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

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

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

Study Overview

• Status: Completed
• Conditions: Menopause
• Intervention / Treatment: Drug: Placebo; Drug: Low dose of Klimadynon®; Drug: Medium dose of Klimadynon®; Drug: High dose of Klimadynon®; Drug: Oestrofeminal®

• Study Type: Interventional
• Enrollment (Actual): 161
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: November 1, 1998
• Primary Completion (Actual): September 1, 2000

Study Registration Dates

• First Submitted: July 8, 2014
• First Submitted That Met QC Criteria: July 8, 2014
• First Posted (Estimate): July 9, 2014

Study Record Updates

• Last Update Posted (Estimate): July 14, 2014
• Last Update Submitted That Met QC Criteria: July 11, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Estrogens, Conjugated (USP)
• Other Study ID Numbers: 563.1