic (n = 93; 37.2%).\nStrategy A facilitated assessments of differential efficacy in the largest possible data set. While the inclusion of all available data has obvious advantages, the presence of failed studies could mask differential treatment effects. If a study failed to detect an overall effect it is unlikely to help detect differential subgroup effects. Therefore strategy B essentially served as a robustness check for strategy A. Pooling strategy C facilitated assessments at the recommended target dose.\n\nEfficacy Measures\nIn all 8 studies, the primary efficacy outcome was mean change from baseline to endpoint in HAMD17 total score. Other efficacy measures assessed in all studies included HAMD17 subscales: anxiety/somatization (Items 10, 11, 12, 13, 15, and 17), Maier (Items 1, 2, 7, 8, 9, and 10), retardation (Items 1, 7, 8, and 14), and sleep (Items 4, 5, and 6); the CGI-S scale; and the Patient Global Impression of Improvement (PGI-I) scale [46]. Response was defined as a decrease from baseline of at least 50% on the HAMD17 total score. Remission was defined as a HAMD17 total score ≤ 7. In Studies 3 – 8, the severity of painful physical symptoms was assessed using Visual Analog Scales (VAS) for pain [47].\n\nStatistical analyses\nPatients with missing melancholia status were not included in the analyses. All other patients with a baseline and at least one postbaseline observation were included in the analyses. Mean changes from baseline to last observation (carried forward) in HAMD17 total score, CGI-S, and PGI-I were assessed using an analysis of covariance (ANCOVA) with models that included baseline score, treatment, melancholia status (features present Yes/No), investigator, and the treatment-by-melancholia status interaction as independent variables. Hereafter this analysis is referred to as LOCF mean change.\nThe treatment-by-melancholic status interaction was the main basis upon which differential treatment effects between the subgroups were assessed. Contrasts between duloxetine and placebo within the melancholic and non-melancholic subgroups were used to assess the clinical relevance of treatment effects.\nLongitudinal mean changes and categorical changes (estimated probabilities) were assessed using a likelihood-based mixed-effects model repeated measures (MMRM) approach. Models for mean changes included treatment, visit, investigator, baseline HAMD17 value, melancholia status, and the two-way and three-way interactions between treatment, visit, and melancholia status. Hereafter this analysis is referred to as MMRM mean change. The categorical longitudinal analyses were similar in concept to the longitudinal mean change analyses, but simplifications were necessary to reduce the computational complexity.\nThe categorical analyses were applied only to patients with melancholic features so that the main effect of melancholic status and its two-way and three-way interactions with visit and treatment could be deleted. Therefore, the model for the categorical analyses included treatment, visit, investigator, baseline HAMD17 value, and the treatment-by-visit interaction. A logit link function and a binomial error structure were included to account for the non-linearity of the response and the non-normality of the data, respectively. Hereafter, this analysis is referred to as categorical MMRM. Remission and response rates at last observation were assessed using Fisher's Exact test.\nThe LOCF mean change analysis of HAMD17, CGI-S and PGI-I was applied to all three databases. The focus for the analyses was on all studies and the positive studies with the primary aim of detecting differential effects of duloxetine in patients with and without melancholic features. The MMRM mean change and categorical MMRM analyses were then applied to a wide variety of outcomes from the focus studies in order to gain an in-depth perspective on the efficacy of duloxetine in patients with melancholic features. In addition, LOCF analyses of data from the focus studies were conducted in order to assess robustness of the MMRM results.\n"}

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PMC:546184 / 8242-17484 JSON TXT