Rationale and design of the GUIDE-IT study: Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure.

OBJECTIVES: The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study is designed to determine the safety, efficacy, and cost-effectiveness of a strategy of adjusting therapy with the goal of achieving and maintaining a target N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of BACKGROUND: Elevations in natriuretic peptide (NP) levels provide key prognostic information in patients with HF. Therapies proven to improve outcomes in patients with HF are generally associated with decreasing levels of NPs, and observational data show that decreases in NP levels over time are associated with favorable outcomes. Results from smaller prospective, randomized studies of this strategy thus far have been mixed, and current guidelines do not recommend serial measurement of NP levels to guide therapy in patients with HF. METHODS: GUIDE-IT is a prospective, randomized, controlled, unblinded, multicenter clinical trial designed to randomize approximately 1,100 high-risk subjects with systolic HF (left ventricular ejection fraction ≤40%) to either usual care (optimized guideline-recommended therapy) or a strategy of adjusting therapy with the goal of achieving and maintaining a target NT-proBNP level of CONCLUSIONS: The GUIDE-IT study is designed to definitively assess the effects of an NP-guided strategy in high-risk patients with systolic HF on clinically relevant endpoints of mortality, hospitalization, quality of life, and medical resource use. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT]; NCT01685840)

Psoriasis Area and Severity Index response in moderate-severe psoriatic patients switched to adalimumab: results from the OPPSA study

Background: Few studies have compared the efficacy of switching to adalimumab in the real-life setting in plaque psoriasis patients. Objective: To evaluate the effect of adalimumab in psoriasis patients previously treated with other biologics. Methods: In this multicentre study, psoriasis patients (N = 262) treated with an anti-TNF-alpha agent, ustekinumab or naïve to biologics then switched to adalimumab were included. Disease severity was assessed by the Psoriasis Area and Severity Index (PASI) at baseline and after 3, 6, 12, 24 and 36 months. The association between clinical risk factors and achievement of PASI response was evaluated by logistic regression. Results: Adalimumab treatment resulted in a decrease in PASI (15.1 ± 6.2 at baseline vs. 2.7 ± 4.8 at 6 months, P < 0.0001), regardless of previous biologic treatment. Furthermore, adalimumab allowed 92.5%, 79% and 56% of patients to achieve PASI response (PASI 50, 75 and 90, respectively) and complete remission (PASI 100 response) in 48.4% of patients, by 6 months and maintained over 3 years, independent of prior biologic treatment. The absence of metabolic syndrome, dyslipidemia, hypertension and lower PASI and lower age at baseline was associated with achievement of PASI response at 3, 6 and 12 months, whereas at later time points (24 and 36 months), PASI 90 and PASI 100 response was associated with diagnosis of psoriasis/psoriatic arthritis. Conclusion: Adalimumab was effective at reducing PASI score over 3 years, irrespective of whether patients were biologic naïve or previously treated with a TNF-alpha or IL-12/23 inhibitor

A stepped-care approach to symptomatic endometriosis management : A participatory research initiative

Objective: To assess the proportion of patients with symptomatic endometriosis satisfied with their medical treatment 12 months after enrollment in a stepped-care management protocol. Design: Prospective, single-arm, self-controlled study. Setting: Academic department. Patient(s): A cohort of 157 consecutive patients referred or self-referred to our center for symptomatic endometriosis. Interventions(s): Systematic detailed information process on medical and surgical treatment followed by a shared decision to start a stepped-care protocol including three subsequent medical therapy steps (oral contraception [OC]; 2.5 mg/d norethindrone acetate [NETA]; 2 mg/d dienogest [DNG]) and a fourth surgical step. Stepping up was triggered by drug inefficacy/intolerance. Main Outcome Measure(s): Satisfaction with treatment was assessed according to a five-category scale (very satisfied, satisfied, neither satisfied nor dissatisfied, dissatisfied, very dissatisfied). Variations were measured in pain symptoms with the use of a 0\u201310-point numeric rating scale (NRS), in quality of life with the use of the Short Form 12 questionnaire (SF-12), and in sexual functioning with the use of the Female Sexual Function Index (FSFI). Result(s): At the end of the 12-month study period, 106 women were still using OC, 23 were using NETA, three were using DNG, and four had undergone surgery. Twenty-one participants (13%) dropped out from the study. In intention-to-treat analysis, excluding five drop-outs for pregnancy desire, the overall satisfaction rate with the stepped-care protocol was 62% (95/152; 95% CI 55%\u201370%). By 12-month follow-up, significant improvements were observed in all pain symptom scores and in SF-12 physical and mental component summary scores, whereas FSFI scores did not vary substantially. Conclusion(s): Most women with endometriosis-associated pelvic pain who chose a stepped-care approach were satisfied with OC and a low-cost progestin for the treatment of their symptoms. The need to step up to an expensive progestin or surgery was marginal

TREatment of ATopic eczema (TREAT) Registry Taskforce: consensus on how and when to measure the core dataset for atopic eczema treatment research registries.

BackgroundComparative, real-life and long-term evidence on the effectiveness and safety of phototherapy and systemic therapy in moderate-to-severe atopic eczema (AE) is limited. Such data must come from well-designed prospective patient registries. Standardization of data collection is needed for direct comparisons and data pooling.ObjectivesTo reach a consensus on how and when to measure the previously defined domain items of the TREatment of ATopic eczema (TREAT) Registry Taskforce core dataset for research registries for paediatric and adult patients with AE.MethodsProposals for the measurement instruments were based on recommendations of the Harmonising Outcome Measures for Eczema (HOME) initiative, the existing AE database of TREATgermany, systematic reviews of the literature and expert opinions. The proposals were discussed at three face-to-face consensus meetings, one teleconference and via e-mail. The frequency of follow-up visits was determined by an expert survey.ResultsA total of 16 experts from seven countries participated in the 'how to measure' consensus process and 12 external experts were consulted. A consensus was reached for all domain items on how they should be measured by assigning measurement instruments. A minimum follow-up frequency of initially 4 weeks after commencing treatment, then every 3 months while on treatment and every 6 months while off treatment was defined.ConclusionsThis core dataset for national AE research registries will aid in the comparability and pooling of data across centres and country borders, and enables international collaboration to assess the long-term effectiveness and safety of phototherapy and systemic therapy used in patients with AE. What's already known about this topic? Comparable, real-life and long-term data on the effectiveness and safety of phototherapy and systemic therapy in patients with atopic eczema (AE) are needed. There is a high diversity of outcomes and instruments used in AE research, which require harmonization to enhance comparability and allow data pooling. What does this study add? Our taskforce has reached international consensus on how and when to measure core domain items for national AE research registries. This core dataset is now available for use by researchers worldwide and will aid in the collection of unified data. What are the clinical implications of this work? The data collected through this core dataset will help to gain better insights into the long-term effectiveness and safety of phototherapy and systemic therapy in AE and will provide important information for clinical practice. Standardization of such data collection at the national level will also allow direct data comparisons and pooling across country borders (e.g. in the analysis of treatment-related adverse events that require large patient numbers)

Methotrexate in rheumatoid arthritis is frequently effective, even if re-employed after a previous failure

Effectiveness of therapy with individual disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) is limited, and the number of available DMARDs is finite. Therefore, at some stage during the lengthy course of RA, institution of traditional DMARDs that have previously been applied may have to be reconsidered. In the present study we investigated the effectiveness of re-employed methotrexate in patients with a history of previous methotrexate failure (original course). A total of 1,490 RA patients (80% female, 59% rheumatoid factor positive) were followed from their first presentation, yielding a total of 6,470 patient-years of observation. We identified patients in whom methotrexate was re-employed after at least one intermittent course of a different DMARD. We compared reasons for discontinuation, improvement in acute phase reactants, and cumulative retention rates of methotrexate therapy between the original course of methotrexate and its re-employment. Similar analyses were peformed for other DMARDs. Methotrexate was re-employed in 86 patients. Compared with the original courses, re-employment was associated with a reduced risk for treatment termination because of ineffectiveness (P = 0.02, by McNemar test), especially if the maximum methotrexate dose of the original course had been low (<12.5 mg/week; P = 0.02, by logistic regression). In a Cox regression model, re-employed MTX was associated with a significantly reduced hazard of treatment termination compared with the original course of methotrexate, adjusting for dose and year of employment (hazard ratio 0.64, 95% confidence interval 0.42–0.97; P = 0.04). These findings were not recapitulated in analyses of re-employment of other DMARDs. Re-employment of MTX despite prior inefficacy, but not re-employment of other DMARDs, is an effective therapeutic option, especially in those patients in whom the methotrexate dose of the original course was low

Finnish multiple sclerosis patients treated with cladribine tablets : a nationwide registry study

Background: Cladribine tablets for adult patients with highly active relapsing multiple sclerosis (MS) have been available in Finland since 2018. Real-world data from different genetic and geographical backgrounds are needed to complement data from clinical trials.Methods: We investigated the use of cladribine tablets in Finland in a non-interventional cohort study, based on real-world data from the nationwide Finnish MS registry. All eligible patients who had initiated treatment with cladribine tablets in 2018-2020 were included. Descriptive analyses for outcomes were conducted using summary statistics. Time-dependent endpoints were analyzed using cumulated events analysis based on 1-Kaplan-Meier estimates and curves. Subgroups were analyzed separately according to the number of previous disease-modifying therapies (DMTs) and the most common last preceding therapies.Results: Data of 179 patients were analyzed. Median follow-up time was 19.0 months (interquartile range [IQR] 12.0-26.2). Of the 134 patients who were followed for at least 12 months, 112 patients (83.6%) remained relapse-free during follow-up. Mean annualized relapse rate (ARR) was 1.0 (standard deviation [SD] 0.89) at baseline, and 0.1 (SD 0.30) at follow-up. Patients with two or more previous DMTs had shorter time to first relapse (median 2.5 months, IQR 0.6-9.3) when compared to patients with 0-1 previous DMTs (median 11.4 months, IQR 8.7-13.1) (p=0.013). After excluding patients switching from fingolimod (n=33), a statistically significant difference in time to first relapse was no longer observed between the two groups (p=0.252). Adverse events (AEs) were reported in 30 patients (16.8%). The most frequent AE was headache (n=14, 7.8%). One patient (0.6%) died of cardiac arrest. Discontinuation of cladribine tablets was reported in nine patients (5.0%).Conclusion: The mean ARR observed in this cohort was similar to what has been reported in clinical trials. Approximately half of the patients had used two or more previous DMTs before cladribine tablets. These patients had a shorter time to first relapse when compared to patients with 0-1 previous DMTs, mostly driven by early relapses in patients switching from fingolimod.Peer reviewe

Switching between Three Types of Mesalazine Formulation and Sulfasalazine in Patients with Active Ulcerative Colitis Who Have Already Received High-Dose Treatment with These Agents

Background and aim: Oral mesalazine and sulfasalazine (SASP) are key drugs for treating ulcerative colitis (UC). The efficacy of switching from one of the several mesalazine formulations to another is largely unknown. This study assessed the efficacy of switching among three types of mesalazine formulation and SASP for UC therapy. Methods: UC patients receiving high-dose mesalazine/SASP who switched to other formulations due to disease activity were considered eligible. Efficacy was evaluated 2, 6, and 12 months after switching. Results: A total of 106 switches in 88 UC patients were analyzed. The efficacy at 2 months after switching was observed in 23/39 (59%) cases from any mesalazine formulation to SASP, in 18/55 (33%) cases from one mesalazine to another, and in 2/12 (17%) cases from SASP to any mesalazine formulation. Nine of 43 effective cases showed inefficacy or became intolerant post-switching. Delayed efficacy more than two months after switching was observed in four cases. Steroid-free remission was achieved in 42/106 (39%) cases—within 100 days in 35 of these cases (83%). Conclusions: Switching from mesalazine to SASP was effective in more than half of cases. The efficacy of switching between mesalazine formulations was lower but may be worth attempting in clinical practice from a safety perspective

Performance-Based Quality Specifications: The Link between Product Development and Clinical Outcomes

The design of drug delivery systems and their corresponding dosing guidelines are critical product development functions supported by clinical pharmacokinetic (PK) and pharmacodynamic (PD) data. Largely, the importance of variance and covariance in product and patient attributes is poorly understood. The existence of PK/PD diversity among myriad patient sub-populations further complicates efforts to gauge the importance of product quality variation. Nevertheless, a platform capable of evaluating the effects of product and patient variability on clinical performance was constructed. This dissertation was predicated on requests to re-define pharmaceutical quality in terms of risk by relating clinical attributes to production characteristics. To avoid in vivo studies, simulated experimental trials were conducted using the model drug, theophylline, for which data and models could be acquired from the literature. Where comprehensive data were unavailable (e.g., production variability statistics), initial estimates were acquired via laboratory-scale experiments. Model asthmatic patients were generated using Monte Carlo simulation and published population distributions of various anothropometric measurements, disease rates, and lifestyle factors. Mathematical constructs for in vitro-in vivo correlations provide a linkage between Quality by Design (QbD) product and process models, PK/PD models, and patient population statistics. The combined models formed the foundation for Monte Carlo risk assessments, which characterized the risk of inefficacy and toxicity for dosing of extended-release theophylline tablets. Sensitivity analyses revealed that patient compliance and content uniformity significantly influenced the probability of observing an adverse event. The Monte Carlo risk assessment platform defined the link between the critical quality attributes (CQAs) and clinical performance (i.e., performance-based quality specifications (PBQS)). The PBQS were subsequently utilized to generate process independent design spaces conditioned on inefficacy and toxicity risk. These design spaces, which directly account for the conditional relationships between product quality and patient variability, can be transferred to a specific process via models that relate process critical control parameters to the CQAs. Process Analytical Technology, therefore, can be integrated into the QbD production environment to control the safety and efficacy of the final product. This work demonstrated that process and product knowledge can be used to estimate the risk that final product quality imparts to clinical performance

Understanding motivation to abstain from Pathological Gambling: The influence of negative expectancies and moderation inefficacy

The present investigation aimed to test a theory-guided model of problem gambling cessation in a sample who were quitting without professional assistance. The main hypothesis was that higher levels of moderation inefficacy (MIE) and higher levels of negative outcome expectancies (NOE) would combine to produce higher levels of both readiness to change (RTC) and commitment to abstinence (CTA). Respondents consisted of 62 community-dwelling problematic gamblers whose change goal was abstinence. Regression and moderation analyses were performed. Results showed that higher levels of NOE predicted residual criterion variance in RTC, but not CTA. MIE was not found to be a significant predictor, and the predicted interaction between NOE and MIE was non-significant. Post-hoc analyses revealed that there may be significant gender differences. Results of the present study have important implications for the development of brief online motivation enhancements which aim to reduce the public health burden of problematic gambling

Premature Treatment Termination in Integrated Primary Care: A Mixed Methods Investigation Among African American Adults with Chronic Pain

Premature Treatment Termination in Integrated Primary Care: A Mixed Methods Investigation Among African American Adults with Chronic Pai