Subjective Adverse Events Research Articles

A randomized, double-blind, placebo-controlled study of the safety and tolerance of regadenoson in subjects with stage 3 or 4 chronic kidney disease

BackgroundThe safety and tolerability of regadenoson, a pharmacologic stress agent that is excreted primarily by the kidneys, were examined in subjects with chronic kidney disease (CKD). MethodsThis multicenter, double-blind, randomized, placebo-controlled study involved men and women, ≥18 years of age, with stage 3 or 4 [estimated glomerular filtration rate (eGFR) 30-59 mL/minute/1.73 m2 and 15-29 mL/minute/1.73 m2, respectively] CKD and known or suspected coronary artery disease. Subjects were randomized 2:1 to receive one 10-second intravenous injection of regadenoson 0.4 mg or placebo. The primary outcome measure was the frequency of serious adverse events over 24-h post-dose. ResultsThe study included 432 subjects with stage 3 (regadenoson n = 287; placebo n = 145) and 72 with stage 4 (regadenoson n = 47; placebo n = 25) CKD. No serious adverse events or deaths were reported over 24-h post-dose. The overall adverse event incidence was higher with regadenoson than placebo (62.6% vs 21.2%; P < .0001). Of the most common adverse events (≥5%) reported by subjects receiving regadenoson, headache (24.9% vs 7.1%), dyspnea (19.2% vs 0.6%), chest discomfort (14.7% vs 0.6%), nausea (14.7% vs 1.2%), flushing (12.0% vs 1.8%), and dizziness (9.6% vs 0.6%) occurred significantly more often (P < .0001) with regadenoson than placebo. There were no trends for clinically meaningful changes in eGFR from baseline to 24-h post-dose in subjects with stage 3 or 4 CKD. ConclusionsRegadenoson was not associated with any serious or unexpected adverse events in subjects with stage 3 or 4 CKD.

A Randomized, Double‐Blind, Placebo‐Controlled Evaluation of the Safety and Efficacy of Avanafil in Subjects with Erectile Dysfunction

Phosphodiesterase type 5 (PDE5) inhibitors have become standard treatment for erectile dysfunction (ED). To prospectively evaluate the safety and efficacy of avanafil, a novel PDE5 inhibitor, in men with mild to severe ED. In this multicenter, double-blind, Phase 3 trial, 646 subjects were randomized to receive avanafil (50 mg, 100 mg, 200 mg) or placebo throughout a 12-week treatment period. Subjects were instructed to take study drug 30 minutes prior to initiation of sexual activity. At least a 12-hour separation time between doses was required; no restrictions were placed on food or alcohol intake. Improvement in erectile function (EF) was measured by Sexual Encounter Profile questions 2 and 3 (SEP2 and SEP3) and by the EF domain of the International Index of Erectile Function (IIEF) questionnaire. Mean change in percentage of successful sexual attempts (SEP2 and SEP3) and IIEF-EF domain score significantly favored all doses of avanafil over placebo (P ≤ 0.001). Secondary analyses demonstrated achievement of successful intercourse by subjects within 15 minutes of dosing. Of the 300 sexual attempts made during this interval, 64% to 71% were successful in avanafil-treated subjects compared with 27% in placebo-treated subjects. Successful intercourse was also demonstrated >6 hours post dosing, with 59% to 83% of the 80 sexual attempts successful in avanafil-treated subjects compared with 25% of placebo-treated subjects. The most commonly reported adverse events in subjects taking avanafil included headache, flushing, and nasal congestion; there were no drug-related serious adverse events. Following 12 weeks of avanafil treatment without food or alcohol restrictions, significant improvements in sexual function were observed with all 3 doses of avanafil compared with placebo. Successful intercourse was observed as early as 15 minutes and >6 hours after dosing in some subjects. Avanafil was generally well tolerated for the treatment of ED.

Is it safe to use propofol in the emergency department? A randomized controlled trial to compare propofol and midazolam

BackgroundThis study examined the safety and effectiveness of the procedural sedation analgesia (PSA) technique carried out in the emergency department (ED) of a university hospital over a period of 1 year. The research was done to compare the effectiveness and efficacy of moderate sedation of fentanyl combined with either midazolam or propofol for any brief, intense procedure in the ED setting.AimsThe objectives were to observe the occurrence of adverse events in subjects undergoing PSA for intense and painful procedures in the emergency department and to implement the use of capnography as a method of monitoring the patients when they were under PSA.MethodsForty patients were selected for this study. They were randomly divided into two equal groups using the computer-generated random permuted blocks of four patients. Twenty patients were grouped together as group A and the remaining 20 patients as group B. Drugs used were single blinded to prevent any bias. Drug A was propofol and fentanyl, while drug B was midazolam and fentanyl. The procedures involved included orthopedic manipulation such as reduction of fractures, reduction of dislocated joints, abscess drainage, wound debridement, laceration wound repair and cardioversion. All of the subjects were monitored for their vital signs and end tidal carbon dioxide level every 10 min till the PSA was completed. The duration of stay in the ED was documented when the subjects had completed the procedure and were released from the department.ResultOf the study population, 75.6% were males. The mean age was 37.8 years (95% CI 33.2, 39.8). None of the patients developed any major complications while under PSA. The vital signs pre-, intra- and post-procedure were not significantly different in either the propofol or mizadolam groups (p value >0.05).ConclusionThis study had proven that there was no difference in adverse event occurrence between the studied drugs during PSA. Propofol can be recommended for use in PSA if the operator is well trained and familiar with the drug.

Parathyroid Hormone-Related Protein for the Treatment of Postmenopausal Osteoporosis: Defining the Maximal Tolerable Dose

PTH is the only approved skeletal anabolic agent for the treatment of human osteoporosis. Unlike PTH, which is a mixed anabolic and catabolic agent, PTHrP displays features suggesting that it may be a pure anabolic agent when intermittently administered. The full dose range of PTHrP is unknown. The primary objective of the study was to define the complete therapeutic window and dose-limiting toxicities of PTHrP. The secondary objective was to determine whether PTHrP retains a pure anabolic profile at the highest usable doses. This was a single-blinded, two-part, dose-escalating clinical trial. The study was conducted in a university academic setting. Participants included 41 healthy postmenopausal women between the ages of 45 and 75 yr. INTERVENTIONs included PTHrP(1-36) or placebo in a dose-escalating design for 3 wk. Safety measures (hypercalcemia, nausea, vomiting, hemodynamics, flushing, miscellaneous) and bone turnover markers were measured. Intermittent PTHrP was administered safely and without serious adverse events in subjects receiving 500 and 625 microg/d for 3 wk. Subjects receiving 750 microg/d developed mild hypercalcemia. Bone turnover markers suggested that even at the highest doses, daily sc PTHrP may not activate bone resorption, i.e. may be purely anabolic. Interestingly, when hypercalcemia occurred, it may have resulted not from bone resorption but from activation of intestinal calcium absorption by 1,25 dihydroxyvitamin D. In doses as high as 750 microg/d, in contrast to PTH, intermittently administered PTHrP appears to act as a pure skeletal anabolic agent. Surprisingly, PTHrP in the high doses studied activates 1,25 dihydroxyvitamin D production. Dosing information obtained herein can be used to design a longer term head-to-head comparative efficacy trial of PTHrP vs. PTH.

Potential of Albiglutide, a Long-Acting GLP-1 Receptor Agonist, in Type 2 Diabetes

OBJECTIVETo evaluate the efficacy, safety, and tolerability of incremental doses of albiglutide, a long-acting glucagon-like peptide-1 receptor agonist, administered with three dosing schedules in patients with type 2 diabetes inadequately controlled with diet and exercise or metformin monotherapy.RESEARCH DESIGN AND METHODSIn this randomized multicenter double-blind parallel-group study, 356 type 2 diabetic subjects with similar mean baseline characteristics (age 54 years, diabetes duration 4.9 years, BMI 32.1 kg/m2, A1C 8.0%) received subcutaneous placebo or albiglutide (weekly [4, 15, or 30 mg], biweekly [15, 30, or 50 mg], or monthly [50 or 100 mg]) or exenatide twice daily as an open-label active reference (per labeling in metformin subjects only) over 16 weeks followed by an 11-week washout period. The main outcome measure was change from baseline A1C of albiglutide groups versus placebo at week 16.RESULTSDose-dependent reductions in A1C were observed within all albiglutide schedules. Mean A1C was similarly reduced from baseline by albiglutide 30 mg weekly, 50 mg biweekly (every 2 weeks), and 100 mg monthly (−0.87, −0.79, and −0.87%, respectively) versus placebo (−0.17%, P < 0.004) and exenatide (−0.54%). Weight loss (−1.1 to −1.7 kg) was observed with these three albiglutide doses with no significant between-group effects. The incidence of gastrointestinal adverse events in subjects receiving albiglutide 30 mg weekly was less than that observed for the highest biweekly and monthly doses of albiglutide or exenatide.CONCLUSIONSWeekly albiglutide administration significantly improved glycemic control and elicited weight loss in type 2 diabetic patients, with a favorable safety and tolerability profile.

Predictors of Adverse Events Following Chiropractic Care for Patients With Neck Pain

Objective This study examines which variables may predict adverse events in subjects undergoing chiropractic treatment for neck pain. Methods This was a prospective, multi-center, cohort study. All new patients, 18 to 65 years of age with neck pain of any duration, who had not undergone chiropractic care or manual therapy in the prior 3 months, were eligible. Sources of data were questionnaires administered during the first 3 treatments. In all, 60 putative prognostic variables were examined, including descriptors of the patient, chiropractor, and type of treatment delivered. Adverse events were defined as either a new complaint, or the worsening of an existing complaint by more than 30% on an 11-point numerical rating scale. Multivariate random coefficients logistic regression analyses were conducted to determine predictors for the following outcome variables: (1) any adverse event after any of the first 3 visits, (2) any type of adverse event after the first visit only, and (3) specific types of adverse events after the first visit only (ie, headache, increased neck pain, pain and/or stiffness at the treated area). Results In total, 579 patients were recruited, of whom 529 fulfilled the inclusion criteria. The reported use of a manipulative technique involving cervical rotation, and working status of the patient (sick leave or workers' compensation) were moderately associated with an adverse event after any of the first 3 visits. Patients who had visited their general practitioner in the 6 months before treatment, however, were less likely to have an adverse event. A longer duration with neck pain in the preceding year was moderately associated with specific types of events after the first visit, namely, headache or worsening of the presenting neck pain. Increased neck pain after the first visit was the easiest outcome variable to predict (area under the curve, 0.88; 95% confidence interval, 0.84-0.91). Conclusions Of the 60 independent variables examined, only 4 were found to be predictive of adverse events after chiropractic treatment for neck pain, one of which was found to be protective. The chiropractic practitioner can identify 3 of these variables before initiating treatment.

Adverse Events and Discontinuations During 18 Months of Silicone Hydrogel Contact Lens Wear

To report differences in the incidence of adverse events and discontinuations found in a group of neophyte contact wearers using two different silicone hydrogel contact lenses on a daily- and continuous-wear basis during an 18-month period. Sixty-one subjects were initially examined, and 53 were eligible to participate in the study. Eligible subjects were randomly assigned to wear one of two silicone hydrogel materials: lotrafilcon A or balafilcon A lenses on a daily- or continuous-wear basis. After an initial screening, subjects were monitored weekly for the first month and then after 3, 6, 12, and 18 months. The incidence of adverse events, including corneal infiltrative events, superior epithelial arcuate lesions, and contact lens-induced papillary conjunctivitis, and discontinuations in each of the four contact lens groups were recorded. Twenty-two adverse events were found. A higher incidence of adverse events was found in subjects wearing lotrafilcon A lenses than in those wearing balafilcon A lenses (chi(2) = 4.40, P=0.04). There were fewer adverse events in subjects wearing lenses on a daily-wear basis than in those wearing lenses on a continuous-wear basis (chi(2) = 5.98, P=0.01). Eight subjects discontinued from the study as a result of recurrent corneal infiltrative events (one), vision problems (two), excessive ocular discomfort (one), relocation (one), noncompliance with the study protocol (one), and being lost to follow-up (two). No significant differences were found in the number of discontinuations between the two lens types (chi(2) = 0.66, P=0.42) and wearing regimens (chi(2) = 0.08, P=0.78). Lotrafilcon A lenses were associated with a higher incidence of adverse events than balafilcon A lenses were, and this difference is attributed to the difference in the incidence of corneal infiltrative events. Subjects wearing lenses on a daily-wear basis had fewer adverse events than did subjects wearing lenses on a continuous-wear basis. Both lens types and wearing regimens showed a similar incidence of discontinuations.

Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist

AbstractEltrombopag (SB-497 115) is a first-in-class, oral, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), being developed as a treatment for thrombocytopenia of various etiologies. In this phase 1 placebo-controlled clinical trial in 73 healthy male subjects, eltrombopag was administered as once-daily oral capsules for 10 days at doses of 5, 10, 25, 30, 50, and 75 mg. The pharmacokinetics of eltrombopag were dose dependent and linear, and eltrombopag increased platelet counts in a dose-dependent manner. There were no apparent differences in the incidence or severity of adverse events in subjects receiving active or placebo study medication. These observations indicate that eltrombopag is a once-daily, oral TpoR agonist with demonstrated thrombopoietic activity in human subjects, encouraging further studies in patients with thrombocytopenia.

Issue Highlights

HomeCirculationVol. 114, No. 15Issue Highlights Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIssue Highlights Originally published10 Oct 2006https://doi.org/10.1161/circ.114.15.1555Circulation. 2006;114:1555IMPLICATIONS OF THE FAILURE TO IDENTIFY HIGH-RISK ELECTROCARDIOGRAM FINDINGS FOR THE QUALITY OF CARE OF PATIENTS WITH ACUTE MYOCARDIAL INFARCTION: RESULTS OF THE EMERGENCY DEPARTMENT QUALITY IN MYOCARDIAL INFARCTION (EDQMI) STUDY, by Masoudi et al.The appropriate diagnosis and treatment of patients with an acute myocardial infarction depends largely on the correct interpretation of the electrocardiogram in the emergency department. Despite the importance of the skill of correctly interpreting the electrocardiogram, relatively little is known about the prevalence of misinterpretations and their consequences. This retrospective study by Masoudi et al examined the failure to identify high-risk electrocardiographic findings in patients presenting to 1 of 5 emergency departments in California and Colorado. The authors report the failure to identify important ST-segment depressions, elevations or T-wave inversions on the first electrocardiogram of patients with a confirmed acute myocardial infarction. They also investigated the association of the misinterpretations with the quality of patient care and in-hospital mortality. The present study identifies an important opportunity for us to improve care. See p 1565.DRAWBACKS AND PROGNOSTIC VALUE OF FORMULAS ESTIMATING RENAL FUNCTION IN PATIENTS WITH CHRONIC HEART FAILURE AND SYSTOLIC DYSFUNCTION, by Smilde et al.The adverse prognostic impact of impaired renal function has been well demonstrated across the entire spectrum of cardiovascular diseases. In this issue of Circulation, Smilde and colleagues performed a detailed comparison of the 2 widely-used creatinine-based estimates of renal function (Cockcroft-Gault and Modification of Diet in Renal Disease equations) with the much more difficult to perform “gold standard” iothalamate clearance, in patients with chronic heart failure and reduced left ventricular ejection fraction. Although subtle differences were observed between these assessments of renal function, each provided important prognostic information regarding subsequent cardiovascular outcomes. See p 1572.HIGH SERUM C-REACTIVE PROTEIN LEVEL IS NOT AN INDEPENDENT PREDICTOR FOR STROKE: THE ROTTERDAM STUDY, by Bos et al.Increasingly, C-reactive protein (CRP) is recommended for cardiovascular risk prediction. Major adverse events in subjects at risk or in patients with cardiovascular disease not only include acute coronary syndromes and sudden death, but also stroke. The 2 clinical entities differ considerably, however, and stroke itself is heterogenous and includes ischemic as well as hemorrhagic stroke. Thus, predictive markers for stroke or acute coronary syndromes may differ. Bos et al used the Rotterdam cohort of over 6000 subjects without previous stroke to address this issue. During a follow-up period of more than 8 years, almost 500 strokes occurred. High CRP levels were associated with the risk of any stroke and of ischemic strokes. However, CRP did not improve stroke risk prediction as assessed by the Framingham score, age, or sex. Thus, it appears that the clinical utility of CRP for stroke prediction above and beyond simple clinical parameters is quite limited. It is possible that CRP might reflect the degree of inflammation that is caused by the risk factors of a given patient, but CRP, by itself, does not add predictive value. Nevertheless, vascular inflammation may still be involved in the development of cerebrovascular disease. See p 1591.Visit http://circ.ahajournals.org:Cardiology Patient PageThe Metabolic Syndrome. See p e528.Images in Cardiovascular MedicineCough Cardiopulmonary Resuscitation Revisited. See p e530.Case of Anomalous Right Superior Vena Cava. See p e532.Hiccups and Dysphonic Metallic Voice: A Unique Presentation of Twiddler Syndrome. See p e534. Download figureDownload PowerPointCorrespondenceSee p e536. Previous Back to top Next FiguresReferencesRelatedDetails October 10, 2006Vol 114, Issue 15 Advertisement Article InformationMetrics https://doi.org/10.1161/circ.114.15.1555 Originally publishedOctober 10, 2006 PDF download Advertisement

Evaluation of the Safety of Palivizumab in the Second Season of Exposure in Young Children at Risk for Severe Respiratory Syncytial Virus Infection

Palivizumab reduces respiratory syncytial virus (RSV) hospitalisations in high-risk infants. Those with severe bronchopulmonary dysplasia may require two seasons of prophylaxis. There is concern that this humanised antibody might cause an adverse immune response in a second season of use. To evaluate and compare the occurrence of anti-palivizumab antibodies and clinical adverse events in subjects receiving monthly palivizumab injections for a first and second season, and to assess frequency and severity of RSV disease in the two groups. Subjects aged <or=2 years at severe risk for RSV disease were designated as first season (no previous palivizumab exposure) or second season subjects (received palivizumab in previous RSV season). Palivizumab injections (15 mg/kg) were administered monthly for up to 5 months. Anti-palivizumab antibody titres and serum palivizumab concentrations were measured; adverse events were recorded. No first (n = 71) or second (n = 63) season subjects experienced a significant anti-palivizumab antibody response (titre >or=1 : 80). Serum palivizumab concentrations were similar for the two groups. Nine (12.7%) first season and 8 (12.7%) second season subjects experienced one or more serious adverse events; most were respiratory and all were considered to be not or probably not related to palivizumab. No deaths occurred during the study. Monthly palivizumab injections were not associated with adverse immune responses or adverse events in young children receiving palivizumab for one or two seasons. Children receiving palivizumab for a second season did not experience more severe adverse events than those receiving it for the first time.

Allergy to local anaesthetics in dentistry. Myth or reality?

Local anesthetics (LA) are frequently used in dentistry. Although these drugs are usually well-tolerated, they can sometimes provoke adverse reactions of various types and severity. The true incidence of LA allergic reactions is unknown. The objectives of this study were (i) to evaluate the incidence of immediate adverse events in subjects requiring local anesthetic injection in order to receive dental treatment; (ii) to assess the incidence of anaphylactic allergic reactions among those recorded as adverse events and (iii) to analyze the relationship between the atopic antecedents of these patients and documented allergic reactions. A prospective, open-label, non-comparative study including 5,018 subjects who received LA during dental treatment, despite their age, was carried out in 7 private or public odontological centers. All the possible reactions that could appear during the first hour of anesthetic administration were assessed. Twenty-five adverse reactions were diagnosed, representing 0.5 % of the study population. None of these reactions was due to an allergic cause. Most (22/25) were mild, quickly reversible psychogenic or vasovagal reactions. One case was related to defects in the anesthetic technique. In two further cases, allergic etiology was ruled out after skin and dose provocative challenge tests with the anesthetic. In conclusion, allergic reactions to LA are very rare. Most adverse reactions are psychogenic or vasovagal. Physicians and dentists should be aware of these facts in order to minimize the frequent fears and myths concerning the use of LA in the dentist's office.

A look at the safety profile of over-the-counter naproxen sodium: a meta-analysis.

As the trend for Americans to self-medicate continues to increase, it becomes important to review the safety of over-the-counter (OTC) medications. This article will review the safety of an OTC analgesic, Aleve (naproxen sodium). The objective of this meta-analysis is to evaluate the frequency of occurrence of all adverse events in subjects taking various doses of OTC naproxen sodium as compared to placebo. These varying doses and dosage regimens were studied individually and consisted of 220 to 880 mg administered in single, multiple, and PRN (as needed) doses of naproxen sodium. This meta-analysis confirmed the favorable safety profile of naproxen sodium at OTC doses and established that the overall occurrence of adverse events with naproxen sodium was comparable and in some cases significantly lower than placebo. These results indicate that treatment with naproxen sodium may be highly beneficial from a clinical and economical perspective and safe when adhering to labeled directions.

Support Systems for Clinical Trials in Kyoto University Hospital

Pharmacists play various roles other than merely dispensing test drugs at our hospital for the appropriate performance of clinical trials in accordance with the new GCP guidelines : e.g. do a preliminary review, function as the office of the Institutional Review Board, prepare for monitoring and auditing by the sponsor, conduct the follow-up of patients involved in clinical trials, check for inclusion/exclusion criteria on enrollment. Pharmacists thus contributed to the successful completion of 93 cases from July 1997 to January 2000. The items of management were as follows : 1) the prevention of protocol deviations (46 cases), 2) the follow-up of subjects (22 cases), 3) managing the financial affairs and payments to subjects (14 cases), 4) corresponding to adverse events in subjects (9 cases) etc. Especially, 18 cases of protocol deviation occurred at the time of enrollment, and most of them were a contravention of exclusion criteria such as medication using prohibited combinations. Supports for the appropriate enrollment of patients into clinical trials was thus suggested to be important to ensure the safety of patients. Based on the above information, pharmacists should therefore play an active roll in clinical drug trials since their professional knowledge and skill are often of vital importance.