E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Vasomotor symptoms (hot flushes) |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the influence of a 8-weeks multiple dose treatment with two oral doses of ZK 283197 in comparison to E2 and placebo on the reduction of moderate to severe hot flushes |
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E.2.2 | Secondary objectives of the trial |
Safety and tolerability, Pharmacodynamics incl. vaginal cytology, endometrial thickness, endometrial histology and exploratory mRNA expression profiling of endometrial biopsies and blood cells, Pharmacokinetics, Exposure - response relationship
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Women with at least 35 moderate to severe hot flushes in seven consecutive days during the 2-week run-in phase •Age: 45 – 65 years (inclusive) •Body mass index (BMI) : 20 - 30 kg/m² (inclusive) •Signed informed consent prior to study participation •Postmenopausal status, revealed by last spontaneous bleeding at least 12 months prior to enrollment or 6 months spontaneous amenorrhea with serum FSH levels 40 mIU/ml or bilateral oophorectomy (without hysterectomy) at least six weeks prior to enrollment
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E.4 | Principal exclusion criteria |
Medical and surgical history •Incompletely cured pre-existing diseases for which it can be assumed that the absorption, distribution, metabolism, excretion and effect of the study drugs will not be normal •Previous diagnosis of cancer of any type as well as benign tumors of the liver and pituitary, including after treatment or suspicion thereof •Known or suspected liver disorders •History of thrombophlebitis, venous / arterial thromboembolic diseases (particularly deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, cerebrovascular accident, ischemic heart disease) •Other conditions that increase susceptibility to thromboembolic diseases (e.g. known disturbance of the coagulation system, thromboembolic diseases in close relatives at young age) •Migraine accompanied by disturbances in sensory perception and / or locomotion (migraine accompagnée) •Diabetes mellitus with vascular involvement •Severe hypertriglyceridemia •Known sensitivity to the study drugs or components of the preparations •Abnormal, clinically significant findings which, according to the assessment of the investigator, may worsen under hormonal treatment
Medication and drug use •Hormonal therapy (estrogen mono-therapy or combined hormone therapy, i.e. including progestin, oral, transdermal) or intrauterine hormone releasing device within 4 weeks prior to study entry or any long-acting injectable or implant up to 6 months before study entry, or any other therapy of menopausal symptoms, e.g. plant-based products within 4 weeks prior to study entry •Intake of an investigational compound within 8 weeks before study screening •Concomitant repeated medication with drugs which could affect the study aim under consideration of their elimination and/or the duration of their influencing effects on the study drug: Drugs which might affect absorption (e.g. laxatives, loperamide, metoclopramide, antacids, H2-receptor antagonists) Anticoagulants (e.g. heparin, coumarin) Antiepileptics (hydantoin derivates e.g. phenytoin, or carboxamid derivates e.g. carbamazepin, oxcarbamazepin, other antiepileptics e.g. Felbamat, Topiramate) Hypnotica and sedativa (barbiturate derivates e.g. phenobarbital, primidone) Tuberculostatics (e.g. rifampicin) Oral antimycotics (e.g. griseofulvin, ketoconazol, itraconazol, fluoconazol) Virostatic agents (systemic, e.g. oral, or genital administration, e.g. ritonavir) Selective estrogen receptor modulators (e.g. raloxifene, tamoxifen) Products containing St. John’s wort, grapefruit juice Continuous systemic use of antibiotics for >14 days Corticosteroids (systemic, e.g. oral, or genital administration) •Suspicion of drug or alcohol abuse (within the last 2 years)
Special behavioral patterns •Smoking (former smokers who have stopped smoking at least 3 months before study drug administration may be included)
Electrocardiogram (ECG), blood pressure, heart rate •Clinically relevant ECG findings •Systolic blood pressure > 160 mmHg (after at least 3 min in supine position) •Diastolic blood pressure > 95 mmHg (after at least 3 min in supine position) •Heart rate < 45 or > 100 beats/min (after at least 3 min in supine position)
Physical examination •Clinically relevant findings in the physical examination (e.g. pronounced varicosis, thrombophlebitis, evidence of peripheral circulatory disturbances)
Mammography •Suspicious structures in mammography (to be performed within the last 9 months before screening) that may indicate a malignant tumor
Gynecological history and examination, •Clinically relevant findings in the gynecological examination, especially a cervical cytological smear classified higher than II according to Papanicolaou (grading scale I – V), •Known, suspected, or history of breast cancer •Clinically relevant changes of endometrium (diagnosed by transvaginal ultrasound) especially endometrial thickness 5 mm (double-layer) •Undiagnosed genital bleeding �Uterus myomatosus (excluding isolated intramural myoma) •Prior hysterectomy
Laboratory examination •Presence of hepatitis B virus surface antigen (HbsAg), hepatitis C virus antibodies (anti-HCV) or human immunodeficiency virus antibodies (anti-HIV) •Clinically relevant deviations of the screened laboratory parameters from reference ranges as outlined in section 8.5.4Standard laboratory parameters.
Other •Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the patient’s safety •Patient is in custody by order of an authority or a court of law •Exclusion periods from other studies or simultaneous participation in other clinical studies •Previous assignment to treatment in this study
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in frequency of moderate to severe hot flushes per week between baseline (at least 2 week run-in phase) and week 8 of the treatment phase
Standard safety laboratory parameters in blood/urine, vital signs (blood pressure/heart rate), electrocardiogram (ECG), adverse events, body weight, endometrial thickness, endometrial histology, vaginal cytology, bone resorption markers in blood, marker of hepatic estrogenicity in blood, bleeding pattern |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of study is defined as last patient data available |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 10 |