Fused tricyclic gamma-amino acid derivative pharmaceutical composition

Abstract

The invention provides a pharmaceutical composition which comprises a compound shown as a formula (I) or pharmaceutically acceptable salts thereof, and acetyl levocarnitine or salts thereof, and application of the pharmaceutical composition in preparation of drugs for treating diabetic peripheral neuralgia. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition and an application thereof, in particular to a fused tricyclic γ-amino acid derivative pharmaceutical composition and an application thereof in treating diabetic peripheral neuropathy, belonging to the technical field of pharmaceutical compositions. Background Art

[0002] my country is the country with the largest number of diabetes patients. With the aging of the population and the change of lifestyle in recent years, the prevalence of diabetes has increased from 0.67% in 1980 to 11.2% in 2015-2017. In 2010, the National Center for Disease Control and Prevention and the Endocrinology Branch of the Chinese Medical Association conducted a survey on the prevalence of diabetes in people over 18 years old in China. According to the 1999 diagnostic criteria of the World Health Organization (WHO), the prevalence of diabetes is 9.7%; and with glycated hemoglobin (HbA1c) ≥ 6.5% as the diagnostic standard, the prevalence is 11.6%. It is estimated that the number of diabetes patients in my country has reached 110 million.

[0003] Diabetic peripheral neuropathy (DPNP) refers to peripheral neuropathic pain caused by diabetes or prediabetes, which is often manifested as symmetrical peripheral neuropathic pain with distal limb involvement as the main symmetry. It can also be manifested as mononeuropathy or brachial plexus and lumbar plexus neuralgia. The mechanism of DPNP formation is complex, including peripheral sensitization, central sensitization, dysfunction of the descending inhibitory system, changes in ion channels, etc., and different mechanisms influence each other. Among them, multiple ion channel abnormalities are involved in the occurrence of neuropathic pain. Nerve injury causes high expression of α2δ subunits on the presynaptic membrane of the spinal cord posterior horn calcium ion channel, abnormal opening of calcium ion channels, increased calcium ion influx, increased release of excitatory neurotransmitters, excessive neuronal excitation, and hyperalgesia and allodynia. In addition, hyperglycemia is considered to be the triggering factor of DPNP.

[0004] Pain is a common clinical symptom of DPNP, which is seen in about 50% of patients with diabetes and about 13% of patients with impaired glucose tolerance. It seriously affects their normal physiological and mental state, causing sleep disorders, nutritional disorders, limited movement, and emotional disorders, thereby reducing the quality of life and work ability. DPNP is an exclusive diagnosis. On the basis of diabetes or prediabetes, the presence of peripheral neuropathy is confirmed by clinical manifestations, neurological examinations, and neuroelectrophysiological examinations. Several epidemiological studies have shown that the overall prevalence of DPNP abroad is 10-26%. The American Academy of Neurology (AAN) reported that about 16% of diabetic patients experience neuralgia, of which 39% are not treated. In the UK, 20-30% of diabetic patients experience DPNP. Although there is no large-scale epidemiological survey on DPNP in China, based on the large basic population of diabetic patients in China, it is estimated that the prevalence of DPNP is high, which seriously affects the quality of life of the majority of diabetic patients.

[0005] The clinical treatment of DPNP is mainly based on controlling blood sugar, and pain relief is achieved through individualized use of analgesics, combined treatment and adequate treatment courses. It can also be combined with non-drug treatments such as electrical stimulation, acupuncture, near infrared, laser, etc. Analgesics used for DPNP mainly include systemic medications such as tricyclic antidepressants, 5-HT and NE dual channel reuptake inhibitors, anticonvulsants, opioids, and topical medications such as lidocaine 5% patch and capsaicin cream.

[0006] For the treatment of DPNP, the treatment methods recommended by the Expert Consensus on Diagnosis and Treatment of Diabetic Peripheral Neuropathic Pain (2018 Edition) and other relevant consensus in China are basically the same, with pregabalin, gabapentin, etc. being the main first-line drugs. However, none of the recommended first-line drugs have indications for diabetic peripheral neuropathy in China, and according to domestic clinical research, these drugs are not widely used in clinical practice.

[0007] According to the "Chinese Expert Consensus on the Diagnosis and Treatment of Peripheral Neuropathic Pain (2020 Edition)", combination therapy with drugs of different mechanisms of action is generally better than monotherapy, and combination therapy is often used clinically according to the pathological characteristics of peripheral neuropathy. The consensus suggests that treatment should effectively relieve pain and accompanying symptoms, restore body function, improve quality of life, reduce recurrence rate, and promote nerve repair. In clinical practice, the treatment of DPNP patients often combines analgesics with one or more drugs such as nerve nutrition, anti-oxidative stress, and inhibition of aldose reductase activity, which can relieve pain and repair nerve damage.

[0008] α-Lipoic acid (abbreviated as lipoic acid) is a powerful antioxidant factor that can inhibit lipid peroxidation, increase blood flow in nerve nutrient vessels, improve nerve Na+-K+-ATPase activity, directly remove reactive oxygen species and free radicals, and protect endothelial function. In the "Evaluation of the Rationality of the Use of Diabetic Peripheral Neuropathy Treatment Drugs" reported in the "China New Drug Journal" in 2017, a drug use rationality evaluation survey was conducted on the use of diabetic peripheral neuropathy treatment drugs in diabetic patients. The survey results showed that lipoic acid injection is one of the most used drugs in patients with diabetic peripheral neuropathy. The article conducted a comparative analysis of the treatment regimen of lipoic acid injection + injection of adenosylcobalamin for DPN inpatients with combined symptoms before and after medication. The patients' neurological symptoms and sensory function were significantly improved when they were discharged from the hospital. It was reported in the "China Diabetes Journal" that the use of α-lipoic acid for injection can significantly improve the number of abnormal foot pressure sensation points and neuropathy symptoms in patients with painful diabetic peripheral neuropathy.

[0009] α-Lipoic acid injection is a product in the national medical insurance catalogue, mainly used for paresthesia caused by diabetic peripheral neuropathy (DPN). The 2021 medical insurance catalogue has a clear recommendation, limited to patients diagnosed with painful diabetic peripheral neuropathy with clear neuroelectrophysiological evidence, and this restriction was lifted in 2022. Recommended use of α-lipoic acid injection: 600 mg / d of α-lipoic acid for 3 months; patients with obvious symptoms of diabetic peripheral neuropathy (DPN) should first use 600 mg / d of α-lipoic acid injection intravenous drip for 2 to 4 weeks, followed by 600 mg / d oral sequential treatment.

[0010] Acetyl-L-carnitine is produced by carnitine acetyltransferase and can promote cellular energy synthesis. Its mechanism of action includes stimulating aerobic metabolism in the brain, reducing cell oxidative stress damage, reducing cell excitotoxicity, etc. It can also reduce the concentration of glutamate in synapses to reduce hyperalgesia, and is closely related to nervous system diseases. Acetyl-L-carnitine can effectively relieve pain in patients with diabetic neuropathy, improve nerve fiber regeneration and vibration perception, and improve neuroelectrophysiological parameters in patients with diabetic neuropathy. Recommended use: Oral administration of 250-500 mg, 2-3 times a day, for a course of 6 months. The drug has good safety and few adverse reactions.

[0011] Several principles should be followed when choosing drugs to treat DPNP: individualized medication, combined therapy, adequate course of treatment, effective blood sugar management, etc. Combination therapy means that when many patients with diabetic peripheral neuropathy are not satisfied with the efficacy of a single drug, the combined use of two or more drugs with different mechanisms of action can often improve the therapeutic effect. The clinical efficacy of lipoic acid and acetyl-L-carnitine has been proven.

[0012] In 1985, the trade name "NICETILE" (acetyl-L-carnitine hydrochloride) developed by Sigma-Tau of Italy was first marketed for the treatment of Alzheimer's disease. Subsequently, the Italian Medicines Agency (AIFA) approved its indications for mechanical and inflammatory damage to peripheral nerve trunks or nerve roots. The 0.25g and 0.5g acetyl-L-carnitine hydrochloride tablets held by Haisike Pharmaceutical (Meishan) Co., Ltd. are the exclusive first domestic generics and have been approved for marketing in China in 2018 (formerly Class 3.1 chemical drugs) to relieve paresthesia caused by diabetic peripheral neuropathy. The completed Phase II study has confirmed that the drug is not inferior to the positive control drug methylcobalamin in the treatment of DPN patients in China, and the Phase III study has confirmed that the drug is safe in Chinese DPN patients and has sufficient efficacy data.

[0013] The original manufacturer of lipoic acid injection is Germany's Star Pharmaceuticals. It is a Class B drug covered by the National Medical Insurance and is mainly used for paresthesia caused by diabetic peripheral neuropathy. Lipoic acid reduces lipid oxidation in nerve tissue, inhibits protein glycosylation, inhibits aldose reductase, and thus prevents the conversion of glucose or galactose into sorbitol. It is used to prevent diabetes, control blood sugar, and prevent neuropathy caused by hyperglycemia. Clinical indications: paresthesia caused by diabetic peripheral neuropathy. The original research of lipoic acid tablets was authorized in Germany in December 1999.

[0014] WO2020011257A1 discloses a pharmaceutical composition of a fused tricyclic γ-amino acid derivative as shown in formula (I) and its application in the field of analgesia.

[0015]

[0016] The compound of formula (I) can bind to the calcium channel α2δ subreceptors α2δ-1 and α2δ-2, reduce the calcium ion influx of the voltage-dependent calcium channels of the central nervous system, and thus reduce the release of excitatory neurotransmitters such as glutamate, NE and substance P, and has anti-epileptic, analgesic and antianxiety activities. The target indications of the capsules of the compound of formula (I) include: diabetic peripheral neuropathy, post-herpetic neuralgia, acute and chronic pain after infection with the new coronavirus, auxiliary analgesia, etc. In the face of the current status of combined drug use in clinical practice, the compound of formula (I) is in urgent need of a safe and effective drug combination regimen, and a compound composition containing the compound of formula (I) is in urgent need of clinical practice. Summary of the invention

[0017] The present invention provides a pharmaceutical composition comprising:

[0018] (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0019] (ii) acetyl-L-carnitine or a pharmaceutically acceptable salt thereof;

[0020] The compound of formula (I) has the following structure:

[0021]

[0022] In some embodiments, the structure of Formula (I) is as follows:

[0023]

[0024] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is the benzenesulfonate salt of the compound of formula (I), and the pharmaceutically acceptable salt of acetyl-L-carnitine is acetyl-L-carnitine hydrochloride; the structural formula of the benzenesulfonate salt of the compound of formula (I) is as follows:

[0025]

[0026] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is C 12 H 19 NO2 is reacted with acetyl-L-carnitine or its pharmaceutically acceptable salt in the form of C9H 17 The weight ratio of NO4 is 1:10 to 1:80.

[0027] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is C 12 H 19 NO2 is reacted with acetyl-L-carnitine or its pharmaceutically acceptable salt in the form of C9H 17 The weight ratio of NO4 is 1:10 to 1:70.

[0028] Further, the compound of formula (I) or a pharmaceutically acceptable salt thereof is C 12 H 19 NO2 is reacted with acetyl-L-carnitine or its pharmaceutically acceptable salt in the form of C9H 17 The weight ratio of NO4 is 1:20 to 1:60.

[0029] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is C 12 H 19 NO2 is reacted with acetyl-L-carnitine or its pharmaceutically acceptable salt in the form of C9H 17 The weight ratio of NO4 is 1:20 to 1:50.

[0030] Further, the compound of formula (I) or a pharmaceutically acceptable salt thereof is C 12 H 19 NO2 is reacted with acetyl-L-carnitine or its pharmaceutically acceptable salt in the form of C9H 17 The weight ratio of NO4 is 1:30~1:40.

[0031] Furthermore, the compound of formula (I) or a pharmaceutically acceptable salt thereof is C 12 H 19 NO2 is reacted with acetyl-L-carnitine or its pharmaceutically acceptable salt in the form of C9H 17 The weight ratio of NO4 is 1:36~1:39.

[0032] In some embodiments, the weight ratio of the benzenesulfonate salt of the compound of formula (I) to acetyl-L-carnitine hydrochloride is 1:5 to 1:50.

[0033] In some embodiments, the weight ratio of the benzenesulfonate salt of the compound of formula (I) to acetyl-L-carnitine hydrochloride is 1:10 to 1:40.

[0034] In some embodiments, the weight ratio of the benzenesulfonate salt of the compound of formula (I) to acetyl-L-carnitine hydrochloride is 1:10 to 1:30.

[0035] In some embodiments, the weight ratio of the benzenesulfonate salt of the compound of formula (I) to acetyl-L-carnitine hydrochloride is 1:15 to 1:30.

[0036] Furthermore, the weight ratio of the benzenesulfonate of the compound of formula (I) to acetyl-L-carnitine hydrochloride is 1:20 to 1:30.

[0037] Furthermore, the weight ratio of the benzenesulfonate salt of the compound of formula (I) to acetyl-L-carnitine hydrochloride is 1:22 to 1:28.

[0038] The present invention also provides the use of (i) and (ii) as active ingredients in the preparation of a drug for treating diabetic peripheral neuropathy, wherein:

[0039] (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0040] (ii) acetyl-L-carnitine or a pharmaceutically acceptable salt thereof;

[0041] The compound of formula (I) has the following structure:

[0042]

[0043] Optionally, (i) and (ii) may be administered simultaneously or sequentially, for example, (i) is administered first and then (ii), or (ii) is administered first and then (i).

[0044] Furthermore, in the above application, the structure of formula (I) is as follows:

[0045]

[0046] At the same time, the present invention also provides the use of the benzenesulfonate salt of the compound of formula (I) in treating diabetic peripheral neuropathy, comprising administering an oral benzenesulfonate preparation of the compound of formula (I) and an oral acetyl-L-carnitine hydrochloride preparation, wherein the benzenesulfonate salt of the compound of formula (I) has the following structural formula:

[0047]

[0048] In some embodiments, the unit dosage form of the oral benzenesulfonate salt of the compound of formula (I) contains 5 mg, 20 mg, 40 mg or 60 mg, preferably 20 mg, of the compound of formula (I), and the unit dosage form of the oral acetyl-L-carnitine hydrochloride contains 0.5 g or 0.25 g of acetyl-L-carnitine.

[0049] In some embodiments, the besylate oral preparation of the compound of formula (I) is administered at a dose of 20 mg twice a day, and the acetyl-L-carnitine hydrochloride oral preparation is administered at a dose of 0.5 g three times a day.

[0050] In some embodiments, the oral preparation of the besylate salt of the compound of formula (I) is a capsule, and the oral preparation of acetyl-L-carnitine hydrochloride is a tablet.

[0051] The present invention also provides a pharmaceutical composition, which comprises a) lipoic acid injection and / or zinc sulfate tablets, and b) acetyl-L-carnitine hydrochloride tablets.

[0052] In addition, the present invention also provides the use of a) and b) in combination in the preparation of a drug for treating diabetic peripheral neuropathy, wherein

[0053] a) selected from lipoic acid injection and / or zinc sulfate tablets, and b) selected from acetyl-L-carnitine hydrochloride tablets;

[0054] Optionally, a) and b) may be administered simultaneously or sequentially, for example, a) is administered first and then b), or b) is administered first and then a).

[0055] In some embodiments, in the first week, lipoic acid injection is administered once a day at a dose of 0.6 g each time, and acetyl-L-carnitine hydrochloride tablets are administered three times a day at a dose of 0.5 g each time; in weeks 2-12, zinc sulfate tablets are administered once a day at a dose of 0.6 g each time, and acetyl-L-carnitine hydrochloride tablets are administered three times a day at a dose of 0.5 g each time.

[0056] Definitions of Abbreviations and Key Terms:

[0057]

[0058]

[0059] Beneficial effects of the present invention:

[0060] The compound composition containing the compound of formula (I) and acetyl-L-carnitine provided by the present invention has good safety and efficacy in treating diabetic peripheral neuropathy. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1 The overall research design flow chart of the efficacy and safety study of the compound of formula (I) capsules combined with acetyl-L-carnitine hydrochloride tablets in Chinese patients with diabetic peripheral neuropathy;

[0062] Figure 2 Diagnostic step diagram of DPNP of the present invention;

[0063] Figure 3 This is a distribution diagram of the subjects of the present invention. DETAILED DESCRIPTION

[0064] The drug information used in the clinical research related to the present invention is as follows: Capsules of the compound of formula (I) are prepared by Sichuan Hiseko Pharmaceutical Co., Ltd. with a specification of 20 mg (preparation method reference WO2020011257A1); Acetyl-L-carnitine hydrochloride tablets are produced by Hiseko Pharmaceutical (Meishan) Co., Ltd. with a specification of 0.5 g (marketed drug), lipoic acid injection is produced by Dongyi Chuang Pharmaceutical Co., Ltd. / Chengdu Beite Pharmaceutical Co., Ltd. with a specification of 12 ml: 0.3 g; lipoic acid tablets are produced by Shandong Qidu Pharmaceutical Co., Ltd. with a specification of 0.3 g.

[0065] Test example: Study on the efficacy and safety of the compound of formula (I) capsules combined with acetyl-L-carnitine hydrochloride tablets in Chinese patients with diabetic peripheral neuropathy

[0066] The clinical study related to the present invention adopts a multi-center, randomized, positive control, parallel group design.

[0067] The clinical research methods related to the present invention are basically as follows:

[0068] After signing the informed consent form, the subjects will enter the screening period. Subjects who complete the screening examination specified in the protocol during the screening period and meet the inclusion criteria and do not meet the exclusion criteria will enter a 1-week introduction period. During the introduction period, the subjects will not receive any DPNP-related treatment. If the subjects are intolerant to pain, they can be given NSAIDs analgesics at the discretion of the research doctor. Subjects will undergo random standard assessment on the baseline day (D0). The researchers will assess the qualified subjects and randomize them 1:1 to the group of formula (I) compound capsules combined with acetyl-L-carnitine hydrochloride (formula (I) compound group) or lipoic acid combined with acetyl-L-carnitine hydrochloride group (lipoic acid group).

[0069] The subjects randomized to the compound of formula (I) group received the compound of formula (I) capsules (20 mg bid) + acetyl-L-carnitine hydrochloride tablets (0.5 g tid) for oral administration for 12 consecutive weeks.

[0070] The subjects randomized to the lipoic acid group received lipoic acid injection (0.6 g qd) + acetyl-L-carnitine hydrochloride tablets (0.5 g tid) in the first week, and lipoic acid tablets (0.6 g qd) + acetyl-L-carnitine hydrochloride tablets (0.5 g tid) from the 2nd to the 12th week.

[0071] After treatment completion, subjects will receive a telephone safety follow-up on day 7 after the last dose of the trial drug. For subjects who do not complete 12 weeks of treatment, an early termination visit must be completed.

[0072] From the beginning of the lead-in period until the end of the study treatment period, the subjects filled in the diary card to evaluate the daily worst pain intensity (NRS) and the daily sleep disturbance assessment scale (DSIS). The SF-MPQ (including VAS) scores were performed during the screening period, baseline day (D0), and after 12 weeks of trial drug treatment (W12, V6 visit), and only VAS scores were performed during the screening period. EQ-5D-5L scores were performed on the baseline day (D0), 6 weeks of trial drug treatment (W6, V5 visit), and the last visit / early termination visit.

[0073] Safety assessments will be performed throughout the study based on vital signs, physical examination, 12-lead electrocardiogram (12-lead ECG), clinical laboratory tests, and adverse events.

[0074] A statistical non-inferiority design was used. It was assumed that the ADPS difference between the experimental group and the control group was -0.6 after 12 weeks of treatment, the non-inferiority margin was 0.3, the standard deviation was 1.7, the one-sided significance level was α=0.025, and the power was 80%. The sample size in each group was 57 cases. Considering the dropout rate of 15%, a total of 136 cases needed to be included, with 68 subjects in each group.

[0075] The detailed research plan is as follows:

[0076] Study objective: To evaluate the efficacy and safety of the compound of formula (I) capsules combined with acetyl-L-carnitine hydrochloride tablets and lipoic acid combined with acetyl-L-carnitine hydrochloride tablets in the treatment of Chinese patients with diabetic peripheral neuropathy.

[0077] Overall study design

[0078] This trial is a 16-week, multicenter, randomized, positive-controlled Phase II clinical study to evaluate the efficacy and safety of the compound of formula (I) capsules combined with acetyl-L-carnitine hydrochloride tablets and lipoic acid combined with acetyl-L-carnitine hydrochloride tablets in the treatment of Chinese patients with diabetic peripheral neuropathy. This trial includes a 2-week screening period (14 days before the lead-in period), a 1-week lead-in period [including baseline (D0)], a 12-week treatment period, and a 1-week safety follow-up period.

[0079] Study treatment and follow-up: After signing the informed consent form (ICF), the subjects will enter the screening period. Subjects who complete the screening examination specified in the protocol and meet the inclusion criteria and do not meet the exclusion criteria during the screening period will enter the introduction period. During the introduction period, the subjects will not receive any DPNP-related treatment. If the subjects are intolerant to pain, the research doctor may determine and give NSAIDs analgesics (aspirin, acetaminophen, diclofenac sodium, loxoprofen sodium, ibuprofen, celecoxib, etc.) as appropriate. Subjects will undergo random standard assessment at baseline (D0), and qualified subjects will be randomized 1:1 to the group of formula (I) compound capsules combined with acetyl-L-carnitine hydrochloride (formula (I) compound group) or lipoic acid combined with acetyl-L-carnitine hydrochloride group (lipoic acid group).

[0080] During the treatment period, the subjects randomized to the compound of formula (I) group received the compound of formula (I) capsules (20 mg, bid) + acetyl-L-carnitine hydrochloride tablets (0.5 g, tid) for treatment, which was taken orally for 12 consecutive weeks; the subjects randomized to the thioctic acid group received thioctic acid injection (intravenous drip, 0.6 g, Qd) + acetyl-L-carnitine hydrochloride tablets (0.5 g, tid) in the first week, and received thioctic acid tablets (0.6 g, Qd) + acetyl-L-carnitine hydrochloride tablets (0.5 g, tid) from the 2nd to the 12th week.

[0081] After treatment completion, subjects will receive a telephone safety follow-up on day 7 after the last dose of the trial drug. For subjects who do not complete 12 weeks of treatment, an early termination visit must be completed.

[0082] The overall research design flow chart of this study is shown in the attached Figure 1 shown.

[0083] Study endpoints:

[0084] Primary End Point

[0085] The changes in the average daily pain score (ADPS) compared with the baseline at week 12 were compared between the capsules of the compound of formula (I) combined with acetyl-L-carnitine hydrochloride tablets and the lipoic acid combined with acetyl-L-carnitine hydrochloride tablets.

[0086] Secondary End Points

[0087] Comparison of the changes in ADPS from baseline at week 8 between the two groups

[0088] To evaluate the change of the Short Form McGill Pain Questionnaire (SF-MPQ) score at week 12 compared with the baseline between the two groups

[0089] To evaluate the change in the mean daily sleep disturbance score (ADSIS) between the two groups at week 12 compared with baseline

[0090] To evaluate the changes in the European EQ-5D-5L at week 12 compared with the baseline between the two groups

[0091] Safety indicators

[0092] Safety indicators included adverse events, laboratory tests, electrocardiograms, vital signs, and physical examinations during the study.

[0093] Study population

[0094] Inclusion Criteria

[0095] Subjects who meet all of the following criteria can be included in this study:

[0096] ·Be able to understand and voluntarily sign the written informed consent;

[0097] Male or female aged 18 years or older (including the cutoff value);

[0098] ·Consistent with the diagnosis of diabetic peripheral neuropathy (DPNP);

[0099] The average pain visual analogue scale (VAS) score in the past 24 hours was ≥40 mm and <90 mm during screening.

[0100] Exclusion criteria

[0101] Subjects who meet any of the following criteria are not eligible for this study:

[0102] Have peripheral neuropathy or pain unrelated to DPN that the investigator determines may confound the assessment of DPNP;

[0103] · History of malignant tumor within 5 years before screening (excluding cured basal cell carcinoma of the skin, carcinoma in situ and papillary thyroid carcinoma) or history of anti-tumor treatment within 5 years before screening;

[0104] Severe liver and kidney dysfunction, as indicated by any of the following clinical laboratory test results:

[0105] Liver function: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 × upper limit of normal (ULN);

[0106] or total bilirubin (TBIL)>1.5×ULN;

[0107] Estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2 (calculated according to the simplified MDRD formula);

[0108] · Known history of allergy to the components of the investigational drug or other drugs or excipients with similar chemical structures;

[0109] Those who have had suicidal behavior or suicidal tendencies in the past;

[0110] Women who are pregnant, preparing to become pregnant or breastfeeding during the study; women who are unwilling to take reliable contraceptive measures (including condoms, spermicides or intrauterine devices, etc.) from the signing of the ICF to the last administration of the trial drug within 28 days, or women who plan to use progestin-containing contraceptives during this period;

[0111] Participated in any other clinical studies within 30 days before screening;

[0112] · The researcher judges that there are other circumstances that are not suitable for participation in this study.

[0113] Screening failed:

[0114] If there is evidence that the reason for a subject's exclusion from the study has changed, or the researcher believes that some of the exclusions are due to accidental reasons, the subjects who do not meet the eligibility requirements can be screened again after communication and agreement with the sponsor and medical monitor, and after determining the content that needs to be rescreened. In this study, each subject is only allowed to be screened once. There is no time limit for rescreening, and the screening number needs to be reassigned.

[0115] Study early withdrawal

[0116] The subject may decide to withdraw from the study at any time during the study, and it will not affect his / her continued appropriate clinical treatment. If one of the following situations occurs, the investigator should arrange for the subject to withdraw from the study early and complete the end-of-study treatment (EOT) visit assessment as much as possible:

[0117] The subject experiences an adverse event and the investigator determines that continuing to participate in the trial will increase the risk to the subject or the subject finds it difficult to continue the clinical trial (including but not limited to clinical blood sampling, safety evaluation, etc.);

[0118] The subject refuses to continue to participate in the trial and withdraws informed consent;

[0119] The subject seriously deviates from or violates the requirements of the clinical trial protocol, and the researcher believes that the clinical trial cannot be continued;

[0120] The subject is pregnant (applicable to females);

[0121] · Subjects lost to follow-up.

[0122] Subject replacement

[0123] There is no plan for subject replacement in this study.

[0124] Study Drugs

[0125] Experimental drugs

[0126] The experimental drugs used in this study include capsules of the compound of formula (I), acetyl-L-carnitine hydrochloride tablets, lipoic acid injection and lipoic acid tablets. The specific information is shown in the table below.

[0127] Trial Drugs

[0128]

[0129] Abbreviations: BID = twice daily, TID = three times daily, QD = once daily. * The manufacturer of lipoic acid injection will select one of the two manufacturers as the test drug based on actual needs.

[0130] Instructions on packaging and labeling of experimental drugs

[0131] Packaging: The applicant or a third party commissioned by the applicant shall package the capsules of the compound of formula (I). Acetyl-L-carnitine hydrochloride tablets, lipoic acid injection and lipoic acid tablets are marketed products and shall use commercially available packaging.

[0132] The content of the investigational drug label includes: clinical trial number, drug name, drug number, specifications, packaging specifications, storage conditions, batch number, expiration date, usage and dosage, and the name of the sponsor. The label must state "For clinical trials only, use under the guidance of researchers, and keep out of reach of children."

[0133] Study medication method

[0134] There is no blinding for the randomized treatment period. On the randomized day, each subject will receive the study drug, among which the subjects in the compound of formula (I) group will receive the compound of formula (I) capsules and acetyl-L-carnitine hydrochloride tablets, and the subjects in the lipoic acid group will receive lipoic acid injection and acetyl-L-carnitine hydrochloride tablets. They will receive lipoic acid injection at the research center every day during the first week of the treatment period, receive lipoic acid tablets at the V4 visit, and start taking lipoic acid tablets the next day. At the end of the treatment, the subjects should return the remaining study drugs and outer packaging to the research institution for drug recovery.

[0135] The administration method of the compound capsule (20 mg / tablet) of formula (I) is oral administration, 2 times a day, 1 tablet each time, and continuous medication for 12 weeks. The administration method of acetyl-L-carnitine hydrochloride tablets (0.25 g / tablet) is oral administration after meals, 3 times a day, 2 tablets each time, and continuous medication for 12 weeks. The administration method of lipoic acid injection (0.3 g / branch) is intravenous drip, once a day, 0.6 g each time, for 1 week. The administration method of lipoic acid tablets (0.3 g / tablet) is taken half an hour before breakfast, once a day, 2 tablets each time, for 11 weeks.

[0136] During the study treatment period, the trial drugs should be administered at the same time every day as much as possible. If you miss a dose of oral trial drugs during the trial, you should make up for it as soon as possible; if you still miss the next dose, skip that dose and continue to take the drug as planned until the next dose.

[0137] Researchers need to remind subjects of medication precautions, including but not limited to: do not chew the medicine after swallowing, take the medicine as many times a day as required by the regimen, and keep the medication time consistent as much as possible.

[0138] Study Treatment Assignment (Randomization)

[0139] This trial will adopt randomization. After the subject signs the informed consent form, the subject screening number will be assigned, and then the screening period examination will be carried out. Subjects who complete the screening examination specified in the protocol during the screening period and meet the inclusion criteria and do not meet the exclusion criteria will enter the introduction period. Subjects will undergo random standard assessment on the baseline day (D0), and qualified subjects will be randomly assigned to the formula (I) compound capsule combined with acetyl-L-carnitine hydrochloride group (formula (I) compound group) and lipoic acid combined with acetyl-L-carnitine hydrochloride group (lipoic acid group) in a 1:1 ratio using the principle of block randomization.

[0140] Medication management, distribution and recovery

[0141] The drug management of the research center is the responsibility of the investigator. The investigator must ensure that all research therapeutic drugs are only used for the subjects of this clinical trial, and their dosage and usage should comply with the protocol. The remaining research therapeutic drugs must be returned to the sponsor. The above process must be managed by a person authorized by the investigator and recorded. The research therapeutic drugs must be managed by a dedicated person. The investigator shall not transfer the research therapeutic drugs to any non-clinical research participants. The outer packaging of the drug and the remaining research therapeutic drugs must be recovered, and the amount of recovered drugs must be recorded in the original records and eCRF.

[0142] At the end of the study, all research treatment drugs in the research center, including all unused, partially used research treatment drugs and all recovered drug packaging, must be returned to the sponsor or destroyed after inventory by the sponsor.

[0143] Transport, handling, storage and destruction / return

[0144] Drugs provided to the study centers by the sponsor directly or through suppliers with whom the sponsor has a working relationship must be kept in an appropriate secure area (e.g., a locked medicine cabinet / pharmacy) and stored according to the instructions on the drug label.

[0145] Site personnel must maintain and accurately and timely record all study medications received, administered to subjects, unused medications collected from subjects, and unused or expired study medications subsequently returned to the Sponsor. Copies of these records must be provided to the Sponsor at the end of the study. Site personnel may not destroy any study medication labels or any used or unused study medications until instructed to do so by the Sponsor or its designee after an inventory check.

[0146] Supply and inventory records must be backed up and available for inspection by the sponsor's designated representative or regulatory authorities.

[0147] Study Treatment Inventory / Adherence

[0148] During this study, the study medication and any medication events that deviate from the study protocol will be recorded in the eCRF, including the date and reason of medication, etc. The investigator must explain to the subjects the importance of receiving the study treatment as specified in the protocol and require the subjects to take the medication as specified in the protocol.

[0149] The investigators and research staff will be responsible for counting all investigational drugs and keeping records (dispensing, inventory, and return) according to the sponsor's instructions and in compliance with Good Clinical Practice (GCP) and applicable international and / or domestic regulations. Subjects should be asked to return all unused study medications and used study medication packaging at each visit to assess study medication compliance.

[0150] Blinding and emergency unblinding

[0151] This study was not blinded.

[0152] Concomitant / prohibited medications and treatments

[0153] This study does not restrict the subjects' treatment of underlying diseases, and they can use and / or continue to use them under the supervision of the researcher.

[0154] All previous medications and treatments received by the subject within 30 days before screening, as well as any concomitant medications and treatments received by the subject from the signing of the ICF to the end of the study (V7), including over-the-counter medications and non-drug therapies (such as physical therapy), must be recorded in the subject's original data. This will be recorded in the concomitant medication / concomitant non-drug treatment section according to the eCRF filling guidelines. Any new treatments that change existing treatments will also be recorded in the eCRF concomitant medication page / concomitant non-drug treatments and kept updated throughout the subject's participation in the study.

[0155] Study Visits

[0156] Screening period (within 14 days before introduction): V1 visit

[0157] Before any research procedures are carried out, all potential subjects will sign the ICF, and their eligibility will be determined before enrollment in the study, and they will sign the informed consent form as required. The detailed research process and evaluation schedule are shown in the research flow table 1.

[0158] Study flow chart 1

[0159]

[0160]

[0161] Obtain written informed consent.

[0162] Collect demographic information.

[0163] ·Collect and review medical and surgical history.

[0164] Collect and review allergy history.

[0165] ·Collect and review DPNP diagnosis and treatment history.

[0166] Measure height and weight.

[0167] Physical examination.

[0168] Vital sign measurement.

[0169] 12-lead ECG examination.

[0170] Laboratory examination: blood routine, urine routine, blood biochemistry, coagulation function, test results within 7 days before screening.

[0171] Blood pregnancy test: For women who are not postmenopausal (last menstrual period less than 2 years ago) or have not undergone surgical sterilization, a serum β-human chorionic gonadotropin (β-hCG) pregnancy test is required.

[0172] After the researchers explained the SF-MPQ scoring (including VAS) rules to the subjects, the subjects only needed to complete the VAS scoring in the SF-MPQ.

[0173] ·Inclusion / exclusion criteria review.

[0174] Collect AE information.

[0175] Collect information on previous medication, concomitant medication, and treatment.

[0176] Before the subject leaves the research center, the researcher should remind him / her of the next visit date.

[0177] Note: This study allows one re-screening. Whether the subject can be re-screened will be decided by the investigator, medical monitor and sponsor. There is no time limit for re-screening, and the screening number needs to be re-assigned.

[0178] Introduction period (including baseline)

[0179] The introduction period is 7 days and no longer than 9 days.

[0180] V2 visit (first day of introduction period)

[0181] The run-in period will begin after the subject completes the assessment process and confirms that they meet the eligibility criteria for inclusion in the morning of the V2 visit (Day 1 of the run-in period). The specific study process for the V2 visit is as follows:

[0182] ·Supplement / update medical history (if applicable).

[0183] Vital sign measurement.

[0184] Issue patient diaries: used to record possible concomitant medications and / or treatments; record daily pain NRS, DSIS scores, etc.

[0185] The researcher explained the pain NRS and DSIS scoring rules and the requirements for filling out the patient diary to the subjects. The subjects completed the pain NRS and DSIS scores and filled in the pain NRS and DSIS scores in the patient diary (if not assessed before the visit on the day).

[0186] Collect AE information.

[0187] Collect information on concurrent medication and treatment.

[0188] Before the subject leaves the research center, the researcher should remind him / her of the next visit date.

[0189] Baseline: Visit V3 (D0, W-1)

[0190] After completing the 6-day run-in period, the subjects must return to the research center for the V3 baseline visit. The subjects will undergo the following study procedures at the V3 visit (baseline, D0, W-1):

[0191] ·Supplement / update medical history (if applicable).

[0192] Physical examination.

[0193] Vital sign measurement.

[0194] Randomization criteria determination.

[0195] Randomization: Randomization will be performed after all baseline examination results are obtained and the randomization eligibility is determined by the investigator.

[0196] ·Collect completed patient diaries and review them.

[0197] ·Issuance of patient diaries: Investigators or their authorized personnel are required to be trained on the rules and requirements for filling out diaries. Used to record the use of investigational drugs.

[0198] And other possible concomitant medications and / or treatments; record daily pain NRS, DSIS scores, etc.

[0199] The subjects completed the pain NRS and DSIS scores and filled in the pain NRS and DSIS scores in the patient diary (if not assessed before the visit on the same day).

[0200] After the researchers explained the SF-MPQ scoring (including VAS) rules to the subjects, the subjects completed the SF-MPQ scoring (including VAS).

[0201] After the researchers explained the EQ-5D-5L scoring rules to the subjects, the subjects completed the EQ-5D-5L scoring.

[0202] ·Distribute the trial drugs. At the same time, the researchers need to inform the subjects of the study drug requirements during the treatment period, such as the usage and dosage of oral drugs. The subjects in the lipoic acid group need to receive intravenous medication at the research center, etc.

[0203] Collect AE information.

[0204] Collect information on concurrent medication and treatment.

[0205] Before the subject leaves the research center, the researcher should remind him / her of the next visit date.

[0206] Study treatment period (D1~D84)

[0207] V4 visit (D7-1 / +1, W1)

[0208] Subjects will undergo the following study procedures at Visit V4 (D7-1 / +1, W1):

[0209] Vital sign measurement.

[0210] ·Recover used test drug packaging and unused drugs and take inventory.

[0211] ·Collect completed patient diaries and review them.

[0212] Issue patient diaries: used to record the use of trial drugs and other possible concomitant medications and / or treatments; record daily pain NRS, DSIS scores, etc.

[0213] The subjects completed the pain NRS and DSIS scores and filled in the pain NRS and DSIS scores in the patient diary (if not assessed before the visit on the same day).

[0214] Distribute experimental drugs.

[0215] · The subjects took and recorded the experimental drugs. The subjects in the lipoic acid group received the last lipoic acid injection and started taking lipoic acid tablets orally the next day.

[0216] Collect AE information.

[0217] Collect information on concomitant medications and treatments.

[0218] Before the subject leaves the research center, the researcher should remind him / her of the next visit date.

[0219] V5 visit (D43-3 / +3, W6)

[0220] Subjects will undergo the following study procedures at Visit V5 (D43-3 / +3, W6):

[0221] Physical examination.

[0222] Vital sign measurement.

[0223] ·Recover used test drug packaging and unused drugs and take inventory.

[0224] ·Collect completed patient diaries and review them.

[0225] Issue patient diaries: used to record the use of trial drugs and other possible concomitant medications and / or treatments; record daily pain NRS, DSIS scores, etc.

[0226] The subjects completed the pain NRS and DSIS scores and filled in the pain NRS and DSIS scores in the patient diary (if not assessed before the visit on the same day).

[0227] After the researchers explained the EQ-5D-5L scoring rules to the subjects, the subjects completed the EQ-5D-5L scoring.

[0228] Distribute experimental drugs.

[0229] ·The subjects took and recorded the test drugs.

[0230] Collect AE information.

[0231] Collect information on concomitant medications and treatments.

[0232] Before the subject leaves the research center, the researcher should remind him / her of the next visit date.

[0233] End of treatment visit (EOT visit, V6, D85-1 / +3, W12)

[0234] Subjects will undergo the following study procedures at Visit V6 (EOT Visit, D85-1 / +3, W12):

[0235] ·Weight measurement.

[0236] Vital sign measurement.

[0237] Physical examination.

[0238] 12-lead ECG examination.

[0239] Laboratory examination: routine blood test, routine urine test, blood biochemistry.

[0240] Blood pregnancy test: For women who are not postmenopausal (last menstrual period less than 2 years ago) or have not undergone surgical sterilization, a serum β-hCG pregnancy test is required.

[0241] The subjects completed the pain NRS and DSIS scores and filled in the pain NRS and DSIS scores in the patient diary (if not assessed before the visit on the same day).

[0242] After the researchers explained the SF-MPQ scoring (including VAS) rules to the subjects, the subjects completed the SF-MPQ scoring (including VAS).

[0243] After the researchers explained the EQ-5D-5L scoring rules to the subjects, the subjects completed the EQ-5D-5L scoring.

[0244] ·Collect completed patient diaries and review them.

[0245] ·Recover used test drug packaging and unused drugs and take inventory.

[0246] Collect AE information.

[0247] Collect information on concomitant medications and treatments.

[0248] Telephone safety follow-up: V7 visit [7 (-2 / +3) days after the last dose of study drug]

[0249] Subjects who have completed 12 weeks of study treatment will be followed up by telephone at Visit V7 [7 (-2 / +3) days after the last dose of study drug] to collect the following information:

[0250] Collect AE information.

[0251] Collect information on concomitant medications and treatments.

[0252] Early termination of visit

[0253] Subjects who terminate the study early must return to the research center as soon as possible to complete the following study procedures required by the early termination visit:

[0254] ·Weight measurement.

[0255] Vital sign measurement.

[0256] Physical examination.

[0257] 12-lead ECG examination.

[0258] Laboratory examination: routine blood test, routine urine test, blood biochemistry.

[0259] Blood pregnancy test: For women who are not postmenopausal (last menstrual period less than 2 years ago) or have not undergone surgical sterilization, a serum β-hCG pregnancy test is required.

[0260] ·Recover used test drug packaging and unused drugs and take inventory.

[0261] The subjects completed the pain NRS and DSIS scores and filled in the pain NRS and DSIS scores in the patient diary (if not assessed before the visit on the same day).

[0262] After the researchers explained the SF-MPQ scoring (including VAS) rules to the subjects, the subjects completed the SF-MPQ scoring (including VAS).

[0263] After the researchers explained the EQ-5D-5L scoring rules to the subjects, the subjects completed the EQ-5D-5L scoring.

[0264] ·Collect completed patient diaries and review them.

[0265] Collect AE information.

[0266] Collect information on concomitant medications and treatments.

[0267] Unplanned visits

[0268] If the subject urgently needs to see the investigator between scheduled visits for any medical reason or any persistent AE requires the investigator's judgment, an unscheduled visit may be performed.

[0269] Research Process and Evaluation

[0270] Information collection during screening period

[0271] Demographic Information

[0272] During the screening period, the subjects' demographic information, including ethnicity, age (date of birth), height, gender, etc., needs to be collected.

[0273] Medical history / surgical history / allergy history collection

[0274] During the screening period, the medical history, surgical history, and allergy history of the subject before signing the ICF should be recorded. During the lead-in period and baseline (D0), the medical history information can be supplemented and updated if applicable.

[0275] Target disease diagnosis and treatment history

[0276] DPNP Diagnosis

[0277] Diabetes is diagnosed according to the 1999 WHO Diabetes Diagnosis Criteria, and DPNP diagnosis should refer to the expert consensus on the diagnosis and treatment of diabetic peripheral neuropathic pain (2018). The diagnostic steps of DPNP are as follows: Figure 2 shown.

[0278] History of diabetes and DPNP treatment

[0279] · History of hypoglycemic drug treatment.

[0280] History of systemic and local medications used to relieve pain in DPNP.

[0281] Efficacy evaluation

[0282] Daily efficacy evaluation items

[0283] Pain NRS score: The pain NRS score divides a straight line into 10 equal segments, with 0 to 10 indicating pain severity (a total of 11 points), 0 indicating no pain, and 10 indicating severe pain. The subjects will review their pain in the past 24 hours before taking the trial drug every morning, and circle the number that can describe the pain severity. The above score results will be recorded in a paper patient diary.

[0284] From the run-in period to the end of the study treatment period, and early exit visits (if applicable), subjects will review their pain status in the past 24 hours before taking the trial medication (including oral and intravenous infusion) every morning, complete the pain NRS score, and record the results in a paper patient diary.

[0285] DSIS score: DSIS score divides a straight line into 10 equal segments, represented by 0 to 10 (a total of 11 points), 0 means no interference with sleep, 10 means pain completely interferes with sleep (unable to fall asleep due to pain). Subjects will review their sleep status in the past 24 hours before taking the trial drug in the morning and circle the number that describes the impact of pain on sleep. The above score results will be recorded in a paper patient diary.

[0286] From the lead-in period to the end of the study treatment period, and early exit visits (if applicable), subjects will review their sleep status in the past 24 hours before taking the trial medication (including oral and intravenous infusion) every morning, complete the DSIS score, and record the results in a paper patient diary.

[0287] Weekly efficacy evaluation items

[0288] ADPS score:

[0289] Baseline ADPS: the mean of the daily pain numerical rating scale (NRS) scores during the run-in period (Note: there should be at least 4 NRS scores during the run-in period, otherwise the baseline ADPS is considered missing).

[0290] ADPS during the treatment period: starting from the first medication date after randomization, every 7 natural days is considered a week, and the NRS average value is calculated (Note: there should be at least 4 NRS scores per week, otherwise the ADPS of that week will be considered missing).

[0291] ADSIS score:

[0292] Baseline ADSIS: the mean of daily sleep disturbance scores (DSIS) during the run-in period (Note: there should be at least 4 DSIS scores during the run-in period, otherwise the baseline DSIS is considered missing).

[0293] ADSIS during the treatment period: starting from the first medication date after randomization, every 7 natural days is considered a week, and the average DSIS value is calculated (Note: there should be at least 4 DSIS scores per week, otherwise ADSIS for that week will be considered missing).

[0294] Study visit efficacy evaluation items

[0295] SF-MPQ score (including VAS): includes (1) Pain Rating Index (PRI): 11 sensory scores to describe pain sensation; 4 emotional scores to describe pain emotion. In the above two parts, each item is scored from 0 to 3, representing four levels of pain: “none”, “mild”, “moderate”, and “severe” respectively; (2) VAS score: 0 represents no pain, 100 mm represents severe pain, and there is a 100 mm long horizontal line without scale marks in between. When reading the data, a ruler will be used to measure, and the corresponding length value between 0 and 100 mm will be recorded (or the scale on the back can be read directly). The cross line drawn on the line where the subject can reflect the pain level indicates the average pain level in the past 24 hours. (3) Current pain status (PPI) includes 6 pain levels, and the subject marks the corresponding score according to his subjective feelings.

[0296] During the screening period, baseline day (D0), after 12 weeks of trial drug treatment (V6 visit), and early exit visit (if applicable), the subjects will be scored on the SF-MPQ (including VAS) under the guidance of the investigator. Only VAS score in SF-MPQ will be performed during the screening period.

[0297] EQ-5D-5L score: It includes two parts: EQ-5D-5L health description system and EQ-VAS. EQ-5D-5L assessment includes five dimensions: "mobility", "self-care", "daily activities", "pain or discomfort" and "anxiety or depression". Each dimension is divided into five levels, namely "no difficulty", "some difficulty", "moderate difficulty", "severe difficulty" and "extremely severe difficulty". In addition, EQ-VAS is a 20cm long visual scale, 0 means "the worst health status in mind" and 100 means "the best health status in mind". The subjects will rate their health status on the assessment day.

[0298] At baseline (D0), after 6 weeks of trial drug treatment (W6, V5 visit), after completion of 12 weeks of trial drug treatment (V6 visit), and at the early exit visit (if applicable), subjects will perform EQ-5D-5L scores under the guidance of the investigator.

[0299] Safety Assessment

[0300] Safety will be monitored by vital signs, physical examination, 12-lead ECG, laboratory tests, and collection of all AEs.

[0301] In addition to completing all planned safety assessments according to the visit frequency specified in the study flow chart 1, the investigator may arrange unplanned visits based on the subject's clinical condition.

[0302] Vital sign check

[0303] Vital sign examinations include: body temperature, blood pressure (systolic and diastolic), pulse rate, and respiratory rate. During the study treatment period, vital sign examinations are required before the first medication on the day of the visit. The detailed examination plan is shown in the study flow chart 1. After the subjects have fully rested to a resting state, the sitting blood pressure and pulse rate are measured.

[0304] Physical examination

[0305] Physical examination items include: general condition, skin and mucous membranes, lymph nodes, head and neck (including thyroid), chest (heart, respiratory system), abdomen (liver, gallbladder, spleen, kidney), skeletal muscle system, etc. The detailed examination plan is shown in the study flow chart 1.

[0306] 12-lead ECG

[0307] Before each examination, the subjects were tested after fully resting to a resting state. The detailed examination plan is shown in the study flow table 1.

[0308] During the study, inspections must be performed according to the procedures specified in the protocol, and the operating requirements are consistent with the screening period.

[0309] If an abnormal ECG is found during the visit, the investigator and / or research staff may decide whether to repeat the test based on the subject's clinical condition and evaluate the test results. If clinically indicated, an unplanned visit for a 12-lead ECG may also be arranged.

[0310] Laboratory tests

[0311] Laboratory tests (blood routine, urine routine, blood biochemistry, coagulation function, and blood pregnancy test) were performed according to the planned time in the study flow chart 1.

[0312] A copy of the laboratory qualification certificate of the research center must be provided to the sponsor (if applicable), and the normal value range and unit of each parameter must be collected in the eCRF. Any changes in the normal value range and unit of laboratory test items during the study must be updated accordingly in the eCRF, and the date of reconfirmation of the qualification certificate must be indicated. The researcher needs to review all laboratory test reports of the subjects and evaluate the clinical significance of abnormal results. The laboratory test items are shown in the table below.

[0313] Laboratory test parameters

[0314]

[0315] Laboratory test parameters

[0316]

[0317] Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-hcg = β-human chorionic gonadotropin; INR = international normalized ratio; pH = pH; TBIL = total bilirubin.

[0318] Adverse Events

[0319] Definition of Adverse Events

[0320] AE: refers to all adverse medical events that occur in clinical research subjects, which can be manifested as symptoms / signs, diseases or laboratory test abnormalities, but not necessarily have a causal relationship with the test drug. Therefore, AE can be any unfavorable, unexpected abnormal test indicators, symptoms / signs or diseases (new occurrence or aggravation of existing conditions).

[0321] Treatment-emergent adverse events (TEAEs) refer to all adverse events that occur after the subjects use the investigational drug.

[0322] AE does not include:

[0323] Chronic diseases that were not aggravated before participating in this clinical study;

[0324] · Elective medical examinations or surgical procedures before entering the clinical study;

[0325] Overdose of the investigational drug or concomitant medication did not result in any symptoms or signs.

[0326] Abnormal test results should be considered as AEs:

[0327] Abnormal laboratory values ​​(e.g., blood biochemistry, blood routine, and urine routine) or other abnormal test values ​​(e.g., ECG) should be recorded as AEs when they meet at least one of the following criteria:

[0328] ·Accompanying symptoms or signs;

[0329] The test results require additional diagnostic tests or treatment measures (such as surgical intervention);

[0330] The inspection results lead to changes in the dosing regimen of the investigational drug (e.g., dose change, delayed dosing, discontinuation of the drug) or termination of the study;

[0331] The researchers believe that the results are clinically significant.

[0332] An abnormal test that is only repeated but does not meet any of the above conditions, or an abnormal laboratory test due to a previous or current medical history, is not an AE. Any abnormal test result that is judged to be erroneous or an abnormal value that is normal after reexamination or an abnormality that has no clinical significance is not an AE.

[0333] The "procedure itself" of a diagnostic or therapeutic invasive (e.g., surgery) or non-invasive procedure should not be reported as an AE, but if the disease condition leading to the procedure meets the definition of an AE (or SAE), it should be reported as an AE (or SAE). For example, acute appendicitis that develops during the AE reporting period should be reported as an AE, and the appendectomy performed as a result should be recorded as the treatment for the AE.

[0334] SAE: refers to AE that meets any of the following criteria:

[0335] Causes death;

[0336] Life-threatening (meaning that the subject is at risk of death immediately when the adverse event occurs, not that death may occur if it develops seriously in the future);

[0337] ·Requires hospitalization or prolonged hospitalization;

[0338] Permanent or severe disability or loss of function (AE results may cause serious inconvenience or interference to the subject's normal life and activities);

[0339] Congenital anomalies or birth defects;

[0340] Other important medical events (which may not be immediately life-threatening, death or hospitalization, but require medical measures to prevent the occurrence of one of the above situations, are also generally considered serious. For example, intensive treatment in the emergency room or at home for allergic bronchospasm, cachexia or convulsions without hospitalization, drug dependence or addiction, etc.)

[0341] Hospitalizations that do not need to be recorded as SAEs:

[0342] Hospitalization or prolonged hospital stay not associated with an exacerbation of an AE is not an SAE in itself and does not need to be recorded as an SAE. For example:

[0343] Hospitalization for the underlying medical condition, not due to a new AE or aggravation of an existing medical condition;

[0344] Hospitalization not related to AE (e.g. cosmetic surgery);

[0345] · Pre-planned hospitalization (e.g., surgery or hospitalization planned or scheduled before entering the study);

[0346] Temporary observation in hospital for non-therapeutic purposes (lasting less than 24 hours);

[0347] Admission for administrative reasons (e.g., annual physical examination).

[0348] However, the reasons for the above hospitalization must be clearly recorded in the medical records.

[0349] Adverse drug reaction (ADR): refers to any harmful or unexpected reaction to the human body that may be related to the investigational drug during clinical trials. There is at least a reasonable possibility of a causal relationship between the investigational drug and the AE, that is, the correlation cannot be ruled out.

[0350] In this study, when the researcher or Hiseco judged the correlation as definitely related, very likely related, or possibly related, it was determined to be ADR.

[0351] Suspected and unexpected serious adverse reactions (SUSAR) refer to suspected and unexpected serious adverse reactions whose nature and severity of clinical manifestations exceed the existing information such as the Investigator's Brochure (IB) of the investigational drug, the instructions for use of the marketed drug, or the Summary of Product Characteristics.

[0352] In this study, the determination of SUSAR must meet the following three points at the same time:

[0353] Severe: Meets the definition of SAE in this study protocol.

[0354] Suspicious: According to this study protocol, when the correlation is judged to be definitely related, very likely related, or possibly related, it is classified as an adverse drug reaction and is considered suspicious. If either the researcher or Hiseco determines it to be suspicious, it is considered suspicious. If the researcher provides a causal relationship judgment other than the protocol, such as "unable to judge" due to missing information, this situation also falls into the category of suspicious because the correlation with the drug cannot be ruled out.

[0355] Unexpected: The nature, severity, consequence or frequency of the adverse reaction is different from the expected safety information in the IB RSI section of the investigational drug Formula (I) Compound Capsules (when judging the anticipation, the IB version in force when the serious adverse reaction occurs is used, and the follow-up report uses the IB consistent with the initial report version).

[0356] Recording of adverse events

[0357] Time range for AE collection: AEs should be collected from the time the subject signs the informed consent form until the 7th day after the last dose of the trial drug. All AEs should be recorded in the adverse event table in the original documents and eCRF. Diseases and abnormal baseline values ​​that occur between the signing of the ICF and the administration of the trial drug are generally recorded as medical history, unless they meet the SAE definition or are judged to be related to the study procedures (such as study operations or auxiliary medications, etc.), and need to be recorded as AEs or SAEs; from the administration of the trial drug to the 7th day after the last dose of the trial drug, all adverse medical conditions are recorded as AEs (or SAEs).

[0358] Note: In this study, exacerbations of DPNP were not recorded as AEs unless they met the definition of SAEs, in which case they were recorded as SAEs.

[0359] AE name: AE name should be a medical term. Diagnostic terms are preferred; if there is no clear diagnosis, symptoms / signs can be selected; if there is no diagnosis, symptoms / signs, abnormal values ​​can be selected. If the abnormal value reflects the aggravation of the underlying disease, the AE name is recorded as "aggravated disease".

[0360] The investigator should determine the severity of the AE and its relevance to the investigational drug, and should pay attention to the development of the AE and take appropriate medical measures when necessary until the AE is cured or stabilized. The investigator should ensure that subsequent follow-up includes additional investigations into the nature or causal relationship of the AE (or SAE).

[0361] After learning of the AE (or SAE), the investigator needs to collect all the subject's event-related information (such as medical records, laboratory tests, and diagnostic reports) and record the relevant information in the original documents and the adverse event table of the eCRF. If it is an SAE, it should be reported in accordance with Section 0.

[0362] Severity Assessment:

[0363] Investigators should refer to the Common Criteria for Adverse Events (CTCAE) version 5.0 to grade the severity of all AEs. If an AE not described in CTCAE 5.0 occurs, the investigator may refer to the general principles in the table below to grade the severity.

[0364] Adverse event severity grading

[0365]

[0366] *: Instrumental ADLs include cooking, shopping for clothes, using the phone, managing finances, etc.

[0367] **: Self-care daily living activities refer to bathing, dressing and undressing, eating, washing, taking medicine, etc., and are not bedridden.

[0368] Note the difference between severity and severity of AEs. “Severe” is used to describe severity, not necessarily SAEs. For example, a headache may be severe in severity, but it cannot be included as an SAE simply because it is a “severe” headache unless it meets the SAE criteria.

[0369] Assessment of the relevance of AEs to investigational drugs:

[0370] Researchers need to determine the relevance of each AE to the investigational drug. The causal relationship between AE and investigational drugs can be divided into "definitely related", "very likely related", "possibly related", "possibly unrelated", and "definitely unrelated". Among them, the judgment of "definitely related, very likely related, and possibly related" to the investigational drug is ADR.

[0371] The investigator (or a qualified clinician designated by the investigator) uses medical judgment to evaluate the relevance of the AE to the investigational drug. The classification provided in the table below can be used to evaluate the relationship between the AE and the investigational drug or the research process. Other factors to be considered include underlying diseases, concomitant treatments, other predisposing factors, etc. At the same time, the investigator's manual or product information can be referred to to complete the judgment.

[0372] Reference for determining the correlation between adverse events and investigational drugs

[0373] index Definitely related Probably related May be related Probably not relevant Definitely not related Reasonable time sequence yes yes yes yes no The reaction type of the known test drug yes yes yes no no Discontinuation of the test drug may improve yes yes Yes or No Yes or No no The phenomenon can be repeated with the test drug yes ？ ？ ？ no The reaction may have another explanation no no yes yes yes

[0374] Note: ? indicates uncertainty, which can be either “yes” or “no”.

[0375] Measures taken for AEs: Appropriate medical measures are required for all AEs, which may include: no direct intervention, only close observation; drug treatment; non-drug treatment, etc. Measures taken for investigational drugs must be recorded, which may include: increasing the dose, reducing the dose, continuing the drug, stopping the drug, suspending the drug, unknown or not applicable, etc.

[0376] Outcome of AEs: The outcomes of AEs should be collected and recorded in a timely manner during the study. Possible AE outcomes include:

[0377] Recovery: The event has returned to normal or baseline levels / is considered stable by the investigator, and the termination date of the event is recorded.

[0378] Improved: The event has improved but not cured, and follow-up is required. The end date of the event will not be recorded.

[0379] Continuing: There is no obvious outcome trend of the event and follow-up is required. The end date of the event will not be recorded.

[0380] Recovery with sequelae: If the event is cured but sequelae still exist or may continue to exist (such as mild paralysis after stroke), the end date of the event shall be recorded.

[0381] Death: The event resulted in the death of the subject (other events accompanying death but not contributing to the cause of death are still recorded as “not recovered / persistent”), and the end date of the event leading to death is the date of death.

[0382] Unknown: If the researcher is unable to obtain outcome information due to reasons such as loss to follow-up, the event termination date will not be recorded.

[0383] Follow-up of adverse events

[0384] All AEs occurring from the time the subject signs the informed consent to the 7th day after the last dose of the trial drug must be followed up until recovery, return to baseline levels, the investigator determines that there will be no further changes with continued follow-up, the subject refuses follow-up, the subject is lost to follow-up, the subject dies, or there is another reasonable explanation for the event.

[0385] If the AE progresses to "SAE" during the AE follow-up, the researcher must immediately report it as SAE.

[0386] Serious adverse events

[0387] SAE collection will start from the time the subject signs the informed consent form until the 7th day after the last dose of the trial drug. During this period, if an SAE occurs, the researcher should immediately make a comprehensive evaluation of the event, take relevant treatment measures as needed, and promptly fill out the "FOR-PV-ICSR-001-R01 Serious Adverse Event Report Form", and describe the occurrence time, severity, relationship with the trial drug, and measures taken of the AE in detail, and sign and sign the report form. The researcher must report the SAE to the Haisco Pharmacovigilance Department (email: safety@haisco.com) within 24 hours after being informed of the SAE (in special circumstances, no later than 72 hours), and copy relevant personnel. A detailed written follow-up report should be provided in a timely manner. The method and time limit of the follow-up report are the same as the requirements for the first report.

[0388] The original copy of the Serious Adverse Event Report Form and the record files of the reporting sponsor must be kept at the research center.

[0389] For reports involving death, researchers should provide the sponsor and the ethics committee with other required materials, such as autopsy reports and final medical reports.

[0390] After the end of the clinical trial or the follow-up period and before the review and approval conclusion is obtained (if applicable), if the researcher learns of an SAE and judges that it is "definitely related / probably related / possibly related" to the investigational drug, it should also be collected and reported to the Hisense Pharmacovigilance Department.

[0391] Overdose

[0392] Drug overdose: refers to the situation where the subject intentionally or accidentally takes the investigational drug in excess of the single dose, total dose or frequency of administration specified in the study protocol, regardless of whether it is accompanied by AEs or sequelae.

[0393] If a drug overdose occurs from the time the subject first receives the investigational drug compound of formula (I) capsules to the time the subject exits the study, the researcher should fill out the "FOR-PV-ICSR-001-R03 Drug Overdose Report Form" and report it to the Hisense Pharmacovigilance Department within 24 hours (or no later than 72 hours in special circumstances) after being informed, and copy it to relevant personnel.

[0394] If drug overdose is accompanied by or causes an AE, the AE information must be entered into the original file and the adverse event table in the eCRF; if the SAE criteria are met, it must also be reported in accordance with the requirements of Section 0.

[0395] The following situations require reporting of "drug overdose":

[0396] 1. If a subject takes a single dose of the test drug compound of formula (I) capsules exceeding the dosage specified in the study protocol, regardless of the frequency of administration, it shall be considered as "drug overdose".

[0397] For example: When the subject was enrolled, the protocol stipulated that the dosage was "20 mg, BID", but the subject actually took "40 mg, BID or higher (low) frequency", then "drug overdose" would be reported.

[0398] 2. The single dose of the compound of formula (I) capsules administered to the subject did not exceed the dose specified in the study protocol, but the daily dose frequency exceeded the dose specified in the study protocol.

[0399] For example: When the subject was enrolled, the protocol stipulated that the dosage was "20 mg, BID". If the subject actually took the drug "20 mg, TID or more frequently", it would be reported as "drug overdose".

[0400] The following situations do not require reporting of an overdose:

[0401] 1. Non-compliance with medication treatment will not be reported as "drug overdose".

[0402] For example: After evaluation due to AEs and other reasons, the researcher suspends / stops the subject's medication or reduces the dosage or frequency of medication. However, the subject is subjectively unwilling to follow the researcher's instructions or objectively has not received relevant notifications, and continues to take the medication at the original dosage or frequency specified in the research protocol. This situation does not need to be reported as "drug overdose".

[0403] pregnancy

[0404] If a female subject or the partner of a male subject becomes pregnant during the study (using the trial drug at least once), the researcher should fill out the "FOR-PV-ICSR-001-R02 Pregnancy Report Form" and report it to the Haisike Pharmacovigilance Department within 24 hours (no later than 72 hours in special circumstances) and copy it to the relevant personnel department, and report it to the Ethics Committee in accordance with the requirements of the Ethics Committee of the clinical research institution of each center. After a female subject becomes pregnant, she will immediately withdraw from the study due to protocol violations; after a male subject's partner becomes pregnant, the male subject is not required to withdraw from the study, but his partner needs to be recorded, reported, and followed up in the same way as a female subject's pregnancy. When collecting pregnancy information on the male subject's partner, the partner's informed consent must be obtained.

[0405] Pregnancy itself is not considered an AE or SAE, but any complications during pregnancy or termination of pregnancy for medical reasons will be recorded, reported, and followed up as AE or SAE according to the protocol. Artificial abortion without abnormal medical examinations is not treated as an AE unless it meets the SAE definition and needs to be recorded as an SAE. If the outcome of the pregnancy meets the criteria for an SAE, such as spontaneous abortion (including threatened abortion, inevitable abortion, incomplete abortion, habitual abortion, etc.), stillbirth, neonatal death or congenital malformations, the researcher should report it according to the SAE reporting procedure.

[0406] All neonatal deaths occurring within one month of life, regardless of cause, should be reported as SAEs. In addition, any infant death after one month of age that the investigator believes may be related to the investigational drug should also be reported as an SAE.

[0407] Pregnancy events need to be followed up until 28 days after termination of pregnancy or birth of the fetus. After the researcher learns of the pregnancy outcome, he / she must complete the pregnancy report form follow-up report within 24 hours (no later than 72 hours in special circumstances) of learning the outcome and report it to the Haisike Pharmacovigilance Department (Hospital Ethics Committee, if necessary) by email.

[0408] Sponsor SUSAR Report

[0409] The sponsor shall report to the Center for Drug Evaluation (CDE) of the National Medical Products Administration and the National Health Commission of the People's Republic of China in accordance with the relevant guidelines of the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and the requirements of China's GCP:

[0410] Fatal or life-threatening SUSAR

[0411] The sponsor should report to the above-mentioned institutions as soon as possible within 7 days after first being informed, and should submit a follow-up report with as complete information as possible within 8 days after the first report. When new information is subsequently submitted in the form of a follow-up report or the information in the previous report is changed, the reporting period is within 15 days from the date of obtaining the new information.

[0412] All other SUSAR

[0413] The applicant shall report to the above-mentioned agency within 15 days after becoming aware of the incident.

[0414] Minimum reporting requirements:

[0415] The final description and evaluation of the report may not be available within the time limit required for the report. However, for management purposes, the initial report must meet the following requirements within the specified time limit: ① identifiable subjects; ② suspected drug; ③ confirmed source of the report; ④ name, severity and relevance of the AE. Follow-up information should be actively obtained and reported in a timely manner.

[0416] The sponsor shall report to the investigator, clinical trial institution and ethics committee in accordance with the requirements of China's GCP:

[0417] SUSAR: Rapidly report to all researchers, clinical trial institutions, and ethics committees participating in clinical trials.

[0418] Note: After receiving the relevant safety information of the clinical trial provided by the sponsor, the researcher should sign for and read it in a timely manner, consider the treatment of the subjects, and whether to make corresponding adjustments. If necessary, communicate with the subjects as soon as possible, and report the SUSAR provided by the sponsor to the ethics committee.

[0419] Safety update report during development

[0420] Sponsors should prepare a Development Safety Update Report (DSUR) every year in accordance with regulatory requirements and submit it to the CDE within the prescribed time limit. Sponsors should also report the DSUR to all researchers participating in the clinical trial, clinical trial institutions, and ethics committees.

[0421] Data Management

[0422] The clinical trial data management process of this study will be based on GCP and relevant regulatory requirements and comply with the SOP of the data management department to ensure the authenticity, accuracy, completeness, reliability and traceability of the clinical trial data. The details of clinical trial data management will be specified in the data management plan. The electronic data management system (EDC) is used for data management of this clinical study.

[0423] Electronic Case Report Form (eCRF) Design

[0424] Design the data collection form according to the requirements of the plan, define the research process, the name of the data form and the data items it collects, and formulate the corresponding data filling guide, which will be finalized after review and approval.

[0425] Database establishment, testing and authority management

[0426] The database builder builds the EDC data entry interface according to the research plan and CRF, and the data administrator conducts the test. The test content includes: page design, visit period setting, the order of entry forms in the visit and the order of each data point; the accuracy of browsing permissions for different users, etc.

[0427] The EDC system users adopt dual control of roles and permissions. All users accessing EDC need to fill out the user account application form. After confirmation and approval, the system administrator will create accounts such as researchers, clinical research coordinators (CRC), monitors, auditors, medical staff and data managers, and grant different permissions to access EDC.

[0428] Logical verification rule establishment and testing

[0429] Logical verification is a verification method conducted by data administrators for the integrity, consistency and accuracy of database data. It can be done in two ways: automatic system logical verification and manual logical verification. Data construction personnel design logical programs based on the characteristics of the EDC system and the actual requirements of the project. EDC performs automatic logical verification while data is being entered, and issues system questions in real time. In addition to system questions, data administrators manually verify text data and issue manual questions if there are any problems. The logical verification test is completed by the data administrator according to the data verification plan to test whether the EDC system can accurately trigger and close the query prompt according to the pre-designed method. The test process generates and saves relevant files for archiving.

[0430] Data collection and entry

[0431] The data of this study were directly entered into the eCRF. The researcher or his / her authorized clinical coordinator filled in the subject information in the eCRF accurately, timely, completely and in accordance with the original data of the subject.

[0432] The primary responsibility of the investigator is to ensure that the data reported in the eCRF or other forms are accurate, complete, and timely, and that the data on the eCRF are derived from the subjects' original data, and any differences must be explained.

[0433] Clinical monitors should supervise whether clinical trials follow the trial protocol, verify the original data, and confirm that all eCRFs are consistent with the original data. If there are errors and discrepancies, the investigators should be notified and the corresponding questions should be recorded based on the errors or discrepancies found to ensure that all data are recorded and reported correctly and completely.

[0434] Data Verification and Challenge Management

[0435] The clinical trial data management personnel conduct data verification according to the data verification plan, which mainly includes manual verification and computer system logic verification. The questions generated by the verification need to be answered by the researcher or his authorized personnel. If the researcher's answer solves the question, the data management personnel will close the question. If the question is not solved, it will be issued again. This process continues until the data cleaning is completed.

[0436] Database Lock

[0437] According to the database locking process, once all pre-locking steps are completed, the database lock should be approved in writing, the database data editing permissions should be revoked, and the database should be locked. If problems found after the database is locked need to be modified, the data should be modified strictly in accordance with the unlocking and re-locking process.

[0438] eCRF Archiving and EDC Closure

[0439] At the end of the study, an eCRF and PDF electronic document will be generated for each subject and burned to a CD for storage. After the study is over, the EDC will continue to operate for a period of time. After the overall project is completed, the project team will jointly decide whether to complete the EDC offline / shutdown operation.

[0440] Statistical analysis

[0441] The detailed statistical analysis strategy and steps will be described in a separate statistical analysis plan (SAP). After the start of the trial, if there are changes to the statistical analysis methods, they will be revised in SAP and finalized before the database is locked. After the database is locked, additional exploratory analyses not covered by the protocol and SAP need to be described in detail in the clinical study report.

[0442] General statistical considerations

[0443] This study will use statistical analysis software (SAS) EG 8.3 or above for statistical programming and analysis. All trial tables are summarized according to treatment groups unless otherwise specified.

[0444] All data will be described statistically. The statistics used include the number of cases (missing cases), mean, standard deviation (SD), median, upper quartile, lower quartile, minimum and maximum values ​​for continuous variables; frequency, percentage, etc. for categorical variables. Unless otherwise specified, the number of decimal places for the minimum and maximum values ​​is consistent with the original data recorded in the database. The number of decimal places for the mean and median is one more decimal place than the original data recorded in the database, and the SD is two more decimal places than the original data recorded in the database. The number of decimal places for all statistical data does not exceed four. For categorical variables, descriptive statistics include the number of cases and percentages. Percentages are retained to one decimal place, and percentages with a frequency of 0 are not reported.

[0445] Missing Value Handling

[0446] Efficacy indicator data: The missing data of the efficacy indicator ADPS were filled using multiple imputation methods.

[0447] For missing data of other efficacy indicators involved in the secondary efficacy analysis, no filling process will be performed unless otherwise specified.

[0448] Safety data: If there is no special instruction, no missing data will be filled in. Missing data will only be filled in and summarized when time division is required for summary analysis. The dates in the list are listed according to the information filled in on the CRF.

[0449] The treatment of outliers will be judged from both medical and statistical perspectives, especially based on medical industry knowledge.

[0450] Analyze the dataset

[0451] Full analysis set (FAS): Based on the intention-to-treat (ITT) principle, it includes all subjects who have been randomized, received at least one trial drug, and had post-drug efficacy evaluation.

[0452] Per-protocol analysis set (PPS): all subjects in FAS who had good compliance during the study, had complete data on the primary efficacy indicators, and were not affected by protocol deviation (PD).

[0453] Safety analysis set (SS): all subjects who received at least one dose of the trial drug after randomization and had post-drug safety evaluation data.

[0454] Deviation from the plan

[0455] PD refers to the failure to comply with the protocol during the trial. PD is divided into mild PD and major PD according to the severity. Mild PD means that PD does not affect the safety of the subjects and the integrity of the research data, but should be treated appropriately. Major PD refers to the presence of obvious PD, which may affect the rights, safety, willingness to continue to participate in the trial and / or the integrity, accuracy and reliability of the research data. If major PD occurs, the subject may be excluded from the PPS. The specific details will be discussed and decided at the Data Review Meeting (DRM) before the database is locked, including but not limited to:

[0456] Violation of inclusion / exclusion criteria.

[0457] Non-adherence to study treatment, such as use of the wrong study medication / treatment.

[0458] Sample size estimation

[0459] A statistical non-inferiority design was used. It was assumed that the ADPS difference between the experimental group and the control group was -0.6 after 12 weeks of treatment, the non-inferiority margin was 0.3, the standard deviation was 1.7, the one-sided significance level was α=0.025, and the power was 80%. The sample size in each group was 57 cases. Considering the dropout rate of 15%, a total of 136 cases needed to be included, with 68 subjects in each group.

[0460] Distribution of subjects

[0461] Summarize the distribution of all subjects. Describe the subjects' enrollment and randomization, screening failure, reasons for screening failure, completion of the trial, and withdrawal from the trial by group. For subjects who withdrew from the trial, summarize them by their main reasons for withdrawal.

[0462] Provide a list of subject distribution arranged by group and subject number.

[0463] Demographics / Baseline Analysis

[0464] Demographic and baseline characteristic variables will be summarized: including age, sex, height, weight, BMI, etc.

[0465] Medical history / allergy history / surgical history, etc. will be summarized by treatment group according to the system organ class (SOC) and preferred term (PT) classification in the Medical Dictionary for Regulatory Activities (MedDRA version 26.0 or higher).

[0466] Provide a listing of demographic / baseline data results organized by group and subject number.

[0467] Concomitant medication

[0468] Data on concomitant medications will be summarized.

[0469] The WHO Drug Dictionary Global Chinese B3 September, 2022 or later version will be used for coding, and the coded combined medications will be summarized according to the therapeutic subgroup (ATC level 2) and the preferred drug name (Preferred Name, PN), and the number of cases, cases and percentages will be calculated. Multiple medication records in the same ATC level 2 or PN classification for the same subject will be counted as only one case.

[0470] Medication exposure and adherence

[0471] The analysis of compliance will be performed in SS.

[0472] For each treatment group, descriptive statistics were performed using the number of subjects taking the study drug and information related to drug exposure. The respective exposure durations, actual cumulative doses, dose intensities, and relative dose intensities were summarized, and compliance with the trial drug was evaluated.

[0473] Compliance calculation:

[0474] Drug exposure compliance (%) = actual cumulative dose / planned cumulative dose × 100%

[0475] Adherence will be summarized as <80%, 80-120%, and >120%. A list of all drug exposures will be provided.

[0476] Primary Efficacy End Point

[0477] The primary endpoint of this study was to compare the change in ADPS from baseline at week 12 between the compound of formula (I) capsules combined with acetyl-L-carnitine hydrochloride tablets and lipoic acid combined with acetyl-L-carnitine hydrochloride tablets. The covariance analysis (ANCOVA) model was used to take the change in ADPS from baseline after 12 weeks of treatment as the dependent variable, and the research center, group, and ADPS baseline value as the explanatory variables. The least squares means and standard errors of the adjusted change values ​​of each group were listed, and the difference in the mean of the change in ADPS from baseline after 12 weeks of treatment between the compound of formula (I) capsules combined with acetyl-L-carnitine hydrochloride group and the lipoic acid combined with acetyl-L-carnitine hydrochloride group was calculated, as well as its 95% confidence interval.

[0478] When the upper limit of the 95% confidence interval of the least square mean after correcting the difference between the relative baseline value change of the group of capsules of the compound of formula (I) combined with acetyl-L-carnitine hydrochloride and the group of lipoic acid combined with acetyl-L-carnitine hydrochloride is less than 0.3, it is declared that the therapeutic effect of the capsules of the compound of formula (I) combined with acetyl-L-carnitine hydrochloride is non-inferior to that of lipoic acid combined with acetyl-L-carnitine hydrochloride.

[0479] Secondary Efficacy End Points

[0480] The secondary efficacy indicators of changes from baseline [ADPS at week 8, SF-MPQ, ADSIS and EQ-5D-5L scores at week 12] were compared between the groups using covariance analysis (ANCOVA). The factors considered in the model included research center, treatment and baseline ADPS as covariates, and the efficacy differences between the group of capsules of the compound of formula (I) combined with acetyl-L-carnitine hydrochloride and the group of lipoic acid combined with acetyl-L-carnitine hydrochloride were compared.

[0481] Security Analysis

[0482] Safety assessment variables include AEs, ECG, laboratory values, and vital signs, etc. Safety data will be summarized by treatment group in SS and tabulated for all subjects.

[0483] Adverse event analysis

[0484] All AEs and TEAEs were summarized by treatment group.

[0485] All AEs were coded using MedDRA version 26.0 or higher to provide SOC and PT for each event.

[0486] The number and percentage of subjects by treatment group are summarized for the following categories:

[0487] All TEAEs

[0488] TEAEs related to study drug

[0489] TEAEs with CTCAE ≥ grade 3

[0490] TEAEs related to study drug of CTCAE grade ≥3

[0491] Serious adverse events during treatment TESAE

[0492] TESAE related to study drug

[0493] TEAEs leading to death

[0494] TEAEs leading to withdrawal from the trial

[0495] Statistical descriptions were performed according to system organ class (SOC), preferred term (PT), severity, relationship with investigational drugs, etc. A table detailed all AEs that occurred in this study.

[0496] Laboratory test values ​​and 12-lead electrocardiogram

[0497] Laboratory tests include: routine blood test, blood biochemistry, urine routine test, coagulation function test, etc.

[0498] SS was used to perform descriptive statistics on the laboratory test indicators based on the baseline, each measurement time point after medication, and the changes from the baseline, as well as the results of laboratory test indicators in each group. The clinical judgment of the laboratory indicators and 12-lead ECG of the subjects before and after medication and the clinical significance (based on the judgment of the researchers) were summarized in the form of a cross-tabulation, and the number of cases and percentages were calculated. The table detailed the results of each examination indicator of each visit of the subjects.

[0499] Vital signs

[0500] Vital signs include: blood pressure (systolic, diastolic), pulse, respiration and body temperature.

[0501] SS was used to perform descriptive statistics on the results of vital signs based on the baseline, each measurement time point after medication, changes compared with the baseline, and each group. The table details the results of each examination indicator of each visit of the subject.

[0502] Other safety indicators

[0503] The table details the results of each examination indicator of each visit of the subject.

[0504] Ethics and Regulation

[0505] The implementation of this study will be in accordance with the sponsor's SOP, which is designed to ensure compliance with GCP guidelines. When signing the protocol, the investigator will agree to follow the instructions and procedures described in the protocol and follow the GCP principles and relevant domestic regulations that this protocol complies with.

[0506] Ethics Committee

[0507] Before the start of the study, the researcher is responsible for providing the ethics committee with the clinical research plan, ICF and information materials provided to the subjects (subject recruitment advertisements, etc.) in order to obtain the approval of the ethics committee and obtain approval to implement the clinical research. The approval document of the ethics committee must be delivered to the researcher in written form, and the researcher will then provide a copy of the approval document to the sponsor. The approval document of the ethics committee must be accompanied by a list of all committee members who participated in the discussion of the approval document and their respective professional backgrounds.

[0508] During the clinical research process, any issues related to clinical research safety, such as changes in the clinical research protocol or the ICF of the subjects and SUSAR in the clinical research, must be reported to the ethics committee in a timely manner. The end or early termination of the clinical research must also be reported to the ethics committee in a timely manner.

[0509] Informed consent of the subjects

[0510] The rights, safety, and physical and mental health of the subjects are the most important considerations and take precedence over scientific and social interests. In the informed consent, the researcher must clearly and comprehensively inform each subject, or his or her guardian if the subject is unable to give an opinion, of the nature, purpose, relevant procedures, expected time, potential risks and benefits, and any discomfort that may occur in this study. Each subject must know that participation in this study is voluntary and that he or she may withdraw the study and withdraw informed consent at any time without affecting his or her subsequent treatment and relationship with the treating physician. The ICF should comply with the regulatory requirements of the regulatory authorities and adopt a standard writing format, using non-professional language as much as possible. Each ICF must include all of the above relevant content and a voluntary statement. The ICF must be submitted to the relevant ethics committee for approval.

[0511] After the researcher has explained the basic contents of the study and confirmed that the subject understands the purpose of the study, each subject should be asked to sign the name and date on the ICF. The subject should carefully read and consider his statement before signing his name and date, and obtain the signed ICF. Before starting any clinical research-related procedures, the subject's signed ICF must be obtained, including informed consent for any screening process to determine the subject's eligibility to participate in this study. Without informed consent, the subject shall not enter the study.

[0512] For subjects who cannot sign the ICF themselves for any reason, their guardians must sign it. The ICF signed and dated by the subject and the researcher must be properly kept by the researcher and recorded in the original records of the relevant research.

[0513] Researcher

[0514] Before the subjects are enrolled in the study, the researchers should explain the significance of the study to the selected subjects or guardians, obtain their consent and sign the ICF. When an AE occurs, the researchers need to investigate the cause and make appropriate arrangements, and report to the researchers. If the subject dies, they should be responsible for providing the relevant information of the subject. The researchers must enter the data into the medical records and eCRF truthfully, accurately, completely, promptly and legally. The researchers cooperate with the clinical monitors appointed by the sponsor for regular monitoring. Laboratory test records, clinical records and original medical records of the subjects must be kept intact. In addition, AEs need to be followed up (see Section 0).

[0515] Data protection and human tissue sampling

[0516] Data protection will be enforced in accordance with the principles of the Data Protection Directive (1998) 95 / 46 / EC and will apply equally to all research data collected and recorded in any format.

[0517] Any scan data, images, 12-lead ECG and other examination results collected in this study will be retained in the subject's medical records held by the investigator.

[0518] Samples used for safety analysis (urine and blood) will not be retained after the analysis is completed.

[0519] Quality Assurance and Inspection Requirements

[0520] The sponsor is responsible for establishing and maintaining a quality control and quality assurance system to ensure that the conduct of the trial and the generation of data, records and reports comply with current GCP and applicable local regulatory requirements.

[0521] The sponsor will ensure that appropriate monitoring is implemented before, during, and after the study. The sponsor representative will review the study sites, investigational drug storage locations, eCRFs, investigator source files, and all other study documents to ensure they are accurate and in compliance with the protocol and GCP.

[0522] Source document verification will compare the contents of the eCRF records with the corresponding source documents to ensure accuracy. Any discrepancies will be reviewed with the investigator and / or relevant research staff. If corrections are required, the investigator and / or relevant research staff will directly correct or issue a query form on the eCRF. The monitoring procedures require verification of informed consent, compliance with inclusion / exclusion criteria, SAE documents, and correct recording of SAEs. Other monitoring activities may be listed in the study-specific monitoring plan.

[0523] In addition to routine monitoring procedures, the sponsor's quality assurance department may audit clinical research work to assess whether it complies with clinical trial standards guidelines and regulations. Investigators must allow ethics committees, regulatory agencies (such as NMPA, etc.) reviewers and company authorized representatives to enter the research center to directly review source documents, eCRFs and applicable supporting records. During audits and / or inspections, researchers should be present as much as possible. If the researcher receives an inspection notice from the regulatory agency, he or she should immediately contact the sponsor or its authorized personnel.

[0524] The study will be organized, conducted and reported in accordance with the protocol and the sponsor's SOPs. In ICH E6, quality assurance (QA) is defined as "all planned and systematic actions designed to ensure that the conduct of the trial and the generation, recording and reporting of data conform to GCP and applicable regulatory requirements". ICH E6 Section 5.19.3 (b) states that the development of the audit plan and trial audit process should be guided by the importance of the trial in the submission to the competent regulatory authorities, the number of subjects, the type and complexity of the trial, the risk level of the subjects, and any problems found. QA work can be outsourced to CROs or independent institutions. Investigators are required to support audit activities, attend as required by auditors, and allow auditors to directly access raw data / documents.

[0525] A qualified regulatory authority and / or an authorized third party may also conduct an inspection (during or after the study is completed). If a regulatory authority makes an inspection request, the investigator must immediately notify the sponsor of the receipt of the inspection request.

[0526] The detailed research results are as follows:

[0527] Distribution of subjects

[0528] This study was initiated in 4 research centers, and a total of 155 subjects were screened, of which 18 subjects failed the screening and 137 subjects were successfully screened and randomized. The reasons for screening failure included: 11 subjects did not meet the inclusion criteria / met the exclusion criteria, and 7 subjects withdrew their consent.

[0529] The subjects randomly enrolled were randomly assigned to the compound group (I) (69 cases) and the lipoic acid group (68 cases). A total of 15 subjects (10.9%) withdrew from the trial early, including 7 subjects from the compound group (I) and 8 subjects from the lipoic acid group. The reasons for early withdrawal included: 6 subjects (4.4%) withdrew their informed consent, 3 subjects (2.2%) were judged by the researchers to be unsuitable for continuing the study treatment due to AE, 2 subjects (1.5%) were lost to follow-up, and 4 subjects (2.9%) were others.

[0530] Among the randomized subjects, 133 subjects received study treatment (68 in the formula (I) compound group and 65 in the lipoic acid group). All 133 subjects who received study treatment were included in FAS and SS, and all 122 subjects who completed the study (62 in the formula (I) compound group and 60 in the lipoic acid group) were included in PPS.

[0531] The distribution of subjects is summarized in the attached Figure 3 shown.

[0532] Effectiveness Analysis

[0533] Primary Efficacy Endpoint Analysis

[0534] Analysis results based on FAS

[0535] The primary endpoint of this study was to compare the change in average daily pain score (ADPS) at week 12 compared with baseline between the capsules of the compound of formula (I) combined with acetyl-L-carnitine hydrochloride tablets and the lipoic acid combined with acetyl-L-carnitine hydrochloride tablets.

[0536] Based on FAS, at baseline, the number of subjects in the compound of formula (I) group and the lipoic acid group were 67 and 65, respectively, with baseline mean (SD) ADPS of 5.769 (1.0000) and 5.883 (0.9326), respectively, medians of 5.444 and 6.000, and ranges of 4.10-7.89 and 4.00-7.88, respectively.

[0537] At week 12 after receiving the trial drug, the mean (SD) ADPS changes compared with baseline in the subjects in the formula (I) compound group and the lipoic acid group were -4.033 (1.8883) and -2.153 (1.6110), respectively, the medians were -4.393 and -2.000, and the ranges were -7.03 to 0.78 and -5.44 to 1.11, respectively.

[0538] Based on FAS, the results of the change in ADPS from the baseline after 12 weeks of treatment showed that the LSMean (SE) of ADPS in the compound of formula (I) group was -4.0 (0.20), and that in the lipoic acid group was -2.1 (0.20). The least square mean difference of ADPS between the compound of formula (I) group and the lipoic acid group (compound of formula (I) group-lipoic acid group) and its 95% CI were -1.9 (-2.458, -1.357), P value <0.0001, and the upper limit of 95% CI was less than 0, indicating that the difference was statistically significant, indicating that the compound of formula (I) group was significantly better than the lipoic acid group.

[0539] Analysis results based on PPS

[0540] The primary endpoint of this study was to compare the change in average daily pain score (ADPS) at week 12 compared with baseline between the capsules of the compound of formula (I) combined with acetyl-L-carnitine hydrochloride tablets and the lipoic acid combined with acetyl-L-carnitine hydrochloride tablets.

[0541] Based on PPS, at baseline, the number of subjects in the compound of formula (I) group and the lipoic acid group were 61 and 60, respectively, with baseline mean (SD) ADPS of 5.769 (1.0042) and 5.905 (0.9555), medians of 5.556 and 6.000, and ranges of 4.10-7.89 and 4.00-7.88, respectively.

[0542] At week 12 after receiving the trial drug, the mean (SD) ADPS changes compared with baseline in the subjects in the formula (I) compound group and the lipoic acid group were -4.033 (1.8883) and -2.169 (1.6203), respectively, the medians were -4.393 and -2.000, and the ranges were -7.03 to 0.78 and -5.44 to 1.11, respectively.

[0543] Based on PPS, the results showed that the LSMean (SE) of ADPS in the compound of formula (I) group was -4.1 (0.20), and that in the lipoic acid group was -2.2 (0.20). The least square mean difference of ADPS between the compound of formula (I) and the lipoic acid group (compound of formula (I) group-lipoic acid group) and its 95% CI were -2.0 (-2.522, -1.401), P value <0.0001, and the upper limit of 95% CI was less than 0, which was statistically significant, indicating that the compound of formula (I) group was significantly better than the lipoic acid group. The PPS results were consistent with the FAS results.

[0544] Sensitivity analysis of the main efficacy indicators

[0545] Based on FAS, for subjects who dropped out and other subjects with missing 12-week ADPS, the last observation carried forward (LOCF) was used to fill in the missing data of 12 weeks, and an ANCOVA model was constructed for the complete data after missing filling, with the change in ADPS relative to baseline after 12 weeks of treatment as the dependent variable, and the study center, group, and ADPS baseline value as the explanatory variables.

[0546] The results showed that the LSMean (SE) of ADPS in the compound group of formula (I) was -4.0 (0.20), and that in the lipoic acid group was -2.0 (0.20). The least square mean difference of ADPS between the compound group of formula (I) and the lipoic acid group (compound group of formula (I)-lipoic acid group) and its 95% CI were -1.9 (-2.510, -1.388), P value <0.0001, and the upper limit of 95% CI was less than 0, and the difference was statistically significant, indicating that the compound group of formula (I) was significantly better than the lipoic acid group.

[0547] Analyses of Secondary Efficacy End Points

[0548] ADSIS score

[0549] Based on FAS, at baseline, the number of subjects in the compound of formula (I) group and the lipoic acid group were 67 and 65, respectively, and the baseline mean (SD) ADSIS were 5.134 (1.8114) and 5.054 (1.8749), respectively, the medians were 5.222 and 5.556, and the ranges were 0.00-8.11 and 0.00-7.88, respectively.

[0550] At week 12 after receiving the trial drug, the mean (SD) ADPS of the subjects in the formula (I) compound group and the lipoic acid group compared with the baseline change in ADSIS were -3.785 (2.2040) and -2.162 (1.9432), respectively, the medians were -4.143 and -1.889, and the ranges were -7.75 to 0.89 and -6.88 to 1.78, respectively.

[0551] Based on FAS, the results showed that the LSMean (SE) of ADSIS of the compound of formula (I) group was -3.8 (0.22), and that of the lipoic acid group was -2.2 (0.22). The least square mean difference of ADSIS of the compound of formula (I) and the lipoic acid group (compound of formula (I) group-lipoic acid group) and its 95% CI were -1.6 (-2.217, -1.016), P value <0.0001, and the upper limit of 95% CI was less than 0, and the difference was statistically significant, indicating that the compound of formula (I) group was significantly better than the lipoic acid group.

[0552] Changes in ADPS from baseline at week 8

[0553] Based on FAS, at week 8 after receiving the trial drug, the mean (SD) ADPS changes from baseline in the subjects in the formula (I) compound group and the lipoic acid group were -3.164 (1.8627) and -1.665 (1.4774), respectively, and the medians were -3.608 and -1.286, respectively, with ranges of -6.29 to 0.78 and -5.66 to 1.92, respectively.

[0554] Based on FAS, the results showed that the LSMean (SE) of the ADPS change from baseline at week 8 in the compound (I) group was -3.3 (0.20), and that in the lipoic acid group was -1.7 (0.20). The least square mean difference of ADPS between the compound (I) group and the lipoic acid group (compound (I) group-lipoic acid group) and its 95% CI were -1.6 (-2.205, -1.084), P value <0.0001, and the upper limit of 95% CI was less than 0, indicating that the compound (I) group was significantly better than the lipoic acid group.

[0555] VAS score

[0556] Based on FAS, the mean (SD) changes of SF-MPQ (VAS) from baseline in the subjects of the compound of formula (I) group and lipoic acid group at week 12 were -40.3 (18.60) and -21.1 (16.96), respectively, the medians were -41.5 and -19.5, respectively, and the ranges were -75 to 14 and -53 to 11, respectively. The results showed that the LSMean (SE) of the changes of SF-MPQ (VAS) from baseline at week 12 was -40.2 (2.07) in the compound of formula (I) group and -21.6 (2.06) in the lipoic acid group. The least square mean difference of SF-MPQ (VAS) between the compound of formula (I) and the lipoic acid group (compound of formula (I) group-lipoic acid group) and its 95% CI were -18.6 (-24.323, -12.869), P value <0.0001, the upper limit of 95% CI was less than 0, and the difference was statistically significant, indicating that the compound of formula (I) group was significantly better than the lipoic acid group.

[0557] PRI

[0558] Based on FAS, the mean (SD) changes of SF-MPQ (PRI-emotional score) of the subjects in the compound of formula (I) group and the lipoic acid group compared with the baseline at week 12 were -2.4 (2.21) and -1.7 (1.98), respectively, the medians were -2.0 and -1.0, and the ranges were -9 to 4 and -9 to 1, respectively; the mean (SD) changes of SF-MPQ (PRI-sensory score) of the subjects in the compound of formula (I) group and the lipoic acid group compared with the baseline at week 12 were -5.0 (4.97) and -3.1 (3.72), with medians of -4.0 and -2.0, respectively, and ranges of -16 to 19, and -15 to 5, respectively; at week 12, the mean (SD) changes of SF-MPQ (PRI-total pain score) from baseline in the compound of formula (I) group and lipoic acid group were -7.4 (6.61) and -4.7 (5.20), respectively, with medians of -6.0 and -3.5, respectively, and ranges of -23 to 23, and -24 to 4, respectively. The results showed that the LSMean (SE) of the changes of SF-MPQ (PRI-total score) from baseline at week 12 was -7.2 (0.51) in the compound of formula (I) group and -4.8 (0.51) in the lipoic acid group. The least square mean difference of SF-MPQ (PRI-total score) between the compound of formula (I) and the lipoic acid group (compound of formula (I) group-lipoic acid group) and its 95% CI were -2.5 (-3.892, -1.050), P = 0.0008, and the upper limit of 95% CI was less than 0, indicating that the compound of formula (I) group was statistically significantly superior to the lipoic acid group.

[0559] PPI

[0560] At baseline, in the compound of formula (I) group, 3 subjects (4.4%) reported "mild pain", 34 subjects (50.0%) reported "uncomfortable", and 31 subjects (45.6%) reported "pain and irritability". In the lipoic acid group, among the 65 subjects included in FAS, 5 subjects (7.7%) reported "mild pain", 36 subjects (55.4%) reported "uncomfortable", 23 subjects (35.4%) reported "pain and irritability", and 1 subject (1.5%) reported "terrible". The CMH chi-square test was used to compare the incidence of the outcomes reported by the two groups of subjects, and there was no statistically significant difference between the two groups (P=0.4478).

[0561] After 12 weeks of treatment, 9 subjects (13.2%) reported "no pain" in the compound of formula (I) group, 47 subjects (69.1%) reported "mild pain", 5 subjects (7.4%) reported "uncomfortable", and 1 subject (1.5%) reported "terrible"; in the lipoic acid group, 3 subjects (4.6%) reported "no pain", 30 subjects (46.2%) reported "mild pain", 25 subjects (38.5%) reported "uncomfortable", and 2 subjects (3.1%) reported "painful and irritable". The CMH chi-square test was used to compare the incidence of the outcomes reported by the two groups, and the difference between the two groups was statistically significant (P=0.0001).

[0562] EQ-5D-5L score

[0563] Based on FAS, the mean (SD) changes of EQ-5D-5L (EQ-VAS) from baseline in the compound of formula (I) group and lipoic acid group at week 12 were 25.7 (15.60) and 16.2 (11.36), respectively, the medians were 25.0 and 15.0, respectively, and the ranges were -20 to 60 and -10 to 48, respectively. The results showed that the LSMean (SE) of the change of EQ-5D-5L (EQ-VAS) from baseline at week 12 was 25.1 (1.51) in the compound of formula (I) group and 16.4 (1.49) in the lipoic acid group. The least square mean difference of EQ-5D-5L (EQ-VAS) between the compound of formula (I) and the lipoic acid group (compound of formula (I) group-lipoic acid group) and its 95% CI were 8.6 (4.456, 12.782), P value <0.0001, and the lower limit of 95% CI was greater than 0, indicating that the compound of formula (I) group was significantly superior to the lipoic acid group.

[0564] Effectiveness Conclusion

[0565] Based on FAS, at week 12 after receiving the test drug, the mean (SD) ADPS of the subjects in the compound group (I) and the lipoic acid group were -4.033 (1.8883) and -2.153 (1.6110), respectively; the missing values ​​of the primary efficacy index were filled by the multiple imputation method, and the primary endpoint was statistically compared by the ANCOVA model. The results showed that the LSMean (SE) of the ADPS of the compound group (I) was -4.0 (0.20), and that of the lipoic acid group was -2.1 (0.20). The least square mean difference of the ADPS of the compound group (I) and the lipoic acid group (compound group (I)-lipoic acid group) and its 95% CI were -1.9 (-2.458, -1.357), P value <0.0001, and the upper limit of 95% CI was less than 0, which was statistically significant, indicating that the compound group (I) was significantly better than the lipoic acid group. The results of PPS and FAS analysis were consistent. The results of PPS were consistent with those of FAS.

[0566] Based on FAS, for subjects who dropped out and other subjects with missing ADPS at 12 weeks, the last observation carried forward (LOCF) was used to fill in the missing data of 12 weeks for statistical analysis; the change value of ADPS relative to baseline after 12 weeks of treatment was used as the dependent variable, and the research center, group, and ADPS baseline value were used as explanatory variables. The results showed that the LSMean (SE) of ADPS in the formula (I) compound group was -4.0 (0.20), and that in the lipoic acid group was -2.0 (0.20). The least square mean difference of ADPS between the formula (I) compound group and the lipoic acid group (formula (I) compound group-lipoic acid group) and its 95% CI were -1.9 (-2.510, -1.388), P value <0.0001, and the upper limit of 95% CI was less than 0, which was statistically significant, indicating that the formula (I) compound group was significantly better than the lipoic acid group, and the results were robust.

[0567] The compound of formula (I) group was significantly superior to the lipoic acid group in the primary efficacy indicator ADPS at week 12, and the secondary efficacy indicators ADPS, ADSIS, SF-MPQ (VAS, PRI, PPI), and EQ-5D-5L scores at week 8, indicating that the compound of formula (I) combined with L-carnitine hydrochloride tablets can effectively relieve the pain of patients with diabetic peripheral neuropathy, improve the patients' sleep, and improve their quality of life.

[0568] Security Analysis

[0569] Among the 68 subjects in the compound of formula (I) group who were included in SS, 39 subjects (57.4%) had 68 TEAEs, of which 27 were related to the compound of formula (I) capsules in 19 subjects (27.9%), and 13 were related to acetyl-L-carnitine hydrochloride tablets in 10 subjects (14.7%). 4 TEAEs in 4 subjects (5.9%) had a CTCAE grade of ≥3, and 4 were serious adverse events (SAEs) in 4 subjects (5.9%). Among the 65 subjects in the lipoic acid group who were included in SS, 31 subjects (47.7%) had 57 TEAEs, of which 10 were related to acetyl-L-carnitine hydrochloride tablets in 9 subjects (13.8%), and 11 were related to lipoic acid in 10 subjects (15.4%). Three (4.6%) subjects had 3 TEAEs with a CTCAE grade ≥ 3, and three (4.6%) subjects had 3 TEAEs that were serious adverse events (SAEs).

[0570] According to PT classification, TEAEs related to study drugs (compound of formula (I) vs. lipoic acid) with a total incidence of ≥1.0% included: dizziness [10 cases (14.7%) vs. 0 cases], somnolence [6 cases (8.8%) vs. 0 cases], nausea [3 cases (4.4%) vs. 0 cases], upper abdominal pain [0 cases vs. 2 cases (3.1%)], chronic gastritis [1 case (1.5%) vs. 1 case (1.5%)], and diarrhea [2 cases (2.9%) vs. 0 cases].

[0571] In SS, 7 subjects (5.3%) experienced 7 TEAEs with CTCAE ≥ 3, 4 subjects (5.9%) in the compound of formula (I) group and 3 subjects (4.6%) in the lipoic acid group experienced 4 TEAEs with CTCAE ≥ 3, and all were judged to be unrelated to the study drug.

[0572] The vital signs, physical examinations, and ECG test results of most subjects were normal or abnormal without clinical significance. Only a few subjects had abnormal test results with clinical significance. Those that met the AE judgment criteria were recorded as AEs.

[0573] For laboratory tests, the main abnormal results with clinical significance are blood biochemistry and urine routine tests. Among them, the blood biochemistry parameters with abnormal results with clinical significance are mainly total cholesterol, triglycerides, uric acid, blood sugar, etc., and the urine routine parameters with abnormal results with clinical significance are mainly white blood cells, glucose, red blood cells, protein, etc. The abnormal results have been recorded as AEs according to the definition and judgment criteria of AEs in the protocol.

[0574] The vital signs, physical examinations, and ECG test results of most subjects were normal or abnormal without clinical significance. Only a few subjects had abnormal test results with clinical significance. Those that met the AE judgment criteria were recorded as AEs.

[0575] Safety Conclusion

[0576] Most adverse events in this study were mild to moderate and could be relieved without drug or non-drug treatment. A few AEs required drug or non-drug treatment to improve or heal. During the treatment period, the common AEs (≥1.0%) in this study were mainly dizziness, drowsiness, nausea, upper abdominal pain, chronic gastritis, diarrhea, and urinary tract infection. The common adverse reactions in the lipoic acid group were abdominal pain, diarrhea, and urinary tract infection, and the most common adverse reactions in the compound of formula (I) group were dizziness and drowsiness. The types and incidences of the remaining adverse reactions were similar in the two groups. Overall, the overall safety of the compound of formula (I) combined with L-carnitine hydrochloride tablets for the treatment of diabetic peripheral neuropathy pain is good and controllable.

Claims

1. A pharmaceutical composition comprising: (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) acetyl-L-carnitine or a pharmaceutically acceptable salt thereof; The compound of formula (I) has the following structure:

2. The composition of claim 1, wherein the structure of formula (I) is as follows:

3. The composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt of the compound of formula (I) is the benzenesulfonate of the compound of formula (I), and the pharmaceutically acceptable salt of acetyl-L-carnitine is acetyl-L-carnitine hydrochloride; the structural formula of the benzenesulfonate of the compound of formula (I) is as follows:

4. The composition according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is C 12 H 19 NO2 is reacted with acetyl-L-carnitine or its pharmaceutically acceptable salt in the form of C9H 17 The weight ratio of NO4 is selected from 1:10 to 1:80, 1:20 to 1:60, 1:30 to 1:40 or 1:36 to 1:

39.

5. The composition as claimed in claim 3, wherein the weight ratio of the benzenesulfonate salt of the compound of formula (I) to acetyl-L-carnitine hydrochloride is selected from 1:5 to 1:50, 1:10 to 1:40, 1:20 to 1:30 or 1:22 to 1:

28.

6. Use of (i) and (ii) as active ingredients in the preparation of a drug for treating diabetic peripheral neuropathy, wherein: (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) acetyl-L-carnitine or a pharmaceutically acceptable salt thereof; The compound of formula (I) has the following structure: Optionally, (i) and (ii) may be administered simultaneously or sequentially, for example, (i) is administered first and then (ii), or (ii) is administered first and then (i).

7. The use according to claim 6, wherein the structure of formula (I) is as follows:

8. The use as claimed in claim 7, wherein the pharmaceutically acceptable salt of the compound of formula (I) is benzenesulfonate of the compound of formula (I), and the pharmaceutically acceptable salt of acetyl-L-carnitine is acetyl-L-carnitine hydrochloride; the unit dosage form of the oral preparation of benzenesulfonate of the compound of formula (I) contains 5 mg, 20 mg, 40 mg, 60 mg of the compound of formula (I), preferably 20 mg, and the unit dosage form of the oral preparation of acetyl-L-carnitine hydrochloride contains 0.5 g or 0.25 g of acetyl-L-carnitine.

9. The use as claimed in claim 8, wherein the benzenesulfonate oral preparation of the compound of formula (I) is administered twice a day at a dose of 20 mg each time, and the acetyl-L-carnitine hydrochloride oral preparation is administered three times a day at a dose of 0.5 g each time.

10. The use according to claim 8 or 9, wherein the oral preparation of benzenesulfonate of the compound of formula (I) is a capsule, and the oral preparation of acetyl-L-carnitine hydrochloride is a tablet.

11. A pharmaceutical composition comprising a) lipoic acid injection and / or zinc sulfate tablets, and b) acetyl-L-carnitine hydrochloride tablets.

12. Use of a combination of a) and b) in the preparation of a drug for treating diabetic peripheral neuropathy, wherein a) selected from lipoic acid injection and / or zinc sulfate tablets, and b) selected from acetyl-L-carnitine hydrochloride tablets; Optionally, a) and b) may be administered simultaneously or sequentially, for example, a) is administered first and then b), or b) is administered first and then a).

13. The use as claimed in claim 12, wherein the lipoic acid injection is administered once a day at a dosage of 0.6 g each time, and the acetyl-L-carnitine hydrochloride tablets are administered 3 times a day at a dosage of 0.5 g each time in the first week; and the zinc sulfate tablets are administered once a day at a dosage of 0.6 g each time, and the acetyl-L-carnitine hydrochloride tablets are administered 3 times a day at a dosage of 0.5 g each time in the 2nd to 12th week.

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