Differences In Discontinuation Rates Research Articles

Treatment Discontinuation in Patients with Psoriasis Treated with Biologics: A Retrospective Analysis of German Health Claims Data.

Plaque psoriasis is a common, often debilitating, chronic autoimmune inflammatory skin disease. Moderate-to-severe forms of psoriasis can be treated with biologics such as anti-interleukin and anti-tumor necrosis factor antibodies. We aimed to investigate treatment discontinuation among patients with psoriasis who initiated biologic treatment. We conducted a retrospective, non-interventional cohort study based on anonymized claims data from the German statutory health insurance which covered the years from 2016 to 2021. We included adult patients with psoriasis who initiated biologic treatment in drug-specific cohorts. Over a 365-day follow-up period, we assessed the frequencies and the time until treatment discontinuation for different biologics. Differences in discontinuation rates were compared using a multivariate Cox proportional hazards model. A total of 2565 patients with psoriasis who initiated treatment with secukinumab (n = 612), adalimumab (n = 454), guselkumab (n = 354), ixekizumab (n = 259), ustekinumab (n = 241), tildrakizumab (n = 205), brodalumab (n = 166), risankizumab (n = 145), etanercept (n = 91), certolizumab (n = 29), and infliximab (n = 9) were included. A total of 1290 patients (50.29%) discontinued treatment during the follow-up period, ranging from 30.34% (risankizumab) to 69.23% (etanercept). Median time until discontinuation of treatment ranged from 102days (etanercept) to 208days (risankizumab). Once the biologic treatment was discontinued, 45.05% of patients restarted the treatment with the same agent, 23.10% of patients switched to another biologic, and 31.86% received no further biologic agent. Compared to patients treated with risankizumab, the treatment discontinuation rate was significantly higher (p < 0.05) in patients treated with the other biologics except ustekinumab (p = 0.12). Further research should explore reasons leading to treatment discontinuation in order to support treatment choices for patients with moderate-to-severe psoriasis.

Efficacy and tolerability of dolutegravir/lamivudine versusdolutegravir/rilpivirine in switching from a three-drug regimen based on nonnucleoside reverse transcriptase inhibitors: A retrospective cohort study.

Real-life comparisons of dolutegravir/rilpivirine (DTG/RPV) and DTG/lamivudine (3TC) regimens in people living with human immunodeficiency virus (PLWHIV) who switched from a standard three-drug regimen based on nonnucleoside reverse transcriptase inhibitors (NNRTIs) are missing.This study aimed to compare DTG/3TC and DTG/RPV in virologically suppressed patients (HIV-RNA < 50 copies/mL) coming from any NNRTI-based regimen in terms of discontinuation due to virologic failure (VF) discontinuation rates due to all causes, and adverse events. As a secondary outcome, we evaluated the difference in creatinine, total cholesterol, CD4, and triglycerides from baseline to weeks 48 after the switch.Of the 415 PLWHs included in the study, 278 (66.9%) switched to DTG/3TC, and 137 (33.1%) switched to DTG/RPV. Overall, 48 PLWHs (11.6%) discontinued the treatment:38 with DTG/3TC and 10 with DTG/RPV with similar discontinuation rates: 5.01 × 100 py (95% confidence interval [CI] 3.64-6.94)and 4.66 × 100 py (95% CI 2.51-8.67), respectively. The most common reason for discontinuation was toxicity (26 patients, 22/278 [7.9%]in the DTG/3TC group and 4/137 [2.9%]in the DTG/RPV group), mainly neurologic toxicity (never above grade 2). We found no differences in discontinuation rates due to treatment adverse events. Two study participants experienced virological failure in the DTG/3TC arm. We observed no significant difference in CD4 cell counts, lipid parameters, or renal function between the two groups at 48 weeks.This study demonstrated that, in clinical practice, a two-drug regimen with DTG/3TC or DTG/RPV is characterized by a low discontinuation rate and VF in virologically suppressed PLWHs switched from an NNRTI-based three antiretroviral drugs regimen.

Early Discontinuation of Apremilast in Patients with Psoriasis and Gastrointestinal Comorbidities: Rates and Associated Risk Factors.

Apremilast, the first oral targeted treatment for moderate to severe psoriasis, is associated with diarrhea, nausea, and vomiting, which have contributed to treatment discontinuation. This study describes early apremilast discontinuation rates in patients with psoriasis, including a cohort with gastrointestinal (GI) comorbidities, and associated characteristics. This retrospective cohort study used IBM® (now Merative™) MarketScan® commercial and Medicare claims data to identify adults with psoriasis who filled their first apremilast prescription between September1, 2014 and March31, 2020. Discontinuation was defined as a gap of > 30days after exhausting the days' supply of a prescription fill. The GI comorbidity cohort included patients with ≥ 1 claim for inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), or other GI comorbidity during the study period. Discontinuation rates were high, regardless of previous biologic treatment or GI comorbidities. Among all patients, 25.5% discontinued within 60days and 56.4% discontinued within 180days. Patients who discontinued were more likely to be younger, female, and have IBD, Crohn's disease, or a mental health disorder. At 180days, patients who used biologics previously were more likely to discontinue than biologic-naive patients. Patients with IBD discontinued at a greater rate than those without IBD at 60days (30.3% vs 24.4%; P = 0.018) and 180days (63.6% vs 57.2%; P = 0.026). Differences in discontinuation rates were minimal between GI comorbidity groups; patients with IBS discontinued at numerically higher rates than those without IBS. High rates of early discontinuation were observed for patients with and without GI comorbidities. Early discontinuation, whether attributable to poor tolerability or effectiveness, suggests the need for additional oral treatment options.

SWOG 1815: A phase III randomized trial of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in newly diagnosed, advanced biliary tract cancers.

LBA490 Background: Biliary tract cancers (BTCs) are a heterogeneous group of malignancies with a dismal prognosis. Gemcitabine-based regimens are the standard of care in advanced disease, but median overall survival (OS) is roughly 12 months. The addition of albumin-bound paclitaxel to gemcitabine and cisplatin (GAP) demonstrated promising efficacy in a 60 patient, single-arm phase II study (Shroff et al, JAMA Oncol 2019), with observed median OS of 19.2 months. Methods: SWOG 1815 is a randomized, open-label, phase III trial comparing GAP to gemcitabine/cisplatin (GC). The study included newly diagnosed advanced BTC patients (pts), randomized 2:1 to GAP vs. GC. GAP included gemcitabine at 800 mg/m2, cisplatin at 25 mg/m2 and albumin-bound paclitaxel at 100 mg/m2 on days 1 and 8 of a 21-day cycle. GC included standard dosing of gemcitabine at 1000 mg/m2 and cisplatin at 25 mg/m2 on days 1 and 8 of a 21-day cycle. Pts were treated until progression. The primary endpoint was overall survival (OS) with a target hazard ratio of 0.7 with 90% power and a 1-sided alpha of 0.025; randomization was stratified by disease site (intrahepatic cholangiocarcinoma [CCA] vs gallbladder adenocarcinoma [GBC] vs extrahepatic CCA), disease stage (locally advanced vs metastatic), and Zubrod PS 0 vs 1. Results: Of 441 eligible pts randomized, 55% were female. 67% of patients had intrahepatic CCA, 16% had GBC and 17% had extrahepatic CCA. Most pts had metastases (73%). Median OS with GAP vs. GC was 14 vs. 12.7 mo respectively (HR 0.93, 95% CI 0.74-1.19, p=0.58), ORR (confirmed and unconfirmed) 34% vs 25% (p=0.11) and median PFS 8.2 vs 6.4 mo (HR 0.92, 95% CI 0.72-1.16, p=0.47), respectively. Grade 3 and 4 treatment related adverse events (TRAEs) in ≥10% of pts for GAP and GC were anemia, neutropenia, and thrombocytopenia. GAP had more ≥ grade 3 hematologic AEs compared to the GC arm (60% vs. 45%, p=0.003). Discontinuation due to toxicity was at 24% vs 19% (p=0.26) with GAP vs GC. In exploratory subset analyses, GAP vs GC improved OS in pts with locally advanced disease (medians 19.2 vs 13.7 mo; HR 0.67, 95% CI 0.42-1.06, p=0.09) and in GBC pts (medians 17.0 vs 9.3 mo; HR 0.74, 95% CI 0.41-1.35, p=0.33). ORR for GAP vs GC in GBC was 50% vs 24% (p=0.09) and for locally advanced disease 28 vs 21% p=0.74. Conclusions: SWOG 1815 did not result in a statistically significant improvement in median OS with GAP vs. GC. The GAP regimen had higher rates of TRAEs without a statistically significant difference in discontinuation rates. Pts with locally advanced disease and GBC may benefit from the use of GAP. Further analyses are ongoing to understand potential benefit of GAP in subsets of BTC pts. Funding: NIH/National Cancer Institute grants CA180888, CA180819, CA180820, CA180821, and CA180868; and in part by Celgene Corporation, Summit, NJ (subsidiary of Bristol Myer Squibb). Clinical trial information: NCT#03768414 .

Transcranial direct current stimulation effects in late life depression: A meta-analysis of individual participant data

• tDCS showed a modest but non-null effect in improving depressive symptoms in late life depression • Acceptability was high for tDCS treatment in late life depression • tDCS is a potential new treatment for late life depression • Large scale, randomised controlled trials of tDCS treatment in late life depression are required Late life depression (LLD) refers to major depressive disorder (MDD) in adults over 65 years. LLD is associated with high morbidity and poor treatment outcomes. Transcranial direct current stimulation (tDCS) is a novel treatment for MDD. Efficacy in LLD though is unclear. Our aim was to investigate tDCS efficacy by pooling randomised controlled trials (RCT) in an individual participant data meta-analysis. Databases were searched for sham controlled RCTs of tDCS in MDD and bipolar depression. Individual participant data (IPD) were requested. Primary outcome was change in depressive symptoms. Bayesian multilevel modelling meta-analysis was conducted with individual participants nested within studies. 6 RCTs were eligible, consisting of 43 participants (22 women), mean age 69.2 years. Active anodal tDCS over left dorsolateral prefrontal cortex (n=19) was associated with an improvement in depressive severity, effect size 0.14 (95% credible interval [-0.44;0.15]) as compared to sham tDCS, which was not statistically significant. There was an 82% probability that tDCS treatment has a modest but non-null effect in improving depressive symptoms. Acceptability was high with no significant differences in discontinuation rates between active and sham groups. The total sample size was small, limiting power. In LLD, tDCS demonstrates a modest but non-null effect in improving depressive symptoms. Acceptability was high as measured by discontinuation rates. tDCS is a potential novel treatment option in LLD, though large scale RCTs in LLD are required to investigate this important clinical application.

Attrition and Withdrawal Amongst Patients with Multiple Myeloma Participating in Randomized Clinical Trials: A Systematic Review

Introduction: In clinical trials, and in the real-world, patients with multiple myeloma (MM) discontinue treatment for a variety of reasons including death, disease progression, and toxicity of treatments. Patients may also discontinue trial treatment due to the other reasons such as a physician withdrawing the patient from the trial, or patient deciding to withdraw. The proportion of patients discontinuing treatment for each of these reasons has not previously been reported for MM randomized controlled trials (RCTs). Furthermore, a large number of patients withdrawing from one arm of a trial may raise concern for informative censoring and biased data. To date, there is no prior study evaluating MM RCTs analyzing trial discontinuation and attrition. Due to this, we aimed to assess reasons for discontinuing treatment amongst participants in trials, imbalances in attrition between trial arms, and the practice of reporting this data through a systematic review of all MM RCTs published between 2015-2020. Methods: Three databases were searched (MEDLINE/PubMed, Embase, and Cochrane Registry of Controlled Trials) for all RCTs in MM from 2015 to 2020. Studies reported as abstracts (without full manuscript available for review), or those that assessed purely supportive care strategies were excluded. We collected documentation of patient discontinuation and reasons for discontinuation in intervention arms, control arms, and in total. As discontinuation due to progression, toxicity and death is expected, we aimed to quantify and assess for rates of discontinuation due to other reasons beside these, such as patient withdrawal or physician decision to withdraw patient. Trials in which the absolute difference in discontinuation rate for these "other” reasons was greater than 5% between the intervention and control arms were thus determined to be outliers. Trials were also assessed for concordance to recommendations outlined by CONSORT guidelines for RCTs. Results: A total 47 RCTs were analyzed that met our inclusion criteria. Table 1 lists characteristics of included studies. Primary endpoint was progression free survival in 33 (70.2%) of these studies and overall survival in 4 (8.5%) studies. In these RCTs, a total of 21,985 patients were randomized to treatment. A total of 10,572 (48.1%) patients had discontinued the RCT by time of primary endpoint ascertainment. The causes of discontinuation in decreasing order of frequency included disease progression (n=4,893; average rate per study (ARPS)=26.4%); toxicity (n=2,691; ARPS=11.7%); patient or physician withdrawal in absence of toxicity/progression/death (n=1,136; ARPS=7.3%) and death (n=527; ARPS=2.6%). A total of 21,540 (98.4%) patients were included in primary endpoint analyses with 45 of 47 trials citing the use of intention to treat analysis. In regard to withdrawal due to reasons other than toxicity, progression or death, a total of 13 (27.7%) of the RCTs were outliers as defined in methods. Amongst these 13 RCTs, attrition was higher in control arm in 10 trials, and higher in intervention arm in 3 trials. Outliers were more commonly found in trials that met their primary endpoint compared to those that did not (10 vs 3 trials, respectively). In the 10 trials meeting their primary endpoint, attrition rate was higher in 8 trials in control arm, and 2 in intervention arm. Although a minority [19 (40.4%)] of trials followed the full recommended guidelines for RCT reporting, the majority 45 (95.7%) of the trials included a CONSORT diagram. Conclusion: Our analysis demonstrates that although disease progression is the most common reason for discontinuation of treatment in patients with MM on RCT's, over 10% of patients discontinue treatment due to toxicity prior to disease progression or death. Furthermore, 27.7% of trials showed substantial imbalances between the control and intervention arms in the number of patients withdrawn for reasons other than progression, toxicity, or death. This raises concern for informative censoring and bias in results and emphasizes the importance of detailed characterization of reasons for withdrawal in MM RCTs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Systematic Review and Network Meta-Analysis of Frontline Targeted Therapy in Chronic Lymphocytic Leukemia Shows Comparable Efficacy but Distinct Toxicity

Introduction: Targeted therapies inhibiting Bruton Tyrosine Kinase (BTK) (ibrutinib, acalabrutinib, and zanubrutinib) and Bcl-2 (venetoclax) have improved survival when given first line (1L) to patients with chronic lymphocytic leukemia (CLL). However, no head-to-head trials of 1L targeted therapies exist to guide clinicians on selection of optimal therapy for their patients. We performed a systematic review and network meta-analysis (NMA) to understand the relative efficacy and toxicity of 1L CLL regimens, including newer regimens of ibrutinib/venetoclax (IV) and zanubrutinib not previously assessed in NMA. Methods: We performed a systematic literature search from 2009-2022 for randomized trials of treatment-naïve adults with CLL who were deemed unfit due to age or comorbidities. Endpoints were progression free survival (PFS) at 24 and 48 months, overall response rate (ORR), percentage of patients with grade 3 or higher adverse event (AE), discontinuation due to AE, and rates of AEs of clinical interest. We used a Bayesian hierarchical random-effects models for mixed multiple treatment comparisons to estimate the relative treatment effect of each intervention compared with a common comparator. Results: Our search yielded 12 clinical trials including 15 unique 1L regimens (Fig 1). PFS and ORR of common comparators were consistent across trials except 24-month PFS for chlorambucil/obinutuzumab (CO) which ranged from 31%-64% likely due to variable duration of chlorambucil and variable inclusion of patients with del(17p). Compared to CO, only acalabrutinib/obinutuzumab (AO) showed statistically significant improvement in 24-month PFS with hazard ratio (HR) 0.13 and 95% confidence interval (CI) 0.017-0.97 (Fig 1). In general, targeted therapies trended towards longer PFS compared to chemotherapy-based regimens, though there is insufficient power to demonstrate statistical significance. We found no statistically significant differences in 24-month PFS, 48-month PFS, or ORR between targeted therapies. Regarding toxicity, no statistically significant differences in proportion of patients experiencing grade 3 or higher AE were found across regimens, though single agent acalabrutinib and zanubrutinib trended toward less toxicity than CO with risk ratio (RR) 0.71, 95% CI 0.45-1.1 and RR 0.66, 95% CI 0.30-1.5, respectively. No statistically significant differences in discontinuation rates were found, though IV trended towards higher discontinuation rate than CO (RR 6.1, 95% CI 0.71-74). There were no statistically significant differences in rates of atrial fibrillation, infection, anemia, or neutropenia. However, grade 3 or higher thrombocytopenia was significantly lower with zanubrutinib than CO (RR 0.069, 95% CI 0.0048-0.92). Conclusions: Using NMA, we demonstrate that PFS is improved from the pre-targeted therapy standard of care by AO, but, amongst targeted therapies, no significant differences in efficacy were identified. Our results differ from previously published NMAs which have shown superior PFS with AO compared to other targeted therapies, likely due to inclusion of additional trials of common comparators (Foa et al, CLL5) as well as newer trials assessing IV and zanubrutinib (GLOW, SEQUOIA cohort 1) in this analysis. All four trials add heterogeneity to common comparator outcomes, resulting in widened confidence intervals and loss of statistical significance. This is the first assessment, to our knowledge, of relative rates of specific AEs, and we found that zanubrutinib showed lower rates of thrombocytopenia than pre-targeted therapy standard of care. Establishing the absence of significant difference in efficacy of frontline targeted therapies in CLL allows the clinician and patient to select therapy based on other factors, namely planned duration, toxicity profile, medication interactions, and cost. Figure 1. 24-month PFS Network and Forest Plot 1Chl = Chlorambucil; Acal = Acalabrutinib; Acal/Obin = Acalabrutinib/Obinutuzumab; BR = Bendamustine/Rituximab; Chl/Ofa = Chlorambucil/Ofatumumab; Chl/Ritux = Chlorambucil/Rituximab; Chl/Ritux + Mtn = Chlorambucil/Rituximab + maintenance Rituximab; Flu = Fludarabine; Ibr = Ibrutinib; Ibr/Obin = Ibrutinib/Obinutuzumab; Ibr/Ritux = Ibrutinib/Rituximab; Ibr/Ven = Ibrutinib/Venetoclax; Ven/Obin = Venetoclax/Obinutuzumab; Zan = Zanubrutinib Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Health care resource utilization and costs in patients receiving long-acting injectable vs oral antipsychotics: A comparative analysis from the Disease Recovery Evaluation and Modification (DREaM) study.

BACKGROUND: Given relapse frequency early in the course of schizophrenia, recently diagnosed patients may benefit from longacting injectable antipsychotics, which are associated with reduced risk of relapse and hospitalization compared with oral antipsychotics (OAPs). OBJECTIVE: To compare health care resource utilization (HCRU) and costs in patients with recent-onset schizophrenia treated with continuous paliperidone palmitate (PP) or continuous OAP or who switched from OAP to PP. METHODS: In this analysis, we combined the 2 randomized phases of the prospective, open-label Disease Recovery Evaluation and Modification (DREaM) clinical study using the principal stratification method to generate 3 treatment strategies: continuous PP for 18 months (PP-PP), continuous OAP for 18 months (OAP-OAP), and initial OAP switched to PP after 9 months (OAP-PP). HCRU metrics included psychiatric hospitalizations, psychiatric and nonpsychiatric emergency department visits, and ambulatory visits. Costs were analyzed using generalized linear models with inverse-probability weighting based on time-varying probabilities of exposure. Robust SEs were estimated using individual-level clustered bootstrapping. Subgroup analyses were performed by region and prior antipsychotic use (< 6 vs ≥ 6 months). RESULTS: A total of 181 patients were included in the PP-PP (n = 61), OAP-OAP (n = 61), and OAP-PP (n = 59) groups. The majority of patients (73%) were enrolled at study sites in the United States, and 48% had received an antipsychotic for less than 6 months prior to study entry. Baseline characteristics were well balanced, and no significant differences in discontinuation rates were observed across treatment strategies. Compared with OAP-OAP, significantly lower cumulative HCRU and costs were apparent before 9 months in the PP-PP group and after 9 months in the OAP-PP group. The cumulative 18-month effects of PP-PP and OAP-PP vs OAP-OAP on the number of psychiatric hospitalizations were ‒0.28 (95% CI = ‒0.51 to ‒0.08) and ‒0.27 (95% CI = ‒0.50 to 0.04), respectively, and those on cumulative mean per-patient total health care costs (in 2020 USD) were -$2,867 (95% CI = ‒$5,133 to ‒$750) and ‒$2,789 (95% CI = ‒$5,155 to ‒$701), respectively. Subgroup analyses indicated a greater reduction in psychiatric hospitalizations and costs with PP-PP or OAP-PP relative to OAP-OAP in patients with less than 6 vs 6 or more months of prior antipsychotic therapy. CONCLUSIONS: Continuous early use of PP in adults with recentonset schizophrenia significantly reduced psychiatric hospitalizations and associated estimated costs compared with OAP; these effects were particularly notable for patients with a shorter duration of prior antipsychotic use. As this was a post hoc analysis of a study that was not powered for HCRU assessments, future studies calibrating these effects to larger real-world populations will be useful. DISCLOSURES: Dr Basu reports consulting fees through Salutis Consulting LLC related to this work. Ms Benson, Dr Turkoz, Ms Patel, Dr Baker, and Dr Brown are employees of Janssen Scientific Affairs, LLC, and stockholders of Johnson & Johnson, Inc. This research was funded by Janssen Scientific Affairs, LLC. The sponsor was involved in the study design; collection, analysis, and interpretation of data; development and review of the manuscript; and decision to submit the manuscript for publication.

Statin discontinuation in persons with and without Alzheimer’s disease

BackgroundAlthough statin use is reported to decrease after dementia diagnosis, time to statin discontinuation and factors associated with discontinuation have not been studied in persons with Alzheimer’s disease (AD). We compared the risk of discontinuation and factors associated with discontinuation, including secondary and primary prevention indication, in statin users with and without AD.MethodsThe register-based Medication Use and Alzheimer’s Disease (MEDALZ) cohort includes community dwellers with a clinically verified AD diagnosed during 2005–2011 in Finland. On the AD diagnosis date (index date), each person with AD was matched with a comparison person without AD. We included 25,137 people with AD and 22,692 without AD who used statin on the index date or initiated within 90 days after. Cox regression models restricted to 4-year follow-up were conducted.ResultThe median time to statin discontinuation was 1.46 years in people with AD and 1.36 years in people without AD. People with AD were more likely to discontinue than people without AD (adjusted HR (aHR) 1.20 (95% CI 1.18–1.24)). This was observed for both primary (aHR 1.11 (1.06–1.16)) and secondary prevention (aHR 1.30 (1.25–1.35)) purpose. Factors associated with discontinuation included higher age and female gender, whereas concomitant cardiovascular drug use and previous statin use were associated with decreased risk.ConclusionThe absolute difference in discontinuation rates was small, and the same factors were associated with statin discontinuation in people with and without AD. The findings suggest that cognitive decline plays a minor role on statin discontinuation.

Objective medication adherence and persistence in people with multiple sclerosis: a systematic review, meta-analysis, and meta-regression.

BACKGROUND: Medication adherence is critical for the realization of pharmacotherapy benefits and reduced healthcare expenditure. Studies have shown up to 60% of people with Multiple sclerosis (MS) experience suboptimal medication adherence, which is associated with poorer health outcomes and subsequent discontinuation. The current systematic review reported on objectively measured adherence and discontinuation rates for self-administered oral and injectable disease-modifying therapies (DMTs). OBJECTIVES: To identify whether, in people with MS, the introduction of oral DMTs has improved medication adherence when compared with injectable DMTs. The secondary aim was to report synthesized objectively measured medication adherence and persistence rates for both oral and injectable DMTs in MS across varying study durations. METHODS: Literature searches were conducted through PubMed, Web of Science, Scopus, and PsycINFO. Inclusion criteria were limited to English, peer-reviewed, objective, self-administered DMT articles, published between July 1993 to December 2019. Publications reporting combined intravenous and self-administered DMT data, or that did not account for DMT switching in discontinuation rates, were excluded. Data were synthesized into observation lengths ranging from less than 8 months to greater than 36 months. Meta-analysis and meta-regression were undertaken on both oral and injectable 12-month adherence and discontinuation data. RESULTS: In total, 61 articles were included; 46 articles examined adherence and 26 examined discontinuation. Twelve-month adherence ranged between 53.0% to 89.2% for oral (N = 7) and 47.0% to 77.4% for injectable DMTs (N = 7). Results from the meta-analysis and meta-regression show significantly higher pooled mean medication possession ratio (MPR) adherence for oral DMTs (91.0%) when compared to injectable DMTs (77.0%) over 12 months (β = -0.146; 95% CI: -0.263 to -0.029). Results indicate major asymmetry across studies (LFK index: -5.18), proposing the presence of significant publication bias. Mean discontinuation over 12 months was between 10.5% to 33.3% for oral (N = 7) and 15.2% to 50.8% for injectable DMTs (N = 10), with meta-analysis results indicating the presence of significant heterogeneity (I2 Injectable: 99.5%; I2 Oral: 93.1%) between studies included in each subgroup. However, no appreciable difference in mean discontinuation rates across groups (Injectable: 27%; 95% Cl: 19.0%-34.0%; Oral: 24%; 95% CI: 17.0%-31.0%) was found. CONCLUSIONS: Medication adherence for oral DMTs suggests a significant improvement compared to adherence for injectable DMTs. No significant difference in discontinuation rates between oral and injectable DMTs was found. Oral DMT adherence and persistence studies are limited, given their relatively recent introduction. Suboptimal medication adherence and discontinuation issues remain present for both oral and injectable DMTs. Future studies would benefit from improved consistency in methodology, such as comparable adherence and persistence definitions. DISCLOSURES: The authors did not receive any funding for this study. Mardan and Hussain have nothing to disclose. Grech reports grants from Merck Pharmaceutical, outside the submitted work. Allan reports grants received from Merck Pharmaceutical outside the submitted work. Allan holds advisory board and consulting positions with Merck and advisory board positions for Bristol Myers Squibb and Novartis, for which Monash Institute of Neurological Diseases receives consulting fees.

Lurasidone, olanzapine, and quetiapine extended‐release for bipolar depression: A systematic review and network meta‐analysis of phase 3 trials in Japan

AimThis systematic review and random‐effect model, network meta‐analysis of the phase 3 trials in Japan assessed the efficacy and safety profile of lurasidone compared with olanzapine and quetiapine extended‐release (QUE‐XR) for the treatment of bipolar depression.MethodsThe study included double‐blind, randomized, placebo‐controlled, phase 3 trials in Japan that included patients with bipolar depression. Outcomes included response rate (primary), remission rate (secondary), improvement of Montgomery‐Åsberg Depression Rating Scale (MADRS) total score, discontinuation rates, and incidence of individual adverse events.ResultsThree studies were included (n = 1223). Lurasidone and olanzapine but not QUE‐XR were superior to placebo in response rate [risk ratio (95% credible interval): lurasidone = 0.78 (0.66, 0.92); olanzapine = 0.84 (0.71, 0.99); QUE‐XR = 0.87 (0.73, 1.03)]. Lurasidone, olanzapine and QUE‐XR were superior to placebo in remission rate [lurasidone = 0.90 (0.83, 0.98); olanzapine = 0.87 (0.77, 0.99); QUE‐XR = 0.84 (0.73, 0.98)] and the improvement of MADRS total score. There were not differences in discontinuation rates between each antipsychotic and placebo. Compared with placebo, lurasidone was higher incidence of akathisia, and increased body weight and blood prolactin level; olanzapine was higher incidence of somnolence and ≥7% weight gain, and increased body weight, blood total cholesterol level, blood LDL cholesterol level, and blood triglyceride levels; QUE‐XR was higher incidence of extrapyramidal symptoms, akathisia, somnolence, dry mouth, constipation and ≥7% weight gain, and increased body weight, blood total cholesterol level, blood LDL cholesterol level, and blood triglyceride levels.ConclusionsOur results suggested although the efficacy of three SGAs was similar, there were the differences in the safety profile among the SGAs.

Adherence to study drug in a stroke prevention trial"?>

ObjectiveStandards for reporting and analyzing adherence to medical therapy have recently improved due to international consensus efforts. If applied to clinical trial research in patients with stroke, these improvements have the potential to identify when in the sequence of trial operations participants are at risk for non-adherence and opportunities to safeguard adherence. MethodsWe analyzed three phases of adherence according to the European Society for Patient Adherence, COMpliance, and Persistence (ESPACOMP) Medication Adherence Reporting Guideline (EMERGE) taxonomy in the Insulin Resistance Intervention after Stroke (IRIS) trial: initiation (did patient start drug), implementation (did patient take a drug holiday, defined as temporary cessation lasting ≥14 days), and persistence (did patient prematurely and permanently discontinue drug). IRIS was a randomized, placebo controlled, double-blind trial testing pioglitazone to prevent stroke or myocardial infarction in patients with a recent ischemic stroke or transient ischemic attack. Adherence was classified by self-report. Researchers used coaching algorithms to seek adherence recovery if participants went off drug. ResultsDuring 2005-2013, 3876 participants were enrolled from 179 sites in seven countries and followed for a mean of 4.8 years. Less than 1% of participants in each group did not initiate study drug. 20% of patients assigned to pioglitazone and 17% assigned to placebo took at least one drug holiday. 36% and 30%, respectively, discontinued the study drug prematurely with or without a prior holiday. The risk for stopping the study drug (temporarily or permanently) in the first year after randomization was twice the risk in each of the subsequent four years. This was true both for patients assigned to active therapy and placebo. More participants assigned to pioglitazone, compared to placebo, took a drug holiday or permanently stopped study drug, but the difference in rates of discontinuation was only evident in year one. In years two through five, rates of discontinuation were similar in the two treatment groups. The difference in rates during year one was the result of adverse effects related to the active study drug, pioglitazone. During the remainder of the trial, the attribution of discontinuations to adverse effects potentially related to pioglitazone was reduced but still higher in those assigned to active drug. Other reasons for discontinuation were similar between treatment groups and were largely unrelated to pharmacodynamic effects of the study drug. Rates of discontinuation varied widely among research sites. ConclusionPatients in a drug trial for stroke prevention are at greatest risk for premature drug discontinuation early after randomization. Reasons for discontinuation change over time. Variable discontinuation rates among sites suggests that adherence can be improved by using best practices from high-performing sites.

Improving the evaluation of COPD exacerbation treatment effects by accounting for early treatment discontinuations: a post-hoc analysis of randomized clinical trials

BackgroundChronic obstructive pulmonary disease (COPD) clinical trials aimed at evaluating treatment effects on exacerbations often suffer from early discontinuations of randomized treatment. Treatment discontinuations imply a loss of information and should ideally be considered in the statistical analysis of trial results, particularly if the discontinuations are related to the disease or treatment itself. Here, we explore this issue by investigating (1) whether there exists an association between the risks of exacerbation and treatment discontinuation in COPD clinical trials and (2) whether disregarding this association can cause bias in exacerbation treatment effect estimates. We focus on the hypothetical estimand, i.e. the treatment effect that would have been observed had all subjects completed the trial as planned.MethodsThe association between exacerbation and discontinuation risks was analysed by applying a joint frailty (random effect) model – allowing for the simultaneous analysis of multiple types of correlated events – to data from five Phase III-IV COPD clinical trials. Specifically, the impact of the association on exacerbation treatment effect estimates was assessed by comparing the treatment hazard ratios of the joint frailty model to the rate/hazard ratios of two related statistical models (the negative binomial and shared frailty models), which both assume discontinuations to be unrelated to the trial outcome. The models were also compared using simulated data.ResultsA statistically significant (p < 0.0001), positive association between exacerbation and discontinuation risks was found in all trials. Importantly, simulations confirmed that – with such an association – models disregarding the association risk producing biased results (> 5 percentage point difference in hazard/rate ratio). For some treatment comparisons in the clinical trials, the difference in treatment effect estimates between the joint frailty and the other models was as high as 10–15 percentage points. The difference was affected by the strength of the exacerbation-discontinuation association, the population heterogeneity in exacerbation risk, and the difference in discontinuation rates between treatment arms.ConclusionsWe have identified an association between the risks of exacerbation and treatment discontinuation in five COPD clinical trials. We recommend using the joint frailty model to account for this association when estimating exacerbation treatment effects, particularly when targeting the hypothetical estimand.

Efficacy and tolerability of paroxetine in adults with social anxiety disorder: A meta-analysis of randomized controlled trials.

The present study aimed to estimate the comprehensive efficacy and tolerability of paroxetine in adult patients with social anxiety disorder (SAD). We conducted a comprehensive literature review of the PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials databases for eligible randomized controlled trials (RCTs). The efficacy outcome was the mean change of different kinds of scale scores as well as response and remission rates. The secondary outcome was tolerability, defined as the discontinuation rate and the incidence of adverse events (AEs). Our meta-analysis included 13 RCTs. Mean changes in the Liebowitz Social Anxiety Scale (LSAS) total score, fear and avoidance subscale of LSAS scores were all significantly greater in patients with SAD that received paroxetine compared to those received placebo (total: MD = 13.46, 95%CI 10.59-16.32, P < .00001; fear: MD = 6.76, 95%CI 4.89-8.62, P < .00001; avoidance: MD = 6.54, 95%CI 4.63-8.45, P < .00001). Response and remission rates were both significantly greater in patients with SAD that received paroxetine compared to those received placebo (response: OR = 3.02, 95%CI 2.30-3.97, P < .00001; remission: OR = 3.14, 95%CI 2.25-4.39, P < .00001). There was no significant difference in discontinuation rate due to any reason between two groups (OR = 1.06, 95%CI 0.81-1.39, P = .65). Discontinuation rate due to AEs was higher in paroxetine than placebo group (OR = 3.41, 95%CI 2.45-4.72, P < .00001) whereas the rate due to lack of efficacy was higher in placebo as compared with paroxetine group (OR = 0.14, 95%CI 0.09-0.22, P < .00001). The incidence of any AE was significantly increased in patients that received paroxetine (OR = 1.83, 95%CI 1.43-2.35, P < .00001). Paroxetine was an effective and well-tolerated treatment option for adult patients with SAD.

Cognitive Behavioral Treatments for Anxiety in Children With Autism Spectrum Disorder

Anxiety is common among youth with autism spectrum disorder (ASD), often interfering with adaptive functioning. Psychological therapies are commonly used to treat school-aged youth with ASD; their efficacy has not been established. To compare the relative efficacy of 2 cognitive behavioral therapy (CBT) programs and treatment as usual (TAU) to assess treatment outcomes on maladaptive and interfering anxiety in children with ASD. The secondary objectives were to assess treatment outcomes on positive response, ASD symptom severity, and anxiety-associated adaptive functioning. This randomized clinical trial began recruitment in April 2014 at 3 universities in US cities. A volunteer sample of children (7-13 years) with ASD and maladaptive and interfering anxiety was randomized to standard-of-practice CBT, CBT adapted for ASD, or TAU. Independent evaluators were blinded to groupings. Data were collected through January 2017 and analyzed from December 2018 to February 2019. The main features of standard-of-practice CBT were affect recognition, reappraisal, modeling/rehearsal, in vivo exposure tasks, and reinforcement. The CBT intervention adapted for ASD was similar but also addressed social communication and self-regulation challenges with perspective-taking training and behavior-analytic techniques. The primary outcome measure per a priori hypotheses was the Pediatric Anxiety Rating Scale. Secondary outcomes included treatment response on the Clinical Global Impressions-Improvement scale and checklist measures. Of 214 children initially enrolled, 167 were randomized, 145 completed treatment, and 22 discontinued participation. Those who were not randomized failed to meet eligibility criteria (eg, confirmed ASD). There was no significant difference in discontinuation rates across conditions. Randomized children had a mean (SD) age of 9.9 (1.8) years; 34 were female (20.5%). The CBT program adapted for ASD outperformed standard-of-practice CBT (mean [SD] Pediatric Anxiety Rating Scale score, 2.13 [0.91] [95% CI, 1.91-2.36] vs 2.43 [0.70] [95% CI, 2.25-2.62]; P = .04) and TAU (2.93 [0.59] [95% CI, 2.63-3.22]; P < .001). The CBT adapted for ASD also outperformed standard-of-practice CBT and TAU on parent-reported scales of internalizing symptoms (estimated group mean differences: adapted vs standard-of-practice CBT, -0.097 [95% CI, -0.172 to -0.023], P = .01; adapted CBT vs TAU, -0.126 [95% CI, -0.243 to -0.010]; P = .04), ASD-associated social-communication symptoms (estimated group mean difference: adapted vs standard-of-practice CBT, -0.115 [95% CI, -0223 to -0.007]; P = .04; adapted CBT vs TAU: -0.235 [95% CI,-0.406 to -0.065]; P = .01); and anxiety-associated social functioning (estimated group mean difference: adapted vs standard-of-practice CBT, -0.160 [95% CI, -0.307 to -0.013]; P = .04; adapted CBT vs TAU: -0.284 [95% CI, -0.515 to -0.053]; P = .02). Both CBT conditions achieved higher rates of positive treatment response than TAU (BIACA, 61 of 66 [92.4%]; Coping Cat, 47 of 58 [81.0%]; TAU, 2 of 18 [11.1%]; P < .001 for each comparison). In this study, CBT was efficacious for children with ASD and interfering anxiety, and an adapted CBT approach showed additional advantages. It is recommended that clinicians providing psychological treatments to school-aged children with ASD consider developing CBT expertise. ClinicalTrials.gov identifier: NCT02028247.

Real-World Evidence on Etanercept Biosimilar SB4 in Etanercept-Naïve or Switching Patients: A Systematic Review.

IntroductionIn 2016, SB4 (Benepali®) became the first etanercept (ETN) biosimilar to obtain marketing authorisation in Europe. Despite robust analytical and clinical comparisons, outstanding questions remain on SB4 use in routine practice.MethodsA systematic search for publications on real-world evidence of SB4 effectiveness, safety and drug survival was undertaken using search terms (SB4 OR Benepali OR biosimilar etanercept OR innovator etanercept) in the BIOSIS® Toxicology, BIOSIS Previews®, Embase® and MEDLINE® databases up to 17 January 2019.ResultsOf 959 articles identified, eight journal articles, two journal letters and 23 congress abstracts were selected on criteria of original real-world evidence with a clinical focus. As expected with real-world evidence, quality scoring showed that the evidence had high external validity but lower internal validity. A total of 13,552 patients were described across nine European countries and all approved SB4 indications: 2499 were ETN-naïve and 11,053 switched from reference ETN to SB4 (switchers). Switch acceptance rates (a combination of clinicians offering and patients accepting initiation on SB4) ranged between 51.6% and 99.0%; patient support programmes positively contributed to acceptance. Disease activity was generally similar pre- and post-switch (typically 3-month timeframe). Retention rates across studies were at least 75% (up to 12 months follow-up). No new safety signals were identified. Differences in discontinuation rates versus historic controls reported in some studies may have been influenced by differences in treatment practices, lack of clinician confidence and nocebo effects.ConclusionNearly 2500 ETN-naïve patients have been initiated on SB4 and outcomes are similar to those patients receiving reference ETN. Overall this systematic review of real-world evidence provides additional reassurance that SB4 is as effective and safe as reference ETN in both switched and naïve patients.FundingBiogen International GmbH.Electronic Supplementary MaterialThe online version of this article (10.1007/s40744-019-00169-4) contains supplementary material, which is available to authorized users.

Tolerability and discontinuation rates in teriflunomide-treated patients. A real-world clinical experience.

Objectives:To assess the real-world tolerability of teriflunomide in multiple sclerosis (MS) patients from a large Canadian MS Centre of Care to determine whether previously treated (PT) patients have different tolerability thresholds than treatment-naive (TN) patients, leading to differing discontinuation rates.Methods:This non-interventional, single-center, retrospective chart review examined all patients who were prescribed commercial teriflunomide between July 2014 and May 2015 at the MS Clinic in the Ottawa General Hospital and Research Institute, Ottawa, Canada.Results:A total of 119 patient charts were reviewed (29 TN and 90 PT). Overall, 19 (15.9%) patients discontinued teriflunomide after a mean treatment duration of 35 weeks. The most common reason for discontinuation was side effects in 8 patients (42%).Discontinuation due to intolerability alone occurred in 13 patients. The number of discontinuations was not sufficient to demonstrate a statistically significant difference between TN and PT patients (p=0.1).Conclusions:This retrospective chart review provides some evidence about the real-world tolerability of teriflunomide. Discontinuations were low overall and consistent with previously reported clinical trial data. There was no significant difference in discontinuation rates between patients in the TN and PT groups. We believe that teriflunomide is a safe and well-tolerated oral alternative to injectable therapies.

Real-life persistence and tolerability with dimethyl fumarate

BackgroundDimethyl fumarate (DMF) has been registered for the treatment of relapsing-remitting multiple sclerosis (RRMS). Differences in tolerability between multiple sclerosis clinics in patients treated with DMF has not been examined. AimWe examined real-world tolerability to DMF, and also compared adherence data between two MS clinics. MethodsAdverse events (AE), discontinuation rates, and causes of discontinuation were investigated. Results253 patients participated in this retrospective study. In the total cohort, 27.7% of the patients discontinued DMF. Higher rate of discontinuation was associated with higher number of previous disease modifying treatments (p < 0.001). Reasons for discontinuation were primarily flushing (15%) and gastrointestinal AEs (51%). Grade III lymphopenia was detected only in 6 cases (2.4%). We observed differences between the two clinics: discontinuation because of AEs was different (Odds ratio 6.13, 95% CI: 3.0–12.7, p < 0.001), the mean treatment duration also differed (305.3 ± 186.3 vs 140.5 ± 114.4 days, p < 0.001), and dissimilarities in adherence were mainly related to flushing, gastrointestinal AEs, and consideration of lymphopenia (p < 0.0001). Better adherence was associated with prospectively planned management of gastrointestinal AEs and flushing. ConclusionAdherence in real-life was similar to pivotal trials. Differences in discontinuation rates at two MS clinics underline importance of AE management.

First-line antiretroviral therapy with efavirenz plus tenofovir disiproxil fumarate/emtricitabine or rilpivirine plus tenofovir disiproxil fumarate/emtricitabine: a durability comparison.

The aim of this study was to compare the durabilities of efavirenz (EFV) and rilpivirine (RPV) in combination with tenofovir/emtricitabine (TDF/FTC) in first-line regimens. A multicentre prospective and observational study was carried out. We included all patients participating in the Italian Cohort Naive Antiretrovirals (ICONA) Foundation Study who started first-line combination antiretroviral therapy (cART) with TDF/FTC in combination with RPV or EFV, with a baseline viral load < 100 000 HIV-1 RNA copies/mL. Survival analyses using Kaplan-Meier (KM) curves and Cox regression with time-fixed covariates at baseline were employed. Overall, 1490 ART-naïve patients were included in the study, of whom 704 were initiating their first cART with EFV and 786 with RPV. Patients treated with EFV, compared with those on RPV, were older [median 36 (interquartile range (IQR) 30-43) years vs. 33 (IQR 27-39) years, respectively; P < 0.001], were more frequently at Centers for Disease Control and Prevention (CDC) stage C (3.1% vs. 1.4%, respectively; P = 0.024), and had a lower median baseline CD4 count [340 (IQR 257-421) cells/μL vs. 447 (IQR 347-580) cells/μL, respectively; P < 0.001] and a higher median viral load [4.38 (IQR 3.92-4.74) log10 copies/mL vs. 4.23 (IQR 3.81-4.59) log10 copies/mL, respectively], (P = 0.004). A total of 343 patients discontinued at least one drug of those included in the first cART regimen, more often EFV (26%) than RPV (13%), by 2 years (P < 0.0001). After adjustment, patients treated with EFV were more likely to discontinue at least one drug for any cause [relative hazard (RH) 4.09; 95% confidence interval (CI) 2.89-5.80], for toxicity (RH 2.23; 95% CI 1.05-4.73) for intolerance (RH 5.17; 95% CI 2.66-10.07) and for proactive switch (RH 10.96; 95% CI 3.17-37.87) than those starting RPV. In our nonrandomized comparison, RPV was better tolerated, less toxic and showed longer durability than EFV, without a significant difference in rates of discontinuation because of failures.

Long-Acting Injectable Antipsychotics for Schizophrenia: Sociodemographic Characteristics and Treatment Adherence.

Long-acting injectable (LAI) antipsychotic medications are employed universally for the treatment of schizophrenia. This study retrospectively assessed the variables that factor into an individual's adherence to LAIs. The data sample was obtained from the adult ambulatory services of a large general hospital mental health center located in Elizabeth, New Jersey. Reports were run in November 2015 to identify patients who had received at least 1 LAI between January 1, 2014, and October 14, 2015. In September 2016, an additional report was run to collect follow-up data. The sample included 120 women and 178 men, ranging in age from 18-81 years, who received at least 1 LAI during a 23-month period. A hazard analysis for single-decrement, nonrepeatable events was used to assess the risk of discontinuation of LAIs during the study period. Separate χ² analyses were conducted to assess differences in discontinuation rates for sociodemographic variables, program type variables, type of long-acting medication, and time effects. The cumulative continuation rate across the study period was 73%. Main effect differences were found in continuation rates for program type (χ²₂undefined= 10.252, P = .006), LAI type (χ²₅ = 23.365, P < .000), and prescribed frequency of LAI (χ²₂ = 7.622, P = .022). In addition, multiple time-dependent effect differences were found. No significant main effect results were found for LAI continuation rates and patient age (χ²₃ = 3.689, P = .297), sex (χ²₁ = 0.904, P = .342), race (χ²₃ = 5.785, P = .123), or enrollment in involuntary outpatient commitment (χ²₁ = 2.989, P = .084). The findings of the current research suggest that medication type, frequency of medication appointments, and program type may be key in increasing and maintaining LAI adherence.