Anisodine Hydrobromide For The Preventive Treatment Of Episodic Migraine

In this study,288 adult migraine patients aged 18-65 years (diagnosed with migraine without aura and/or migraine with aura, with at least a 1-year history)will be collected to evaluate the efficacy, safety and tolerability of Anisodine Hydrobromide in preventing migraine attacks in episodic migraine in adults.

1. Research contents:

   In this study,288 adult migraine patients aged 18-65 years (diagnosed with migraine without aura and/or migraine with aura, with at least a 1-year history)will be collected to evaluate the efficacy, safety and tolerability of Anisodine Hydrobromide in preventing migraine attacks in episodic migraine in adults.
2. Research target:

   To evaluate the efficacy, safety and tolerability of oral Anisodine Hydrobromide in preventing migraine attacks in episodic migraine in adults, we used the change from baseline in migraine days per 4 weeks during the 12-week treatment period as the primary endpoint.
3. Research design:

   This study uses a multicenter, randomized, double-blind, placebo-controlled, parallel design and plans to enroll 288 adult patients with episodic migraine.

   A total of 288 patients were planned to be enrolled, and all subjects were randomly assigned to group A (Anisodine Hydrobromide 1 mg bid) and group B (placebo 1 mg bid) according to a 1:1 ratio, with 144 subjects in each group.Both anisodine hydrobromide and placebo were produced and supplied by Chengdu First Pharmaceutical Limited Company.

   The enrolled subjects were orally administered Anisodine Hydrobromide 1 mg bid or placebo 1 mg bid for 12 consecutive weeks of treatment, and followed up for 4 weeks. That means doing face-to-face visits at the 4th, 8th, 12th and 16th weeks after dosing ,while affected by the epidemic or other special circumstances, video or telephone follow-up can be used.

   This study is divided into 3 phases: screening/baseline period (4 weeks, D-28\~D-1), double-blind treatment period (12 weeks, D1\~D84), follow-up period (4 weeks, D85-D112), a total of About 20 weeks.
4. In order to ensure the quality of the trial, the sponsor and the researcher shall discuss and formulate the clinical research plan before the trial officially begins. Good Clinical Practice(GCP) training was given to the relevant researchers who participated in the experiment. The research center must manage experimental drugs in accordance with (SOP), including receipt, storage, distribution and recycling. In accordance with the GCP guidelines, necessary steps should be taken during the design and implementation phase of the study to ensure that the data collected are accurate, consistent, complete and credible. All observed results and abnormal findings in clinical trials should be verified and recorded in time to ensure the reliability of the data. The instruments, equipment, reagents and standards used in various examination items in clinical trials should have strict quality standards and ensure that they work under normal conditions. The researcher inputs the information required by the program into the eCRF, and the inspector verifies whether the filling is complete and accurate, and instructs the staff of the research center to make necessary corrections and supplements. The drug regulatory department, the institutional review committee (IRB)/ independent ethics committee (IEC), sponsor inspectors and / or inspectors may conduct systematic inspections of clinical trial-related activities and documents to evaluate whether trials are conducted in accordance with the requirements of the study program, SOP and relevant regulations (e.g. GCP, GMP), and whether trial data are recorded in a timely, true, accurate and complete manner. The inspection should be carried out by personnel who are not directly involved in the clinical trial.
5. Statistical analysis plan： Efficacy evaluation: The primary endpoint was analyzed by Mixed Model for Repeated Measures(MMRM).And the primary endpoint analysis was based on the analysis results of Full Analysis Set(FAS) and Per Protocol Set(PPS).

Eligibility Criteria:
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 both ends)；
2. According to ICHD-3(Headache Classification Committee of the International Headache Society,2018), individuals should be diagnosed with migraine without aura and/or migraine 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 screening 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 of participating in this experiment and within 28 days after the last time taking investigational product;
7. Understand and abide by the research procedures and methods, voluntarily participate in this experiment, and sign the informed consent in writing, agreeing to enter the baseline period.

   The following criteria must be met during the baseline period to be eligible for entering 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 on the 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 baseline period(Within 28 days of the baseline period, the electronic diary has been completed for 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 participate in this experiment, and sign the informed consent in writing, agreeing to enter the randomized, 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 painful cranial neuropathy other than migraine(diagnostic criteria are defined according to ICHD-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, or severity 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 (anisodine hydrobromide) (eg donepezil, donepezil hydrochloride, rivastigmine, etc.) in the 2 months prior to the baseline period and throughout the study period；
5. Use of prohibited drugs, Chinese patent drug, Chinese herbal medicines, instruments or therapies, 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 or cosmetic Botulinum Toxin(such as Dysport, Botox, Xeomin, Myobloc and JeuvwauTM) during the 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 (more details are in Annex- The List of Migraine Preventive Medications ) (If only one prophylactic drug is used, the dose must be stable for the two months prior to the baseline 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 (more details 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) or PHQ-9 score≥15；Subjects are allowed to enter the double-blind treatment period if they had a history of anxiety or depression and were taking no more than one psychotropic drug (excluding contraindicated drugs) (Subjects must have taken a stable therapeutic dose within 3 months prior to the baseline period);
12. Have a serious neurological disorder other than migraines (Note: Do not rule out single children febrile convulsion);
13. Patients with a history of malignant tumour within five years prior to the screening period, excluding non-melanoma skin cancer, cervical or breast ductal carcinoma in situ;
14. The screening period meets any of the following laboratory values:

    * Alanine transaminase (ALT) or aspartate aminotransferase (AST) \>1.5×（upper limit of normal, ULN）, or
    * Total bilirubin(TBIL) \>1.5×ULN （Subjects with diagnosed Gilbert syndrome excluded）
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 at significant risk or may confound the results of the study; The subject has any medical or other reasons for being unfit to participate in the study;
17. According to clinical interviews or C-SSRS questionnaires, the researcher believes that 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 medical records 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 a positive urine pregnancy test result at screening;
20. During the study period, female subjects of childbearing potential were reluctant to use an acceptable method of effective contraception; Infertile women are defined as follows:

    -Have a history of menopause, defined as: Age: ≥55 years old, Menopause ≥12 months, or Age:\<55 years old, no spontaneous menstruation for at least 2 years，or Age:\<55 years old, have spontaneous menstruation in the past 1 year, but current is amenorrhea (spontaneous or secondary to hysterectomy), and abnormal 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
21. Subjects who participated in other clinical trials within 3 months before the screening period;
22. Subjects who are allergic to anisodine hydrobromide or anisodine hydrobromide excipients;
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 screening period or after enrollment;
25. Subject is a researcher involved in the study or an immediate family member (parent, spouse, sibling or child).