Ventricular assist devices (VADs) have been increasingly implanted in pediatric patients. Paracorporeal VADs are generally chosen when intracorporeal continuous (IC) devices are too large. Superiority between IC and paracorporeal pulsatile (PP) devices remains unclear in smaller pediatric patients. Our study analyzes outcomes of IC and PP VADs in pediatric patients who could be considered for either of these options. Using the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) database, we identified children between 10 and 30 kg who received a VAD between June 2018 and September 2021. Survival and stroke outcomes were analyzed based on VAD type. There were 41 patients in the IC group and 54 patients in the PP group. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile at the time of implant was higher in the PP cohort ( p < 0.02). The PP cohort was younger ( p < 0.001) and smaller ( p < 0.001) than the IC cohort. The diagnosis was similar between cohorts. Overall survival was similar between groups. Stroke was more common in the PP cohort, but did not reach statistical significance ( p = 0.07). Discharge was possible only in the IC group, but the discharge rate was low (9.5%). Direct comparisons remain challenging given differences in INTERMACS profiles, age, and size.

OBJECTIVES The goal of this study was to assess the safety and tolerability of omecamtiv mecarbil treatment during symptom-limited exercise in patients with ischemic cardiomyopathy and angina. These patients may have increased vulnerability to prolongation of the systolic ejection time.BACKGROUND Omecamtiv mecarbil is a selective cardiac myosin activator that augments cardiac contractility in patients with systolic heart failure through a dose-dependent increase in systolic ejection time.METHODS In this double-blind, placebo-controlled study, patients with chronic heart failure were randomized 2:1 to receive omecamtiv mecarbil or placebo in 2 sequential cohorts of escalating doses designed to achieve plasma concentrations previously shown to increase systolic function. Patients underwent 2 symptom-limited exercise treadmill tests (ETTs) at baseline (ETT1 and ETT2) and again before the end of a 20-h infusion of omecamtiv mecarbil (ETT3).RESULTS The primary pre-defined safety endpoint (i.e., the proportion of patients who stopped ETT3 because of angina at a stage earlier than baseline) was observed in 1 patient receiving placebo and none receiving omecamtiv mecarbil. No dose-dependent differences emerged in the proportion of patients stopping ETT3 for any reason or in the pattern of adverse events.CONCLUSIONS Doses of omecamtiv mecarbil producing plasma concentrations previously shown to increase systolic function were well tolerated during exercise in these study patients with ischemic cardiomyopathy and angina. There was no indication that treatment increased the likelihood of myocardial ischemia in this high-risk population. (Pharmacokinetics [PK] and Tolerability of Intravenous [IV] and Oral CK-1827452 in Patients With Ischemic Cardiomyopathy and Angina; NCT00682565) (C) 2015 by the American College of Cardiology Foundation.

Abstract Objective: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo in patients with amyotrophic lateral sclerosis. Methods: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled clinical trial. Participants tolerating 2 weeks of open-label tirasemtiv (125 mg twice daily) were randomized 3:2:2:2 to placebo or one of three target tirasemtiv dose levels, using an escalating dosage protocol lasting 28 days. The primary outcome measure was changed in slow vital capacity (SVC) at 24 weeks. Secondary endpoints included a change in muscle strength and time to respiratory milestones of disease progression. Results: Of 744 participants, 565 tolerated open-label tirasemtiv and received randomized treatment. By 24 weeks, 23 (12.2%) placebo-treated participants discontinued study treatment vs. 129 (34.2%) randomized to tirasemtiv. SVC declined by 14.4% (95% CI: −16.8, −11.9) in the placebo group and 13.4% (95% CI: −15.3, −11.6) in the tirasemtiv group (p = 0.56). Secondary endpoints did not show significant differences. However, participants who tolerated tirasemtiv at their randomized dose showed a numeric trend toward a dose-related slowing of decline in SVC (p = 0.11). Dizziness, fatigue, nausea, weight loss, and insomnia occurred more frequently on tirasemtiv. Serious adverse events were similar across groups. Conclusions: Tirasemtiv did not alter the decline of SVC or significantly impact secondary outcome measures. Poor tolerability of tirasemtiv may have contributed to this result. However, participants tolerating their intended dose exhibited a trend toward treatment benefit on SVC, suggesting the underlying mechanism of action may still hold promise, as is being tested with a different fast skeletal muscle troponin activator (NCT03160898). Trial registration: ClinicalTrials.gov identifier: NCT02496767.

Objective: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo on respiratory function and other functional measures in patients with amyotrophic lateral sclerosis (ALS). This study was designed to confirm and extend results from a large phase IIb trial and maximize tolerability with a slower dose escalation. Methods: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled, parallel-group study in ALS patients. Participants who tolerated two weeks of open-label tirasemtiv (125mg twice a day) were randomized 3:2:2:2 to placebo or one of three target total daily dose levels of tirasemtiv (250, 375, or 500mg). Participants randomized to tirasemtiv escalated their dose every two weeks to their target dose level or maximum tolerated dose. The primary outcome measure was change in slow vital capacity from baseline to 24 weeks. Secondary endpoints assessed the effect of tirasemtiv on muscle strength and certain respiratory milestones of disease progression. A four-week randomized withdrawal phase followed 48 weeks of treatment to evaluate the possibility of sustained benefit or rebound decline. Results: Data collection will be complete in the fourth quarter of 2017. Conclusions: VITALITY-ALS was a phase III trial designed to evaluate the efficacy, safety, and tolerability of tirasemtiv in ALS.

Abstract Our objectives were to evaluate the safety and tolerability of tirasemtiv over 12 weeks and its effect on the revised ALS Functional Rating Scale (ALSFRS-R) and other secondary functional measures. This randomized, double-blind, placebo-controlled trial enrolled adults with ALS and slow vital capacity (SVC) > 50% from 73 centers in eight countries. Patients who tolerated open-label tirasemtiv 125 mg b.i.d. for one week were randomized to double-blind treatment either to placebo or tirasemtiv, escalating to a maximum tolerated dose up to 250 mg b.i.d. The primary endpoint was the change from baseline in ALSFRS-R; secondary endpoints included SVC, maximum voluntary ventilation, sniff nasal inspiratory pressure, isometric muscle strength, and sub-maximum handgrip fatigue. Of 711 patients enrolled, 596 were randomized and received at least one dose of double-blind treatment. The primary endpoint showed no treatment effect (tirasemtiv: −2.98 ± 0.28, placebo: −2.40 ± 0.25, p = 0.114); however, SVC and muscle strength declined significantly more slowly on tirasemtiv (95% CI p = 0.0006, p = 0.0158, respectively). Dropouts and serious adverse events occurred more frequently in the tirasemtiv group. In conclusion, this was a negative study with respect to the primary endpoint; however, the effects on SVC and muscle strength suggest a potentially important effect of tirasemtiv warranting further evaluation over a longer period in ALS.

Objective: This study was designed to determine the safety, tolerability, and efficacy of tirasemtiv administered at a maximum tolerated dose up to 500 mg daily in ALS patients. Background: Tirasemtiv is a fast skeletal muscle activator that sensitizes the sarcomere to calcium and increases the force of muscle contraction at submaximal nerve stimulation frequencies. In both single and repeated dose studies, ALS patients have tolerated it well and dose dependent improvements in muscle strength and functional measures were suggested. Design/Methods: Approximately 680 ALS patients were recruited from 75 centers in North America and Europe. Slow vital capacity was greater than 50% of predicted, at least one handgrip was moderately weak, and at least 4 items of the ALSFRS-R were of intermediate grade. All patients were treated for 1 week with open label tirasemtiv 125 mg BID prior to randomization. Patients who tolerated open label tirasemtiv were then randomized 1:1 to either placebo or tirasemtiv and began a 3 week dose escalation to a maximum tolerated daily dose of up to 500 mg daily for a total of 12 weeks. Efficacy measures included ALSFRS-R, quantitative respiratory and extremity muscle strength, and measures of endurance. In patients taking riluzole and randomized to tirasemtiv, riluzole dose was reduced to 50 mg daily because tirasemtiv increases riluzole concentrations. No riluzole dose-adjustment was done in placebo patients. Results: All patients will be enrolled by November 2013, with the last patient completing dosing by March 2014. Safety and efficacy results will be presented. Conclusions: This study tests the hypothesis that improvements in skeletal muscle performance can have a meaningful effect on ALS patient function. Study Supported by: Cytokinetics, Inc

This study was designed to evaluate the safety and tolerability of single doses of CK-2017357, an orally bioavailable fast skeletal muscle troponin activator, in patients with amyotrophic lateral sclerosis (ALS), and to explore pharmacodynamic markers related to strength, endurance, and function. Sixty-seven patients with ALS received single doses of placebo, CK-2017357 at 250 mg and 500 mg in random order, separated by one week. Safety measures assessments were performed, as well as tests of pulmonary function, limb muscle strength and endurance, and global impression of change. Pharmacokinetics of both CK-2017357 and riluzole were studied. Sixty-three patients completed all three dosing periods. CK-2017357 was well tolerated, with dizziness and general fatigue being the most frequent adverse events. Both patients and investigators perceived a dose-dependent benefit of CK-2017357 as measured by global impression of change. Maximum voluntary ventilation and submaximal handgrip endurance also improved. Only small changes were seen in maximal strength. In conclusion, single doses of 250 mg and 500 mg of CK-2017357 were safe and well tolerated by patients with ALS. Measures of endurance appear to be improved in a dose-related fashion, and both patients and investigators perceived a global benefit. Further study of this agent is warranted.

Objective: The primary objective of this study was to determine the safety and tolerability of CK-357 as the dose was increased over 3 weeks in ALS patients taking concomitant riluzole at a dose half that normally prescribed. Measures of strength, endurance, and function were obtained to pilot assessments for a planned efficacy study. Background CK-357 is an orally bioavailable fast skeletal muscle troponin activator that increases the force response of muscle to neuronal input. In a single-dose Evidence of Effect Phase 2a study, both patient- and investigator global assessments reflected dose-related improvement; and gains were noted in some measures of respiratory function and muscle fatigue. Additionally, small strength improvements were observed in some muscles 24 hours post-dose. Plasma riluzole levels were increased approximately 2 to 3-fold after a single dose of CK-357. Design/Methods: Eligible patients had a Slow Vital Capacity (SVC) of greater than 50% of predicted, and diminished but measurable grip strength in at least one hand. All 24 enrolled patients took 50 mg riluzole each morning. Patients were randomized to receive placebo or CK-357 tablets, administered twice daily. The dose of CK-2017357 was increased at weekly intervals starting at 125 mg BID, increasing to 250 mg BID (500 mg total daily dose) over a 3-week period. Safety and efficacy measures were collected prior to and at the end of dosing, and one week after study drug was discontinued. Clinical outcome measures included ALSFRS-R, strength of selected muscle groups, submaximal handgrip endurance, respiratory function (SVC, Sniff Nasal Inspiratory Pressure, and Maximum Voluntary Ventilation), nocturnal pulse oximetry, and Timed Up-and-Go test. Results: Demographic data, safety and tolerability information, and outcomes data will be presented. Conclusions: This study will provide information to aid in dose selection for future Phase 3 studies of CY-2017357 in ALS. Supported by: Cytokinetics, Inc. Disclosure: Dr. Shefner has received personal compensation for activities with Biogen Idec, GlaxoSmithKline, Cytokinetics, Inc., and Trophos. Dr. Shefner has received personal compensation in an editorial capacity for UpToDate. Dr. Shefner has received research support from the National Institutes of Health, the ALS Association, the ALS Therapy Alliance, GlaxoSmithKline, Neuralstem, Isis Pharmaceuticals, Biogen Idec, Cytokinetics, Inc., and Sanofi Pharmaceuticals. Dr. Andrews has received personal compensation for activities with AVANIR. Dr. Bedlack has received personal compensation for activities with Pfizer Inc, Athena Diagnostics, Eli Lilly & Company, UCB Pharma and Guidepoint Pharmacy as a speaker and/or consultant. Dr. Berry has nothing to disclose. Dr. Goslin has nothing to disclose. Dr. Jackson has received personal compensation for activities with Avanir Pharmaceuticals.Dr. Jackson has received research support from Knopp Pharmaceuticals, Biogen Idec and Cytokinetics. Dr. Kissel has nothing to disclose. Dr. Lange has nothing to disclose. Dr. Licht has received research support from Avanir Pharmaceuticals. Dr. Mozaffar has nothing to disclose. Dr. Pestronk has received personal compensation or activities with Athena Diagnostics.Dr. Pestronk has received (royalty or license fee or contractual rights) payments from Athena Diagnostics.Dr. Pestronk holds stock and/or stock options in Johnson & Johnson.Dr. Pestronk has received research support from Knopp, ISIS, Sanofi-Aventis, and Prosensa. Dr. Rosenfeld has received personal compensation for activities with Avanir Pharmaceuticals, Cytokinetics, Gerson Lehrman Group and Guidepoint Global as a speaker and consultant. Dr. Wolff has received personal compensation for activities with Cytokinetics, Inc as an employee. Dr. Wolff holds stock and/or stock options in Cytokinetics, Inc which sponsored research in which Dr. Wolff was involved as an investigator. Dr. Wolff holds stock and/or stock options in Cytokinetics, Inc. Dr. Wolff has received research support from Cytokinetics, Inc. Dr. Lee has received personal compensation for activities with Cytokinetics as an employee. Dr. Masonek has received personal compensation for activities with Cytokinetics, Inc., as an employee. Dr. Jones has received personal compensation for activities with Cytokinetics, Inc. as an employee. Dr. Meng has received personal compensation for activities with Cytokinetics, Inc., as an employee. Dr. Cedarbaum has received personal compensation for activities with Cytokinetics, Inc. as an employee.

Background Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings.Methods In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0.005 to 1.0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223.Findings The maximum tolerated dose of omecamtiv mecarbil was 0.5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r(2)=0.99 by dose), associated with increases in stroke volume (15 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; all p<0.0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0.625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time.Interpretation These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure.

Background Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. Methods We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. Findings 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. Interpretation Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. Funding Cytokinetics Inc.

Introduction: CK-1827452 (CK-452) increases systolic function by directly activating cardiac myosin. In healthy volunteers and stable heart failure (HF) patients, CK-452 infusions resulted in concentration-dependent increases in systolic ejection time (SET), stroke volume, fractional shortening, and left ventricular ejection fraction. Hypothesis: The dose limiting effect of CK-452 is related to excessive prolongation of SET, which can limit diastolic coronary flow and ventricular filling. This study investigated whether symptom-limited exercise capacity in HF patients with ischemic cardiomyopathy and angina was deleteriously affected by CK-452 at pharmacodynamically active concentrations. Methods: This double-blind, randomized, placebo-controlled Phase II clinical trial evaluated two dose regimens of CK-452, each including both IV and oral formulations. Two sequential cohorts (randomized 2:1, CK-452:placebo) underwent exercise treadmill testing at baseline and during a 20-hour infusion of study drug. Target IV Cmax for Cohorts 1 and 2 (C1 and C2) was 295 and 550 ng/mL, respectively. Patients then received oral study drug for 7 days. The primary safety endpoint was the proportion of patients who stopped exercise due to angina at a stage earlier than baseline. The study was specifically designed to gain clinical safety experience with CK-452 and not to test statistical hypotheses. Results: A total of 94 patients were treated: 29 with placebo, 31 with CK-452 in C1, 34 with CK-452 in C2. The primary safety endpoint was observed in one patient on placebo and no patients on CK-452. A total of 19 patients (5 placebo, 2 CK-452 C1, 12 CK-452 C2) experienced 27 unique adverse events (21 reported as mild in severity, 4 as moderate, and 2 as severe). No clinically important changes in other safety assessments, including vital signs, ECGs, and cardiac biomarkers, were observed for patients randomized to CK-452 vs. placebo. Conclusions: Results from this study demonstrate that CK-452 did not adversely affect exercise capacity at concentrations that improve cardiac function. The absence of deleterious effect on a broad range of safety assessments in a high risk HF population supports further clinical assessment.

Tabled 1[CK-1827452] (ng/mL)1-100>100-200>200-300>300-400>400-500>500Difference of Least Squares Means ± SEMStroke Volume ≤ 50 mL at baseline (n=9 pts)SET (msec)2 ± 818 ± 7#53 ± 8&58 ± 13&69 ± 9&88 ± 8&SV (mL)∧4 ± 38 ± 3∗6 ± 316 ± 5∗14 ± 4†6 ± 3FS (%)2 ± 23 ± 12 ± 26 ± 2#4 ± 2#5 ± 2†Stroke Volume > 50 mL at baseline (n=34 pts)SET (msec)0 ± 419 ± 5†45 ± 6&57 ± 7&53 ± 8&76 ± 6&SV (mL)∧-2 ± 2-2 ± 26 ± 3#9 ± 3∗6 ± 412 ± 3&FS (%)0 ± 11 ± 13 ± 1†2 ± 11 ± 24 ± 1&∧Doppler Derived, #≤ 0.05, ∗≤ 0.01, †≤ 0.001, &≤ 0.0001 Open table in a new tab ∧Doppler Derived, #≤ 0.05, ∗≤ 0.01, †≤ 0.001, &≤ 0.0001

Introduction: CK-1827452 (CK-452) is a novel small molecule activator of cardiac myosin. In a dog heart failure model, it increased left ventricular (LV) systolic function and cardiac output, while filling pressures, heart rate, and total peripheral resistance decreased. Intravenous (iv) CK-452 also increased LV systolic function in healthy subjects, and is now under study in heart failure patients. An oral formulation of CK-452 could enable chronic oral inotropic therapy for heart failure. Purpose: The objective of the current study was to determine the absolute bioavailability of CK-452 in healthy volunteers. Methods: CK-452 (0.125 mg/kg) was administered in a randomized four-period crossover design to male volunteers as a 1 hr iv infusion, as an oral dose of the iv formulation in the fasted state, and as a capsule in the fasted and fed states. Results: All formulations of CK-452 were well tolerated. Three subjects were withdrawn due to adverse events unrelated to study drug as assessed by the investigator. There were no deaths or serious adverse events. There were no significant effects on vital signs, ECGs or laboratory tests. Conclusions: - Absolute bioavailability of CK-452 in liquid or capsule formulations approached 100%. - Food delayed absorption from the capsules in 4/7 subjects with no reduction in AUC. - All formulations were well tolerated. - Essentially complete oral bioavailability with no first-pass effect suggests that inhibitors of CYP450 enzymes that metabolize CK-452 will not increase the Cmax of a given dose. - An oral CK-452 formulation for the chronic treatment of heart failure is confirmed to be feasible.Tabled 1Pharmacokinetics of CK-18274521Intravenous infusionP.O. Liquid (fasted)P.O. Capsule (fasted)P.O. Capsule (fed)Number Dosed62777Cmax (ng/mL)92.7 (27.3)72.8 (27.9)56.9 (19.3)64.5 (34.8)tmax (h)1.0 (0.5-1.0)0.5 (0.5-1.0)1.0 (1.0-2.0)3.0 (0.5-4.9)AUCinf (ng•h/mL)800 (140)788 (123)936 (514)981 (547)t 1/2 (h)18.2 (2.70)20.7 (2.71)25.7 (12.2)23.8 (13.1)CL(i.v.) or CL/F (p.o.) (L/h/kg)0.160 (0.023)0.162 (0.026)0.158 (0.044)0.148 (0.044)Vz (i.v.) or Vz/F (p.o.) (L/kg)4.12 (0.40)4.79 (0.67)5.13 (0.83)4.38 (0.064)1Mean (SD) reported except for tmax where median (range) is reported 2 One subject was excluded due to an uncharacteristic plasma profile. Open table in a new tab 1Mean (SD) reported except for tmax where median (range) is reported 2 One subject was excluded due to an uncharacteristic plasma profile.