Adverse Events In Clinical Trials Research Articles

A new method to analyze adverse events longitudinally in oncology clinical trials.

3622 Background: There are significant limitations to the current method for displaying treatment-related adverse events (AE) in clinical trials. Tables displaying grade 3 and 4 AEs do not capture toxicity profiles that evolve over time and do not provide clinically relevant information on when a given AE could arise, its probable duration and its severity at a given point in therapy. We developed a novel method of analysis to better capture and represent longitudinal AE data. Methods: Graphical and analytical routines were developed to analyze adverse events longitudinally. Mean symptom and toxicity values are plotted over time on a single axis for direct comparison. Butterfly plots compare adverse events by treatment arms longitudinally. Multiple longitudinal techniques (repeated measures modeling, profile analysis, area under the curve analysis, change from baseline, and time to event) are included. Heat maps, event charts and stream plots are produced for individual patient results over time. Results: The methodology was validated in two completed clinical trials in colorectal cancer treatment (N9741) and cancer control (979254). In N9741, a higher incidence and severity of diarrhea, nausea and vomiting in patients on IROX (irinotecan/oxaliplatin) versus FOLFOX (fluorouracil/oxaliplatin) was most pronounced in the first treatment cycle and declined sharply by cycle 2. An increased incidence of alopecia in this cohort was also most apparent upfront, from the first to the second cycle, as compared to a lower overall incidence of alopecia with a gradual rise from cycles 1 through 5 in patients on FOLFOX. In study 979254, a higher incidence of dry mouth in patients using venlafaxine 150 mg/d as compared with placebo was most prominent only later in therapy, at weeks 4 and 5 (incidence of 22% for placebo and 13% for venlafaxine 150 mg/d at week 1, p=0.25, versus, 2.2% and 49%, respectively, at week 5, p=0.0001). Conclusions: A new method of analyzing AEs in clinical trials that incorporates the dimension of time offers a more complete depiction of chemotherapy toxicity than current methods. Longitudinal analyses of toxicity over time can provide enhanced patient education and guide clinical management on a given chemotherapy strategy.

NLA Task Force on Statin Safety--2014 update.

1933-2874/$ see front matter 2014 http://dx.doi.org/10.1016/j.jacl.2014.03 Statins are the most widely prescribed class of medications in the United States and their benefits for lowering lowdensity lipoprotein cholesterol (LDL-C) and reducing the risk for coronary heart disease (CHD) are well documented. Statins have been the cornerstone of pharmacotherapy for the management of high blood cholesterol levels virtually since their development. The American Heart Association /American College of Cardiology 2013 guidelines recently expanded the number of individuals eligible for statin therapy by recommending it for those with: (1) clinical atherosclerotic cardiovascular disease (ASCVD), (2) LDL-C $190 mg/dL, (3) type 2 diabetes and age between 40 and 75 years with LDL-C 70 to 189 mg/dL, and (4) an estimated 10-year risk of ASCVD $7.5% and age 40 to 75 years. Considering only those who qualify according to their estimated 10-year risk of ASCVD, it has been reported that of the 101 million people in the United States age 40 to 79 years who do not have cardiovascular disease, 33 million have an estimated 10-year risk of ASCVD $7.5%, and another 13 million have a risk between 5% and 7.4%. Using crude global estimates, 920 million people worldwide would be expected to be

Emergence Of New Responders To Treatment And New Adverse Events In Clinical Trials Of Pregabalin In Diabetic Peripheral Neuropathy And Postherpetic Neuralgia (P7.299)

Emergence Of New Responders To Treatment And New Adverse Events In Clinical Trials Of Pregabalin In Diabetic Peripheral Neuropathy And Postherpetic Neuralgia (P7.299)

Managing flushing and gastrointestinal events associated with delayed-release dimethyl fumarate: Experiences of an international panel

Strategies for monitoring and managing the known adverse event (AE) profile of therapies for relapsing–remitting multiple sclerosis have become key to the optimization of patient outcomes. Delayed-release dimethyl fumarate (DMF) was associated with an increased risk of flushing and gastrointestinal (GI) AEs in clinical trials. A survey of clinicians with significant research experience using delayed-release DMF was conducted to provide guidance to clinicians using delayed-release DMF in clinical practice on the management of flushing and GI tolerability AEs. Recommendations for prophylaxis included educating the patient about flushing and GI AEs associated with delayed-release DMF and recommending administration with food. A variety of symptomatic treatments were utilized during the delayed-release DMF clinical trials in patients presenting with delayed-release DMF–related flushing or GI AEs that were severe or bothersome enough to warrant pharmacological intervention.

(396) Pregabalin is effective irrespective of antidepressant class in fibromyalgia patients currently receiving antidepressant medication for comorbid depression

(396) Pregabalin is effective irrespective of antidepressant class in fibromyalgia patients currently receiving antidepressant medication for comorbid depression

(399) Emergence of new responders to treatment and new adverse events in clinical trials of pregabalin in patients with neuropathic pain due to spinal cord injury

Patients with spinal cord injury (SCI) commonly experience chronic neuropathic pain for which pregabalin is currently the only FDA-approved treatment. A greater understanding of when these patients first respond to treatment and when adverse events (AEs) emerge or worsen could aid design of new proof-of-concept studies and help guide treatment of patients. This was a pooled analysis of two 12- and 16-week, randomized, placebo-controlled, double-blind trials of pregabalin (150-600mg/day) in SCI patients with neuropathic pain (n=356).

Roflumilast in the management of chronic obstructive pulmonary disease

The pharmacology, pharmacokinetics, efficacy, and safety of roflumilast-the first in a new class of agents for managing chronic obstructive pulmonary disease (COPD)-are reviewed. Roflumilast (Daliresp, Forest Pharmaceuticals) is an oral phosphodiesterase-4 (PDE-4) inhibitor that targets inflammatory cells involved in triggering COPD exacerbations. The only PDE-4 inhibitor approved by the Food and Drug Administration, roflumilast is available in 500-μg tablets to be administered once daily. In six placebo-controlled trials involving nearly 4500 patients with COPD of varying severity, the use of roflumilast was associated with reduced COPD exacerbations and improved lung function, as determined by spirometry, with the greatest benefits observed in patients with severe COPD who had chronic bronchitis and a history of frequent exacerbations; clinical efficacy was demonstrated in patients receiving roflumilast alone as well as those receiving concomitant inhaled long-acting β2-agonist (LABA) therapy. The most common adverse events in clinical trials of roflumilast were diarrhea, nausea, and headache. Weight loss and an increased risk of psychiatric events have also been reported in association with roflumilast use. As roflumilast is rapidly converted to its active metabolite via cytochrome P-450 (CYP) isoenzymes, coadministration with strong CYP inducers is not recommended. Research to better define roflumilast's role in COPD management, including a study to determine whether it confers additive benefits when used in combination with standard inhaled therapies other than LABAs, is ongoing. Roflumilast is a safe and effective option for controlling COPD exacerbations in a defined subset of patients for whom the available treatment alternatives are very limited.

Paliperidone Extended-Release: Safety and Tolerability from a Metabolic Profile Perspective

Pharmacologic management strategies for schizophrenia, a relatively common psychotic disorder, include the use of typical and atypical antipsychotic drugs. In general, typical (or conventional) antipsychotics have a proven track record in effectively managing the positive symptoms of schizophrenia but sometimes lack efficacy in treating negative symptoms. The conventional agents are also associated with adverse neurologic effects such as extrapyramidal symptoms (EPS). The development of atypical antipsychotics has partly ameliorated the issue of EPS induced by typical antipsychotics. However, several of these atypical antipsychotic agents have been associated with adverse metabolic effects, including weight gain, dyslipidemia, and increased serum glucose levels. Paliperidone (9-hydroxy-riperidone) extended-release (ER) is an atypical antipsychotic indicated for the treatment of schizophrenia which utilizes a patented oral osmotic system technology that provides constant drug delivery over the course of the day. The efficacy and safety of paliperidone ER in patients with schizophrenia have been established. This review focuses on the metabolic safety of paliperidone ER in patients with schizophrenia. Clinical trials have demonstrated a lack of significant change in lipid profiles with paliperidone ER; furthermore, reported incidences of glucose-related adverse events in clinical trials were very low and similar to those seen with placebo. While dose-related increases in bodyweight of 1-2 kg have been observed with paliperidone ER, there are few reports of clinically relevant increases in bodyweight during treatment. Placebo-controlled trials indicate that the risk of developing metabolic disorders with paliperidone ER is low and similar to that seen with placebo. Furthermore, the ER formulation of paliperidone may offer potential advantages over atypical antipsychotics such as risperidone, particularly with regard to side effects and compliance, but comparative studies are needed.

Rasagiline meta-analysis: a spotlight on clinical safety and adverse events when treating Parkinson's disease

Introduction: Rasagiline (Azilect, AGN 1135) is a selective irreversible inhibitor of monoamine oxidase B (MAO-B). MAO-B regulates the brain concentrations of important neurotransmitters that are related to movement, emotion, and cognition. Oral rasagiline, as monotherapy or as adjunctive therapy to levodopa, was effective in the symptomatic treatment of adult patients with Parkinson's disease participating in double-blind, placebo-controlled, international studies.Areas covered: This article reviews the reported adverse effects of rasagiline. A MEDLINE search was performed for all articles from 1990 to present, which reported any adverse effects from rasagiline or related references. We conducted an analysis of the adverse effects of rasagiline based on the reported clinical studies. Furthermore, we compared the incidence of adverse events in clinical trials for rasagiline and placebo.Expert opinion: Among the most frequently reported adverse effects for rasagiline as monotherapy are headache, dizziness, and insomnia. Depression, dizziness, somnolence, and other sleep disorders are reported when used in combination therapy. Our analysis demonstrates that the most frequently reported adverse effects in trials did not occur more often with rasagiline than placebo. In conclusion, rasagiline is a well-tolerated MAO-B inhibitor that may help to achieve the desired level of clinical benefit in Parkinson's disease.

Bayesian Inference on Risk Differences: An Application to Multivariate Meta-Analysis of Adverse Events in Clinical Trials

Multivariate meta-analysis is useful in combining evidence from independent studies that involve several comparisons among groups based on a single outcome. For binary outcomes, the commonly used statistical models for multivariate meta-analysis are multivariate generalized linear mixed effects models which assume risks, after some transformation, follow a multivariate normal distribution with possible correlations. In this article, we consider an alternative model for multivariate meta-analysis where the risks are modeled by the multivariate beta distribution proposed by Sarmanov. This model has several attractive features compared to the conventional multivariate generalized linear mixed effects models, including simplicity of likelihood function, no need to specify a link function, and a closed-form expression of distribution functions for study-specific risk differences. We investigate the finite sample performance of this model through simulation studies and illustrate its use with an application to multivariate meta-analysis of adverse events of tricyclic antidepressant treatment in clinical trials.

Opioid related adverse events in clinical trials- indicators for abuse liability

Opioids are effective at managing moderate to severe pain; however, several liabilities are associated with their use including abuse potential and risk for dependence. Detecting abuse signals early on can guide future clinical development and influence trial design around the understanding of those liabilities. One approach involves collecting abuse-related AEs in studies with recreational opioid users, who are particularly sensitive to positive opioid effects. This analysis explores the potential for AEs to signal abuse and other liabilities early on. Adverse Event and PD data for opioids were obtained from single-dose, randomized, double-blind crossover studies in recreational opioid users (8 Studies; N=185). Opioids included Hydromorphone (4, 8, 16mg); Hydrocodone 60 mg; Morphine 120mg; Oxymorphone 15 and 30mg; Oxycodone 30, 40, and 60mg3; and intravenous Hydromorphone 30μg/kg and Oxycodone 0.07mg/kg. AEs were coded and categorized as Actual Abuse/Dependence [AD] and those suggestive of Mood-Elevating (ME) or Sedative (SED) effects. Percentage of AE incidence (% of subjects) across treatments was summarized and correlations between PD measures and AEs were performed. No AD adverse events were reported in >750 exposures. The highest incidence of ME events was observed with oxycodone (50%) followed by hydromorphone (∼25%). Sedative effects were reported less often than ME effects. The highest incidence of sedative effects was reported in oxycodone (∼45%) followed by placebo (24%) and oxymorphone (∼21%). Across opioids, the most common ME event was ‘euphoric mood', and ‘somnolence’ was the most common SED event. Drug Liking/Overall Drug Liking scores were higher in subjects who reported euphoric mood as an AE. There was a significant correlation (p<0.001) between median Drug Liking/Overall Drug Liking scores and euphoric mood AE incidence. This evaluation indicated that AEs were generally consistent with PD results suggesting that clinical trial AE patterns may be useful for detecting abuse liability in early drug development. Opioids are effective at managing moderate to severe pain; however, several liabilities are associated with their use including abuse potential and risk for dependence. Detecting abuse signals early on can guide future clinical development and influence trial design around the understanding of those liabilities. One approach involves collecting abuse-related AEs in studies with recreational opioid users, who are particularly sensitive to positive opioid effects. This analysis explores the potential for AEs to signal abuse and other liabilities early on. Adverse Event and PD data for opioids were obtained from single-dose, randomized, double-blind crossover studies in recreational opioid users (8 Studies; N=185). Opioids included Hydromorphone (4, 8, 16mg); Hydrocodone 60 mg; Morphine 120mg; Oxymorphone 15 and 30mg; Oxycodone 30, 40, and 60mg3; and intravenous Hydromorphone 30μg/kg and Oxycodone 0.07mg/kg. AEs were coded and categorized as Actual Abuse/Dependence [AD] and those suggestive of Mood-Elevating (ME) or Sedative (SED) effects. Percentage of AE incidence (% of subjects) across treatments was summarized and correlations between PD measures and AEs were performed. No AD adverse events were reported in >750 exposures. The highest incidence of ME events was observed with oxycodone (50%) followed by hydromorphone (∼25%). Sedative effects were reported less often than ME effects. The highest incidence of sedative effects was reported in oxycodone (∼45%) followed by placebo (24%) and oxymorphone (∼21%). Across opioids, the most common ME event was ‘euphoric mood', and ‘somnolence’ was the most common SED event. Drug Liking/Overall Drug Liking scores were higher in subjects who reported euphoric mood as an AE. There was a significant correlation (p<0.001) between median Drug Liking/Overall Drug Liking scores and euphoric mood AE incidence. This evaluation indicated that AEs were generally consistent with PD results suggesting that clinical trial AE patterns may be useful for detecting abuse liability in early drug development.

Everolimus (RAD001): First Systemic Treatment for Subependymal Giant Cell Astrocytoma Associated with Tuberous Sclerosis Complex

Everolimus (RAD001), a mTOR inhibitor, was initially used as an immunosuppressant in organ transplant patients; however, it also has significant antineoplastic properties. In patients with subependymal giant cell astrocytomas (SEGAs) associated with tuberous sclerosis complex who are not candidates for surgery, single-agent everolimus has demonstrated the ability to significantly reduce SEGA volume with good tolerability. In the Phase III, randomized, placebo-controlled trial, everolimus was associated with a SEGA response rate of 35% compared with 0% in the placebo group. The most common adverse events in clinical trials were stomatitis/mouth ulceration and upper respiratory tract infections, and most adverse events were grade 1 or 2; grade 4 events were rare.

The Feasibility, Perceived Satisfaction, and Value of Using Synchronous Webinars to Educate Clinical Research Professionals on Reporting Adverse Events in Clinical Trials

Clinical research professionals are faced with decreased funding and increased workloads; innovative methods of professional development programs are necessary to accommodate these factors. This study evaluated the feasibility, perceived satisfaction, and value of using webinars to educate clinical research professionals on reporting adverse events commonly experienced in pediatric oncology clinical trials. The setting incorporated synchronous web-based educational technology. Constructivist learning provides the theoretical framework for this study. Participants evaluated the professional development program at 2 time points: (a) at the conclusion and (b) 4 to 6 weeks afterward, using survey method. Synchronous webinars were both economical and effective in educating clinical research professionals across institutional sites. Participants reported exceptionally high levels of satisfaction with the accessibility, scope, quality, and interactivity of the professional development program. The vast majority of participants reported that the education would assist with reporting adverse events in pediatric oncology clinical trials and this perception persisted into clinical practice. Although the results of this study were intended to guide future educational efforts of the Children's Oncology Group, they may also apply to other cooperative groups.

Failure to report harms and adverse events in clinical trials: Why does the problem continue?

Good Clinical Practice (GCP) is an internationally adoptedstandard for clinical trials, and one important component ofthis document is the requirement that investigators informtrial sponsors of serious adverse events, defined as ‘‘anyuntoward medical occurrence that results in hospitalizationor prolongation of hospitalization, or is life-threatening, orresults in death or disability, including birth defects.’’

Linking Toxicity to the Target

Linking Toxicity to the Target

Challenges in Coding Adverse Events in Clinical Trials: A Systematic Review

BackgroundMisclassification of adverse events in clinical trials can sometimes have serious consequences. Therefore, each of the many steps involved, from a patient's adverse experience to presentation in tables in publications, should be as standardised as possible, minimising the scope for interpretation. Adverse events are categorised by a predefined dictionary, e.g. MedDRA, which is updated biannually with many new categories. The objective of this paper is to study interobserver variation and other challenges of coding.MethodsSystematic review using PRISMA. We searched PubMed, EMBASE and The Cochrane Library. All studies were screened for eligibility by two authors.ResultsOur search returned 520 unique studies of which 12 were included. Only one study investigated interobserver variation. It reported that 12% of the codes were evaluated differently by two coders. Independent physicians found that 8% of all the codes deviated from the original description. Other studies found that product summaries could be greatly affected by the choice of dictionary. With the introduction of MedDRA, it seems to have become harder to identify adverse events statistically because each code is divided in subgroups. To account for this, lumping techniques have been developed but are rarely used, and guidance on when to use them is vague. An additional challenge is that adverse events are censored if they already occurred in the run-in period of a trial. As there are more than 26 ways of determining whether an event has already occurred, this can lead to bias, particularly because data analysis is rarely performed blindly.ConclusionThere is a lack of evidence that coding of adverse events is a reliable, unbiased and reproducible process. The increase in categories has made detecting adverse events harder, potentially compromising safety. It is crucial that readers of medical publications are aware of these challenges. Comprehensive interobserver studies are needed.

Intranasal Ketorolac

Ketorolac is a member of the pyrrolo-pyrrole group of NSAIDs, and has been available in several formulations for some time, for the treatment of pain. Intranasal ketorolac has recently become available. Intranasal ketorolac was effective in providing short-term relief from postoperative pain in four well designed, phase II or III trials. In the two phase III trials, a single intranasal dose of ketorolac 31.5 mg, with or without backup analgesia, was associated with significantly higher 6-hour summed post-treatment pain intensity difference scores (primary endpoint) than placebo in adult patients with acute pain following major surgery, including abdominal and orthopaedic surgery. Intranasal ketorolac 31.5 mg up to three or four times daily for ≤5 days also had an opioid-sparing effect in these trials, with significantly less morphine used among ketorolac than among placebo recipients over the first 48 hours of treatment. Moreover, a greater proportion of ketorolac recipients experienced analgesia onset within 1 and 1.5 hours but not 2 hours than placebo recipients, indicating a more rapid onset with intranasal ketorolac. In adult patients with acute pain following major surgery, intranasal ketorolac 31.5 mg three or four times daily for ≤5 days was generally well tolerated. Most adverse events in clinical trials were considered to be of mild severity and transient in nature, with those in the phase III trials generally being characteristic of common events following major abdominal surgery and morphine administration.

Axitinib: Oral tyrosine kinase inhibitor for renal cell carcinoma

Axitinib: Oral tyrosine kinase inhibitor for renal cell carcinoma

Tranexamic Acid

Tranexamic acid, a synthetic derivative of the amino acid lysine, is an antifibrinolytic agent that acts by binding to plasminogen and blocking the interaction of plasmin(ogen) with fibrin, thereby preventing dissolution of the fibrin clot. Tranexamic acid (Transamin®) is indicated in Japan for use in certain conditions with abnormal bleeding or bleeding tendencies in which local or systemic hyperfibrinolysis is considered to be involved. This article reviews the efficacy and tolerability of tranexamic acid in conditions amenable to antifibrinolytic therapy and briefly overviews the pharmacological properties of the drug. In large, randomized controlled trials, tranexamic acid generally significantly reduced perioperative blood loss compared with placebo in a variety of surgical procedures, including cardiac surgery with or without cardiopulmonary bypass, total hip and knee replacement and prostatectomy. In many instances, tranexamic acid also reduced transfusion requirements associated with surgery. It also reduced blood loss in gynaecological bleeding disorders, such as heavy menstrual bleeding, postpartum haemorrhage and bleeding irregularities caused by contraceptive implants. Tranexamic acid significantly reduced all-cause mortality and death due to bleeding in trauma patients with significant bleeding, particularly when administered early after injury. It was also effective in traumatic hyphaema, gastrointestinal bleeding and hereditary angioneurotic oedema. While it reduces rebleeding in subarachnoid haemorrhage, it may increase ischaemic complications. Pharmacoeconomic analyses predicted that tranexamic acid use in surgery and trauma would be very cost effective and potentially life saving. In direct comparisons with other marketed agents, tranexamic acid was at least as effective as ε-aminocaproic acid and more effective than desmopressin in surgical procedures. It was more effective than desmopressin, etamsylate, flurbiprofen, mefenamic acid and norethisterone, but less effective than the levonorgestrel-releasing intra-uterine device in heavy menstrual bleeding and was as effective as prednisolone in traumatic hyphaema. Tranexamic acid was generally well tolerated. Most adverse events in clinical trials were of mild or moderate severity; severe or serious events were rare. Therefore, while high-quality published evidence is limited for some approved indications, tranexamic acid is an effective and well tolerated antifibrinolytic agent.

Indacaterol

Indacaterol inhalation powder (Onbrez® Breezhaler®) is a long-acting, selective β(2)-adrenoceptor agonist that is indicated for the maintenance bronchodilator treatment of airflow obstruction in adults with chronic obstructive pulmonary disease (COPD). This article reviews the clinical efficacy and tolerability of indacaterol 150 and 300 μg once daily in adults with moderate to severe COPD, as well as reviewing indacaterol's pharmacological properties and results of a cost-utility analysis. Indacaterol has a fast onset of action after the first dose and is effective over 24 hours, allowing for once-daily administration. In short-term trials (≤21 days) in patients with COPD, once-daily indacaterol 150 or 300 μg significantly improved lung function, exercise endurance and lung hyperinflation relative to placebo. In large, longer-term clinical studies (12 weeks to 1 year) in patients with moderate to severe COPD, once-daily indacaterol 150 or 300 μg improved lung function (primary endpoint) significantly more than placebo, and improvements were significantly greater than twice-daily formoterol 12 μg or salmeterol 50 μg, and noninferior to once-daily tiotropium bromide 18 μg (all agents were administered via inhalation). Overall, indacaterol improved dyspnoea, use of rescue medication and general health status significantly more than placebo, salmeterol or tiotropium bromide, and the degree of improvement in these endpoints was similar to or greater than that achieved with formoterol. Improvements were sustained over the long term (1 year), with no evidence of tolerance. Combination therapy with indacaterol plus tiotropium bromide improved lung function, dyspnoea, rescue medication use and general health status significantly more than tiotropium bromide alone in patients with moderate to severe COPD. Indacaterol is generally well tolerated when used alone or in combination with tiotropium bromide in patients with COPD and has not been associated with any safety issues. The most common adverse event in clinical trials was COPD worsening, which occurred more commonly with placebo than indacaterol. Indacaterol was not associated with an increased risk of cardiovascular adverse events. In a cost-utility analysis from a German healthcare payer perspective, once-daily indacaterol 150 μg was dominant (i.e. more effective with lower total costs) to once-daily tiotropium bromide 18 μg and twice-daily salmeterol 50 μg in the treatment of patients with COPD. In conclusion, indacaterol provides a valuable option for the maintenance treatment of adults with COPD.