Klimadynon® in Comparison to Conjugated Oestrogens in Women Suffering From Menopausal Complaints

Study Overview
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Brief Summary
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To investigate, relative to placebo and conjugated oestrogens, the efficacy, safety and tolerability of a 12 weeks peroral treatment twice daily with a cimicifuga racemosa extract corresponding to 20 mg, 75 mg or 150 mg plant material on menopause-related neurovegetative and mental complaints

Official Title
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Double-blind Dose/Response Study Comparing Klimadynon® With Conjugated Oestrogens in Women Suffering From Menopausal Complaints

Conditions
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Menopause

Intervention / Treatment
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* Drug: Low dose of Klimadynon®
* Drug: Medium dose of Klimadynon®
* Drug: High dose of Klimadynon®
* Drug: Oestrofeminal®
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Only postmenopausal (amenorrhea for 6 months at least) women may be enrolled in the study Women after ovariectomy may also be enrolled if surgery was carried out at least 6 months prior to the enrollment. Only women between the age of 40 and 60 may be included 2 weeks (control -1, week -2, day -14) before the beginning of the treatment the following hormone values must have been analyzed: estradiol-17ß ≤ 0.15 nmol/l corresponding to ≤ 40 pg/ml and follicle stimulating hormone (FSH) ≥ 25 milliunits per milliliter (mU/ml) These hormone analyses must be carried out at the competent local laboratory In addition to other menopausal complaints the women must have hot flushes / outbreaks of sweating: Diary: During the run-in period daily ≥ 3 hot flushes / outbreaks of sweating Modified Menopause Rating Scale, 1st item twofold (week -2 and 0) ≥ 0.3 A sum score taken twice from the modified (only items 1 - 6) Menopause Rating Scale within 2 weeks (week - 1 and 0) before the beginning of treatment must be ≥ 1.7 In case of a pretreatment with estrogen a wash-out phase of 6 weeks is necessary in case of oral or transdermal administration. After the 4th week of wash-out the patient may be included in the run-in period Exclusion Criteria: General criteria for exclusion: Non-responder (= no therapeutic success) under a pretreatment with estrogen Amenorrhea for < 6 months In case of an estrogen pretreatment last menstruation (menopause) > 3 years earlier Sum score of the modified Menopause Rating Scale (items 1 - 6) during the run-in period twice (week -2 and 0) < 1.7 No hot flushes / outbreaks of sweating (see Inclusion criteria) At one of the appointments of the run-in period (week -2 and 0) more than one question of items 1 - 6 of the modified Menopause Rating Scale (MMRS) not answered During the run-in period at the appointment week -2: estradiol-17ß > 40 pg/ml corresponding to > 0.15 nmol/l and FSH < 25 mU/ml Condition after hysterectomy Simultaneous ingestion of estrogen-containing products in addition to the test products Any addition ingestion of psychotropic drugs, antidepressants and sleeping aids (hypnotics / sedatives) Treatment with another study drug in the 2 months preceding the beginning of the study Considerable overweight (exceeding the target body weight [height in cm minus 100] by more than 30%) Poor general condition Alcohol or drug abuse Poor compliance Exclusion criteria based on conjugated estrogens or medroxyprogesterone: Any contraindication for estrogen Unresolved genital bleeding Suspicion / existence of estrogen-dependent mammary carcinoma (mammography and/or endometrial carcinoma) Endometriosis Endometrial hyperplasia (including hyperplastic polypoid endometrium, which has not yet reached the stage of a glandular cystic hyperplasia) Thickness of endometrium > 5 mm Existing thromboembolism or thromboembolism in the past Phlebitis in the past 2 years or actually existing Acute or chronic hepatic lesion (aspartate transaminase and/or alanine transaminase and/or gamma glutamyl transferase twice the normal range) Metabolic disorders of bile pigments (Dubin-Johnson's syndrome, Rotor syndrome, pregnancy icterus with/without pruritus in previous pregnancy) Sickle cell anemia Clinically relevant hypertriglyceridemia or hypercholesterolemia Heart attack in the past Severe varicosis Known sensitivity to medroxyprogesterone Case history of anaphylactic reaction Any neoplasm at the genitals Case history of antidepressant treatment Diabetes mellitus with or without treatment

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose of Klimadynon®<br> | Drug: Low dose of Klimadynon®<br> <br> |
| Experimental: Medium dose of Klimadynon®<br> | Drug: Medium dose of Klimadynon®<br> <br> |
| Experimental: High dose of Klimadynon®<br> | Drug: High dose of Klimadynon®<br> <br> |
| Active Comparator: Oestrofeminal®<br> | Drug: Oestrofeminal®<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of score in menopause-related symptom categories of the modified menopausal rating scale (MRS) |  | baseline, week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of score of MRS items 7-10 and items 1-10 |  | baseline, week 12 | 
| Change of menopause index according to Kupperman | a 4 point numerical scale rating of 11 weighted menopause-related symptom complexes | Baseline up to day 98 | 
| Changes in daily frequency of menopausal lead symptoms | diary information | Up to day 105 | 
| Changes from baseline in serum concentration of oestradiol-17ß |  | Up to day 98 | 
| Changes from baseline in serum concentration of FSH |  | Up to day 98 | 
| Changes from baseline in serum concentration of luteinising hormone |  | Up to day 98 | 
| Changes from baseline in serum concentration of osteocalcin |  | Up to day 98 | 
| Changes from baseline in serum concentration of ß-CrossLaps |  | Up to day 98 | 
| Changes from baseline in serum concentration of bone specific alkaline phosphatase |  | Up to day 98 | 
| Changes from baseline in serum concentration of cholesterol |  | Up to day 98 | 
| Changes from baseline in serum concentration of high density lipoproteins |  | Up to day 98 | 
| Changes from baseline in serum concentration of low density lipoproteins |  | Up to day 98 | 
| Changes from baseline in serum concentration of triglycerides |  | Up to day 98 | 
| Changes from baseline in serum concentration of glucose |  | Up to day 98 | 
| Changes from baseline in maturity index of the vaginal epithelium |  | Baseline, day 84 | 
| Assessment of global efficacy evaluated by patient and investigator on a 4-point rating scale |  | At day 98 | 
| Changes from baseline in thickness of endometrium | measured in millimeters, assessed by transvaginal ultrasonography | Baseline, day 84 | 
| Diary information regarding frequency, duration and intensity of vaginal bleeding on treatment |  | Up to day 105 | 
| Changes from baseline for mammography/ ultrasonography assessment of the breasts |  | Baseline, day 98 | 
| Changes from baseline in vital signs (blood pressure, heart rate) |  | Baseline up to day 98 | 
| Number of patients with adverse events |  | Up to day 105 | 
| Changes from baseline in clinical laboratory including coagulation parameters |  | Baseline, day 56, day 98 | 
| Assessment for incidence of withdrawal bleeding upon peroral gestagen administration |  | At day 105 | 
| Assessment of global tolerability evaluated by patient and investigator (4-point rating scale) |  | At day 98 | 
| Change in scores of major climacteric complaints (MRS items 1, 4, 9, 10) |  | baseline, week 12 | 
| Change in scores of somatic complaints (MRS items 1, 2, 8, 9, 10) |  | baseline, week 12 | 
| Changes from baseline in body weight |  | Baseline up to day 98 |