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Efficacy and Safety of Mirogabalin for the Treatment as Add-On to NSAIDs in patients with Peripheral Neuropathic Pain caused by Lumbar Spinal Stenosis : Multi-institutional, randomized, open, parallel-design and interventional Study

MiroTAS (MiroTAS)

220

220 patients who met the eligibility criteria were enrolled in this study, and each 110 patients were assigned to the NSAIDs and mirogabalin combination therapy group and to the NSAIDs monotherapy group. The efficacy analysis set included 110 patients in the NSAIDs and mirogabalin combination therapy group and 104 patients in the NSAIDs monotherapy group. 6 patients in the NSAIDs monotherapy group were excluded from the efficacy analysis set, because 4 of 6 patients took no NSAIDs at all, and in 6 of 6 patients there was no VAS score except for their baseline (4 patients are double-counted). About the efficacy analysis set, the mean +- SD age at IC was 67.8+-11.3 years in the NSAIDs and mirogabalin combination therapy group, and 70.9+-9.2 in the NSAIDs monotherapy group. The mean +- SD VAS score at enrollment (baseline VAS score) was 63.3+-13.7 mm in the NSAIDs and mirogabalin combination therapy group, and 65.3+-16.9 mm in the NSAIDs monotherapy group. And about the efficacy analysis set, there were 50 males (45.5%) and 60 females (54.5%) in the NSAIDs and mirogabalin combination therapy group, and 53 males (51.0%) and 51 females (49.0%) in the NSAIDs monotherapy group, so they were nearly the same proportion.

IC was obtained from 233 patients, 13 of these patients were turned out to be screening failure, and 220 patients who met the eligibility criteria were enrolled in this study. The reason of screening failure was that 5 patients did not meet the criteria and 8 patients requested to discontinue. After start of this study, 162 patients completed (87 patients in the NSAIDs and mirogabalin combination therapy group and 75 patients in the NSAIDs monotherapy group), meanwhile 54 patients withdrew (23 patients in the NSAIDs and mirogabalin combination therapy group and 31 patients in the NSAIDs monotherapy group). About the most reasons of withdrawal, 19 patients requested change or discontinuation of therapy (3 patients in the NSAIDs and mirogabalin combination therapy group and 16 patients in the NSAIDs monotherapy group), 16 patients requested to withdraw from this study (9 patients in the NSAIDs and mirogabalin combination therapy group and 7 patients in the NSAIDs monotherapy group), and in 10 patients AEs occurred (9 patients in the NSAIDs and mirogabalin combination therapy group and 1 patient in the NSAIDs monotherapy group).

216 patients in the safety analysis set were evaluated (110 patients in the NSAIDs and mirogabalin combination therapy group and 106 patients in the NSAIDs monotherapy group). About AEs that investigators judged were related to study drugs or study itself, adverse drug reactions occurred in 63 patients (57.3%) in the NSAIDs and mirogabalin combination therapy group and 4 patients (3.8%) in the NSAIDs monotherapy group. The adverse drug reactions that occurred in 5 or more patients in the NSAIDs and mirogabalin combination therapy group were as follows in descending order: somnolence in 33 patients (30.0%), dizziness in 28 patients (25.5%), constipation in 6 patients (5.5%), and oedema peripheral in 6 patients (5.5%). Treatment-emergent SAE in the NSAIDs monotherapy group was breast cancer in 1 patient (0.9%), that did not cause to discontinue, was not judged to related with study drugs, but the outcome was turned to be resolving. Meanwhile, no treatment-emergent SAE occurred in the NSAIDs and mirogabalin combination therapy group. No death was reported during the study period. Both treatment-emergent AE and adverse drug reaction occurred more likely in the NSAIDs and mirogabalin combination therapy group than in the NSAIDs monotherapy group, and the rate of study drug discontinuation due to AE was higher in the NSAIDs and mirogabalin combination therapy group than in the NSAIDs monotherapy group, the rates were 9 patients (8.2%) in the NSAIDs and mirogabalin combination therapy group or 0 patient in the NSAIDs monotherapy group. TEAEs that brought 2 or more patients to study drug discontinuation were as follows in descending order: dizziness in 2 patients (1.8%), somnolence in 2 patients (1.8%), and diarrhea in 2 patients (1.8%).

About the primary endpoint, the least square (LS) mean change +- standard error (SE) in VAS score from baseline to Week 12 in the efficacy analysis set, calculated by a linear mixed model for repeated measures, was - 24.1+-2.8 mm (P<0.0001) in the NSAIDs and mirogabalin combination therapy group, and -14.2+-3.0 mm (P<0.0001) in the NSAIDs monotherapy group, so there were significant differences in both groups. The LS mean difference between the two groups (the NSAIDs and mirogabalin combination therapy group - NSAIDs monotherapy group) +- SE was -9.9+-4.1 mm (P=0.0174), so there turned to be significant decrease in the NSAIDs and mirogabalin combination therapy group. The LS mean change +- Standard Deviation (SD) in VAS score at Week 12 was -24.7+-27.8 mm in the NSAIDs and mirogabalin combination therapy group, and -14.8+-26.3 mm in the NSAIDs monotherapy group, so more change in VAS score was seen in NSAIDs and mirogabalin combination therapy. And the estimate difference of change in VAS score from baseline to week 12 (NSAIDs and mirogabalin combination therapy - NSAIDs monotherapy) was -13.7 mm at Week 8 (P=0.0009), and -9.9 mm at Week 12 (P=0.0229), so significant difference was seen from Week 8. About the secondary endpoint, the EQ-5D-5L score improved from baseline to Week 12 in both treatment groups, and change in EQ-5D-5L score from baseline to Week 12 was more improved in the NSAIDs and mirogabalin combination therapy group than in NSAIDs monotherapy group. And estimate difference of change between the two groups (the NSAIDs and mirogabalin combination therapy group - NSAIDs monotherapy group) was 0.0529 (P=0.0357), so it was turned out that change in the NSAIDs and mirogabalin combination therapy group is more than that in the NSAIDs monotherapy group. About the other secondary endpoint, the proportion of patients with a PGIC score <= 3 (the sum of minimally, much, and very much improved) at week 12 was significantly higher in the NSAIDs and mirogabalin combination therapy group than in the NSAIDs monotherapy group, 76.2% in the NSAIDs and mirogabalin combination therapy group and 50.0% in the NSAIDs monotherapy group. The proportion of patients with a PGIC score <= 2 (the sum of much, and very much improved) was 47.6% in the NSAIDs and mirogabalin combination therapy group and 32.4% in the NSAIDs monotherapy group.

From this study, it was indicated that NSAIDs and mirogabalin combination therapy showed efficacy to the Lumbar Spinal Stenosis patients to whom pain management by NSAIDs monotherapy had been insufficient. Though it was necessary to pay attention to the occurrence of somnolence, dizziness, and so on when adding mirogabalin to NSAIDs, no difference was seen about frequency of AE occurrence in comparison with previous study, and no new concern was found about safety.

July. 27, 2022

July. 20, 2022

https://link.springer.com/article/10.1007/s40122-022-00410-z

No

No

https://jrct.mhlw.go.jp/latest-detail/jRCTs021200007

Nikaido Takuya

Fukushima Medical University Hospital

1 Hikarigaoka, Fukushima-shi Fukushima-ken, 960-1295 Japan

tnikaido@fmu.ac.jp

Nikaido Takuya

Fukushima Medical University Hospital

1 Hikarigaoka, Fukushima-shi Fukushima-ken, 960-1295 Japan

+81-24-547-1276

tnikaido@fmu.ac.jp

Complete

April. 01, 2020

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1) Patients who have lower limb pain caused by nerve root-type Lumber Spinal Stenosis and can be judged that more than 3 months have passed since the occurrence of the pain has started. (Refer to "Procedure for diagnosis of nerve root-type Lumber Spinal Stenosis" for details.)
2) Patients who is administrated NSAIDS at the enrollment and have not changed dose for more than 4 weeks before the enrollment.
3) Patients with more 40mm of VAS for lower limb pain at informed consent and the enrollment.
4) Patients with 20 years old or older at the enrollment.
5) Patients who are able to understand the procedure of the clinical study, answer a question appropriately and give their voluntary written consent to participate in the study.

1) Patients who used prohibited drugs within 7 days before the enrollment of the study.
2) Patients who changed administration and dosage of limited drugs within 4 weeks before the enrollment of the study.
3) Patients who have severe pain caused by symptoms except for Lumber Spinal Stenosis and have difficulty being evaluated for the study.
4) Patients with cauda equina type or mixed-type Lumber Spinal Stenosis.
5) Patients who have past history of lumber spine surgery
6) Patients who have complication of cancer, infectious disease and fracture at the enrollment.
7) Patients who have past history of hypersensitivity to ingredients of Mirogabalin.
8) Patients who have difficulty participating in the study due to severe complication of liver disease, kidney disease and heart disease.
9) Pregnancy patients or patients who have possibility of pregnancy.
10) Patients with creatinine clearance less than 30mL/min by Cockroft-Gault Equation at enrollment
11) Patients with more than 11 points or 10 points in physician version of "the Brief Scale for Psychiatric Problems in Orthopaedic Patients" (BS POP) and also 15 points in patient version of BS POP.
12) Patients who are inappropriate for participation in the study for othe reason in the opinion of the investigator or sub-investigator.
13) Previous treatment with Mirogabalin.

Both

Lumber Spinal Stenosis

Comparison in the effect and safety of Mirogabalin add-on therapy to NSAIDs and NSAIDs monotherapy for patients with Lumber Spinal Stenosis and administrated of NSAIDs.
1) NSAIDs monotherapy as a study drug are prescribed in accordance with a package insert and each of their administration and dosage is not changed while a study drug is administrated.
2) Mirogabalin add-on therapy to NSAIDs: NSAIDs as a study drug are prescribed in accordance with a package insert and each of their administration and dosage is not changed while a study drug is administrated. Mirogabalin is prescribed as follows in accordance with renal function of a subject.
Patients with creatinine clearance more than 60mL/min: Mirogabalin is administrated in dose of 5mg twice a day at the first week. At the next week, Mirogabalin is administrated in dose of 10mg twice a day. At week 5(after Visit3), dose of Milogabalin is increased to 15mg twice a day unless there is no problem with the safety. After that, the dose of Mirogabalin is controlled by 10mg twice a day or 15mg twice a day depending on safety findings.
Patients with creatinine clearance 30-60mL/min: Mirogabalin is administrated in dose of 2.5mg twice a day at the first week. At the next week, Mirogabalin is administrated in dose of 5mg twice a day. At week 5(after Visit3), dose of Milogabalin is increased to 7.5mg twice a day unless there is no problem with the safety. After that, the dose of Mirogabalin is controlled by 5mg twice a day or 7.5mg twice a day depending on safety findings.
Also, more than 7 days washout period before enrollment is required for target patients administrated of prohibited drugs.
If the administration of Mirogabalin is discontinued, down-titration is needed in accordance with the insert package.

Visual analogue scale of lower limb pain; Amount of the change of pain intensity(VAS providing a range scores from 0-100: no pain 0mm and the worst severe pain imaginable 100mm)from the enrollment(baseline) to at 12 weeks of the study.

1. Amount of the changes of QOL scores from responses of the EQ-5D-5L.
2. PGIC

+81-24-547-1825

April. 23, 2020

none