Use of huolingshengji keli granules for treatment of amyotrophic lateral sclerosis

Abstract

Use of Huolingshengji Keli granules in the preparation of a pharmaceutical composition for treating amyotrophic lateral sclerosis (ALS). The traditional Chinese medicine composition comprises: 60-130 parts by weight of Epimedii folium, 60-150 parts by weight of raw Rehmanniae radix, 60-100 parts by weight of alcohol-processed Cornus officinalis, 90-150 parts by weight of Astragali radix, 40-110 parts by weight of Atractylodis macrocephalae rhizoma stir-fried with bran, and 30-90 parts by weight of Poria. The amyotrophic lateral sclerosis is non-familial amyotrophic lateral sclerosis.

Description

Use of Hoilingshengji granules for treating amyotrophic lateral sclerosis TECHNICAL FIELD

[0001] The present application belongs to the field of traditional Chinese medicine, and specifically relates to use of Hoilingshengji granules for treating amyotrophic lateral sclerosis. BACKGROUND

[0002] Amyotrophic lateral sclerosis (ALS), commonly known as "frozen disease", is a rare neurodegenerative disease involving cerebral cortex, brainstem and spinal motor neurons. The clinical manifestations include muscle weakness, muscle atrophy, bulbar paralysis and pyramidal signs, and eventually respiratory failure due to respiratory muscle weakness. Generally, it occurs in the middle and old age, and the survival period of patients is usually 3-5 years, with the characteristics of insidious onset, rapid progression, disability and death.

[0003] About 90%-95% of patients belong to sporadic amyotrophic lateral sclerosis (sALS), and the remaining 5%-10% are familial amyotrophic lateral sclerosis (fALS), which is mostly autosomal dominant. The discovery of ALS-related genes began with SOD1 gene in 1993. With the progress of genetic technology, more pathogenic genes related to ALS have been gradually discovered, such as TDP-43, C9ORF72, FUS, ATAX2, etc. Other possible pathogenesis includes abnormal RNA processing, glutamate excitotoxicity, cytoskeletal disarray, mitochondrial dysfunction, viral infection, apoptosis, growth factor abnormalities, inflammatory response, etc.

[0004] ALS is still an incurable disease, and the focus of treatment is to maximize the quality of life of patients. So far, FDA has only approved three therapeutic drugs (Riluzole, Edaravone and Qalsody). In addition to the above drugs, various new therapies are also being carried out in full swing, such as AAV gene therapy, Treg cell therapy, antibody therapy, which are steadily advancing. However, the above approved drugs still cannot fully meet the treatment needs, especially the survival improvement for non-familial patients is still limited. SUMMARY

[0005] The purpose of the present application is to provide a traditional Chinese medicine composition for preparing a pharmaceutical composition or a combination of drugs for treating amyotrophic lateral sclerosis (ALS).

[0006] In the first aspect of the present application, a traditional Chinese medicine composition for preparing a pharmaceutical composition or a combination of drugs for treating amyotrophic lateral sclerosis (ALS) is provided, wherein the traditional Chinese medicine composition comprises:

[0007] Epimedium 60-130 parts by weight, Rehmannia 60-150 parts by weight, wine cornus officinalis 60-100 parts by weight, Astragalus 90-150 parts by weight, fried atractylodes 40-110 parts by weight, Poria cocos 30-90 parts by weight; preferably, the traditional Chinese medicine composition comprises: Epimedium 70-90 parts by weight, Rehmannia 80-120 parts by weight, wine cornus officinalis 80-90 parts by weight, Astragalus 120-130 parts by weight, fried atractylodes 70-80 parts by weight, Poria cocos 70-80 parts by weight.

[0008] In another preferred embodiment, the amyotrophic lateral sclerosis is non-familial amyotrophic lateral sclerosis.

[0009] In another preferred embodiment, the traditional Chinese medicine composition is an oral preparation; preferably a granule.

[0010] In another preferred embodiment, the traditional Chinese medicine composition is prepared by the following method:

[0011] (a) water extraction of the mixture of each raw material to obtain water extraction juice;

[0012] (b) steam concentration of the juice to obtain a concentrated product;

[0013] (c) drying of the concentrated product to obtain a dry extract;

[0014] (d) mixing and granulating the dry extract with excipients to obtain the traditional Chinese medicine composition granules.

[0015] In another preferred embodiment, in step (a), the water extraction includes: decocting the mixture of each raw material with water to obtain the water extraction juice.

[0016] In another preferred embodiment, in step (b), the steam concentration is carried out at a steam pressure less than 0.3 MPa; preferably at -0.01-0.3 MPa.

[0017] In another preferred embodiment, in step (b), the steam concentration is carried out at a vacuum degree of -0.01 MPa to 0.1 MPa.

[0018] In another preferred embodiment, in step (b), the relative density of the concentrated product is 1.10-1.45.

[0019] In another preferred embodiment, in step (c), the drying is carried out at a steam pressure of 0.10-0.30 MPa.

[0020] In another preferred embodiment, in step (c), the drying is carried out at a vacuum degree of -0.04-0.1 MPa.

[0021] In another preferred embodiment, in step (c), the drying is performed at 20-100 °C.

[0022] In another preferred embodiment, in step (d), the excipient is selected from the group consisting of sucralose, magnesium stearate, dextrin, or a combination thereof.

[0023] In another preferred embodiment, the pharmaceutical composition is used for improving the disease status of the patient in a patient with amyotrophic lateral sclerosis.

[0024] In another preferred embodiment, the improvement of the disease status comprises improvement of one or more indicators selected from the group consisting of:

[0025] (i) reduction in the degree of reduction in the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score from baseline;

[0026] (ii) improvement in the bulbar function of the patient;

[0027] (iii) improvement in the gross motor function of the patient;

[0028] (iv) improvement in the fine motor function of the patient;

[0029] (v) improvement in the respiratory function of the patient;

[0030] (vi) prolongation of the survival time of the patient.

[0031] In another preferred embodiment, the prolongation of the survival of the patient means prolongation of the survival of the patient by 5-6 months relative to the use of riluzole.

[0032] In another preferred embodiment, the patient is a patient in stage I, II or III according to the King's staging.

[0033] In another preferred embodiment, the patient is a patient with a fast rate of disease progression (rate of disease progression > 0.3 points / month).

[0034] In another preferred embodiment, the patient is a patient under 65 years of age.

[0035] In another preferred embodiment, the patient is a patient with FVC% > 80%.

[0036] In another preferred embodiment, the patient is a patient with clinically probable ALS - laboratory supported.

[0037] In another preferred embodiment, the patient is a female patient.

[0038] In another preferred embodiment, the pharmaceutical composition is used for improving the symptoms related to amyotrophic lateral sclerosis in patients who are not responsive to other drugs; preferably, the other drugs are riluzole and / or edaravone.

[0039] In another preferred embodiment, the patient is one who has already used the traditional Chinese medicine composition.

[0040] It should be understood that, within the scope of the present application, each of the technical features described above and each of the technical features described in detail below (e.g., in the examples) can be combined with each other to form a new or preferred technical solution. Due to the limited space, they will not be listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 is a flow chart of subject distribution;

[0042] Figure 2 is the result of subgroup analysis of the main efficacy indicators (mITT); wherein, the mean difference represents the least squares mean difference of ALSFRS-R score change from baseline after 48 weeks of treatment between the Huoling Shengji granules treatment group and the riluzole treatment group, in units of points.

[0043] Figure 3 is the analysis result of ALSFRS-R score in different functional domains. DETAILED DESCRIPTION

[0044] The present inventors have conducted long-term and in-depth research and unexpectedly found that the use of Huoling Shengji granules for the treatment of amyotrophic lateral sclerosis patients, especially non-familial amyotrophic lateral sclerosis patients, can effectively improve the disease progression of such patients, and the effect is better than that of the positive control drug. Based on the above findings, the present inventors completed the present application.

[0045] Use of Huoling Shengji granules for the treatment of amyotrophic lateral sclerosis

[0046] The prescription of Huoling Shengji granules is derived from a clinical experience formula, which is used to treat diseases such as muscle atrophy, limb weakness, muscle tremor, etc. caused by damage to essence, deficiency of qi and blood, deficiency of zang-fu organs, and malnutrition of meridians and muscles.

[0047] Huoling Shengji granules (HLSJ) are prepared by water extraction of Epimedium, Astragalus, Winey Meat, Fried Bupleurum, Rehmannia, and Poria cocos. Studies have shown that HLSJ granules contain a variety of different active ingredients derived from different traditional Chinese medicinal materials. However, studies have shown that a single active ingredient of traditional Chinese medicine cannot be used to treat ALS, as no improvement in muscle weakness and other symptoms in ALS has been observed. In addition, before the present application, there has been no research and report that HLSJ granules can be used to treat non-familial ALS.

[0048] The inventors found that HLSJ (18.9 or 25.2 g / kg / d) can significantly prolong the survival time of SOD1G93A mice, similar to riluzole (30 mg / kg / d). Unexpectedly, HLSJ granules can significantly improve the symptoms of ALS patients, including significantly improving gross motor function, significantly improving fine motor function, significantly improving respiratory function, thereby significantly improving the survival of patients.

[0049] The inventors analyzed more than 10 years of clinical data and unexpectedly found that HLSJ not only slows the progression of ALS to some extent, but also improves symptoms such as shortness of breath, self-sweating, dry throat, irritability, tinnitus, and soreness of the waist and knees, and has certain advantages in the treatment of ALS. Based on the results of animal models and human use experience, HLSJ is used to delay the progression of ALS and is compared with riluzole.

[0050] As the effective component of the present application, the Huoling Shengji granules are mainly made of raw medicinal materials in the following weight parts: Herba Epimedii 2-5 parts, Fried Atractylodes 1-3 parts, Poria 1-3 parts; preferably, the above-mentioned Huoling Shengji granules are mainly made of raw medicinal materials in the following weight parts: Herba Epimedii 2-4 parts, Fried Atractylodes 1-2 parts, Poria 1-2 parts.

[0051] In some preferred embodiments, other drugs can be added to the above-mentioned three Chinese medicines, such as one or more drugs selected from the following group: Radix Astragali 2-6 parts, Radix Codonopsis 2-6 parts, Wine-processed Fructus Corni 1-4 parts, Schisandra 1-4 parts, Radix Rehmanniae 2-4 parts, Cortex Moutan 2-4 parts.

[0052] In the most preferred embodiment of the present application, the above-mentioned Huoling Shengji granules comprise: Herba Epimedii 2-4 parts, Fried Atractylodes 1-2 parts, Poria 1-2 parts, Radix Rehmanniae 2-4 parts, Wine-processed Fructus Corni 1-4 parts, Radix Astragali 2-4 parts, Cortex Moutan 2-4 parts, Fructus Schisandrae 1-4 parts, Radix Codonopsis 1-3 parts, and Radix Paeoniae Alba 1-3 parts.

[0053] Herba Epimedii 70-90 parts by weight, Radix Rehmanniae 80-120 parts by weight, Wine-processed Fructus Corni 80-90 parts by weight, Radix Astragali 120-130 parts by weight, Fried Atractylodes 70-80 parts by weight, and Poria 70-80 parts by weight.

[0054] However, it should be understood that other similar formulations can also achieve similar effects to the present application to varying degrees.

[0055] The compound of the present application can be prepared by conventional methods of Chinese medicine preparations, such as water decoction or extraction with an alcohol-water mixture of raw medicinal materials, followed by concentration and drying of the decoction or extract, preparation of dry extract powder, addition of appropriate excipients to the extract powder, and preparation of Chinese medicine oral granules by conventional pharmaceutical methods of those skilled in the art. In the most preferred embodiment of the present application, the Chinese medicine composition is prepared by the following method:

[0056] (a) water extraction of a mixture of raw materials to obtain a water extract;

[0057] (b) steam concentration of the water extract to obtain a concentrated product;

[0058] (c) drying of the concentrated product to obtain a dry extract;

[0059] (d) mixing of the dry extract with excipients and granulation to obtain the granules of the traditional Chinese medicine composition.

[0060] The main advantages of the present application include:

[0061] (a) The present application provides a new clinically valuable drug (Hualing Shengji granules) and treatment method for ALS.

[0062] (b) The present application not only improves the symptoms of muscle weakness and significantly increases the strength of the limbs, but also significantly delays the progression of muscle atrophy. Especially for patients with non-familial amyotrophic lateral sclerosis of unknown etiology, the efficacy is better than that of the positive control drug in the clinic.

[0063] (c) The treatment method of the present application has significant efficacy for patients under 65 years of age (although such patients have a faster or more severe disease course), and the benefits are particularly significant.

[0064] (d) The present application also has obvious efficacy for patients who have not responded well to drug treatment or have been treated with clinical drugs (such as riluzole and / or edaravone), and can significantly improve various related symptoms of amyotrophic lateral sclerosis.

[0065] (e) The drug or treatment of the present application can significantly prolong the survival period, and the effect is better than that of the current positive control drug in the clinic.

[0066] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. The experimental methods in the following examples are not specified, and are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are by weight.

[0067] Example 1 Hualing Shengji granules process

[0068] 1. Decoction

[0069] Epimedium, 70 kg of Rehmannia glutinosa, 85 kg of Jumeiru, 125 kg of Astragalus membranaceus, 75 kg of Bupleurum chinense decocted with wheat bran, 80 kg of Poria cocos were decocted twice. Water was added for extraction (twice) and the two times of drug juice were combined for standby.

[0070] 2. Concentration

[0071] The obtained secondary medicinal juice is concentrated to a relative density of 1.10-1.45 to obtain a concentrated liquid.

[0072] 3. Filtration

[0073] The concentrated medicinal liquid 2 is filtered to obtain an extract.

[0074] 4. Drying and pulverization

[0075] Drying: The concentrated extract is spread into a stainless steel tray and dried in a vacuum drying device, with the steam pressure controlled at ≤0.30 Pa, and the vacuum degree controlled at above -0.04-0.1 MPa, and the heating can be turned on. The temperature can be adjusted according to the material, and the heating and vacuum are turned off after the moisture content is less than 8.0%.

[0076] Pulverization: The dried extract powder is slowly added into a pulverizer for pulverization, with a screen mesh of φ0.3, to obtain a dried extract powder.

[0077] 5. Premixing, granulation and general mixing

[0078] Premixing: The dried extract powder is added with sucralose, magnesium stearate and dextrin, with a rotation speed of 10 rpm and a mixing time of 5-25 minutes.

[0079] Granulation operation: A screen mesh is installed, and the granules are added into a dry granulator, and the granulation is performed according to the standard operation procedure of the dry granulator, with a feeding speed of 20-30 rpm, a roller speed of 6-18 rpm, an oil pressure of 70-160 bar and a granulation speed of 100-140 rpm. The granules after granulation are poured into a vibrating screen, and the fine powder (fine granules that can pass through the lower bottom 80 mesh screen) and the coarse granules (coarse granules that cannot pass through the upper bottom screen mesh of 30 mesh) are collected. The collected fine powder is re-granulated, and the granulation is repeated.

[0080] General mixing: The granules prepared by the dry method are further mixed, with a rotation speed of 10 rpm and a mixing time of 5 minutes.

[0081] 6. Inner packaging

[0082] The inner packaging is performed using a composite film for medicine packaging, adjusting the temperature, with a longitudinal sealing temperature of 120-150°C and a transverse sealing temperature of 140-190°C, preheating, adjusting the loading amount to a loading amount difference of 20g±4%.

[0083] The prepared traditional Chinese medicine granules are used in the following experiments.

[0084] Example 2 Clinical study of HLSJ for ALS treatment

[0085] Study design and supervision

[0086] The clinical study of Huolingshengji Granules for the treatment of ALS adopts a randomized, double-blind, double-dummy, positive control, and superiority test design. It is conducted in 11 clinical centers in China. Patients who meet all the inclusion criteria and do not meet the exclusion criteria are randomly assigned to the test group and the control group in a 1:1 ratio to receive intervention and evaluation. The trial is divided into two phases, with a total duration of about 49 weeks:

[0087] The longest 1 week at baseline, 48 weeks of treatment period. The ethical approval procedure is authorized by the ethics committee of each clinical trial institution and fully complies with the current Helsinki Declaration ethical standards for human medical research. Relevant data are monitored by an independent data monitoring committee.

[0088] Study population

[0089] Patients aged 45-70 years old, meeting the diagnostic criteria for ALS (definite, probable, or probable laboratory support), normal ALSFRS-R respiratory function score, other scores of 2 points or more, FVC% of 70% or more, disease duration of 3 years or less (from the first appearance of any symptoms of ALS), diagnosed as non-familial ALS, TCM syndrome of qi deficiency and kidney yang deficiency, and voluntarily participating in this clinical trial and signing the informed consent form, meet the inclusion criteria. Detailed exclusion criteria please refer to the previously published literature. The researcher ensures that each patient voluntarily provides informed consent before entering the trial, and obtains written informed consent after the patient (or guardian) and the researcher sign.

[0090] Randomization, blinding, and procedures

[0091] This trial uses block randomization. After selecting the appropriate block size, an independent statistician generates a random sequence of 144 subjects (test and control groups) in a 1:1 ratio according to version 9.4 of SAS (SAS Institute) and lists the random table for this study. Import into the interactive network response system. Patients are randomly assigned to receive equal opportunities for HLSJ or riluzole treatment without stratification. This trial is blinded to researchers and participants through the use of placebo and uniformity of drug packaging. After randomization, patients are given HLSJ (20g) + riluzole placebo or riluzole tablets (50mg) + HLSJ placebo, twice a day, for 48 weeks. During this period, 4 visits are made at 12, 24, 36, and 48 weeks after starting medication.

[0092] Results

[0093] The primary outcome measure was the change from baseline in ALSFRS-R score at Week 48. Secondary outcomes included the change from baseline in ALSFRS-R score at Weeks 12, 24, and 36; the change from baseline in ROADS score, ALSAQ-40 score, TCM syndrome score, and FVC% at Weeks 12, 24, 36, and 48; and the incidence and time to occurrence of endpoint events (death, tracheostomy, or persistent ventilator dependence) after treatment.

[0094] Sample size

[0095] According to the literature reports and expert discussions, the test group was improved by 2 points (μ T -μ C = 2) compared with the control group, with a combined standard deviation S = 4.0; α = 0.05 (two-sided), β = 0.20, power = 0.80, and the test group and the control group were allocated at a ratio of 1:1. The statistical sample size was 64 cases per group, for a total of 128 cases. Considering a 10% dropout rate, 72 cases in the test group and 72 cases in the control group were enrolled in the trial, for a total of 144 cases.

[0096] Statistical analysis

[0097] The modified Intention to treat Set (mITT) was based on the principle of intention to treat, including all randomized cases that received at least one dose of the test drug and had post-dose evaluation data, as the primary efficacy analysis set. For safety feature research, the safety analysis set (SS) included all patients who received at least one dose of the test drug and had post-dose safety evaluation data.

[0098] The primary outcome was evaluated using mixed-effect models for repeated measures (MMRM), with ALSFRS-R score at each visit as the dependent variable, and baseline covariates age stratification (not required for mITT), ALS diagnostic classification, visit time, treatment group, and visit time x treatment group interaction included in the model. The least squares mean (LSMEAN) and its 95% CI were calculated, with the confidence interval adjusted by α. When the P value of the group effect test was less than 0.049 and the lower limit of the confidence interval of the difference between the least squares means of the test group and the control group was greater than zero, the test group was considered superior to the control group. Subgroup analysis related to clinical stratification was performed in the same way (e.g., medulla and non-medulla).

[0099] In the safety analysis, all adverse events (AEs) that occurred during the period were summarized according to the system organ classification and preferred terms, and χ 2The incidence of AEs or adverse reactions between groups was compared using the Fisher's exact probability test.

[0100] Missing values for primary, secondary, and safety outcomes were not imputed. Statistical analyses were performed using SAS, version 9.4 (SAS Institute). In all statistical analyses, a two-sided test was considered statistically significant at P < 0.049.

[0101] Subjects

[0102] A total of 144 patients were enrolled in 11 hospitals in China from July 22, 2021 to May 26, 2022. Among them, 1 patient was randomly excluded due to not meeting the inclusion criteria, and the remaining 143 patients (71 in the HLSJ group and 72 in the Riluzole group) received medical intervention and were included in the SS. 128 patients (64 in the HLSJ group and 64 in the Riluzole group) were included in the mITT (Figure 1).

[0103] The mean age of patients receiving HLSJ was 53.4 years (SD, 5.61), and the mean baseline ALSFRS-R total score was 42.5 (SD, 2.42), while the mean age of the Riluzole group was 55.6 years (SD, 5.63), and the mean baseline ALSFRS-R total score was 42.4 (SD, 2.34).

[0104] The baseline demographic and clinical characteristics of the study population were evenly distributed (Table 1).

[0105] Table 1. Baseline demographic and clinical characteristics of the study population (mITT)

[0106] Abbreviations: ALS, amyotrophic lateral sclerosis; ALSAQ-40, Amyotrophic Lateral Sclerosis Patient Self-Assessment Questionnaire-40; ALSFRS-R, revised ALS Functional Rating Scale; FVC, forced vital capacity; ROADS, Rasch Overall Amyotrophic Lateral Sclerosis Disability Scale; TCM, traditional Chinese medicine; WFN, World Federation of Neurology.

[0107] a Calculated as weight (kg) divided by height (m) squared.

[0108] b According to the El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral published by the WFN Research Group in 2000, there are 4 types: definite, probable, probable laboratory-supported, and possible diagnosis.

[0109] c Calculated as randomized date minus date of first symptom onset.

[0110] d Calculated as 48-minute reduction minus baseline ALSFRS-R total score, divided by duration of disease (months).

[0111] e According to the “Diagnosis and Treatment Scheme of Shi Disease (Motor Neuron Disease)” published by the Chinese Society of Traditional Chinese Medicine in 2018.

[0112] Efficacy outcomes

[0113] The LSMEAN (95% CI) of ALSFRS-R score change from baseline after 48 weeks of treatment in the HLSJ group and the riluzole group were -10.25 (-11.24-9.26) and -12.55 (-13.52-11.58), respectively. The difference between the two groups was 2.88 (1.02-4.73, P=0.0025) by the Mixed-effect Models for Repeated Measures (MMRM), indicating that after 48 weeks of treatment, HLSJ Granules could reduce the ALSFRS-R score by 2.88 points compared with riluzole, and the difference was statistically significant.

[0114] In patients with rapid disease progression (binary classification), the LSMEAN difference was 2.68 (95% CI, 0.39-4.97; P=0.022).

[0115] Subgroup analysis also showed that for patient subgroups such as those with FVC% ≥80%, those clinically very likely to have ALS-laboratory supported, and female patients, the HLSJ effect was statistically significant compared with riluzole (Figure 2).

[0116] ALSFRS-R score includes 12 sub-items, which can be divided into 4 functional domains: fine motor action (fine motor function), large muscle action (gross motor function), medulla (brain) function, and respiratory function.

[0117] Analysis of functional domains showed that HLSJ Granules had a certain positive effect on all 4 functional domains compared with riluzole. In particular, in the respiratory function domain and the fine motor action domain, HLSJ Granules had a significant difference compared with riluzole: the difference between the two groups in the respiratory function domain score was 0.54 (95% CI 0.06-1.02), P=0.0269, and the difference in the fine motor action score was 1.03 (95% CI 0.05-2.00), P=0.0387, indicating that HLSJ Granules had a better effect on improving the respiratory function and fine motor action function of ALS patients than riluzole (Figure 3).

[0118] Safety outcomes

[0119] The total number of AEs reported by 57 patients (80.28%) in the HLSJ group was 232, and the total number of AEs reported by 58 patients (80.56%) in the riluzole group was 225, with no significant difference between the two groups (P = 0.9671). The number and percentage of patients with AEs showed no significant difference between the groups, regardless of the severity level or the degree of relevance to the test drug. Six patients died, of which five were caused by ALS disease progression and its complications, and the remaining one was caused by COVID-19, with no causal relationship with the test drug. No adverse reactions above grade 3, serious adverse reactions, or adverse reactions leading to death occurred in the HLSJ group. In terms of laboratory tests, there were no hematological-related adverse reactions, and no cases of severe liver and kidney damage occurred in the HLSJ group. Mild effects on the liver and kidneys were tolerable and did not affect drug compliance. One patient with a history of coronary atherosclerosis who received HLSJ treatment experienced a cardiac-related adverse event (abnormal T wave on electrocardiogram, 1.41%), which did not affect the test drug treatment and recovered naturally.

[0120] Table 2. Safety analysis of Hualing Shengji and riluzole groups during the randomized control period (safety analysis set)

[0121] Abbreviation: TEAE, treatment-emergent adverse event.

[0122] a If multiple cases of the same adverse event occur in the same subject, the severity level or related category of adverse events in the subject is counted only once, but the number of events is counted according to the actual number of occurrences. If the severity or causality of these same adverse events is different, count once in the most severe or most relevant category.

[0123] b Calculated based on the number of subjects in each group.

[0124] c According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, it is graded from 1 to 5.

[0125] Summary

[0126] This multicenter clinical trial evaluated the effectiveness and safety of Hualing Shengji granules in the treatment of amyotrophic lateral sclerosis (spleen deficiency and kidney yang deficiency) compared with riluzole. The results showed that Hualing Shengji granules showed clinical efficacy in ALS patients, and the efficacy evaluation indicators used internationally recognized multiple functional evaluation scales showed improvement in patient dysfunction and quality of life.

[0127] The research of the present application shows that the drug of the present application is obviously superior to the first-line clinical drug Riluzole in improving dysfunction. The research shows that the ALSFRS-R reduction rate is reduced by 16.5%, and the median survival time is prolonged by 4-5 months. Considering that in the population with an age less than or equal to 65 years, compared with Riluzole, HLSJ slows down the ALSFRS-R reduction by 23% (2.88 ÷ 12.5 x 100% = 23%), the above results suggest that compared with Riluzole, HLSJ can further prolong the median survival time by 5.7-7.1 months.

[0128] In addition, the multicenter clinical study first found that Huoling Shengji Granules have particularly significant clinical treatment effects on ALS patients with a confirmed clinical diagnosis of ALS, a history of Edaravone treatment, an onset site located in the bulb, a lung function test score FVC% less than 80%, and fast disease progression (disease progression rate > 0.3 points / month).

[0129] The above research results fully highlight the treatment advantages and values of the Huoling Shengji Granules of the present application for amyotrophic lateral sclerosis, and the long-term use safety is good, which is an innovative, breakthrough, and demonstrative traditional Chinese medicine innovative new drug variety.

[0130] All the documents mentioned in the present application are cited as references in the present application, just as each document is cited as a reference individually. In addition, it should be understood that those skilled in the art can make various modifications or amendments to the present application after reading the above teaching of the present application, and these equivalent forms also fall within the scope defined by the claims attached to the present application.

Claims

1. Use of a traditional Chinese medicine composition for the preparation of a pharmaceutical composition or a pharmaceutical combination for treating amyotrophic lateral sclerosis (ALS), the traditional Chinese medicine composition comprising: Epimedium 60-130 parts by weight, Rehmannia 60-150 parts by weight, wine cornus 60-100 parts by weight, Astragalus 90-150 parts by weight, fried Atractylodes 40-110 parts by weight, Poria 30-90 parts by weight; preferably, the traditional Chinese medicine composition comprises: Epimedium 70-90 parts by weight, Rehmannia 80-120 parts by weight, wine cornus 80-90 parts by weight, Astragalus 120-130 parts by weight, fried Atractylodes 70-80 parts by weight, Poria 70-80 parts by weight. ​ 2. Use according to claim 1, characterized in that, The amyotrophic lateral sclerosis is non-familial amyotrophic lateral sclerosis.

3. Use according to claim 1, characterized in that, The traditional Chinese medicine composition is an oral preparation; preferably a granule.

4. The use according to claim 1, characterized in that, The traditional Chinese medicine composition is prepared by the following method: (a) water extraction of the mixture of each raw material to obtain water extract juice; (b) steam concentration of the juice to obtain a concentrated product; (c) drying of the concentrated product to obtain a dry extract; (d) mixing of the dry extract with excipients and granulation to obtain the traditional Chinese medicine composition granules.

5. The use according to claim 1, characterized in that, The pharmaceutical composition is used to improve the disease state of patients with amyotrophic lateral sclerosis.

6. Use according to claim 5, characterized in that, The improvement of the disease state includes one or more indicators selected from the group: (i) the degree of reduction in the reduction of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score compared with baseline; (ii) improvement of the patient's bulbar function; (iii) improvement of the patient's gross motor function; (iv) improvement of the patient's fine motor function; (v) improvement of the patient's respiratory function; (vi) prolongation of the patient's survival time.

7. Use according to claim 5, characterized in that, The patient is a patient in King stage I, II or III.

8. The use according to claim 5, characterized in that, The patient is a patient with fast disease progression rate (disease progression rate > 0.3 points / month).

9. The use according to claim 5, characterized in that, The patient is a patient under 65 years old.

10. The use according to claim 5, characterized in that, The pharmaceutical composition is used to improve the symptoms related to amyotrophic lateral sclerosis in patients who do not respond well to other drugs; preferably, the other drugs are riluzole and / or edaravone.

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