| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| moderate to severe vasomotor symptoms associated with the menopause |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020411 |
|
| 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 demonstrate superior efficacy in at least one of the four doses of Org 50081 as compared to placebo on the four following co-primary endpoints:
1) the mean change from baseline in average daily frequency of moderate to severe vasomotor symptoms at Week 4;
2) the mean change from baseline in average daily frequency of moderate to severe vasomotor symptoms at Week 12;
3) the mean change from baseline in average daily severity of moderate and severe vasomotor symptoms at Week 4;
4) the mean change from baseline in average daily severity of moderate and severe vasomotor symptoms at Week 12. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of four different doses of Org 50081 compared to placebo on:
• the mean change from baseline in average daily frequency, severity and composite score of vasomotor symptoms for each of the 12 weeks of treatment (both including and excluding mild vasomotor symptoms);
• the percentage of responders and the percentage of remitters during each of the 12 weeks of treatment;
• health status assessment as measured by the Women’s Health Questionnaire
during 12 weeks of treatment;
• safety as measured by routine laboratory parameters, vital signs and (serious) adverse events during 12 weeks of treatment. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. postmenopausal women, defined as:
• 12 months of spontaneous amenorrhea; OR
• 6 months of spontaneous amenorrhea with serum FSH levels>40 mIU/mL; OR
• 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
In case the menopausal status of a subject is unclear because of a hysterectomy,
the serum FSH level must be >40 mIU/mL. If the date of the last menstruation is
not clear because of perimenopausal hormone use, then the subject must have a
serum FSH level >40 mIU/mL after completion of a washout period (see exclusion
criteria below).
2. age ≥ 40 and ≤ 65 years;
3. body mass index (BMI) ≥ 18 and ≤ 32 kg/m2;
4. minimum of 7 moderate to severe hot flushes per day or 50 per week, as
quantified from daily diary recordings during at least 7 days preceding
randomization to trial medication;
5. able to handle the electronic diary device after training and having at least 80%
compliance on complete daily diary entries during the period prior to randomization;
6. give voluntary written informed consent after the scope and nature of the
investigation have been explained, before screening evaluations. |
|
| E.4 | Principal exclusion criteria |
7. history or presence of any malignancy, except non-melanoma skin cancers;
8. any clinically unstable or uncontrolled renal, hepatic, endocrine, respiratory,
hematological, neurological, cardiovascular or cerebro-vascular disease that
would put the subject at safety risk or mask measure of efficacy;
9. history of seizures or epilepsy;
10. history or presence of clinically significant depression or other psychiatric
disorder which, in the opinion of the investigator, might compromise or confound
the subject’s participation in the trial;
11. abnormal, clinically relevant vaginal bleeding;
12. any clinically relevant (opinion of investigator) abnormal finding during physical,
gynecological and breast examination at screening;
13. abnormal, clinically relevant results of mammography. Mammography must have
been performed within the last 9 months prior to screening, otherwise it must be
done before inclusion into the trial. For non-US sites, if local laws or guidelines
do not allow or advise such frequent mammograms, the documented local laws
or guidelines should be followed;
14. abnormal cervical smear test results (corresponding to Pap III and higher,
including LSIL, HSIL, CIN 1 and higher). A cervical smear must have been performed within the last 9 months prior to screening, otherwise it must be done
before inclusion into the trial;
15. hematological or biochemical values at screening outside the reference ranges
considered clinically relevant in the opinion of the investigator;
16. high blood pressure (sitting systolic BP > 170 mmHg and/or diastolic BP > 100
mmHg);
17. use of any drug product containing estrogens, progestins, androgens or tibolone
prior to screening (and up to and including randomization) within:
• 1 week for prior vaginal hormonal products (rings, creams, gels)
• 4 weeks for prior transdermal products
• 8 weeks for prior oral products
• 8 weeks for intrauterine therapy
• 6 months for prior implant, pellet or injectable drug product;
18. any of the following treatments within the last 4 weeks prior to screening (and up to and including randomization):
• tricyclic antidepressants, SNRIs, SSRIs, MAO-inhibitors, mirtazapine
• antianxiety drugs, antipsychotics
• coumarin-derivatives
• α-adrenergic agents (e.g. clonidine, methyldopa)
• β-blockers (e.g., propranolol)
• dopamine agonists/antagonists (e.g., veralipride, bromocriptine, domperidone)
• opiates, barbiturates
• raloxifene
• homeopathic menopausal preparations or other preparations intended to treat
climacteric or CNS symptoms (e.g. Black Cohosh, St. John’s Wort, isoflavone
supplements)
• hepatic microsomal enzyme-inducing drugs or drugs known to affect or
interfere with the pharmacokinetics of mirtazapine;
19. any condition or disease that could affect or interfere with the pharmacokinetics
of mirtazapine;
20. subjects sensitive to trial medication or its components;
21. use of any investigational drug and/or participation in another clinical trial within
the last 8 weeks prior to screening;
22. history of alcohol and/or drug abuse within the last two years prior to screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) the mean change from baseline in average daily frequency of moderate to severe vasomotor symptoms at Week 4;
2) the mean change from baseline in average daily frequency of moderate to severe vasomotor symptoms at Week 12;
3) the mean change from baseline in average daily severity of moderate and severe vasomotor symptoms at Week 4;
4) the mean change from baseline in average daily severity of moderate and severe vasomotor symptoms at Week 12. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | Yes |
| 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) | Yes |
| 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) | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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