Anisodine Hydrobromide For The Preventive Treatment Of Episodic Migraine

Inclusion Criteria: Subjects must meet all of the following inclusion criteria to participate in this study.

1. The age at entry for trails involving adult subjects is 18-65 years (including bothends)；
2. According to ICHD-3(Headache Classification Committee of the International HeadacheSociety,2018), individuals should be diagnosed with migraine without aura and/ormigraine with aura, and should have a history of at least 1 year;
3. The age at first migraine onset should be <50 years;
4. Migraine attacks ≥ 4 days/month and < 15 days/month within 3 months prior to screeningperiod (Refer to the definition of migraine days);
5. Within 3 months before entering the screening period, the number of headache (including migraine and other types of headache) attack days per month is less than 15days/month (Refer to the definition of headache days);
6. Be willing to take effective contraceptive measures during the period of participatingin this experiment and within 28 days after the last time taking investigationalproduct;
7. Understand and abide by the research procedures and methods, voluntarily participatein this experiment, and sign the informed consent in writing, agreeing to enter thebaseline period. The following criteria must be met during the baseline period to be eligible forentering the randomized, double-blind, placebo-controlled trial of the drug:
8. Migraine days ≥4 and <14 days within 4 weeks of baseline period(Evaluation based onthe Annex 14.-Electronic Headache Diary);
9. Headache days < 14 days within 4 weeks of baseline period;
10. Completion of at least 80% of the electronic diary within 4 weeks of the baselineperiod(Within 28 days of the baseline period, the electronic diary has been completedfor at least 23 days), and the investigator believes that the subject is able to read,understand, and complete the study questionnaire and headache diary;
11. Understand and abide by the research procedures and methods, voluntarily participatein this experiment, and sign the informed consent in writing, agreeing to enter therandomized, double-blind, placebo-controlled trials of the drug.

Exclusion Criteria: Subjects with any of the following cannot participate in this study:

1. Subject diagnosed with possible migraine according to ICHD-3(2018);
2. Current and previous diagnosis of primary headache, secondary headache, or painfulcranial neuropathy other than migraine(diagnostic criteria are defined according toICHD-3,2018);
3. Past use of more than two of the following 7 drugs is ineffective after adequate use,the types of these drugs are as follows:

• Type 1: Divalproex, Sodium Valproate
• Type 2: Topiramate
• Type 3: Beta blockers(such as: Atenolol, Bisoprolol, Metoprolol, Nadolol,Nebivolol, Pindolol, Propranolol, Timolol)
• Type 4: Tricyclic antidepressants(TCA) (such as: Amitriptyline, Nortriptyline,Protriptyline)
• Type 5: Serotonin-norepinephrine reuptake inhibitors (SNRIs) (such as:Venlafaxine, Desvenlafaxine, Duloxetine, Milnacipran)
• Type 6: Flunarizine, Verapamil
• Type 7: lisinopril, Candesartan Definition of treatment failure: No reduction in headache frequency, duration, orseverity after 6 weeks of administration of the above drugs. The following conditions are not defined as treatment failure:
• Lack of sustained response to medication;
• Can not be tolerated dose of drug

4. Use of drugs known to have significant interactions with the study drug (anisodinehydrobromide) (eg donepezil, donepezil hydrochloride, rivastigmine, etc.) in the 2months prior to the baseline period and throughout the study period；
5. Use of prohibited drugs, Chinese patent drug, Chinese herbal medicines, instruments ortherapies, etc. 2 months before the baseline period or during the baseline period (more details are in Prohibited Drugs/Treatments);
6. Subjects who intend to undergo head, face or neck injections of therapeutic orcosmetic Botulinum Toxin(such as Dysport, Botox, Xeomin, Myobloc and JeuvwauTM) duringthe study period or within 4 months before screening;
7. Simultaneous use of two or more drugs that may have migraine preventive effects within 2 months before the start of the baseline period or during the baseline period (moredetails are in Annex- The List of Migraine Preventive Medications ) (If only oneprophylactic drug is used, the dose must be stable for the two months prior to thebaseline period and throughout the study);
8. The following occurred within two months prior to the start of the baseline period:

• Taking Ergotamines or Triptans for ≥10 days per month, or
• Taking NSAIDs alone for ≥15 days compound or preparation of NSAIDs≥10 days, or
• Taking Opioid or Barbiturate analgesics for ≥4 days per month

9. Subjects are expected to use the following prohibited drugs, Chinese patent drug,Chinese herbal medicines, instruments or protocols during double-blind treatment (moredetails are in Prohibited Drugs/Treatments);
10. Subject has active chronic pain syndrome (eg, fibromyalgia, chronic pelvic pain,facial pain, etc.);
11. Subject has a history of mental illness (eg, schizophrenia or bipolar disorder) orPHQ-9 score≥15；Subjects are allowed to enter the double-blind treatment period if theyhad a history of anxiety or depression and were taking no more than one psychotropicdrug (excluding contraindicated drugs) (Subjects must have taken a stable therapeuticdose within 3 months prior to the baseline period);
12. Have a serious neurological disorder other than migraines (Note: Do not rule outsingle children febrile convulsion);
13. Patients with a history of malignant tumour within five years prior to the screeningperiod, excluding non-melanoma skin cancer, cervical or breast ductal carcinoma insitu;
14. The screening period meets any of the following laboratory values:

• Alanine transaminase (ALT) or aspartate aminotransferase (AST) >1.5×（upper limitof normal, ULN）, or
• Total bilirubin(TBIL) >1.5×ULN （Subjects with diagnosed Gilbert syndromeexcluded）

15. Heart disease such as coronary heart disease, severe heart failure and arrhythmia;history of glaucoma, bleeding disorders, stroke, transient ischemic attack (TIA),reconstructive surgery;
16. The subject has factors that the investigator believes may put the subject atsignificant risk or may confound the results of the study; The subject has any medicalor other reasons for being unfit to participate in the study;
17. According to clinical interviews or C-SSRS questionnaires, the researcher believesthat the subject is at risk of self-harm or harm to others;
18. Within 12 months before the screening period, according to the subject's medicalrecords or the subject's self-reported history of drug or alcohol abuse;
19. Subjects expected to be pregnant or breastfeeding during the study period, or had apositive urine pregnancy test result at screening;
20. During the study period, female subjects of childbearing potential were reluctant touse an acceptable method of effective contraception; Infertile women are defined asfollows: -Have a history of menopause, defined as: Age: ≥55 years old, Menopause ≥12 months, orAge:<55 years old, no spontaneous menstruation for at least 2 years，or Age:<55 yearsold, have spontaneous menstruation in the past 1 year, but current is amenorrhea (spontaneous or secondary to hysterectomy), and abnormal postmenopausal Gonadotropinlevels: luteinizing hormone(LH), follicle-stimulating hormone(FSH)>40IU/L orpostmenopausal estradiol level <5ng/dL, or

• Have a history of bilateral oophorectomy, or
• Have a history of hysterectomy, or
• Have a history of bilateral salpingectomy

21. Subjects who participated in other clinical trials within 3 months before thescreening period;
22. Subjects who are allergic to anisodine hydrobromide or anisodine hydrobromideexcipients;
23. Subjects who cannot maintain their original diet and living habits during the trial;
24. Subjects who intend to take estrogen and/or progesterone drugs during the screeningperiod or after enrollment;
25. Subject is a researcher involved in the study or an immediate family member (parent,spouse, sibling or child).