| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hormone withdrawal associated symptoms of headache and pelvic pain suffered by patients receiving LNG containing oral contraception. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10030970 |
| E.1.2 | Term | Oral contraception |
|
| 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 show superiority to Microgynon with regard to changes in frequency and intensity of the hormone withdrawal associated symptoms headache and pelvic pain on cycle days 22-28 from baseline to cycle 6 in approximately 880 women. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to show superiority to Microgynon with regard to
• rescue medication consumption, baseline to cycle 6
• frequency and intensity of other hormone-related symptoms (bloating or swelling, breast tenderness, and nausea or vomiting) during cycle days 22 to 28, baseline to cycle 6
• prevalence of individual hormone-related symptoms during cycle days 1 to 21, baseline to cycle 6
• prevalence of individual hormone-related symptoms during hormone-free interval, i.e. cycle days 27+28 for EV/DNG capsules and cycle days 22 to 28 for the comparator
• change in VAS of the hormone withdrawal associated symptoms pelvic pain or headache during cycle days 22 to 28 from baseline to cycle 3
• bleeding pattern and cycle control
• QoL Questionnaires: Psychological General Well-Being Index (PGWBI), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and Clinical Global Index (CGI). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated informed consent
2. Age between 18 and 50 years (inclusive) at visit 1, for smokers up to 30 years (inclusive)
3. Otherwise healthy female subjects requesting contraception and currently using a LNG containing OC in a 21-day regimen for at least 3 cycles before visit 1 and suffering from at least moderate pelvic pain, headache or both defined by an average value of ≥ 35 mm on a VAS during cycle days 22-28.
4. Normal or clinically insignificant cervical smear not requiring further follow-up (a cervical smear has to be taken at the screening visit or a normal result has to be documented that was obtained within the last 6 months before screening)
5. Able to tolerate ibuprofen and willing to use only ibuprofen supplied for the study. |
|
| E.4 | Principal exclusion criteria |
1. Pregnancy or lactation (delivery, abortion, or lactation within less than three cycles before the start of treatment)
2. Body mass index (BMI) > 32 kg/m2
3. Hypersensitivity to any of the study drug ingredients
4. Any diseases or conditions that can compromise the function of the body systems and could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the study medication (such as but not limited to duodenal ulcers, gastritis, gastrectomy or gastric resection surgery, or renal compromise)
5. Any diseases or conditions that might interfere with the conduct of the study or the interpretation of the results
6. Any disease or condition that may worsen under hormonal treatment such as:
Cardiovascular
• presence or a history of venous or arterial thrombotic / thromboembolic events (e.g. deep venous thrombosis, pulmonary embolism, myocardial infarction) or of a cerebrovascular accident, including prodromi (e.g. transient ischemic attack, angina pectoris) and conditions which could increase the risk of suffering from any of the above mentioned disorders, e.g. a family history indicating a hereditary predisposition
• repeated measurements of systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg
Liver
• presence or history of liver tumors (benign or malignant)
• presence or history of severe hepatic disease as long as liver function values have not returned to normal
• jaundice and / or pruritus related to cholestasis (Gilbert’s syndrome excepted)
• history of cholestatic jaundice associated with pregnancy or previous COC use
Metabolic diseases
• uncontrolled diabetes mellitus and/or diabetes mellitus with vascular involvement
• severe dyslipoproteinemia
Other diseases
• malignant or premalignant disease
• uncontrolled thyroid disorder
• chronic inflammatory bowel disease
• severe renal insufficiency or acute renal failure
• hemolytic uremic syndrome
• sickle cell anemia
• porphyria
• history of hypertriglyceridemia-associated pancreatitis
• systemic lupus erythematosus, pemphigoid gestationis during a previous pregnancy
• Sydenham chorea
• history of herpes gestationis
• otosclerosis-related hearing loss
• history of migraine with focal neurologic symptoms
• epilepsy
• clinically significant depression
• hereditary angioedema
7. Undiagnosed abnormal genital bleeding
8. Abuse of alcohol, drugs, or medicines (e.g. laxatives)
9. Other contraceptive methods:
• sterilization
• oral, vaginal or transdermal hormonal contraception during treatment
• intra-uterine devices (IUD) with or without hormone release still in place within 30 days of visit 1
• implants/depots still in place within 30 days of visit 1
• long acting preparations (e.g. depot medroxyprogesterone acetate, monthly contraceptive injection) within a period of three times of the injection interval before start of treatment.
10. Any medication that could result in excessive accumulation, impaired metabolism, or altered excretion of the study drug or interfere with the conduct of the study or the interpretation of the results such as:
• products containing St. John’s wort (Hypericum perforatum) within 28 days before start of treatment
• antibiotics within nine days before start of treatment
• anticoagulants (e.g. heparin, coumarin) within 28 days before start of treatment
• antiepileptics (hydantoin derivatives [e.g. phenytoin] or carboxamide derivatives [e.g. carbamazepine, oxcarbamazepine], others [e.g. felbamate, topiramate, keppra, zonisamide]) within 28 days before start of treatment
• hypnotics and sedatives (e.g. barbiturate derivatives, primidone) within 28 days before start of treatment
• tuberculostatics (e.g. rifampicin) within 28 days before start of treatment
• oral antimycotics (e.g. griseofulvin, ketoconazole, itraconazole, fluoconazole) within 28 days before start of treatment (no wash-out period necessary for single shot treatment)
• virostatic agents (except for topical use, e.g. ritonavir) within 28 days before start of treatment
• phenylbutazone within 28 days before start of treatment
• additional sex steroids and other drugs impairing ovarian function within 28 days before start of treatment (for exceptions, long acting drugs and contraceptives refer to exclusion criterion 10)
- Gonadotropin releasing hormone (GnRH) analog 3 months depot within 6 months before start of treatment
- GnRH analog 1 month depot within 3 months before start of treatment
11. Simultaneous participation in another clinical trial or participation in another clinical trial prior to study entry that might have an impact on the study objectives at the discretion of the investigator
12. Major surgery scheduled for the study period
13. Inability to cooperate with the study procedures for any reason, including the following examples: language comprehension, psychiatric illness, inability to get to the study site.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable is the individual change of pelvic pain (stratum 1) or the individual change of headache (stratum 2) as determined by the change of VAS during cycle days 22 to 28 from baseline to cycle 6. |
|
| 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 | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| 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) | 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 | 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 | No |
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 | 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
|
| The end of study is defined as the last visit of the last subject. |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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