TIzanidine for the Preventive Treatment of Episodic MigrainE （TIME）

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 toscreening period (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 15 days/month (Refer to the definition of headache days);

6. Be willing to take effective contraceptive measures during the period ofparticipating in this experiment and within 28 days after the last time takinginvestigational product;

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 beencompleted for at least 23 days), and the investigator believes that the subject isable 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. Previous use of more than two of the following 7 drugs is ineffective after adequateuse, 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

• Type 8: Drugs acting on the CGRP pathway（Monoclonal antibodies and Gepants） 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 prohibited drugs, Chinese patent drug, Chinese herbal medicines, instrumentsor therapies, etc. 2 months before the baseline period or during the baseline period (more details are in Prohibited Drugs/Treatments);

5. Subjects who intend to undergo head, face or neck injections of therapeutic orcosmetic Botulinum Toxin(such as Dysport, Botox, Xeomin, Myobloc and JeuvwauTM)during the study period or within 4 months before screening;

6. Simultaneous use of two or more drugs that may have migraine preventive effectswithin 2 months before the start of the baseline period or during the baselineperiod (more details are in Annex- The List of Migraine Preventive Medications ) (Ifonly one prophylactic drug is used, the dose must be stable for the two months priorto the baseline period and throughout the study);

7. 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

8. Fluvoxamine, ciprofloxacin (cytochrome oxidase P450IA2 inhibitor), fluoroquinolones,zileuton, antiarrhythmics (amiodarone, mexiletine, propafenone, and verapamil) ,cimetidine, famotidine, acyclovir, ticlopidine, metoprolol, propranolol and otherbeta-blockers, clonidine and other alpha2-adrenergic agonists , Chinese patentmedicine, Chinese herbal medicine, instrument or program (see 5.7.2 ProhibitedDrugs/Treatment for details)

9. Subject has active chronic pain syndrome (eg, fibromyalgia, chronic pelvic pain,facial pain, etc.);

10. Subject has a history of mental illness (eg, schizophrenia or bipolar disorder) orPHQ-9 score≥15；Subjects PHQ-9 score<15 are allowed to enter the double-blindtreatment period if they had a history of anxiety or depression and were taking nomore than one psychotropic drug (excluding contraindicated drugs) (Subjects musthave taken a stable therapeutic dose within 3 months prior to the baseline period);

11. Have a serious neurological disorder other than migraines (Note: Do not rule outsingle children febrile convulsion);

12. 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;

13. The screening period meets any of the following laboratory values:

• Alanine transaminase (ALT) or aspartate aminotransferase (AST) >1.5×（upperlimit of normal, ULN）, or

• Total bilirubin(TBIL) >1.5×ULN （Subjects with diagnosed Gilbert syndromeexcluded）,or

• The creatinine clearance rate is less than 25 mg/min, and the creatinineclearance rate decreases by 50%;

14. Previous heart disease, heart failure, bradycardia, orthostatic hypotension andother types of hypotension, stroke, transient ischemic attack (TIA);

15. 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 anymedical or other reasons for being unfit to participate in the study;

16. According to clinical interviews or C-SSRS questionnaires, the researcher believesthat the subject is at risk of self-harm or harm to others;

17. 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;

18. Subjects expected to be pregnant or breastfeeding during the study period, or had apositive urine pregnancy test result at screening;

19. 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 ≥12months, or Age:<55 years old, no spontaneous menstruation for at least 2years，or Age:<55 years old, have spontaneous menstruation in the past 1 year,but current is amenorrhea (spontaneous or secondary to hysterectomy), andabnormal postmenopausal Gonadotropin levels: luteinizing hormone(LH),follicle-stimulating hormone(FSH)>40IU/L or postmenopausal estradiol level <5ng/dL, or

• Have a history of bilateral oophorectomy, or

• Have a history of hysterectomy, or

• Have a history of bilateral salpingectomy

20. Subjects who participated in other clinical trials within 3 months before thescreening period;

21. .Subjects who are allergic to tizanidine hydrochloride or tizanidine hydrochlorideexcipients;

22. Subjects who cannot maintain their original diet and living habits during the trial;

23. Subjects who intend to take estrogen and/or progesterone drugs during the screeningperiod or after enrollment;

24. Subject is a researcher involved in the study or an immediate family member (parent,spouse, sibling or child).