| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| women suffering from primary dysmenorrhea |
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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 evaluate efficacy and safety of the combined oral contraceptive [COC] SH T00186D (0.02 mg ethinylestradiol [EE]; 3 mg drospirenone [DRSP]) applied in a conventional and an extended flexible regimen in the treatment of moderate to severe primary dysmenorrhea
Primary efficacy variables:
• Number of days with dysmenorrheic pain over 140 days of treatment
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| E.2.2 | Secondary objectives of the trial |
Secondary efficacy variables:
• Number of days with at least moderate dysmenorrheic pain over 140 days of treatment
• Number of days with pelvic pain (independent of occurrence of vaginal bleeding) over 140 days of treatment
• Number of days with dysmenorrheic pain associated with withdrawal bleedings over 140 days of treatment
• Number of days with dysmenorrheic pain associated with unscheduled bleedings over 140 days of treatment
• Use of rescue medication (standardized intake of ibuprofen)
• Interference with daily activity
• Bleeding patterns
• Investigator assessment of total improvement of primary dysmenorrhea by Clinical Global Impression (CGI) scale
• Subjective assessment of treatment by the patient
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Medical history of moderate to severe primary dysmenorrhea (i.e., moderate to severe menstruation-related pelvic pain in at least 4 out of 6 preceding cycles)
2. Prospective self-rated sum pain score of 8 over the 2 baseline cycles
3. Age between 18 and 40 years (inclusive) with smoking habits regulated as follows
- Between 18 and 30 years of age, daily cigarette consumption not above 10
- Above 30 years of age, no smoking
4. Non-suspicious cervical smear taken at Visit 1 or within the last 3 months before Visit 1
5. Signed and dated informed consent.
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| E.4 | Principal exclusion criteria |
1. Current signs or history of any forms of secondary dysmenorrhea (e.g., due to underlying endometriosis, fibroids, adenomyosis of the uterus, hematometra)
2. Any concomitant disease or condition that requires any intake of analgesic medication
3. Occurrence of less than six menstrual cycles before Visit 1 following delivery, abortion, or lactation
4. Known hypersensitivity to any ingredient of the study drug and/or rescue medication (see Section 5.1)
5. Any known diseases or conditions that compromise the function of the body systems and could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the study medication
6. Any known severe systemic disease that might interfere with the conduct of the study or the interpretation of the results
7. Known uncontrolled thyroid disorders
8. Clinically significant depression (current or in the last year)
9. Any known abnormal clinically significant findings which, according to the assessment of the investigator, may worsen under hormonal treatment
10. Laboratory values outside inclusion range at Screening
11. Participation in another clinical study or administration of an investigational drug within 1 month prior to study entry (Visit 1) (or 6 months in case of long-acting progestins)
12. Surgeries scheduled in the study period
13. Known liver diseases:
Previous, acute and chronic progressive liver diseases, e.g., disturbances of bilirubin excretion in the bile (Dubin-Johnson and Rotor syndromes), disturbances of bile secretion, disturbances of bile flow (cholestasis, also a history thereof), idiopathic icterus or pruritus during a former pregnancy or estrogen-progestin treatment
Between the subsidence of a viral hepatitis (normalization of liver parameters) and the beginning of the study there must be an interval of at least 6 months.
Previous or current liver tumors
14. Known vascular diseases:
Existing or previous venous thromboembolic diseases (deep vein thrombosis, pulmonary embolism), existing or previous arterial thromboembolic diseases (myocardial infarction, stroke), as well as any condition increasing the disposition to any of the above, e.g., coagulation disorders with tendency to blood clot formation, hereditary anti-thrombin III deficiency, protein-C and/or protein-S deficiency, any venous thromboembolic event occurred in a sibling or a parent at an early age ( 50 years), valvular heart disease, atrial fibrillation, cardiac dysfunction (NYHA I-IV) , strong predisposition to varicose veins, previous phlebitis.
Uncontrolled arterial hypertension (confirmed systolic blood pressure > 140 mmHg and/or confirmed diastolic blood pressure > 90 mmHg).
Known diabetes mellitus, impaired glucose tolerance
Known disturbances of lipid metabolism
15. Known sickle-cell anemia
16. Known or suspected malignant or premalignant disease, in particular steroid-hormone dependent malignant or premalignant diseases (e.g., endometrial cancer, ovarian cancer, breast cancer), also a history thereof
17. Known other diseases:
Pemphigoid gestationis during a previous pregnancy, middle-ear deafness (otosclerosis), endometrial hyperplasia, migraine with neurological symptoms (complicated migraine), genital bleeding of unknown origin, manifest kidney disease with impaired renal function, porphyria, past or current uterus myomatosus, worsening of chronic bowel disease (Crohn’s disease or ulcerative colitis) under hormonal treatment
18. Known alcohol, drug, or medicine abuse (e.g., laxatives)
19. Prohibited concomitant medication:
Additional sex steroids (excluding topical use of Progestogel®), anticoagulants (e.g., heparin, coumarin); antiepileptics (hydantoin derivatives [e.g., phenytoin] or carboxamide derivatives [e.g., carbamazepine, oxcarbamazepine], other antiepileptics [e.g., felbamate, topiramate]); hypnotics and sedatives (e.g., barbiturate derivatives, primidone); tuberculostatics (e.g., rifampicin); oral antimycotics (except for a so-called single shot treatment)(e.g., griseofulvin, ketoconazole, itraconazole, fluoconazole); virostatic agents (except for topical use) (e.g., ritonavir); phenylbutazone; products containing St. John’s wort (Hypericum perforatum); and consecutive systemic use of antibiotics for >10 days
20. Sex hormones prior to start of treatment:
Oral, transdermal or intravaginal administration within 3 cycles prior to start of treatment
Use of hormone implants within 1 month prior to Visit 1
Use of intrauterine devices (IUDs) with or without hormone release within 1 month prior to Visit 1
Use of long-acting progestins within 6 months prior to Visit 1
21. Considerable overweight (body mass index [BMI] > 30)
22. Requirement of special surveillance due to the following risk factors: Epilepsy, asthma, multiple sclerosis, chorea minor, tetany
23. Patient is a dependent person, e.g., a relative, family member, or member of the investigator’s staff
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy variables:
• Number of days with dysmenorrheic pain over 140 days of treatment
It is assumed, that the primary variable is equally distributed in both treatment groups with an at least approximately normal distribution.
Let µt denote the mean number of days with dysmenorrheic pain during 140 days of treatment with an extended flexible regimen of SH T 00186 D, and µp denote the mean number of days with dysmenorrheic pain with the conventional regimen (24 + 4 days) of SH T00186D.For the primary target variable, the hypothesis
H0: | µt - µp | = 0
will be tested against the alternative hypothesis
H1: | µt - µp | > 0 at a 2-sided level of significance of alpha = 0.05.
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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 | No |
| 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 | No |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 35 |
| E.8.5 | The trial involves multiple Member States | No |
| 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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| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
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