Treatment-emergent Side Effects Research Articles

Buspirone for the treatment of anxiety in Williams syndrome: a retrospective chart review study

ABSTRACT Background Williams syndrome (WS) is a rare genetic disorder associated with a high prevalence of anxiety disorders. Evidence-based pharmacologic treatments for anxiety in WS are lacking. The purpose of this study is to provide naturalistic data on the use of buspirone for the treatment of anxiety in WS. Research design and methods Medical records of 24 individuals with Williams syndrome (ages 7–47 years) and anxiety who received treatment with buspirone were reviewed. Treatment response to buspirone was rated by assigning a retrospective Clinical Global Impression Improvement subscale (CGI-I) score. Results Twenty-three of 24 (96%) patients completed at least a 16-week treatment course with buspirone. Sixteen patients (67%; 95% CI 47%, 82%) were treatment responders (CGI-I ≤ 2). Only 1 (4%) patient discontinued buspirone due to a treatment-emergent side effect (nausea and vomiting). The most common side effect was nausea (13%). Twenty (84%) patients remained on buspirone at the time of their most recent follow-up visit. Conclusions In this retrospective study, the majority of patients responded to a 16-week course of buspirone. Prospective studies are warranted to further assess the efficacy and tolerability of buspirone for anxiety in WS.

A Preliminary Analysis of Athn 16: Safety of Coagulation Factor VIIa (recombinant)-Jncw for the Treatment of Bleeding Events in Patients with Congenital Hemophilia a or B with Inhibitors

Background: Eptacog beta (rFVIIa-jncw) (brand name SEVENFACT®) was approved by the U.S. Food and Drug Administration (FDA) in 2020 for the treatment of bleeding events (BEs) in individuals 12 years of age and older with hemophilia A or B (HAB) complicated by inhibitors. ATHN 16: Safety of Coagulation Factor VIIa (recombinant)-jncwforthe Treatment of Bleeding Events in Patients with Hemophilia A or B with Inhibitors was designed to collect real-world evidence on the safety of eptacog beta. Objective: To evaluate the safety of eptacog beta when used to treat BEs in participants with HAB with inhibitors with or without FDA-approved prophylactic treatment. Methods: ATHN 16 (NCT04647227) is a phase IV, United States-centric multicenter, open-label safety study enrolling participants with HAB with inhibitors aged 12 years and older, who are either on an FDA-approved prophylaxis and at risk of experiencing a breakthrough BE or who are not on prophylactic treatment and may need to control a BE. Exclusion criteria include any bleeding disorder in addition to HAB, a known hypersensitivity to eptacog beta or rabbit proteins, or the inability to provide informed consent. The maximum study duration for any participant in the study will be up to 2 years from the time of enrollment. Safety of eptacog beta is evaluated based on events included in the European Haemophilia Safety Surveillance (EUHASS) protocol, including allergic or other acute events, treatment-emergent side effects, transfusion-transmitted infections, inhibitor (FVII) development, thrombosis, cardiovascular events, malignancies, neurological events, and deaths. After informed consent is obtained, demographics, bleeding disorder history, inhibitor history, baseline medical and surgical history are recorded for the baseline data. Each participant receives nine 75 µg/kg doses of eptacog beta supplied by the study funder. Eptacog beta is administered by the participant or by study staff at the time of a BE. The doses and duration of treatment are determined at the discretion of the treating physician. BE details including timing of BE, any treatments associated with the BE (including eptacog beta) and timing of resolution of the event, are collected as well as surgical procedures, EUHASS events, adverse events of special interest (AESIs), and serious adverse events (SAEs). Results: At the time of abstract submission, ATHN 16, having received central IRB approval, is rolled out to ATHN-affiliated sites across the United States. The study is currently open to enrollment at 11 sites and an additional 21 sites are proceeding with start-up approvals. A total of seven participants have been enrolled. One BE, unrelated to study product, has been reported. One SAE, unrelated to study product, has been reported. Conclusions: To date, a total of seven participants have enrolled in ATHN 16. One bleeding event has been treated with eptacog beta. The results will be updated, and all safety endpoints will be updated prior to the December 2022 meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

OR27-2 Growth Hormone Reduces Hepatic Steatosis, Inflammation and Fibrosis in Adults with Overweight/Obesity and Nonalcoholic Fatty Liver Disease

Abstract Background Overweight/obesity are associated with relative growth hormone (GH) deficiency, and GH deficiency has been implicated in the development of nonalcoholic fatty liver disease (NAFLD). NAFLD and its progressive form, nonalcoholic steatohepatitis (NASH), are associated with significant morbidity and mortality, and no approved therapies currently exist. We hypothesized that GH administration would reduce hepatic steatosis, inflammation and fibrosis in individuals with overweight/obesity and NAFLD. Methods A randomized, double-blind, placebo-controlled trial of GH administration in adults with overweight/obesity and NAFLD was conducted (NCT02217345). Fifty-three adults ages 18-70 years with BMI ≥25 kg/m2 and NAFLD were randomly assigned to receive daily subcutaneous GH or placebo for 6 months. Target IGF-1 was upper quartile of normal. Primary endpoints included intrahepatic lipid content (IHL) by proton magnetic resonance spectroscopy (1H-MRS) and radiographic inflammation and fibrosis by LiverMultiScan corrected T1 score (cT1). Secondary endpoints included alanine transaminase (ALT), visceral adipose tissue (VAT) by dual-energy x-ray absorptiometry (DEXA), hsCRP and HOMA-IR. Data are reported as mean ± SD. Results Forty-one subjects completed the 6-month study. Mean age (45±12 years), BMI (33±5 kg/m2), sex distribution (50% female) and baseline IHL (21.4±14.5%) did not differ between the GH and placebo groups. Over the 6-month study period, there was no difference in change in weight between the groups (GH -0.7±3.8% and placebo -0.6±4.0%, p=0.7). Change in absolute percent IHL was significantly greater in the GH vs placebo group (-5.1±10.5% vs 3.8±6.9%, p=0.003), resulting in a net treatment effect of an 8.9% reduction in IHL (95% CI 3.3-14.6%). Improvements in serum ALT (-10±13 IU/L vs -2±12 IU/L, p=0.009) and cT1 score (-11±63 ms vs 27±57 ms, p=0.037) were greater in the GH vs placebo group. There were also significant reductions in DEXA VAT area (-10±9 cm2 vs 0±20 cm2, p=0.050) and hsCRP (-0.8±0.9 mg/dL vs -0.3±1.7 mg/dL, p=0.017) in the GH vs placebo group. In multivariable models controlling for age, sex, change in weight and change in HOMA-IR, significant effects of GH vs placebo were observed on IHL (p=0.012) and ALT (p=0.015) with a trend towards improvement in cT1 score (p=0.088). In a secondary analysis excluding all subjects with >3% weight loss, which has been shown to independently impact NAFLD outcomes, there were significant improvements in IHL (p=0.001), ALT (p=0.040) and cT1 score (p=0.050) in the GH vs placebo group. No subjects were discontinued due to hyperglycemia (fasting glucose ≥126 mg/dL or HbA1c ≥6.5%). Mild edema was the only treatment-emergent side effect that had a significantly greater incidence in the GH vs placebo group (19% vs 0%, p=0.048). Conclusion GH administration reduces hepatic steatosis and markers of hepatic inflammation and fibrosis in adults with overweight/obesity and NAFLD. The GH/IGF-1 axis may offer targetable therapeutic options for NAFLD/NASH. Presentation: Tuesday, June 14, 2022 10:00 a.m. - 10:15 a.m.

Longitudinal Real-World Neuropathy and Patient-Reported Outcomes With Bortezomib and Lenalidomide in Newly Diagnosed Multiple Myeloma.

Peripheral neuropathy is a common treatment-emergent side effect during the treatment of newly diagnosed multiple myeloma. Although bortezomib is most commonly implicated, real-world data suggest that lenalidomide and dexamethasone (VRd) and autologous stem cell transplantation (ASCT) may also contribute to neuropathy and health-related quality of life (HRQoL). The Multiple Myeloma Research Foundation (MMRF) CoMMpass Registry was queried for all patients who received frontline VRd or bortezomib, cyclophosphamide and dexamethasone (VCd). Incidence of neuropathy and patient-reported HRQoL outcomes over the first 12 months after diagnosis were compared between patients receiving VRd or VCd with or without early ASCT before 6 months. There were 368 and 191 patients treated with VRd and VCd, respectively. VRd with early ASCT was associated with worse grade 1 neuropathy compared to VRd without early ASCT, as well as compared to VCd with early ASCT. There were no differences in neuropathy between VRd and VCd without early ASCT, and no differences in grade ≥2 neuropathy. There were significant improvements in HRQoL between baseline and 12 months in both VRd and VCd cohorts, regardless of early ASCT. Development of neuropathy was not associated with decrements in progression-free survival or overall survival. In this longitudinal database analysis, there were no differences in grade ≥2 neuropathy between VRd and VCd frontline induction, and overall HRQoL significantly improved across all cohorts. However, differences in grade 1 neuropathy between VRd and VCd induction suggest that lenalidomide and high-dose melphalan may augment the risk of neuropathy in newly diagnosed multiple myeloma.

Newer antipsychotics: Brexpiprazole, cariprazine, and lumateperone: A pledge or another unkept promise?

Antipsychotic agents are used for various indications in the treatment of psychiatric disorders. Despite their proven roles in multiple conditions, the treatment-emergent side effects of antipsychotic medications, such as metabolic side effects, are often the limiting factor for their long-term and short-term uses. Moreover, antipsychotic medications are often criticized for being less effective in treating different disabling symptoms such as negative symptoms of schizophrenia. As a result, the search for safer and more efficacious antipsychotic agents is ongoing. Newer antipsychotic agents are gaining attention related to emerging efficacy and tolerability data in treating neuropsychiatric conditions. In this review, we attempt to appraise the scientific data on psychopharmacology, safety profile, and efficacy of the newer additions to the list of second-generation antipsychotics, namely brexpiprazole, cariprazine, and lumateperone. We conducted a selective review utilizing PubMed, clinicaltrials.gov, and Cochrane databases to gather appropriate publications, keeping broad inclusion criteria. There were no restrictions on the age of the study population or the year of publication. We also cross-referenced articles and references to capture all existing studies. Our review of the current literature indicates that all three antipsychotic agents appear to be promising based on their short-term studies, while long-term studies remain limited. There is also a need for a head to head comparison between the newer antipsychotics with the other antipsychotic agents to ascertain if the newer agents are any better than the others.

Athn 16: Safety of Coagulation Factor VIIa (recombinant)-Jncw for the Treatment of Bleeding Events in Patients with Congenital Hemophilia a or B with Inhibitors with or without Prophylactic Treatment

Athn 16: Safety of Coagulation Factor VIIa (recombinant)-Jncw for the Treatment of Bleeding Events in Patients with Congenital Hemophilia a or B with Inhibitors with or without Prophylactic Treatment

ATHN Transcends: A Natural History Cohort Study of the Safety, Effectiveness and Practice of Treatment in People with Non-Neoplastic Hematologic Disorders

Background: Clinical researchers affiliated with the American Thrombosis and Hemostasis Network (ATHN) conduct multi-institutional, observational cohort studies assessing the safety and effectiveness of various interventions for people affected by bleeding and clotting disorders. In parallel with the growth of ATHN's clinical studies, the number of new therapies for all congenital and acquired hematologic conditions, not just those for bleeding and clotting disorders, is increasing. Some of the recently FDA-approved therapies for congenital and acquired hematologic conditions have yet to demonstrate long-term safety and effectiveness. In addition, results from well-controlled, pivotal studies often cannot be replicated once a therapy has been approved for general use. With this explosion of potential new therapies on the horizon, it is imperative that clinicians and clinical researchers in the field of non-neoplastic hematology have a uniform, secure, unbiased, and enduring method to collect long-term safety and efficacy data. The overarching objective of ATHN Transcends (NCT04398628) is to characterize the safety, effectiveness, and practice of treatments for all people with congenital and acquired hematologic disorders in the United States.Study Design and Methods: ATHN Transcends is a longitudinal, natural history, observational cohort study being conducted at approximately 150 ATHN-affiliated sites (ATHN Affiliate Network). Participants will be followed for a minimum of 15 years. Specific data will be collected for participants enrolled in cohort-specific arms. Each participant will be assigned in a single cohort: Hemophilia, Von Willebrand Disease, Congenital Platelet Disorder, Rare Bleeding Disorders, Bleeding Not Otherwise Specified, Thrombosis/Thrombophilia, or Non-Neoplastic Hematologic Conditions (see Figure 1).Inclusion criteria include: any age, any congenital or acquired non-neoplastic hematologic disorder, having a bleeding phenotype with an unknown diagnosis, or having a connective tissue disorder with a bleeding tendency. Exclusion criteria include not qualifying for a cohort and the unwillingness or inability to give informed consent or assent.Data will be collected at baseline, every three months, annually and at study exit (Figure 2). Participant biologic samples will be collected at enrollment and yearly thereafter. Safety endpoints mirror those collected by the European Haemophilia Safety Surveillance and include allergic and other acute events, treatment-emergent side effects of therapy, transfusion-transmitted infections, inhibitor development, thrombosis and cardiovascular events, malignancies, neurologic events, and deaths. Adverse events of special interest including thrombotic microangiopathies, anti-drug antibodies, unanticipated bleeding, and hospitalizations will be collected. A panel of patient-reported outcomes (Table 1) will be collected at baseline and annually.Descriptive statistics will be calculated to analyze the primary and secondary outcomes. If there are questions involving multiple cohorts, given there is adequate power to make comparisons between cohorts, for a discrete outcome, we will report estimated difference in percentage between cohorts as well as the 95% confidence interval (CI) of such a difference. If the outcome measurement is a continuous variable, we will report the mean difference and its associated 95% CI.Discussion: The key advantages of an independent study conducted by the ATHN Affiliate Network include the ability to observe participants on a variety of treatment regimens regardless of regimen dosing, frequency, or time of initiation; the ability to observe participants on recently FDA-approved therapies as well as continued monitoring of well-established therapies; the ability to enrich the ATHNdataset; and the ability to be the initial cohort study involving potentially all ATHN-affiliated sites to provide the infrastructure for all congenital and acquired hematologic disorders-related sub-studies in cooperation with other funders, including federal, foundation, academic and industry sources. ATHN Transcends received central institutional review board approval in April 2020. The protocol is currently being rolled out throughout the ATHN Affiliate Network. [Display omitted] DisclosuresMalec: HEMA Biologics: Consultancy; Genentech: Consultancy; Sanofi: Consultancy, Research Funding; Pfizer: Consultancy; CSL Behring: Consultancy; Takeda: Consultancy. Recht: uniQure: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Genentech: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders: Speakers Bureau; American Thrombosis and Hemostasis Network: Current Employment; Oregon Health & Science University: Current Employment.

New drugs for myeloid neoplasms with ring sideroblasts: Luspatercept vs imetelstat.

New drugs for myeloid neoplasms with ring sideroblasts: Luspatercept vs imetelstat.

Music and rTMS; Novel combination approach for the treatment of depression

Abstract: Background: Standard treatments are often ineffective in Major Depressive Disorder (MDD). Repetitive Transcranial Magnetic Stimulation (rTMS) is effective in treatment resistant MDD. Music therapy is an established health profession with proven benefits in depression and anxiety. Combining treatments with rTMS often improves outcomes. We introduce proof of concept for novel combination approach, music with rTMS. Methods/Design: Nine adult patients with treatment resistant MDD were treated. TMS was delivered using H1-coil to left dorsolateral prefrontal cortex using standard high frequency parameters. Patients listened to music simultaneously with stimulation every session for 20 minutes. The type of music played was based on the patient’s preference. They were asked to choose something that induces positive emotions in them, possibly chills or Goosebumps (i.e intense pleasure). Response was measured with Hamilton Depression Rating Scale (HAM-D). Results: Response and remission rates were 89% and 56% respectively. Mean change in total HAM-D score was –15.3 (SD=3.6). There were no treatment emergent side effects. Conclusion: We demonstrate the feasibility of combining music with rTMS in this open label proof of concept series. This method is easy to set up and deliver. We encourage more research into this area for finding proof of efficacy. Disclosures – None

A Retrospective Chart Review Evaluating Efficacy, Tolerability, and Cost of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors (PCSK9i) in Older Adults.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are proven to have profound lowering of low-density lipoprotein cholesterol (LDL-C) in patients with clinical atherosclerotic cardiovascular disease or familial hypercholesterolemia. The primary purpose of this study was to evaluate PCSK9i utilization in older adults, with a focus on efficacy outcomes within 6months of initiation. Secondary outcomes included tolerability, out-of-pocket expenses (OPE), and barriers to initiation of therapy. We conducted a retrospective chart review of patients ≥65 years prescribed PCSK9i therapy by a pharmacist-run lipid clinic within a cardiology practice. A total of 136 older adults were prescribed PCSK9i therapy for a Food and Drug Administration-approved indication between September 2015 and March 2019 with 98 patients included in the analyses. In terms of efficacy, 51 patients who took ≥ 3 doses of PCSK9i with baseline and follow-up lipid panels were assessed. On average, LDL-C reduced by 60% (169-67 mg/dL, p < 0.001). For tolerability, 15 patients reported treatment-emergent side effects, resulting in 10 therapy discontinuations. For the cost analysis, 72 patients reported anticipated OPE for 1 month of therapy. Ultimately 17 patients were approved for manufacturer patient assistance with $0 OPE and 31 patients utilized insurance coverage to obtain therapy reporting a median OPE of $9 United States Dollars ($0-$450). The main barrier to initiation was high OPE. PCSK9i are effective at lowering LDL-C in older adults. Tolerability was high among patients without a history of statin intolerance. PCSK9i remain high-cost medications to both insurance companies and patients in terms of cost-sharing responsibilities.

Effects of safinamide on pain in Parkinson's disease with motor fluctuations: an exploratory study.

Pain is a common and disabling non-motor symptom (NMS) of Parkinson's disease (PD), which occurs through the course of the disease, often unrecognized and undertreated. For this study, we evaluated the efficacy and safety of safinamide to reduce pain in PD patients with motor fluctuations. A total of 13 PD patients with pain receiving safinamide (Xadago®, 100mg/daily) were prospectively evaluated for 12weeks. The primary outcome measures were changes in the total score of the King's Pain Scale for Parkinson's Disease (KPPS), Brief Pain Inventory (BPI) Intensity and Interference, and the Numeric Rating Scale (NRS). Secondary outcomes were the proportion of pain responders, changes in the Clinical Global Impression of Change (CGI), the Parkinson's disease Quality of Life 39 (PDQ39), the Unified Parkinson's Disease Rating Scale parts III and IV (UPDRS III and IV), and laser-evoked potentials (LEPs). LEPs were used to assess potential changes in the central processing of nociceptive inputs. The safety profile was evaluated based on the occurrence of treatment-emergent side effects and the dropout rate. After 12weeks of add-on safinamide therapy, a significant improvement was noted in the primary (KPPS, BPI Intensity and interference, and NRS) and the secondary outcomes (UPDRS III, IV, CGI, and PDQ39). No significant changes in LEP complexes were observed. All patients completed the study and no treatment-emergent side effects were reported. Our preliminary findings suggest that safinamide 100mg/day may be effective for the management of pain in PD patients with motor fluctuations and is safe. Further randomized controlled trials are needed to confirm its efficacy.

Reported Side Effects, Weight and Blood Pressure, After Repeated Sessions of Transcranial Photobiomodulation.

Background: Transcranial photobiomodulation (t-PBM) consists in the delivery of near-infrared light (NIR) to the scalp, directed to cortical areas of the brain. NIR t-PBM recently emerged as a potential therapy for depression, although safety of repeated treatments has not been adequately explored. Objective: This study assessed incidence of side effects, including weight and blood pressure changes, during repeated sessions of NIR t-PBM using a light-emitting diode source. Methods: We performed a secondary analysis of a double-blind clinical trial on t-PBM for major depressive disorder. Eighteen individuals received NIR t-PBM (n = 9) or sham (n = 9) twice weekly for 8 weeks. Side effects were assessed using the Systematic Assessment for Treatment-Emergent Effects-Specific Inquiry. In 14 individuals (nNIR = 6 vs. nsham = 8), body weight and systemic blood pressure were recorded at baseline and end-point. Results: More subjects in the NIR t-PBM group experienced side effects compared to sham, but only a trend for statistical significance was observed (χ2 = 3.60; df = 1; p = 0.058). The rate of side effects described by participants as "severe" in intensity was low and similar between the treatment groups (χ2 = 0.4; df = 1; p = 0.53), with no serious adverse events. Most side effects resolved during the study and treatment interruption were not required. Changes in weight and systolic blood pressure across groups were neither significant nor approached significance. In the NIR t-PBM group, diastolic blood pressure increased and reached statistical-however not clinical-significance (5.67 ± 7.26 vs. -6.13 ± 6.88; z = -2.40, p = 0.016). Conclusions: This small-sample, exploratory study indicates repeated sessions of NIR t-PBM might be associated with treatment-emergent side effects. The systemic metabolic and hemodynamic profile of repeated t-PBM appeared benign. Future studies with larger samples and longer follow-up are needed to more accurately determine the side-effect profile and safety of NIR t-PBM.

Meta-Analysis of the Long-Term Efficacy and Tolerance of Tadalafil Daily Compared With Tadalafil On-Demand in Treating Men With Erectile Dysfunction.

BackgroundErectile dysfunction (ED) is highly prevalent in aging men. Tadalafil daily and on-demand are widely used for the treatment of ED.AimWe performed a meta-analysis to evaluate the efficacy and safety of tadalafil daily compared with tadalafil on-demand in treating men with ED after at least 24 weeks of long-term treatment.MethodsRandomized controlled trials of tadalafil daily vs on-demand in treating men with ED were searched using MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. Systematic review was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-analyses. The data was calculated by RevMan version 5.3.0. The references of related articles were also searched.OutcomesInternational Index of Erectile Function-Erectile Function domain, sexual encounter profile question 2 (SEP2), SEP question 3 (SEP3), any treatment-emergent adverse event (AE), discontinuation due to AEs, myalgia, back pain, headache, dyspepsia, and nasopharyngitis.Results4 articles, including 1,035 participants were studied. The analysis found that tadalafil daily had a greater improvement than tadalafil on-demand in terms of International Index of Erectile Function-Erectile Function (mean difference (MD) 1.24; 95% CI 0.03−2.44; P = .04), SEP2 (MD 10.08; 95% CI 9.15−11.01; P < .00001) and SEP3 (MD 8.19; 95% CI 2.09−14.29; P = .009) in treating ED after at least 24 weeks treatment cycle. For safety, tadalafil on-demand had a higher incidence of any treatment-emergent AE (odds ratio 0.73; 95% CI 0.56−0.96; P = .02) compared with tadalafil daily, but for other aspects, including discontinuation due to AEs, myalgia, back pain, headache, dyspepsia, and nasopharyngitis, there were no significant difference between the 2 treatments.Clinical ImplicationsTadalafil daily may offer a better effect for ED than on-demand for long-term treatment.Strengths and LimitationsFrom the perspective of evidence-based medicine, we evaluated the efficacy and safety of tadalafil daily compared with tadalafil on-demand in treating men with ED after a long-term treatment. The quality of these studies included is flawed, primarily in difference in tadalafil doses and severity of the ED.ConclusionTadalafil daily provides a preferable therapeutic effect for ED with a lower incidence of treatment-emergent side effects relative to tadalafil on-demand after at least 24 weeks of long-term treatment.Zhou Z, Chen H, Wu J, et al. Meta-Analysis of the Long-Term Efficacy and Tolerance of Tadalafil Daily Compared With Tadalafil On-Demand in Treating Men With Erectile Dysfunction. J Sex Med 2019;7:282–291.

850-P: Modeling Pathways between Psychological Distress, Emergent Symptoms and Side Effects, and Endpoint A1C during Treatment

Achieving glycemic targets is often hampered by emerging symptoms and side effects (SSE). We previously showed that higher baseline psychological distress was associated with worsening treatment-related SSE; however, causal pathways among demographic, psychological and endpoint A1C (E-A1C) measures remain unclear. To explore these pathways, we used latent variable, structural equation models (SEM) and pooled data from 17 randomized clinical trials (N = 5209 patients, 712 centers) employing 32 different regimens of insulin and oral agents alone or in combination during 24 -52 weeks of treatment. Questionnaires of psychological distress (PD) and well-being (PWB) (24 items), and SSE distress (54 items) were completed longitudinally. At baseline, 707 patients (13.6%) were T1D (54.2% male, age 32.7 ± 14.4 years, A1C 8.0 ± 1.0%, BMI 25.1 ± 3.9 kg/m²) and 4,502 (86.4%) were T2D (58.5% male, age 57.3 ± 10.3 years, A1C 8.7 ± 1.3%, BMI 30.8 ± 5.2 kg/m²). The PD latent variable consisted of depression, anxiety, and loss of behavioral control scales. Controlling for baseline age, sex, A1C, BMI and SSE, the SEM model indicated that for T2D a 1 standard deviation (sd) better baseline PD in the PD --&amp;gt;SSE path resulted in an 11% sd improvement in SSE, while a 1 sd improvement in the SSE --&amp;gt; E-A1C path resulted in a 15% sd decrease in A1C (both p &amp;lt; 0.001). Neither coefficient was significant for T1D. Adding a PWB latent variable to the combined T1D and T2D SEM added no explanatory value, while adding an additional feedback path (E-A1C--&amp;gt;SSE) showed that influences could be bidirectional (p &amp;lt; 0.001). Results indicate that pre-existing mental health conditions, as well as worsening treatment-emergent symptoms and side effects, can interfere with A1C lowering. These findings support therapeutic regimens that include a plan for the proactive treatment of psychological and symptom distress to improve diabetes medication acceptance and adherence in order to better achieve diabetes treatment goals. Disclosure M.A. Testa: Stock/Shareholder; Spouse/Partner; GI Windows, Inc. Stock/Shareholder; Self; Phase V Technologies, Inc. M. Su: None. D.C. Simonson: Stock/Shareholder; Self; GI Windows, Inc. Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. Funding Patient-Centered Outcomes Research Institute (CE1304-6756)

Citalopram in first episode schizophrenia: The DECIFER trial

Antidepressants are frequently prescribed in first episode schizophrenia (FES) patients for negative symptoms or for subsyndromal depressive symptoms, but therapeutic benefit has not been established, despite evidence of efficacy in later-stage schizophrenia. We conducted a 52 week, placebo-controlled add-on trial of citalopram in patients with FES who did not meet criteria for major depression to determine whether maintenance therapy with citalopram would improve outcomes by preventing or improving negative and depressive symptoms. Primary outcomes were negative symptoms measured by the Scale for Assessment of Negative Symptoms and depressive symptoms measured by the Calgary Depression Scale for Schizophrenia; both were analyzed by an intent-to-treat, mixed effects, area-under-the-curve analysis to assess the cumulative effects of symptom improvement and symptom prevention over a one-year period. Ninety-five patients were randomized and 52 (54%) completed the trial. Negative symptoms were reduced with citalopram compared to placebo (p = .04); the effect size of citalopram versus placebo was 0.32 for participants with a duration of untreated psychosis (DUP) of <18 weeks (median split) and 0.52 with a DUP >18 weeks. Rates of new-onset depression did not differ between groups; improvement in depressive symptoms was greater with placebo than citalopram (p = .02). Sexual side effects were more common with citalopram, but overall treatment-emergent side effects were not increased compared to placebo. In conclusion, citalopram may reduce levels of negative symptoms, particularly in patients with longer DUP, but we found no evidence of benefit for subsyndromal depressive symptoms.

Facilitating Resolution of Life-Threatening Acute Graft-Versus-Host Disease By Supplementation of Human Chorionic Gonadotropin and Epidermal Growth Factor (Pregnyl): A Phase I Study

INTRODUCTIONPatients with severe acute graft-versus-host disease (aGVHD) are at high risk of death due to damaged organs and tissues. We have previously shown that severe aGVHD is characterized by an imbalance of circulating tissue repair factors, with elevated amphiregulin (AREG) and very low (<10 pg/ml) plasma epidermal growth factor (EGF). We hypothesized that giving supplemental EGF, contained in an inexpensive, commercially available drug (urinary-derived human chorionic gonadotropin [hCG], Pregnyl®) in addition to standard aGVHD therapy would improve outcomes. HCG has well-known immunomodulatory properties, including shifting the balance of T cells toward a regulatory (Treg) phenotype that could also be beneficial in severe aGVHD. Therefore, we tested the use of hCG/EGF in patients with Minnesota High Risk and steroid dependent or refractory aGVHD to enhance both hCG-mediated immunologic tolerance and tissue repair via supplemental EGF in a phase I study. PATIENTS AND METHODSTwenty-six patients received hCG/EGF in addition to standard aGVHD therapy. We treated 13 patients with onset Minnesota High Risk aGVHD with high-dose steroids (methylprednisolone 48 mg/m2) plus subcutaneous (SQ) injections of hCG/EGF every other day for 7 days. In the 2nd line therapy cohort, we treated 13 patients with hCG/EGF SQ every other day for 14 days, recognizing the time to response may be longer in this cohort relative to those with onset aGVHD, along with increased steroids (steroid dependent, N=5) and intensified immune suppression (steroid refractory, N=8). We then assessed response after 7 days in High Risk aGVHD and after 14 days in steroid dependent/refractory aGVHD. In both cohorts, patients with a complete or partial response (CR/PR) at the end of the initial dosing period were eligible to receive maintenance hCG/EGF SQ twice weekly for up to 5 weeks, whereas patients with no response (NR) received no further study drug doses and received best available therapy from their treating physicians. Initial hCG dosing was at 500 units hCG/m2 SQ, escalating to 2,000 units hCG/m2 in cohorts of 2, with dose assignment by the continual reassessment method. We analyzed GVHD-associated plasma biomarkers and enumerated circulating CD4+FoxP3+CD127- Tregs and CD8+ T lymphocytes during therapy. RESULTSHCG/EGF was well tolerated, with no dose-limiting toxicities. The median EGF dose was 50,833 pg/ml. The most common treatment emergent side effect was edema (N=16, 62%). At day 28 of study, responses for initial therapy were 8/13 CR (62%), 0/13 PR (0%), and 5/13 NR (38%), higher than institutional historical (n=269) 26% CR, 16% PR, 57% NR (Figure 1A). Responses for 2nd line therapy were 7/13 CR (54%), 1/13 PR (8%), 5/13 NR (38%), 4 of which were deaths (31%), improved relative to historical outcomes (n=85) of 18% CR, 19% PR, 63% NR (including 16% deaths, Figure 1A). Cytopenias were not worse during hCG/EGF; responders had a slight leukocytosis (day 7 median white blood cells [WBC] 9.7 x 109/L), returning to baseline (WBC 5.8 x 109/L, p=0.015) by day 56. Patients had increases in serum hCG (median 1.5 vs 138 IU/L, p<0.001), estradiol (median 12 vs 36 pg/ml, p=0.003), and testosterone (median 106 vs 450 ng/dl, p=0.01) from baseline to day 7; all returned to baseline by day 56. In initial therapy patients, plasma EGF rose from baseline 3 pg/ml to 25.4 pg/ml at 6 hours post-hCG/EGF dose (p=0.02); while in 2nd line patients, plasma EGF never rose from baseline 5 pg/ml. Treg expansion peaked at 131% of baseline at day 7 in Arm 1, and 145% of baseline at day 14 in Arm 2. Patients with a day 28 CR/PR had a higher median Treg/CD8 ratio at day 28 (0.11 vs 0.01, p=0.03) and a 4.6-fold reduction in plasma AREG over time (baseline median 99.6 pg/ml to 21.8 pg/ml at day 56, p=0.006, Figure 1B). CONCLUSIONSHCG/EGF is a novel and well-tolerated adjunct therapy in high-risk and steroid-dependent/refractory aGVHD, associated with minimal toxicity and encouraging response rates. The mechanisms of benefit may include immunomodulation via Treg expansion despite high-dose steroids and facilitation of tissue repair with detectable increases in circulating EGF. The optimal dose and duration of hCG/EGF are under investigation, with ongoing dose escalation in patients with steroid-refractory aGVHD based upon these initial results. Decreasing plasma AREG over time may reflect successful treatment of life-threatening aGVHD. DisclosuresHoltan:Incyte: Consultancy. Bachanova:Gamida Cell: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding. Brunstein:Gamidacell: Research Funding. Ustun:novartis: Speakers Bureau. Wagner:Novartis: Research Funding; Magenta Therapeutics: Consultancy, Research Funding. Blazar:Kadmon Corporation, LLC: Consultancy, Research Funding. MacMillan:Angiocrine: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Equillium: Consultancy. Weisdorf:SL Behring: Consultancy; FATE: Consultancy; Equillium: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy.

Effect of Aromatase Inhibitor Therapy on Sleep and Activity Patterns in Early-stage Breast Cancer

IntroductionAdherence to aromatase inhibitor (AI) therapy is poor, often because of treatment-emergent side effects, including musculoskeletal symptoms, fatigue, and insomnia. In the present analysis, we examined the sleep patterns and daytime function both objectively using actigraphy and subjectively using validated questionnaires in women initiating AI therapy. Patients and MethodsPostmenopausal women with stage 0-III hormone receptor-positive breast cancer who were initiating AI therapy were eligible. The patients wore actigraphy devices for 10 consecutive days and completed questionnaires at baseline before the initiation of AI and after 3 months of AI therapy. Associations between the baseline demographics and symptoms, changes in patient-reported outcomes and actigraphy measures from baseline to 3 months of AI therapy and discontinuation of AI therapy were examined using sign tests, logistic regression models, Spearman's correlation, and linear mixed models. ResultsForty-two patients (86%) completed the baseline assessments and 23 patients (47%) completed both the baseline and the 3-month assessments. Objectively measured daytime function as measured by total daytime activity decreased during the 3 months after starting AI (232,566 activity count vs. 204,205 activity count; P = .023), and the decrease was more evident in women with higher baseline physical function. Reduced daytime activity correlated with increased fatigue (ρ = −0.49; P = .017). ConclusionDaytime function decreased after initiation of AI therapy and correlated moderately with increased fatigue, although no association was identified with changes in pain or sleep quality. Additional studies are required to understand why function is reduced, which could have implications for interventions to improve patient tolerance of, and persistence with, AI therapy.

Use of Prazosin for Pediatric PTSD-Associated Nightmares and Sleep Disturbances: A Retrospective Chart Review

IntroductionYouth exposed to trauma have an increased risk for developing posttraumatic stress disorder (PTSD) and associated sleep disturbances and nightmares. The alpha-1 antagonist prazosin reduces sleep disturbances and nightmares in adults with PTSD; however, its use in youth with PTSD has not been systematically evaluated. We retrospectively examined the tolerability and clinical outcomes associated with prazosin treatment in youth with PTSD-related nightmares and dysomnias.MethodA retrospective chart review identified youth with PTSD (N = 40) treated with prazosin between 2014 and 2016 in a trauma clinic. We assessed the UCLA PTSD Reaction Index for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition scores (and sub-scores for intrusive, hyperarousal, avoidant and negative cognition/mood symptoms) and sleep scale, as well as adverse events and vital signs. Linear mixed effects models were utilized to evaluate the change in symptom severity, and vital signs were monitored throughout treatment.ResultFollow-up data were available for 34 patients with PTSD (mean age 13.4 ± 2.9 years, 82% female), of whom 76% had a history of sexual abuse and 65% had at least one comorbid psychiatric disorder. The mean duration of prazosin treatment was 10.2 ± 8.1 (range 2–30) weeks, and the mean number of follow-up visits was 3 ± 1.23. Of these 34 patients, 79% received trauma-focused cognitive behavioral therapy. The dose range of prazosin was 1–15 mg at every bedtime (0.02–0.3 mg/kg), with 35% receiving ≥5 mg/day. Treatment-emergent side effects were reported by 26% (n = 8) of patients, including dizziness (18%), anxiety (9%) and headaches (6%). Prazosin treatment was associated with improved sleep and nightmares over time (pre-treatment 7.3 ± 0.9, post-treatment 3.1 ± 2.4; p < 0.001).ConclusionPrazosin was well-tolerated and associated with improvements in nightmares and sleep in youth with PTSD. Adverse events were consistent with the known side-effect profile of prazosin and included dizziness and nausea.

Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review.

Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis.

Subjective well-being under clozapine measured with the Serbian version of GASS-C: Preliminary results

IntroductionClinical benefits of antipsychotic treatment depend on the efficacy and on the patients’ tolerability and compliance. To reduce patient initiated treatment discontinuation, timely detection of treatment emergent side effects is essential. The Glasgow Antipsychotic Side-effects scale for clozapine (GASS-C) is a recently developed instrument to measure subjectively experienced clozapine side effects.ObjectivesTimely detection of unreported clozapine related side-effects.AimDocumenting the prevalence of side-effects in schizophrenia or chronic psychotic disorder with the Serbian version of the GASS-C.MethodsThe sample included 95 in and outpatients with schizophrenia or chronic psychotic disorder. All subjects filled out the Serbian version of the GASS-C and a sociodemographic questionnaire.ResultsThe median age was 46.1 years; 53.7% of subjects were male. Clozapine doses ranged from 25 to 423 mg. Drowsiness (78%) was the most commonly reported side-effect. Overall, 16.8% of the patients added other complaints, such as headache, pain, hand or leg numbing or nightmares. According to GASS-C total score categorization [2], only 4.2. % of subjects were rated with severe side-effects, while 14% of themselves rated their symptoms as severe or distressing. More side effects were reported by female patients and by inpatients. Only a weak positive correlation was found between the severity of the side effects and clozapine dosage.ConclusionsWe found the GASS-C to be a useful instrument that elicits both unknown side-effects and patients rating of their severity. Side effects did not clearly relate to the prescribed dose. Future research should include the relation of clozapine plasma levels with side effects assessed with GASS-C.Disclosure of interestThe authors have not supplied their declaration of competing interest.