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Clinical effect of NTN tablets on lumbar spinal canal stenosis with low back pain
-Multicenter,Randomized,Active-control open-label trial-

Clinical effect of NTN tablets on lumbar spinal canal stenosis with low back pain

66

Women were 58.3% (14/24 patients) in the NL group, 60.0% (12/20 patients) in the N group, and 60.0% (12/20 patients) in the L group with a p-value of 1.000 by Fisher's exact test, and the age (mean +- standard deviation) was 71.2 +- 8.1 years in the NL group (24 patients), 76.2 +- 6.2 years in the N group (20 patients), and 74.4 +- 7.8 years in the L group (20 patients), with no statistically significant differences among the three groups (p>=0.05). There were no statistically significant differences between the three groups in the baseline values for patient background (height, weight, disease duration, intermittent claudication distance, spinal canal stenosis site), VAS score, LBP/QOL score, psychological factors, walking activity, standing balance, and concomitant analgesics (p >= 0.05) .

In this study, written consent was obtained from 73 trial subjects, 7 of whom withdrew consent or did not meet eligibility criteria and dropped out before enrollment, and 66 patients who met the eligibility criteria were enrolled in this study. After enrollment, 24 patients were assigned to the NL group, 22 to the N group, and 20 to the L group. Study drug administration was completed in 22 patients (2 patients discontinued) in the NL group, 17 patients (5 patients discontinued) in the N group, and 19 patients (1 patient discontinued) in the L group. Of the patients assigned to the N group, two patients were rejected because they had not taken the study drug, and 24 patients in the NL group, 20 patients in the N group, and 20 patients in the L group were included in the analysis.

Disease or the like occurred in 4 cases of two patients (eczema 3 cases, edema peripheral 1 case), but no serious disease or the like occurred. In both patients, the study drug was discontinued, one patient recovered, and one patient was transferred to another hospital, but no serious disease or the like was observed, indicating no major safety issues.

1. Primary outcome The amount of change in VAS values (mean for the three days before each Visit) from Visit 3 (baseline) to Visit 9 (12 weeks after administration) for lower limb pain were as follows. - The amount of change (mean +- standard deviation) in each group was 0.7 +- 21.5 mm in the NL group (22 patients), -9.1 +- 21.5 mm in the N group (17 patients), and -11.7 +- 20.0 mm in the L group (19 patients). - Adjusted mean estimates [95% confidence interval] and p-values for each group were 3.1 mm [-6.4, 12.7], p = 0.512 in the NL group, -3.2 mm [-13.9, 7.5], p = 0.552 in the N group, -11.3 mm [-21.5, -1.1], p = 0.031 in the L group. - The main analysis, the adjusted between-group difference estimate [95% confidence interval] and the p-value were 14.4 mm [0.5, 28.3], p = 0.042 in the NL vs. L groups. 2. Secondary outcome <Efficacy secondary outcomes> (1) Amount of change in each group The following 1) to 3) were the amount of change in the VAS values of each group at Visit 4 to Visit 9 for the VAS values of Visit 3(adjusted mean estimate). 1) Lower limb pain: No statistically significant improvement was observed in any group from Visit 4 to Visit 8. See the primary outcome for the amount of change in Visit9. 2) Numbness of the lower limbs: No statistically significant improvement was observed in any group. 3) Low back pain: A statistically significant improvement was observed at Visit 5 and Visit 6 in the N group. 4) Walking-related activity test (the amount of change in each group at Visit 4 to Visit 9 using the Visit 3 values as baseline (adjusted mean estimate)): - The average speed of the 20-second walking speed test was significantly increased at Visits 4, 5, 6, and 9 in the NL group and Visit 5 in the N group, and the average stride length was significantly increased at Visit 9 in the NL group and Visit 5 in the N group. - The going in the gait & balance test was significantly decreased at Visit 5 and Visit 6 in the NL group, and the returning was significantly increased at Visit 9 in the NL group. - The TUG test showed a significant decrease at Visit 5 to Visit 9 in the NL group, Visit 9 in the N group, and Visit 8 and Visit 9 in the L group. - FTSST showed a significant decrease at Visit 4 to Visit 9 in the NL group, Visit 5 to Visit 9 in the N group, and Visit 6 to Visit 9 in the L group. 5) Quality of Life Score (the amount of change in each group at Visit 5, Visit 7, and Visit 9 using the Visit 3 score as baseline (adjusted mean estimate)): - ODI significantly decreased at Visit 9 in the NL group, Visit 5, Visit 7, and Visit 9 in the L group. - EQ-5D-5L showed a significant increase at Visit 5 in the L group. - RDQ significantly decreased at Visit 9 in the NL group, Visit 7, Visit 9 in the N group, and Visit 5, Visit 7, Visit 9 in the L group. - PCS significantly decreased at Visit 7 in the NL group and Visit 5 in the L group. - No significant changes were observed in PSEQ in all groups. (2) Comparison of the amount of change between the three groups 1) Lower limb pain: The amount of decrease in the L group was significantly greater than that in the NL group at Visits 6 and 9. 2) Numbness of lower extremities: No significant difference was observed at any time point. 3) Low back pain: The amount of decrease in the N group was significantly greater than that in the NL group at Visit 6. 4) Walking-related activity test: - In the mean speed of the 20-second walking speed test, the increase in the NL group was greater than that in the N group at Visit 4, and the increase in the NL group was greater than that in the L group at Visit 6, showing significant differences. - There was a significant difference in the average speed of returning in the gait & balance test, with a large increase in the NL group compared to the L group at Visit 9. - There were no significant differences at any time point in the group comparisons of changes in each of the average stride length of the 20-second walking speed test, the average going speed of the gait & balance test, the TUG test time, and the FTSST test time. 5) Quality of Life score: In the RDQ score, the amount of decrease in the L group compared to the NL group at Visit 7 was large, and a significant difference was observed, but there were no significant differences at any time point in the group comparison of changes in ODI score, EQ-5D-5L score, PCS score, and PSEQ score. <Safety outcomes> - Incidence of adverse events Adverse events occurred in 3 out of 24 patients (12.5%) in the NL group, 3 out of 20 patients (15.0%) in the N group, and 2 out of 20 patients (10.0%) in the L group.

We exploratory investigated the improvement effects of NTN tablets, Limaprost tablets, and the combination of both drugs on low back pain, leg pain/numbness, and Gait-related activity in lumbar spinal canal stenosis patients with low back pain. There was no additional effect on lower limb pain in the combination group compared to single drug groups, but the additional effect on walking speed was suggested.

Jan. 23, 2023

Jan. 16, 2023

https://link.springer.com/article/10.1007/s40122-022-00472-z

No

No

https://jrct.niph.go.jp/latest-detail/jRCTs031200282

Eguchi Yawara

Chiba University Hospital

1-8-1 Inohana,Chuo-ku,Chiba-shi,Chiba-ken

cafa0892@chiba-u.jp

Eguchi Yawara

Chiba University Graduate School of Medicine

1-8-1 Inohana,Chuo-ku,Chiba-shi,Chiba-ken

+81-43-222-7171

cafa0892@chiba-u.jp

Complete

Jan. 04, 2021

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1) Patients who receive enough explanation about this study and sign written informed consents
2) Patients whose ages are over 20 years old
3) Patients who have low back pain
4) Patients with lumbar spinal canal stenosis checked with MRI
5) Patients with intermittent claudication
6) Patients who fill with the below conditions for clinical test results before the registration
(1) ALT is less than 2.5 times the upper limit of the normal range
(2) AST is less than 2.5 times the upper limit of the normal range
7) Patients who have not received the below drugs before obtaining consent
(1) Within 12 weeks before obtaining consent
a) An Extract from Inflamed Cutaneous Tissue of Rabbits Inoculated with Vaccinia Virus
b) Limaprost Alfadex
c) Study drug or other study drug under clinical study
(2) Within 7 days before obtaining consent
a) Prostaglandin formulation

1) Patients with a surgical history of lumbar spinal tube
2) Suitable patients for surgery of lumbar spinal canal stenosis
3) Patients with spinal disc herniation
4) Patients with peripheral arterial occlusive disease
5) Patients who have or are suspected of peripheral neuropathy (diabetic, alcoholic and drug-induced etc.)
6) Patients with other gait disorders that have possible influence on effectiveness assessment, and patients who have pain and numbness in lumbar which are not caused by lumbar spinal canal stenosis
7) Patients who have nerve root block injections which may affect efficacy evaluation within 3 months before obtaining consent, or who plan to have the injection during the study period after obtaining consents
8) Patients with a history of hypersensitivity for An Extract from Inflamed Cutaneous Tissue of Rabbits Inoculated with Vaccinia Virus and Limaprost Alfadex
9) Patients who show symptoms associated with cerebropathy, cerebral infarction and cerebral hemorrhage, or have shown within 6 months after administration of study drugs
10) Patients who have or history of compilations of convulsive seizure or epileptic seizure
11) Patients who have severe respiratory diseases, cardiac diseases, kidney diseases, liver diseases and hematologic diseases
12) Patients who have mental disorder including depression, and who are judged to be significant danger by participating in the study, by a research representative physician or a research physician
13) Women who are pregnant, lactating, and pregnancy potential, or who hope to be pregnant during this study
14) Patients who take other study drugs and investigational agents within 12 weeks after starting study drugs administration
15) Others, patients who are judged as unsuitable for participating, by a research representative physician or a research physician

Both

Lumber Spinal Canal Stenosis

Patients enroll in the below 3 arms and administrate each study drug for 12 weeks.
1) Neurotropin (N) arm : 2 NTN tablets, twice a day (after breakfast and dinner)
2) Limaprost (L) arm: 1 Limaprost Alfadex tablet, 3 times a day (after breakfast, lunch and dinner)
3) Neurotropin Limaprost (NL) arm : 2 NTN tablets, twice a day (after breakfast and dinner) and 1 Limaprost Alfadex tablet, 3 times a day (after breakfast, lunch and dinner)

VAS change of inferior limb pain from Visit 3 to 9

<Efficacy Secondary Outcomes>
1) The amount of change in VAS from Visit4 to Visit9 for 3days before the baseline (VAS for 3days before Visit3) for the lower limb pain.
2) The amount of change in VAS from Visit4 to Visit9 for 3days before the baseline (VAS for 3days before Visit3) for the numbness of the lower limbs.
3)The amount of change in VAS from Visit4 to Visit9 for 3days before the baseline (VAS for 3days before Visit3) for the low back pain.
4) The amount of change in the Gait-related activity (20seconds walking speed, gait & balance, 3m timed up and go test, 5times standing up) from Visit4 to Visit9 based on the Visit3 score at each measured value.
5) Quality of Life (QOL) (ODI, EQ-5D-5L, RDQ, PCS, PSEQ)in Visit5, Visit7, and Visit9 based on the Visit3 score at each measured value.
<Safety Secondary Outcomes>
Occurrence rate of Adverse Events

+81-43-226-2616

Nov. 18, 2020

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