Apremilast Long-Term Safety Up to 5 Years from 15 Pooled Randomized, Placebo-Controlled Studies of Psoriasis, Psoriatic Arthritis, and Behçet's Syndrome.

BACKGROUND: Since US FDA approval in 2014, apremilast has consistently demonstrated a favorable benefit-risk profile in 706,585 patients (557,379 patient-years of exposure) worldwide across approved indications of plaque psoriasis, psoriatic arthritis, and Behçet's syndrome; however, long-term exposure across these indications has not been reported. OBJECTIVE: The aim of this study was to conduct a pooled analysis of apremilast data from 15 clinical studies with open-label extension phases, focusing on long-term safety. METHODS: We analyzed longer-term safety and tolerability of apremilast 30 mg twice daily across three indications for up to 5 years, focusing on adverse events of special interest, including thrombotic events, malignancies, major adverse cardiac events (MACE), serious infections, and depression. Data were pooled across 15 randomized, placebo-controlled studies and divided into placebo-controlled or all-apremilast-exposure groups. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Overall, 4183 patients were exposed to apremilast (6788 patient-years). Most TEAEs were mild to moderate in the placebo-controlled period (96.6%) and throughout all apremilast exposure (91.6%). TEAE rates of special interest were similar between treatment groups in the placebo-controlled period and remained low throughout all apremilast exposure. Exposure-adjusted incidence rates per 100 patient-years during all apremilast exposure were MACE, 0.30; thrombotic events, 0.10; malignancies, 1.0; serious infections, 1.10; serious opportunistic infections, 0.21; and depression, 1.78. Safety findings were consistent across indications and regions. No new safety signals were identified. CONCLUSIONS: The incidence of serious TEAEs and TEAEs of special interest was low despite long-term exposure, further establishing apremilast as a safe oral option for long-term use across indications with a favorable benefit-risk profile. CLINICAL TRIAL REGISTRATION: NCT00773734, NCT01194219, NCT01232283, NCT01690299, NCT01988103, NCT02425826, NCT03123471, NCT03721172, NCT01172938, NCT01212757, NCT01212770, NCT01307423, NCT01925768, NCT00866359, NCT02307513.

Patient and Physician Perceptions of Psoriatic Disease in the United States: Results from the UPLIFT Survey.

INTRODUCTION: The Understanding Psoriatic Disease Leveraging Insights for Treatment (UPLIFT) survey study was conducted globally in 2020 to understand how disease perceptions, including disease severity, treatment goals, and quality of life (QoL), have evolved recently, especially for mild-to-moderate psoriatic disease. Here, key findings from the UPLIFT survey based on respondents located in the US are presented. Leveraging results from the UPLIFT survey could lead to more effective interactions between patients and physicians and greater patient satisfaction. METHODS: UPLIFT was a multinational web-based survey of dermatologists, rheumatologists, and patients who self-reported a healthcare provider diagnosis of psoriasis (PsO) and/or psoriatic arthritis (PsA) conducted from March 2, 2020, to June 3, 2020. RESULTS: US respondents included 1006 patients (26.4% of global population; PsO only, n = 535; PsA only, n = 72; PsO and PsA, n = 399) and 216 physicians (dermatologists, n = 115; rheumatologists, n = 101). Most patients (66.4%) reported a body surface area (BSA; assessed by number of palms) of ≤ 3; of these, 56.2% rated their disease as moderate or severe. Most patients with PsO felt they were somewhat (40.1%) or very (49.3%) closely aligned with their dermatologists regarding treatment goals. Alternately, most patients with PsA felt that they were not too closely (32.1%) or not at all (59.3%) aligned with their rheumatologists. Most patients reported either a moderate (PsO, 35.5%; PsA, 31.8%) or strong (PsO, 47.7%; PsA, 53.9%) need for better treatments. Across BSA subgroups, most patients (60.8% to 86.1%) had a Dermatology Life Quality Index score ≥ 6, indicating at least a moderately impacted QoL. CONCLUSIONS: Despite more treatment options, management of psoriatic disease remains suboptimal, with many patients reporting moderate-to-severe disease and impaired QoL, even with limited skin involvement. Results further suggest an unmet need for alignment between patients and physicians in the US to optimize the management of PsO and PsA.

The Understanding Psoriatic Disease Leveraging Insights for Treatment (UPLIFT) survey was an online survey conducted in 2020. The participants were patients who self-reported a healthcare provider diagnosis of psoriasis and/or psoriatic arthritis, dermatologists, and rheumatologists. The survey was distributed in several countries in North America, Europe, and Japan and a total of 3806 patients responded to the survey. Results from US patients and physicians are presented here.UPLIFT was designed to understand current perceptions of patients and physicians relating to psoriasis and psoriatic arthritis, especially for mild-to-moderate disease. Participants were surveyed regarding treatments, severity of disease, impact on quality of life, treatment goals, and patient-physician interactions.In the US, 1006 patients and 216 physicians completed the survey and were included in the analysis. Most patients had limited skin involvement but still rated their disease as moderate or severe. Regardless of whether patients had a small or large amount of skin involved, most reported at least a moderately impacted quality of life. The survey results suggested that there was disconnect between patients and physicians regarding treatment goals, treatment satisfaction, disease severity, and their recollection of what occurred during physician office visits. Despite new treatment options in recent years, the UPLIFT survey results show that US patients with psoriasis and psoriatic arthritis still experience a great disease burden and could benefit from better communication with physicians to optimize their treatment.

Efficacy and safety of apremilast in patients with limited skin involvement, plaque psoriasis in special areas and impaired quality of life: Results from the EMBRACE randomized trial.

INTRODUCTION/BACKGROUND: Manifestations of psoriasis in special areas are difficult to treat and are associated with a high disease burden and significant quality of life (QoL) impairment. Topical therapies may be inadequate for these patients, necessitating systemic treatment. OBJECTIVE: The objective of EMBRACE was to evaluate the impact on QoL, efficacy and safety of apremilast 30 mg BID in patients with limited skin involvement with plaque psoriasis manifestations in special areas and impaired QoL. METHODS: EMBRACE (NCT03774875) was a phase 4, randomized, placebo-controlled, multinational study. Patients had plaque psoriasis not controlled by topical therapy; lack of response, contraindication or intolerance to conventional first-line systemic therapy; psoriasis in ≥1 special area (including visible locations, scalp, nails, genital areas or palmoplantar areas); Psoriasis Area and Severity Index (PASI) ≥3 to ≤10; and Dermatology Life Quality Index (DLQI) >10. The primary endpoint was DLQI response (≥4-point reduction) at Week 16. RESULTS: Of 277 randomized patients (apremilast: n = 185; placebo: n = 92), 221 completed Week 16 (apremilast: n = 152; placebo: n = 69). The primary endpoint (≥4-point reduction in DLQI at Week 16) was met by significantly more patients receiving apremilast (73.3%) versus placebo (41.3%; p < 0.0001). Significantly greater improvement in affected body surface area (BSA) and PASI was observed with apremilast versus placebo at Week 16. There were also significantly greater improvements with apremilast versus placebo in itch numeric rating scale (-2.5 vs. -0.9, p < 0.0001) and skin discomfort/pain visual analog scale (-21.5 vs. -5.4, p = 0.0003) and greater achievement of Patient Benefit Index ≥1 (77% vs. 40%, p < 0.0001) at Week 16. No new safety signals were observed. CONCLUSIONS: Apremilast significantly improved skin-related QoL in patients with limited skin involvement with plaque psoriasis in special areas and highly impaired QoL. The safety profile was consistent with prior apremilast studies.

Relationship Between Low-Density Lipoprotein Cholesterol and Lipoprotein(a) Lowering in Response to PCSK9 Inhibition With Evolocumab.

Background Beyond their potent LDL (low-density lipoprotein) cholesterol ( LDL -C)-lowering efficacy (50-60%), PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors also reduce Lp(a) (lipoprotein[a]) levels by 25% to 30%, suggesting a 2:1 response ratio. We aimed to characterize the relationship between LDL -C and Lp(a) lowering by evolocumab, a PCSK 9 inhibitor, in a large clinical trial population and to determine the prevalence of concordant/discordant LDL -C and Lp(a) responses to PCSK 9 inhibition. Methods and Results Data were analyzed from 4 randomized, 12-week, multicenter, phase 3 evolocumab trials. Patients with familial hypercholesterolemia, nonfamilial hypercholesterolemia, or statin intolerance participated in the trials. The main measure was the degree of concordance or discordance of LDL -C and Lp(a) in response to PCSK 9 inhibition; concordant response was defined as LDL -C reduction >35% and Lp(a) reduction >10%. The study cohort comprised 895 patients (438 female; median age: 59.0 years [interquartile range: 51-66 years]). Baseline mean level of LDL -C was 133.6 mg/dL (SE: 1.7) and median Lp(a) level was 46.4 mg/dL (interquartile range: 18.4-82.4 mg/dL). A discordant response was observed in 165 (19.7%) patients. With these cutoffs, the prevalence of discordance was higher when considering baseline Lp(a) concentrations >30 mg/dL (26.5%) or >50 mg/dL (28.6%). Conclusions We demonstrate high prevalence of discordance in LDL -C and Lp(a) reduction in response to evolocumab, particularly when considering higher baseline Lp(a) concentrations, indicating the possibility of alternative pathways beyond LDLR ( LDL receptor)-mediated clearance involved in Lp(a) reduction by evolocumab. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 01763827, NCT 01763866, NCT 01763905, NCT 01763918.

Persistent Safety and Efficacy of Evolocumab in Patients with Statin Intolerance: a Subset Analysis of the OSLER Open-Label Extension Studies.

PURPOSE: Evolocumab reduced low-density lipoprotein cholesterol (LDL-C) in 12-week trials in statin-intolerant patients (GAUSS-1 and GAUSS-2); however, the persistence of efficacy during longer-term treatment is unknown. This subset analysis of the open-label extension studies (OSLER-1 and OSLER-2) aimed to evaluate the safety and efficacy of evolocumab up to 2 years in statin-intolerant patients. METHODS: Patients who completed GAUSS-1 and GAUSS-2 were enrolled in the OSLER studies and rerandomized 2:1 to evolocumab (140 mg biweekly or 420 mg monthly) plus standard of care (SOC) or SOC during year 1, and thereafter, evolocumab plus SOC. RESULTS: A total of 382 statin-intolerant patients who completed the GAUSS-1 and GAUSS-2 parent studies were enrolled and rerandomized into the OSLER studies. After year 1, 246 (98%) patients randomized to evolocumab plus SOC and 124 (95%) on SOC during year 1 remained in the OSLER studies; after year 2, 364 (95%) remained on study. Mean parent study baseline LDL-C concentration was 4.97-5.02 mmol/L (192-194 mg/dL). The median percentage reduction from baseline in LDL-C was 13% for SOC and 57% for evolocumab plus SOC at year 1, and 59% for evolocumab plus SOC at year 2. The patient incidence of muscle-related adverse events during year 1 in the SOC and evolocumab plus SOC groups was 16% and 14%, respectively, and 11% for evolocumab plus SOC at year 2. No patient discontinued the study due to adverse events. CONCLUSION: Evolocumab plus SOC was persistently safe, tolerable, and efficacious for up to 2 years in statin-intolerant patients.

A Systematic Review of Function-Based Replacement Behavior Interventions for Students With and At Risk for Emotional and Behavioral Disorders.

Students with emotional and behavioral disorders and students considered at risk often have social deficits. Although social skills interventions are often provided to this student population, there are some concerns regarding how these interventions are conceived and provided. One possible way to improve the effectiveness of social skills interventions is to use functional behavior assessment data to tailor the interventions to a student's individual needs and the contexts in which social skills deficits and problem behaviors occur. This approach is commonly referred to as replacement behavior training. In this study, the literature on function-based replacement behavior interventions is systematically reviewed. In addition, studies are evaluated according to the What Works Clearinghouse design and evidence standards for single-case research. Although this research base does not meet the What Works Clearinghouse replication standards, function-based replacement behavior interventions appear to be a promising practice for addressing problem behaviors. Implications for practice, areas for future research, and study limitations are discussed.

Validity and Reliability of GraphClick and DataThief III for Data Extraction.

Researchers frequently rely on meta-analyses of prior research studies to efficiently evaluate a broad spectrum of results on a particular topic. In the realm of single-subject experimental designs (SSEDs), meta-analyses have a particular cachet: retaining the rigor of single-subject designs with the added robustness of replication to more fully determine the strength of a given approach or intervention. Until recently, researchers wishing to undertake meta-analytic research themselves have had limited options for synthesizing the intervention effects of a collection of studies. Researchers consistently use two software programs, DataThief III and GraphClick, to conduct meta-analytic work using SSEDs. The purpose of this study was to evaluate and compare the validity and reliability of the results yielded by each of these programs when evaluating the results of multiple research studies on the Good Behavior Game, a classroom-based intervention that has been in practice since 1969. Study findings suggest that both GraphClick and DataThief III provide valid methods of data extraction. In addition, both programs allow for reliable extraction of data between raters and between software programs. Limitations and directions for future research are explored.

Behavior problems and children's academic achievement: A test of growth-curve models with gender and racial differences.

The aim of this study was to examine the longitudinal association between externalizing and internalizing behavior and children's academic achievement, particularly in terms of whether these variables varied as a function of gender and race. Data pertaining to externalizing and internalizing behavior, academic achievement, gender, and race from three waves of the Child Development Supplement of the Panel Study of Income Dynamics (N = 2028) were used. Results indicate that behavior problems had a negative relationship with academic performance and some of these associations endured over time. Externalizing behavior impacted reading scores more negatively for females compared to males at baseline, but the impact of externalizing behavior on long-term reading outcomes did not vary by gender. Externalizing behavior impacted reading scores more negatively for Black children than White children at multiple points in time. Differences between males, females, Black, and White children concerning behavior and achievement are explained. Implications, limitations, and ideas for future research are also presented.

Effects of the Good Behavior Game on classwide off-task behavior in a high school basic algebra resource classroom.

This study investigated the effects of the Good Behavior Game (GBG) on classwide off-task behavior in two ninth-grade basic algebra resource classes. Ten students with a variety of disabilities, in two classrooms, and their special education resource teacher participated in this study. A reversal design was employed, in which the special education teacher implemented GBG compared to typical practice-algebra readiness instruction. Results showed that classwide off-task behavior decreased in the GBG conditions compared to the baseline and reversal conditions. Fidelity measures indicated that the teacher implemented GBG with fidelity. Students and the teacher rated GBG favorably. Overall findings support the use of GBG for reducing classwide off-task behavior. Implications for practice and future research directions are presented.