Symptomatic Endpoints Research Articles

P2710Anti-ischemic effect of 2-week cycle of heparin plus exercise-to-ischemia twice daily in patients with “no-option” angina: the CARHEXA trial

Abstract Background Coronary collateral circulation (CCC) exerts protective effects on myocardial ischemia due to coronary artery disease (CAD), but the anti-ischemic, pro-CCC effects of exercise (E) with or without heparin (H) co-administration remain unclear. Purpose To establish the anti-ischemic functional efficacy of 2-week cycle of E-to-ischemia twice daily, with or without unfractionated i.v. H immediately before E, in patients with “no-option” CAD Methods In a prospective, single-center, parallel group study design we recruited 32 “no-option” patients (27 males; mean age of 61±8 years) with at least one chronically occluded coronary artery and stable angina, refractory to optimal medical management, not suitable for revascularization therapy and with E-induced ischemia. All underwent a 2-week cycle of E (2 E test per day, 5 days a week, for 2 weeks) and were randomized, with a double-blind design, to i.v. placebo (0.9% saline) versus unfractionated H (100 IU/kg up to a maximum of 5.000 IU iv, 10 min prior to E). Seattle stable angina questionnaire (SAQ), 12-lead E-ECG for time-to-ischemia (treadmill exercise testing), and MDCT angiography for CCC imaging (Rentrop score, from 0= absent to 3= full opacification of occluded vessel) were assessed at entry and re-assessed after treatment for symptomatic, ECG, and anatomic end-points respectively. Results In H+E group (n=16), time to 1 mm ST segment depression (ST-D) increased, and CCC improved, p<0.05. On the contrary, no difference was observed in E group (n=16) in the pre-specified end-points (p>0.05) (see table). Clinically important change of more 10 points in SAQ was observed regarding physical limitation, angina stability and disease perception in H+E patients, and in only angina frequency in E group. The ECG and angiographic results Heparin + Exercise Placebo + Exercise Rentrop baseline 0.73±0.88 1.06±1.06 Rentrop 2-week 1.6±0.99* 1.19±1.05 Time to ST-D base (s) 269±64 273±176 Time to ST-D 2-week (s) 328±65* 306±151 *p<0.05. Conclusion A 2-week, 10 E test cycles are well tolerated and effective particularly with H in ameliorating symptoms, E-induced ischemia and CCC in “no-option” CAD patients with refractory angina.

350 Efficacy of Budesonide Oral Suspension for Eosinophilic Esophagitis in Adolescents and Adults: Results From a Phase 3, Randomized, Placebo-Controlled Trial

INTRODUCTION: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease for which there is an unmet clinical need for new therapies. The safety and efficacy of budesonide oral suspension (BOS) for the treatment of EoE has been demonstrated in a previous phase 2 study. The current phase 3 study evaluated the efficacy and safety of BOS in a large cohort of patients with EoE. METHODS: This randomized, double-blind, placebo-controlled trial (SHP621-301; NCT02605837) investigated the safety and efficacy of BOS in patients (11–55 years) with EoE and dysphagia. Patients were randomized 2:1 to 2.0 mg BOS or placebo twice daily (b.i.d.) for 12 weeks (Figure 1). Co-primary endpoints were histologic (peak eosinophil count ≤6 eosinophils/high-powered field [eos/hpf]) and dysphagia symptom (≥30% decrease in symptoms as measured by the Dysphagia Symptom Questionnaire [DSQ]) responses after 12 weeks of therapy. Secondary endpoints included change in DSQ score and change in EoE Endoscopic Reference Score (EREFS) from baseline to final treatment period. Safety was also assessed. RESULTS: A total of 322 patients were randomized (BOS, n = 215; placebo, n = 107), of whom 318 patients received at least one dose of double-blind therapy (BOS, n = 213; placebo, n = 105) (Table 1). The primary outcomes were achieved, with significantly more histologic and symptom responders in the BOS-treated than the placebo-treated group (53.1% vs 1.0%, P < 0.001; 52.6% vs 39.1%, P = 0.024, respectively; Figure 2). Improvements in mean DSQ score from baseline to week 12 were significantly greater in the BOS group (n = 197) than the placebo group (n = 89) (−13.0 vs −9.1; P = 0.015). Similarly, improvements in mean EREFS scores were significantly greater with BOS (n = 202) than placebo (n = 93) (−4.0 vs −2.2; P < 0.001). In total, 61.0% of patients reported a treatment-emergent adverse event (TEAE) (BOS, 61.0%; placebo, 61.0%). Only 2.5% of patients experienced a TEAE leading to dose discontinuation (BOS, 1.4%; placebo, 4.8%). Few patients had severe or serious TEAEs on BOS or placebo. No life-threatening TEAEs were reported. CONCLUSION: This phase 3 trial demonstrated the efficacy of BOS as induction therapy for EoE. BOS resulted in significant improvements in histologic, symptomatic and endoscopic endpoints compared with placebo. The majority of TEAEs were mild to moderate and comparable between placebo and BOS. A double-blind, placebo-controlled maintenance study (SHP621-302) is ongoing.

Relationship Between Tumor Response and Tumor-Related Symptoms in RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses From 3 Panitumumab Trials

Relationship Between Tumor Response and Tumor-Related Symptoms in RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses From 3 Panitumumab Trials

P395 Etrolizumab demonstrated no difference among doses in symptomatic and endoscopic-based evaluation of remission in anti-TNF-α-naïve patients in a post-hoc analysis of the phase 2 ulcerative colitis trial (EUCALYPTUS)

Background: The use of the Physician Global Assessment (PGA) subscore, a component of the full Mayo Clinic Score (MCS), has been discouraged as a primary endpoint by the US Food and Drug Administration (FDA) and the European Medicines Agency in 2016 draft guidance. Instead, a composite, clinical remission primary endpoint based on stool frequency (SF), rectal bleeding (RB), and endoscopic subscores (ES) (i.e. MCS w/o PGA) is recommended by the FDA. Etrolizumab, a humanized anti-β7 mAb, showed greater clinical remission at week (wk) 10 based on the full MCS (w/PGA) compared with placebo (PBO) in the phase 2 EUCALYPTUS trial (Vermeire et al. Lancet 2014). The percentage of patients (pts) achieving clinical remission was numerically lower with higher vs lower etrolizumab dose. This treatment effect was more prominent in anti-tumour necrosis factor-a (aTNF)-naive pts. We evaluated overall symptomatic and endoscopic remission endpoints in aTNF-naive pts enrolled in EUCALYPTUS. Methods: EUCALYPTUS was an international, multicentre, double-blind, PBO-controlled, randomised, phase 2 study (NCT01336465) in 124 pts with moderate-to-severe UC who had not responded to conventional therapy. Eligible pts were randomly assigned (1:1:1) to subcutaneous etrolizumab (100 mg at wks 0, 4 and 8, with PBO at wk 2; or 420-mg loading dose at wk 0, followed by 300 mg at wks 2, 4 and 8), or matching PBO. The primary endpoint was clinical remission (full MCS ≤2, with no individual subscore >1 at wk 10). Post-hoc analyses assessed SF remission (SF ≤1 and ≥1-point decrease from baseline), RB remission (RB =0), symptomatic remission (SF and RB remission — SFRB), endoscopic remission (ES ≤1), and a composite of both SFRB and ES remission in aTNF-naive pts at wk 10. Results: PBO-adjusted treatment differences observed with symptomatic and endoscopic remission assessments were similar (30–37%) to those of the primary full MCS remission endpoint (36%), except for RB remission, which had the highest PBO rate and the smallest treatment effect size (24%). Remission rates based on symptomatic remission (SF, SFRB), endoscopic remission (ES) or ES + SFRB were similar between the 100 and 300 mg etrolizumab arms. Conclusions: When PGA is removed from the MCS-defined remission assessment, aTNF-naive pts experienced similar rates of remission whether treated with low- or high-dose etrolizumab. Treatment effects observed with SFRB remission and ES + SFRB remission were of similar magnitude to that observed for the primary MCS remission endpoint.

Inconsistent approaches of the G-BA regarding acceptance of primary study endpoints as being relevant to patients - an analysis of three disease areas: oncological, metabolic, and infectious diseases.

BackgroundPrevious evaluations of oncological medicines in the German early benefit assessment (EBA) procedure have demonstrated inconsistent acceptance of endpoints by regulatory authorities and the Federal Joint Committee (G-BA). Accepted standard endpoints for regulatory purposes are frequently not considered as patient-relevant in the German EBA system.In this study the acceptance of clinically acknowledged primary endpoints (PEPs) from regulatory trials in EBAs conducted by the G-BA was evaluated across three therapeutic areas.MethodsMedicines for oncological, metabolic and infectious diseases with EBAs finalised before 25 January 2016 were evaluated. Respective manufacturer’s dossiers, regulatory assessments, G-BA appraisals and oral hearing minutes were reviewed, and PEPs were examined to determine whether they were considered relevant to patients by the G-BA. Furthermore, the acceptance of symptomatic vs asymptomatic PEPs was also analysed.ResultsA total of 65 EBAs were evaluated. Mortality PEPs were widely accepted as patient-relevant but were only used in a minority of EBAs and exclusively in oncological diseases. Morbidity PEPs constituted around 72 % of assessed PEPs, but were excluded from the EBA in over half of the corresponding assessments as they were not considered patient-relevant. Symptomatic endpoints were largely deemed patient-relevant, whereas acceptance of asymptomatic endpoints varied between therapeutic areas.ConclusionsThis evaluation identified inconsistencies in patient relevance of morbidity-related PEPs as well as in acceptance of asymptomatic endpoints by the G-BA in all three disease areas examined. Better harmonisation between the regulatory authorities and the G-BA is still required after 5 years of AMNOG health technology assessment in Germany.Electronic supplementary materialThe online version of this article (doi:10.1186/s12913-016-1902-8) contains supplementary material, which is available to authorized users.

An Integrated Analysis of Fluticasone Furoate/Vilanterol (FF/VI) Versus FF Safety Data Across Phase II and III Asthma Studies

An integrated analysis was performed using safety data from 18 randomized, parallel-group studies from the fluticasone furoate/vilanterol (FF/VI) GSK asthma clinical study program. Efficacy data from four pivotal studies were also analyzed. Data were integrated from 18 Phase IIb and Phase III clinical studies. Key treatment arms were FF/VI 200/25 µg, FF/VI 100/25 µg, FF 200 µg, FF 100 µg, VI [with inhaled corticosteroids (ICSs)] 25 µg, and placebo. Safety endpoints included adverse events (AEs), AEs of special interest, 24-h urinary cortisol, vital signs, electrocardiograms, and asthma composite endpoints (defined as asthma-related hospitalizations, intubations, or death). Key efficacy endpoints included lung function assessments and symptomatic measures. In total, 7229 patients were randomized to one of six key treatment groups. The most frequently experienced AEs across key treatment groups were headache, nasopharyngitis, and upper respiratory tract infection. A greater incidence of local steroid effects was reported with FF-containing treatment groups versus placebo. No statistically significant difference was observed in asthma composite endpoint (asthma-related hospitalizations, intubations, or death) analysis of all FF/VI doses versus all ICS doses. A statistically significant difference in trough forced expiratory volume in one second (FEV1), 0–24 h weighted mean FEV1, and rescue-free and symptom-free 24 h periods was reported between FF/VI and FF treatment groups in all studies except one (NCT01165138). There was no evidence of an increased safety risk associated with FF/VI versus FF, VI, or placebo. FF/VI improved lung function and symptomatic endpoints versus FF alone. These data support the positive benefit:risk ratio of FF/VI versus FF alone and of having two approved FF/VI strengths to ensure appropriate treatment for patients with different asthma severity. GSK.

Loss of lung function after chemo-radiotherapy for NSCLC measured by perfusion SPECT/CT: Correlation with radiation dose and clinical morbidity

ABSTRACTBackground. The purpose of the study was to assess dose and time dependence of radiotherapy (RT)-induced changes in regional lung function measured with single photon emission computed tomography (SPECT) of the lung and relate these changes to the symptomatic endpoint of radiation pneumonitis (RP) in patients treated for non-small cell lung cancer (NSCLC).Material and methods. NSCLC patients scheduled to receive curative RT of minimum 60 Gy were included prospectively in the study. Lung perfusion SPECT/CT was performed before and three months after RT. Reconstructed SPECT/CT data were registered to treatment planning CT. Dose to the lung was segmented into regions corresponding to 0–5, 6–20, 21–40, 41–60 and > 60 Gy. Changes (%) in regional lung perfusion before and after RT were correlated with regional dose and symptomatic RP (CTC grade 2–5) outcome.Results. A total of 58 patients were included, of which 45 had three-month follow-up SPECT/CT scans. Analysis showed a statistically significant dose-dependent reduction in regional perfusion at three-month follow-up. The largest population composite perfusion loss was in 41–60 Gy (42.2%) and > 60 Gy (41.7%) dose bins. Lung regions receiving low dose of 0–5 Gy and 6–20 Gy had corresponding perfusion increase (-7.2% and -6.1%, respectively). Regional perfusion reduction was different in patients with and without RP with the largest difference in 21–40 Gy bin (p = 0.02), while for other bins the difference did not reach statistical significance. The risk of symptomatic RP was higher for the patients with perfusion reduction after RT (p = 0.02), with the relative risk estimate of 3.6 (95% CI 1.1–12).Conclusion. Perfusion lung function changes in a dose-dependent manner after RT. The severity of radiation-induced lung symptoms is significantly correlated with SPECT perfusion changes. Perfusion reduction early after RT is associated with a high risk of later development of symptomatic RP.

Eosinophilic esophagitis in children.

Eosinophilic esophagitis (EoE) is a relatively common chronic immune-mediated disease of the esophagus characterized clinically by symptoms of esophageal dysfunction that vary by age. Histologically, EoE results in marked esophageal eosinophilia despite treatment with high-dose proton pump inhibition. The cornerstone of treatment is dietary restriction and/or pharmacologic therapy, mainly with topical steroids. This review briefly describes dietary therapy, but focuses on the various medical options in the treatment of EoE, with an emphasis on steroid-based therapy. Numerous landmark studies are reviewed describing the symptomatic and histologic endpoints as well as safety data. The literature strongly supports the use of topical steroid therapy as a means of significantly decreasing eosinophilic mucosal disease. Specifically, high-dose fluticasone propionate appears to be very effective, and has been shown to result in the resolution of mucosal eosinophilia in a large percentage of treated patients. Long-term studies over many years will need to determine whether mucosal healing will change the natural history of this stricture-causing disease. In addition to topical therapy, various other drug-based therapies are reported, including newer immune-based monoclonal antibodies.

P230 Symptomatic benefit of olodaterol QD delivered via Respimat® vs placebo and formoterol BID in patients with COPD: combined analysis from two 48-week studies

BackgroundThe novel LABA olodaterol has 24-h bronchodilator activity.ObjectiveTo evaluate the symptomatic benefit of olodaterol QD in patients with GOLD 2–4 COPD.MethodsIn replicate, randomised, double-blind, placebo-controlled, parallel-group studies, patients with post-bronchodilator...

Multiple comparisons in complex clinical trial designs

Multiple comparisons have drawn a great deal of attention in evaluation of statistical evidence in clinical trials for regulatory applications. As the clinical trial methodology is increasingly more complex to properly take into consideration many practical factors, the multiple testing paradigm widely employed for regulatory applications may not suffice to interpret the results of an individual trial and of multiple trials. In a large outcome trial, an increasing need of studying more than one dose complicates a proper application of multiple comparison procedures. Additional challenges surface when a special endpoint, such as mortality, may need to be tested with multiple clinical trials combined, especially under group sequential designs. Another interesting question is how to study mortality or morbidity endpoints together with symptomatic endpoints in an efficient way, where the former type of endpoints are often studied in only one single trial but the latter type of endpoints are usually studied in at least two independent trials. This article is devoted to discussion of insufficiency of such a widely used paradigm applying only per-trial based multiple comparison procedures and to expand the utility of the procedures to such complex trial designs. A number of viable expanded strategies are stipulated.

Seasonal variation in cardiac death of patients with angiographic coronary artery disease from the ET-CHD registry, 1997–2006

Seasonal variation in cardiac death of patients with angiographic coronary artery disease from the ET-CHD registry, 1997–2006

A reduction in total isovolumic time with cardiac resynchronisation therapy is a predictor of clinical outcomes

A reduction in total isovolumic time with cardiac resynchronisation therapy is a predictor of clinical outcomes

Sensitivity Analysis of Irritable Bowel Syndrome with Constipation Response in Patients Treated with Lubiprostone in Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Studies

Purpose: Symptoms of IBS-C are inherently variable over time and challenging to evaluate. Criteria for response definitions have evolved in efforts to determine clinically meaningful measures of treatment benefit that capture the most significant symptoms of IBS. Here, a sensitivity analysis was conducted comparing previously established global response criteria for IBS-C treatment with improvement in individual symptoms. Methods: Data from IBS-C patients receiving lubiprostone 8 mcg twice daily (BID; N=988) or placebo (N=433) in 2 double-blind, randomized, 12-week studies were pooled. The validity of the primary endpoint (overall responder status) for measuring treatment benefit was assessed by comparison with changes in severity of individual symptoms. The primary endpoint was based on patient response to the following question, “How would you rate your relief of IBS symptoms (abdominal discomfort/pain, bowel habits, and other IBS symptoms) over the past week compared to how you felt before you entered the study?”, which was rated on a 7-point balanced scale from “significantly relieved” to “significantly worse.” Monthly response was defined based on patient rating of symptoms as “significantly relieved” for ≥2 weeks or “moderately relieved” for four weeks without having any of the following: 1) increase from baseline in rescue medication use, 2) discontinuation due to lack of efficacy; or 3) any ratings of “moderately worse” or “significantly worse”. A generalized estimating equation analysis was used to determine whether treatment had an effect across the 3-month period. Individual secondary symptomatic endpoints (abdominal discomfort/pain, abdominal bloating, and constipation severity) were rated on a 5-point scale from 0 (absent) to 4 (very severe). A 1-point shift on the 5-point scale was considered a clinically meaningful change. Results: Lubiprostone treatment resulted in a robust favorable global response compared with placebo (P<0.0005). For responders, there was a ≥1-point shift in the mean change from baseline for each symptom, whereas non-responders demonstrated little change (mean change from baseline <1 for each symptom), suggesting global response was strongly correlated with individual symptom improvement. The global response criteria demonstrated high sensitivity for detecting treatment-dependent changes in individual IBS-C symptoms (abdominal discomfort/pain, 0.923; abdominal bloating, 0.936; constipation severity, 0.935). Conclusion: The global response criteria defining the primary efficacy end-point provided clinically meaningful measures of treatment benefit for IBS-C symptoms, consistent with improvement in individual secondary symptomatic endpoints in patients treated with lubiprostone 8 mcg BID compared with placebo. Disclosure: Dr. Panas - Consultant, Stockholder/Ownership Interest: Sucampo Dr. Dolecek - Employee, Stockholder/Ownership Interest: Sucampo Dr. Scott - Prior Employee: Sucampo Dr. Ueno - Employee, Stockholder/Ownership Interest, Patent Holder: Sucampo

Dextranomer in Stabilized Sodium Hyaluronate (Solesta®)

Dextranomer in stabilized sodium hyaluronate, hereafter referred to as dextranomer/hyaluronic acid, is a biocompatible bulking agent administered by submucosal injection. It is hypothesized to expand the submucosal layer of the proximal anal canal, thereby augmenting bowel control. Treatment with dextranomer/hyaluronic acid was associated with symptomatic improvements in adult patients with faecal incontinence participating in a randomized, double-blind, sham-controlled, multinational study and a noncomparative, multinational study. In the double-blind study, patients in the dextranomer/hyaluronic acid group met the primary efficacy objective in that a significantly higher proportion of patients responded to treatment (≥50% reduction from baseline in the number of incontinence episodes) at the 6-month post-treatment timepoint than in the sham group (two of three primary response criteria), with the durability of the treatment response (≥25% reduction from baseline in the number of incontinence episodes) confirmed at the 12-month post-treatment timepoint (third primary response criterion). For the most part, dextranomer/hyaluronic acid did not significantly differ from the sham treatment in terms of quality of life and various other symptomatic endpoints at 6 months post-treatment in the double-blind study, although there were significant improvements from baseline in various parameters, such as the mean number of incontinence-free days, the median number of incontinence episodes and mean Faecal Incontinence Quality of Life domain scores, at 12 months post-treatment. In general, dextranomer/hyaluronic acid was well tolerated for up to 18 months post-treatment, with the majority of treatment-related adverse events considered mild or moderate in intensity.

Therapeutic Drug Monitoring of Biologics for Inflammatory Bowel Disease

Although tumor necrosis factor (TNF) antagonists are effective for the treatment of Crohn's disease and ulcerative colitis, lack and loss of clinical response is a clinical challenge. Accordingly, the use of therapeutic drug monitoring has been proposed as a means to optimize treatment. This article reviews the mechanisms of and factors which influence clearance of biologics, the relationship between serum drug concentrations and antidrug antibody presence and treatment efficacy, and identifies areas for future research needs regarding the use of therapeutic drug monitoring in clinical practice. Publications regarding these topics were identified from literature searching and supplemented by review of gastroenterology meeting presentations and reference lists. The clearance of monoclonal antibodies and pegylated antibody fragments is complex, and may be affected by demographic variables, concomitant medications, inflammatory burden, and immunogenicity, leading to high interpatient variability in plasma concentration of drug and clinical response. Several observational studies have demonstrated a relationship between anti-TNF agent serum drug concentrations and/or antidrug antibody presence and various symptomatic and objective clinical endpoints. However, these relationships are not absolute, and although some algorithms for the use of therapeutic drug monitoring in clinical practice have been proposed, none have yet been validated in a prospective clinical trial. Further research to identify the most appropriate use of therapeutic drug monitoring is needed.

Cost-utility analysis of indacaterol in Germany: A once-daily maintenance bronchodilator for patients with COPD

Cost-utility analysis of indacaterol in Germany: A once-daily maintenance bronchodilator for patients with COPD

Schizophrenia: Treatment Targets Beyond Monoamine Systems

We develop the proposal in this review that schizophrenia is a syndrome made up of component symptom complexes, each with distinctive clinical correlates, pathophysiology, and selective treatments. Psychosis is the necessary component of the syndrome; it has a young-adult onset and is sensitive to current antipsychotic drugs. Cognitive dysfunction often precedes psychosis onset, does not present an episodic course, and is poorly responsive to antipsychotic drugs. Treatments for cognition are being developed largely on the basis of animal pharmacology. Drugs for component symptom complexes will theoretically be coadministered to independent symptomatic end points. Animal models, some with genetic characteristics, can be more easily and directly developed to match an individual component than to match an illness definition as broad as schizophrenia.

Clinical Trials Update AHA Congress 2010

The clinical trials described in this article were presented at the Late Breaking Trials and the Clinical Science: Clinical Reports sessions of the American Heart Association Congress held in November 2010 in Chicago. The sessions and topics chosen for this article reflect the scope of interest of Cardiovascular Drugs and Therapy. The presentations should be considered preliminary, as further analyses may be done, which could alter the final publication of the results of these studies. PROTECT (ProBNP Outpatient Tailored Chronic Heart Failure Therapy) was designed to test the hypothesis that adjustment of intensity of chronic heart failure (HF) therapy on the basis of NT-proBNP plasma level monitoring would improve outcomes. The results provided some support of this concept, but needs further evaluation in larger, blinded trials. REVEAL (Reduction of Infarct Expansion and Ventricular Remodeling with erythropoietin after large myocardial infarctions) evaluated in the clinical setting of ischemia-reperfusion following STEMI that erythropoietin could salvage ischemic myocardium. The results did not show a reduction in infarct size, but, in contrast, an increase in adverse event rates in the erythropoietin group. GRAVITAS (Gauging Responsiveness with a VerifyNow assay-Impact on Thrombosis and Safety trial) investigated the effect of a standard vs. high maintenance clopidogrel dose in patients with stable myocardial ischemia or NSTEMI and drug-eluting stent insertion. Patients with high PRU values as determined by VerfyNow assay were randomized to 75 mg or 150 mg clopidogrel daily. The study did not show a significant difference in primary event rate between both groups. The Cholesterol Treatment Trialists' Collaboration Studies group evaluated the concept proposed in the JUPITER study that HDL levels on statin treatment may not provide useful prognostic information. The CTTC in a large sample size of statin-treated patients observed, on the contrary, a significantly increased risk of CV events, even in patients with low LDL cholesterol levels. DEFINE (Determining the Efficacy and Tolerability of CETP inhibition with Anacetrapib) evaluated possible safety aspects with the CETP inhibitor anacetrapib (increase in blood pressure). The study did not show adverse safety aspects, but significantly reduced LDL cholesterol and increased HDL cholesterol levels. ASSERT, a phase 2 dose-ranging study, investigated whether RVX-208 would increase Apo-A1 production. Apo-A1 may induce cholesterol efflux from macrophages and facilitate atherosclerosis regression. The study did not meet its primary endpoint, but significant prominent effects on lipids were found. ASCEND-HF was a large trial of nesiritide in >7000 patients with acute heart failure. The study did not show convincing symptom benefit, but on the other hand did not show harmful effects of nesiritide. EMPHASIS-HF evaluated the long term effects of eplerenone in patients with mild (NYHA class II) heart failure and systolic dysfunction. The study was prematurely ended because of highly significant beneficial effects. CUPID (Calcium Up-regulation by Percutaneous administration of gene therapy In cardiac Disease) is the first human study with gene transfer of SERCA2a (AVV1/SERCA2a: Mydicar). In a small placebo-controlled dose-ranging study in advanced heart failure patients a multiple endpoint analysis provided positive effects of the highest dose on symptomatic, functional and structural efficacy endpoints without adverse effects.

Detecting acute neurotoxicity during platinum chemotherapy by neurophysiological assessment of motor nerve hyperexcitability

BackgroundPlatinum-based drugs, such as cisplatin and oxaliplatin, are well-known for inducing chronic sensory neuropathies but their acute and motor neurotoxicities are less well characterised. Use was made of nerve conduction studies and needle electromyography (EMG) to assess motor nerve excitability in cancer patients during their first treatment cycle with platinum-based chemotherapy in this study.MethodsTwenty-nine adult cancer patients had a neurophysiological assessment either before oxaliplatin plus capecitabine, on days 2 to 4 or 14 to 20 after oxaliplatin plus capecitabine, or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin, undertaken by a neurophysiologist who was blinded to patient and treatment details. Patients completed a symptom questionnaire at the end of the treatment cycle.ResultsAbnormal spontaneous high frequency motor fibre action potentials were detected in 100% of patients (n = 6) and 72% of muscles (n = 22) on days 2 to 4 post-oxaliplatin, and in 25% of patients (n = 8) and 13% of muscles (n = 32) on days 14 to 20 post-oxaliplatin, but in none of the patients (n = 14) or muscles (n = 56) tested prior to oxaliplatin or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin. Repetitive compound motor action potentials were less sensitive and less specific than spontaneous high frequency motor fibre action potentials for detection of acute oxaliplatin-induced motor nerve hyperexcitability but were present in 71% of patients (n = 7) and 32% of muscles (n = 32) on days 2 to 4 after oxaliplatin treatment. Acute neurotoxicity symptoms, most commonly cold-induced paraesthesiae and jaw or throat tightness, were reported by all patients treated with oxaliplatin (n = 22) and none of those treated with carboplatin plus paclitaxel or cisplatin (n = 6).ConclusionsAbnormal spontaneous high frequency motor fibre activity is a sensitive and specific endpoint of acute oxaliplatin-induced motor nerve hyperexcitability, detectable on EMG on days 2 to 4 post-treatment. Objective EMG assessment of motor nerve excitability could compliment patient-reported symptomatic endpoints of acute oxaliplatin-induced neurotoxicity in future studies.

Difficulty in Assessing Quality of Life Outcomes in a Fluctuating Disease: A Hypothesis Based on Gastroparesis

An underlying assumption of quality of life outcome research is that after some intervention a “steady-state” of quality of life is reached which can be identified as an endpoint, and, hence, the “outcome.” However, in some disease processes, no so such steady-state is reached. The hypothesis presented is that a disease process with a waxing and waning course will make it difficult to determine a quality of life endpoint. After clinical observation, a pilot study of patients with either diabetic or idiopathic gastroparesis with gastric neurostimulation their records were reviewed to identify the number of clinic visits, the number of clinic visits in which the patients were asymptomatic, much improved, improved, no change, worse, or much worse. These changes were defined as “transitions.” A “transition ratio” was calculated by dividing the number of transitions by the number of clinic visits. Preliminary results showed that of 32 patients, the median number of clinic encounters was 8 (1–35), and the median number of transitions 4 (0–22). The average transition ration was 0.56 ± 0.31. In the case of gastroparesis, over half of all clinical encounters were associated with a transition. The implication of the hypothesis and preliminary finding suggests a difficulty to identify when the symptomatic endpoint was reached. Other methods to assess the effects of treatment in such a disease process are required to fully understand the effects of treatment on quality of life.