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A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design
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JJCC-1927; No. of Pages 8 Journal of Cardiology xxx (2019) xxx–xxx
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Original article
A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design Shigeki Kobayashi (MD, PhD, FJCC)a,*, Takatoshi Wakeyama (MD, PhD, FJCC)b, Shiro Ono (MD, PhD, FJCC)c, Yasuhiro Ikeda (MD, PhD)d, Masato Omura (MD, PhD)e, Tsuyoshi Oda (MD, PhD)f, Yuji Hisamatsu (MD, PhD)g, Kozaburo Seki (MD, PhD)h, Akira Satoh (MD, PhD)i, Mitsuyuki Hiromoto (MD, PhD)j, Shintaro Akashi (MD, PhD)k, Kosuke Uchida (MD, PhD)l, Masahiko Harada (MD, PhD)m, Yuhji Furutani (MD, PhD)n, Yasuma Nakamura (MD, PhD)o, Masateru Kohno (MD, PhD)p, Shuji Kawamura (MD, PhD)q, Masakazu Obayashi (MD, PhD)r, Hiroyuki Michishige (MD, PhD)s, Masafumi Yano (MD, PhD, FJCC)a,* a
Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan Division of Cardiology, JCHO Tokuyama Central Hospital, Shunan, Japan Division of Cardiology, Saiseikai Yamaguchi General Hospital, Yamaguchi, Japan d Division of Cardiology, Yamaguchi Prefectural Grand Medical Center, Hofu, Japan e Division of Cardiology, Saiseikai Shimonoseki General Hospital, Shimonoseki, Japan f Division of Cardiology, Shimane Prefectural Central Hospital, Izumo, Japan g Division of Cardiology, JCHO Shimonoseki Medical Center, Shimonoseki, Japan h Division of Cardiology, Yamaguchi Rosai Hospital, Sanyo-Onoda, Japan i Division of Cardiology, Ehime Rosai Hospital, Niihama, Japan j Division of Cardiology, Shuto General Hospital, Yanai, Japan k Division of Cardiology, Hamada Medical Center, Hamada, Japan l Division of Cardiology, Hagi Civil Hospital, Hagi, Japan m Division of Cardiology, Ube-kohsan Central Hospital, Ube, Japan n Department of Cardiology, Kanmon Medical Center, Shimonoseki, Japan o Department of Cardiovascular Medicine, Hikari City General Hospital, Hikari, Japan p Department of Cardiovascular Medicine, Shunan City Shinnanyo Hospital, Shunan, Japan q Department of Cardiovascular Medicine, Konan Saint Hill Hospital, Ube, Japan r Department of Cardiovascular Medicine, Sanyo-Onoda City Hospital, Sanyo-Onoda, Japan s Department of Cardiovascular Medicine, Japanese Red Cross Society Yamaguchi Hospital, Yamaguchi, Japan b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 21 June 2019 Received in revised form 14 August 2019 Accepted 26 August 2019 Available online xxx
Background: Leakage of Ca2+ from the sarcoplasmic reticulum (SR) is a critical contributing factor to heart failure pathophysiology. Therefore, reducing SR Ca2+ leaks may provide significant additive benefits when used in combination with conventional therapies. Dantrolene, a drug routinely used to treat malignant hyperthermia, also stabilizes the cardiac isoform of the release channel (RyR2), thus decreasing SR Ca2+ leaks. The purpose of this study is to evaluate the effect of chronic administration of dantrolene on heart failure and lethal arrhythmia in patients with chronic heart failure and reduced ejection fraction in a multicenter, randomized, double-blind, controlled study. Methods: Patients with chronic heart failure who had functional status of New York Heart Association class II and III and a left ventricular ejection fraction <40% were treated according to the Japanese Circulation Society, the European Society of Cardiology, and the American Heart Association/the American College of Cardiology guidelines for diagnosis and treatment of acute and chronic heart failure. Patients were randomized and divided into two groups in a double-blind fashion: dantrolene group and
Keywords: Heart failure Dantrolene Ventricular arrhythmia Ryanodine receptor
* Corresponding authors at: Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan. E-mail address: [email protected] (S. Kobayashi). https://doi.org/10.1016/j.jjcc.2019.08.020 0914-5087/© 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kobayashi S, et al. A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.020
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placebo group (target sample size: 300 cases). These drugs were administered for 96 weeks. The primary endpoint is cardiovascular death, first hospitalization for exacerbation of heart failure, or lethal arrhythmia [ventricular tachycardia (VT) storm, sustained VT, ventricular fibrillation] for 2 years after starting administration of dantrolene 1 cap (25 mg) three times daily (if not tolerable, two times daily) or matching placebo. Results: This paper presents the rationale and trial design of the study. Recruitment for the study started on 8 December 2017. Conclusions: The results of this trial will clarify the efficacy and safety of dantrolene for ventricular arrhythmia, as well as mortality and morbidity in patients with chronic heart failure and reduced ejection fraction during guideline-directed medical treatment. © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Introduction Chronic heart failure (CHF) is thought to be the end-image of all heart diseases, and progression of heart failure (HF) and lethal arrhythmia worsen the prognosis of CHF patients [1–4]. Guideline-directed medical treatment (GDMT), according to the guidelines of the Japanese Circulation Society (JCS), the European Society of Cardiology (ESC), and the American Heart Association (AHA)/the American College of Cardiology (ACC) for the diagnosis and treatment of acute and chronic heart failure improves patient prognosis. This is mainly through protecting patients from the activation of the sympathetic nerve system and renin-angiotensin-aldosterone system using angiotensin-converting enzyme (ACE) inhibitors [if they are not tolerable, angiotensin receptor blockers (ARBs)], beta blockers, and mineral corticoid antagonists. However, despite the great deal of effort being made to treat CHF, HF remains the most common cause of death from heart disease [5,6]. Dantrolene is a drug heavily used for the treatment of malignant hyperthermia (MH), which is a point mutation disease of the skeletal ryanodine receptor (RyR1) [7]. The pathophysiology of MH involves Ca2+ ion leakage from the sarcoplasmic reticulum (SR). The molecular mechanism of the leaky MH-RyR1 channel is thought to be the conformational change of the regulatory domains composed of the N-terminal and central domains within RyR1, which is caused by a single point mutation at the regulatory domains of RyR1 [8]. We previously proposed that dantrolene bound to amino acids Leu590-Cys609 of the N-terminal domain and restored the defective inter-domain interaction between Nterminal and central domains in MH-type RyR [9,10]. Interestingly, it was demonstrated that dantrolene specifically bound to the corresponding domain Leu601-Cys620 in RyR2, which is completely preserved [11,12]. In catecholaminergic polymorphic ventricular tachycardia (CPVT), which is an inherited disease with RyR2 mutation-linked disorder and the mutation distribution is similar to that of the MH-RyR1-mutation, we found that with the same molecular mechanism, dantrolene prevents CPVT by the inhibition of diastolic Ca2+ leakage through RyR2 in a CPVT-associated RyR2R2474S/+ knock-in (KI) mouse model [13,14]. Jung et al. reported a dantrolene-suppressed diastolic Ca2+ leakage through a RyR2 mutant channel in a patient-specific stem cell CPVT model [15]. More recently, Penttinen et al. reported that dantrolene reduced the number of premature ventricular complexes, on average, by 74% in four CPVT patients, who had a point mutation within the domain switch composed of N-terminal and central domains of RyR2 [16]. In a 4-week rapid pacing HF model, we reported that dantrolene restored cardiac dysfunction, prevented cardiac remodeling, and prevented delayed after depolarization (DAD) by correcting the defective inter-domain interaction between Nterminal and central domains in HF-type RyR [12]. Similarly, Maxwell et al. reported that dantrolene prevented diastolic Ca2+
leakage from the SR, subsequently recovered the depletion of SR Ca2+, and improved function in failing rabbit cardiomyocytes [17]. Hartmann et al. reported that ex vivo administration of dantrolene improved myocardial function in tissue isolated from patients with HF [18]. These many preclinical studies have suggested that dantrolene is a promising drug for the treatment of HF and lethal arrhythmia. However, little is known about safety and effectiveness of dantrolene in patients with HF and ventricular arrhythmia in clinical settings. The aim of the present study is to evaluate the effect of dantrolene against HF and arrhythmia in patients with CHF and reduced ejection fraction in a multicenter, randomized, double-blind, controlled study.
Materials and methods Ethics The study conforms to the principles outlined in the Declaration of Helsinki and all subjects provided written informed consent prior to participation. This study (Research identification number; H29-013) was initially approved by Institutional Review Boards of Yamaguchi University Hospital on May 12, 2017. The registry number of the study in Japan Registry of Clinical Trials is jRCTs61180059. Study population Inclusion criteria at the time of screening included an age of at least 20 years, New York Heart Association (NYHA) class II and III, and a left ventricular ejection fraction (LVEF) <40%. Patients were required to have a plasma B-type natriuretic peptide (BNP) level of at least 150 pg/ml; if they had been hospitalized for HF within the previous 12 months, a BNP of at least 100 pg/ml was required, while there was no minimum BNP level required for patients who had been diagnosed with ventricular tachycardia /ventricular fibrillation within the previous 12 months. Patients received guideline-directed medical treatment according to the JCS, ESC, or ACC/AHA heart failure guidelines, but, for at least 4 weeks before screening, patients were required to take a stable dose of a betablocker and an ACE inhibitor (or ARBs). Key exclusion criteria were as follows: (1) patients with severe cardiac dysfunction (NYHA IV): e.g. during administration of intravenous catecholamine and/or phosphodiesterase (PDE) III inhibitors and/or vasodilators and/or diuretics, (2) patients with chronic obstructive pulmonary disease (COPD) and severe dysfunction of respiratory function, (3) patients diagnosed with myasthenia gravis, (4) patients with severe liver dysfunction, (5) patients with ileus, (6) patients who could not receive oral medication. The inclusion criteria and the exclusion criteria are shown in detail in Table 1.
Please cite this article in press as: Kobayashi S, et al. A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.020
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JJCC-1927; No. of Pages 8 S. Kobayashi et al. / Journal of Cardiology xxx (2019) xxx–xxx Table 1 Inclusion and exclusion criteria for the SHO-IN trial. Inclusion criteria: 1) Age 20 years or older 2) Male or female sex 3) In-patient or out-patient status 4) Fulfillment of all the following criteria a) NYHA II and III classification b) LVEF less than 40% c) Patients are required to have a plasma B-type natriuretic peptide (BNP) level of at least 150 pg/ml or, if they were hospitalized for HF within the previous 12 months, a BNP of at least 100 pg/ml or, if they had ventricular tachycardia /ventricular fibrillation within the previous 12 months, there was no minimum BNP level. d) Patients received guideline-directed medical treatment according to the JCS, ESC, or ACC/AHA heart failure guidelines. e) For at least 4 weeks before screening, patients were required to take a stable dose of a beta-blocker and an ACE inhibitor (or ARB). f) Written informed consent was obtained from each patient at the time of enrollment. Exclusion criteria 1) Patients with severe cardiac dysfunction (NYHA IV): e.g. during administration of intravenous catecholamine and/or PDE III inhibitors and/or vasodilators and/or diuretics. 2) Patients with COPD and severe dysfunction of respiratory function. 3) Patients diagnosed with myasthenia gravis. 4) Patients with severe liver dysfunction. 5) Patients with ileus. 6) Patients who could not receive oral medication. 7) Pregnancy or lactation 8) History of allergies and hypersensitivity to dantrolene 9) Acute coronary syndrome, stroke, transient ischemic attack within 3 months prior to obtaining informed consent 10) Cardiac, carotid, or other major CV surgery, percutaneous coronary intervention (PCI), or carotid angioplasty performed within 3 months of obtaining informed consent 11) Coronary or carotid artery disease likely to require surgical or PCI within 2 years after starting oral administration of dantrolene or placebo 12) Implantation of a cardiac resynchronization therapy device (CRTD) performed within 3 months prior to obtaining informed consent 13) CRTD likely to be required within 2 years after starting oral administration of dantrolene or placebo or intent to implant CRTD 14) Diagnosis of peripartum or chemotherapy induced cardiomyopathy within 12 months of obtaining informed consent 15) History of heart transplant, on a transplant list, or using left ventricular assistance device (LVAD) 16) Symptomatic bradycardia or second/third degree heart block without a pacemaker. 17) Severe valvular heart disease and severe HOCM 18) Severe inflammatory diseases such as sepsis and pneumonia 19) Active cardiac sarcoidosis 20) Amyloidosis 21) Fabry disease 22) Patients on dialysis 23) Patients with cancer 24) Patients whose primary investigator/investigators considered them unsuitable for the present study. ACC; American College of Cardiology, ACE; angiotensin converting enzyme, AHA; American Heart Association, ARB; angiotensin II receptor blocker, BNP; B type natriuretic peptide, COPD; chronic obstructive pulmonary disease, CV; cardiovascular, ESC; European Society of Cardiology, HOCM; hypertrophic obstructive cardiomyopathy, JCS; Japanese Circulation Society, LVEF; left ventricular ejection fraction, NYHA; New York Heart Association, PDE; phosphodiesterase, SHO-IN trial; A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure and reduced ejection fraction, VF; ventricular fibrillation, VT; ventricular tachycardia.
Study design This SHO-IN study is a multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene for ventricular arrhythmia, as well as mortality and morbidity in patients with CHF and reduced ejection fraction by comparing two groups (daily dose of dantrolene or daily placebo) (Fig. 1). This
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study is an investigator-initiated trial (independent of all companies), including Yamaguchi University Hospital and 19 neighboring hospitals located in the Yamaguchi, Shimane, and Ehime prefectures (Appendix A). The study consists of three periods: the screening period, double-blind randomized treatment in the two groups, and the follow-up period. After obtaining informed consent, patients are randomized and divided into two groups in a double-blind fashion: dantrolene group and placebo group. Randomized drugs are administered for 96 weeks. After giving the drugs for 96 weeks, a 12-week follow-up will confirm the safety after stopping the drugs (Fig. 1). The randomized drugs (dantrolene cap and placebo cap) are built-to-order from Orphan Pacific Inc. (Tokyo, Japan); the study drugs (dantrolene and placebo) are identical in appearance. Patients and investigators are blinded from treatment allocation during all processes of this clinical trial. Randomization and blinding procedures After receiving informed consent from all patients, screening examinations (Visit 0) will be carried out for double-blind randomization (Fig. 1, Table 2), which will be stratified by clinical center. Patients will be assessed to ensure that they fulfill the inclusion criteria. Eligible patients will be randomly assigned in a 1:1 ratio to the dantrolene group or the placebo group by adjusted factors for randomized allocation using computer-generated assignments with the following adjusted factors: age, sex, facility, systolic blood pressure, heart rate, body mass index, estimated glomerular filtration rate (eGFR), LVEF, BNP, NYHA classification, past history of ischemic heart disease, diabetes mellitus, myocardial infarction, stroke, VT within the previous 12 months, ongoing medical treatment [Class III anti-arrhythmic drugs (amiodarone), beta-blockers, ACE-I inhibitors, ARBs, or mineral corticoid antagonists], implantable cardioverter-defibrillator (ICD), and cardiac resynchronization therapy (CRT-D). Dantrolene (1 cap, 25 mg) or placebo will be administered daily for 1 week; then the dosage will be increased to 2 caps daily for 1 week. Finally, if tolerable, 3 caps will be administered daily according to manufacturer instructions for the drug. If the 3-cap dose is not tolerable, daily administration of 2 caps daily will continue, but administration of 1 cap daily will not be continued (Fig. 1). Outcome measures The schedule of the study visits and assessments is shown in Table 2. The primary efficacy outcome measure is cardiovascular death or hospitalization for HF or lethal arrhythmia (electrical storm of VT, sustained VT, and ventricular fibrillation). The secondary outcome measures include all-cause admission, admission due to cardiovascular events, exacerbation of HF, myocardial infarction, or lethal arrhythmia, all-cause death, death due to cardiovascular events, worsening heart failure, myocardial infarction, lethal arrhythmia, other cardiovascular events, or noncardiovascular events, and introduction of renal replacement therapy. Besides, there are exploratory objectives listed in Table 3. Data from each enrolled patient will be gathered by the center of the steering committee at Yamaguchi University Hospital via case report form from each visit (from Visit 1 to Visit 13). Definition of cardiovascular events and adverse effects/serious adverse effects is shown in Table 4. Cardiovascular death contains worsening HF, myocardial infarction, lethal arrhythmia, other cardiovascular events (unstable angina, stroke, arrhythmia other than lethal arrhythmia, pulmonary embolism, cardiovascular procedure-related death, aortic aneurysm rupture, and other cardiovascular death). Lethal arrhythmia includes electrical storm of VT, sustained VT, and VF. Hospital admission for worsening HF is
Please cite this article in press as: Kobayashi S, et al. A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.020
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Fig. 1. Overall outline of SHO-IN trial. SHO-IN trial, A multicenter, randomized, double-blind, controlled Study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure and reduced ejection fraction.
Table 2 Schedule of visits and assessments in the SHO-IN trial.
AEs, adverse effects; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BNP, B type natriuretic peptide; CPX, cardiopulmonary exercise training; Cr, creatinine; CV, cardiovascular vascular; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; g-GTP, gamma glutamyl transferase; HF, heart failure; SAEs, serious adverse effects; *, not necessary.
defined as admission with new or increasing symptoms and signs of the disorder, including signs of fluid retention or objective evidence of HF, and a significant change in treatment for improving HF, as defined by the initiation of intravenous diuretic agents, other intravenous drugs (excluding cardiac glycosides), and mechanical ventilation or mechanical support. An executive committee was responsible for the design and the clinical and scientific conduct of the study. The steering committee is the representative body for the study investigators and consists of members of the Yamaguchi University Hospital Center for clinical research. An endpoint validation committee, blinded to study treatment, will review and adjudicate all prespecified events according to the definitions in Table 4. This trial is being overseen by the steering committee, that is blinded throughout. The safety and conduct of the study are being monitored by an independent data monitoring committee.
Safety outcomes include: the discontinuation of study medication, non-cardiovascular disease-related hospitalization, adverse experiences, and laboratory abnormalities detected during followup. Statistical considerations The primary hypothesis is that medical treatment with chronic administration of dantrolene will be superior to the placebo, as assessed by the effect on the composite event rate of cardiovascular death and/or hospitalization for HF and/or lethal arrhythmia. The initial sample size calculation is based on the assumption that the 2-year rate of cardiovascular mortality, hospitalization for HF, and lethal arrhythmia (VT/VF), based on results of the PARADIGM clinical trial [19] and the VANISH clinical trial [20], would be 36% and that this rate would be reduced by 16% in the dantrolene group
Please cite this article in press as: Kobayashi S, et al. A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.020
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Table 3 Post hoc expiratory analyses.
Table 4 Definition of key clinical efficacy endpoints for the SHO-IN trial.
To investigate the effects of dantrolene on: The profile of indices of cardiac remodeling and cardiac function from baseline to pre-defined time points
Cardiovascular death Cardiovascular death includes death classified in any of the following categories: Worsening heart failure (HF)
The profile of the number of SVT, NSVT, PVC from baseline to pre-defined time points
Myocardial infarction (MI) Lethal arrhythmia
The incidence rate of paroxysmal AF, transition rate of sinus rhythm to persistent AF or chronic AF. The rate of decline in eGFR The rate of decline in proteinuria Time to ‘treatment failure’, defined as: the addition of a new drug, intravenous treatment, or a persistent increase in dose of diuretic dose (>1 month) for the treatment of worsening HF NYHA classification at 24 weeks, 48weeks, 72 weeks, and 96weeks Time to new-onset diabetes mellitus
Other CV events (unstable angina, stroke, arrhythmia other than lethal arrhythmia, pulmonary embolism, cardiovascular procedure-related death, aortic aneurysm rupture, other cardiovascular death) Lethal arrhythmia Lethal arrhythmia includes electrical storm of VT, sustained VT and VF. Electrical storm of VT is defined as any one of the following: three or more episodes of VT within 24 hours treated by antitachycardia pacing or shock. Sustained VT is defined as symptomatic VT sustained for more than 30 seconds. Hospitalization for worsening HF Hospitalization for HF is defined as a presentation to an acute care facility requiring an overnight hospitalization (change in calendar day) with an exacerbation of HF requiring treatment meeting the following criteria: 1 Symptoms and signs of HF AND
The rate of decline in HbA1c in patients with DM Time to new-onset of dyslipidemia The profile of lipid markers (T-cho, TG, HDL-c, LDL-c) The profile of liver function (AST, ALT, g-GTP)
2 Treatment with intravenous (IV) diuretics, IV vasodilators, IV inotropes, mechanical fluid removal (e.g., ultrafiltration or dialysis), or insertion of an intra-aortic balloon pump for hemodynamic compromise. Initiation of standing oral diuretics or intensification of the maintenance diuretic dose will also qualify as treatment Note: Adjudicated HF events associated with elevation in cardiac biomarkers (e.g. cardiac troponin) not thought to be evidence of an associated MI will be noted by the Clinical Endpoint Committee
The incidence of coronary revascularization procedures The profile of biomarkers (e.g. BNP, oxidative stress, and inflammatory biomarkers) from baseline to pre-defined time points
AF, atrial fibrillation; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BNP, B type natriuretic peptide; DM, diabetes mellitus; eGFR, estimated glomerular filtration; g-GTP, g-glutamyl transferase; HDL-c, highdensity lipoprotein cholesterol; HF, heart failure; LDL-c, low-density lipoprotein cholesterol; NSVT, non-sustained ventricular tachycardia; NYHA, New York Heart Association functional classification; PVC, premature ventricular contraction; SVT, sustained ventricular tachycardia; T-cho, total cholesterol; TG, triglyceride.
Adverse event and serious adverse event An adverse event is defined as any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment. A serious adverse event is defined as any adverse event (appearance of undesirable signs, symptoms or medical conditions) which meets any one of the following criteria: Is fatal or life-threatening Results in persistent or significant disability/incapacity Constitutes a congenital anomaly/birth defect
[hazard reduction of 45%, or hazard ratio (HR): 0.9]. To provide approximately 90% power at the 10% significance level (two-sided, adjusted for interim analysis), a target of 280 patients with primary events was set as an effective sample size. The primary endpoint will be summarized with time-to event methods. Cox’s proportional hazards model including a factor for the randomized treatment group will be used to estimate the treatment effect, and will include 95% confidence intervals (CI), and associated p-values. The proportionality of hazard will be checked by addition of an interaction between log (time) and randomized treatment to the Cox model. Time-to-event curves will be estimated with KaplanMeier curves.
Discussion General considerations This study is the first trial to evaluate the efficacy and safety of dantrolene against HF and arrhythmias in patients with CHF (NYHA II-III) and a reduced ejection fraction in a multicenter, randomized double-blind, and controlled study. This trial has been conducted as a final component of our series of translational researches focused on leaky RyR2 channels as a therapeutic target for arrhythmias and HF. The aim of this study is to clarify whether chronic oral administration of dantrolene for 2 years, given a dose
Requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is for: - Routine treatment or monitoring of the studied indication, not associated with any deterioration in condition - Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study and has not worsened since signing the informed consent - Treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a SAE given above and not resulting in hospital admission - Social reasons and respite care in the absence of any deterioration in patient’s general condition - Is medically significant, i.e. defined as an event that jeopardizes the patient or may require medical or surgical intervention However, concomitant symptoms derived from original cardiac disease as well as progression of heart failure are excluded from adverse events and serious adverse events. CV, cardiovascular; SAE, serious adverse event; VF, ventricular fibrillation; VT, ventricular tachycardia.
equivalent to that given in skeletal muscle disease such as spinal epilepsy, improves prognosis when assessing composite endpoints including cardiovascular death, and hospital admission for acute exacerbation of HF and lethal arrhythmia. Many basic science and
Please cite this article in press as: Kobayashi S, et al. A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.020
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Fig. 2. Proposed molecular mechanism by which dantrolene inhibits diastolic Ca2+ leakage through failing RyR2 channel. In a stabilized ryanodine receptor (normal RyR, left), there is no Ca2+ leakage through the RyR channel in the diastolic phase, because domain-interactions between the Nterminal and central domains occur in the zipping state (Zipping). On the other hand, in a de-stabilized ryanodine receptor (leaky RyR, right), there is Ca2+ leakage through the RyR channel in the diastolic phase because the domain-interaction is in an unzipped state (Unzipping). Subsequently, the Ca2+ causes LV dysfunction, LV remodeling, and lethal arrhythmia. CaM, calmodulin; CPVT, catecholaminergic polymorphic ventricular tachycardia; LV, left ventricle; RyR, ryanodine receptor; SR, sarcoplasmic reticulum.
preclinical studies have elucidated that one of the critical causes of HF and lethal arrhythmia is leaky RyR2 channels. HF results from acquired heart disease and is characterized by oxidative stress and chronic hyperactivation of the sympathetic nerve system causing leaky RyR2 channels; in turn, overload of intracellular Ca2+ and depression of SR Ca2+ content leads to systolic and diastolic LV dysfunction and lethal arrhythmia [12– 24]. The Ca2+ leakage from SR may increase in HF patients due to the “domain switch hypothesis” that occurs within RyR2 channels [8,9,12–14,21–24]. According to this hypothesis, tight interactions between the N-terminal and central domains within RyRs stabilize the channel in the closed state. Weakening of these interactions, in RyR-mutation diseases (e.g. MH and CPVT) [21], as well as in HF resulting from acquired heart diseases, would lead to destabilization of this state and caused Ca2+ leakage through RyRs (Fig. 2). This conformational change of the hot domains within RyR2 (from domain zipping to unzipping) causes the dissociation of calmodulin (CaM) from RyR2 and the subsequent Ca2+ leakage through the RyR2 channel (Fig. 2) [8,9,12–14,21–24]. We will be able to clarify whether stabilization of leaky RyR2 due to chronic oral administration of dantrolene plus GDMT, according to the JCS, the ESC, and AHA/ACC guidelines, further improves the composite endpoints including cardiovascular death and hospital admission due to acute exacerbation of HF.
and inhibits Ca2+ leakage though RyR2. Intracellular Ca2+ overload and depletion of SR Ca2+ content are restored to normal. Subsequently, cardiac function is improved and progression of cardiac remodeling is inhibited [8,9,12–14,21–24]. Dantrolene prevented triggered activity-associated ventricular arrhythmia, which was induced by diastolic Ca2+ leakage through failing RyR2 [12–14]. These results suggested that dantrolene works for heart disease as well as it does for skeletal disease. More than 60% of ventricular arrhythmia cases are thought to be caused by triggered activity, leading to HF [25]. Therefore, dantrolene for the treatment of HF and lethal arrhythmia, which targets RyR2, is a promising novel treatment (Fig. 2).
Possible mechanism by which dantrolene inhibits progression of HF as well as lethal arrhythmia in HF patients
Clinical implications
Many basic and preclinical researches reported that dantrolene inhibited Ca2+ leakage through RyR1 and RyR 2 by correcting the defective inter-domain interaction (unzipping) between the Nterminal domain and the central domains of RyRs (Fig. 2) [8–14,21– 24]. The dantrolene binding site is located at amino acid residues 601–620 of the N-terminal domain in RyR2; this amino-acid sequence is identical to the sequence prevalent in RyR1 and inhibits diastolic Ca2+ leakage through a failing RyR2 channel, but has no appreciable effect on a normal RyR2 channel with zipped configulation [12]. Stabilization of failing RyR2 (unzipping to zipping configuration between the N-terminal domain and central domain) by dantrolene increases the binding affinity of CaM to RyR
Limitations The effective dose of dantrolene for the treatment of HF and lethal arrhythmia is not known. In previous in vitro experiments, the half maximal inhibitory concentration (IC50) of Ca2+ leakage from the SR by dantrolene for cardiac and skeletal muscle was the same (0.3 mM) and Ca2+ leakage from the SR was completely inhibited at a concentration of 1 mM dantrolene [9,12]. Therefore, in the SHO-IN trial, the oral dose of dantrolene is set to 75 mg daily (if not tolerable, 50 mg daily), which is identical to the clinical dose given for skeletal muscle disease.
HF has been associated with SR Ca2+ leakage but is likely only one of the multiple contributing factors. However, reducing the leakage of Ca2+ from the SR may provide significant additive benefits when used in combination with conventional therapies. Dantrolene has been used for decades to acutely treat MH and is used chronically to decrease muscle spasticity associated with spinal cord injury, cerebral palsy, multiple sclerosis, or after strokes [26,27]. The chronic administration of dantrolene is generally well tolerated and safe, although patients must be screened for hepatic toxicity. If dantrolene has similar benefits in vivo in patients with established HF, this study will be significant for identifying a widely available agent that specifically targets RyR2 to reduce SR Ca2+ leakage. This could be a powerful tool.
Please cite this article in press as: Kobayashi S, et al. A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.020
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Conclusions Stabilization of failing RyR2 channels by chronic oral administration of dantrolene may become a novel strategy for treatment of HF, if the efficacy and safety of dantrolene for ventricular arrhythmia, as well as mortality and morbidity in patients with CHF and reduced ejection fraction during GDMT, were demonstrated by this trial.
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17 Department of Cardiovascular Medicine, Konan Saint Hill Hospital, Ube, Japan. 18 Department of Cardiovascular Medicine, Sanyo-Onoda City Hospital, Sanyo-Onoda, Japan. 19 Department of Cardiovascular Medicine, Japanese Red Cross Society Yamaguchi Hospital, Yamaguchi, Japan. 20 Department of Cardiovascular Medicine, Nagato General Hospital, Nagato, Japan.
Funding This research was supported bygrants-in-aid for scientific research from the Ministry of Educationin Japan (grant no, 18K08076 to SK, grant no, 17H04178 to MY). The funding sources were not involved in any aspect of this study. We thank the patients and their families for the participation in this study. Disclosures The authors declare that there is no conflict of interest. Author contributions All authors have approved the final article should be true and included in the disclosure. Acknowledgments We thank Mr Yasunobu Koki, Mrs Yoshie Takeuchi, Mr Fumitaka Mizuki, Mrs Hitomi Kawamoto, and Mr Reo Kawano for their excellent clinical research coordination and assistance for making the protocol of the study.
Appendix A The following institutions participated in the SHO-IN trial. 1 Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan. 2 Division of Cardiology, JCHO Tokuyama Central Hospital, Shunan, Japan. 3 Division of Cardiology, Saiseikai Yamaguchi General Hospital, Yamaguchi, Japan. 4 Division of Cardiology, Yamaguchi Prefectural Grand Medical Center, Hofu, Japan. 5 Division of Cardiology, Saiseikai Shimonoseki General Hospital, Shimonoseki, Japan. 6 Division of Cardiology, Shimane Prefectural Central Hospital, Izumo, Japan. 7 Division of Cardiology, JCHO Shimonoseki Medical Center, Shimonoseki, Japan. 8 Division of Cardiology, Yamaguchi Rosai Hospital, SanyoOnoda, Japan. 9 Division of Cardiology, Ehime Rosai Hospital, Niihama, Japan. 10 Division of Cardiology, Shuto General Hospital, Yanai, Japan. 11 Division of Cardiology, Hamada Medical Center, Hamada, Japan. 12 Division of Cardiology, Hagi Civil Hospital, Hagi, Japan. 13 Division of Cardiology, Ube-kohsan Central Hospital, Ube, Japan. 14 Department of Cardiology, Kanmon Medical Center, Shimonoseki, Japan. 15 Department of Cardiovascular Medicine, Hikari City General Hospital, Hikari, Japan. 16 Department of Cardiovascular Medicine, Shunan City Shinnanyo >Hospital, Shunan, Japan.
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[21] Yano M, Yamamoto T, Ikeda Y, Matsuzaki M. Mechanisms of disease: ryanodine receptor defects in heart failure and fatal arrhythmia. Nat Clin Pract Cardiovasc Med 2006;3:43–52. [22] Oda T, Yang Y, Nitu FR, Svensson B, Lu X, Fruen BR, et al. In cardiomyocytes, binding of unzipping peptide activates ryanodine receptor 2 and reciprocally inhibits calmodulin binding. Circ Res 2013;112:487–97. [23] Yano M, Okuda S, Oda T, Tokuhisa T, Tateishi H, Mochizuki M, et al. Correction of defective interdomain interaction within ryanodine receptor by antioxidant is a new therapeutic strategy against heart failure. Circulation 2005;112:3633–43. [24] Ono M, Yano M, Hino A, Suetomi T, Xu X, Susa T, et al. Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ release in heart failure. Cardiovasc Res 2010;87:609–17.
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Original article
A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design Shigeki Kobayashi (MD, PhD, FJCC)a,*, Takatoshi Wakeyama (MD, PhD, FJCC)b, Shiro Ono (MD, PhD, FJCC)c, Yasuhiro Ikeda (MD, PhD)d, Masato Omura (MD, PhD)e, Tsuyoshi Oda (MD, PhD)f, Yuji Hisamatsu (MD, PhD)g, Kozaburo Seki (MD, PhD)h, Akira Satoh (MD, PhD)i, Mitsuyuki Hiromoto (MD, PhD)j, Shintaro Akashi (MD, PhD)k, Kosuke Uchida (MD, PhD)l, Masahiko Harada (MD, PhD)m, Yuhji Furutani (MD, PhD)n, Yasuma Nakamura (MD, PhD)o, Masateru Kohno (MD, PhD)p, Shuji Kawamura (MD, PhD)q, Masakazu Obayashi (MD, PhD)r, Hiroyuki Michishige (MD, PhD)s, Masafumi Yano (MD, PhD, FJCC)a,* a
Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan Division of Cardiology, JCHO Tokuyama Central Hospital, Shunan, Japan Division of Cardiology, Saiseikai Yamaguchi General Hospital, Yamaguchi, Japan d Division of Cardiology, Yamaguchi Prefectural Grand Medical Center, Hofu, Japan e Division of Cardiology, Saiseikai Shimonoseki General Hospital, Shimonoseki, Japan f Division of Cardiology, Shimane Prefectural Central Hospital, Izumo, Japan g Division of Cardiology, JCHO Shimonoseki Medical Center, Shimonoseki, Japan h Division of Cardiology, Yamaguchi Rosai Hospital, Sanyo-Onoda, Japan i Division of Cardiology, Ehime Rosai Hospital, Niihama, Japan j Division of Cardiology, Shuto General Hospital, Yanai, Japan k Division of Cardiology, Hamada Medical Center, Hamada, Japan l Division of Cardiology, Hagi Civil Hospital, Hagi, Japan m Division of Cardiology, Ube-kohsan Central Hospital, Ube, Japan n Department of Cardiology, Kanmon Medical Center, Shimonoseki, Japan o Department of Cardiovascular Medicine, Hikari City General Hospital, Hikari, Japan p Department of Cardiovascular Medicine, Shunan City Shinnanyo Hospital, Shunan, Japan q Department of Cardiovascular Medicine, Konan Saint Hill Hospital, Ube, Japan r Department of Cardiovascular Medicine, Sanyo-Onoda City Hospital, Sanyo-Onoda, Japan s Department of Cardiovascular Medicine, Japanese Red Cross Society Yamaguchi Hospital, Yamaguchi, Japan b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 21 June 2019 Received in revised form 14 August 2019 Accepted 26 August 2019 Available online xxx
Background: Leakage of Ca2+ from the sarcoplasmic reticulum (SR) is a critical contributing factor to heart failure pathophysiology. Therefore, reducing SR Ca2+ leaks may provide significant additive benefits when used in combination with conventional therapies. Dantrolene, a drug routinely used to treat malignant hyperthermia, also stabilizes the cardiac isoform of the release channel (RyR2), thus decreasing SR Ca2+ leaks. The purpose of this study is to evaluate the effect of chronic administration of dantrolene on heart failure and lethal arrhythmia in patients with chronic heart failure and reduced ejection fraction in a multicenter, randomized, double-blind, controlled study. Methods: Patients with chronic heart failure who had functional status of New York Heart Association class II and III and a left ventricular ejection fraction <40% were treated according to the Japanese Circulation Society, the European Society of Cardiology, and the American Heart Association/the American College of Cardiology guidelines for diagnosis and treatment of acute and chronic heart failure. Patients were randomized and divided into two groups in a double-blind fashion: dantrolene group and
Keywords: Heart failure Dantrolene Ventricular arrhythmia Ryanodine receptor
* Corresponding authors at: Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan. E-mail address: [email protected] (S. Kobayashi). https://doi.org/10.1016/j.jjcc.2019.08.020 0914-5087/© 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kobayashi S, et al. A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.020
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placebo group (target sample size: 300 cases). These drugs were administered for 96 weeks. The primary endpoint is cardiovascular death, first hospitalization for exacerbation of heart failure, or lethal arrhythmia [ventricular tachycardia (VT) storm, sustained VT, ventricular fibrillation] for 2 years after starting administration of dantrolene 1 cap (25 mg) three times daily (if not tolerable, two times daily) or matching placebo. Results: This paper presents the rationale and trial design of the study. Recruitment for the study started on 8 December 2017. Conclusions: The results of this trial will clarify the efficacy and safety of dantrolene for ventricular arrhythmia, as well as mortality and morbidity in patients with chronic heart failure and reduced ejection fraction during guideline-directed medical treatment. © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Introduction Chronic heart failure (CHF) is thought to be the end-image of all heart diseases, and progression of heart failure (HF) and lethal arrhythmia worsen the prognosis of CHF patients [1–4]. Guideline-directed medical treatment (GDMT), according to the guidelines of the Japanese Circulation Society (JCS), the European Society of Cardiology (ESC), and the American Heart Association (AHA)/the American College of Cardiology (ACC) for the diagnosis and treatment of acute and chronic heart failure improves patient prognosis. This is mainly through protecting patients from the activation of the sympathetic nerve system and renin-angiotensin-aldosterone system using angiotensin-converting enzyme (ACE) inhibitors [if they are not tolerable, angiotensin receptor blockers (ARBs)], beta blockers, and mineral corticoid antagonists. However, despite the great deal of effort being made to treat CHF, HF remains the most common cause of death from heart disease [5,6]. Dantrolene is a drug heavily used for the treatment of malignant hyperthermia (MH), which is a point mutation disease of the skeletal ryanodine receptor (RyR1) [7]. The pathophysiology of MH involves Ca2+ ion leakage from the sarcoplasmic reticulum (SR). The molecular mechanism of the leaky MH-RyR1 channel is thought to be the conformational change of the regulatory domains composed of the N-terminal and central domains within RyR1, which is caused by a single point mutation at the regulatory domains of RyR1 [8]. We previously proposed that dantrolene bound to amino acids Leu590-Cys609 of the N-terminal domain and restored the defective inter-domain interaction between Nterminal and central domains in MH-type RyR [9,10]. Interestingly, it was demonstrated that dantrolene specifically bound to the corresponding domain Leu601-Cys620 in RyR2, which is completely preserved [11,12]. In catecholaminergic polymorphic ventricular tachycardia (CPVT), which is an inherited disease with RyR2 mutation-linked disorder and the mutation distribution is similar to that of the MH-RyR1-mutation, we found that with the same molecular mechanism, dantrolene prevents CPVT by the inhibition of diastolic Ca2+ leakage through RyR2 in a CPVT-associated RyR2R2474S/+ knock-in (KI) mouse model [13,14]. Jung et al. reported a dantrolene-suppressed diastolic Ca2+ leakage through a RyR2 mutant channel in a patient-specific stem cell CPVT model [15]. More recently, Penttinen et al. reported that dantrolene reduced the number of premature ventricular complexes, on average, by 74% in four CPVT patients, who had a point mutation within the domain switch composed of N-terminal and central domains of RyR2 [16]. In a 4-week rapid pacing HF model, we reported that dantrolene restored cardiac dysfunction, prevented cardiac remodeling, and prevented delayed after depolarization (DAD) by correcting the defective inter-domain interaction between Nterminal and central domains in HF-type RyR [12]. Similarly, Maxwell et al. reported that dantrolene prevented diastolic Ca2+
leakage from the SR, subsequently recovered the depletion of SR Ca2+, and improved function in failing rabbit cardiomyocytes [17]. Hartmann et al. reported that ex vivo administration of dantrolene improved myocardial function in tissue isolated from patients with HF [18]. These many preclinical studies have suggested that dantrolene is a promising drug for the treatment of HF and lethal arrhythmia. However, little is known about safety and effectiveness of dantrolene in patients with HF and ventricular arrhythmia in clinical settings. The aim of the present study is to evaluate the effect of dantrolene against HF and arrhythmia in patients with CHF and reduced ejection fraction in a multicenter, randomized, double-blind, controlled study.
Materials and methods Ethics The study conforms to the principles outlined in the Declaration of Helsinki and all subjects provided written informed consent prior to participation. This study (Research identification number; H29-013) was initially approved by Institutional Review Boards of Yamaguchi University Hospital on May 12, 2017. The registry number of the study in Japan Registry of Clinical Trials is jRCTs61180059. Study population Inclusion criteria at the time of screening included an age of at least 20 years, New York Heart Association (NYHA) class II and III, and a left ventricular ejection fraction (LVEF) <40%. Patients were required to have a plasma B-type natriuretic peptide (BNP) level of at least 150 pg/ml; if they had been hospitalized for HF within the previous 12 months, a BNP of at least 100 pg/ml was required, while there was no minimum BNP level required for patients who had been diagnosed with ventricular tachycardia /ventricular fibrillation within the previous 12 months. Patients received guideline-directed medical treatment according to the JCS, ESC, or ACC/AHA heart failure guidelines, but, for at least 4 weeks before screening, patients were required to take a stable dose of a betablocker and an ACE inhibitor (or ARBs). Key exclusion criteria were as follows: (1) patients with severe cardiac dysfunction (NYHA IV): e.g. during administration of intravenous catecholamine and/or phosphodiesterase (PDE) III inhibitors and/or vasodilators and/or diuretics, (2) patients with chronic obstructive pulmonary disease (COPD) and severe dysfunction of respiratory function, (3) patients diagnosed with myasthenia gravis, (4) patients with severe liver dysfunction, (5) patients with ileus, (6) patients who could not receive oral medication. The inclusion criteria and the exclusion criteria are shown in detail in Table 1.
Please cite this article in press as: Kobayashi S, et al. A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.020
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JJCC-1927; No. of Pages 8 S. Kobayashi et al. / Journal of Cardiology xxx (2019) xxx–xxx Table 1 Inclusion and exclusion criteria for the SHO-IN trial. Inclusion criteria: 1) Age 20 years or older 2) Male or female sex 3) In-patient or out-patient status 4) Fulfillment of all the following criteria a) NYHA II and III classification b) LVEF less than 40% c) Patients are required to have a plasma B-type natriuretic peptide (BNP) level of at least 150 pg/ml or, if they were hospitalized for HF within the previous 12 months, a BNP of at least 100 pg/ml or, if they had ventricular tachycardia /ventricular fibrillation within the previous 12 months, there was no minimum BNP level. d) Patients received guideline-directed medical treatment according to the JCS, ESC, or ACC/AHA heart failure guidelines. e) For at least 4 weeks before screening, patients were required to take a stable dose of a beta-blocker and an ACE inhibitor (or ARB). f) Written informed consent was obtained from each patient at the time of enrollment. Exclusion criteria 1) Patients with severe cardiac dysfunction (NYHA IV): e.g. during administration of intravenous catecholamine and/or PDE III inhibitors and/or vasodilators and/or diuretics. 2) Patients with COPD and severe dysfunction of respiratory function. 3) Patients diagnosed with myasthenia gravis. 4) Patients with severe liver dysfunction. 5) Patients with ileus. 6) Patients who could not receive oral medication. 7) Pregnancy or lactation 8) History of allergies and hypersensitivity to dantrolene 9) Acute coronary syndrome, stroke, transient ischemic attack within 3 months prior to obtaining informed consent 10) Cardiac, carotid, or other major CV surgery, percutaneous coronary intervention (PCI), or carotid angioplasty performed within 3 months of obtaining informed consent 11) Coronary or carotid artery disease likely to require surgical or PCI within 2 years after starting oral administration of dantrolene or placebo 12) Implantation of a cardiac resynchronization therapy device (CRTD) performed within 3 months prior to obtaining informed consent 13) CRTD likely to be required within 2 years after starting oral administration of dantrolene or placebo or intent to implant CRTD 14) Diagnosis of peripartum or chemotherapy induced cardiomyopathy within 12 months of obtaining informed consent 15) History of heart transplant, on a transplant list, or using left ventricular assistance device (LVAD) 16) Symptomatic bradycardia or second/third degree heart block without a pacemaker. 17) Severe valvular heart disease and severe HOCM 18) Severe inflammatory diseases such as sepsis and pneumonia 19) Active cardiac sarcoidosis 20) Amyloidosis 21) Fabry disease 22) Patients on dialysis 23) Patients with cancer 24) Patients whose primary investigator/investigators considered them unsuitable for the present study. ACC; American College of Cardiology, ACE; angiotensin converting enzyme, AHA; American Heart Association, ARB; angiotensin II receptor blocker, BNP; B type natriuretic peptide, COPD; chronic obstructive pulmonary disease, CV; cardiovascular, ESC; European Society of Cardiology, HOCM; hypertrophic obstructive cardiomyopathy, JCS; Japanese Circulation Society, LVEF; left ventricular ejection fraction, NYHA; New York Heart Association, PDE; phosphodiesterase, SHO-IN trial; A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure and reduced ejection fraction, VF; ventricular fibrillation, VT; ventricular tachycardia.
Study design This SHO-IN study is a multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene for ventricular arrhythmia, as well as mortality and morbidity in patients with CHF and reduced ejection fraction by comparing two groups (daily dose of dantrolene or daily placebo) (Fig. 1). This
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study is an investigator-initiated trial (independent of all companies), including Yamaguchi University Hospital and 19 neighboring hospitals located in the Yamaguchi, Shimane, and Ehime prefectures (Appendix A). The study consists of three periods: the screening period, double-blind randomized treatment in the two groups, and the follow-up period. After obtaining informed consent, patients are randomized and divided into two groups in a double-blind fashion: dantrolene group and placebo group. Randomized drugs are administered for 96 weeks. After giving the drugs for 96 weeks, a 12-week follow-up will confirm the safety after stopping the drugs (Fig. 1). The randomized drugs (dantrolene cap and placebo cap) are built-to-order from Orphan Pacific Inc. (Tokyo, Japan); the study drugs (dantrolene and placebo) are identical in appearance. Patients and investigators are blinded from treatment allocation during all processes of this clinical trial. Randomization and blinding procedures After receiving informed consent from all patients, screening examinations (Visit 0) will be carried out for double-blind randomization (Fig. 1, Table 2), which will be stratified by clinical center. Patients will be assessed to ensure that they fulfill the inclusion criteria. Eligible patients will be randomly assigned in a 1:1 ratio to the dantrolene group or the placebo group by adjusted factors for randomized allocation using computer-generated assignments with the following adjusted factors: age, sex, facility, systolic blood pressure, heart rate, body mass index, estimated glomerular filtration rate (eGFR), LVEF, BNP, NYHA classification, past history of ischemic heart disease, diabetes mellitus, myocardial infarction, stroke, VT within the previous 12 months, ongoing medical treatment [Class III anti-arrhythmic drugs (amiodarone), beta-blockers, ACE-I inhibitors, ARBs, or mineral corticoid antagonists], implantable cardioverter-defibrillator (ICD), and cardiac resynchronization therapy (CRT-D). Dantrolene (1 cap, 25 mg) or placebo will be administered daily for 1 week; then the dosage will be increased to 2 caps daily for 1 week. Finally, if tolerable, 3 caps will be administered daily according to manufacturer instructions for the drug. If the 3-cap dose is not tolerable, daily administration of 2 caps daily will continue, but administration of 1 cap daily will not be continued (Fig. 1). Outcome measures The schedule of the study visits and assessments is shown in Table 2. The primary efficacy outcome measure is cardiovascular death or hospitalization for HF or lethal arrhythmia (electrical storm of VT, sustained VT, and ventricular fibrillation). The secondary outcome measures include all-cause admission, admission due to cardiovascular events, exacerbation of HF, myocardial infarction, or lethal arrhythmia, all-cause death, death due to cardiovascular events, worsening heart failure, myocardial infarction, lethal arrhythmia, other cardiovascular events, or noncardiovascular events, and introduction of renal replacement therapy. Besides, there are exploratory objectives listed in Table 3. Data from each enrolled patient will be gathered by the center of the steering committee at Yamaguchi University Hospital via case report form from each visit (from Visit 1 to Visit 13). Definition of cardiovascular events and adverse effects/serious adverse effects is shown in Table 4. Cardiovascular death contains worsening HF, myocardial infarction, lethal arrhythmia, other cardiovascular events (unstable angina, stroke, arrhythmia other than lethal arrhythmia, pulmonary embolism, cardiovascular procedure-related death, aortic aneurysm rupture, and other cardiovascular death). Lethal arrhythmia includes electrical storm of VT, sustained VT, and VF. Hospital admission for worsening HF is
Please cite this article in press as: Kobayashi S, et al. A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.020
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Fig. 1. Overall outline of SHO-IN trial. SHO-IN trial, A multicenter, randomized, double-blind, controlled Study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure and reduced ejection fraction.
Table 2 Schedule of visits and assessments in the SHO-IN trial.
AEs, adverse effects; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BNP, B type natriuretic peptide; CPX, cardiopulmonary exercise training; Cr, creatinine; CV, cardiovascular vascular; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; g-GTP, gamma glutamyl transferase; HF, heart failure; SAEs, serious adverse effects; *, not necessary.
defined as admission with new or increasing symptoms and signs of the disorder, including signs of fluid retention or objective evidence of HF, and a significant change in treatment for improving HF, as defined by the initiation of intravenous diuretic agents, other intravenous drugs (excluding cardiac glycosides), and mechanical ventilation or mechanical support. An executive committee was responsible for the design and the clinical and scientific conduct of the study. The steering committee is the representative body for the study investigators and consists of members of the Yamaguchi University Hospital Center for clinical research. An endpoint validation committee, blinded to study treatment, will review and adjudicate all prespecified events according to the definitions in Table 4. This trial is being overseen by the steering committee, that is blinded throughout. The safety and conduct of the study are being monitored by an independent data monitoring committee.
Safety outcomes include: the discontinuation of study medication, non-cardiovascular disease-related hospitalization, adverse experiences, and laboratory abnormalities detected during followup. Statistical considerations The primary hypothesis is that medical treatment with chronic administration of dantrolene will be superior to the placebo, as assessed by the effect on the composite event rate of cardiovascular death and/or hospitalization for HF and/or lethal arrhythmia. The initial sample size calculation is based on the assumption that the 2-year rate of cardiovascular mortality, hospitalization for HF, and lethal arrhythmia (VT/VF), based on results of the PARADIGM clinical trial [19] and the VANISH clinical trial [20], would be 36% and that this rate would be reduced by 16% in the dantrolene group
Please cite this article in press as: Kobayashi S, et al. A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.020
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Table 3 Post hoc expiratory analyses.
Table 4 Definition of key clinical efficacy endpoints for the SHO-IN trial.
To investigate the effects of dantrolene on: The profile of indices of cardiac remodeling and cardiac function from baseline to pre-defined time points
Cardiovascular death Cardiovascular death includes death classified in any of the following categories: Worsening heart failure (HF)
The profile of the number of SVT, NSVT, PVC from baseline to pre-defined time points
Myocardial infarction (MI) Lethal arrhythmia
The incidence rate of paroxysmal AF, transition rate of sinus rhythm to persistent AF or chronic AF. The rate of decline in eGFR The rate of decline in proteinuria Time to ‘treatment failure’, defined as: the addition of a new drug, intravenous treatment, or a persistent increase in dose of diuretic dose (>1 month) for the treatment of worsening HF NYHA classification at 24 weeks, 48weeks, 72 weeks, and 96weeks Time to new-onset diabetes mellitus
Other CV events (unstable angina, stroke, arrhythmia other than lethal arrhythmia, pulmonary embolism, cardiovascular procedure-related death, aortic aneurysm rupture, other cardiovascular death) Lethal arrhythmia Lethal arrhythmia includes electrical storm of VT, sustained VT and VF. Electrical storm of VT is defined as any one of the following: three or more episodes of VT within 24 hours treated by antitachycardia pacing or shock. Sustained VT is defined as symptomatic VT sustained for more than 30 seconds. Hospitalization for worsening HF Hospitalization for HF is defined as a presentation to an acute care facility requiring an overnight hospitalization (change in calendar day) with an exacerbation of HF requiring treatment meeting the following criteria: 1 Symptoms and signs of HF AND
The rate of decline in HbA1c in patients with DM Time to new-onset of dyslipidemia The profile of lipid markers (T-cho, TG, HDL-c, LDL-c) The profile of liver function (AST, ALT, g-GTP)
2 Treatment with intravenous (IV) diuretics, IV vasodilators, IV inotropes, mechanical fluid removal (e.g., ultrafiltration or dialysis), or insertion of an intra-aortic balloon pump for hemodynamic compromise. Initiation of standing oral diuretics or intensification of the maintenance diuretic dose will also qualify as treatment Note: Adjudicated HF events associated with elevation in cardiac biomarkers (e.g. cardiac troponin) not thought to be evidence of an associated MI will be noted by the Clinical Endpoint Committee
The incidence of coronary revascularization procedures The profile of biomarkers (e.g. BNP, oxidative stress, and inflammatory biomarkers) from baseline to pre-defined time points
AF, atrial fibrillation; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BNP, B type natriuretic peptide; DM, diabetes mellitus; eGFR, estimated glomerular filtration; g-GTP, g-glutamyl transferase; HDL-c, highdensity lipoprotein cholesterol; HF, heart failure; LDL-c, low-density lipoprotein cholesterol; NSVT, non-sustained ventricular tachycardia; NYHA, New York Heart Association functional classification; PVC, premature ventricular contraction; SVT, sustained ventricular tachycardia; T-cho, total cholesterol; TG, triglyceride.
Adverse event and serious adverse event An adverse event is defined as any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment. A serious adverse event is defined as any adverse event (appearance of undesirable signs, symptoms or medical conditions) which meets any one of the following criteria: Is fatal or life-threatening Results in persistent or significant disability/incapacity Constitutes a congenital anomaly/birth defect
[hazard reduction of 45%, or hazard ratio (HR): 0.9]. To provide approximately 90% power at the 10% significance level (two-sided, adjusted for interim analysis), a target of 280 patients with primary events was set as an effective sample size. The primary endpoint will be summarized with time-to event methods. Cox’s proportional hazards model including a factor for the randomized treatment group will be used to estimate the treatment effect, and will include 95% confidence intervals (CI), and associated p-values. The proportionality of hazard will be checked by addition of an interaction between log (time) and randomized treatment to the Cox model. Time-to-event curves will be estimated with KaplanMeier curves.
Discussion General considerations This study is the first trial to evaluate the efficacy and safety of dantrolene against HF and arrhythmias in patients with CHF (NYHA II-III) and a reduced ejection fraction in a multicenter, randomized double-blind, and controlled study. This trial has been conducted as a final component of our series of translational researches focused on leaky RyR2 channels as a therapeutic target for arrhythmias and HF. The aim of this study is to clarify whether chronic oral administration of dantrolene for 2 years, given a dose
Requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is for: - Routine treatment or monitoring of the studied indication, not associated with any deterioration in condition - Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study and has not worsened since signing the informed consent - Treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a SAE given above and not resulting in hospital admission - Social reasons and respite care in the absence of any deterioration in patient’s general condition - Is medically significant, i.e. defined as an event that jeopardizes the patient or may require medical or surgical intervention However, concomitant symptoms derived from original cardiac disease as well as progression of heart failure are excluded from adverse events and serious adverse events. CV, cardiovascular; SAE, serious adverse event; VF, ventricular fibrillation; VT, ventricular tachycardia.
equivalent to that given in skeletal muscle disease such as spinal epilepsy, improves prognosis when assessing composite endpoints including cardiovascular death, and hospital admission for acute exacerbation of HF and lethal arrhythmia. Many basic science and
Please cite this article in press as: Kobayashi S, et al. A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.020
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Fig. 2. Proposed molecular mechanism by which dantrolene inhibits diastolic Ca2+ leakage through failing RyR2 channel. In a stabilized ryanodine receptor (normal RyR, left), there is no Ca2+ leakage through the RyR channel in the diastolic phase, because domain-interactions between the Nterminal and central domains occur in the zipping state (Zipping). On the other hand, in a de-stabilized ryanodine receptor (leaky RyR, right), there is Ca2+ leakage through the RyR channel in the diastolic phase because the domain-interaction is in an unzipped state (Unzipping). Subsequently, the Ca2+ causes LV dysfunction, LV remodeling, and lethal arrhythmia. CaM, calmodulin; CPVT, catecholaminergic polymorphic ventricular tachycardia; LV, left ventricle; RyR, ryanodine receptor; SR, sarcoplasmic reticulum.
preclinical studies have elucidated that one of the critical causes of HF and lethal arrhythmia is leaky RyR2 channels. HF results from acquired heart disease and is characterized by oxidative stress and chronic hyperactivation of the sympathetic nerve system causing leaky RyR2 channels; in turn, overload of intracellular Ca2+ and depression of SR Ca2+ content leads to systolic and diastolic LV dysfunction and lethal arrhythmia [12– 24]. The Ca2+ leakage from SR may increase in HF patients due to the “domain switch hypothesis” that occurs within RyR2 channels [8,9,12–14,21–24]. According to this hypothesis, tight interactions between the N-terminal and central domains within RyRs stabilize the channel in the closed state. Weakening of these interactions, in RyR-mutation diseases (e.g. MH and CPVT) [21], as well as in HF resulting from acquired heart diseases, would lead to destabilization of this state and caused Ca2+ leakage through RyRs (Fig. 2). This conformational change of the hot domains within RyR2 (from domain zipping to unzipping) causes the dissociation of calmodulin (CaM) from RyR2 and the subsequent Ca2+ leakage through the RyR2 channel (Fig. 2) [8,9,12–14,21–24]. We will be able to clarify whether stabilization of leaky RyR2 due to chronic oral administration of dantrolene plus GDMT, according to the JCS, the ESC, and AHA/ACC guidelines, further improves the composite endpoints including cardiovascular death and hospital admission due to acute exacerbation of HF.
and inhibits Ca2+ leakage though RyR2. Intracellular Ca2+ overload and depletion of SR Ca2+ content are restored to normal. Subsequently, cardiac function is improved and progression of cardiac remodeling is inhibited [8,9,12–14,21–24]. Dantrolene prevented triggered activity-associated ventricular arrhythmia, which was induced by diastolic Ca2+ leakage through failing RyR2 [12–14]. These results suggested that dantrolene works for heart disease as well as it does for skeletal disease. More than 60% of ventricular arrhythmia cases are thought to be caused by triggered activity, leading to HF [25]. Therefore, dantrolene for the treatment of HF and lethal arrhythmia, which targets RyR2, is a promising novel treatment (Fig. 2).
Possible mechanism by which dantrolene inhibits progression of HF as well as lethal arrhythmia in HF patients
Clinical implications
Many basic and preclinical researches reported that dantrolene inhibited Ca2+ leakage through RyR1 and RyR 2 by correcting the defective inter-domain interaction (unzipping) between the Nterminal domain and the central domains of RyRs (Fig. 2) [8–14,21– 24]. The dantrolene binding site is located at amino acid residues 601–620 of the N-terminal domain in RyR2; this amino-acid sequence is identical to the sequence prevalent in RyR1 and inhibits diastolic Ca2+ leakage through a failing RyR2 channel, but has no appreciable effect on a normal RyR2 channel with zipped configulation [12]. Stabilization of failing RyR2 (unzipping to zipping configuration between the N-terminal domain and central domain) by dantrolene increases the binding affinity of CaM to RyR
Limitations The effective dose of dantrolene for the treatment of HF and lethal arrhythmia is not known. In previous in vitro experiments, the half maximal inhibitory concentration (IC50) of Ca2+ leakage from the SR by dantrolene for cardiac and skeletal muscle was the same (0.3 mM) and Ca2+ leakage from the SR was completely inhibited at a concentration of 1 mM dantrolene [9,12]. Therefore, in the SHO-IN trial, the oral dose of dantrolene is set to 75 mg daily (if not tolerable, 50 mg daily), which is identical to the clinical dose given for skeletal muscle disease.
HF has been associated with SR Ca2+ leakage but is likely only one of the multiple contributing factors. However, reducing the leakage of Ca2+ from the SR may provide significant additive benefits when used in combination with conventional therapies. Dantrolene has been used for decades to acutely treat MH and is used chronically to decrease muscle spasticity associated with spinal cord injury, cerebral palsy, multiple sclerosis, or after strokes [26,27]. The chronic administration of dantrolene is generally well tolerated and safe, although patients must be screened for hepatic toxicity. If dantrolene has similar benefits in vivo in patients with established HF, this study will be significant for identifying a widely available agent that specifically targets RyR2 to reduce SR Ca2+ leakage. This could be a powerful tool.
Please cite this article in press as: Kobayashi S, et al. A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.020
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Conclusions Stabilization of failing RyR2 channels by chronic oral administration of dantrolene may become a novel strategy for treatment of HF, if the efficacy and safety of dantrolene for ventricular arrhythmia, as well as mortality and morbidity in patients with CHF and reduced ejection fraction during GDMT, were demonstrated by this trial.
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17 Department of Cardiovascular Medicine, Konan Saint Hill Hospital, Ube, Japan. 18 Department of Cardiovascular Medicine, Sanyo-Onoda City Hospital, Sanyo-Onoda, Japan. 19 Department of Cardiovascular Medicine, Japanese Red Cross Society Yamaguchi Hospital, Yamaguchi, Japan. 20 Department of Cardiovascular Medicine, Nagato General Hospital, Nagato, Japan.
Funding This research was supported bygrants-in-aid for scientific research from the Ministry of Educationin Japan (grant no, 18K08076 to SK, grant no, 17H04178 to MY). The funding sources were not involved in any aspect of this study. We thank the patients and their families for the participation in this study. Disclosures The authors declare that there is no conflict of interest. Author contributions All authors have approved the final article should be true and included in the disclosure. Acknowledgments We thank Mr Yasunobu Koki, Mrs Yoshie Takeuchi, Mr Fumitaka Mizuki, Mrs Hitomi Kawamoto, and Mr Reo Kawano for their excellent clinical research coordination and assistance for making the protocol of the study.
Appendix A The following institutions participated in the SHO-IN trial. 1 Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan. 2 Division of Cardiology, JCHO Tokuyama Central Hospital, Shunan, Japan. 3 Division of Cardiology, Saiseikai Yamaguchi General Hospital, Yamaguchi, Japan. 4 Division of Cardiology, Yamaguchi Prefectural Grand Medical Center, Hofu, Japan. 5 Division of Cardiology, Saiseikai Shimonoseki General Hospital, Shimonoseki, Japan. 6 Division of Cardiology, Shimane Prefectural Central Hospital, Izumo, Japan. 7 Division of Cardiology, JCHO Shimonoseki Medical Center, Shimonoseki, Japan. 8 Division of Cardiology, Yamaguchi Rosai Hospital, SanyoOnoda, Japan. 9 Division of Cardiology, Ehime Rosai Hospital, Niihama, Japan. 10 Division of Cardiology, Shuto General Hospital, Yanai, Japan. 11 Division of Cardiology, Hamada Medical Center, Hamada, Japan. 12 Division of Cardiology, Hagi Civil Hospital, Hagi, Japan. 13 Division of Cardiology, Ube-kohsan Central Hospital, Ube, Japan. 14 Department of Cardiology, Kanmon Medical Center, Shimonoseki, Japan. 15 Department of Cardiovascular Medicine, Hikari City General Hospital, Hikari, Japan. 16 Department of Cardiovascular Medicine, Shunan City Shinnanyo >Hospital, Shunan, Japan.
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Please cite this article in press as: Kobayashi S, et al. A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.020