Prospective, Randomized, Open-label, Blinded Endpoint Research Articles

Effects of spironolactone on serum markers of fibrosis in people at high risk of developing heart failure: rationale, design and baseline characteristics of a proof-of-concept, randomised, precision-medicine, prevention trial. The Heart OMics in AGing (HOMAGE) trial.

Asymptomatic patients with coronary artery disease (CAD), hypertension and/or type 2 diabetes mellitus (T2DM) are at greater risk of developing heart failure (HF). Fibrosis, leading to myocardial and vascular dysfunction, might be an important pathway of progression. The Heart OMics in AGing (HOMAGE) trial aims to investigate the effects of spironolactone on serum markers of collagen metabolism and on cardiovascular structure and function in people at risk of developing HF and potential interactions with a marker of fibrogenic activity, galectin-3. The HOMAGE trial is a prospective, randomised, open-label, blinded endpoint (PROBE) study comparing spironolactone (up to 50 mg/day) and standard care over 9 months in people with clinical risk factors for developing HF, including hypertension, CAD and T2DM, and elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP, 125 to 1000 ng/L) or B-type natriuretic peptide (BNP, 35 to 280 ng/L). Exclusion criteria included left ventricular ejection fraction < 45%, atrial fibrillation, severe renal dysfunction, or treatment with loop diuretics. The primary endpoint was the interaction between change in serum concentrations of procollagen type III N-terminal propeptide (PIIINP) and treatment with spironolactone according to median plasma concentrations of galectin-3 at baseline. For the 527 participants enrolled, median (interquartile range) age was 73 (69-79) years, 135 (26%) were women, 412 (78%) had hypertension, 377 (72%) CAD, and 212 (40%) T2DM. At baseline, medians (interquartile ranges) were for left ventricular ejection fraction 63 (58-67) %, for left atrial volume index 31 (26-37) mL/m2 , for plasma NT-proBNP 214 (137-356) ng/L, for serum PIIINP 3.9 (3.1-5.0) ng/mL, and for galectin-3 16.1 (13.5-19.7) ng/mL. The HOMAGE trial will provide insights on the effect of spironolactone on pathways that might drive progression to HF. ClinicalTrials.gov NCT02556450.

Determining the optimal dose of tenecteplase before endovascular therapy for ischemic stroke (EXTEND-IA TNK Part 2): A multicenter, randomized, controlled study.

Intravenous thrombolysis with tenecteplase is more effective than alteplase in achieving substantial reperfusion at initial angiographic assessment and improves functional outcome. However, the optimal dose of tenecteplase remains uncertain. We hypothesized that 0.40 mg/kg tenecteplase is superior to 0.25 mg/kg tenecteplase in achieving reperfusion at initial angiogram, when administered within 4.5 h of ischemic stroke onset, in patients planned to undergo endovascular therapy. EXTEND-IA TNK part 2 is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) study. Eligibility requires a diagnosis of ischemic stroke within 4.5 h of stroke onset, pre-stroke modified Rankin Scale (mRS)≤3 (no upper age limit), absence of contraindications to intravenous thrombolysis, and large vessel occlusion (internal carotid, basilar, or middle cerebral artery) on multimodal CT. Patients are randomized to IV tenecteplase at either 0.40 mg/kg (max 40 mg) or 0.25 mg/kg (max 25 mg) prior to thrombectomy. The primary outcome measure is reperfusion on the initial catheter angiogram, assessed as modified Treatment In Cerebral Infarction (mTICI) 2b/3, or the absence of retrievable intracranial thrombus. Secondary outcomes include mRS at day 90 and early neurological improvement (reduction in National Institutes of Health Stroke Scale (NIHSS) by ≥8 points or reaching 0-1) at day 3. Safety outcomes are death and symptomatic intracerebral hemorrhage. Trial registration: ClinicalTrials.gov NCT03340493.

The effect of SENATOR (Software ENgine for the Assessment and optimisation of drug and non-drug Therapy in Older peRsons) on incident adverse drug reactions (ADRs) in an older hospital cohort \u2013 Trial Protocol

BackgroundThe aim of this trial is to evaluate the effect of SENATOR software on incident, adverse drug reactions (ADRs) in older, multimorbid, hospitalized patients. The SENATOR software produces a report designed to optimize older patients’ current prescriptions by applying the published STOPP and START criteria, highlighting drug-drug and drug-disease interactions and providing non-pharmacological recommendations aimed at reducing the risk of incident delirium.MethodsWe will conduct a multinational, pragmatic, parallel arm Prospective Randomized Open-label, Blinded Endpoint (PROBE) controlled trial. Patients with acute illnesses are screened for recruitment within 48 h of arrival to hospital and enrolled if they meet the relevant entry criteria. Participants’ medical history, current prescriptions, select laboratory tests, electrocardiogram, cognitive status and functional status are collected and entered into a dedicated trial database. Patients are individually randomized with equal allocation ratio. Randomization is stratified by site and medical versus surgical admission, and uses random block sizes. Patients randomized to either arm receive standard routine pharmaceutical clinical care as it exists in each site. Additionally, in the intervention arm an individualized SENATOR-generated medication advice report based on the participant’s clinical and medication data is placed in their medical record and a senior medical staff member is requested to review it and adopt any of its recommendations that they judge appropriate. The trial’s primary outcome is the proportion of patients experiencing at least one adjudicated probable or certain, non-trivial ADR, during the index hospitalization, assessed at 14 days post-randomization or at index hospital discharge if it occurs earlier. Potential ADRs are identified retrospectively by the site researchers who complete a Potential Endpoint Form (one per type of event) that is adjudicated by a blinded, expert committee. All occurrences of 12 pre-specified events, which represent the majority of ADRs, are reported to the committee along with other suspected ADRs. Participants are followed up 12 (+/− 4) weeks post-index hospital discharge to assess medication quality and healthcare utilization.This is the first clinical trial to examine the effectiveness of a software intervention on incident ADRs and associated healthcare costs during hospitalization in older people with multi-morbidity and polypharmacy.Trial registration numberClinicaltrials.gov NCT02097654, 27 March 2014.

Abstract TP285: Ongoing Clinical Trial: Treatment With Exenatide in Acute Ischaemic Stroke (TEXAIS) Trial: Prospective, Randomised, Open Label, Blinded End-point Study of Exenatide vs. Standard Care in Post Stroke Hyperglycaemia

Background and Aims: Post-stroke hyperglycaemia (PSH) occurs in up to 50% of patients presenting with acute ischaemic stroke (AIS). It reduces the efficacy of thrombolysis, increases infarct size, and worsens clinical outcomes. Insulin-based therapies have generally not been beneficial in treating PSH as they are difficult to implement, may cause hypoglycaemia, possibly increase mortality and worse clinical outcomes. Exenatide may be a safer, simple, and more effective alternative to insulin in AIS. Methods: TEXAIS is a 3-year, Phase 2, multi-centre, prospective, randomised, open label, blinded end-point (PROBE) trial comparing Exenatide to Standard of Care. It aims to recruit 528 patients with a primary end point of major neurological improvement1 at 7 days defined as a ≥8-point improvement in NIHSS score, or NIHSS 0-1. Secondary outcomes of hyper- and hypoglycaemia at 5 days and NIHSS and mRS at 90 days will be measured. The treatment arm will receive Exenatide 5μg subcutaneously twice daily. The control arm will receive standard stroke unit care. Continuous glucose monitors will track the dynamic variability of glucose. Results: Recruitment in TEXAIS is continuing with over 40 patients enrolled to date. Conclusion: TEXAIS aims to show that Exenatide is safe and effective in the treatment of PSH. It has been designed to be highly generalisable with an ability to enroll a large percentage of patients with AIS, regardless of admission blood glucose level, diabetes status, or stroke severity, with very low risk of hypoglycaemia.

A Prospective, Randomized, Open-Label, Blinded, Endpoint Study Exploring Platelet Response to Half-Dose Prasugrel and Ticagrelor in Patients with the Acute Coronary Syndrome: HOPE-TAILOR Study

Background: The optimal dosing of novel oral P2Y₁₂ receptor platelet inhibitors such as prasugrel or ticagrelor is unclear and especially challenging in East Asians. We hypothesize that half-dose prasugrel and ticagrelor may be sufficient for long-term maintenance management in Korean patients with the acute coronary syndrome (ACS) compared with conventional dosages. Design: HOPE-TAILOR (Half Dose of Prasugrel and Ticagrelor in Platelet Response after Acute Coronary Syndromes) is a prospective, randomized, open-label, blinded, endpoint (PROBE) single-center, clinical trial. A total of 100 patients with ACS undergoing drug-eluting stent implantation will be randomly assigned to prasugrel, ticagrelor, or clopidogrel, and the patients in each treatment group will receive 1-month therapy with 100 mg q.d. aspirin plus prasugrel 10 mg q.d., ticagrelor 90 mg b.i.d., or clopidogrel 75 mg q.d., followed by half-dose prasugrel 5 mg q.d. or ticagrelor 45 mg b.i.d. for maintenance treatment but without clopidogrel dose reduction. The primary endpoint will be optimal platelet reactivity 3 months after coronary intervention, defined by VerifyNow Analyzer (PRU: 85-208) and vasodilator-stimulated phosphoprotein P2Y₁₂ flow cytometry assay (platelet reactivity indices: 16-50%). Clinical outcomes will also be assessed, including major efficacy (composite of cardiac death, nonfatal myocardial infarction, repeat revascularization, or stroke) and safety (bleeding ≥2 according to the Bleeding Academic Research Consortium). Conclusion: HOPE-TAILOR is a prospective, randomized, open-label, blinded, endpoint study to explore the efficacy and safety of novel P2Y₁₂ receptor inhibitors administered orally at half the dose in Korean patients with ACS. The results will be available late in 2017.

HEALTHY AGEING THROUGH INTERNET COUNSELLING IN THE ELDERLY

Cardiovascular disease and dementia share a number of risk factors. It is unknown whether treatment of these risk factors reduces the risk of dementia. eHealth offers great opportunities for large-scale delivery of prevention programs encouraging self-management of risk factors. We aim to investigate whether a multi-domain interactive internet intervention to optimise self-management of cardiovascular risk factors can improve the cardiovascular risk profile and reduce the risk of CVD, cognitive decline and dementia. We developed an interactive internet-intervention with coach-support based on 1) previous experiences in three dementia prevention trials (preDIVA, MAPT and FINGER); 2) existing national and European guidelines on CVRM; 3) focus groups with the target population and nurses involved in CVRM. We currently test this internet-intervention in a multi-national, multi-centre, prospective, randomised, open-label blinded endpoint (PROBE) trial with 18-months intervention in persons >=65 years at increased risk of cardiovascular disease and dementia. The trial runs in the Netherlands, Finland and France. The intervention group uses an interactive internet-platform supported by a coach to stimulate a healthy lifestyle. The control group has access to a static platform with general health information. Primary outcome is a composite score of systolic blood pressure, low-density-lipoprotein and body mass index. Main secondary outcomes include effect on individual cardiovascular risk factors, incident CVD, mortality, cognitive functioning, mood and cost-effectiveness. Between March 2015 and August 2016 we have recruited 2725 persons. Median age is 69 (IQR67–73), 40% has higher education and 30% has a history of cardiovascular disease. During the first 12 months of the trial, adherence to the intervention was good with over 50% logging in at least 5 times per 3 months and only 20% logging in less than 2 times per 3 months. The 18-months follow-up is expected to be complete in December 2017. A large multi-national RCT using an internet intervention to improve the cardiovascular risk profile and prevent cardiovascular disease and cognitive decline is feasible. Whether this leads to a reduction in risk of CVD and dementia is under investigation. Final trial results are expected in mid-2018.

Low versus high dose erythropoiesis-stimulating agents in hemodialysis patients with anemia: A randomized clinical trial.

The increased risks of death and adverse events with erythropoiesis-stimulating agent (ESA) therapy targeting a higher hemoglobin level are established. It is uncertain whether the adverse effects of ESA therapy are related to dose and are mitigated when a fixed low ESA dose is used. We conducted a multicenter, prospective randomized open-label, blinded-endpoint (PROBE) trial to evaluate fixed low versus high dose ESA therapy on patient outcomes. We intended to recruit 2104 hemodialysis patients >18 years with anemia or receiving ESA treated at dialysis clinics in Italy. The intervention was fixed low (4000 IU epoetin alfa equivalent weekly) or high (18,000 IU epoetin alfa equivalent weekly) dose ESA for 12 months. Primary outcomes were serum transferrin, ferritin, albumin, C-reactive protein and ESA dose. Secondary outcomes were the composite of death or cardiovascular event, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, cardiovascular hospitalization, and quality of life. Study recruitment was terminated after inclusion of 656 participants with convergence of ESA dose between groups during follow up. Fixed low dose ESA had uncertain effects on serum ferritin (delta of delta (DD) 3.9 ng/ml, 95% CI -85.0 to 92.8), transferrin (9.2 mg/dl, -6.3 to 24.8), transferrin saturation (3.7%, -5.0 to 12.3), serum albumin (-0.03 g/dl, -0.2 to 0.1), or C-reactive protein (-0.6 mg/l, -3.3 to 2.1). In addition, fixed dose therapy had inconclusive effects on the composite endpoint of mortality and cardiovascular events (hazard ratio [HR] 0.95, 95% CI 0.66 to 1.37), death (0.98, 0.64 to 1.52), nonfatal myocardial infarction (0.52, 0.18 to 1.52), nonfatal stroke (no events), hospital admission for cardiovascular causes (0.93, 0.50 to 1.72) or health-related quality of life. A fixed low ESA dose in hemodialysis patients has uncertain effects on serum parameters, mortality, cardiovascular events, and quality of life. Hemoglobin targets may be so entrenched in nephrology practice that a trial of ESA dose is no longer possible.

No effect of vitamin D supplementation on cardiovascular risk factors in subjects with metabolic syndrome: a pilot randomised study.

IntroductionPatients with metabolic syndrome (MetS) may have lower 25-hydroxyvitamin D (25(OH)VitD) serum levels compared with non-MetS individuals. Vitamin D (VitD) deficiency is associated with various cardiovascular disease (CVD) risk factors. Yet, the effect of VitD supplementation on MetS remains uncertain. Our aim was to examine the effect of VitD supplementation on CVD risk factors in MetS subjects.Material and methodsThis pilot study had a PROBE (prospective, randomised, open-label, blinded end-point) design. Fifty patients with MetS were included and randomised either to dietary instructions (n = 25) (control group) or dietary instructions plus VitD 2000 IU/day (n = 25) (VitD group) for 3 months. This study is registered in ClinicalTrials.gov (NCT01237769).ResultsIn both groups a similar small weight reduction was achieved. In the VitD group serum 25(OH)VitD levels significantly increased by 91% (from 16.0 (3.0–35.0) to 30.6 (8.4–67.0) ng/ml, p < 0.001), while in the control group no significant change was observed (from 10.0 (4.0–39.6) to 13.0 (3.5–37.0) ng/ml). In both groups triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting glucose, haemoglobin A1c, homeostasis model assessment index and diastolic blood pressure did not significantly change. Systolic blood pressure decreased by 3.7% (from 134 ±14 to 129 ±13 mm Hg, p = 0.05) in the VitD group, while it decreased by 1.5% (from 132 ±13 to 130 ±16 mm Hg, p = NS) in the control group (p = NS between groups). In the VitD group serum 25(OH)VitD increase was negatively correlated with SBP decrease (r = –0.398, p = 0.049).ConclusionsVitD supplementation (2000 IU/day) did not affect various CVD risk factors in patients with MetS.

The Effect of Sitagliptin on Carotid Artery Atherosclerosis in Type 2 Diabetes: The PROLOGUE Randomized Controlled Trial.

BackgroundExperimental studies have suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors provide cardiovascular protective effects. We performed a randomized study to evaluate the effects of sitagliptin added on to the conventional therapy compared with conventional therapy alone (diet, exercise, and/or drugs, except for incretin-related agents) on the intima-media thickness (IMT) of the carotid artery, a surrogate marker for the evaluation of atherosclerotic cardiovascular disease, in people with type 2 diabetes mellitus (T2DM).Methods and FindingsWe used a multicenter PROBE (prospective, randomized, open label, blinded endpoint) design. Individuals aged ≥30 y with T2DM (6.2% ≤ HbA1c < 9.4%) were randomly allocated to receive either sitagliptin (25 to 100 mg/d) or conventional therapy. Carotid ultrasound was performed at participating medical centers, and all parameters were measured in a core laboratory. Of the 463 enrolled participants with T2DM, 442 were included in the primary analysis (sitagliptin group, 222; conventional therapy group, 220). Estimated mean (± standard error) common carotid artery IMT at 24 mo of follow-up in the sitagliptin and conventional therapy groups was 0.827 ± 0.007 mm and 0.837 ± 0.007 mm, respectively, with a mean difference of −0.009 mm (97.2% CI −0.028 to 0.011, p = 0.309). HbA1c level at 24 mo was significantly lower with sitagliptin than with conventional therapy (6.56% ± 0.05% versus 6.72% ± 0.05%, p = 0.008; group mean difference −0.159, 95% CI −0.278 to −0.041). Episodes of serious hypoglycemia were recorded only in the conventional therapy group, and the rate of other adverse events was not different between the two groups. As it was not a placebo-controlled trial and carotid IMT was measured as a surrogate marker of atherosclerosis, there were some limitations of interpretation.ConclusionsIn the PROLOGUE study, there was no evidence that treatment with sitagliptin had an additional effect on the progression of carotid IMT in participants with T2DM beyond that achieved with conventional treatment.Trial RegistrationUniversity Hospital Medical Information Network Clinical Trials Registry UMIN000004490

Activating blood circulation to remove stasis treatment of hypertensive intracerebral hemorrhage: A multi-center prospective randomized open-label blinded-endpoint trial.

To investigate the efficacy and safety of the Chinese herbal therapeutic regimen of activating blood circulation (TRABC) in treatment of hypertensive intracerebral hemorrhage (HICH). This was a multi-center prospective randomized open-label blinded-endpoint (PROBE) trial with HICH admitted to 12 hospitals. Totally 240 participants were randomized to the treatment group treated with TRABC in addition to conventional Western treatment or the control group with conventional Western treatment equally for 3 months. Primary outcome was degree of disability as measured by modified Rankin Scale (mRS). Secondary outcomes were the absorption of hematoma and edema, National Institutes of Health Stroke Scale (NIHSS) scores and patient-reported outcome measures for stroke and Barthel activities of daily living index. Adverse events and mortality were also recorded. After 3 months of treatment, the rate of mRS 0-1 and mRS 0-2 in the treatment group was 72.5% and 80.4%, respectively, and in the control group 48.1% and 63.9%, respectively, with a significant difference between groups (P<0.01). Hematoma volume decreased significantly at day 7 of treatment in the treatment group than the control group (P=0.038). Average Barthel scores in the treatment group after treatment was 89.11±19.93, and in the control group 82.18±24.02 (P=0.003). NIHSS scores of the two groups after treatment decreased significantly compared with before treatment (P=0.001). Patient-reported outcomes in the treatment group were lower than the control group at day 21 and 3 months of treatment (P<0.05). There were 4 deaths, 2 in each group, and 11 adverse events, 6 in the treatment group and 5 in the control group. The integrative therapy combined TRABC with conventional Western treatment for HICH could promote hematoma absorption thus minimize neurologic impairment, without increasing intracerebral hematoma expansion and re-bleeding.

Vitamin D receptor activator and prevention of cardiovascular events in hemodialysis patients—rationale and design of the Japan Dialysis Active Vitamin D (J-DAVID) trial

Activation of vitamin D is severely impaired in patients with advanced stages of chronic kidney disease, particularly those on hemodialysis. Observational studies have shown that the use of vitamin D receptor activators (VDRAs) is associated with lower risk of death from all-cause and cardiovascular disease (CVD) in dialysis populations regardless of serum parathyroid hormone (PTH) level. So far, however, there is no prospective trial to evaluate the effect of VDRAs administration on CVD prevention in hemodialysis patients. The Japan Dialysis Active Vitamin D (J-DAVID) trial is a multi-center study with a prospective randomized open-label blinded endpoint (PROBE) design. The subjects are maintenance hemodialysis patients whose serum calcium is ≤10.0 mg/dL, phosphate is ≤6.0 mg/dL, and intact PTH is ≤180 pg/mL without taking any VDRA. The subjects (target number is 972) are randomized to one of the two treatment arms: treatment with oral alfacalcidol or treatment without using any VDRA and followed up for 48 months. The primary outcome is the composite of fatal and nonfatal cardiovascular events (myocardial infarction, heart failure requiring hospitalization, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death, coronary revascularization, and leg artery revascularization). The secondary outcome is all-cause death. The primary analysis will be the intention-to-treat analysis of the primary endpoint. Between July 2008 and January 2011, a total of 976 participants were randomized. The final results are expected in the second half of 2016. The J-DAVID trial will provide valuable information whether or not administration of VDRA reduces the risk of CVD in hemodialysis patients. UMI01194

Methods of a large prospective, randomised, open-label, blinded end-point study comparing morning versus evening dosing in hypertensive patients: the Treatment In Morning versus Evening (TIME) study

IntroductionNocturnal blood pressure (BP) appears to be a better predictor of cardiovascular outcome than daytime BP. The BP lowering effects of most antihypertensive therapies are often greater in the first...

Treatment in the Morning versus Evening (TIME) Study: Feasibility of an Online Study

Aims: The Treatment in Morning versus Evening (TIME) pilot study sought to establish the feasibility of an onlineonly study detecting whether evening dosing of antihypertensives is more cardio protective than morning dosing. Methods: The TIME study uses a prospective, randomised, open-label, blinded end-point (PROBE) design. In response to various forms of advertising, patients from primary and secondary care, and databases of patients who had previously consented to being contacted about research in the UK, enrolled on the study website (www.timestudy.co.uk). Furthermore, 1,794 hypertensive subjects were written to in three primary care practices as a form of targeted advertising. Participants had to be over 18, prescribed at least one hypertensive drug and have a valid email address. Subjects self-registered, consented, and entered demographics and drug treatments online, before being randomised to taking their antihypertensive therapy in the morning or evening. Automated email followup was used to track patient reported cardiovascular outcomes for the year-long pilot study. Result: 355 participants were randomised and followed up for ≥ 12 months. During this period, 14 participants withdrew from the randomised time of treatment. 59 patients were randomised from 3 practices which wrote to patients publicising the study, giving a rate of 33 randomised per 1,000 patients written to. The 10-year ASSIGN cardiovascular risk of the randomised participants varied by age; 21% for all ages (n=355), 25% for >55 yrs (n=269), 27% for >60 yrs (n=227) and 30% for >65 yrs (n=150). Based on participant cardiovascular risk during the pilot, a full trial with 80% power to detect a 20% improved outcome of nocturnal dosing would require 631 events to occur. Conclusion: The TIME study pilot achieved recruitment efficiently. Based on the pilot data, the TIME study appears viable and has been funded by the British Heart Foundation to recruit over 10,269 subjects and to follow them up for 4 years.

Can early counselling and support for Alzheimer′s disease caregivers reduce burden? Study protocol for a multicenter randomized controlled trial

Background: The activity of caregiving for people affected with Alzheimer's disease (AD) is associated with an augmentation in health problems (anxiety, depression, stress, increased mortality), as well as in social and financial problems. Different methods of counselling, to reduce caregiver anxiety and depression, have been shown to be effective. Methods/Design: This study will be a multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) controlled superiority trial with two parallel groups. Two hundred and sixty-four caregivers of AD patients will be randomly allocated to the modified Mittelmann psychosocial intervention or an educational intervention. The treatment will consist of 6 hours of counselling and psychosocial support to caregivers, administered by psychologists, along with a specific telephone support service, whereas the active control treatment will be 6 hours of general information about AD. The primary endpoint is change in caregiver burden measured with the Zarit Burden Interview. Secondary endpoints comprise caregiver depression, anxiety and quality of life. All endpoints will be measured at baseline, 6, 12 and 24 months post treatment. Discussion: The results of this trial will be helpful to supply the efficacy of early counselling and psychosocial support for AD caregivers and offer in-depth useful information for stakholders and policy makers to implement strategies for caregivers. Trial registration: Clinical Trials.gov identifier: NCT02685787; registered on 6 February 2016. Ethics: This trial has been approved by Umbria Ethical Review Committee, Italy and will be performed in accordance with the norms on Good Clinical Practice and the Helsinki Declaration. Informed consent: Written informed consent will be obtained from the caregivers.

Development of opioid-induced constipation: post hoc analysis of data from a 12-week prospective, open-label, blinded-endpoint streamlined study in low-back pain patients treated with prolonged-release WHO step III opioids.

BackgroundOpioid-induced constipation is the most prevalent patient complaint associated with longer-term opioid use and interferes with analgesic efficacy, functionality, quality of life, and patient compliance.ObjectivesWe aimed to compare the effects of prolonged-release (PR) oxycodone plus PR naloxone (OXN) vs PR oxycodone (OXY) vs PR morphine (MOR) on bowel function under real-life conditions in chronic low-back pain patients refractory to World Health Organization (WHO) step I and/or II analgesics.Research design and methodsThis was a post hoc analysis of the complete data set from a prospective, randomized, open-label, blinded endpoint (PROBE) streamlined study (German pain study registry: 2012-0012-05; European Union Drug Regulating Authorities Clinical Trials [EudraCT]: 2012-001317-16), carried out in 88 centers in Germany, where a total of 901 patients requiring WHO step III opioids to treat low-back pain were enrolled and prospectively observed for 3 months. Opioid allocation was based on either optional randomization (n=453) or physician decision (n=448). In both groups, treatment doses could be adjusted as per the German prescribing information, and physicians were free to address all side effects and tolerability issues as usual. The primary endpoint was the proportion of patients maintaining normal bowel function throughout the complete treatment period, assessed with the Bowel Function Index (BFI). Secondary analyses addressed absolute and relative BFI changes, complete spontaneous bowel movements, use of laxatives, treatment emergent adverse events, analgesic effects, and differences between randomized vs nonrandomized patient groups.ResultsBFI changed significantly with all three WHO step III treatments, however significantly less with OXN vs OXY and MOR despite a significantly higher use of laxatives with the latter ones (P<0.001). The percentage of patients who maintained normal BFI scores despite opioid treatment was 54.5% (164/301) with OXN and was significantly superior to those seen with OXY (32.8% [98/300]) (odds ratio [OR]: 2.47, 95% confidence interval [CI]: 1.77–3.44; P<0.001) or MOR (29.7% [89/300]) (OR: 2.84, 95% CI: 2.03–3.97; P<0.001). Absolute BFI changes of ≥12mm 100 mm horizontal visual analog scale (VAS100) vs. baseline were seen for OXN in 41.4%, for OXY in 68.7%, and for MOR in 72.3%. Complete spontaneous bowel movements decreased at least by one per week in 10.3% with OXN vs 42.3% for OXY (OR: 6.39, 95% CI 4.13–9.89; P<0.001) and 42.0% for MOR (OR: 6.31, 95% CI: 4.08–9.76; P<0.001). Overall, 359 treatment emergent adverse events (78 [OXN], 134 [OXY], and 147 [MOR]) in 204 patients (41 [OXN], 80 [OXY], and 83 [MOR]) occurred, most affecting the gastrointestinal (49.3%) and the nervous system (39.3%). Treatment contrasts between randomized vs nonrandomized patients were insignificant.ConclusionIn this post hoc analysis of data from a real-life 12-week study, OXN treatment was associated with a significantly lower risk of opioid-induced constipation, superior tolerability, and significantly better analgesic efficacy compared with OXY and MOR.

Safety and efficacy of oxycodone/naloxone vs. oxycodone vs. morphine for the treatment of chronic low back pain: results of a 12 week prospective, randomized, open-label blinded endpoint streamlined study with prolonged-release preparations

Background:Opioid-induced constipation (OIC) is the most prevalent patient complaint associated with opioid use and interferes with analgesic efficacy.Objectives:This PROBE trial compares the overall safety and tolerability of oxycodone/naloxone (OXN) with those of traditional opioid therapy with oxycodone (OXY) or morphine (MOR) in the setting of the German healthcare system.Research design and methods:This was a prospective, randomized, open-label, blinded endpoint (PROBE) streamlined study (German pain study registry: 2012-0012-05; EudraCT: 2012-001317-16), carried out in 88 centers in Germany, where a total of 453 patients, requiring WHO step III opioids to treat low back pain, were randomized to OXN, OXY or MOR (1:1:1) for 3 months. The primary outcome was the percentage of patients without adverse event-related study discontinuations who presented with a combination of a ≥50% improvement of pain intensity, disability and quality-of-life and a ≤50% worsening of bowel function at study end.Results:Significantly more OXN patients met the primary endpoint (22.2%) vs. OXY (9.3%; OR: 2.80; p < 0.001) vs. MOR (6.3%; OR: 4.23; p < 0.001), with insignificant differences between OXY vs. MOR (p = 0.155). A ≥50% improvement of pain intensity, functional disability and quality-of-life has been found for OXN in 75.0/61.1/66.0% of patients and thus for all parameters significantly more than with OXY (58.9/49.0/48.3; p < 0.001 for each) or MOR (52.5/46.2/37.3; p < 0.001 for each). A total of 86.8% of OXN patients kept normal BFI scores during treatment, vs. 63.6% for OXY (p < 0.001) vs. 53.8% for MOR (p < 0.001). Overall 189 TEAEs (OXN: 45, OXY: 69, MOR: 75) in 92 patients (OXN: 21, OXY: 44, MOR: 37) occurred, most gastrointestinal (50.8%). One limitation is the open-label design, which presents the possibility of interpretive bias.Conclusion:Under the conditions of this PROBE design, OXN was associated with a significantly better tolerability, a lower risk of OIC and a significantly better analgesic efficacy than OXY or MOR.

Factors affecting adherence in cardiovascular protective medications: An UMPIRE sub-study

Background Adherence to protective cardiovascular medications is of huge importance in the prevention of serious morbidity and mortality [1]. This study seeks to identify factors that influence adherence to the treatment of cardiovascular medications and to analyse the characteristics of the baseline non-adherence Irish cohort of the UMPIRE study. UMPIRE (“Use of a Multidrug Pill In Reducing cardiovascular Events”) was a prospective, randomised, open-label, blinded-endpoint (PROBE) clinical trial carried out in three locations in Europe (Ireland, The Netherlands and the UK) as well as India. The Irish cohort was a total of 333 participants (total trial 2,004 of which half in India). It had a key eligibility criterion of established cardiovascular disease (CVD) or an estimated 5year CVD risk of ≥15%. The results were present at the American Heart Association 2012 Scientific Sessions.

Postprescription review improves in-hospital antibiotic use: A multicenter randomized controlled trial

Although review of antibiotic therapy is recommended to optimize antibiotic use, physicians do not always perform it. This trial aimed to evaluate the impact of a systematic postprescription review performed by antimicrobial stewardship program (ASP) infectious disease physicians (IDP) on the quality of in-hospital antibiotic use. A multicenter, prospective, randomized, parallel-group trial using the PROBE (Prospective Randomized Open-label Blinded Endpoint) methodology was conducted in eight surgical or medical wards of four hospitals. Two hundred forty-six patients receiving antibiotic therapy prescribed by ward physicians for less than 24 hours were randomized to receive either a systematic review by the ASP IDP at day 1 and days 3 to 4 (intervention group, n = 123) or no systematic review (usual care, n = 123). The primary outcome measure was appropriateness of antimicrobial therapy, a composite score of appropriateness of antibiotic use at days 3 to 4 and appropriate treatment duration, adjudicated by a blinded committee. Analyses were performed on an intention-to-treat basis. In the intervention group, appropriateness of antimicrobial therapy was more frequent (55/123, 44.7% vs. 35/123, 28.5%; odds ratio 2.03, 95% confidence interval 1.20–3.45). Antibiotic treatment duration was lower in the intervention group (median (interquartile range) 7 (3–9) days vs. 10 (7–12) days; p 0.003). ASP IDP counseling to change therapy was more frequent at days 3 to 4 than at day 1 (114/123; 92.7% vs. 24/123; 19.5%, p <0.001). Clinical outcome was similar between groups. This study suggests that a systematic postprescription antibiotic review performed at days 1 and 3 to 4 results in higher quality of antibiotic use and lower antibiotic duration. This trial was registered at ClinicalTrials.gov (NCT01136200).

Effect of Switch to the Highest Dose of Rosuvastatin Versus Add‐on‐Statin Fenofibrate Versus Add‐on‐Statin Nicotinic Acid/Laropiprant on Oxidative Stress Markers in Patients with Mixed Dyslipidemia

Oxidative stress plays an important role in atherosclerosis. Both F2-isoprostane (8-iso-PGF2a) and oxidized low-density lipoprotein (ox-LDL) have emerged as biomarkers of oxidative stress and have been proposed as useful biomarkers that could potentially be used as indicators of cardiovascular disease. This is a prespecified analysis of a prospective, randomized, open-label, blinded endpoint (PROBE) study (ClinicalTrials.gov identifier: NCT01010516). Patients (N=100) with mixed dyslipidemia on a standard statin dose (10-40mg simvastatin or 10-20mg atorvastatin or 5-10mg rosuvastatin) who had not achieved lipid targets were randomized to switch to the highest dose of rosuvastatin (40mg/day) or to add-on-statin extended release nicotinic acid (ER-NA)/laropiprant (LRPT) (1000/20mg/day for the first 4weeks followed by 2000/40mg/day for the next 8weeks) or to add-on-statin micronized fenofibrate (200mg/day) for a total of 3months. Levels of plasma and urine F2-isoprostane and plasma ox-LDL were assessed at baseline and 3months later. Plasma F2-isoprostane levels decreased similarly in all groups. On the other hand, both ox-LDL and urine F2-isoprostane levels decreased similarly in the add-on ER-NA/LRPT and rosuvastatin monotherapy group, while a less pronounced decrease was observed in the add-on fenofibrate group. All treatment interventions reduced the concentration of the assessed oxidative stress markers, but the reduction was more pronounced in the add-on ER-NA/LRPT and rosuvastatin monotherapy groups, compared with add-on fenofibrate. Specifically designed studies should address the abovementioned risk factors modulation in terms of cardiovascular risk.

Intravenous transplantation of mesenchymal stem cells preconditioned with early phase stroke serum: current evidence and study protocol for a randomized trial

BackgroundRecovery after a major stroke is usually limited, but cell therapy for patients with fixed neurologic deficits is emerging. Several recent clinical trials have investigated mesenchymal stem cell (MSC) therapy for patients with ischemic stroke. We previously reported the results of a controlled trial on the application of autologous MSCs in patients with ischemic stroke with a long-term follow-up of up to 5 years (the 'STem cell Application Researches and Trials In NeuroloGy’ (STARTING) study). The results from this pilot trial are challenging, but also raise important issues. In addition, there have been recent efforts to improve the safety and efficacy of MSC therapy for stroke.Methods and designThe clinical and preclinical background and the STARTING-2 study protocol are provided. The trial is a prospective, randomized, open-label, blinded-endpoint (PROBE) clinical trial. Both acute and chronic stroke patients will be selected based on clinical and radiological features and followed for 3 months after MSC treatment. The subjects will be randomized into one of two groups: (A) a MSC group (n = 40) or (B) a control group (n = 20). Autologous MSCs will be intravenously administered after ex vivo culture expansion with autologous ischemic serum obtained as early as possible, to enhance the therapeutic efficacy (ischemic preconditioning). Objective outcome measurements will be performed using multimodal MRI and detailed functional assessments by blinded observers.DiscussionThis trial is the first to evaluate the efficacy of MSCs in patients with ischemic stroke. The results may provide better evidence for the effectiveness of MSC therapy in patients with ischemic stroke.Trial registrationThis trial was registered with ClinicalTrials.gov, number NCT01716481.