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An Asian, phase 3, multicenter, randomized, double-blind, placebo-controlled 14-week study of DS-5565 in patients with diabetic peripheral neuropathic pain followed by a 52-week open-label extension

DS-5565 phase 3 study for diabetic peripheral neuropathic pain

834

In the randomized analysis set (834 subjects) , the mean (SD) age at informed consent was 61.4 (9.78) years. Overall, 72.5% (605/834) of subjects were male and 27.5% (229/834) were female. The mean (SD) body weight was 69.08 (13.119) kg, and mean (SD) body mass index (BMI) was 25.28 (4.096) kg/m2. The median (min, max) duration of painful DPN was 36.0 (6, 300) months. The mean (SD) baseline ADPS was 5.59 (0.964). The mean (SD) VAS in SF-MPQ was 58.5 (10.81) mm at screening (Visit 1), and 58.3 (9.91) mm at randomization (Visit 2). Overall, about 72.3% of subjects were enrolled in Japan, and the subjects were randomized approximately equally among the treatment groups. No notable differences were found in the demographic or other baseline characteristics among the treatment groups.

834 subjects were randomized to one of the treatment groups (334 subjects in the placebo group, 166 subjects in the 15-mg QD group, 168 subjects in the 10-mg BID group, and 166 subjects in the 15-mg BID group). A total of 755 subjects (90.5%) completed the study: 309 subjects (92.5%) in the placebo group, 154 subjects (92.8%) in the 15-mg QD group, 150 subjects (89.3%) in the 10-mg BID group, and 142 subjects (85.5%) in the 15-mg BID group.

The incidence of TEAEs was 61.2% (202/330) in the placebo group, 68.3% (112/164) in the 15-mg QD group, 68.5% (113/165) in the 10-mg BID group, and 77.6% (128/165) in the 15-mg BID group. As the dose of DS-5565 increased, the incidence of TEAEs numerically increased. The most common TEAEs (reported for >= 5% of subjects in any treatment group) were nasopharyngitis (12.7% in the placebo group, 13.4% in the 15-mg QD group, 14.5% in the 10-mg BID group, and 16.4% in the 15-mg BID group; hereinafter, the same order), somnolence (3.9%, 8.5%, 12.1%, and 14.5%), dizziness (2.1%, 4.9%, 8.5%, and 10.9%), oedema peripheral (1.2%, 4.9%, 2.4%, and 8.5%), weight increased (0.6%, 2.4%, 3.0%, and 6.7%), and contusion (1.8%, 1.2%, 1.8%, and 5.5%). Of the most common TEAEs above, the incidence of the TEAEs of nasopharyngitis, somnolence, dizziness, and weight increased was higher as the daily dose of DS-5565 was increased. Most of the TEAEs of somnolence, dizziness, oedema peripheral, and weight increased were resolved without any treatment.

The time course of LS mean ADPS showed a gradual decrease from Week 1 through Week 14 in all groups. The decrease was greatest in the 15-mg BID group, showing the lowest score in all weeks compared with other groups. The next greatest decrease was seen in the 10-mg BID group. The LS mean (SE) changes from baseline in imputed ADPS at Week 14 were -1.31 (0.095) in the placebo group, -1.34 (0.136) in the 15-mg QD group, -1.47 (0.135) in the 10-mg BID group, and -1.81 (0.136) in the 15-mg BID group. The LS mean ADPS at Week 14 decreased from baseline in all groups. The LS mean changes from baseline were greater as the daily dose of DS-5565 was increased. The LS mean (95% CI, P-value) differences versus placebo in change from baseline in the imputed ADPS at Week 14 were statistically significant in the 15-mg BID group after taking multiplicity into account: -0.03 (-0.35 to 0.30, P = 0.8773) in the 15-mg QD group, -0.15 (-0.48 to 0.17, P = 0.3494) in the 10-mg BID group, and -0.50 (-0.82 to -0.17, P = 0.0027) in the 15-mg BID group.

In the 15-mg QD group, the changes from baseline in SF-MPQ at Week 14/LOCF were greater than in the placebo group in all SF-MPQ subscales (sensory score, affective score, total score, VAS, and present pain intensity), and the LS mean difference versus placebo in total score was statistically significant. In the 10-mg BID group, the changes from baseline in SF-MPQ at Week 14/LOCF were greater than in the placebo group in all SF-MPQ subscales except for present pain intensity, and the LS mean differences versus placebo in sensory score, affective score, and total score were statistically significant. In the 15-mg BID group, the changes from baseline in SF-MPQ at Week 14/LOCF were greater than in the placebo group in all SF-MPQ subscales, and the LS mean differences versus placebo in all SF-MPQ subscales were statistically significant.

In this study, DS-5565 was administered at doses of 15 mg QD, 10 mg BID, or 15 mg BID for 14 weeks, including the titration period, to evaluate the efficacy and safety of DS-5565 in Asian patients with DPNP. The mean changes from baseline in ADPS at Week 14 were greater as the daily dose of DS-5565 was increased, and the differences versus placebo were statistically significant in the 15 mg BID group. DS-5565 at a dose of 15 mg BID or below is considered safe and well tolerated.

Jan. 23, 2019

https://onlinelibrary.wiley.com/doi/full/10.1111/jdi.13013

Yes

Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/ Supporting Documents: - Study Protocol - Statistical Analysis Plan - Clinical Study Report Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication. Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent. URL: https://vivli.org/ourmember/daiichi-sankyo/

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

DAIICHISANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

completed

Jan. 24, 2015

Interventional

A double-blind study followed by open-label extension

treatment purpose

3

- Type 1 or type 2 diabetes mellitus
- Painful distal symmetric polyneuropathy
- Average daily pain score >= 4

- HbA1c > 10.0%
- Uncontrolled blood glucose that may require changes in diabetes treatment (non-insulin drug therapy, exercise therapy, diet therapy) during study
- Other severe pain unrelated to diabetic peripheral neuropathy, that may confound the assessment of diabetic peripheral neuropathic pain
- Neurologic disorders unrelated to diabetic peripheral neuropathy, that may confound the assessment of diabetic peripheral neuropathic pain

Both

Diabetic peripheral neuropathic pain

investigational material(s)
Generic name etc : DS-5565
INN of investigational material : mirogabalin
Therapeutic category code : 119 Other agents affecting central nervous system
Dosage and Administration for Investigational material : Oral administration (15mg/day, 20mg/day, 30mg/day)

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

efficacy
confirmatory
Average daily pain score

safety
efficacy
pharmacokinetics
- Short-Form McGill Pain Questionnaire
- Safety

-

Nov. 20, 2014