Efficacy and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir with low-dose ribavirin in patients with chronic hepatitis C virus genotype 1a infection without cirrhosis.

Patients infected with hepatitis C virus (HCV) treated with interferon-free direct-acting antivirals may still require ribavirin. However, ribavirin is associated with adverse events that can limit its use. This open-label, multicentre, Phase 3 study evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir + dasabuvir (OBV/PTV/r + DSV) with low-dose ribavirin for 12 weeks in genotype 1a-infected patients without cirrhosis. The primary efficacy endpoint was sustained virologic response at post-treatment Week 12 (SVR12). The primary safety endpoint was haemoglobin <10 g/dL during treatment and decreased from baseline. Overall, 105 patients enrolled. The SVR12 rate was 89.5% (n/N = 94/105; 95% CI, 83.7-95.4). The study did not achieve noninferiority versus the historic SVR12 rate for OBV/PTV/r + DSV plus weight-based ribavirin. Five patients experienced virologic failure, four discontinued, and two had missing SVR12 data. Excluding nonvirologic failures, the SVR12 rate was 94.9% (n/N = 94/99). One patient met the primary safety endpoint. OBV/PTV/r + DSV plus low-dose ribavirin offers an alternative option for patients in whom full-dose ribavirin may compromise tolerability, although noninferiority to the weight-based ribavirin regimen was not met.

On estimands and the analysis of adverse events in the presence of varying follow-up times within the benefit assessment of therapies.

The analysis of adverse events (AEs) is a key component in the assessment of a drug's safety profile. Inappropriate analysis methods may result in misleading conclusions about a therapy's safety and consequently its benefit-risk ratio. The statistical analysis of AEs is complicated by the fact that the follow-up times can vary between the patients included in a clinical trial. This paper takes as its focus the analysis of AE data in the presence of varying follow-up times within the benefit assessment of therapeutic interventions. Instead of approaching this issue directly and solely from an analysis point of view, we first discuss what should be estimated in the context of safety data, leading to the concept of estimands. Although the current discussion on estimands is mainly related to efficacy evaluation, the concept is applicable to safety endpoints as well. Within the framework of estimands, we present statistical methods for analysing AEs with the focus being on the time to the occurrence of the first AE of a specific type. We give recommendations which estimators should be used for the estimands described. Furthermore, we state practical implications of the analysis of AEs in clinical trials and give an overview of examples across different indications. We also provide a review of current practices of health technology assessment (HTA) agencies with respect to the evaluation of safety data. Finally, we describe problems with meta-analyses of AE data and sketch possible solutions.

Efficacy and safety of adalimumab every other week versus methotrexate once weekly in children and adolescents with severe chronic plaque psoriasis: a randomised, double-blind, phase 3 trial.

BACKGROUND: Adalimumab is indicated for the treatment of moderate to severe psoriasis in adults. We assessed the efficacy and safety of adalimumab in children and adolescents with severe plaque psoriasis. METHODS: This randomised, double-blind, multiperiod, phase 3 trial was done at 38 clinics in 13 countries. Patients (aged ≥4 to <18 years) with severe plaque psoriasis who had not responded to topical therapy were randomly assigned with an interactive voice or web-response system (1:1:1) to receive adalimumab 0·8 mg/kg or 0·4 mg/kg subcutaneously at week 0, then every other week starting at week 1, or oral methotrexate once weekly (0·1-0·4 mg/kg) for 16 weeks. Randomisation was stratified by history of etanercept treatment, with a block size of three. Responders were withdrawn from treatment (for up to 36 weeks) and re-treated with adalimumab (for 16 weeks) if disease became uncontrolled. Ranked primary efficacy endpoints were the proportion of patients who achieved at least 75% improvement from baseline in Psoriasis Area and Severity Index (PASI75) score and clear or minimal physician global assessment (PGA) score at week 16, comparing adalimumab 0·8 mg/kg with methotrexate. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01251614, and has been completed. FINDINGS: Between Dec 14, 2010, and Feb 5, 2015, 114 patients were randomly assigned to adalimumab 0·8 mg/kg (n=38), adalimumab 0·4 mg/kg (n=39) or methotrexate (n=37). At week 16, PASI75 was achieved in 22 (58%) of 38 patients in the adalimumab 0·8 mg/kg group compared with 12 (32%) of 37 patients in the methotrexate group (p=0·027). 23 (61%) of 38 patients in the adalimumab 0·8 mg/kg group and 15 (41%) of 37 in the methotrexate group achieved clear or minimal PGA (p=0·083). In the adalimumab 0·4 mg/kg group, 17 (44%) of 39 patients achieved PASI75 and 16 (41%) achieved clear or minimal PGA. The most frequent adverse events were infections (17 [45%] of 38 in the adalimumab 0·8 mg/kg group during initial treatment; 22 [56%] of 39 in the adalimumab 0·4 mg/kg group; 21 [57%] of 37 in the methotrexate group). Three serious adverse events were reported, all in patients in the adalimumab 0·4 mg/kg group, and were not judged to be related to study drug. INTERPRETATION: Treatment with adalimumab 0·8 mg/kg in children and adolescents with severe plaque psoriasis provided significant improvements in PASI75 and a non-significant increase in the proportion of patients who achieved clear or minimal PGA compared with methotrexate. No new safety risks were identified. FUNDING: AbbVie.

Reduction in C-Reactive-Protein Levels With Adalimumab Therapy in Patients With Moderate-to-Severe Hand and/or Foot Psoriasis.

INTRODUCTION: We evaluated post hoc the relationship between Humira® (adalimumab) therapy and high-sensitivity C-reactive protein (hs-CRP) levels in patients with moderate-to-severe hand and/or foot psoriasis from the 16-week placebo-controlled period of REACH.
METHODS: REACH was a phase 4, multicenter, randomized, double-blind trial, evaluating adalimumab treatment for patients with psoriasis of the hands and/or feet. Adults were randomized 2:1 to adalimumab 40 mg every other week (following 80 mg at week 0) or matching placebo from weeks 1 to 16, followed by a 12-week, open-label extension. In this post hoc analysis, changes in hs-CRP were reported as observed from baseline to week 16.
RESULTS: Of the 72 patients (23 placebo, 49 adalimumab) who participated in REACH, 63 (19 placebo, 44 adalimumab) with hs-CRP measurements at baseline and at week 16 were included in this analysis. Baseline median hs-CRP values were 1.6 mg/L (placebo) and 2.2 mg/L (adalimumab), and were 3 times higher for patients with, as compared with those without, psoriatic arthritis (5.45 vs 1.8 mg/L). At week 16, the adalimumab group showed greater improvements (median reduction) from baseline than the placebo group in hs-CRP overall (-0.55 vs +0.10 mg/L), regardless of achievement of PGA of the hands and/or feet (hfPGA) 0 or 1 at week 16 (-0.80 vs 0 mg/L for patients who achieved hfPGA 0/1; -0.40 vs +0.30 mg/L, patients who did not achieve hfPGA 0/1), baseline psoriatic arthritis history (-2.35 mg/L with history [adalimumab group; no history for placebo group]; -0.40 vs +0.10 mg/L without history), and body mass index (BMI) category (defined by median BMI) (-0.80 vs +0.20 mg/L for BMI <30.28 kg/m2; -0.40 vs 0 mg/L for BMI ≥30.28 kg/m2).
CONCLUSION: Treatment with adalimumab 40 mg every other week resulted in greater overall reductions in hs-CRP levels among patients in this post hoc analysis, compared with placebo at 16 weeks regardless of baseline characteristics.

ClinicalTrials.gov Registry for REACH: NCT00735787

J Drugs Dermatol. 2016;15(5):562-566.

Efficacy of Adalimumab Compared With Methotrexate or Placebo Stratified by Baseline BMI in a Randomized Placebo-Controlled Trial in Patients With Psoriasis.

INTRODUCTION: In the Comparative Study of Humira vs Methotrexate vs Placebo In Psoriasis Patients (CHAMPION) study, significantly more patients achieved ≥75% improvement in the Psoriasis Area and Severity Index (PASI75) and ≥90% improvement (PASI90) after 16 weeks of treatment with adalimumab (80 mg at week 0, then 40 mg every other week starting at week 1) compared with methotrexate (up to 25 mg/week orally) or placebo. In this exploratory analysis, the efficacy of adalimumab was evaluated in a subset of the CHAMPION patient population stratified by baseline body mass index (BMI). METHODS: PASI responses and Dermatology Life Quality Index (DLQI) scores through 16 weeks of treatment were examined by baseline BMI category (<25 kg/m2 [normal], 25 to <30 kg/m2 [overweight], and ≥30 kg/m2 [obese]) in patients with psoriasis with a baseline PASI total score ≥12. Treatment differences between the adalimumab and the methotrexate or placebo groups were compared using Fisher's exact test for PASI responses and 1-way analysis of variance for DLQI scores. RESULTS: In all BMI categories, adalimumab treatment led to significantly greater rates of PASI75/90 responses at weeks 12 and 16 compared with methotrexate or placebo (P<0.05 for all). In normal weight, overweight, and obese patients at week 16, the respective PASI75 response rates were 85.0%, 85.7%, and 61.3% with adalimumab; 43.3%, 29.3%, and 26.1% with methotrexate; and 28.6%, 16.7%, and 0% with placebo. PASI90 response rates were 70.0%, 53.6%, and 35.5% with adalimumab; 26.7%, 7.3%, and 8.7% with methotrexate; and 9.5%, 16.7%, and 0% with placebo. Across all BMI subgroups, the greatest decreases in DLQI scores from baseline occurred in the adalimumab group. CONCLUSION: Significantly higher PASI75/90 response rates and more pronounced improvements in DLQI scores at week 16 were identified in patients treated with adalimumab, compared with methotrexate or placebo, regardless of baseline BMI category.

A 52-week trial comparing briakinumab with methotrexate in patients with psoriasis.

BACKGROUND: Briakinumab is a monoclonal antibody against the p40 molecule shared by interleukin-12 and interleukin-23, which is overexpressed in psoriatic skin lesions. We assessed the efficacy and safety of briakinumab as compared with methotrexate in patients with psoriasis. METHODS: In this 52-week trial, we randomly assigned 317 patients with moderate-to-severe psoriasis to briakinumab, at a dose of 200 mg at weeks 0 and 4 and 100 mg at week 8 and every 4 weeks thereafter (154 patients), or methotrexate, at a dose of 5 to 25 mg weekly (163 patients). The primary end points were the percentages of patients with at least 75% improvement in the score on the psoriasis area-and-severity index (PASI) at weeks 24 and 52 and a score on the physician's global assessment of 0 (clear; i.e., no apparent disease) or 1 (minimal disease) at weeks 24 and 52. A total of 248 patients were enrolled in an ongoing 160-week open-label continuation study. RESULTS: At week 24, a total of 81.8% of the patients in the briakinumab group versus 39.9% in the methotrexate group had at least 75% improvement in the PASI score, and 80.5% versus 34.4% had a score of 0 or 1 on the physician's global assessment. The corresponding percentages at week 52 were 66.2% versus 23.9% with at least a 75% improvement in the PASI score and 63.0% versus 20.2% with a score of 0 or 1 on the physician's global assessment (P<0.001 for all comparisons). During the 52-week study, serious adverse events occurred in 9.1% of the patients in the briakinumab group (12.9 events per 100 patient-years) and in 6.1% in the methotrexate group (10.6 events per 100 patient-years). Serious infections occurred in 2.6% of the patients in the briakinumab group (4.1 events per 100 patient-years) and in 1.8% in the methotrexate group (2.7 events per 100 patient-years); cancers occurred in 1.9% (2.0 events per 100 patient-years) versus 0%. CONCLUSIONS: Briakinumab showed higher efficacy than methotrexate in patients with moderate-to-severe psoriasis. Serious infections and cancers occurred more frequently with briakinumab, but the differences were not significant. (Funded by Abbott Laboratories; ClinicalTrials.gov number, NCT00679731.).

Less Invasive Surfactant Administration: A Review of Current Evidence of Clinical Outcomes With Beractant.

Evidence supporting clinical recommendations or approval for less invasive surfactant administration (LISA) has primarily examined heterogeneous or small-volume (e.g., 1.25-2.5 mL/kg) animal-derived surfactant regimens. To address the evidence gap for larger-volume (e.g., 4-5 mL/kg) animal-derived surfactants, the aim of this review was to evaluate and summarize LISA literature for widely used larger-volume beractant. Surfactant treatment and the LISA technique were initially summarized. The available literature on beractant with LISA was thoroughly assessed and reviewed, including a recent systematic analysis, studies from regions where access or preferences may influence reliance on larger-volume surfactants, and investigations of short- and long-term outcomes. The available literature indicated improved short-term outcomes, including less need for mechanical ventilation, death, or bronchopulmonary dysplasia, and no negative long-term developmental outcomes when beractant was administered via LISA compared with older, more invasive techniques. The rates of short-term outcomes were similar to those previously observed in examinations of LISA with small-volume surfactants, including in populations reflecting very preterm infants. As uptake of LISA is expected to increase, future research directions for larger-volume surfactants include cost-effectiveness evaluations and robust examinations of repeat dosing and surfactant reflux to further inform clinical practice. This review provides a detailed assessment of the literature describing surfactant and LISA, with a focus on studies of beractant. Collectively, the available evidence supports the use of beractant with LISA based both on short-term and long-term outcomes relative to more invasive techniques and comparability of outcomes with small-volume surfactants and may be valuable in guiding clinical decision-making.

Beractant and poractant alfa in premature neonates with respiratory distress syndrome: a systematic review of real-world evidence studies and randomized controlled trials.

Findings from previous meta-analyses of randomized clinical trials (RCTs) in premature infants with respiratory distress syndrome (RDS) varied as to whether clinical outcomes differed by type of animal-derived pulmonary surfactant; real-world evidence (RWE) was excluded. We extracted study characteristics and outcomes from full-text articles from a systematic search for studies that compared beractant with poractant alfa for RDS in preterm infants. RWE data were tabulated; RCT data were subjected to meta-analyses. Designs, patient characteristics, and follow-up durations varied widely among studies (4 RWE, 15 RCT). RWE studies with adjusted odds ratios (ORs) found no statistically significant between-treatment differences in outcomes. In RCT meta-analyses, no statistically significant between-treatment differences were observed for death (OR [95% confidence interval], 1.35 [0.98-1.86]), bronchopulmonary dysplasia (1.25 [0.96-1.62]), pneumothorax (1.21 [0.72-2.05]), and air leak syndrome (2.28 [0.82-6.39]). Collectively, outcomes were similar with beractant and poractant alfa in RWE studies and pooled RCTs.

An open-label pilot study of the effectiveness of adalimumab in patients with rheumatoid arthritis and previous infliximab treatment: relationship to reasons for failure and anti-infliximab antibody status.

This prospective open-label pilot study evaluated the effectiveness and safety of adalimumab and the relationship to antibodies against infliximab (IFX) in adult patients with active rheumatoid arthritis (RA) who had been treated previously with IFX and experienced treatment failure owing to lack or loss of response or intolerance. Patients self-administered adalimumab 40 mg subcutaneously every other week for 16 weeks, followed by maintenance therapy for up to Week 56. Measures of effectiveness included American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria, 28-joint Disease Activity Score, and the Health Assessment Questionnaire Disability Index. Serum IFX concentrations, human antichimeric antibody against IFX (HACA), adalimumab serum concentrations, antiadalimumab antibody, and safety also were assessed. Of the 41 enrolled patients, 37 completed 16 weeks and 30 completed 56 weeks of treatment. Patients experienced clinically meaningful improvements in all measures of RA activity, with greater response rates observed for patients who had experienced loss of initial response to or intolerance of IFX. At Week 16, 46% of patients achieved an ACR20 and 28% achieved an ACR50; 61% achieved an at least moderate and 17% achieved a good EULAR response. Clinical benefit was maintained through Week 56 in all effectiveness parameters. Baseline HACA status did not significantly impact effectiveness. No new safety signals were observed; neither former IFX intolerance status nor baseline HACA status had a clinically relevant impact on adverse event frequency or severity. Adalimumab was effective and well-tolerated in patients with RA who previously failed IFX therapy, irrespective of reason for discontinuation and of HACA status.

Predictors of RSV LRTI Hospitalization in Infants Born at 33 to 35 Weeks Gestational Age: A Large Multinational Study (PONI).

BACKGROUND: Preterm infants are at high risk of developing respiratory syncytial virus (RSV)-associated lower respiratory tract infection (LRTI). This observational epidemiologic study evaluated RSV disease burden and risk factors for RSV-associated LRTI hospitalization in preterm infants 33 weeks+0 days to 35 weeks+6 days gestational age not receiving RSV prophylaxis. METHODS: Preterm infants ≤6 months of age during RSV season (1 October 2013-30 April 2014) were followed at 72 sites across 23 countries from September 2013-July 2014 (study period). RSV testing was performed according to local clinical practice. Factors related to RSV-associated hospitalization for LRTI were identified using multivariable logistic regression with backward selection. RESULTS: Of the 2390 evaluable infants, 204 and 127 were hospitalized for LRTI during the study period and RSV season, respectively. Among these subjects, 64/204 and 46/127, respectively, were hospitalized for confirmed RSV LRTI. Study period and RSV season normalized RSV hospitalization rates (per 100 infant years) were 4.1 and 6.1, respectively. Factors associated with an increased risk of RSV-related LRTI hospitalization in multivariable analyses were smoking of family members (P<0.0001), non-hemodynamically significant congenital heart disease diagnosis (P = 0.0077), maternal age of ≤25 years at delivery (P = 0.0009), low maternal educational level (P = 0.0426), household presence of children aged 4 to 5 years (P = 0.0038), age on 1 October ≤3 months (P = 0.0422), and presence of paternal atopy (P<0.0001). CONCLUSIONS: During the 2013-2014 RSV season across 23 countries, for preterm infants 33-35 weeks gestation ≤6 months old on 1 October not receiving RSV prophylaxis, confirmed RSV LRTI hospitalization incidence was 4.1 per 100 infant years during the study period and 6.1 per 100 infant years during the RSV season. This study enhances the findings of single-country studies of common risk factors for severe RSV infection in preterm infants and suggests that combinations of 4-6 risk factors may be used to accurately predict risk of RSV hospitalization. These findings may be useful in the identification of infants most at risk of severe RSV infection.

Randomized Crossover Comparison of Injection Site Pain with 40 mg/0.4 or 0.8 mL Formulations of Adalimumab in Patients with Rheumatoid Arthritis.

INTRODUCTION: Adalimumab, an anti-tumor necrosis factor antibody, is currently available in a 40 mg/0.8 mL formulation. The objective of this analysis was to evaluate injection site-related pain, safety, and tolerability of a 40 mg/0.4 mL formulation of adalimumab that had fewer excipients, a smaller volume, and a delivery presentation with a smaller gauge needle, versus the current 40 mg/0.8 mL formulation in patients with rheumatoid arthritis (RA). METHODS: Two identically designed, phase 2, randomized, single-blind, two-period crossover studies were conducted in Belgium and the Czech Republic (Study 1) and Australia, Canada, and Germany (Study 2). In both studies, adults with RA [biologic-naive or current users of 40 mg/0.8 mL adalimumab with an average injection site-related pain rating ≥3 cm on a visual analog scale (VAS; 0-10 cm)] were randomized to receive 40 mg/0.8 mL or 40 mg/0.4 mL adalimumab at visit 1. After 1-2 weeks (depending on patient medication schedule), patients received the other formulation at visit 2. A pain VAS [McGill Pain Questionnaire (MPQ-SF)] and the Draize scale were evaluated immediately after injection and 15 min postinjection. The primary endpoint was immediate pain after injection. RESULTS: 64 and 61 patients were randomized in Studies 1 and 2, respectively. Both studies found a clinically relevant and statistically significant lower immediate pain after injection for the 40 mg/0.4 mL versus the 40 mg/0.8 mL formulation. The mean difference on the VAS for the pooled data (-2.48 cm) was also clinically relevant. Most other endpoints in both studies favored the 40 mg/0.4 mL formulation, and its tolerability and safety profile were consistent with 40 mg/0.8 mL adalimumab. CONCLUSION: A 40 mg/0.4 mL adalimumab formulation was well tolerated and associated with less injection site-related pain than the 40 mg/0.8 mL adalimumab formulation. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01561313 and NCT01502423. FUNDING: AbbVie.

Effect of acupuncture compared with placebo-acupuncture at P6 as additional antiemetic prophylaxis in high-dose chemotherapy and autologous peripheral blood stem cell transplantation: a randomized controlled single-blind trial.

PURPOSE: The purpose is to investigate an additional antiemetic effect to ondansetron with needle acupuncture at P6 compared with nonskin-penetrating placebo acupuncture in patients undergoing high-dose chemotherapy and autologous peripheral blood stem cell transplantation. EXPERIMENTAL DESIGN: Eighty patients who were admitted to hospital for high-dose chemotherapy and autologous peripheral blood stem cell transplantation were included into a randomized placebo-controlled single-blind trial. The patients were randomized to receive acupuncture (n = 41) or noninvasive placebo acupuncture (n = 39) at the acupuncture point P6 30 min before first application of high-dose chemotherapy and the day after. All patients received 8 mg ondansetron/day i.v. as basic antiemetic prophylaxis. The main outcome measure was the rate of patients who either had at least one episode of vomiting or required any additional antiemetic drugs on the first 2 days of chemotherapy. RESULTS: The main outcome measure showed no significant difference (P = 0.82): 61% failure in the acupuncture group and 64% in the placebo acupuncture group (95% confidence interval of 3% difference: -18.1 and 24.3%). Comparing nausea, episodes of vomiting or retching and number of additionally required antiemetic drugs did not provide any discrepancy with the main result. CONCLUSIONS: This study suggests that in combination with ondansetron i.v., invasive needle acupuncture at P6 compared with nonskin-penetrating placebo acupuncture has no additional effect for the prevention of acute nausea and vomiting in high-dose chemotherapy.

HEGPOL: randomized, placebo controlled, multicenter, double-blind clinical trial to investigate hepatoprotective effects of glycine in the postoperative phase of liver transplantation [ISRCTN69350312].

BACKGROUND: Kupffer cell-dependent ischemia/reperfusion (I/R) injury after liver transplantation is still of high clinical relevance, as it is strongly associated with primary dysfunction and primary nonfunction of the graft. Glycine, a non-toxic, non-essential amino acid has been conclusively shown in various experiments to prevent both activation of Kupffer cells and reperfusion injury. Based on both experimental and preliminary clinical data this study protocol was designed to further evaluate the early effect of glycine after liver transplantation. METHODS/DESIGN: A prospective double-blinded randomized placebo-controlled multicenter study with two parallel groups in a total of 130 liver transplant recipients was designed to assess the effect of multiple intravenous doses of glycine after transplantation. Primary endpoints in hierarchical order are: peak levels of both aspartat-amino-transaminase (AST) and alanine-amino-transaminase (ALT) as surrogates for the progression of liver related injury, as well as both graft and patient survival up to 2 years after transplantation. Furthermore, the effect of glycine on cyclosporine A-induced nephrotoxicity is evaluated. DISCUSSION: The ongoing clinical trial represents an advanced element of the research chain, along which a scientific hypothesis has to go by, in order to reach the highest level of evidence; a randomized, prospective, controlled double-blinded clinical trial. If the data of this ongoing research project confirm prior findings, glycine would improve the general outcome after liver transplantation.

A Randomized, Double-Blind, Placebo-Controlled Multicenter Study of Adalimumab in Pediatric Patients With Enthesitis-Related Arthritis.

OBJECTIVE: Enthesitis-related arthritis (ERA) is a juvenile idiopathic arthritis (JIA) category, primarily affecting entheses and peripheral joints. This study evaluated efficacy, safety, and pharmacokinetics of adalimumab versus placebo in patients with ERA. METHODS: This is a phase III, multicenter, randomized double-blind study in patients ages ≥6 to <18 years with ERA treated with adalimumab (24 mg/m(2) , maximum dose 40 mg every other week) or placebo for 12 weeks, followed by up to 192 weeks of open-label adalimumab. The primary end point was percent change from baseline in number of active joints with arthritis (AJC) at week 12. Samples were collected to determine adalimumab serum concentrations. Adverse events (AEs) were assessed throughout the study. RESULTS: Forty-six patients were randomized (31 adalimumab/15 placebo). At baseline, mean age was 12.9 years, mean duration of ERA symptoms was 2.6 years, mean AJC was 7.8, and mean enthesitis count was 8.1. Mean percent change from baseline in AJC at week 12 was greater in the adalimumab group versus placebo (-62.6% versus -11.6%; P = 0.039). Most secondary variables favored adalimumab versus placebo at week 12. Treatment response further increased with continued adalimumab therapy through week 52. Mean steady-state adalimumab serum concentrations were 7.5-11.8 µg/ml, similar to patients age ≥2 years with polyarticular JIA. AE rates were similar between placebo and adalimumab: any AE (53.3% versus 67.7%), serious AEs (0% versus 3.2%), and infectious AEs (20.0% versus 29.0%). CONCLUSION: Adalimumab reduced signs and symptoms of ERA at week 12, with improvement sustained through week 52. The safety profile was consistent with previous adalimumab studies.

Prognostic value of serial cardiac assessment and familial screening in patients with dilated cardiomyopathy.

OBJECTIVES: This prospective study was performed to analyse whether routine clinical follow-up investigations at 12+/-6 months add to risk stratification and improve survival rates in patients with a first diagnosis of dilated cardiomyopathy (DCM). METHODS: Four hundred and eighty consecutive patients (mean age 53.4+/-12.3 years, 369 males, mean NYHA class 2.4+/-0.8) with invasively confirmed DCM were included and followed for 3.9+/-3.5 years. Patients were requested to adhere to a follow up investigation within 6-18 months either at the referring physicians or at our out patient department. Two hundred and eighty-one of the 480 patients presented for follow up which consisted of a detailed evaluation of symptoms, standardized physical examination, 12-lead-electrocardiogram recording and echocardiography. Seventeen patients were lost for follow up, 182 did not seek specialized medical follow up. Patients outcome was assessed by structured telephone interviews. RESULTS: Independent predictors of death or transplantation at initial diagnosis were LV-ejection fraction <30% (P=0.0001, risk ratio 2.25), LV-end diastolic pressure >or=15 mmHg (P=0.002, risk ratio 2.0), age >or=54 years, (P=0.04, risk ratio 1.55), and presence of left bundle branch block (P=0.046, risk ratio 1.53). On follow up investigations only deterioration of clinical status by at least one NYHA-class (P=0.001, risk ratio 2.6) and new onset or worsening of mitral regurgitation (P=0.02, risk ratio 1.8), remained independent prognostic factors for cardiac death. Patients who presented for routine follow up revealed significant better 5-year survival rates (n=281, 70%) than those who did not (n=153, 55%, P=0.005). CONCLUSIONS: Routine clinical follow up investigations within 6-18 months after first diagnosis of DCM adds to risk stratification and improves survival rates.

Symmetry of bilateral lesions in geographic atrophy in patients with age-related macular degeneration.

BACKGROUND: As a cause for severe visual loss, geographic atrophy of the retinal pigment epithelium is about half as common as choroidal neovascularization in patients with advanced age-related macular degeneration. To assess symmetry, we determined intraindividual variations of various features of bilateral geographic atrophy in patients with atrophic age-related macular degeneration in a cross-sectional study. METHODS: Patients were examined with the use of a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph; Heidelberg Engineering, Heidelberg, Germany). Digital infrared reflection images (excitation, 830 nm) and fundus autofluorescence images (excitation, 488 nm) were recorded. The eyes of each patient were compared regarding number, size, and convex hull of the atrophic areas with the use of image analysis software and with respect to fundus autofluorescence changes in the junctional zone. RESULTS: Seventy-two patients (mean +/- SD age, 76.3 +/- 7.9 years) were examined. The number of atrophic areas ranged from 1 to 23 (mean +/- SD, 4.9 +/- 4.6); the size of geographic atrophy, from 0.18 to 30.20 (mean +/- SD, 7.0 +/- 6.6) mm(2); and the size of the convex hull, from 0.18 to 39.20 (mean +/- SD, 11.7 +/- 8.4) mm(2). No statistically significant difference was found when comparing these variables between each left and right eye: number, P =.62; size, P =.81; and convex hull, P =.78. Identical patterns of fundus autofluorescence were observed in 43 (80%) of 54 patients. CONCLUSIONS: There is intraindividual symmetry in eyes with bilateral geographic atrophy in the presence of a wide range of interindividual variability. The findings are in accordance with the view that age-related macular degeneration is not merely the result of a nonspecific aging process. Symmetric manifestations, rather, reflect specific individual determinants in the pathogenesis and manifestation of the disease.

Safety and Effectiveness of Palivizumab in Children at High Risk of Serious Disease Due to Respiratory Syncytial Virus Infection: A Systematic Review.

INTRODUCTION: Lower respiratory tract infection (LRTI) is the leading cause of infant mortality globally in post-neonatal infants (i.e., 28-364 days of age). Respiratory syncytial virus (RSV) is the most commonly identified pathogen for infant LRTI and is the second most important cause of death in post-neonatal infants. Despite 50 years of RSV vaccine research, there is still no approved vaccine. Therefore, passive immunity with the monoclonal antibody palivizumab is the sole regulatory-approved option for the prevention of serious LRTI caused by RSV in pediatric patients at high risk of RSV disease. METHODS: We conducted a comprehensive systematic literature review of randomized controlled trials (RCTs), open-label non-comparative clinical trials, and prospective observational studies/registries, and summarized the evidence related to the safety, efficacy, and effectiveness of palivizumab. RESULTS: The efficacy of palivizumab, as measured by the relative reduction in RSV-related hospitalization rate compared with placebo ranged from 39% to 78% (P < 0.05) in the 2 pivotal RCTs. A meta-analysis of the RSV-related hospitalization rate from 5 randomized placebo-controlled trials yielded an overall odds ratio of 0.41 (95% CI, 0.31-0.55) in favor of palivizumab prophylaxis over placebo (P < 0.00001). Low rates of RSV-related hospitalizations were observed in palivizumab recipients consistently over time in more than 42,000 pediatric subjects across 7 RCTs, 4 open-label non-comparative trials, and 8 observational studies/registries conducted in 34 countries. In addition, among palivizumab-prophylaxed subjects with breakthrough RSV LRTI, rates of intensive care unit admission and mechanical ventilation from RSV hospitalization also were low and consistent across studies. With respect to safety, no differences were observed between palivizumab and placebo in the blinded RCTs. CONCLUSION: Rates of RSV hospitalizations and RSV hospitalization-related endpoints in pediatric subjects who received prophylaxis with palivizumab were low and constant over time and across RCTs, open-label non-comparative trials, and observational studies/registries.

Safety and effectiveness of adalimumab in patients with rheumatoid arthritis over 5 years of therapy in a phase 3b and subsequent postmarketing observational study.

INTRODUCTION: Patients with active rheumatoid arthritis who had failed at least one disease-modifying anti-rheumatic drug (DMARD) were treated with adalimumab (ADA) in the ReAct study with the option to continue treatment for 5 years in ReAlise. The purpose of this study was to evaluate the long-term safety and effectiveness of ADA as prescribed from the first injection in ReAct to the last observation in ReAlise. METHODS: Patients received ADA alone or in combination with DMARDs according to usual clinical care practices. Adverse events (AEs) were tabulated by five time windows after the first ADA injection. Effectiveness measures included achievement of low disease activity (LDA), defined as Simplified Disease Activity Index (SDAI) ≤11, or remission, (REM), defined as SDAI ≤3.3. RESULTS: Of the 6,610 ReAct patients, 3,435 (52%) continued in ReAlise. At baseline in ReAct, mean age was 54 years, mean DAS28 was 6.0 and mean HAQ DI was 1.64. The mean treatment duration was 1,016 days, representing 18,272 patient-years (PYs) of ADA exposure. Overall incidence rates of serious AEs and serious infections were 13.8 and 2.8 events (E)/100 PYs, respectively. Serious AEs occurred most frequently in the first 6 months and deceased thereafter. Standardised mortality ratio was 0.71 (95% CI 0.57 to 0.87) and standardised incidence ratio for malignancies was 0.64 (95% CI 0.53 to 0.76). LDA was achieved by 50% and REM by 21% of patients at last observation. CONCLUSIONS: Results of this large observational study of ADA in routine clinical practice were consistent with controlled trials, with no new safety concerns during a follow-up of more than 5 years. Effectiveness of ADA was maintained during long-term observation. TRIAL REGISTRATION: NCT00448383, NCT00234884.

Influence of psoriatic arthritis on the efficacy of adalimumab and on the treatment response of other markers of psoriasis burden: subanalysis of the BELIEVE study.

BACKGROUND: Adalimumab is a fully human anti-TNF monoclonal antibody with demonstrated efficacy and safety in patients with moderate to severe psoriasis and psoriatic arthritis (PsA). OBJECTIVE: This study examined the effect of PsA on adalimumab treatment response in patients from the Phase IIIb BELIEVE trial (NCT00574249, ClinicalTrials.gov registry), and response of other markers of disease burden to adalimumab treatment. METHODS: In this post hoc analysis, patients with or without a history of PsA and with moderate to severe psoriasis were randomized to adalimumab plus adjunctive topical therapy (calcipotriol/betamethasone dipropionate) or monotherapy (adalimumab plus matching topical vehicle). RESULTS: Regardless of baseline PsA, improvement at Week 16 was seen in PASI 75, pruritus, PSSI, and DLQI (all patients), and mean NAPSI scores. Patients with PsA had HAQ improvement at Week 16, and compared to patients without PsA, had higher VAS pain scores. This analysis represents the first publication of the influence of PsA and PsA plus body weight on patient response to adalimumab, and response of scalp psoriasis, nail psoriasis, and patient-reported outcomes to adalimumab. The incidence of AEs was similar among all patients (62%), those with PsA (65%) and without PsA (60%). The most common AEs were infections (27%); 4.2% of all patients reported serious AEs. CONCLUSION: Adalimumab treatment resulted in comprehensive, clinically relevant improvements from baseline PsA status, in skin, nails, quality of life, pain and pruritus. Despite having more severely affected disease and quality of life, patients with PsA did not respond to adalimumab significantly differently from patients without PsA.

Adalimumab for treatment of moderate to severe chronic plaque psoriasis of the hands and feet: efficacy and safety results from REACH, a randomized, placebo-controlled, double-blind trial.

OBJECTIVE: To determine the efficacy, safety, and sustainability of response to adalimumab therapy for moderate to severe chronic plaque psoriasis involving hands and/or feet. DESIGN: Sixteen-week, randomized, double-blind, placebo-controlled evaluation of adalimumab therapy for moderate to severe chronic plaque psoriasis involving the hands and/or feet with a 12-week open-label extension (Randomized Controlled Evaluation of Adalimumab in Treatment of Chronic Plaque Psoriasis of the Hands and Feet [REACH]). SETTING: Multicenter outpatient study in the United States and Canada. PARTICIPANTS: Patients with chronic plaque psoriasis on the hands and/or feet with a Physician's Global Assessment of hands and/or feet (hfPGA) score of "moderate" or above. INTERVENTION: Patients were randomized 2:1 to adalimumab (80 mg at week 0, then 40 mg every other week starting at week 1) or to matching placebo. MAIN OUTCOME MEASURE: Percentage of patients achieving an hfPGA score of "clear" or "almost clear" at week 16. RESULTS: Seventy-two patients (adalimumab [n = 49];placebo [n = 23]) were evaluated. Baseline percentages of patients with moderate and severe hfPGA scores were 76% and 24%, respectively, for the adalimumab group and 74% and 26%, respectively, for the placebo group. At week 16, 31% and 4% of patients randomized to adalimumab and placebo, respectively, achieved an hfPGA score of clear or almost clear (P = .01). At week 28, 80% of the hfPGA clear or almost clear response was maintained from week 16 (25% for patients randomized to adalimumab). Adverse events in both groups were generally mild to moderate. In both periods combined, nasopharyngitis (27% and 13% for adalimumab- and placebo-treated patients, respectively) was most frequently reported. CONCLUSION: Adalimumab is efficacious and well tolerated for treatment of chronic plaque psoriasis of hands and/or feet, with efficacy largely maintained to 28 weeks. Trial Registration clinicaltrials.gov Identifier: NCT00735787.