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A confirmatory (phase III) study of the efficacy and safety of NS-304 (selexipag) in patients with chronic thromboembolic pulmonary hypertension (CTEPH)

A confirmatory (phase III) study of the efficacy and safety of NS-304 (selexipag) in patients with chronic thromboembolic pulmonary hypertension (CTEPH)

78

In terms of sex, age, height, weight, BMI, disease duration, disease classification, prior pulmonary endarterectomy (PEA), prior balloon pulmonary angioplasty (BPA) or percutaneous transluminal pulmonary angioplasty (PTPA), concomitant use of riociguat, concomitant use of ERA, concomitant use of PDE5I, concomitant use of pulmonary vasodilator, baseline PVR, baseline 6-minute walk distance and baseline WHO functional class, there were no significant differences between the NS-304 and placebo groups in any of the items.

Provided informed consent: 104 subjects Randomized: 78 subjects (NS-304: 39 subjects, Placebo: 39 subjects) Treatment: 78 subjects (NS-304: 39 subjects, Placebo: 39 subjects) Completed: 69 subjects (NS-304: 34 subjects, Placebo: 35 subjects) Discontinued: 9 subjects (NS-304: 5 subjects, Placebo: 4 subjects)

The incidence of adverse events was 97.4% (38/39) in the NS-304 group and 82.1% (32/39) in the placebo group. The incidence of adverse events by severity was mild in 71.8% (28/39), moderate in 25.6% (10/39) and severe in 0.0% (0/39) in the NS-304 group, and mild in 59.0% (23/39), moderate in 17.9% (7/39) and severe in 5.1% (2/39) in the placebo group. Severe adverse event was not reported in the NS-304 group. An adverse event leading to death was cardio-respiratory arrest in 1 subject in the placebo group, and no event leading to death was reported in the NS-304 group. Serious adverse events were atrial tachycardia and right ventricular failure each in 1 subject (2.6%) in the NS-304 group, and cardio-respiratory arrest, colon cancer and haemoptysis each in 1 subject (2.6%) in the placebo group. Of these, a causal relationship with the study drug was not ruled out in atrial tachycardia and haemoptysis. The incidence of adverse events leading to discontinuation of the study treatment was 7.7% (3/39) in the NS-304 group, and 10.3% (4/39) in the placebo group. That of adverse reactions leading to discontinuation of the study treatment was 7.7% (3/39) in the NS-304 group and 7.7% (3/39) in the placebo group. The incidence of adverse events leading to dose interruption of the study treatment was 17.9% (7/39) in the NS-304 group and 2.6% (1/39) in the placebo group. That of adverse reactions leading to dose interruption of the study treatment was 15.4% (6/39) in the NS-304 group and 0.0% (0/39) in the placebo group. The incidence of adverse events leading to dose reduction was 33.3% (13/39) in the NS-304 group and 5.1% (2/39) in the placebo group. Causal relationship with the study drug was not ruled out in any of the events.

The mean change in the primary endpoint of PVR from baseline (standard deviation) was -98.2 (111.3) dyn*sec/cm5 in the NS-304 group and -4.6 (163.6) dyn*sec/cm5 in the placebo group at the end of treatment (Week 20). The difference of mean change of PVR from that of the placebo group by the end of the double-blind period (95% confidence interval) was -93.5 dyn*sec/cm5 (-156.8, -30.3). PVR was significantly decreased in the NS-304 group compared with the placebo group (P=0.006, Wilcoxon rank sum test).

Concerning the secondary endpoints, in the changes of mRAP from baseline to the end of the double-blind period (Week 20), no significant difference was observed between the groups.

The result of the examination of efficacy of NS-304 compared with placebo, based on the primary endpoint of PVR, in patients with CTEPH showed that PVR in the NS-304 group significantly decreased compared with that in the placebo group, demonstrating superiority of NS-304 to placebo. Concerning safety, the incidences of headache and diarrhoea were high, but all events were non-serious. There was no clinically significant adverse event, and NS-304 demonstrated favorable tolerability.

No

Nippon Shinyaku Co., Ltd.

14, Nishinosho-Monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan

kouhou@mb.nippon-shinyaku.co.jp

Nippon Shinyaku Co., Ltd.

14, Nishinosho-Monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan

kouhou@mb.nippon-shinyaku.co.jp

completed

June. 10, 2016

Interventional

Randomization, double-blind, placebo-controlled, parallel-group, comparative study

treatment purpose

3

-Patients who have a diagnosis of CTEPH based on 2 or more tests out of pulmonary ventilation/perfusion scan, pulmonary angiography, and chest contrast enhanced CT
-Patients with a diagnosis of PH confirmed by right heart catheterization according to the following criteria : Resting mean pulmonary arterial pressure (mPAP) >= 25 mmHg, Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure <= 15 mmHg
-Patients with a baseline pulmonary vascular resistance (PVR) of > 360 dyn sec/cm5 as measured by a screening/baseline right heart catheterization
-Patients treated with an anticoagulant at its effective dose defined in the package insert from 90 days before or earlier from the date of baseline measurement until the start of study drug administration

-Patients with severe obstructive lung disease
-Patients with severe restrictive pulmonary disease
-Patients with acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements (in particular with 6-minute walking test), e.g., angina pectoris, intermittent claudication
-Patients with acute symptomatic pulmonary embolism within 180 days before the start of study drug administration
-Patients with moderate or severe hepatic impairment
-Patients with moderate or severe renal impairment

Both

Chronic thromboembolic pulmonary hypertension (CTEPH)

investigational material(s)
Generic name etc : NS-304
INN of investigational material : Selexipag
Therapeutic category code : 219 Other cardiovascular agents
Dosage and Administration for Investigational material : Oral administration

control material(s)
Generic name etc : NS-304 Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Oral administration

efficacy
plumonary vascular resistance

efficacy
mean pulmonary arterial pressure

April. 25, 2016