Ixekizumab treatment of biologic-naïve patients with active psoriatic arthritis: 3-year results from a phase III clinical trial (SPIRIT-P1).

OBJECTIVE: The aim was to assess the safety and efficacy of up to 156 weeks of ixekizumab (an IL-17A antagonist) treatment in PsA patients. METHODS: In a phase III study, patients naïve to biologic treatment were randomized to placebo, adalimumab 40 mg every 2 weeks (ADA; active reference) or ixekizumab 80 mg every 2 weeks (IXEQ2W) or every 4 weeks (IXEQ4W) after an initial dose of 160 mg. At week 24 (week 16 for inadequate responders), ADA (after 8-week washout) and placebo patients were re-randomized to IXEQ2W or IXEQ4W. Outcomes were evaluated using a modified non-responder imputation [linear extrapolation for radiographic progression (modified total Sharp score = 0)] during extended treatment until week 156. RESULTS: Of 417 patients, 381 entered the extension, and 243 of 381 (63.8%) completed the 156-week study. Incidence rates of treatment-emergent and serious adverse events, respectively, were 38.0 and 5.2 with IXEQ2W (n = 189) and 38.1 and 8.0 with IXEQ4W (n = 197). One death occurred (IXEQ4W). With IXEQ2W and IXEQ4W, respectively, the response rates persisted to week 156 as measured by the ACR response ≥20% (62.5 and 69.8%), ≥50% (56.1 and 51.8%) and ≥70% (43.8 and 33.4%), psoriasis area and severity index (PASI) 75 (69.1 and 63.5%), PASI 90 (64.5 and 51.2%) and PASI 100 (60.5 and 43.6%). Inhibition of radiographic progression also persisted to week 156 in 61% of IXEQ2W and 71% of IXEQ4W patients. CONCLUSION: In this 156-week study of ixekizumab, the safety profile remained consistent with previous reports, and improvements in signs and symptoms of PsA were observed, including persistent low rates of radiographic progression. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01695239, EudraCT 2011-002326-49.

Safety and Efficacy of Open-label Subcutaneous Ixekizumab Treatment for 48 Weeks in a Phase II Study in Biologic-naive and TNF-IR Patients with Rheumatoid Arthritis.

OBJECTIVE: To evaluate ixekizumab, an anti-interleukin 17A monoclonal antibody, for safety and effectiveness through 64 weeks in biologic-naive and tumor necrosis factor-inadequate responder (TNF-IR) patients with rheumatoid arthritis. METHODS: Patients completing the 16-week double-blind period of a phase II study were eligible to enter the open-label extension (OLE) for an additional 48 weeks of ixekizumab treatment. After a treatment hiatus between weeks 10 to 16, 232 biologic-naive and 158 TNF-IR patients entered the OLE with all patients receiving 160 mg ixekizumab at weeks 16, 18, and 20, and then every 4 weeks through Week 64. RESULTS: A total of 201 (87%) biologic-naive and 99 (62%) TNF-IR patients completed the OLE. Treatment-emergent adverse events (AE) occurred in 168 (72%) biologic-naive and 115 (73%) TNF-IR patients during the OLE. Most AE were mild to moderate in severity and did not lead to study discontinuation. Serious AE (SAE) occurred in 17 (7%) biologic-naive patients, including 5 (2%) serious infections and 2 (1%) deaths. SAE occurred in 18 (11%) TNF-IR patients, including 4 (3%) serious infections and 1 (1%) death. No mycobacterial or invasive fungal infections were reported. Clinical responses [American College of Rheumatology (ACR) 20, ACR50, ACR70, and 28-joint Disease Activity Score with C-reactive protein] observed at Week 16 were maintained or improved through Week 64. CONCLUSION: Ixekizumab was well tolerated, and safety findings in the OLE were consistent overall with those in the double-blind period of this study. Clinical improvements observed with ixekizumab through Week 16 were maintained or improved in patients participating in the OLE through Week 64. TRIAL REGISTRATION NUMBER: NCT00966875.

Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial.

This 56-week, randomized, placebo-controlled trial examined the efficacy and safety of naltrexone plus bupropion as an adjunct to intensive behavior modification (BMOD). A total of 793 participants (BMI = 36.5 ± 4.2 kg/m²) was randomly assigned in a 1:3 ratio to: (i) placebo + BMOD (N = 202); or (ii) naltrexone sustained-release (SR, 32 mg/day), combined with bupropion SR (360 mg/day) plus BMOD (i.e., NB32 + BMOD; N = 591). Both groups were prescribed an energy-reduced diet and 28 group BMOD sessions. Co-primary end points were percentage change in weight and the proportion of participants who lost ≥5% weight at week 56. Efficacy analyses were performed on a modified intent-to-treat population (ITT; i.e., participants with ≥1 postbaseline weight while taking study drug (placebo + BMOD, N = 193; NB32 + BMOD, N = 482)). Missing data were replaced with the last observation obtained on study drug. At week 56, weight loss was 5.1 ± 0.6% with placebo + BMOD vs. 9.3 ± 0.4% with NB32 + BMOD (P < 0.001). A completers analysis revealed weight losses of 7.3 ± 0.9% (N = 106) vs. 11.5 ± 0.6% (N = 301), respectively (P < 0.001). A third analysis, which included all randomized participants, yielded losses of 4.9 ± 0.6 vs. 7.8 ± 0.4%, respectively (P < 0.001). Significantly more NB32 + BMOD- vs. placebo + BMOD-treated participants lost ≥5 and ≥10% of initial weight, and the former had significantly greater improvements in markers of cardiometabolic disease risk. NB32 + BMOD was generally well tolerated, although associated with more reports of nausea than placebo + BMOD. The present findings support the efficacy of combined naltrexone/bupropion therapy as an adjunct to intensive BMOD for obesity.

An open-label study of naltrexone and bupropion combination therapy for smoking cessation in overweight and obese subjects.

A combination of sustained release (SR) naltrexone (32 mg/day) and bupropion SR (360 mg/day) plus behavioral counseling was evaluated for the treatment of smoking cessation and mitigation of nicotine withdrawal and weight gain. Thirty overweight or obese nicotine-dependent subjects were enrolled in a 24-week, open-label study; 85% and 63% completed 12 and 2 4weeks, respectively. The target quit date was Week 4. Week 4-12 continuous abstinence rate was 48%, 78% of subjects achieved CO < or = 10 ppm, serum cotinine decreased from 185 to 48 microg/L, and tobacco use decreased from 129 to 14 cigarettes/week. Similar results were seen at Week 24. Body weight was essentially unchanged (Week 12: -0.1%; Week 24: +0.4%). Except for a transient significant increase 1 week after the target quit date (p<0.05), nicotine withdrawal scores did not change. The most common adverse events were nausea, insomnia, and constipation. These tended to be transient and mild or moderate in severity. In overweight or obese smokers, naltrexone/bupropion combination therapy with behavioral counseling was associated with decreased nicotine use, limited nicotine withdrawal symptoms, and no significant weight gain.

Implications of pain in generalized anxiety disorder: efficacy of duloxetine.

OBJECTIVE: To conduct a post hoc evaluation of the prevalence of clinically significant pain and the efficacy of duloxetine in patients with generalized anxiety disorder (GAD) and concurrent pain. METHOD: Data from two 9- to 10-week double-blind, placebo-controlled, randomized clinical trials of duloxetine (60 to 120 mg) in DSM-IV-defined GAD were analyzed (study 1 was conducted from July 2004 to September 2005; study 2 was conducted from August 2004 to June 2005). Efficacy was assessed with the Hamilton Rating Scale for Anxiety (HAM-A), visual analog scales (VAS) for pain, the Hospital Anxiety Depression Scale (HADS), the Clinical Global Impressions-Improvement of Illness (CGI-I) scale, the Patient Global Impressions-Improvement (PGI-I) scale, and the Sheehan Disability Scale (SDS) global functional impairment scale. RESULTS: Of 840 patients randomly assigned to treatment, 61.3% (302 duloxetine, 213 placebo) had VAS scores ≥ 30 mm on at least 1 of the pain scales, indicating clinically significant pain. Among those patients with concurrent pain at baseline, change from baseline to endpoint in the HAM-A total score (42.9% change in mean scores for duloxetine, 31.4% for placebo), HADS anxiety scale (40.3% vs. 22.8%), HADS depression scale (36.1% vs. 20.5%), HAM-A psychic factor (45.9% vs. 29.9%), and SDS global functional improvement score (45.5% vs. 22.1%) was significantly (all p's < .001) greater for duloxetine compared with placebo. Improvement on the CGI-I (p = .003) and PGI-I (p < .001) was also significantly greater for duloxetine. Response (HAM-A total score decrease ≥ 50%) (49% vs. 29%) and remission (HAM-A total score ≤ 7 at endpoint) (29% vs. 18%) rates were significantly greater for duloxetine compared with placebo (p < .001 and p = .041, respectively). Duloxetine demonstrated statistically significantly greater reduction in pain on all 6 VAS pain scales (all p's < .001 except headaches with p < .002) (for duloxetine, percent change in means from baseline to endpoint ranged from 40.1% to 45.2% across the 6 VAS scales; for placebo, 22.0% to 26.3%). CONCLUSION: Duloxetine, relative to placebo, improves anxiety symptoms, pain, and functional impairment among patients with GAD with concurrent clinically significant pain. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00122824 (study 1) and NCT00475969 (study 2).

Efficacy and tolerability of duloxetine in elderly patients with generalized anxiety disorder: a pooled analysis of four randomized, double-blind, placebo-controlled studies.

OBJECTIVE: To assess the efficacy and tolerability of duloxetine in elderly patients with generalized anxiety disorder (GAD). METHODS: Acute-phase data from a subset of patients (>or=65 years) with GAD were pooled from four randomized, double-blind, placebo-controlled trials of duloxetine (3 flexible, 1 fixed dosing). Patients were treated with duloxetine 60-120 mg once daily or placebo for 9-10 weeks. The primary outcome measure was the mean baseline-to-endpoint change in Hamilton anxiety scale (HAMA) total score. Secondary measures included the HAMA psychic and somatic anxiety subscales and the Hospital Anxiety Depression Scale (HADS). RESULTS: Of 1491 patients randomly assigned to treatment, 4.9% (duloxetine, n = 45; placebo, n = 28) were >or= 65 years old. Compared with placebo-treated patients, duloxetine-treated patients experienced significantly greater improvements on the HAMA-total (p = 0.029), the HAMA-psychic anxiety factor (p = 0.034), HADS-anxiety (p = 0.049) and -depression scales (p = 0.026), but not the HAMA somatic anxiety factor (p = 0.074). Nausea was reported significantly more often in duloxetine-treated patients (30.0% vs. 7.1%, p = 0.023); duloxetine-treated patients experienced greater weight loss (p = 0.018). More duloxetine-treated patients discontinued treatment due to an adverse event (22.2% vs. 0%; p = 0.006). CONCLUSION: Duloxetine was effective in an elderly patient subset with GAD, although there was a high rate of discontinuations due to adverse events.

Efficacy of duloxetine in the treatment of generalized anxiety disorder in patients with clinically significant pain symptoms.

Anxiety disorders often are accompanied by painful physical symptoms. This report assessed the effectiveness of duloxetine in improving anxiety symptoms, pain severity, and patient functioning in adults diagnosed with generalized anxiety disorder (GAD), who presented with clinically significant pain symptoms. Data were pooled from two multicenter, randomized, double-blind, placebo-controlled clinical studies evaluating the efficacy of duloxetine 60-120 mg once daily compared with placebo in the treatment of GAD. The primary patient population for these analyses was patients with baseline Visual Analog Scale (VAS) overall pain severity score > or =30. Of the 798 randomized patients that had baseline VAS scores, approximately 44.4% of GAD patients were identified as having baseline VAS overall pain severity score > or =30 (duloxetine N=208, placebo N=146). Duloxetine-treated patients had significantly greater improvement compared with placebo-treated patients on anxiety symptoms (measured by Hamilton Anxiety Scale total score), on patient functioning (measured by the Sheehan Disability Scale Global Functional Impairment Score and across all Sheehan Disability Scale domains), and on all VAS pain items. Patients achieving remission at endpoint, and patients with lower scores on the Clinical Global Impression of Improvement and Patient Global Impression of Improvement scales had greater improvement in VAS pain severity scores. These results suggest that in patients with GAD who present with clinically significant pain symptoms, duloxetine is effective in reducing anxiety symptoms, pain severity, and in improving patient functioning.

Pain Assessment for the Dementing Elderly (PADE): reliability and validity of a new measure.

OBJECTIVES: To establish the reliability and validity of a measure to assess pain in individuals with advanced dementia. DESIGN: Sixty-five residents of long-term care facilities were assessed using a new rating tool, the Pain Assessment for the Dementing Elderly (PADE), in two separate studies: (1) Residents were assessed simultaneously by two different raters, at Time 1 and 2, to establish interrater reliability, stability, and internal consistency. (2) Validity was established by assessing the correlation between an agitation scale and the PADE; by comparing groups with pain as a significant clinical factor (as assessed by an independent rater) versus not a significant factor, and by assessing individuals receiving versus not receiving psychoactive medications. SETTING: Four different long-term care facilities, three skilled nursing facilities, and a locked dementia assisted-living facility. PARTICIPANTS: Twenty-five residents of long-term care facilities with advanced levels of dementia in Study 1, and 40 residents with similar level of dementia in Study 2; 42% of the total sample were rated as having significant painful conditions. MEASUREMENTS: For Study 1, the PADE was administered; for Study 2, the PADE and the Cohen-Mansfield Agitation Inventory (CMAI) were administered. RESULTS: Reliability coefficients were adequate (interrater = 0.54-0.95; stability = 0.70-0.98; and internal consistency = 0.24-0.88). Validity coefficients were likewise encouraging, with the PADE demonstrating the expected relationship with a measure of agitation. The PADE also differentiated between groups that were independently judged to suffer clinically problematic pain versus those who were not. CONCLUSION: The PADE is a reliable and valid tool to assess pain in dementing elderly residents of long-term care facilities.