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An open-label, dose escalation, multicenter study to determine the effect on coronary blood flow and safety of NMB46 in subjects undergoing a clinically indicated cardiac catheterization.

An open-label, dose escalation, multicenter study to determine the effect on coronary blood flow and safety of NMB46 in subjects undergoing a clinically indicated cardiac catheterization.

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The ages (mean (standard deviation), hereafter the same) of 30, 100, and 400 microgram group included in FAS were 66.0 (14.1), 64.7 (3.5), and 72.0 (3.2) years, the body weights of them were 74.80 (4.88), 67.40 (20.83) and 64.08 (3.33) kg, the left ventricular ejection fractions of them were 63.87 (10.90), 64.23 (3.59) and 65.25 (8.77) %.

In this study, 15 subjects received NMB46 (5 in the 30 microgram group, 4 in the 100 microgram group, and 6 in the 400 microgram group) were included in the safety analysis set. Among them, 10 subjects (3 in the 30 microgram group, 3 in the 100 microgram group, and 4 in the 400 microgram group) whose APV values deemed to be evaluable after administration of NMB46 at 1-time point or more in the core lab were included in the FAS. PPS was the same population as FAS.

Of the 15 subjects in the safety analysis set, 1 subject (20.0%) in the 30 microgram group, 1 subject (25.0%) in the 100 microgram group, and 3 subjects (50.0%) in the 400 microgram group experienced at least one adverse event. The AEs occured in 1 subject (25.0%) in 100 microgram group, and 2 subjects (33.3%) in 400 microgram group were drug-related: 1 subject (25.0%) in the 100 microgram group experienced feeling hot, and 1 subject (16.7%) experienced palpitations and electrocardiogram QT prolonged, another one (16.7%) experienced feeling hot and heart rate increased in the 400 microgram group. However, all drug-related AEs were mild, and all subjects recovered without any treatment. Even though two SAEs were reported by one subject (20.0%) in the 30 microgram group: one SAE was influenza and another one was pneumonia, both were not related to NMB46. As for the severity of AEs, the severe AEs were influenza and pneumonia occurred in 1 subject (20.0%) in the 30 microgram group, and the moderate AE was pruritus occurred in 1 subject (16.7%) in the 400 microgram group. However, these AEs were not related to NMB46, and all other AEs were mild.

For 10 subjects in FAS, the time (mean (standard deviation)) that at least a 2-fold increase in mean APV from baseline following administration of NMB46 maintained by 30, 100, and 400 microgram group were 18.03 (15.65), 31.90 (55.26), and 509.88 (330.67) seconds. In this study, 3 of 4 subjects in the 400 microgram group reached the target standard, increased APV to twice the baseline level for at least 2 minutes, which was set for visualizing the ischemic region during MPI by increasing coronary blood flow. The remaining 1 subject failed to reach the standard "increased APV to twice the baseline level for at least 2 minutes" because even though the ratio of APV to baseline value reached to 2.21 at the 30 seconds after administration of NMB46, then this ratio fluctuated between 1.68 and 2.16 until 210 seconds after administration.

Efficacy results: The ratio (mean (standard deviation), hereafter the same) of peak APV to baseline APV following administrating NMB46 of 30, 100, and 400 microgram group were 2.533 (0.516), 2.134 (0.629), and 3.289 (1.251). Following the administration of NMB46, the time required for reaching the peak APV they took was 70.00 (10.00), 70.00 (17.32), and 110.00 (79.58) seconds. The value of (the ratio of peak APV to baseline APV following NMB46 administration) / (the ratio of peak APV to baseline APV following adenosine administration) of 30, 100, and 400 microgram group were 0.823 (0.074), 0.893 (0.251), and 1.049 (0.282). Safety results: Refer to adverse events.

Efficacy and safety results suggested that a single intravenous bolus of 400 microgram NMB46 had a sufficient coronary blood flow-increasing effect on visualizing the ischemic region during MPI. Also, considering there was no problem with safety, we decided to consider 400 microgram as the evaluation dose for the next phase study.

No

Nihon Medi-Physics Co., Ltd.

3-4-10, Shinsuna, Koto-ku, Tokyo 136-0075, Japan

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Nihon Medi-Physics Co., Ltd.

3-4-10, Shinsuna, Koto-ku, Tokyo 136-0075, Japan

+81-3-5634-7363

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completed

Jan. 15, 2019

Interventional

Open-label, dose escalation, multicenter study

diagnostic purpose

2

Included un the study will be subjects who:
1. Are undergoing a clinically indicated cardiac catheterization for evaluation and/ or treatment of suspected ischemic heart disease
2. Have a normal ECG or an abnormal ECG not considered to reflect ongoing or frequently recurrent ischemia at screening

Exclusion from the study will be subjects who:
1. Have a history of coronary revascularization by either PCI or CABG within 6 months prior to dosing
2. Have a documented history of acute myocardial infarction or unstable angina within 1 month of dosing
3. Have uncontrolled hypertension
4. Have LVEF < 35%
5. Have aortic stenosis with valve area < 1.5 cm2
6. Have decompensated CHF and/ or New York Heart Association Class IV CHF
7. Have hypertrophic obstructive cardiomyopathy
8. Have asthma , chronic obstructive pulmonary disease or other reactive airway disease for which they are currently receiving treatment
9. Have a history of cardiac transplantation
10. Have a documented history or family history of long QT syndrome
11. Have a documented hypersensitivity to adenosine
12. Have a second- or third-degree AV block
13. Have a sinus node disease, such as sick sinus syndrome or symptomatic bradycardia
14. Have a severe hypotension
15. Known or suspected bronchoconstrictive or bronchospastic lung disease
16. Are unwilling to refrain from all long-acting vasodilating medications
17. Have demonstrable allergy to aminophylline, including allergy to its components (ethylenediamine and theophylline)

Both

Subjects who are planned to be undergoing a clinically indicated cardiac catheterization

investigational material(s)
Generic name etc : Regadenoson
INN of investigational material : Regadenoson
Therapeutic category code : 799 Agents for not mainly purpose of therapeutic, n.e.c.
Dosage and Administration for Investigational material : This study evaluates up to 3 doses levels: 30, 100, and 400 microgram NMB46. When 400 microgram NMB46 is administered, the drug would be used without dilution, but in the situation where 30 or 100 microgram are administered, the drugs are supposed to be diluted with saline to 5 mL. 5 mL of NMB46 is administered as a single intravenous bolus in the vein of the forearm.

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : -

efficacy
Efficacy
The time (in seconds) that the ratio of APV to baseline APV following administration of NMB46 will be at least 2.0-fold.

safety
efficacy
1.Efficacy
2.Safety
1.Efficacy
The ratio of peak APV to baseline APV following administration of NMB46
The time required for reaching the peak APV after NMB46 administration
(Ratio of peak APV to baseline APV following administration of NMB46) / (ratio of peak APV to baseline APV following administration of adenosine)

2.Safety
Adverse event
Vital sign
12-lead ECG
Laboratory tests
Examination

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Dec. 25, 2018