Nail Psoriasis Does Not Affect Skin Response to Ixekizumab in Patients With Moderate-To-Severe Psoriasis.

Background: Presence of nail psoriasis in patients with plaque psoriasis may be an indicator of greater disease severity. Previously, patients with nail psoriasis have had delayed skin clearance after treatment compared to patients without nail psoriasis. Objective: This post-hoc analysis evaluated the efficacy of ixekizumab in clearance of plaque psoriasis in patients with and without nail psoriasis. Methods: Data were integrated from two phase 3 clinical trials (UNCOVER-2 and UNCOVER-3; N=2570) to assess skin response over 12 weeks of treatment with subcutaneous placebo, etanercept, or ixekizumab in patients with and without nail psoriasis. Nail response was assessed using Nail Psoriasis Severity Index (NAPSI) and skin response was assessed as the percentage of patients achieving 75%, 90%, or 100% improvement in Psoriasis Area and Severity Index (PASI 75, PASI 90, PASI 100) or a score of 0 or 1 on the static Physician Global Assessment (sPGA 0 or 0,1). Results: From baseline to week 12, progressive improvement in psoriasis occurred with ixekizumab and etanercept treatment; however, significantly more patients with nail psoriasis than without mild PASI 75 at weeks 8 and 12 and sPGA (0,1) at week 12 with ixekizumab. Significantly more patients with severe nail psoriasis than mild achieved PASI 75 at weeks 8 and 12 with ixekizumab. Conclusion: Patients with and without nail psoriasis responded well to ixekizumab. The presence of nail psoriasis did not negatively affect skin clearance in patients treated with ixekizumab. ClinicalTrials.gov: NCT01597245, NCT01646177 J Drugs Dermatol. 2020;19(8):741-746. doi:10.36849/JDD.2020.5116.

Reduction of Hip and Other Fractures in Patients Receiving Teriparatide in Real-World Clinical Practice: Integrated Analysis of Four Prospective Observational Studies.

The phase 3 teriparatide Fracture Prevention Trial showed significant reductions in vertebral (VF) and nonvertebral (NVF) fractures; however, patient exposure was insufficient for full analysis of low-incidence fractures, including hip. We assessed fracture results in pooled data from four prospective, observational teriparatide studies. Ambulatory women and men with osteoporosis received subcutaneous teriparatide 20 µg/day for up to 24 months per routine clinical practice. Fracture rates were compared between 6-month periods, using 0 to 6 months of treatment as the reference period. Analyses used a piecewise exponential model for first fracture. Hip, NVF, clinical VF (CVF), any clinical, and wrist fractures were assessed. For 8828 patients analyzed, mean age was 71 years; mean (SD) treatment duration was 17.4 (8.6) months. The rate of hip fracture decreased significantly for the > 12 to 18-month (- 47.7%) and > 18-month periods (-85.2%) versus the first 6 months of therapy, and for the > 18 versus the > 6 to 12-month period. NVF, CVF, and all clinical fractures were all significantly decreased in each post-reference period, with maximum decreases (> 18-month period) of 52.7%, 69.4%, and 61.2%, respectively, versus 0 to 6 months. No significant reduction was seen for rates of wrist fracture. Teriparatide treatment was associated with statistically significant decreases in hip fracture rate, particularly for > 18 months of treatment, and in NVF, CVF, and all clinical fracture rate in real-world patients. These results should be interpreted in the context of the non-controlled design of the source studies.

Teriparatide Treatment Increases Mineral Content and Volume in Cortical and Trabecular Bone of Iliac Crest: A Comparison of Infrared Imaging With X-Ray-Based Bone Assessment Techniques.

Teriparatide increases bone mass primarily through remodeling of older or damaged bone and abundant replacement with new mineralizing bone. This post hoc analysis investigated whether dual-energy X-ray absorptiometric (DXA) areal bone mineral density (aBMD) measurement adequately reflects changes of mineral and organic matrix content in cortical and trabecular bone. Paired biopsies and aBMD measurements were obtained before and at end of 2 years of teriparatide treatment from postmenopausal women with osteoporosis who were either alendronate pretreated (mean, 57.5 months) or osteoporosis-treatment naive. Biopsies were assessed by micro-computed tomography (µCT) to calculate mean cortical width (Ct.Wi), cortical area (Ct.Ar), and trabecular bone volume fraction (BV/TV). Fourier transformed infrared imaging (pixel size ∼6.3 × 6.3 µm2 ) was utilized to calculate mineral and organic matrix density (mean absorption/pixel), as well as total mineral and organic contents of cortical and cancellous compartments (sum of all pixels in the compartment). Effect of pretreatment over time was analyzed using mixed model repeated measures. µCT derived Ct.Wi and BV/TV increased, accompanied by similar increases in the overall mineral contents of their respective bone compartments. Mineral density did not change. Marked increases in the total content of both mineral and organic matrix associated with volumetric growth in both compartments consistently exceeded those of aBMD. Increases in organic matrix exceeded increases in mineral content in both cortical and trabecular compartments. For percent changes, only change in Ct.Wi correlated to change in femoral neck aBMD (r = .38, p = 0.043), whereas no other significant correlations of Ct.Wi or BV/TV with lumbar spine, total hip, or femoral neck aBMD were demonstrable. These data indicate that 2 years of teriparatide treatment leads to an increased bone organic matrix and mineral content in the iliac crest. The magnitude of these increases in the iliac crest were not detected with conventional aBMD measurements at other skeletal sites. © 2018 American Society for Bone and Mineral Research.

Real-world effectiveness of teriparatide on fracture reduction in patients with osteoporosis and comorbidities or risk factors for fractures: Integrated analysis of 4 prospective observational studies.

INTRODUCTION: Teriparatide significantly reduces fracture rates in clinical trials; however, those study populations were relatively restricted and included too few patients to analyze fracture outcomes within clinically important patient subgroups. We assessed fracture outcomes in subgroups of osteoporosis patients from 4 real-world teriparatide observational studies. METHODS: Patients received teriparatide 20 µg/day for up to 24 months. Fracture rates were compared between 0 to 6 months versus >6 months using a piecewise exponential model for first fracture. Analyses included incident clinical vertebral fractures (CVF) and nonvertebral fractures (NVF), and clinical fractures (CVF and NVF) by subgroups of gender, age <75 or ≥75 years, diabetes, prior bisphosphonates use, rheumatoid arthritis (RA), glucocorticoid use, prior hip, and prior vertebral fracture. RESULTS: The population included 8828 patients (8117 women, 92%) with mean (SD) age 71 (10.6) years and teriparatide treatment duration 17.4 (8.6) months. Overall, CVF, NVF, clinical fracture, and hip fracture rates decreased by 62%, 43%, 50%, and 56%, respectively (all p < .005) for >6 months versus 0 to 6 months. Subgroup analyses all showed significantly decreased rates after >6 months except for NVF reduction in males (n = 710, fracture rate low during months 0 to 6) and in patients using glucocorticoids, and CVF in patients with prior hip fracture. The effects of teriparatide on CVF, NVF, and clinical fractures over time were statistically consistent in all subgroups except age for CVF (p = .074, patients <75 years of age responded better), and diabetes for clinical fractures (p = .046, patients with diabetes responded better), although all of these subgroups experienced significant reductions over time. Glucocorticoids, prior bisphosphonate, and prior vertebral fracture were associated with increased CVF, NVF, and clinical fracture rates; RA, prior hip fracture and female gender were associated with higher NVF and clinical fracture rates; increased age was associated with higher CVF and clinical fracture rates. CONCLUSIONS: Data from 4 real-world observational studies showed statistically significant reductions during teriparatide treatment in rates of CVF, NVF, and clinical fractures in clinically relevant patient subgroups. These results should be interpreted in the context of the non-controlled design of the source studies.

Teriparatide in patients with osteoporosis and type 2 diabetes.

Despite evidence for higher fracture risk, clinical effects of osteoporosis treatments in type 2 diabetes (T2D) are largely unknown. Post hoc analyses of the DANCE observational study compared T2D patients and patients without diabetes to assess the effect of teriparatide, an osteoanabolic therapy on skeletal outcomes and safety. Patients included ambulatory men and women with osteoporosis receiving teriparatide 20µg/day SQ up to 24months followed by observation up to 24months. Main outcome measures included nonvertebral fracture incidence comparing 0-6months with 6+ months of teriparatide, change from baseline in BMD and back pain severity, and serious adverse events. Analyses included 4042 patients; 291 with T2D, 3751 without diabetes. Treatment exposure did not differ by group. For T2D patients, fracture incidence was 3.5 per 100 patient-years during 0-6months treatment, and 1.6 during 6months to treatment end (47% of baseline, 95% CI 12-187%); during similar periods, for patients without diabetes, fracture incidence was 3.2 and 1.8 (57% of baseline, 95% CI 39-83%). As determinants of fracture outcome during teriparatide treatment, diabetes was not a significant factor (P=0.858), treatment duration was significant (P=0.003), and the effect of duration was not significantly different between the groups (interaction P=0.792). Increases in spine and total hip BMD did not differ between groups; increase in femoral neck BMD was greater in T2D patients than in patients without diabetes (+0.34 and +0.004g/cm(2), respectively; P=0.014). Back pain severity decreased in both groups. Teriparatide was well tolerated without new safety findings. In conclusion, during teriparatide treatment, reduction in nonvertebral fracture incidence, increase in BMD, and decrease in back pain were similar in T2D and non-diabetic patients.

A phase 2 dose-ranging study of subcutaneous tabalumab for the treatment of patients with active rheumatoid arthritis and an inadequate response to methotrexate.

OBJECTIVES: To assess the dose-response relationship, efficacy and safety of tabalumab, a human monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX). METHODS: In this phase 2, 24-week, double-blind, placebo-controlled, dose-ranging study, patients with RA (N=158) on stable  MTX were randomised by Bayesian-adaptive method to receive 1, 3, 10, 30, 60, or 120 mg tabalumab or placebo subcutaneously every 4 weeks for 24 weeks. The primary objective was to test for a significant dose-response relationship using a statistical model of the proportion of patients having ≥50% improvement in American College of Rheumatology (ACR) criteria (ACR50) at week 24 (prespecified α=0.10). RESULTS: At week 24, a significant dose-response relationship was observed using ACR50 (p=0.059) and ACR20 (p=0.044) response rates. Using model-estimated data, only 120 mg had significantly higher ACR50 and ACR20 response rates versus placebo (p<0.05). Observed response rates were significantly higher for 120 mg versus placebo as measured by ACR50 at weeks 12 (p=0.039) and 20 (p=0.018), but not week 24, and by ACR20 at weeks 12 (p=0.011) and 24 (p=0.039). Mean DAS28 C-reactive protein  improved with 120 mg at week 24 (p=0.048). Frequency of TEAEs was similar across groups (range 50-69%, p=0.884). Ten (8.2%) tabalumab and 5 (13.9%) placebo patients reported a serious adverse event (SAE). Infections occurred more frequently in patients exposed to tabalumab (30.3% vs 19.4%). Serious infections were reported in 3 (2.5%) tabalumab-treated patients only. CONCLUSIONS: A dose-response relationship was detected with monthly subcutaneous tabalumab. A significant effect was detected with the 120 mg dose with no unexpected safety signals. CLINICAL TRIAL #: NCT00785928.

Evaluating suicide-related adverse events in clinical trials of fluoxetine treatment in adults for indications other than major depressive disorder.

BACKGROUND: The association between treatment-emergent suicidality as an adverse event and fluoxetine treatment was examined using a fluoxetine double-blind placebo-controlled database of clinical trials for indications other than major depressive disorder. METHOD: The database consisted of 53 trials for 16 different indications (14 psychiatric, two non-psychiatric). Within each study, patient adverse event reports and narratives were searched extensively for treatment-emergent thoughts and behaviors associated with suicide. The incidence of adverse events was classified using Food and Drug Administration (FDA) codes for completed suicide, preparatory acts, suicidal ideation and the summary category of 'all suicidality.' The risk difference and risk ratios between fluoxetine and placebo treatment arms were compared using Mantel-Haenszel methods. RESULTS: Within this large database, patients were randomly assigned to receive treatment with either fluoxetine (n = 7066) or placebo (n = 4382). Treatment groups did not differ in their risk for the emergence of suicidality for any FDA code; the risk ratio for 'all suicidality' was 0.82 (p = 0.406), and there were no completed suicides in either group. Analyses based on treatment indication (bulimia, obsessive-compulsive disorder, other psychiatric and non-psychiatric illness) also showed no significant difference in risk between treatment groups. When examined by age categories (18-24, 25-30, 31-65, and 65 years), fluoxetine and placebo treatments did not result in significant risk difference for the emergence of suicidality. CONCLUSIONS: The risk of treatment-emergent suicidality does not appear to be associated with fluoxetine treatment for adults with various non-MDD conditions.

Effect of raloxifene on the incidence of invasive breast cancer in postmenopausal women with osteoporosis categorized by breast cancer risk.

PURPOSE: To assess the effect of raloxifene, indicated for osteoporosis treatment and prevention, on invasive breast cancer in subgroups of postmenopausal women defined by risk factors for breast cancer. EXPERIMENTAL DESIGN: Data from the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial (N=7,705) and a follow-up study, the 4-year Continuing Outcomes Relevant to Evista (CORE) trial (N=4,011), were analyzed. Prespecified subgroups were defined by age (>or=65 versus<65 years), age at menopause (>or=49 versus<49 years), body mass index (>or=25 versus<25 kg/m2), family history of breast cancer (yes/no), serum estradiol level (5-10 versus<5, >10 versus<5 pmol/L), prior estrogen therapy (yes/no), and bone mass at MORE baseline, and 5-year predicted risk, assessed using the modified Gail model (>or=1.67 versus<1.67%), at CORE baseline. Time-to-first invasive breast cancer was analyzed using Cox proportional hazards models. RESULTS: In the placebo group, older age, higher estradiol level, and a family history of breast cancer were associated with an increased breast cancer risk (P<0.05). Raloxifene therapy was associated with a reduced breast cancer risk in both women at lower and those at higher breast cancer risk. Hazard ratio point estimates were 0.11 to 0.67, corresponding to a 33% to 89% reduction in breast cancer risk with raloxifene versus placebo. The therapy by family history interaction was significant (P=0.04). CONCLUSIONS: Raloxifene therapy was associated with a reduced risk of invasive breast cancer in postmenopausal women irrespective of the presence/absence of risk factors; its effect was greater in women with a family history of breast cancer.

Safety assessment of raloxifene over eight years in a clinical trial setting.

OBJECTIVE: Osteoporosis is a chronic disorder that warrants long-term therapy. If benefits are to outweigh risks, the long-term safety profiles of these therapies must be favorable. The aim of this study was to assess the safety of raloxifene over 8 years in 4011 postmenopausal women with osteoporosis in a clinical trial setting through adverse event reporting. METHODS: Data analyzed comprised all reported adverse events collected at each visit of both the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, and the subsequent Continuing Outcomes Relevant to Evista (CORE) trial. MORE was an international, 4-year double-blind, randomized, placebo-controlled study, designed to assess the effect of raloxifene on bone mineral density and vertebral fracture incidence in 7705 (placebo, 2576; raloxifene, 5129) postmenopausal women with osteoporosis. Breast cancer was a secondary endpoint. Based on the breast cancer findings of MORE, the CORE trial, a 4-year double-blind, placebo-controlled trial of a subset of MORE participants, was subsequently conducted. CORE enrolled 4011 (placebo, 1286; raloxifene, 2725) participants and was designed to examine raloxifene's effect on breast cancer incidence. Safety analyses were performed using the intention-to-treat principle, and comparison between therapies was analyzed using a two-sided Fisher's exact test. RESULTS: Over the 8 years of follow-up of 4011 women, there was no difference in all-cause mortality or hospitalization incidence between raloxifene and placebo groups (p > 0.1). Excluding breast cancer and non-melanoma skin cancer, cancer incidence was 4.6% and 6.3% in the raloxifene and placebo group, respectively (p = 0.027). Raloxifene was associated with a 1.7-fold increase in venous thromboembolism incidence (95% confidence interval 0.93-3.14), with an absolute risk difference of 0.9 per 1000 woman-years. There was no difference in the incidence of myocardial infarction, stroke, uterine cancer, endometrial hyperplasia, ovarian cancer or postmenopausal bleeding between the raloxifene and placebo treatment groups (p > 0.5). Uterine polyps, hot flushes and muscle cramps were more common in those receiving raloxifene versus placebo (p = 0.028, p < 0.001, and p = 0.008, respectively). CONCLUSION: These 8-year data support the known clinical safety profile of raloxifene, established in the MORE trial.

Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene.

BACKGROUND: The randomized, double-blind Multiple Outcomes of Raloxifene Evaluation (MORE) trial found that 4 years of raloxifene therapy decreased the incidence of invasive breast cancer among postmenopausal women with osteoporosis by 72% compared with placebo. We conducted the Continuing Outcomes Relevant to Evista (CORE) trial to examine the effect of 4 additional years of raloxifene therapy on the incidence of invasive breast cancer in women in MORE who agreed to continue in CORE. METHODS: Women who had been randomly assigned to receive raloxifene (either 60 or 120 mg/day) in MORE were assigned to receive raloxifene (60 mg/day) in CORE (n = 3510), and women who had been assigned to receive placebo in MORE continued on placebo in CORE (n = 1703). Breast cancer incidence was analyzed by a log-rank test, and a Cox proportional hazards model was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: During the CORE trial, the 4-year incidences of invasive breast cancer and estrogen receptor (ER)-positive invasive breast cancer were reduced by 59% (HR = 0.41; 95% CI = 0.24 to 0.71) and 66% (HR = 0.34; 95% CI = 0.18 to 0.66), respectively, in the raloxifene group compared with the placebo group. There was no difference between the two groups in incidence of ER-negative invasive breast cancer during CORE (P = .86). Over the 8 years of both trials, the incidences of invasive breast cancer and ER-positive invasive breast cancer were reduced by 66% (HR = 0.34; 95% CI = 0.22 to 0.50) and 76% (HR = 0.24; 95% CI = 0.15 to 0.40), respectively, in the raloxifene group compared with the placebo group. During the CORE trial, the relative risk of thromboembolism in the raloxifene group compared with that in the placebo group was 2.17 (95% CI = 0.83 to 5.70). This increased risk, also observed in the MORE trial, persisted over the 8 years of both trials. CONCLUSIONS: The reduction in invasive breast cancer incidence continues beyond 4 years of raloxifene treatment in postmenopausal women with osteoporosis. No new safety concerns related to raloxifene therapy were identified during CORE.

Repellency and efficacy of a 65% permethrin spot-on formulation for dogs against Aedes aegypti (Diptera: Culicidae) mosquitoes.

A topically applied 65% permethrin spot-on (Defend EXspot Treatment for Dogs, Schering-Plough Animal Health) used for flea and tick control on dogs was evaluated for repellency and efficacy against the yellow fever mosquito, Aedes aegypti, a vector of canine filariasis. Six dogs were randomly assigned to receive a single application of 65% permethrin on Day 0 (n=3) or to remain untreated as controls (n=3). Dogs were anesthetized and exposed to 100 unfed, female mosquitoes in screened cages for 2 hours on Days -6, -4, -1, 0, 1, 7, 14, 21, and 28. Mosquito landing rates, engorgement rates, and mortality were determined for each mosquito challenge. Cages were thoroughly cleaned after each mosquito challenge. Treatment of dogs with 65% permethrin reduced the mosquito landing rates by 96.3% 6 hours after treatment and by 82.5% on Day 1. Mosquito mortality, relative to the control group, was 28.2% 6 hours after treatment, ranged from 84.0% to 90.9% through Day 21, and declined to 50.3% 28 days after treatment. Successful feeding by mosquitoes was significantly (P=.05) reduced on Days 1 through 28. The 65% permethrin spot-on treatment killed and repelled significantly (P =.05) more mosquitoes on treated dogs versus untreated dogs for 28 days after treatment.

Efficacy of two 65% permethrin spot-on formulations against induced infestations of Ctenocephalides felis (Insecta: Siphonaptera) and Amblyomma americanum (Acari: Ixodidae) on beagles.

The efficacy of two formulations of a topically applied 65% permethrin spot-on (Defend Exspot Treatment for Dogs, Schering-Plough Animal Health) was evaluated against experimental infestations of the cat flea Ctenocephalides felis and the lone star tick Amblyomma americanum in dogs. Eighteen dogs were randomly assigned to treatment with 65% permethrin in either diethylene glycol monomethyl ether (DGME; original formulation) or propylene glycol monomethyl ether (PGME) or to be untreated as a control. Treated dogs received either 1 (body weight < 15 kg) or 2 ml (body weight > or =15 kg) of the assigned formulation on Day 0. One hundred unfed, adult C. felis were placed on each dog on Days -6, -1, 4, 11, 18, 25, and 32. Fifty unfed, adult ticks were placed on each dog on Days -1, 3, 9, 16, 23, and 30. Live fleas and ticks were counted and removed on Days 3, 7, 14, 21, and 28. Treatment of dogs with the 65% permethrin in DGME reduced flea numbers by 90.4% to 99.9% from Days 3 through 21 (P < or =.05) and by 48.2% 28 days after treatment. Treatment of dogs with 65% permethrin in PGME reduced flea numbers by 93.7% to 99.7% from Days 3 through 28 and by 78.4% 35 days after treatment (P < or =.05). Treatment with 65% permethrin in DGME reduced tick numbers by 90% or more only on Day 7, whereas treatment with 65% permethrin in PGME reduced the number of live ticks by 90%or more on Days 7 and 14 and approached 90%(87.9%) on Day 21. Efficacy against fleas and ticks for the PGME formulation was significantly better (P < or =.05) than for the DGME formulation on Day 28. Findings in this study indicate that both the DGME and PGME formulations of 65% permethrin performed well in reducing numbers of live C. felis and A. americanum on laboratory beagles; however, the PGME formulation was effective approximately 1 to 2 weeks longer than the DGME formulation.