Clinical Trial to Evaluate the Efficacy of FITOGYN Versus Placebo on the Vasomotor Symptomatology Associated With Menopause

Randomized, Double-blind, Placebo-controlled Clinical Trial, to Evaluate the Efficacy and Tolerability of the Combination of Soy Isoflavones and Red Clover Extract (FITOGYN) in the Treatment of the Hot Flushes in Menopausal Women.

The purpose of this study is to evaluate the efficacy of FITOGYN vs. placebo on the vasomotor symptomatology associated with menopause, to evaluate the symptoms of anxiety, the metabolic parameters in menopause and to evaluate the quality of life associated to the vasomotor symptoms of menopause.

One of the most significant problems for assessing treatment of hot flushes is the placebo effect. A Phase IV study with an innovative design, intended to additionally assess such effect, is reported. The efficacy of Fitogyn for the treatment of hot flushes in menopausal women with moderate symptoms will be assessed. Secondary objectives will include evaluation of the impact of Fitogyn as compared to placebo on overall menopause symptoms (fatigue, joint pain, vaginal dryness, and sleep disturbances), anxiety, quality of life, and cardiovascular parameters. Equol levels in blood will also be measured to study its potential impact on the outcome of treatment with these isoflavones.

The duration of the study participants will be 22 weeks. 7 visits are planned during the study:

After the screening visit (visit 1), women selected will report on the daily occurrence of hot flushes for 2 weeks without treatment. If they experience the required number of hot flushes (35-70 hot flushes in the prior week and 9 or more of them with at least moderate intensity), a 4-week placebo run-in period will start (visit 2). After this time (Visit 3), women with a decrease lower than 25% in the number of hot flushes and a treatment adherence of at least 80% will be randomised to receive treatment (Fitogyn vs placebo) for 16 weeks.

During visit 3, baseline assessments of primary and secondary variables will be carried out. Additionally, blood and urine samples will be obtained to conduct hematological and biochemical tests, and assess thyroid function and lipid profile. In addition, patients will complete the following scales: "Menopausal Rating Scale (MRS)", the scales of anxiety (HADS) and quality of life (Scale of Cervantes).

Visits 4, 5 and 6: To assess every 4 weeks the treatment adherence, to do a safety evaluation and daily collection of hot flashes.

Visit 7: End of study (week 22 of study). During this visit the same activities described for visit 3 will be performed.

SUBSTUDY:

TITLE: "Evaluating the impact of the combination of soy isoflavones and red clover extract (FITOGYN) compared to placebo on some markers of atherogenesis"

The substudy will be conducted in a subsample of approximately 90 patients and will involve those Investigational Sites willing to conduct the substudy, given that they have the means for the proper and correct handling of samples. This study has an exploratory purpose, and will provide useful insight into the specific mechanisms of action of phytoestrogens as well as generate new hypotheses that can guide future research on this product. Additionally, blood equol levels will be measured to study their potential effect on treatment outcome with these isoflavones.

A number of biological parameters have been identified that are clearly related to the process of atherogenesis. This measurement would be from blood collections performed at baseline and the end of the trial, so that new blood collections will not be necessary beyond those already planned.

The selected parameters are:

1. Level of insulin resistance from HOMA.
2. Low density lipoprotein (LDL), oxidized (ox LDL) concentration.
3. Asymmetric dimethyl arginine concentration in endothelial cell culture
4. Measure the ratio of prostacyclin / thromboxane in urine.
5. Genesis of tissue factor in the endothelium.
6. Measurement of blood levels of equol.

Inclusion Criteria:

• Women between 45 and 60 years of age.
• Women in, the immediate or established postmenopausal phase, defined as women with: a) 12 months or more spontaneous amenorrhea or b) 6 months or more spontaneous amenorrhea with levels of follicular stimulating hormone (FSH) above 40 mIU / ml.
• Women with between 35 and 70 episodes of hot flashes (9 or more hot flashes should be of at least moderate intensity) in the week prior to the pre-inclusion period with placebo
• Women who have given written informed consent.

Exclusion Criteria:

• Women with surgical menopause.
• Treatment with HRT within 6 months of the screening visit.
• Patients who needs oncological or immunosuppressive treatment during the expected follow-up period.
• Patient with difficult follow-up or with psycho-neurological problems that hinder proper assessment (alcoholism, depression not caused by menopause, etc.)
• Patients who, at the discretion of the investigator, can not be evaluated according to criteria established in this protocol
• Patients following a vegetarian diet
• Patients with any relevant gastrointestinal disease
• Patients with a prior diagnosis of hypothyroidism or other clinically relevant thyroid disorder.
• Patients treated and / or diagnosed or with suspicion of cancer.
• Patients with diabetes mellitus who require insulin therapy.
• Patients with current diagnosis of an affective disorder (e.g. depression), anxiety disorder, or psychotic disorder.
• Patients with an organic mental disorder
• Patients with neuropathic pain or any other form of pain that receive or need treatment with antidepressives or anticonvulsivants.
• Patients receiving or requiring treatment with antidepressives or anticonvulsivants for other motives (for example, prevention of the migraine).
• Patients consuming more than 2 alcoholic drinks (16-20 gr.) per day
• Patients who have been treated with antibiotics within 3 months of the screening visit.
• Patients receiving or requiring treatment with clonidine or vitamin E.
• Patients who are treated with NSAIDs
• Patients allergic to any of the components of FITOGYN
• Patients who took less than 80% of the capsules in the pre-inclusion period with placebo.
• Patients whose weekly number of hot flushes is reduced by 25% or more during the pre-inclusion period as compared to the week prior to the initiation of that period.