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A randomized, multicenter, open-label, blinded end point trial comparing the effects of spironolactone to chlorthalidone on left ventricular mass in patients with early-stage chronic kidney disease: Rationale and design of the SPIRO-CKD trial.

ABSTRACT: BACKGROUND:Chronic kidney disease (CKD) is associated with increased left ventricular (LV) mass and arterial stiffness. In a previous trial, spironolactone improved these end points compared with placebo in subjects with early-stage CKD, but it is not known whether these effects were specific to the drug or secondary to blood pressure lowering. AIM:The aim was to investigate the hypothesis that spironolactone is superior to chlorthalidone in the reduction of LV mass while exerting similar effects on blood pressure. DESIGN:This is a multicenter, prospective, randomized, open-label, blinded end point clinical trial initially designed to compare the effects of 40weeks of treatment with spironolactone 25mg once daily to chlorthalidone 25mg once daily on the co-primary end points of change in pulse wave velocity and change in LV mass in 350 patients with stages 2 and 3 CKD on established treatment with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Because of slow recruitment rates, it became apparent that it would not be possible to recruit this sample size within the funded time period. The study design was therefore changed to one with a single primary end point of LV mass requiring 150 patients. Recruitment was completed on 31 December 2016, at which time 154 patients had been recruited. Investigations included cardiac magnetic resonance imaging, applanation tonometry, 24-hour ambulatory blood pressure monitoring, and laboratory tests. Subjects are assessed before and after 40weeks of randomly allocated drug therapy and at 46weeks after discontinuation of the study drug.

SUBMITTER: Hayer MK

PROVIDER: S-EPMC5603966 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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A randomized, multicenter, open-label, blinded end point trial comparing the effects of spironolactone to chlorthalidone on left ventricular mass in patients with early-stage chronic kidney disease: Rationale and design of the SPIRO-CKD trial.

Hayer Manvir K MK Edwards Nicola C NC Slinn Gemma G Moody William E WE Steeds Rick P RP Ferro Charles J CJ Price Anna M AM Andujar Cecilio C Dutton Mary M Webster Rachel R Webb David J DJ Semple Scott S MacIntyre Iain I Melville Vanessa V Wilkinson Ian B IB Hiemstra Thomas F TF Wheeler David C DC Herrey Anna A Grant Margaret M Mehta Samir S Ives Natalie N Townend Jonathan N JN

American heart journal 20170524

<h4>Background</h4>Chronic kidney disease (CKD) is associated with increased left ventricular (LV) mass and arterial stiffness. In a previous trial, spironolactone improved these end points compared with placebo in subjects with early-stage CKD, but it is not known whether these effects were specific to the drug or secondary to blood pressure lowering.<h4>Aim</h4>The aim was to investigate the hypothesis that spironolactone is superior to chlorthalidone in the reduction of LV mass while exerting ...[more]

PMID: 28888268

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Project description:Background and objectivesIn a randomized double-blind, placebo-controlled trial, treatment with spironolactone in early-stage CKD reduced left ventricular mass and arterial stiffness compared with placebo. It is not known if these effects were due to BP reduction or specific vascular and myocardial effects of spironolactone.Design, setting, participants, & measurementsA prospective, randomized, open-label, blinded end point study conducted in four UK centers (Birmingham, Cambridge, Edinburgh, and London) comparing spironolactone 25 mg to chlorthalidone 25 mg once daily for 40 weeks in 154 participants with nondiabetic stage 2 and 3 CKD (eGFR 30-89 ml/min per 1.73 m2). The primary end point was change in left ventricular mass on cardiac magnetic resonance imaging. Participants were on treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and had controlled BP (target ≤130/80 mm Hg).ResultsThere was no significant difference in left ventricular mass regression; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was -3.8 g (95% confidence interval, -8.1 to 0.5 g, P=0.08). Office and 24-hour ambulatory BPs fell in response to both drugs with no significant differences between treatment. Pulse wave velocity was not significantly different between groups; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was 0.04 m/s (-0.4 m/s, 0.5 m/s, P=0.90). Hyperkalemia (defined ≥5.4 mEq/L) occurred more frequently with spironolactone (12 versus two participants, adjusted relative risk was 5.5, 95% confidence interval, 1.4 to 22.1, P=0.02), but there were no patients with severe hyperkalemia (defined ≥6.5 mEq/L). A decline in eGFR >30% occurred in eight participants treated with chlorthalidone compared with two participants with spironolactone (adjusted relative risk was 0.2, 95% confidence interval, 0.05 to 1.1, P=0.07).ConclusionsSpironolactone was not superior to chlorthalidone in reducing left ventricular mass, BP, or arterial stiffness in nondiabetic CKD.

Project description:Abstract Background Patients with schizophrenia often display three main types of symptoms: positive symptoms (e.g. auditory hallucinations or delusions), negative symptoms (e.g. blunted affect, lack or decline in speech, social withdrawal) and cognitive symptoms (e.g. impairment of working memory and declarative memory). Treatment of positive symptoms with available antipsychotics is well established, while therapy options for cognitive and negative symptoms are lacking. Neurobiological studies identified an enhanced NRG1-ERBB4 signaling as a risk pathway in schizophrenia. Spironolactone was found to function as an inhibitor of the ERBB4 receptor. In Nrg1 type III transgenic mice, spironolactone treatment led to an improvement of schizophrenia-like symptoms (Wehr et al. 2017). This is the first study to investigate an add-on spironolactone treatment in schizophrenia patients for the treatment of cognitive deficits. Methods This is a multicenter, randomized, double-blind, parallel (3-groups), longitudinal pilot study including 3 x 27 (81) patients with a clinically stable schizophrenia. Patients are randomized in three groups: one group receives add-on spironolactone 100 mg for three weeks (intervention I), one group receives add-on spironolactone 200 mg for three weeks (intervention II) and one group receives add-on placebo for three weeks (control group). The primary endpoint is the modification of the working memory in dependence to the intervention as investigated with the n-back task (0-, 1- and 2-back). Secondary endpoints include: modification of other cognitive functions (e.g. declarative memory and attention), psychopathology (e.g. PANSS and CDSS), overall level of functioning via GAF and severity of disease via CGI, changes in the number of patients in remission using the Andreasen Criteria, modifications of the inhibitory cortical function in the context of the prepuls paradigm with TMS, evaluating possible dose-differences, spironolactone effects on mRNA levels in peripheral blood lymphocytes (PBMC measures). Statistical analysis of the primary endpoint will be based on the intention-to-treat (ITT) population including all randomised patients using a mixed model ANOVA. Results The first patient was recruited in July 2015. Currently 45 patients are included in the trial. The overall tolerance of the medication was satisfactory with 48 reported AE (adverse events). In 3 cases, the causality of the medication was definite, in 4 cases probable and in 5 cases possible. The other cases were probably or definitely not related to the study medication. SAE (serious adverse events) were not reported. The current state of research will be discussed on the conference. Discussion This is the first study to describe the effects of an add-on treatment of spironolactone in patients with a clinically stable schizophrenia. Also, it is the first study with a direct target of a biochemically disturbed signaling pathway in schizophrenia patients with a possibly new treatment option in this severe disease. Funded by Stanley Foundation: (13T-004). EUDRACT: 2014-001968-35, WHO-Clinical-Trials: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE Reference: 1. Wehr, M.C., Hinrichs, W., Brzózka, M.M., Unterbarnscheidt, T., Herholt, A., Wintgens, J.P., Papiol, S., Soto-Bernardini, M.C., Kravchenko, M., Zhang, M., et al. (2017). Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice. EMBO Mol. Med.

Project description:IntroductionSleep-time blood pressure correlates more strongly with adverse cardiovascular events than does daytime blood pressure. The BedMed trial evaluates whether bedtime antihypertensive administration, as compared with conventional morning use, reduces major adverse cardiovascular events. METHODS AND ANALYSIS: DesignProspective randomised, open-label, blinded end-point trial.ParticipantsHypertensive primary care patients using blood pressure lowering medication and free from glaucoma.SettingCommunity primary care providers in 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba and Ontario) are mailing invitations to their eligible patients. Social media campaigns (Google, Facebook) are additionally running in the same provinces.InterventionConsenting participants are allocated via central randomisation to bedtime vs morning use of all antihypertensives.Follow-up(1) Telephone or email questionnaire at 1 week, 6 weeks, 6 months and every 6 months thereafter, and (2) accessing linked governmental healthcare databases tracking hospital and community medical services.Primary outcomeComposite of all-cause death, or hospitalisation for myocardial infarction/acute-coronary syndrome, stroke or congestive heart failure.Secondary outcomesEach primary outcome element on its own, all-cause hospitalisation or emergency department visit, long-term care admission, non-vertebral fracture, new glaucoma diagnosis, 18-month cognitive decline from baseline (via Short Blessed Test).Select other outcomesSelf-reported nocturia burden at 6 weeks and 6 months (no, minor or major burden), 1-year self-reported overall health score (EQ-5D-5L), self-reported falls, total cost of care (acute and community over study duration) and mean sleep-time systolic blood pressure after 6 months (via 24-hour monitor in a subset of 302 sequential participants).Primary outcome analysisCox proportional hazards survival analysis.Sample sizeThe trial will continue until a projected 254 primary outcome events have occurred.Current statusEnrolment ongoing (3227 randomised to date).Ethics and disseminationBedMed has ethics approval from six research ethics review boards and will publish results in a peer-reviewed journal.Trial registration numberNCT02990663.

Project description:BackgroundChronic kidney disease is associated with increased arterial stiffness even in the early stages and this is thought to be a key mediator in the pathophysiology of the increased cardiovascular risk associated with this condition. The use of low-dose spironolactone has previously been shown to improve arterial stiffness and reduce left ventricular mass safely in early-stage chronic kidney disease in the context of careful monitoring at a university hospital. However, the majority of patients with chronic kidney disease are managed by their general practitioners in the community. It is not known whether similar beneficial effects can be achieved safely using spironolactone in the primary care setting. The aim of this study is to determine whether low-dose spironolactone can safely lower arterial stiffness in patients with stage 3 chronic kidney disease in the primary care setting.Methods/designSTOP-CKD is a multicentre, prospective, randomized, double-blind, placebo-controlled pilot trial of 240 adult patients with stage 3 chronic kidney disease recruited from up to 20 general practices in South Birmingham, England. Participants will be randomly allocated using a secured web-based computer randomization system to receive either spironolactone 25 mg once daily or a matching inactive placebo for 40 weeks, followed by a wash-out period of 6 weeks. Investigators, outcome assessors, data analysts and participants will all be blinded to the treatment allocation. The primary endpoint is improved arterial stiffness, as measured by carotid-femoral pulse wave velocity between baseline and 40 weeks. The secondary endpoints are incidence of hyperkalaemia, change in estimated glomerular filtration rate, change in urine albumin:creatinine ratio, change in brachial blood pressure, change in pulse waveform characteristics and overall tolerability of spironolactone. An additional quality control study, aiming to compare the laboratory serum potassium results of samples processed via two methods (utilizing routine transport or centrifugation on site before rapid transport to the laboratory) for 100 participants and a qualitative research study exploring patients' and general practitioners' attitudes to research and the use of spironolactone in chronic kidney disease in the community setting will be embedded in this pilot study.Trial registrationCurrent Controlled Trials ISRCTN80658312.

Project description:IntroductionDual antiplatelet therapy and high-intensity statins are the mainstay treatment in patients with acute stage, symptomatic intracranial atherosclerotic stenosis (ICAS). Alirocumab is a monoclonal antibody that can inhibit proprotein convertase subtilisin-kexin type 9 and effectively lower low-density lipoprotein cholesterol levels with less side effects than statins. We hypothesise that alirocumab treatment in addition to statin therapy could stabilise intracranial plaque and reduce arterial stenosis.Methods and analysisIn this prospective, randomised, open-label, blinded end-point study, we will use high-resolution vessel-wall MRI to evaluate the efficacy and safety of alirocumab in patients who had an acute ischaemic stroke from ICAS. We will recruit 66 patients who had an acute ischaemic stroke within 7 days of symptom onset, who had symptomatic intracranial artery stenosis (>30%) at the middle cerebral artery, basilar artery or intracranial internal carotid artery. Among them, 22 patients will be randomised to the intervention group to receive treatment with 75 mg alirocumab subcutaneously every 2 weeks for a total of 26 weeks, while those in the control group will not. All patients in both groups will receive antiplatelet agents and high-intensity statins, including 20 mg rosuvastatin or 40-80 mg atorvastatin or at the maximum tolerated dose. All of them will undergo MRI at recruitment and after 26 weeks. The primary outcomes are changes in intracranial atherosclerotic plaques in the MRI before and after 6 months treatment. This trial is being conducted at Chang Gung Memorial Hospital at Chiayi, Taiwan.Ethics and disseminationThis trial has been approved by the Institutional Review Board of Chang Gung Memorial Hospital (approval no. 202 002 482A3). Written informed consent will be obtained from all research participants. Study results will be published as peer-reviewed articles.Trial registration numberClinicalTrials.gov, Identifier: NCT05001984; Pre-results.

Project description:ObjectivesBecause of the limitations of randomized controlled trials (RCTs) and observational studies, a prospective, randomized, open-label, blinded endpoint (PROBE) study may be an appropriate alternative, as the design allows the assessment of clinical outcomes in clinical practice settings. The Gastrointestinal (GI) Randomized Event and Safety Open-Label Nonsteroidal Anti-inflammatory Drug (NSAID) Study (GI-REASONS) was designed to reflect standard clinical practice while including endpoints rigorously evaluated by a blinded adjudication committee. The objective of this study was to assess if celecoxib is associated with a lower incidence of clinically significant upper and/or lower GI events than nonselective NSAIDs (nsNSAIDs) in standard clinical practice.MethodsThis was a PROBE study carried out at 783 centers in the United States, where a total of 8,067 individuals aged ≥ 55 years, requiring daily NSAIDs to treat osteoarthritis, participated. The participants were randomized to celecoxib or nsNSAIDs (1:1) for 6 months and stratified by Helicobacter pylori status. Treatment doses could be adjusted as per the United States prescribing information; patients randomized to nsNSAIDs could switch between nsNSAIDs; crossover between treatment arms was not allowed, and patients requiring aspirin at baseline were excluded. The primary outcome was the incidence of clinically significant upper and/or lower GI events.ResultsSignificantly more nsNSAID users met the primary endpoint (2.4% (98/4,032) nsNSAID patients and 1.3% (54/4,035) celecoxib patients; odds ratio, 1.82 (95% confidence interval, 1.31-2.55); P = 0.0003). Moderate to severe abdominal symptoms were experienced by 94 (2.3%) celecoxib and 138 (3.4%) nsNSAID patients (P=0.0035). Other non-GI adverse events were similar between treatment groups. One limitation is the open-label design, which presents the possibility of interpretive bias.ConclusionsCelecoxib was associated with a lower risk of clinically significant upper and/or lower GI events than nsNSAIDs. Furthermore, this trial represents a successful execution of a PROBE study, where therapeutic options and management strategies available in clinical practice were incorporated into the rigor of a prospective RCT.

Dataset Information

A randomized, multicenter, open-label, blinded end point trial comparing the effects of spironolactone to chlorthalidone on left ventricular mass in patients with early-stage chronic kidney disease: Rationale and design of the SPIRO-CKD trial.

Publications

A randomized, multicenter, open-label, blinded end point trial comparing the effects of spironolactone to chlorthalidone on left ventricular mass in patients with early-stage chronic kidney disease: Rationale and design of the SPIRO-CKD trial.

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