Clinical Study to Compare Efficacy and Safety of Indinol Forto® 200 mg Capsules and Visanne 2 mg Tablets in Treatment of Endometriosis

Prospective open-label randomized parallel groups study to compare efficacy and safety of Indinol Forto® 200 mg capsules and Visanne 2 mg tablets in treatment of endometriosis. This is phase 3 study, based on hypothesis of non-inferiority.

The study population consists of females from 18 to 45 years old inclusively at the moment of screening who have been surgically (laparoscopy or laparotomy) diagnosed with endometriosis within not more than 60 months and not less than 2 weeks of study entry, and reported at least moderate pelvic pain within minimum 2 months of study entry.

Study participants are observed during 1 menstrual cycle during screening period (Screening Cycle). Participants who meet inclusion criteria and don't meet exclusion criteria will be randomly assigned to one of two treatment arms (Group 1: Indinol Forto® 200 mg capsules two times per day or Group 2: Visanne 2 mg tablets once per day). After observation on treatment during 24 weeks (monthly Visits 1-7) the study subjects enter post-treatment period and are observed for one more month (Post-Treatment Period, Visit 8).

Visual Analog Scale (VAS) is used in the study as the main tool for assessment of daily pelvic pain. Cyclic and non-cyclic pain, as well as intensity of vaginal bleeding are assessed daily during the study.

The study primary efficacy endpoint is the change in average daily pelvic pain score (cyclic and non-cyclic, combined) during the 6th treatment period (interval between Visit 6 and Visit 7) in comparison to the Screening period.

Inclusion criteria

• The participant provides written informed consent for participation in the study in accordance with current legislation.
• Female participants in reproductive/premenopausal period from 18 to 45 years old inclusively (at the moment of signing informed consent).
• Participants have been surgically (laparoscopy or laparotomy) diagnosed with endometriosis (ICD code #80) within not more than 60 months and not less than 2 weeks of study entry, stage I-III according to endometriosis revised classification of American Fertility Society (R-AFS, 1985)).
• Participant has had spontaneous, (i.e., without hormonal therapy) regular, menstrual cycles with a cycle length between 24 to 38 days (inclusive) for the past 2 cycles before Visit 0 and during screening period.
• Participant has no current indications for surgical treatment of endometriosis.
• Participant has had endometriosis-related pelvic pain assessed with visual analogue scale (VAS) and defined as average daily pain score ≥3.5 cm during 2 menstrual cycles prior to screening (assessed by the participant retrospectively at the moment of screening) and during screening menstrual cycle (according to the data from the participant's diary completed daily).
• Presence of other symptoms of endometriosis (e.g. dysmenorrhea, dyspareunia, dyschezia, data of ultrasound imaging, or magnetic resonance imaging (MRI).
• The participant agrees to use highly effective contraception methods described in the protocol from the time of signing informed consent through the whole duration of the study and for 2 months after the study completion.
• Negative pregnancy test.
• Participant completed daily diary on minimum 75% of days during screening menstrual cycle.

Exclusion criteria

• Presence of contraindications to Indinol Forto (indolcarbinol)
• Presence of contraindications to Visanne (dienogest)
• Participant had undiagnosed (unexplained), abnormal, vaginal or urinary tract bleeding within the past 6 months before screening (Visit 0).
• Participant has chronic pelvic pain not caused by endometriosis, but other gynecological or urological disorders (consequences of inflammatory process, uterine fibroids, pelvic congestion syndrome, etc.).
• Participant has chronic, non-pelvic pain not caused by endometriosis that requires chronic analgesic or other chronic therapy (including, but not limited to, fibromyalgia, chronic back pain or chronic headaches).
• Endometrioid cysts ≥ 3 cm.
• Participant has a surgical history of hysterectomy and/or bilateral oophorectomy; premature ovarian failure. Note: Participants who have undergone surgical sterilization (eg, bilateral salpingectomy, tubal ligation) are permitted in the trial.
• Participant has a clinically significant gynecologic condition identified in the screening evaluation including, but not limited to, ovarian cysts larger than 3 cm and present longer than 4 months, an active sexually transmitted disease, etc. Note: Participants may be rescreened after completing treatment for infection or for simple ovarian cysts.
• Participant with endometriosis-related pelvic pain who didn't respond to previous treatment with combined oral contraceptives, GnRH agonists or antagonist, progestins or aromatase inhibitors. Note: Participants who demonstrated partial response or interrupted their treatment due to side effects, may be enrolled in the study.
• History of malignancy, including suspected malignization of endometriomas within ≤5 years before signing informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
• Severe renal failure (glomerular filtration rate calculated with Cockcroft-Gault formula is below 30 ml/min/1,73 m2).
• Systolic blood pressure >160 mm Hg or diastolic blood pressure >90 mm Hg during screening period.
• Clinically significantly abnormal laboratory tests at Screening, including: alkaline phosphatase (AP), alanine aminotransferase (ALT, SGPT), aspartate aminotransferase (AST, SGOT) >200% of the upper limit of normal, or total bilirubin >150% of the upper limit of normal; hemoglobin <10 g/dl, white blood cell count <2500 in mm³, neutrophil count <1500 in mm³, platelet count <100 х 10³/mm³.
• Hyperthyroidism (TSH below 0.4 mU/L) or hypothyroidism (TSH above 4.0 mU/L).
• Positive pregnancy test (including pregnancy within 3 months prior to screening) or lactation period.
• Other medical conditions that, in the judgment of the Investigator, may increase the risk associated with study participation or may interfere with the interpretation of study results.
• History of alcohol or substance abuse.
• Participation in a clinical study within 90 days before screening.
• Other reasons that, in the judgment of the Investigator, may interfere with participation in the study or may lead to unreasonable risks.
• Conditions requiring surgery in the period of the study.
• Conditions requiring therapy prohibited by the study protocol.