Abstract
Background:
We aimed to investigate the efficacy and safety of landiolol in Japanese patients with recurrent hemodynamically unstable ventricular tachycardia or recurrent ventricular fibrillation (recurrent VT/VF).
Methods and Results:
This was an open-label, uncontrolled, multicenter study. Patients with hemodynamically unstable VT or VF 24 h prior to providing informed consent, and who were refractory to class III antiarrhythmic drugs, were enrolled. Landiolol was started at a dose of 1 μg/kg/min, after VT/VF was suppressed with electrical defibrillation. Landiolol was titrated up to 10 μg/kg/min in 1 h and adjusted between 1 and 40 μg/kg/min for the efficacy assessment (1–49 h). The primary efficacy endpoint was the proportion of patients free from recurrent VT/VF. Secondary efficacy endpoints included the number of recurrent VT/VF events and the survival rate 30 days after the start of landiolol treatment. Adverse events (AEs) were assessed for safety; 27 and 29 patients were analyzed for efficacy and safety, respectively. The proportion of patients free from recurrent VT/VF was 77.8% (95% CI 57.1–89.3). The mean (±standard deviation) number of recurrent VT/VF events was 9.3±7.9. The survival rate was 96.3%. The overall incidence of AEs and of serious AEs was 72.4% and 6.9%, respectively.
Conclusions:
Landiolol may be useful for Japanese patients with recurrent VT/VF who do not respond to class III antiarrhythmic drugs.
Ventricular arrhythmias, including sustained ventricular tachycardia (VT) and ventricular fibrillation (VF), produce a wide variety of symptoms, including palpitations, either skipped or extra beats or sustained palpitations, shortness of breath, chest pain, dizziness, near syncope, and syncope, and may lead to sudden cardiac death.1
Re-entry is the underlying mechanism for most sustained ventricular arrhythmias in the presence of structural heart disease.1
Therefore, class III antiarrhythmic drugs such as amiodarone and nifekalant (a pure potassium-channel blocker) are commonly used for the treatment of ventricular arrhythmia in Japan. However, VT/VF sometimes shows resistance to these drugs. Beta-blockers have a different mechanism of action to that of amiodarone and nifekalant. Their mechanism of antiarrhythmic efficacy involves competitive β-adrenoreceptor blockade of sympathetically mediated triggering mechanisms, slowing of the sinus rate, and inhibition of excess calcium release by the ryanodine receptor channel.2
Beta-blockers are recommended for VT/VF in the American Heart Association/American College of Cardiology/European Society of Cardiology and Japan Circulation Society guidelines.1–4
Landiolol, an ultra-short-acting β-blocker, was developed in Japan. It is rapidly metabolized to inactive forms in the blood and liver, resulting in a short half-life of approximately 4 min in human blood, and selectively binds to β1 receptors.5
Landiolol can be used for patients with tachyarrhythmia with left ventricular dysfunction,6
and has potential as a new therapeutic option for ventricular arrhythmia. However, there are limited data on the efficacy and safety of landiolol for VT/VF. Therefore, data from a prospective multicenter study, such as the present study, are needed. Our objective was to investigate the efficacy and safety of landiolol in patients with recurrent ventricular arrhythmia.
Methods
Study Design
This was an open-label, uncontrolled, multicenter study conducted between October 2015 and January 2018 at 10 centers in Japan. The study design is shown in
Figure 1.
Patients with recurrent ventricular arrhythmia who had recurrent hemodynamically unstable VT or those who had recurrent VF after administration of potassium-channel blockers were recruited. Hemodynamically unstable VT was defined as arrhythmia with systolic blood pressure <80 mmHg or a shock-like clinical condition requiring electrical defibrillation to stop the arrhythmia.
The present study was approved by the institutional review boards of each participating center and was performed in accordance with the Pharmaceuticals and Medical Devices Law and the Japanese Ministerial Ordinance on Good Clinical Practice for Drugs. Written informed consent was obtained from all patients. This study was registered at Japic-CTI (No. JapicCTI-152956).
Patients
The major inclusion criteria were: aged ≥20 years when hospitalized at the time the study drug was administered, with at least 1 episode of recurrent hemodynamically unstable VT or recurrent VF within 24 h prior to providing informed consent despite treatment with a class III antiarrhythmic drug (oral or intravenous potassium-channel blocker: amiodarone, nifekalant, or sotalol). If patients were being treated with oral antiarrhythmic drugs, they must have taken a maximum maintenance dose according to the package insert or the maximum tolerated dose for each patient. Additionally, they must have taken a stable dose for at least 1 month.
The following were major exclusion criteria: temporal reperfusion VT/VF during percutaneous transluminal coronary angioplasty or temporal VT/VF after coronary obstruction or stenosis; cardiogenic shock or systolic blood pressure <90 mmHg despite pressure-raising treatment; diabetic ketoacidosis or metabolic acidosis; bradyarrhythmia such as atrioventricular block (>2nd-degree) or sick sinus syndrome; right cardiac failure caused by pulmonary arterial hypertension; untreated pheochromocytoma; undergoing surgery; high risk of death for reasons other than cardiac disease; using a ventricular assist device; progressive malignant neoplasm; serious allergic history; or a history of treatment with landiolol hydrochloride.
Treatment
Landiolol was administered at an initial dosage of 1 μg/kg/min. The dosage was increased from 1 μg/kg/min to 2.5, 5, and 10 μg/kg/min, in a stepwise manner within the first hour (titration period). The maintenance dosage was kept at ≤10 μg/kg/min during the efficacy assessment period. At recurrence of hemodynamically unstable VT or recurrence of VF, the dosage could be increased to a maximum of 40 μg/kg/min, and tolerability was confirmed (Figure 1). Treatment was administered for a minimum of 49 h (1-h titration period+48-h efficacy assessment period) to a maximum of 5 days (120 h) of post-treatment initiation for follow-up at the discretion of the study investigators. After the efficacy assessment period (49 h from starting study treatment), treatment switch to an oral β-blocker was considered.
The dosage was adjusted (maintained or reduced) at the discretion of the study physicians if the patient had systolic blood pressure <80 mmHg or a heart rate <60 beats/min. In patients with a maintenance dosage ≤10 μg/kg/min, the dosage was reduced by 1 μg/kg/min when the patients met the reduction criteria. In patients with a maintenance dosage of 10–40 μg/kg/min, the dosage was reduced by 1–10 μg/kg/min when the patients met the reduction criteria.
Class I, class II (all β-blockers), and class IV antiarrhythmic drugs; catheter ablation; new implantable cardioverter defibrillator use or changes in its setting; and coronary arterial revascularization were prohibited from the start of landiolol treatment to 49 h post-treatment initiation. Other investigational drugs were prohibited for the entire study period. Concurrent use or change of dosage and administration of the following drugs were prohibited from the start of landiolol treatment to 49 h post-treatment initiation: class III antiarrhythmic drugs (amiodarone, nifekalant, and sotalol), oral β-blockers (carvedilol and bisoprolol), and adrenergic agents.
Efficacy
The primary efficacy endpoint was the proportion of patients free from recurrent hemodynamically unstable VT or the proportion of patients free from recurrent VF during the efficacy assessment period. Hemodynamically unstable VT or VF was defined as recurrent if it occurred more than once. The secondary efficacy endpoints were the number of events of hemodynamically unstable VT or VF and the number of events per unit time (every 12 h) during the efficacy assessment period, and patient outcomes (survival rate) at 30 days after the start of landiolol treatment.
A subgroup analysis of the proportion of patients free from recurrent hemodynamically unstable VT or the proportion of patients free from recurrent VF during the efficacy assessment period was performed for the following subgroups: male or female, age <65 or ≥65 years, type of arrhythmia (VT or VF), presence of ischemic heart disease, implantable cardioverter defibrillator, New York Heart Association classification, left ventricular ejection fraction (<25%, 25% to <50%, or ≥50%), prior use of an oral β-blocker, and formulation of prior class III antiarrhythmic drugs (oral and intravenous).
Safety
Safety outcomes were assessed by the numbers of adverse events (AEs) and adverse drug reactions (ADRs), collected using MedDRA®
ver. 20.1J, together with vital signs, general laboratory tests (blood chemistry and hematology), and 12-lead ECG.
Statistical Analysis
The sample size was not statistically estimated because of the rarity of the disease; thus we set the sample size at 30. We estimated that approximately 20% of the enrolled patients would be excluded; thus, the number of patients in the analysis set was planned to be 25.
The safety analysis set was defined as patients who were administered landiolol at least once during the study period. For efficacy, the following 2 efficacy analysis sets were used: the full analysis set (FAS) and the modified FAS. The FAS was the primary efficacy analysis set used to assess the prevention of VT/VF recurrence with the recommended landiolol dose, and was defined as patients who did not have VT/VF recurrence during the titration period and had at least 1 efficacy assessment during the efficacy evaluation period. The modified FAS was used to confirm the robustness of the results obtained with the FAS population, and was defined as patients who were administered landiolol and had at least 1 efficacy assessment.
The Kaplan-Meier method was used for the analysis of the primary efficacy endpoint, and its 95% confidence interval (CI) was calculated using Greenwood’s formula. If the lower limit of the 95% CI did not fall below the threshold of 20%, this indicated a meaningful clinical benefit with landiolol treatment. The Kaplan-Meier method was used to estimate the proportion of patients free from recurrent hemodynamically unstable VT or the proportion of patients free from recurrent VF and its 95% CI during the 48-h assessment period with landiolol treatment in the patient subgroups. The secondary efficacy endpoints and safety endpoints were summarized using descriptive statistics and/or frequency distribution. The statistical software used was SAS version 9.3 for Windows (SAS Institute, Cary, NC, USA).
Results
Patient Disposition and Baseline Characteristics
The disposition of patients is shown in
Figure 2. A total of 39 Japanese patients were enrolled, but 10 patients were excluded (did not fulfill inclusion criteria or fulfilled the exclusion criteria), so 29 patients were included in the safety analysis set and modified FAS. Among those in the safety analysis set and modified FAS, 2 patients with recurrence of hemodynamically unstable VT or recurrence of VF in the titration period were also excluded to ensure adequate assessment of the prevention of VT/VF recurrence with the recommended landiolol dose; thus, 27 patients were included in the FAS. The primary efficacy analysis set (FAS) included 27 patients, and the secondary efficacy analysis set (modified FAS) included 29 patients.
Patients’ demographic and clinical characteristics are shown in
Table 1. Most patients were male (79.3%) and the mean±standard deviation (SD) age of all patients was 67.4±9.6 years. The most frequent presenting arrhythmia and cardiac disease were VT (86.2%) and heart failure (96.3%), respectively. Oral amiodarone was the most frequently used class III antiarrhythmic drug (44.8%).
Table 1.
Baseline Demographic and Clinical Characteristics of Patients Treated With Landiolol
| |
Safety analysis set (n=29) |
| Age, years |
67.4±9.6 |
| Sex (male/female), n |
23/6 |
| Body weight, kg |
60.88±10.73 |
| Presenting arrhythmia |
| VT |
25 (86.2) |
| VF |
2 (6.9) |
| VT/VF |
2 (6.9) |
| ICD/CRT-D |
21 (72.4) |
| Cardiac disease |
27 (93.1) |
| Heart failure |
26 (96.3) |
| Hypertension |
17 (63.0) |
| Old myocardial infarction |
13 (48.1) |
| Dilated cardiomyopathy |
6 (22.2) |
| Angina pectoris |
4 (14.8) |
| Valvular disease |
3 (11.1) |
| Acute myocardial infarction |
2 (7.4) |
| Hypertrophic cardiomyopathy |
2 (7.4) |
| Other cardiac disease |
17 (63.0) |
| LVEF, % |
30.47±15.56 |
| <25 |
11 (37.9) |
| ≥25 to <50 |
14 (48.3) |
| ≥50 |
4 (13.8) |
| NYHA class III/IV |
12 (41.4) |
| B-type natriuretic peptide, pg/mLa |
731.8±848.6 |
| Previous treatment |
| Oral β-blocker |
21 (72.4) |
| Diuretic |
21 (72.4) |
| Aldosterone antagonist |
18 (62.1) |
| ACEI |
13 (44.8) |
| Catecholamine |
5 (17.2) |
| Class III antiarrhythmic drug |
| Amiodarone (intravenous) |
11 (37.9) |
| Amiodarone (oral) |
13 (44.8) |
| Nifekalant (intravenous) |
4 (13.8) |
| Sotalol (oral) |
5 (17.2) |
Data are n (%) or mean±standard deviation. aArbitrarily selected parameter measured in 26 patients. ACEI, angiotensin-converting enzyme inhibitor; CRT-D, cardiac resynchronization therapy defibrillator; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; VF, ventricular fibrillation; VT, ventricular tachycardia.
The mean±SD dosage at the end of the titration period was 9.5±3.5 μg/kg/min (<10 μg/kg/min in 6 patients, 10 μg/kg/min in 22 patients, and >10 μg/kg/min in 1 patient). The mean±SD dosage from 0 to 49 h post-treatment initiation was 8.5±5.2 μg/kg/min. The mean±SD maximum dosage was 11.8±6.7 μg/kg/min (<10 μg/kg/min in 2 patients, 10 μg/kg/min in 23 patients, and >10 μg/kg/min in 4 patients). The total administration time was <49 h in 7 (24.1%) patients and ≥49 h in 22 (75.9%) patients, with a mean±SD of 63.5±30.9 h. The mean±SD time from last VT/VF to the start of administration of landiolol was 8.5±7.3 h (min.–max.; 0.1–23.6 h).
Efficacy
The proportion of patients free from recurrent hemodynamically unstable VT or the proportion of patients free from recurrent VF during the assessment period by the Kaplan-Meier method (primary efficacy endpoint) was 77.8% (21/27 patients in the FAS) with a 95% CI of 57.1–89.3 (Figure 3). The lower limit of the 95% CI was greater than the threshold of 20%. On the other hand, the proportion of patients free from recurrent hemodynamically unstable VT or recurrent VF in the modified FAS was 72.4% (21/29 patients) with a 95% CI of 52.3–85.1.
Regarding the results of the secondary efficacy endpoints, in patients who had recurrence of ventricular arrhythmia in the FAS (6 patients), the mean±SD number of events of hemodynamically unstable VT or VF events in the efficacy assessment period was 9.3±7.9 (0–48 h) (4.5±6.9 [0–12 h], 2.8±4.7 [12–24 h], 2.5±1.9 [24–36 h], and 1.3±1.5 [36–48 h]), and the mean±SD number of events per unit of time (every 12 h) in the efficacy assessment period were 0.38±0.57/h (0–12 h), 0.51±1.00/h (12–24 h), 0.21±0.16/h (24–36 h), and 0.12±0.14/h (36–48 h). Although the number of events decreased over time, we were unable to evaluate the reduction in the recurrence of ventricular arrhythmia for this drug, as 5 of the 6 patients who presented with events discontinued study drug administration because of hypotension or lack of efficacy, etc. Regarding patient outcomes at 30 days, in the FAS 96.3% (26/27) of patients survived, and in the safety analysis set, 89.7% (26/29) of patients survived.
The results of the subgroup analysis for the proportion of patients free from recurrent hemodynamically unstable VT or the proportion of patients free from recurrent VF during the assessment period are shown in
Table 2. No factors were found to be associated with the efficacy of landiolol.
Table 2.
Subgroup Analysis for the Proportion of Patients Free From Recurrent Hemodynamically Unstable VT or the Proportion of Patients Free From Recurrent VF During the Assessment Period
| |
Full analysis set (n=27) |
| n |
No. of patients
with VT/VF |
VT/VF-free patients,
% (95% CI)a |
| Total |
27 |
6 |
77.8 (57.1–89.3) |
| Sex |
| Male |
22 |
5 |
77.3 (53.7–89.8) |
| Female |
5 |
1 |
80.0 (20.4–96.9) |
| Age, years |
| <65 |
8 |
2 |
75.0 (31.5–93.1) |
| ≥65 |
19 |
4 |
78.9 (53.2–91.5) |
| Diagnosis (type of arrhythmia) |
| VT |
25 |
5 |
80.0 (58.4–91.1) |
| VF, VT/VF |
2 |
1 |
50.0 (0.6–91.0) |
| Ischemic heart disease |
| No |
13 |
4 |
69.2 (37.3–87.2) |
| Yes |
14 |
2 |
85.7 (53.9–96.2) |
| ICD |
| No |
6 |
1 |
83.3 (27.3–97.5) |
| Yes |
21 |
5 |
76.2 (51.9–89.3) |
| NYHA class |
| I |
4 |
1 |
75.0 (12.8–96.1) |
| II |
13 |
2 |
84.6 (51.2–95.9) |
| III |
8 |
2 |
75.0 (31.5–93.1) |
| IV |
2 |
1 |
50.0 (0.6–91.0) |
| LVEF, % |
| <25 |
10 |
2 |
80.0 (40.9–94.6) |
| ≥25 to <50 |
14 |
4 |
71.4 (40.6–88.2) |
| ≥50 |
3 |
0 |
100.0 (100.0–100.0) |
| Oral β-blocker use (prior treatmentb) |
| No |
6 |
1 |
83.3 (27.3–97.5) |
| Yes |
21 |
5 |
76.2 (51.9–89.3) |
| Formulation of class III antiarrhythmics (prior treatmentb) |
| Oral only |
14 |
3 |
78.6 (47.2–92.5) |
| Intravenous only or both oral and intravenous |
13 |
3 |
76.9 (44.2–91.9) |
a
Kaplan-Meier method used for the estimation. bDefined as drugs or treatments used prior to the start of landiolol treatment. CI, confidence interval. Other abbreviations as in Table 1.
The incidences of AEs and ADRs are shown in
Table 3. The overall incidence of AEs was 72.4% (21/29 patients) and that of serious AEs was 6.9% (2/29 patients). AEs reported in more than 2 patients were hypotension (7 patients), abnormal hepatic function (2 patients), and constipation (2 patients). The overall incidence of ADRs was 34.5% (10/29 patients). ADRs reported during the study were hypotension (6 patients), bradycardia (1 patient), heart failure (1 patient), nausea (1 patient), chest discomfort (1 patient), and liver function test increased (1 patient). A total of 3 patients died during the course of the study, the reasons being the natural course of the primary disease (ventricular arrhythmias), myocardial infarction, and cerebral hemorrhage in 1 patient each. Both myocardial infarction and cerebral hemorrhage were considered serious AEs; however, because these events occurred before the study treatment, they were considered to be related to the severity of the underlying disease or a side effect of anticoagulant drugs for treatment while on the artificial heart-lung machine, and thus not related to the study treatment. There were no patients with serious AEs confirmed other than the 2 patients who died. The mean heart rates at the 3 time points (before the administration of the landiolol, 1 h and 49 h after the start of administration of landiolol) were 74.6±11.1, 72.5±11.2, and 73.0±20.7 beats/min, respectively. The mean systolic blood pressures were 107.4±19.1, 100.5±23.6, and 96.1±18.7 mmHg respectively. The mean diastolic blood pressures were 62.3±11.1, 60.3±13.7, and 56.9±9.7 mmHg respectively. The mean values of heart rate and blood pressure remained relatively constant throughout the treatment period (data not shown). There were no special concerns regarding general laboratory tests or 12-lead ECGs.
Table 3.
Incidence of AEs and ADRs in Patients With Recurrent Hemodynamically Unstable VT or Those With Recurrent VF Who Were Treated With Landiolol
| |
Safety analysis set
(n=29) |
| All AEs |
21 (72.4) |
| Serious AEs |
2 (6.9) |
| AEs resulting in drug discontinuation |
4 (13.8) |
| AEs resulting in deaths |
2 (6.9) |
| All ADRs |
10 (34.5) |
| Incidences of ADRs by MedDRA® preferred term |
| Hypotension |
6 (20.7) |
| Bradycardia |
1 (3.4) |
| Heart failure |
1 (3.4) |
| Nausea |
1 (3.4) |
| Chest discomfort |
1 (3.4) |
| Liver function test increased |
1 (3.4) |
Data are n (%). If a patient presented with the same AE more than once, that event was counted as 1 patient having that event. ADR, adverse drug reaction; AE, adverse event; VF, ventricular fibrillation; VT, ventricular tachycardia.
Discussion
The effect of landiolol in the present study is consistent with that in a previous Japanese study of this drug in patients who did not respond to class III antiarrhythmic drugs.7
In the previous study, the inhibition rate (non-occurrence) for VT or VF was 78.6% (33/42 patients) compared with 77.8% (21/27 patients) in the present study. The percentage of patients free from recurrent hemodynamically unstable VT or recurrent VF among the overall patients (modified FAS, 29 patients), which includes 2 patients excluded from the FAS, was 72.4% (21/29 patients), and the efficacy was similar to that in the FAS (77.8%, 21/27 patients).
During the efficacy evaluation period, all 29 patients used class III antiarrhythmic drugs. The efficacy reported in the present study is considered the result of the combined use of landiolol and class III antiarrhythmic drugs. Further, because landiolol is a β-blocker, we investigated the effects of its administration in addition to oral β-blockers. In the subgroup analysis (Table 2), the efficacy of landiolol was shown in patients using oral β-blockers as well as those who were not using oral β-blockers.
The survival rates in the present study (96.3% in the FAS and 89.7% in the safety analysis set) were numerically higher than those reported in the previous Japanese study (60% in all patients).7
This difference could be related to differences in patients’ backgrounds. In the previous Japanese study, 50% of patients had acute myocardial infarction compared with only 7.4% in the present study. Furthermore, there may have been more patients with more severe VF in the previous Japanese study, as VF occurs frequently after acute myocardial infarction. Finally, as there were more patients with an implantable defibrillator in the present study, this led to a lower death rate. Even though the percentage of patients with an implantable defibrillator is unknown in the previous Japanese study, the research was conducted during a period when the adoption rate of implantable defibrillators was low in Japan. In the present study, the subgroup analysis did not reveal any factors associated with the efficacy of landiolol.
The most common ADR in the present study was hypotension, with an incidence of 20.7% (6/29), which was similar to that reported in previous studies of amiodarone injection (18–26%).8,9
The present study targeted patients who did not respond to class III antiarrhythmic drugs, whereas the studies of amiodarone injection enrolled patients who did not respond to class I antiarrhythmic drugs.
The dosage of landiolol is easy to adjust because it is administered by drip infusion, so it is possible to increase the dosage gradually. When adverse reactions occur, these can be controlled by ceasing the landiolol infusion or by decreasing the dosage. One of the advantages of landiolol over amiodarone is its shorter half-life; thus, the occurrence of AEs is easier to control with landiolol than with amiodarone.
Study Limitations
These include those related to an open-label non-randomized study design; the limited sample size from the rarity of the disease, especially for VF; and the lack of a study comparator.
Conclusions
Landiolol may be useful for patients with recurrent hemodynamically unstable VT and patients with recurrent VF who do not respond to class III antiarrhythmic drugs (amiodarone, nifekalant, and sotalol). Although the present study confirmed the efficacy of landiolol for patients who did not respond to class III antiarrhythmic drugs, whether landiolol can be considered the first treatment choice for VT/VF is still unknown. Further investigations comparing landiolol (β-blocker) to amiodarone (class III antiarrhythmic drug) for patients with recurrent hemodynamically unstable VT or those with recurrent VF will be planned.
Acknowledgments
The authors thank the investigators and site staff who participated in the present study (Appendix). The authors also thank Michelle Belanger, MD, and Hikari Chiba of Edanz Medical Writing for providing medical writing assistance, which was funded by Ono Pharmaceutical through EMC K.K. in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).
Conflict of Interest Statement
Takanori Ikeda has received lecture fees from Bayer Yakuhin, Bristol-Myers Squibb, Daiichi-Sankyo, Ono Pharmaceutical, and Pfizer, and scholarship funds from Bayer Yakuhin, Daiichi-Sankyo, Japan Lifeline, and Medtronic. Tsuyoshi Shiga has received research funding from Ono Pharmaceutical. Wataru Shimizu has received lecture fees from Bayer Yakuhin, Bristol-Myers Squibb, Daiichi-Sankyo, and Nippon Boehringer Ingelheim, and scholarship funds from Daiichi-Sankyo and Nippon Boehringer Ingelheim. Takeshi Yamashita has received lecture fees from Bayer Yakuhin, Bristol-Myers Squibb, Daiichi-Sankyo, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Sumitomo Dainippon Pharma, and Toa Eiyo; manuscript fees from Bristol-Myers Squibb and Daiichi-Sankyo; research funding from Bayer Yakuhin, Bristol-Myers Squibb, and Daiichi-Sankyo; and scholarship funds from Daiichi-Sankyo. Kaori Oki and Haruka Okamoto are employees of Ono Pharmaceutical. Koichiro Kinugawa, Atsuhiro Sakamoto, Ryozo Nagai, and Takashi Daimon have no conflicts of interest to disclose. The present study was funded by Ono Pharmaceutical.
Grants
This study was funded by Ono Pharmaceutical.
Appendix
List of Investigators and Site Staff Who Participated in This Clinical Trial and Study Sites
Investigators and Study Sites
Takanori Ikeda, Toho University Omori Medical Center; Yoichi Kobayashi, Showa University Hospital; Tsuyoshi Shiga, Tokyo Women’s Medical University Hospital; Wataru Shimizu, Nippon Medical School Hospital; Kengo Kusano, National Cerebral and Cardiovascular Center Hospital; Hideki Tashiro, St. Mary’s Hospital; Masayoshi Ajioka, Tosei General Hospital; Tetsuya Amano, Aichi Medical University Hospital; Kazuo Kimura, Yokohama City University Medical Center; and Yoshihiro Fukumoto, Kurume University Hospital.
Ono Pharmaceutical Core Team
Tatsuaki Okamura, Akira Ichikawa, Chiaki Minamoto, Masaki Kubota, Yoshimi Hosoya, Ryoko Fujimaki, Mikiko Takagi, Makiko Yamashita, Daisuke Matsuura (data manager), and Toshihiro Yoshikawa (statistician).
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