Prior Randomized Controlled Trials Research Articles

Glucagon-like peptide-1 receptor agonist therapy effects on glycemic control and weight in a primary care clinic population.

Glucagon-like peptide-1 receptor agonist (GLP-1a) medications have been shown in randomized controlled trials (RCTs) to have consistent and impressive effectiveness in lowering hemoglobin A1c (HbA1c) and weight, but limited data exist on the efficacy of GLP-1a medications in clinical practice. We studied the association between GLP-1a therapy and changes in weight and HbA1c in a real-world patient population. In this retrospective cohort study of patients seen in a primary care clinic between 2012 and 2021, we examined the change in weight and HbA1c over 12 months in a cohort of patients with at least one prescription for a GLP-1a. Within this cohort, treatment was defined as having ≥2 GLP-1a prescriptions at a therapeutic dosage separated by ≥10 months. The cohort included 693 patients of whom 393 (57%) were treated with GLP-1a therapy. The treatment group had a mean change in body mass index (BMI) of -0.83 kg/m2 (±2.88) compared to -0.70 kg/m2 (±2.99) in the without GLP-1a group (p = 0.57). Treated patients had a mean change in HbA1c of -1.00% (±2.07) compared to -0.83% (±1.92) in the without GLP-1a group (p = 0.27). For treated and without GLP-1a patients, respectively, the proportion of patients with a decrease in BMI was 65 versus 64% (p = 0.86), and the proportion with a decrease in HbA1c was 73 versus 69% (p = 0.28). In clinical practice, GLP-1a therapy was associated with more modest reductions in weight and HbA1c than shown in prior RCTs. As GLP-1a use continues to expand throughout primary care, the real-world impact of this pharmacotherapy will require further evaluation.

A randomized controlled study of trauma focused cognitive behavioural therapy compared to enhanced treatment as usual with patients in child mental health care traumatized from family violence

PurposeThis study compared the effectiveness of trauma-focused cognitive behavioral therapy (TF-CBT) and enhanced treatment as usual (eTAU) in children and adolescents exposed to family violence and receiving mental health services. MethodsA total of 89 children, aged 5 to 17 years, with severe trauma symptoms participated with their non-offending caregiver in a randomized controlled trial (RCT) comparing TF-CBT and eTAU. Children were assigned a DSM-IV diagnosis at treatment start and after 6 months. Self-reported trauma symptoms and parental reports of children’s psychological well-being and their own psychological symptoms were obtained at treatment start and after 6 and 12 months. Intention-to-treat analyses were performed, and the reliable change index was calculated. ResultsReports from children, parents, and clinicians showed a statistically significant reduction in trauma and other mental health symptoms among children in both the TF-CBT and eTAU groups, with no statistically significant between-group differences. Trauma symptoms and other mental health symptoms decreased, with small to medium effects after both 6 and 12 months. Clinically significant change in core symptoms was however documented in less than half of the sample. Parents’ self-reported psychiatric and trauma symptoms showed small reductions in both groups, with no between-group differences. ConclusionsContrary to findings in prior RCTs, TF-CBT did not significantly outperform the control treatment (eTAU). The non-significant between-group findings and modest positive changes for individuals in both groups may be explained by the multi-traumatized study population, the treatment delivery, and/or the study design.

HTX-011 in Combination with Multimodal Analgesic Regimen Minimized Severe Pain and Opioid Use after Total Knee Arthroplasty in an Open-Label Study.

Total knee arthroplasty (TKA) can be associated with significant postoperative pain despite multimodal analgesic (MMA) protocols, and most patients require the use of opioids postoperatively. HTX-011 is a dual-acting local anesthetic containing bupivacaine and low-dose meloxicam in an extended-release polymer. In a prior randomized controlled trial (RCT), HTX-011 reduced pain and opioid use through 72 hours after TKA compared with bupivacaine hydrochloride. This open-label study (NCT03974932) evaluated the efficacy and safety of HTX-011 combined with an MMA regimen in patients undergoing TKA under spinal anesthesia. All patients received intraoperative HTX-011 (400 mg bupivacaine/12 mg meloxicam) in combination with an MMA regimen consisting of preoperative acetaminophen, celecoxib, and pregabalin and postoperative acetaminophen and celecoxib until discharge. Opioid rescue was allowed upon patient request for additional pain control. Pain scores, opioid consumption, discharge readiness, and adverse events were recorded. Fifty-one patients were treated. Compared with the prior RCT, HTX-011 with this MMA regimen further lowered pain scores and reduced opioid use. Mean patient-reported pain scores remained in the mild range, and 82% of patients or more did not experience severe pain at any individual time point through 72 hours after surgery. Mean total opioid consumption was low over 72 hours: 24.8 morphine milligram equivalents (1-2 tablets of oxycodone 10 mg/day). Approximately 60% of patients were ready for discharge by 12 hours, and 39% were discharged without an opioid prescription and did not call back for pain management. The treatment regimen was well tolerated, and no added risk was observed with the addition of MMA. HTX-011 with an MMA regimen reduced postoperative pain and opioid use following TKA.

PD10-03 HRQOL AFTER ROBOTIC-ASSISTED VERSUS OPEN RADICAL CYSTECTOMY: ANALYSIS OF A RCT

You have accessJournal of UrologyCME1 May 2022PD10-03 HRQOL AFTER ROBOTIC-ASSISTED VERSUS OPEN RADICAL CYSTECTOMY: ANALYSIS OF A RCT Matthew Clements, Benjamin Beech, Thomas Atkionson, Guido Dalbagni, Yuelin Li, Andrew Vickers, Harry Herr, S. Machele Donat, Jaspreet Sandhu, Daniel Sjoberg, Amy Tin, Jonathan Coleman, Bruce Rapkin, Vincent Laudone, and Bernard Bochner Matthew ClementsMatthew Clements More articles by this author , Benjamin BeechBenjamin Beech More articles by this author , Thomas AtkionsonThomas Atkionson More articles by this author , Guido DalbagniGuido Dalbagni More articles by this author , Yuelin LiYuelin Li More articles by this author , Andrew VickersAndrew Vickers More articles by this author , Harry HerrHarry Herr More articles by this author , S. Machele DonatS. Machele Donat More articles by this author , Jaspreet SandhuJaspreet Sandhu More articles by this author , Daniel SjobergDaniel Sjoberg More articles by this author , Amy TinAmy Tin More articles by this author , Jonathan ColemanJonathan Coleman More articles by this author , Bruce RapkinBruce Rapkin More articles by this author , Vincent LaudoneVincent Laudone More articles by this author , and Bernard BochnerBernard Bochner More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002536.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prior randomized-controlled trials (RCTs) comparing RARC to open radical cystectomy (ORC) have evaluated a limited breadth of health-related quality of life (HRQOL) domains. Our objective was to compare the effectiveness of RARC and ORC over a broad range of HRQOL domains longitudinally over two years following surgery. METHODS: We analyzed HRQOL in patients enrolled in a RCT of RARC vs ORC (2010-2013), who also enrolled in a prospective study of HRQOL in RC patients (2008-2014). Both studies enrolled patients receiving surgery and follow up care for non-metastatic disease at MSKCC. The urinary diversion was performed via an open approach in both arms. The prospective study of cystectomy QOL collected 14 patient-reported outcomes measures preoperatively, and at 3-, 6-, 12-, 18-, and 24-months postoperatively. Our primary outcome was differences between arms within each domain. Linear mixed effects models were used to test for changes in mean scores over 24-months, adjusting for baseline scores, with an interaction term for study arm×time. RESULTS: The RCT enrolled 118 subjects, of which 88 also consented to participate in the prospective HRQOL protocol. After excluding 16 ineligible patients, 72 were analyzed (n=32 RARC, n=40 ORC). The rate of continent diversion was similar (66% RARC, 70% ORC). No differences were detected in EORTC QLQ-C30 (scale 0-100, Figure 1) domains such as Global QOL (mean difference -1.1, 95% CI -8.4−6.2, p=0.8), Physical Functioning (mean diff. -0.4, 95% CI -5.8−5.0, p=0.9), or Social Functioning (mean diff. -0.3, 95% CI 9.2−8.7, p>0.9) and with no time interactions (all p >0.05). We did not detect significant differences in bladder cancer-specific domains (EORTC QLQ-BLM30, scale 0-100) including Body Image (mean diff. 2.9, 95% CI -7.2−13.1, p=0.6), Urinary Symptoms (mean diff. 8.0, 95% CI -3.0−19.0, p=0.2), and Sexual Functioning (mean diff. -8.5, 95% CI -17.2−0.19, p=0.052), and without a significant time interaction (all p >0.3). CONCLUSIONS: This analysis of a broad range of HRQOL domains in RCT patients did not detect significant differences between RARC and ORC. While the sample size was relatively small, the randomized design, large number of domains studied, and the longitudinal nature of the study can exclude a strong signal for differences based on surgical approach in the first 2-years postop. Source of Funding: This work was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers,the National Cancer Institute Cancer Center Core grant number P30-CA008748, and the Pin Down Bladder Cancer Fund © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e184 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Matthew Clements More articles by this author Benjamin Beech More articles by this author Thomas Atkionson More articles by this author Guido Dalbagni More articles by this author Yuelin Li More articles by this author Andrew Vickers More articles by this author Harry Herr More articles by this author S. Machele Donat More articles by this author Jaspreet Sandhu More articles by this author Daniel Sjoberg More articles by this author Amy Tin More articles by this author Jonathan Coleman More articles by this author Bruce Rapkin More articles by this author Vincent Laudone More articles by this author Bernard Bochner More articles by this author Expand All Advertisement PDF DownloadLoading ...

Balanced Salt Solutions for Critically Ill Patients: Nonplused and Back to Basics.

The purpose of this article is to summarize the results of major randomized controlled trials (RCTs) comparing clinical outcomes of critically ill patients treated with normal saline (NS) or balanced salt solutions (BSSs), address discordant results of these studies, and provide direction for future investigations. PubMed (2011 to January 2022) with bibliographies of retrieved articles searched for additional articles. RCTs comparing NS and BSSs in critically ill adult patients. Recently published large RCTs comparing NS with BSSs in heterogeneous populations of intensive care unit patients did not find significant differences in mortality, despite positive findings in some end points in prior RCTs. However, there were a number of methodologic issues common to the RCTs including: varying study designs and end points, clinician discretion for the majority or all treatments other than the primary intervention fluid, heterogeneous patients with varying levels of acuity, and lack of power to investigate potential subgroup differences. In addition, there were problematic issues related to blinding and use of nonstudy fluids. Intravenous fluids are a mainstay of supportive care for critically ill patients. Similar to the so-called crystalloid-colloid debate, there has been a long-standing debate among critical care clinicians and researchers concerning the preferred crystalloid solution, NS versus one of the available BSSs. Despite the recent publication of large multicenter RCTs, the preferred resuscitation fluid, NS or a BSS, for critically ill patients is still open for debate, although the available investigations do provide some direction for clinicians and for future investigations.

Editors' Note: Long-term Effects of Cholinesterase Inhibitors on Cognitive Decline and Mortality

Dr. Xu et al. compared cognitive trajectories and the occurrence of severe dementia or death in 11,652 patients started on cholinesterase inhibitors (ChEIs) vs 5,826 untreated patients with Alzheimer dementia (AD) in the Swedish Dementia Registry. During an average of 5 years of follow-up, they found that ChEIs were associated with modest but persistent cognitive benefits with lower mortality. Galantamine was the only ChEI that was associated with a significantly lower risk of developing severe dementia. In response, Dr. Kuschpel noted that there were important baseline differences between patients who were and were not treated with ChEIs, with associated difficulties matching the 2 groups for analyses. Dr. Kuschpel also highlighted the importance of considering the stage and severity of comorbidities about survival estimates and is skeptical of the sizeable mortality reduction with ChEIs seen in the study, given the lack of precedence, the absence of a plausible molecular mechanism, and potential confounding by prescription bias. Concerns are raised about potential discrepancies in numbers between the abstract and the results section about observed differences in Mini-Mental State Examination (MMSE) scores. Responding to these comments, the authors argue that although there were significant baseline differences between the 2 groups, they were able to achieve a well-matched cohort, although they acknowledge the possibility of residual and unknown confounders, especially in the absence of data on comorbidity severity. They cite the previous work by their group observing reductions in myocardial infarction, stroke, and mortality with ChEI use, as well as a lower 2-year mortality with galantamine seen in a prior randomized-controlled trial. They note that previous trials of ChEIs have had considerably shorter follow-up durations. In summary, this exchange highlights the uncertain causal association between ChEI use and lower mortality in patients with AD, and the challenges of convincingly demonstrating such an association with observational data. Robust validation of this association would have important implications for the care of patients with AD. Dr. Xu et al. compared cognitive trajectories and the occurrence of severe dementia or death in 11,652 patients started on cholinesterase inhibitors (ChEIs) vs 5,826 untreated patients with Alzheimer dementia (AD) in the Swedish Dementia Registry. During an average of 5 years of follow-up, they found that ChEIs were associated with modest but persistent cognitive benefits with lower mortality. Galantamine was the only ChEI that was associated with a significantly lower risk of developing severe dementia. In response, Dr. Kuschpel noted that there were important baseline differences between patients who were and were not treated with ChEIs, with associated difficulties matching the 2 groups for analyses. Dr. Kuschpel also highlighted the importance of considering the stage and severity of comorbidities about survival estimates and is skeptical of the sizeable mortality reduction with ChEIs seen in the study, given the lack of precedence, the absence of a plausible molecular mechanism, and potential confounding by prescription bias. Concerns are raised about potential discrepancies in numbers between the abstract and the results section about observed differences in Mini-Mental State Examination (MMSE) scores. Responding to these comments, the authors argue that although there were significant baseline differences between the 2 groups, they were able to achieve a well-matched cohort, although they acknowledge the possibility of residual and unknown confounders, especially in the absence of data on comorbidity severity. They cite the previous work by their group observing reductions in myocardial infarction, stroke, and mortality with ChEI use, as well as a lower 2-year mortality with galantamine seen in a prior randomized-controlled trial. They note that previous trials of ChEIs have had considerably shorter follow-up durations. In summary, this exchange highlights the uncertain causal association between ChEI use and lower mortality in patients with AD, and the challenges of convincingly demonstrating such an association with observational data. Robust validation of this association would have important implications for the care of patients with AD.

Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach

NAFLD is a leading comorbidity in HIV with an exaggerated course compared to the general population. Tesamorelin has been demonstrated to reduce liver fat and prevent fibrosis progression in HIV-associated NAFLD. We further showed that tesamorelin downregulated hepatic gene sets involved in inflammation, tissue repair, and cell division. Nonetheless, effects of tesamorelin on individual plasma proteins pertaining to these pathways are not known. Leveraging our prior randomized-controlled trial and transcriptomic approach, we performed a focused assessment of 9 plasma proteins corresponding to top leading edge genes within differentially modulated gene sets. Tesamorelin led to significant reductions in vascular endothelial growth factor A (VEGFA, log2-fold change − 0.20 ± 0.35 vs. 0.05 ± 0.34, P = 0.02), transforming growth factor beta 1 (TGFB1, − 0.35 ± 0.56 vs. − 0.05 ± 0.43, P = 0.05), and macrophage colony stimulating factor 1 (CSF1, − 0.17 ± 0.21 vs. 0.02 ± 0.20, P = 0.004) versus placebo. Among tesamorelin-treated participants, reductions in plasma VEGFA (r = 0.62, P = 0.006) and CSF1 (r = 0.50, P = 0.04) correlated with a decline in NAFLD activity score. Decreases in TGFB1 (r = 0.61, P = 0.009) and CSF1 (r = 0.64, P = 0.006) were associated with reduced gene-level fibrosis score. Tesamorelin suppressed key angiogenic, fibrogenic, and pro-inflammatory mediators. CSF1, a regulator of monocyte recruitment and activation, may serve as an innovative therapeutic target for NAFLD in HIV.Clinical Trials Registry Number: NCT02196831

Interim analysis of an open-label randomized controlled trial evaluating nasal irrigations in non-hospitalized patients with coronavirus disease 2019.

Interim analysis of an open-label randomized controlled trial evaluating nasal irrigations in non-hospitalized patients with coronavirus disease 2019.

FRI0339 LONG-TERM EFFICACY OF THE ORAL SELECTIVE JANUS KINASE 1 INHIBITOR FILGOTINIB IN PSORIATIC ARTHRITIS: WEEK 52 RESPONSE PATTERNS IN INDIVIDUAL PATIENTS FROM AN OPEN-LABEL EXTENSION (OLE) STUDY (EQUATOR2)

Background:EQUATOR (NCT03101670) was a 16-week, Phase 2, multicenter, double-blind, placebo-controlled, randomized controlled trial (RCT) of filgotinib in patients with active psoriatic arthritis.1Filgotinib demonstrated rapid efficacy compared with placebo across multiple domains, including the primary endpoint of Week 16 American College of Rheumatology (ACR) 20 response.1Patients completing the RCT could join an ongoing 148-week OLE (EQUATOR2;NCT03320876).Objectives:In this prespecified interim analysis at Week 52 of the OLE, individual patient responses with respect to disease activity were evaluated.Methods:Placebo-treated RCT patients switched to filgotinib (200 mg once daily) at Week 16 and entered the OLE; patients previously assigned to filgotinib continued. Individual response patterns at Week 52 of the OLE were evaluated for ACR20/50/70, Psoriatic Arthritis Disease Activity Score (PASDAS) low disease activity (LDA), minimal disease activity (MDA), and MDA/very low disease activity (VLDA).Results:124 patients (95%) completed EQUATOR; 122 (93%) enrolled in the OLE. At Week 52, 11 patients (9%) had discontinued treatment in the OLE. Median (range) exposure to filgotinib was 66.0 (0.4–104.1) weeks. In patients originally assigned to filgotinib, sustained efficacy was seen through to OLE Week 52 for ACR20, 50, and 70; PASDAS LDA; MDA (Table;Figure 1a); and MDA/VLDA. In total, 77% and 93% of those achieving MDA and ACR50 response in the RCT period maintained this at Week 52 (Table). A substantial proportion of RCT non-responders also achieved a treatment response in the OLE, meeting MDA and ACR50 criteria (22% and 37%, respectively;Table). Response patterns in the OLE were similar regardless of prior RCT treatment. In total, at Week 52 of the OLE, 33.6% of patients achieved MDA response (Figure 1a); 55.0% achieved ACR50 response. Figure 1bshows individual patient response over time for MDA.Conclusion:Data from this 52-week OLE interim analysis suggest that further improvement in disease activity can be expected with filgotinib beyond 16 weeks in patients with active psoriatic arthritis. Sustained efficacy was demonstrated across several measures of disease activity, including MDA and ACR50.

Moderators of School Intervention Outcomes for Children with Autism Spectrum Disorder.

A prior cluster randomized controlled trial (RCT) compared outcomes for a comprehensive school intervention (schoolMAX) to typical educational programming (services-as-usual [SAU]) for 103 children with autism spectrum disorder (ASD) without intellectual disability. The schoolMAX intervention was superior to SAU in improving social-cognitive understanding (emotion-recognition), social/social-communication skills, and ASD-related impairment (symptoms). In the current study, a range of demographic, clinical, and school variables were tested as potential moderators of treatment outcomes from the prior RCT. Moderation effects were not evident in demographics, child IQ, language, or ASD diagnostic symptoms, or school SES. Baseline externalizing symptoms moderated the outcome of social-cognitive understanding and adaptive skills moderated the outcome of ASD-related symptoms (no other comorbid symptoms or adaptive skills ratings moderated outcomes on the three measures). Overall, findings suggest that the main effects of treatment were, with two exceptions, unaffected by third variables.

Long-Term Effects of Randomization to a Weight Loss Intervention in Older Adults: A Pilot Study

Randomized, controlled trials (RCTs) show intentional weight loss improves body composition and physical function in older adults; however, the long-term benefits (and risks) are unknown. We conducted a pilot study to assess the feasibility of recalling prior RCT participants to examine the long-term effects of intentional weight loss on body composition and physical function. A weighted, random sample of 60 older adults who were randomized to caloric restriction plus exercise (CR + EX) or exercise (EX) only in 5 prior RCTs (mean age at randomization, 67.3 years; 69% women, 80% white) were invited to participate. Follow-up was obtained on 89% (42 clinic visits, 10 phone interviews, 1 death) an average of 3.5 years (range, 2.2–5.8 years) after RCT completion. Despite greater weight, fat and lean mass loss during the RCT (mean difference in change (95% CI): −4.19 (−7.52, −0.86), −2.75 (−5.10, −0.40), and −2.32 (−3.69, −0.95) kg, respectively) in those randomized to CR + EX, long-term changes in weight (2.05 (−2.35, 6.45) kg) and body composition (1.80 (−1.56, 5.17) and 0.03 (−2.20, 2.26) kg for fat and lean mass, respectively) from baseline and physical function at long-term follow-up (mean difference in 400-m walk and SPPB (95% CI): 23.2 (−19.3, 65.6) sec and −0.03 (−1.02, 0.96) points, respectively) were similar in CR + EX and EX only. Although improvements in weight and body composition following intentional weight loss may not be sustained long-term, physical function does not appear to be negatively impacted. A larger study is needed to confirm these results.

Commentary on Wu et al. (2017): Do very brief reduction interventions increase quitting among smokers not ready to quit?

Some smokers unready to quit will quit in response to a brief smoking reduction intervention. Whether this is due to their being more likely to try to quit, more likely to succeed, or both, and whether the intervention's effectiveness is due to reduction, advice to quit, or both is unclear. Most smokers are not ready to quit in the near future, but reducing cigarettes per day (CPD) is common in such smokers 1. Interventions to reduce CPD aided by nicotine replacement therapy (NRT) increase quitting among smokers not ready to quit 2, but most smokers do not want to use medications 3. Although greater self-selected reduction in CPD appears to predict quitting 4, only one 5 of three prior randomized controlled trials (RCT) found that a reduction intervention without medication increased abstinence among smokers not ready to quit 5-7. Wu and colleagues’ recent pragmatic RCT contributes to the existing literature with evidence that a very brief reduction intervention (approximately 5 minutes in total) with physician's advice to quit but without medication increases point-prevalence abstinence in comparison to no treatment at a 12-month follow-up (13 versus 7%) 8. We commend the authors for a rigorous test of this important topic in a generalizable setting. One concern is that this study's comparison condition did not include clinician advice to quit smoking, which increases cessation more than no treatment 9. Thus, it is unclear whether the effectiveness of Wu and colleagues’ intervention is due to the reduction intervention, advice to quit, or a combination of the two. This is important, because both prior trials that compared a reduction intervention without medication to advice to quit did not find that reduction increased abstinence 5, 6. It is also unclear if the effectiveness of Wu and colleagues’ reduction intervention was due to an increased number of quit attempts (QA) or the increased success of QA. This is important, because the processes that prompt making a QA differ from those that engender the success of a QA 10. The only prior RCT of a reduction intervention without medication that measured QAs found that a reduction intervention did not predict making a QA 6 but self-selected magnitude of reduction did 11. We know of no trials that have tested the effect of a non-pharmacological reduction intervention on quit success (i.e. abstinence among those who made a QA). An intervention that increases QAs (i.e. initiates behavior) could be useful for those with low motivation to quit or low self-efficacy for quitting. In contrast, an intervention that increases quit success (i.e. maintains behavior) could be useful to overcome barriers to staying quit, such as high dependence, among those already motivated. Knowing which of these was the active ingredient in successful reduction studies is important for knowing who would benefit most from reduction interventions. Importantly, this trial is consistent with the finding that reducing CPD increases abstinence among smokers not ready to quit 2 but does not appear to be effective among those who intend to quit now 12. One explanation for this difference is that reducing CPD could be effective by increasing motivation to quit 11 and thus less impactful for those already motivated to quit. Another explanation is that, among smokers who intend to quit now, reducing CPD delays quitting which could decrease motivation to quit 13. In summary, including Wu and colleagues’ recent finding, two of three trials found reduction interventions without medication for smokers not ready to quit increases cessation in comparison to no treatment 5, 7, 8. Whether this is due to the reduction intervention, advice to quit, or both, and whether this is due to increasing QAs or quit success remains unclear. Nonetheless, Wu and colleagues’ findings suggest that a very brief and feasible reduction intervention can increase substantially the odds of future cessation for smokers not ready to quit now. E.M.K. has nothing to disclose. J.R.H. has received consulting and speaking fees from several companies that develop or market pharmacological and behavioral treatments for smoking cessation or harm reduction and from several non-profit organizations that promote tobacco control. He also consults for Swedish Match.

19. Randomized Controlled Trial of a Neurosteroid Intervention in Schizophrenia

Abstract Background: Neurosteroids are endogenous molecules synthesized de novo in brain, adrenals, and other tissues. They demonstrate pleiotropic actions that are highly relevant to the neurobiology of schizophrenia. Clozapine markedly elevates neurosteroids in rodent hippocampus, potentially contributing to its superior therapeutic efficacy. Clinical evidence from a randomized controlled trial (RCT) conducted in Singapore suggests that pregnenolone significantly enhances functional capacity (as demonstrated by improvements in the UPSA Total Score and UPSA Communication Subscale Score) and that neurosteroid changes posttreatment predict therapeutic response (Marx et al 2014; Psychopharmacology). We thus conducted an RCT investigating adjunctive pregnenolone in schizophrenia. Methods: After a 2-week placebo lead-in, 88 participants with schizophrenia were randomized to pregnenolone (n = 42) or placebo (n = 46) for 8 weeks. Neurosteroids were quantified at baseline and posttreatment by mass spectrometry. Functional end points included the UPSA Total Score and UPSA Communication Subscale. Cognitive end points included the MCCB Composite Score and MCCB Subscales. Modified intent-to-treat analyses were conducted. Results: Participants randomized to the pregnenolone group did not outperform placebo on the UPSA Total Score or MCCB Composite Score. However, the pregnenolone group demonstrated significantly greater improvement in the UPSA Communication Subscale compared to participants randomized to placebo (P = .034), replicating prior RCT findings from Singapore. Elevations in pregnenolone post-treatment also predicted improvements in UPSA Total Score (r = .373; P = .039), again replicating prior efforts. In addition, the pregnenolone group demonstrated significantly greater improvement in the MCCB Verbal Learning Subscale compared to placebo (P = .023). Pregnenolone did not outperform placebo in the BACS Composite Score, SANS Total Score, or PANSS Total Score. Pregnenolone was well tolerated. Conclusion: Treatment with pregnenolone appears to improve functional capacity in a US population with schizophrenia, as assessed by the UPSA Communication Subscale and also supported by a significant positive correlation between pregnenolone changes and UPSA Total Score improvements—thus replicating findings from a prior RCT conducted in Singapore. Pregnenolone may also improve verbal memory. Given the positive correlation between pregnenolone increases posttreatment and UPSA Total Score improvements, it is possible that higher doses of pregnenolone may be clinically efficacious, and that neurosteroid quantification has biomarker potential for the predication of therapeutic response. Additional dose-finding investigations will be required to test these hypotheses. A pregnenolone decanoate formulation is currently in preclinical development.

Acupuncture for the Treatment of Peripheral Neuropathy: A Systematic Review and Meta-Analysis.

Neuropathy and its associated pain pose great therapeutic challenges. While there has been a recent surge in acupuncture use and research, little remains known about its effects on nerve function. This review aims to assess the efficacy of acupuncture in the treatment of neuropathy of various etiologies. The Medline, AMED, Cochrane, Scopus, CINAHL, and clintrials.gov databases were systematically searched from inception to July 2015. Randomized controlled trials (RCTs) assessing acupuncture's efficacy for poly- and mononeuropathy were reviewed. Parallel and crossover RCTs focused on acupuncture's efficacy were reviewed and screened for eligibility. The Scale for Assessing Scientific Quality of Investigations in Complementary and Alternative Medicine was used to assess RCT quality. RCTs with score of >9 and active control treatments such as sham acupuncture or medical therapy were included. Fifteen studies were included: 13 original RCTs, a long-term follow-up, and a re-analysis of a prior RCT. The selected RCTs studied acupuncture for neuropathy caused by diabetes, Bell's palsy, carpal tunnel syndrome, human immunodeficiency virus (HIV), and idiopathic conditions. Acupuncture regimens, control conditions, and outcome measures differed among studies, and various methodological issues were identified. Still, the majority of RCTs showed benefit for acupuncture over control in the treatment of diabetic neuropathy, Bell's palsy, and carpal tunnel syndrome. Acupuncture is probably effective in the treatment of HIV-related neuropathy, and there is insufficient evidence for its benefits in idiopathic neuropathy. Acupuncture appears to improve nerve conduction study parameters in both sensory and motor nerves. Meta-analyses were conducted on all diabetic neuropathy and Bell's palsy individual subject data (six RCTs; a total of 680 subjects) using a summary estimate random effects model, which showed combined odds ratio of 4.23 (95% confidence interval 2.3-7.8; p < 0.001) favoring acupuncture over control for neuropathic symptoms. Acupuncture is beneficial in some peripheral neuropathies, but more rigorously designed studies using sham-acupuncture control are needed to characterize its effect and optimal use better.

Abstract 11515: Does Prolonged Dual Antiplatelet Therapy Increase Mortality After Drug-Eluting Stent Implantation?

Introduction: The Dual Antiplatelet Therapy (DAPT) trial found a borderline increase in the rate of all-cause mortality in patients treated with 30 compared with 12 months of DAPT (2.0% vs. 1.5%, HR 1.36, 95% CI 1.00-1.85, P = 0.05). Hypothesis: A finding of borderline significance in a mega-trial may reflect the play of chance. Methods: We used a Bayesian conjugate-normal approach (Figure A) to update the mortality results from the DAPT trial with an empiric prior probability distribution based on results in 9 smaller randomized controlled trials (RCTs). Results: The empiric prior (blue), which suggests that the odds of mortality in the 9 smaller RCTs could be 6% lower or as much as 40% higher after prolonged than after short DAPT, overlaps with the likelihood (red) from the DAPT trial itself. Bayesian inference (black) affirms a significant increase in mortality with prolonged DAPT (posterior mean odds ratio [OR] 1.21, 95% Bayesian confidence interval [BCI] 1.02-1.44). Sensitivity analysis, which weighs the number of effective events by the proportion of patients with acute coronary syndromes, produces a nearly identical point estimate (OR 1.23, 95% BCI 0.96-1.58). Conclusions: Our analysis provides credible evidence that 30 months of DAPT is associated with higher mortality rates than is 12 months of therapy. The mortality increase in the DAPT trial is predictable from prior RCTs and not likely to be a chance finding.

Pharmacists' experiences with a telephonic medication therapy management program for home health care patients.

This study was designed to better understand perceived barriers and facilitators to providing medication therapy management (MTM) services by pharmacists who recently provided telephonic MTM services to home health care patients. These services were provided as part of a randomized, controlled trial (RCT) to develop suggested quality improvement strategies for future service design. This was a qualitative study. A semi-structured individual interview format was used to elicit responses. Interviews were conducted by phone with participants. All pharmacists who recently provided telephonic MTM services as a part of an RCT participated in this study. Pharmacists were asked questions regarding their perceptions of the services, training opportunities, patient perceptions of the services, interactions with physicians, and suggestions for improvement. General demographic information was collected for each pharmacist and summarized using descriptive statistics. Interview data were analyzed using inductive qualitative methods to reveal key themes related to facilitators and barriers of MTM services in home health care patients. The main outcome measures were major themes identified from pharmacist interviews pertaining to barriers, facilitators, and quality improvement strategies for telephonic MTM delivery. A total of four pharmacists (i.e., 100% of those who participated in the prior RCT) were interviewed. Several themes emerged from the analysis, including: communication and relationships, coordinating care and patient self-management, logistics, professional fulfillment, service delivery and content, and training opportunities. This study provides possible strategies to overcome barriers and facilitate service provision for future telephonic MTM services.

SP0174 Eular points to consider when conducting long term extension studies of trials?

Randomized controlled trials (RCT) provide data on clinically measurable outcomes (safety and efficacy) in the short-term. The need for longer-term data requires extended follow-up. The biologic era particularly has witnessed...

Immunosuppressive treatment of idiopathic membranous nephropathy: the dilemma continues

Idiopathic membranous nephropathy(IMN) is one of the most common causes of nephrotic syndrome (NS) in adults and may progress to end-stage renal disease(ESRD). Given the variable course, it remains unclear who to treat with immunosuppression(IS) and with what regimen. Corticosteroids, alkylating agents, calcineurin inhibitors (CNIs), and antimetabolities have all been used in randomized controlled trials (RCTs). Previous meta-analyses of these trials were unable to demonstrate a benefit on death or progression to ESRD compared to no treatment or placebo. Since the last round of these analyses (in 2004) additional RCTs have been published. The Cochrane Central Register of Controlled Trials and Medline were searched from 2003 until February 2012 for new RCTs in the treatment of IMN to update the database. Twelve trials were found. Due to significant heterogeneity of patients and regimens, they are discussed qualitatively only and are integrated with prior RCTs and relevant observational data. In conclusion, patients with non-nephrotic proteinuria should not be offered IS therapy. Those with NS and declining renal function should be treated. The best evidence supports a combined steroid and alkylating agent regimen. Calcineurin inhibitors clearly produce short-term benefit (proteinuria reduction and remission) but their ability to favorably affect death or ESRD remains unproven. There is little support for antimetabolite use. Other agents (rituximab and adrenocorticotropin) require further study. For the large group of patients with NS but normal renal function it remains a dilemma who to treat and with regimen.

A Systematic Examination of the Citation of Prior Research in Reports of Randomized, Controlled Trials

A randomized, controlled trial (RCT) should not be started or interpreted without accounting for evidence from preceding RCTs addressing the same question. Research has suggested that evidence from prior trials is often not accounted for in reports of subsequent RCTs. To assess the extent to which reports of RCTs cite prior trials studying the same interventions. Meta-analyses published in 2004 that combined 4 or more trials were identified; within each meta-analysis, the extent to which each trial report cited the trials that preceded it by more than 1 year was assessed. The proportion of prior trials that were cited (prior research citation index), the proportion of the total participants from prior trials that were in the cited trials (sample size citation index), and the absolute number of trials cited were calculated. 227 meta-analyses were identified, comprising 1523 trials published from 1963 to 2004. The median prior research citation index was 0.21 (95% CI, 0.18 to 0.24), meaning that less than one quarter of relevant reports were cited. The median sample size citation index (0.24 [CI, 0.21 to 0.27]) was similar, suggesting that larger trials were not selectively cited. Of the 1101 RCTs that had 5 or more prior trials to cite, 254 (23%) cited no prior RCTs and 257 (23%) cited only 1. The median number of prior cited trials was 2, which did not change as the number of citable trials increased. The mean number of preceding trials cited by trials published after 2000 was 2.4, compared with 1.5 for those published before 2000 (P < 0.001). The investigators could not ascertain why prior trials were not cited, and noncited trials may have been taken into account in the trial design and proposal stages. In reports of RCTs published over 4 decades, fewer than 25% of preceding trials were cited, comprising fewer than 25% of the participants enrolled in all relevant prior trials. A median of 2 trials was cited, regardless of the number of prior trials that had been conducted. Research is needed to explore the explanations for and consequences of this phenomenon. Potential implications include ethically unjustifiable trials, wasted resources, incorrect conclusions, and unnecessary risks for trial participants. None.

Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial

Idiopathic secondary recurrent miscarriage may be associated with an abnormal maternal immune response to subsequent pregnancies. Intravenous immunoglobulin (IVIG) has been studied in randomized controlled trials (RCTs) with conflicting results. Therefore, a definitive trial was proposed. We conducted an investigator-initiated, multicentered, randomized, double-blinded, placebo-controlled trial comparing IVIG with saline in women with idiopathic secondary recurrent miscarriage, defined as a history of at least one prior ongoing pregnancy followed by three or more consecutive unexplained miscarriages. Subjects received either IVIG 500 mg/kg or the equivalent volume of normal saline. Preconception infusions were administered 14-21 days from the projected next menstrual period. With documentation of pregnancy, the subject received the same infusion every 4 weeks until 18-20 weeks of gestation. The primary outcome was an ongoing pregnancy of at least 20 weeks of gestation. A total of 82 patients enrolled, of whom 47 had an index pregnancy. All ongoing pregnancies resulted in live births. Therefore, the live birth rates were 70% (16/23) in the IVIG group and 63% (15/24) in the control group (P = 0.760); odds ratio (OR) 1.37 [95% confidence interval (CI) 0.41-4.61]. Including only clinical pregnancies (embryo with cardiac activity at 6 weeks of gestation), the live birth rates were equivalent, 94% (16/17) and (15/16), respectively (P > 0.999); OR 1.07 (95% CI 0.06-18.62). Meta-analysis of randomized controlled trials (RCTs) evaluating IVIG for idiopathic secondary recurrent miscarriage revealed live birth rates of 70% (31/44) in the IVIG group and 62% (28/45) in the control group (P = 0.503); common OR 1.44 (95% CI 0.59-3.48). This is the largest RCT to date in which IVIG was evaluated in women with idiopathic secondary recurrent miscarriage; no treatment benefit was found. The meta-analysis, which combined our study results with two prior RCTs, also showed no significant effect of treatment with IVIG.