Erosions on T1-Weighted Magnetic Resonance Imaging Versus Radiography of Sacroiliac Joints in Recent-Onset Axial Spondyloarthritis: 2-Year Data (EMBARK Trial and DESIR Cohort).

OBJECTIVE: (1) To compare the capacity to detect sacroiliac joint (SIJ) erosions and baseline-to-week 104 change in erosions between magnetic resonance imaging (MRI) and radiographs in recent-onset axial spondyloarthritis (axSpA); and (2) to compare treatment-discriminatory capacities of MRI and radiographic scores for erosion detection in patients receiving etanercept in the Effect of Etanercept on Symptoms and Objective Inflammation in Nonradiographic axSpA (EMBARK) trial vs controls in the DESIR (Devenir des Spondylarthropathies Indifférenciées Récentes) cohort. METHODS: Anonymized SIJ MRI and radiographs were assessed at patient and joint surface levels. Three readers evaluated MRI; 3 different readers evaluated radiographs. Final scores for comparison of radiographs and MRI for detection of erosions were assigned based on agreement of ≥ 2 of 3 readers' assessments. RESULTS: At baseline, discordance in erosion detection between imaging methods was more frequent for MRI erosions in the absence of radiographic erosions (48/224 [21.4%] patients) than for radiographic erosions in the absence of MRI erosions (14/224 [6.3%] patients; P < 0.001). After 104 weeks, a decrease in erosions was observed on MRI but not radiographs in 49/221 (22.2%) patients, and on radiographs but not MRI in 6/221 (2.7%) patients (P < 0.001). In the treatment-discriminant capacity analysis, the largest standardized differences between etanercept and control cohorts at week 104 were changes in Spondyloarthritis Research Consortium of Canada MRI erosion discrete score, changes in erosion average score, and meeting the modified New York criteria on radiographs, with unadjusted/adjusted Hedges G effect sizes of 0.40/0.50, 0.40/0.56, and 0.40/0.43, respectively. CONCLUSION: In recent-onset axSpA, SIJ erosions and erosion change were observed more frequently on MRI than radiography. The significance of interval improvement of MRI erosions warrants further research. [ClinicalTrials.gov: NCT01258738, NCT01648907].

Radiographic and clinical effects of 10 mg and 25 mg twice-weekly etanercept over 52 weeks in Japanese patients with active rheumatoid arthritis.

OBJECTIVES: To compare the radiographic and clinical effects of 25 versus 10 mg twice-weekly (BIW) etanercept over 52 weeks in Japanese patients with active rheumatoid arthritis (RA). METHODS: This was a post-hoc analysis of a Phase 3 study where Japanese patients with active RA were randomized to receive BIW etanercept 25 mg (n = 182), etanercept 10 mg (n = 192), or methotrexate (n = 176) for 52 weeks (NCT00445770). This analysis included assessments of week-24 and week-52 disease activity, week-52 radiographic progression, and the relationship between baseline characteristics and week 52 clinical outcomes with clinically relevant radiographic progression (CRRP) at week 52. RESULTS: At week 52, there were no significant differences between 25 and 10 mg etanercept in terms of achieving low disease activity or remission. CRRP was observed in 36% and 32% of patients in the 10 and 25 mg groups, respectively. Predictor analysis suggested that worse background disease status, treatment with methotrexate rather than etanercept, and poorer clinical outcomes at week 52 were associated with CRRP. CONCLUSIONS: The 25 mg BIW etanercept dosage does not appear to be significantly more efficacious than 10 mg in Japanese patients with RA. Further studies evaluating the optimal etanercept dosing regimen in this patient population may be merited. NCT: NCT00445770.

Relationship between disease activity status or clinical response and patient-reported outcomes in patients with non-radiographic axial spondyloarthritis: 104-week results from the randomized controlled EMBARK study.

BACKGROUND: We assessed the external validity of composite indices Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Assessment in SpondyloArthritis international Society (ASAS) 40 response (ASAS40) by evaluating the correlations between the changes in some patient reported outcomes (PROs) for patients with non-radiographic axial spondyloarthritis (nr-axSpA) and the changes in the scores of the composite indices. METHODS: This was a post-hoc analysis of data from the EMBARK study in patients with nr-axSpA treated with etanercept. PROs were grouped according to ASDAS status (inactive [< 1.3], low [≥ 1.3 to < 2.1], high [≥ 2.1 to ≤3.5], and very high [> 3.5]), patient achievement of > 50% improvement in BASDAI (BASDAI50 responders), and > 40% improvement in ASAS (ASAS40 responders) at 104 weeks. Analyses were conducted on observed cases available at Week 104. Changes in PROs from Baseline to Week 104 were assessed using analysis of covariance with adjustment for baseline with linear contrast. RESULTS: Higher ASDAS disease activity at 104 weeks was associated with lower long-term improvement from baseline in PROs (e.g., total back pain [visual analog scale, cm (95% confidence interval): - 4.58 (- 4.95, - 4.21), - 3.86 (- 4.28, - 3.43), - 2.15 (- 2.68, - 1.61), and 1.30 (- 0.51, 3.12) for inactive, low, high, and very high ASDAS disease activity, respectively; Multidimensional Fatigue Inventory (MFI) general fatigue: - 4.77 (- 5.70, - 3.84), - 2.96 (- 4.04, - 1.87), - 1.00 (- 2.32, 0.31), and 2.14 (- 2.10, 6.38); all p < 0.001)]. BASDAI50 non-responders had less improvement in PROs from Baseline to Week 104 vs. responders (e.g., total back pain: - 1.61 (- 2.05, - 1.18) vs. -4.43 (- 4.69, - 4.18); MFI general fatigue: - 0.01 (- 1.12, 1.09) vs. -4.30 (- 4.98, - 3.62); all p < 0.001). ASAS40 non-responders also had less improvement in PROs from Baseline to Week 104 vs. responders (e.g., total back pain: - 1.91 (- 2.30, - 1.52) vs. -4.75 (- 5.05, - 4.46); MFI general fatigue: - 0.63 (- 1.56, 0.30) vs. -4.64 (- 5.37, - 3.91); all p < 0.001). CONCLUSION: Composite indices are valid for monitoring treatment response and adequately reflect treatment-related changes experienced by patients with nr-axSpA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01258738. Registered 9 December 2010.

Radiographic and clinical outcomes following etanercept monotherapy in Japanese methotrexate-naïve patients with active rheumatoid arthritis.

Objectives: Compare outcomes with methotrexate (MTX) or etanercept (ETN) monotherapy in Japanese patients with active rheumatoid arthritis (RA) who were MTX-naïve or with intolerance or inadequate response to prior MTX (MTX-IR).Methods: Post hoc analysis of a phase 3 study comparing MTX, ETN 10 mg twice weekly, and ETN 25 mg twice weekly in Japanese patients with RA. Disease activity was evaluated using American College of Rheumatology (ACR) scores and 28-joint Disease Activity Score (DAS28), radiographic progression evaluated using van der Heijde's modified Total Sharp Score (mTSS), and functional status evaluated using Health Assessment Questionnaire Disability Index (HAQ-DI).Results: Among MTX-naïve and MTX-IR patients, greater proportions of those randomized to either ETN group achieved ACR20, ACR50, ACR70, DAS28 ≤3.2 or <2.6, clinically relevant inhibition of mTSS changes, and reductions in HAQ-DI compared with MTX at the majority of time points. There were very few clinically meaningful differences between ETN groups for any of the variables evaluated.Conclusion: ETN monotherapy was more effective than MTX in both MTX-naïve and MTX-IR patients, with very few clinically meaningful differences between ETN 10 mg and ETN 25 mg when given twice weekly. The relative benefits of ETN were greater in MTX-naïve patients than MTX-IR patients.ClinicalTrials.gov identifierNCT00445770.

Safety of Tofacitinib for Treatment of Ulcerative Colitis, Based on 4.4 Years of Data From Global Clinical Trials.

BACKGROUND & AIMS: Tofacitinib is an oral, small-molecule inhibitor of JAK approved in several countries for the treatment of ulcerative colitis (UC). We report integrated safety analyses of tofacitinib-treated patients with moderate to severe UC. METHODS: Patients receiving placebo or tofacitinib (5 or 10 mg) twice daily were analyzed as 3 cohorts: induction (phase 2 and 3 induction studies, n = 1220), maintenance (phase 3 maintenance study, n = 592), and overall (patients receiving tofacitinib 5 or 10 mg twice daily in phase 2, phase 3, or open-label, long-term extension studies, n = 1157; 1613 patient-years' exposure). Incidence rates (IRs; patients with events per 100 patient-years of exposure) were evaluated for select adverse events. RESULTS: In the maintenance cohort, IRs for select adverse events were similar among treatment groups, except for a numerically higher IR of herpes zoster infection among patients who received tofacitinib 5 mg twice daily (2.1; 95% CI, 0.4-6.0) and statistically higher IR among patients who received tofacitinib 10 mg twice daily (IR, 6.6; 95% CI, 3.2-12.2) vs placebo (IR, 1.0, 95% CI, 0.0-5.4). For the overall cohort (84% received average dose of tofacitinib 10 mg twice daily), IRs were: death, 0.2 (95% CI, 0.1-0.6); serious infections, 2.0 (95% CI, 1.4-2.8); opportunistic infections, 1.3 (95% CI, 0.8-2.0); herpes zoster infection, 4.1 (95% CI, 3.1-5.2); malignancy (excluding non-melanoma skin cancer), 0.7 (95% CI, 0.3-1.2); non-melanoma skin cancer, 0.7 (95% CI, 0.3-1.2); major adverse cardiovascular events, 0.2 (95% CI, 0.1-0.6); and gastrointestinal perforations, 0.2 (95% CI, 0.0-0.5). CONCLUSIONS: In safety analyses of patients with moderate to severe UC treated with tofacitinib, we observed a dose relationship with herpes zoster infection. Although follow-up time was relatively short, the safety profile of tofacitinib for patients with UC appeared similar to that reported for patients with rheumatoid arthritis and for patients with UC treated with biologic agents, except for the higher IR of herpes zoster infection. ClinicalTrials.gov, no: NCT00787202, NCT01465763, NCT01458951, NCT01458574, and NCT01470612.

Modification of structural lesions on MRI of the sacroiliac joints by etanercept in the EMBARK trial: a 12-week randomised placebo-controlled trial in patients with non-radiographic axial spondyloarthritis.

OBJECTIVE: To evaluate the impact on structural lesions observed on MRI in the sacroiliac joints (SIJ) at 12 weeks in patients with non-radiographic axial spondyloarthritis (nr-axSpA) receiving etanercept or placebo in EMBARK (Effect of Etanercept on Symptoms and Objective Inflammation in nr-axSpA, a 104 week study). METHODS: Patients were randomised to double-blind etanercept 50 mg/week or placebo for 12 weeks. Structural lesions at baseline and 12 weeks were scored by two independent readers using the Spondyloarthritis Research Consortium of Canada (SPARCC) SIJ structural score (SSS) on T1-weighted MRI. Change in SPARCC SSS and correlation with improvement in clinical outcomes was evaluated. RESULTS: MRI scans from 185 patients (etanercept, n=88; placebo, n=97) were reviewed. At baseline, there were no significant differences in mean SPARCC SSS between etanercept and placebo. From baseline to 12 weeks, change in mean SPARCC SSS was significantly greater for etanercept than placebo for erosion (-0.57 vs -0.08, respectively, adjusted p value=0.017) and backfill (0.36 vs 0.06, adjusted p value=0.022). A treatment difference was also present for the subgroup of patients with SIJ inflammation on MRI (SPARCC bone marrow oedema ≥2): erosion: -0.81 versus -0.13 for etanercept versus placebo, respectively, p=0.007; backfill: 0.48 versus 0.08, respectively, p=0.032. Decrease in erosion and increase in backfill correlated with improvement in more clinical outcomes for etanercept than placebo. CONCLUSION: Treatment with etanercept was associated with significantly greater reduction in erosions and increase in backfill at 12 weeks compared with placebo, consistent with a very early reparative response to antitumour necrosis factor therapy. The impact on disease progression in spondyloarthritis should be studied further. TRIAL REGISTRATION NUMBER: NCT01258738; Post-results.

Evaluation of the change in structural radiographic sacroiliac joint damage after 2 years of etanercept therapy (EMBARK trial) in comparison to a contemporary control cohort (DESIR cohort) in recent onset axial spondyloarthritis.

OBJECTIVE: To compare 2 years of radiographic sacroiliac joint (SIJ) changes in patients with recent onset axial spondyloarthritis (axSpA) receiving etanercept in a clinical trial (EMBARK) to similar patients not receiving biologics in a cohort study (DESIR). METHODS: Endpoints were changes at week 104 per the modified New York (mNY) grading system in total SIJ score (primary endpoint) and net percentage of patients with progression defined three ways. Treatment effect was analysed with and without adjustment for baseline covariates. RESULTS: At 104 weeks, total SIJ score improved in the etanercept group (n=154, adjusted least-squares mean change: -0.14) and worsened in the control group (n=182, change: 0.08). The adjusted difference between groups (etanercept minus control) was -0.22 (95% CI -0.38 to -0.06), p=0.008. The net percentage of patients with progression was significantly lower in the etanercept versus the control group for two of three binary endpoints: -1.9% versus 1.6% (adjusted difference for etanercept minus control: -4.7%,95% CI -9.9 to 0.5, p=0.07) for change in mNY criteria; -1.9% versus 7.8% (adjusted difference: -18.2%,95% CI -30.9 to -5.6, p=0.005) for change ≥1 grade in ≥1 SIJ; and -0.6% versus 6.7% (adjusted difference: -16.4%,95% CI -27.9 to -5.0, p=0.005) for change ≥1 grade in ≥1 SIJ, with shift from 0 to 1 or 1 to 0 considered no change. CONCLUSION: Despite the slow radiographic SIJ progression rate over 2 years in axSpA, this study suggests a lower rate of progression in the SIJ with etanercept than without anti-tumour necrosis factor therapy. TRIAL REGISTRATION NUMBERS: NCT01258738, NCT01648907; Post-results.

Incidence of Antidrug Antibodies in Rheumatoid Arthritis Patients From Argentina Treated With Adalimumab, Etanercept, or Infliximab in a Real-World Setting.

BACKGROUND: Biologic agents may induce immune responses that could impact drug action. OBJECTIVES: The aims of this study were to assess antidrug antibodies (ADAs) in patients with rheumatoid arthritis (RA) from Argentina treated with etanercept, adalimumab, or infliximab at a single visit and correlate it with efficacy outcomes. METHODS: In this subset analysis of a noninterventional, multinational, cross-sectional study (NCT01981473), adult patients with RA treated continuously for 6 to 24 months with etanercept, adalimumab, or infliximab were evaluated for ADAs and trough drug concentrations of 2 days or less prior to the next scheduled dose. Efficacy measurements included Disease Activity Score based on a 28-joint count-erythrocyte sedimentation rate, low disease activity, and Health Assessment Questionnaire-Disability Index. Targeted medical history of injection site/infusion reactions, serum sickness, and thromboembolic events were reported. RESULTS: Baseline demographics, disease characteristics, and duration of treatment of the 119 patients (etanercept: n = 54, adalimumab: n = 52, infliximab: n = 13) were similar across all groups. No etanercept-treated patient tested positive for ADAs compared with 19 (36.5%) of 52 patients and 4 (30.8%) of 13 patients treated with adalimumab and infliximab, respectively. In adalimumab- and infliximab-treated patients, ADA presence correlated negatively with trough drug levels. A greater proportion of ADA-negative patients achieved Health Assessment Questionnaire-Disability Index of 0.5 or less and had better composite efficacy measures compared with ADA-positive patients. The rate of targeted medical events reported was low. CONCLUSIONS: In this subset analysis, RA patients from Argentina treated with adalimumab or infliximab, but not etanercept, tested positive for ADAs. Antidrug antibody-negative patients showed a tendency toward better clinical outcomes compared with ADA-positive patients.

Clinical and MRI responses to etanercept in early non-radiographic axial spondyloarthritis: 48-week results from the EMBARK study.

OBJECTIVE: To evaluate the efficacy and safety of etanercept (ETN) after 48 weeks in patients with early active non-radiographic axial spondyloarthritis (nr-axSpA). METHODS: Patients meeting Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA, but not modified New York radiographic criteria, received double-blind ETN 50 mg/week or placebo (PBO) for 12 weeks, then open-label ETN (ETN/ETN or PBO/ETN). Clinical, health, productivity, MRI and safety outcomes were assessed and the 48-week data are presented here. RESULTS: 208/225 patients (92%) entered the open-label phase at week 12 (ETN, n=102; PBO, n=106). The percentage of patients achieving ASAS40 increased from 33% to 52% between weeks 12 and 48 for ETN/ETN and from 15% to 53% for PBO/ETN (within-group p value <0.001 for both). For ETN/ETN and PBO/ETN, the EuroQol 5 Dimensions utility score improved by 0.14 and 0.08, respectively, between baseline and week 12 and by 0.23 and 0.22 between baseline and week 48. Between weeks 12 and 48, MRI Spondyloarthritis Research Consortium of Canada sacroiliac joint (SIJ) scores decreased by -1.1 for ETN/ETN and by -3.0 for PBO/ETN, p<0.001 for both. Decreases in MRI SIJ inflammation and C-reactive protein correlated with several clinical outcomes at weeks 12 and 48. CONCLUSIONS: Patients with early active nr-axSpA demonstrated improvement from week 12 in clinical, health, productivity and MRI outcomes that was sustained to 48 weeks. TRIAL REGISTRATION NUMBER: NCT01258738.

Sexual functioning in patients with recurrent major depressive disorder enrolled in the PREVENT study.

The incidence of treatment-emergent sexual dysfunction in the acute and continuation phases of the prevention of recurrent episodes of depression with venlafaxine ER for two years (PREVENT) study was assessed. Adult outpatients with recurrent major depressive disorder were randomly assigned to receive venlafaxine extended release (ER; 75-300 mg/day) or fluoxetine (20-60 mg/day). Sexual dysfunction was assessed using items from the 17-item Hamilton Rating Scale for Depression (HAM-D(17)) and the Inventory of Depressive Symptomatology-Self-Report (IDS-SR). The baseline rates of sexual dysfunction based on the HAM-D(17) and IDS-SR items were 57.9% and 48.8%, respectively. The rates of new-onset sexual dysfunction for the venlafaxine ER-treated (44.8%, HAM-D(17); 38.4%, IDS-SR) and fluoxetine-treated patients (52.9%, HAM-D(17); 50.0%, IDS-SR) were similar; approximately 80% of the cases resolved during treatment. Treatment response was associated with lower rates of new-onset sexual dysfunction compared with nonresponse. The patients who remitted were the least likely to experience sexual dysfunction during antidepressant treatment.

Improved health outcomes with etanercept versus usual DMARD therapy in an Asian population with established rheumatoid arthritis.

BACKGROUND: Patient reported outcomes (PROs) are especially useful in assessing treatments for rheumatoid arthritis (RA) since they measure dimensions of health-related quality of life that cannot be captured using strictly objective physiological measures. The aim of this study was to compare the effects of combination etanercept and methotrexate (ETN + MTX) versus combination synthetic disease modifying antirheumatic drugs (DMARDs) and methotrexate (DMARD + MTX) on PRO measures among RA patients from the Asia-Pacific region, a population not widely studied to date. Patients with established moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate were studied. METHODS: Patients were randomized to either ETN + MTX (N = 197) or DMARD + MTX (N = 103) in an open-label, active-comparator, multicenter study, with PRO measures designed as prospective secondary endpoints. The Health Assessment Questionnaire (HAQ), Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue), Medical Outcomes Short Form-36 Health Survey (SF-36), Hospital Anxiety and Depression Scale (HADS) and the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH) were used. RESULTS: Significantly greater improvements were noted for the ETN + MTX group at week16 for HAQ mean scores and for proportion of patients achieving HAQ score ≤ 0.5, compared to patients in the DMARD + MTX group. SF-36 Summary Scores for physical and mental components and for 6 of 8 health domains showed significantly greater improvements at week16 for the ETN + MTX group; only scores for physical functioning and role-emotional domains did not differ significantly between the two treatment arms. Greater improvements at week16 were noted for the ETN + MTX group for FACIT-Fatigue, HADS, and WPAI:GH mean scores. CONCLUSION: Combination therapy using ETN + MTX demonstrated superior improvements using a comprehensive set of PRO measures, compared to combination therapy with usual standard of care DMARDs plus MTX in patients with established rheumatoid arthritis from the Asia-Pacific region. TRIAL REGISTRATION: clintrials.gov # NCT00422227.

A randomized trial of tigecycline versus ampicillin-sulbactam or amoxicillin-clavulanate for the treatment of complicated skin and skin structure infections.

BACKGROUND: Complicated skin and skin structure infections (cSSSIs) frequently result in hospitalization with significant morbidity and mortality. METHODS: In this phase 3b/4 parallel, randomized, open-label, comparative study, 531 subjects with cSSSI received tigecycline (100 mg initial dose, then 50 mg intravenously every 12 hrs) or ampicillin-sulbactam 1.5-3 g IV every 6 hrs or amoxicillin-clavulanate 1.2 g IV every 6-8 hrs. Vancomycin could be added at the discretion of the investigator to the comparator arm if methicillin-resistant Staphylococcus aureus (MRSA) was confirmed or suspected within 72 hrs of enrollment. The primary endpoint was clinical response in the clinically evaluable (CE) population at the test-of-cure (TOC) visit. Microbiologic response and safety were also assessed. The modified intent-to-treat (mITT) population comprised 531 subjects (tigecycline, n = 268; comparator, n = 263) and 405 were clinically evaluable (tigecycline, n = 209; comparator, n = 196). RESULTS: In the CE population, 162/209 (77.5%) tigecycline-treated subjects and 152/196 (77.6%) comparator-treated subjects were clinically cured (difference 0.0; 95% confidence interval [CI]: -8.7, 8.6). The eradication rates at the subject level for the microbiologically evaluable (ME) population were 79.2% in the tigecycline treatment group and 76.8% in the comparator treatment group (difference 2.4; 95% CI: -9.6, 14.4) at the TOC assessment. Nausea, vomiting, and diarrhea rates were higher in the tigecycline group. CONCLUSIONS: Tigecycline was generally safe and effective in the treatment of cSSSIs. TRIAL REGISTRATION: ClinicalTrials.gov NCT00368537.

Structural changes in the sacroiliac joint on MRI and relationship to ASDAS inactive disease in axial spondyloarthritis: a 2-year study comparing treatment with etanercept in EMBARK to a contemporary control cohort in DESIR.

BACKGROUND: Limited information is available on the impact of treatment with a tumor necrosis factor inhibitor (TNFi) on structural lesions in patients with recent-onset axial spondyloarthritis (axSpA). We compared 2-year structural lesion changes on magnetic resonance imaging (MRI) in the sacroiliac joints (SIJ) of patients with recent-onset axSpA receiving etanercept in a clinical trial (EMBARK) to similar patients not receiving biologics in a cohort study (DESIR). We also evaluated the relationship between the Ankylosing Spondylitis Disease Activity Score (ASDAS) and change in MRI structural parameters. METHODS: The difference between etanercept (EMBARK) and control (DESIR) in the net percentage of patients with structural lesion change was determined using the SpondyloArthritis Research Consortium of Canada SIJ Structural Score, with and without adjustment for baseline covariates. The relationship between sustained ASDAS inactive disease, defined as the presence of ASDAS < 1.3 for at least 2 consecutive time points 6 months apart, and structural lesion change was evaluated. RESULTS: This study included 163 patients from the EMBARK trial and 76 from DESIR. The net percentage of patients with erosion decrease was significantly greater for etanercept vs control: unadjusted: 23.9% vs 5.3%; P = 0.01, adjusted: 23.1% vs 2.9%; P = 0.01. For the patients attaining sustained ASDAS inactive disease on etanercept, erosion decrease was evident in significantly more than erosion increase: 34/104 (32.7%) vs 5/104 (4.8%); P < 0.001. A higher proportion had erosion decrease and backfill increase than patients in other ASDAS status categories. However, the trend across ASDAS categories was not significant and decrease in erosion was observed even in patients without a sustained ASDAS response. CONCLUSIONS: These data show that a greater proportion of patients achieved regression of erosion with versus without etanercept. However, the link between achieving sustained ASDAS inactive disease and structural lesion change on MRI could not be clearly established. TRIAL REGISTRATION: EMBARK: ClinicalTrials.gov identifier: NCT01258738 , Registered 13 December 2010; DESIR: ClinicalTrials.gov identifier: NCT01648907 , Registered 24 July 2012.

Correlation between patient and clinician assessments of depression severity in the PREVENT study.

BACKGROUND: The degree of agreement between patient- and clinician-rated scales of depressive severity varies widely. This study analyzed agreement between commonly used depression rating scales in the Prevention of Recurrent Episodes of Depression with Venlafaxine Extended Release (ER) for Two Years (PREVENT) trial. METHODS: The PREVENT trial was a multiphase, randomized, double-blind study of patients with recurrent major depressive disorder. This secondary analysis evaluated acute (10weeks) and continuation phase (6months) data. Pearson correlation coefficients at each acute-phase (weekly) and continuation-phase (monthly) visit were calculated for patient-rated (30-item Inventory of Depressive Symptomatology-Self-Rated [IDS-SR30] and clinician-rated (17-item Hamilton Rating Scale for Depression [HAM-D17] and Clinical Global Impressions-Severity [CGI-S]) measures and for response and remission. RESULTS: Data from 1,047 patients were analyzed. The respective correlation coefficients at baseline, week 10, and month 6 were: IDS-SR30: HAM-D17: 0.46, 0.75, 0.70; and for IDS-SR30: CGI-S 0.28, 0.67, 0.65. Agreement between IDS-SR30- and HAM-D17-defined remission and response was relatively poor: week 10, 0.52 and 0.34, respectively; month 6, 0.45 and 0.32, respectively. CONCLUSIONS: These findings suggest that patient-rated measures of depression severity do not correspond strongly with clinician ratings, and are particularly poor prior to the initiation of treatment.

An Analysis of Real-World Data on the Safety of Etanercept in Older Patients with Rheumatoid Arthritis.

OBJECTIVE: The aim of this study was to use real-world data to evaluate potential interactions between age, treatment, and the risk of developing four adverse events (AEs) common in the elderly: congestive heart failure, serious infections, non-melanoma skin cancer, and interstitial lung disease. These AEs were identified as important in a prior age-based analysis (≤ 65 vs > 65 years) of etanercept- or placebo-treated patients with rheumatoid arthritis (RA) in controlled clinical trials. METHODS: Real-world data (1 January 2013 to 31 January 2018) were obtained from the IBM Watson Health MarketScan® Database. Patients were included if aged ≥ 18 years, enrolled for ≥ 1 year prior to RA diagnosis, and without any of the four AEs of interest prior to RA diagnosis or between RA diagnosis and first etanercept exposure. Logistic regression analysis was applied following propensity matching of patients receiving or not receiving etanercept based on age at diagnosis, age status at the beginning of observation (> 65 years or not), sex, geographic region, and follow-up duration. RESULTS: The overall cohort comprised 403,689 patients. The absolute risk of each of the four AEs increased with age. In propensity-matched cohorts, etanercept was associated with significantly higher odds of developing each of the four AEs (p < 0.001 for all). However, the relative risk of experiencing the four AEs in patients who received etanercept versus those who did not was similar between patients ≤ 65 years of age and those > 65 years of age. CONCLUSIONS: In patients with RA, the relative increase in etanercept-associated risk of experiencing congestive heart failure, serious infection, non-melanoma skin cancer, or interstitial lung disease was similar between elderly and non-elderly.

A single-arm, open-label study to assess the immunogenicity, safety, and efficacy of etanercept manufactured using the serum-free, high-capacity manufacturing process administered to patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the immunogenicity, safety, and efficacy of etanercept (ETN) manufactured using the serum-free, high-capacity manufacturing (SFHCM) process in patients with rheumatoid arthritis (RA). METHODS: In this global, multicenter, open-label, single-arm study (NCT02378506), 187 adult patients with moderate to severe RA received ETN 50 mg once weekly for 24 weeks manufactured using the SFHCM process. Immunogenicity (presence of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs)) was assessed at 12 and 24 weeks. Safety and efficacy were evaluated at 4, 12, and 24 weeks. RESULTS: Eight (4.5%) patients tested positive for ADA, and there were no NAbs detected at any time throughout the study. Ninety (48.1%) patients reported treatment-emergent adverse events (AEs), of which 27 (14.4%) reported injection-site reactions, and 43 (23.0%) reported infections. The majority of AEs were mild or moderate in severity, and the drug was well tolerated. Throughout the duration of the study (week 4 to week 24), there was a progressive increase in the American College of Rheumatology (ACR)-defined responses (ACR20: 55.9%-82.0%, ACR50: 16.1%-57.8%, and ACR70: 3.2%-26.7%) from baseline and the proportion of patients achieving low disease activity and remission, with a corresponding decrease in measures of disease activity. CONCLUSION: The immunogenicity, safety, and efficacy of ETN manufactured using the SFHCM process were similar to the current approved ETN formulation. ClinicalTrials.gov registration: NCT02378506.

An assessment of drug-drug interactions: the effect of desvenlafaxine and duloxetine on the pharmacokinetics of the CYP2D6 probe desipramine in healthy subjects.

A number of antidepressants inhibit the activity of the cytochrome P450 2D6 enzyme system, which can lead to drug-drug interactions. Based on its metabolic profile, desvenlafaxine, administered as desvenlafaxine succinate, a new serotonin-norepinephrine reuptake inhibitor, is not expected to have an impact on activity of CYP2D6. This single-center, randomized, open-label, four-period, crossover study was undertaken to evaluate the effect of multiple doses of desvenlafaxine (100 mg/day, twice the recommended therapeutic dose for major depressive disorder in the United States) and duloxetine (30 mg b.i.d.) on the pharmacokinetics (PK) of a single dose of desipramine (50 mg). A single dose of desipramine was given first to assess its PK. Desvenlafaxine or duloxetine was then administered, in a crossover design, so that steady-state levels were achieved; a single dose of desipramine was then coadministered. The geometric least-square mean ratios (coadministration versus desipramine alone) for area under the plasma concentration versus time curve (AUC) and peak plasma concentrations (C(max)) of desipramine and 2-hydroxydesipramine were compared using analysis of variance. Relative to desipramine alone, increases in AUC and C(max) of desipramine associated with duloxetine administration (122 and 63%, respectively) were significantly greater than those associated with desvenlafaxine (22 and 19%, respectively; P < 0.001). Duloxetine coadministered with desipramine was also associated with a decrease in 2-hydroxydesipramine C(max) that was significant compared with the small increase seen with desvenlafaxine and desipramine (-24 versus 9%; P < 0.001); the difference between changes in 2-hydroxydesipramine AUC did not reach statistical significance (P = 0.054). Overall, desvenlafaxine had a minimal impact on the PK of desipramine compared with duloxetine, suggesting a lower risk for CYP2D6-mediated drug interactions.

Effects of venlafaxine extended release on resilience in posttraumatic stress disorder: an item analysis of the Connor-Davidson Resilience Scale.

The aim was to evaluate the efficacy of venlafaxine extended release (ER) on characteristics of resilience, measured by the Connor-Davidson Resilience Scale, in patients with posttraumatic stress disorder (PTSD). Data were evaluated from a randomized, 6-month, international, multicenter study of adult outpatients with a primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition PTSD for >or=6 months, and 17-item Clinician-Administered PTSD Scale score >or=60. Patients were assigned randomly to treatment with flexible-dose venlafaxine ER (37.5-300 mg/day) or placebo. Changes from baseline scores and effect sizes of response to treatment with venlafaxine ER compared with placebo were computed for each item, as well as for the newly developed 2-item and 10-item subscales. Effect sizes across items ranged from 0.41 (moderate) to 0.08 (very weak). The effect size for the Resilience Scale-2 (2-item subscale) was 0.32, which was comparable to the effect sizes of 0.35 for the 25-item full scale and 0.34 for the 10-item subscale. Venlafaxine ER improved resilience on individual Connor-Davidson Resilience Scale items that reflect four factors (hardiness, persistence/tenacity, social support, and faith in a benevolent or meaningful world), to varying degrees in patients with PTSD. The findings suggest that assessment of treatment response might be enhanced by routine evaluation of resilience.

Assessing the efficacy of 2 years of maintenance treatment with venlafaxine extended release 75-225 mg/day in patients with recurrent major depression: a secondary analysis of data from the PREVENT study.

The objective of this study was to evaluate the long-term efficacy of venlafaxine extended release (ER) < or =225 mg/day in patients with recurrent major depressive disorder (MDD). In this double-blind trial, outpatients with recurrent MDD (N=1096) were randomized to 10 weeks of acute-phase treatment with venlafaxine ER (75-300 mg/day) or fluoxetine (20-60 mg/day) followed by a 6-month continuation phase and two consecutive 12-month maintenance phases. At the start of each maintenance period, venlafaxine ER responders were randomized to double-blind venlafaxine ER or placebo. In this analysis, data from responders to acute and continuation treatment were analyzed during the combined maintenance phases while receiving venlafaxine ER < or =225 mg/day. Failure to maintain response was defined as an increase in maintenance dose to 300 mg/day or recurrence. Differences were calculated using Kaplan-Meier methods and compared using log-rank tests. Continuation-phase responders (n=114) receiving venlafaxine ER < or =225 mg/day comprised the analysis population (venlafaxine ER: n=55; placebo: n=59). The estimated probability for remaining well across 24 months of maintenance treatment was 67% for venlafaxine ER and 41% for placebo (P=0.007). Venlafaxine ER effectively maintained response at doses < or =225 mg/day for up to 2.5 years in patients with recurrent MDD. The findings are consistent with those of the full data set.

Maintenance of Remission with Etanercept-DMARD Combination Therapy Compared with DMARDs Alone in African and Middle Eastern Patients with Active Rheumatoid Arthritis.

INTRODUCTION: To compare etanercept (ETN) and placebo (PBO) for maintaining low disease activity (LDA) achieved with ETN in patients with rheumatoid arthritis (RA) from Africa and the Middle East. METHODS: In this subset analysis of the Treat-to-Target trial (ClinicalTrials.gov identifier NCT01981473), 53 adult patients with moderate-to-severe RA nonresponsive to methotrexate were treated with 50 mg ETN/week for 24 weeks (Period 1). Patients achieving LDA were randomized to continue ETN treatment or switched to PBO for an additional 28 weeks (Period 2). The proportion of patients maintaining LDA or remission in each arm at the end of Period 2 was determined. Additional efficacy and patient-reported outcomes (PROs) were also evaluated. RESULTS: During Period 1, 51 patients achieved LDA according to the disease activity score-28 joints-erythrocyte sedimentation rate (DAS28-ESR LDA) and 30 achieved remission. At week 52, nine of 22 and eight of 29 in the ETN and PBO groups, respectively, remained in DAS28-ESR LDA without experiencing a flare. Additionally, six of 14 and five of 16 in the ETN and PBO groups, respectively, remained in remission. Among patients experiencing a flare during Period 2, 13 of 22 and 21 of 29 received ETN or PBO, respectively. The median time to flare was 193 and 87 days in the ETN and PBO groups, respectively. At week 52, consistently more patients in the ETN group than in the PBO group achieved predetermined efficacy and PRO endpoints. CONCLUSIONS: These data suggest continuing ETN maintenance therapy is beneficial to patients after they have achieved their treatment target. However, this subset analysis is limited by the small patient population and must be interpreted with caution. FUNDING: Pfizer. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT0198147.