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Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial.

ABSTRACT: Aims:Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. Methods and results:This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n?=?484) were screened; n?=?348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving?> 24 million mesenchymal stem cells (n?=?315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n?=?157) or sham procedure (n?=?158). Procedures were performed as randomized in 271 patients (n?=?120 cardiopoietic cells, n?=?151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value?> 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370?mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. Conclusion:The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

SUBMITTER: Bartunek J

PROVIDER: S-EPMC5381596 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial.

Bartunek Jozef J Terzic Andre A Davison Beth A BA Filippatos Gerasimos S GS Radovanovic Slavica S Beleslin Branko B Merkely Bela B Musialek Piotr P Wojakowski Wojciech W Andreka Peter P Horvath Ivan G IG Katz Amos A Dolatabadi Dariouch D El Nakadi Badih B Arandjelovic Aleksandra A Edes Istvan I Seferovic Petar M PM Obradovic Slobodan S Vanderheyden Marc M Jagic Nikola N Petrov Ivo I Atar Shaul S Halabi Majdi M Gelev Valeri L VL Shochat Michael K MK Kasprzak Jaroslaw D JD Sanz-Ruiz Ricardo R Heyndrickx Guy R GR Nyolczas Noémi N Legrand Victor V Guédès Antoine A Heyse Alex A Moccetti Tiziano T Fernandez-Aviles Francisco F Jimenez-Quevedo Pilar P Bayes-Genis Antoni A Hernandez-Garcia Jose Maria JM Ribichini Flavio F Gruchala Marcin M Waldman Scott A SA Teerlink John R JR Gersh Bernard J BJ Povsic Thomas J TJ Henry Timothy D TD Metra Marco M Hajjar Roger J RJ Tendera Michal M Behfar Atta A Alexandre Bertrand B Seron Aymeric A Stough Wendy Gattis WG Sherman Warren W Cotter Gad G Wijns William W

European heart journal 20170301 9

<h4>Aims</h4>Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort.<h4>Methods and results</h4>This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-di ...[more]

PMID: 28025189

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Project description:IntroductionRemote ischaemic preconditioning (RIPC) using a non-invasive pneumatic tourniquet is a potential method for reducing ischaemia-reperfusion injury. RIPC has been extensively studied in animal models and cardiac surgery, but scarcely in solid organ transplantation. RIPC could be an inexpensive and simple method to improve function of transplanted organs. Accordingly, we aim to study whether RIPC performed in brain-dead organ donors improves function and longevity of transplanted organs.Methods and analysesRIPTRANS is a multicentre, sham-controlled, parallel group, randomised superiority trial comparing RIPC intervention versus sham-intervention in brain-dead organ donors scheduled to donate at least one kidney. Recipients of the organs (kidney, liver, pancreas, heart, lungs) from a randomised donor will be included provided that they give written informed consent. The RIPC intervention is performed by inflating a thigh tourniquet to 300 mm Hg 4 times for 5 min. The intervention is done two times: first right after the declaration of brain death and second immediately before transferring the donor to the operating theatre. The sham group receives the tourniquet, but it is not inflated. The primary endpoint is delayed graft function (DGF) in kidney allografts. Secondary endpoints include short-term functional outcomes of transplanted organs, rejections and graft survival in various time points up to 20 years. We aim to show that RIPC reduces the incidence of DGF from 25% to 15%. According to this, the sample size is set to 500 kidney transplant recipients.Ethics and disseminationThis study has been approved by Helsinki University Hospital Ethics Committee and Helsinki University Hospital's Institutional Review Board. The study protocol was be presented at the European Society of Organ Transplantation congress in Copenhagen 14-15 September 2019. The study results will be submitted to an international peer-reviewed scientific journal for publication.Trial registration numberNCT03855722.

Project description:See Thibault et al. (doi:10.1093/awx033) for a scientific commentary on this article.Neurofeedback training builds upon the simple concept of instrumental conditioning, i.e. behaviour that is rewarded is more likely to reoccur, an effect Thorndike referred to as the 'law of effect'. In the case of neurofeedback, information about specific electroencephalographic activity is fed back to the participant who is rewarded whenever the desired electroencephalography pattern is generated. If some kind of hyperarousal needs to be addressed, the neurofeedback community considers sensorimotor rhythm neurofeedback as the gold standard. Earlier treatment approaches using sensorimotor-rhythm neurofeedback indicated that training to increase 12-15 Hz sensorimotor rhythm over the sensorimotor cortex during wakefulness could reduce attention-deficit/hyperactivity disorder and epilepsy symptoms and even improve sleep quality by enhancing sleep spindle activity (lying in the same frequency range). In the present study we sought to critically test whether earlier findings on the positive effect of sensorimotor rhythm neurofeedback on sleep quality and memory could also be replicated in a double-blind placebo-controlled study on 25 patients with insomnia. Patients spent nine polysomnography nights and 12 sessions of neurofeedback and 12 sessions of placebo-feedback training (sham) in our laboratory. Crucially, we found both neurofeedback and placebo feedback to be equally effective as reflected in subjective measures of sleep complaints suggesting that the observed improvements were due to unspecific factors such as experiencing trust and receiving care and empathy from experimenters. In addition, these improvements were not reflected in objective electroencephalographic-derived measures of sleep quality. Furthermore, objective electroencephalographic measures that potentially reflected mechanisms underlying the efficacy of neurofeedback such as spectral electroencephalographic measures and sleep spindle parameters remained unchanged following 12 training sessions. A stratification into 'true' insomnia patients and 'insomnia misperceivers' (subjective, but no objective sleep problems) did not alter the results. Based on this comprehensive and well-controlled study, we conclude that for the treatment of primary insomnia, neurofeedback does not have a specific efficacy beyond unspecific placebo effects. Importantly, we do not find an advantage of neurofeedback over placebo feedback, therefore it cannot be recommended as an alternative to cognitive behavioural therapy for insomnia, the current (non-pharmacological) standard-of-care treatment. In addition, our study may foster a critical discussion that generally questions the effectiveness of neurofeedback, and emphasizes the importance of demonstrating neurofeedback efficacy in other study samples and disorders using truly placebo and double-blind controlled trials.

Dataset Information

Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial.

Publications

Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial.

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