Efficacy of Vitex Agnus-castus BNO 1095 (20 mg) in Women With Primary Dysmenorrhea

In this Phase III study, the herbal product Vitex agnus-castus BNO 1095 20 mg will be tested.

The sponsor would like to find out if treatment with Vitex agnus-castus BNO 1095 20 mg may improve the cramping pain before or during menstruation (primary dysmenorrhea) (without an organic cause) in women and if this treatment is safe. It is tested, if the pelvic pain and other symptoms during menstruation improve in patients who are treated with Vitex agnus-castus BNO 1095 20 mg and if therefore the standard treatments for primary dysmenorrhea, for example pain relief medications will not have to be increased.

The study has 2 treatment groups. Patients in one group will receive Vitex agnus-castus BNO 1095 20 mg, and patients in the other group will receive a placebo. Placebo tablets look like Vitex agnus-castus BNO 1095 20 mg tablets but have no active ingredient. Patients will be randomly assigned (like tossing a coin) to one of the 2 groups (this process is called randomization). The chance for the patients to receive Vitex agnus-castus BNO 1095 is 50%. Neither the patients nor the investigators know which product the patients are taking (this method is known as "double-blind").

This is a randomized, placebo-controlled, double-blind, multicenter, phase III clinical trial to investigate the efficacy and safety of investigational medicinal product (IMP) Vitex agnus-castus BNO 1095 20 mg in women with primary dysmenorrhea.

The clinical trial will be conducted in Austria, Czech Republic, Germany, Hungary, Poland and Sweden.

About 390 patients will be screened so that about 300 patients (150 patients per treatment group) will be randomized.

Vitex agnus-castus BNO 1095 20 mg is extracted from the fruits of the plant Vitex agnus-castus also called monk's pepper or chaste tree. Vitex agnus-castus BNO 1095 20 mg is currently marketed for the treatment of the premenstrual syndrome (PMS) which means repeated occurrence of physical, behavioral and psychological symptoms the days before the onset of menstruation, but it is not authorized for the treatment of primary dysmenorrhea.

The study has 2 treatment groups. Patients in one group will receive Vitex agnus-castus BNO 1095 20 mg, and patients in the other group will receive a placebo. Patients will be randomly assigned 1:1 to one of the 2 groups. The chance to receive Vitex agnus-castus BNO 1095 is 50%. The study is double blinded, neither the patients nor the investigators know which product the patients are taking.

The study will last about 7 months for each patient. There will be 5 visits at the study site, and in addition the patients will receive 3 phone calls from the study site. On average, each study site visit will take about 2 hours and each phone call about half an hour.

The trial will include 3 phases: a screening and run-in phase of up to 2 menstrual cycles, a treatment phase of 4 menstrual cycles and a follow-up phase of 1 menstrual cycle. The length of each phase depends on the length of women's menstrual cycle. If their menstrual cycle is 28 days, the screening and run-in phase will take up to 59 days (slightly more than 2 menstrual cycles), the treatment phase 113 days (about 4 menstrual cycles), and the follow-up phase 28 days (1 menstrual cycle).

The main objective of this study is to determine if primary dysmenorrhea improves in women treated with Vitex agnus-castus BNO 1095 20 mg compared to placebo over a treatment duration of 3 menstrual cycles (cramping windows of Cycles 3-5).

Vitex agnus-castus BNO 1095 20 mg or placebo tablets are taken orally (means by mouth) once a day during the treatment phase.

If a patient usually takes pain relief medication for primary dysmenorrhea, the patient is allowed to continue taking this pain relief medication during study participation.

The patients will complete the dysmenorrhea daily diary (DysDD) every day in the evening. Depending on her bleeding status, the diary includes questions about menstrual bleeding, pieces of sanitary protection used, severity of the worst pain or cramps in the pelvic area on a numerical rating scale (NRS), intake of pain relief medication, and impact on daily life in an electronic diary (handheld device).

Additionally, the dysmenorrhea associated symptoms nausea, vomiting, diarrhea, fatigue, weakness, fainting, and headache will be assessed by the patients on a NRS in the electronic diary on Days 1-3 of the menstrual cycle. Migraine will be assessed by the investigator at the clinical trial visits. The patient and investigator will assess the efficacy of treatment on a 5-point verbal rating scale at the end of treatment and at the end of the study (EoS).

Eligibility Criteria:
Inclusion Criteria:

1. Women aged 18-49 years who have the capacity for consenting
2. Patient has been informed of the nature, scope, and relevance of the clinical trial, voluntary agrees in participation and the trial provisions, and has duly signed the approved informed consent form (ICF)
3. Diagnosed primary dysmenorrhea
4. If patients take pain relief medication for primary dysmenorrhea, this medication should be taken unchanged with regard to application form and kind of medication including strength during the Screening as well as during the first three treatment cycles.

   Note: Medication (drugs) for primary dysmenorrhea as mono- or combination therapy in form of tablets/capsules regularly used by the patient before Screening is allowed to be used as standard pain relief medication during the trial apart from non-medication methods. A complete list of allowed pain relief medication is attached to the protocol.

   This medication should be taken by the patient at least for 1 cycle before Screening guaranteeing a stable intake of this medication in total for 3 cycles before randomization.
5. Patients with a regular menstrual cycle duration of ≥24 to ≤38 days
6. Patients agreeing to use one of the following contraception methods throughout the trial:

   1. Bilateral tubal occlusion
   2. Vasectomized partner (provided that the partner is the sole sexual partner of the woman and has received medical assessment of the surgical success)
   3. Sexual abstinence Abstinence is only accepted as true abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods and withdrawal) is not an acceptable method of contraception
   4. Male or female condom with or without spermicide
   5. Cap, diaphragm, or sponge with spermicide

Exclusion Criteria:

A patient will not be eligible for inclusion if any of the following criteria applies:

1. Non-menstruating women
2. Clinically diagnosed secondary dysmenorrhea (e.g., fibroids, uterine adenomyosis, endometriosis, pelvic inflammation, ovarian pathologies, or other pelvic diseases)
3. Dysmenorrhea resulting from the use of an intrauterine device
4. Use of hormonal contraceptives (oral, intravaginal, transdermal, injectable, implantable), intrauterine device, or intrauterine hormone-releasing system within 6 months prior to the trial and not willing to waive it during the entire trial period
5. Any surgical treatments in the past (e.g., due to myoma) that may cause pain, adhesions or scarring in the lower abdomen Note: Further diagnostic examination (e.g., laparoscopy for differential diagnosis, exclusion of endometriosis) if deemed necessary by the investigator will be outside the trial protocol and reimbursement
6. Known or suspected gastrointestinal or urological conditions that may cause abdominal and/or pelvic pain, such as colitis, appendicitis, irritable bowel syndrome, cholelithiasis, interstitial cystitis, cystitis, urolithiasis, and other conditions that, according to the investigator's judgement, are not suitable for the trial
7. Known or suspected gynecological complaints e.g., premenstrual abdominal pain, deep dyspareunia, uterine fibroids and polyps, or chronic pain (abdominal, dorsal, urogenital)
8. Known instable diseases e.g., psychiatric, cardiovascular, or endocrine disorders
9. Body mass index \<18.5 or \>34.9 kg/m² at Screening
10. Known or suspected acute infection of gonorrhea, syphilis and/or chlamydia at Screening
11. Current or past estrogen sensitive cancer or pituitary disorder that, in the investigator's opinion, would make the patient not suitable for the trial
12. Women who are breastfeeding, pregnant (positive pregnancy test at Screening), or planning to become pregnant during the trial
13. Fewer than 3 menstrual cycles before Screening following delivery, abortion, miscarriage, or lactation
14. Current severe physical or mental illness
15. Patient does not agree to avoid daily smoking
16. History of alcohol, drug, or medicine abuse within 1 year prior to Screening, or positive for drugs or medicines of abuse in the laboratory analysis performed at Screening
17. Patients with hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
18. Hypersensitivity to Vitex agnus-castus, lactose or any of the excipients of the IMP or to any ingredients of the standard pain relief medication
19. Patients committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
20. Employees of the sponsor or site staff or direct relatives of the site staff
21. Legal incapacity or limited legal capacity
22. Patients not able to follow trial instructions or assessments or to participate in the trial for the whole duration of approximately 7 months or unable to understand written and verbal instruction, in particular regarding the risks and inconveniences that the patients will be exposed to during participation in the clinical trial
23. Participation in another interventional clinical trial during the last month before Screening
24. Use of Vitex agnus-castus containing preparation or product within the last 3 months before Screening
25. Current intake or intake within the last 4 weeks before Screening of dopamine agonists, dopamine antagonists, estrogens, or antiestrogens that would make the patient not suitable for the trial