Reassessing Phase II Heart Failure Clinical Trials

Butler, Javed; Hamo, Carine; Udelson, James E.; O’Connor, Christopher; Sabbah, Hani N.; Metra, Marco; Shah, Sanjiv J.; Kitzman, Dalane W.; Teerlink, John R.; Bernstein, Harold S.; Brooks, Gabriel; Depré, Christophe; DeSouza, Mary M.; Dinh, Wilfried; Donovan, Mark; Frische-Danielson, Regina; Frost, Robert J.; Garza, Dahlia; Göhring, Udo Michael; Hellawell, Jennifer; Hsia, Judith; Ishihara, Shiro; Kay-Mugford, Patricia; Koglin, Joerg; Kozinn, Marc; Larson, Christopher J.; Mayo, Martha; Gan, Li; Mugnier, Pierrre; Mushonga, Sekayi; Roessig, Lothar; Russo, Cesare; Salsali, Afshin; Satler, Carol; Shi, Victor; Ticho, Barry; Laan, M. van der; Yancy, Clyde W.; Stockbridge, Norman; Gheorghiade, Mihai

doi:10.1161/circheartfailure.116.003800

Cited by 15 publications

(30 citation statements)

References 38 publications

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“…An improvement in EF has historically been associated with a clinically meaningful improvement 27. Interestingly, this study provides evidence against that paradigm because both groups experienced improvements in quality of life, highlighting the importance of evaluating a variety of efficacy end points rather than a single functional parameter to determine the overall benefit from cell‐based therapies, an idea supported by several investigators in the field 27, 28, 29, 30. Similarly, several clinical trials evaluating cell‐based therapies for both forms of HF found that stem cells improved quality of life and functional parameters without sustained improvements in EF 31, 32, 33, 34.…”

Section: Discussionmentioning

confidence: 61%

“…The mechanisms by which MSCs may have improved cardiac function in patients with DCM include the restoration of endothelial function, which enhances coronary circulation,6, 38 and the reduction of fibrosis and tumor necrosis factor–α, an inflammatory biomarker associated with worsening HF and contractility 39, 40. Those with ICM likely benefit mostly from the stem cells’ antifibrotic properties through reduction in scar size and subsequent reverse remodeling as indicated by a reduction in SI and ESV 7, 29. This may be explained in part by the enhancement of endogenous cardiomyocyte proliferation and a subsequent increase in ventricular mass 5…”

Section: Discussionmentioning

confidence: 99%

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Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

Tompkins

Rieger²,

Florea³

et al. 2018

JAHA

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BackgroundIschemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) differ in histopathology and prognosis. Although transendocardial delivery of mesenchymal stem cells is safe and provides cardiovascular benefits in both, a comparison of mesenchymal stem cell efficacy in ICM versus DCM has not been done.Methods and ResultsWe conducted a subanalysis of 3 single‐center, randomized, and blinded clinical trials: (1) TAC‐HFT (Transendocardial Autologous Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells in Ischemic Heart Failure Trial); (2) POSEIDON (A Phase I/II, Randomized Pilot Study of the Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem Cells Versus Allogeneic Mesenchymal Stem Cells in Patients With Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction); and (3) POSEIDON‐DCM (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy). Baseline and 1‐year cardiac structure and function and quality‐of‐life data were compared in a post hoc pooled analysis including ICM (n=46) and DCM (n=33) patients who received autologous or allogeneic mesenchymal stem cells. Ejection fraction improved in DCM by 7% (within‐group, P=0.002) compared to ICM (1.5%; within‐group, P=0.14; between‐group, P=0.003). Similarly, stroke volume increased in DCM by 10.59 mL (P=0.046) versus ICM (−0.2 mL; P=0.73; between‐group, P=0.02). End‐diastolic volume improved only in ICM (10.6 mL; P=0.04) and end‐systolic volume improved only in DCM (17.8 mL; P=0.049). The sphericity index decreased only in ICM (−0.04; P=0.0002). End‐diastolic mass increased in ICM (23.1 g; P<0.0001) versus DCM (−4.1 g; P=0.34; between‐group, P=0.007). The 6‐minute walk test improved in DCM (31.1 m; P=0.009) and ICM (36.3 m; P=0.006) with no between‐group difference (P=0.79). The New York Heart Association class improved in DCM (P=0.005) and ICM (P=0.02; between‐group P=0.20). The Minnesota Living with Heart Failure Questionnaire improved in DCM (−19.5; P=0.002) and ICM (−6.4; P=0.03; δ between‐group difference P=0.042) patients.ConclusionsMesenchymal stem cell therapy is beneficial in DCM and ICM patients, despite variable effects on cardiac phenotypic outcomes. Whereas cardiac function improved preferentially in DCM patients, ICM patients experienced reverse remodeling. Mesenchymal stem cell therapy enhanced quality of life and functional capacity in both etiologies.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifiers: TAC‐HFT: NCT00768066, POSEIDON: NCT01087996, POSEIDON‐DCM: NCT01392625.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

Tompkins

Rieger²,

Florea³

et al. 2018

JAHA

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“…Although any individual surrogate endpoint and efficacy markers by themselves in phase II may not be sufficient to inform prospects of success in phase III trials, a combination of markers provides better cumulative information to guide downstream research endeavors 33 , and as such, the results seen in the 12-week anakinra group are promising.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure

Tassell

Canada

Carbone

et al. 2017

Circ: Heart Failure

172

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Background An enhanced inflammatory response predicts worse outcomes in heart failure (HF). We hypothesized that administration of Interleukin-1 (IL-1) receptor antagonist (anakinra) could inhibit the inflammatory response and improve peak aerobic exercise capacity in patients with recently decompensated systolic HF. Methods and Results We randomly assigned 60 patients with reduced left ventricular ejection fraction (<50%) and elevated C-reactive protein (CRP) levels (>2 mg/L), within 14 days of hospital discharge, to daily subcutaneous injections with anakinra 100 mg for 2 weeks, 12 weeks, or placebo. Patients underwent measurement of peak oxygen consumption (VO2 [mL•kg−1•min−1]) and ventilatory efficiency (the VE/VCO2 slope). Treatment with anakinra did not affect peak VO2 or VE/VCO2 slope at 2 weeks. At 12 weeks, patients continued on anakinra showed an improvement in peak VO2 from 14.5 [10.5–16.6] to 16.1 [13.2–18.6] mL•kg−1•min−1 (P=0.009 for within-group changes), whereas no significant changes occurred within the anakinra 2-week or placebo groups. The between groups differences, however, were not statistically significant. The incidence of death or re-hospitalization for HF at 24 weeks was 6%, 31%, and 30%, in the anakinra 12-week, anakinra 2-week and placebo groups, respectively (Log-rank test P=0.10). Conclusions No change in peak VO2 occurred at 2 weeks in patients with recently decompensated systolic HF treated with anakinra, whereas an improvement was seen in those patients in whom anakinra was continued for 12 weeks. Additional larger studies are needed to validate the effects of prolonged anakinra on peak VO2 and re-hospitalization for HF.

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“…As with any traditional new drug, establishing the optimal dose and delivery method is a critical part of the development of new stem cell therapies [36,37,116]. In a phase II-a study, drug development normally comprises an estimate of a non-effective dose and the highest tolerated dose, whereas in a phase II-b the objective is to determine the dose-response relationship by testing doses ranging from clinically non-effective to the highest tolerated.…”

Section: Selection Of Dose and Deliverymentioning

confidence: 99%

Unique Aspects of the Design of Phase I/II Clinical Trials of Stem Cell Therapy

Schulman¹,

Balkan²,

Saltzman³

et al. 2018

The Management of Clinical Trials

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This chapter will review the unique aspects and limitations of the design of phase I/II (safety and efficacy) clinical trials of stem cell therapy. Although the classical pharmacologic principles applicable to drugs are not applicable to biologic (live cell) therapeutic agents, an important stage in the development of any new therapeutic agent is the establishment of an optimal dosage and delivery route. This can be particularly challenging when the treatment is a biologic agent, such as stem cells, that may exert its therapeutic effects via complex or poorly understood mechanisms. To date, clinical studies have shown inconsistent findings regarding the relationship between cell dose and clinical outcomes. This can be at least partially attributed to variations in donor cell type, source, characteristics, dosing/concentration, delivery route, underlying mechanisms of action, and efficacy endpoints tested. The current recommendations will be reviewed herein to give new investigators a general understanding of the unique issues that need to be considered and addressed when designing a stem cell therapy phase I/II clinical trial.

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Reassessing Phase II Heart Failure Clinical Trials

Cited by 15 publications

References 38 publications

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure

Unique Aspects of the Design of Phase I/II Clinical Trials of Stem Cell Therapy

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