Oral contraceptives to prevent pregnancy and diminish premenstrual symptomatology

ES 2 561 491 T3

Oral contraceptives to prevent pregnancy

Description

BACKGROUND OF THE INVENTION

Field of the invention

This invention relates to oral contraceptives that prevent pregnancy.

Previous technique

The human menstrual cycle involves a repetitive sequence of hormonal changes that cause episodic uterine bleeding. Normally, each menstrual cycle has an average interval of 21 to 35 days, conventionally starting with the first day of menstrual flow and ending the day before the next onset of bleeding. The duration of menstrual flow is usually 2 to 6 days with loss of 20 to 60 ml of blood.

The menstrual cycle is divided into follicular and luteal phases, each corresponding to changes that take place in the ovary. These phases can also be described as proliferative or secretory, and correspond to changes observed in the uterine endometrium. Variations in cycle duration are normally due to alterations in the follicular phase, because the duration of the luteal phase remains relatively constant at 12 to 16 days.

During the follicular phase, several primary follicles are recruited for further growth and development. The granule cells of the primary follicles contain follicle-stimulating hormone (FSH) and estradiol receptors. After stimulation of FSH, the granulosa cells produce aromatase. This enzyme converts the androgens androstenedione and testosterone, produced in response to luteinizing hormone (LH) by thecal cells, into estrone and estradiol, respectively. Granule cells respond to estradiol by undergoing mitosis to increase granule cell number and estradiol production. On day 7 of the cycle, an elongated primary follicle is selected by unknown processes to be the follicle that will release the oocyte at ovulation.

The increase in plasma estradiol in the middle of the cycle stimulates the large rapid secretion of LH in the middle of the cycle. This rapid secretion of LH in the middle of the cycle causes the resumption of meiosis within the oocyte and the luteinization of the granule cells within the preovulatory follicle. Immediately before ovulation, the outer follicular wall begins to dissolve and an oocyte is released approximately 24 to 36 hours from the start of rapid LH secretion.

After ovulation, the granulosa cells and the surrounding thecal cells enlarge, accumulate lipids, and transform into luteal cells. This begins the luteal phase of the menstrual cycle. These cells form a new vascularized structure called the corpus luteum, which secretes estradiol and progesterone. LH maintains the corpus luteum during the luteal phase and, acting through the adenyl cyclase system, stimulates progesterone production. If pregnancy does not take place, the luteal cells degenerate, and a decrease in hormone secretion precedes menstruation. Menstruation is immediately followed by the beginning of another menstrual cycle.

Because endometrial proliferation serves to prepare the uterus for impending pregnancy, manipulation of hormones and the uterine environment can provide contraception. For example, estrogens are known to reduce FSH secretion through feedback inhibition. In certain circumstances, estrogens can also inhibit LH secretion, again once again by negative feedback. Under normal circumstances, the rush of circulating estrogen found just before ovulation induces the rapid secretion of gonadotropic hormones that takes place just before ovulation and leads to ovulation. High doses of estrogen immediately after intercourse can also prevent conception, probably due to interference with implantation.

Progestins can also provide contraception. Endogenous progesterone after estrogen is responsible for progestational changes in the endometrium and cyclical changes of cells and tissues in the cervix and vagina. Progestin administration makes the cervical mucus thick, firm, and cellular, which is believed to impede sperm transport. Progestin administration also inhibits LH secretion and blocks ovulation in humans.

The most common form of oral contraception is a pill that combines both an estrogen and a progestin, a preparation also called a combined oral contraceptive preparation. Alternatively, there are contraceptive preparations that comprise only progestin. However, progestin-only preparations have a more varied spectrum of side effects than combination preparations,

ES 2 561 491 T3 especially more breakthrough bleeding. As a result, combination preparations are the preferred oral contraceptives used today (Sheth et al., Contraception 25: 243 (1982)).

US5858405, W098 / 04267, W098 / 04266

When establishing an estrogen-progestin regimen for oral contraceptives, two main issues must be considered. First, efficacy must be maintained and second, further deterioration in endometrial bleeding control must be avoided. In general, commercially available oral contraceptive products even at the lowest dose have shown efficacy but overall cases of bleeding control problems have increased when doses were reduced, as manifested in both breakthrough bleeding (premature discharge or spotting) ) as in deprivation amenorrhea during the “pill-free” week (expected menstruation).

During the luteal phase of the menstrual cycle, as many as 75% of women with regular menstrual cycles experience some symptoms of premenstrual syndrome (PMS), a recurring cyclical disorder, involving behavioral, emotional, social and physical symptoms (Steiner et al. al., Annu. Rev. Med. 48: 447-455 (1997)). Behavioral, emotional, and social symptoms include, but are not limited to, irritability, mood swings, depression, hostility, and social withdrawal. Physical symptoms include, but are not limited to, swelling, tenderness of the breasts, myalgia, migraines or headaches, and fatigue. True PMS only appears during the luteal phase of the menstrual cycle, with a symptom-free period during the follicular phase. The etiology of PMS is still unknown.

A subset of women with PMS, approximately 2-9%, have symptoms that are primarily related to a severe mood disorder. In these women, the diagnosis of premenstrual dysphoric disorder (PMDD) can be applied, which is defined in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). According to DSM-IV, a woman with PMDD must have at least five premenstrual symptoms during the luteal phase, with at least one of the symptoms being an emotional or "core" symptom. The core symptoms should be irritability, anger, mood swings, tension, or depression (and interfere with daily activities), and should be confirmed by prospective daily evaluation for at least two cycles. Three to five percent of women with PMS report that they have PMDD.

There is also a subgroup of women who experience severe PMS, representing approximately 20% of the population with PMS. These women experience severe emotional symptoms that do not meet the strict criteria for PMDD as defined in DSM-IV but require medical attention.

Symptoms of PMDD can begin at any age after menarche, but the mean age of onset appears to be around 26 years and several researchers have found that symptoms, such as estrogen deprivation symptoms, associated with the premenstrual phase are they gradually get worse, and perhaps get longer, over time. It has been suggested that the worsening could occur due to recurrent increases and decreases in hormones from the ovaries. This is supported by data from other cultures: when menstruation is infrequent, premenstrual symptoms are rare. It is also supported by data that associate the low number of deliveries with the risk of PMDD. The low number of deliveries produces a greater number of hormonal cycles, and therefore, a woman has greater exposure to and deprivation of massive amounts of progesterone. Additionally, several studies have found lower rates of PMS among oral contraceptive users, again suggesting that shorter exposure to endogenous progesterone peaks and valleys is protective against PMDD (Yonkers, K., J. Clin. Psychiatry 58 (Suppl. 14): 4-13 (1997)).

Suppression of ovulation has been an important basis for the use of hormonal treatments for PMS. One method to inhibit ovulation is to use oral contraceptives (OC). Combination oral contraceptives inhibit ovulation by suppressing gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). To date, only two controlled studies of treating PMS with oral contraceptives have been published. The results indicate that combination oral contraceptives effectively reduce physical symptoms (especially breast pain and swelling), but the answer on the relief of psychological symptoms has been less clear.

Therapeutic interventions for women who meet the criteria for PMDD include selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and anxiolytics, as well as the antidepressant alprazolam (XANAX®). These interventions have been shown to be effective with minimal side effects. Recent research on selective serotonin reuptake inhibitors has also shown them to be successful at low doses.

Antidepressants that are active at serotonin receptors include clomipramine (ANAFRANIL®), fluoxetine (PROZAC®), paroxetine (PAXIL®), sertraline (ZOLOFT®), nefazodone (SERZONE®), fenfluramine (PONDIMIN®), and venlafaxine (EFFEXOR®) ®).

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The only product currently approved for the treatment of premenstrual dysphoric disorder (PMDD) is SSRI fluoxetine hydrochloride (SARAFEM®). The efficacy of fluoxetine for the treatment of PMDD was established in four randomized, placebo-controlled trials. Fluoxetine at a daily dose of 20 mg or 60 mg was shown to be superior to placebo in reducing symptoms (Steiner et al., New Engl. J. Med. 332: 1529-34 (1995)). However, the combination of an oral contraceptive and fluoxetine was not examined, as women taking oral contraceptives were excluded from the trial.

The object of the present invention is the provision of estrogen-progestin combinations and / or regimens for oral contraceptive use. The proposed 28-day regimen will allow women the option of maintaining the usual 13 menstrual cycles per year.

BRIEF COMPENDIUM OF THE INVENTION

This invention relates to female oral contraceptives that will prevent pregnancy. Furthermore, this invention relates to a method of preventing pregnancy by preventing the total withdrawal of estrogen at the end of the treatment period or between treatment periods, by administering of oral contraceptives. Prementrual symptoms are rare when menstruation is infrequent. What's more, oral contraceptive users have a lower frequency of premenstrual symptoms, suggesting that shorter exposure to the peaks and troughs of endogenous progesterone protects against PMDD. More particularly, the invention relates to a method of preventing pregnancy by administering an oral contraceptive regimen.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to oral contraceptives that will prevent pregnancy. Methods of using these oral contraceptives to prevent pregnancy are also provided. More particularly, these methods involve the administration of an oral contraceptive regimen. It is noteworthy that this regimen does not contain pill- or placebo-free intervals.

This is the so-called twenty-eight-day regimen, which allows women to have the option of maintaining 13 menstrual cycles a year. According to the present invention, a woman in need of contraception will receive a kind of combined dose of estrogen and progestin, preferably monophasically, for 21 to 26 consecutive days, preferably for 3 to 7 days, more preferably for 2-7 days, in the which the daily amounts of estrogen and progestin will be equivalent to 5-50 pg of ethynyl stadiol and 0.025 to 10 mg, preferably 0.05 to 1.5 mg, of levonorgestrel, respectively.

In a preferred embodiment, women are administered on days 1 to 21 of the menstrual cycle, an oral contraceptive containing 150 pg of levonorgestrel and 30 pg of ethinyl estradiol, followed on days 22-28 of the cycle, by a dosage form containing 30 pg of ethinyl estradiol. A typical administration schedule is illustrated in Table 1. Therefore, in a 28-day regimen schedule, there are approximately 13 treatment cycles and menstrual cycles per year.

Table 1. Administration schedule for a 28-day regimen

<td>Days</td><td>Hormone</td><td>Antidepressant</td>

<td> 1-21</td><td>150 pg levonorgestrel and 30 pg ethinyl estradiol</td><td>None</td>

<td> 22-28</td><td>30 pg ethinyl estradiol</td><td>None</td>

The estrogens that can be employed as a component in the regimens of this invention can be any of those conventionally available. Typically, estrogen can be selected from the group comprising natural and synthetic estrogens, including steroidal and non-steroidal estrogens. Synthetic estrogens can be selected, for example, from ethinyl estradiol, ethinodiol diacetate, mestranol, and quinestranol. Of particular interest are 17α-ethinyl estradiol and its esters and ethers. The preferred estrogen is 17α-ethinyl estradiol. Natural estrogens can include, for example, conjugated equine estrogens, esterified estrogens, 17βestradiol, estradiol valerate, estrone, piperazine-estrone sulfate, estriol, estriol succinate, and polyestrol phosphate.

The progestin component can be any progestationally active compound. Thus, progestin can be selected from progesterone and its derivatives such as, for example, 17-hydroxyprogesterone esters, 19-nor-17-hydroxy-progesterone esters, 17a-ethynyltestosterone and its derivatives, 17a-ethynyl-19 -nortestosterone and its derivatives, norethindrone, norethindrone acetate, ethinodiol diacetate, dydrogesterone, medroxy-progesterone acetate, norethindrel, allylstrenol, linoestrenol, fuingestanol acetate, medrogestone, norgestrienone, dimethiderome, ethisterone, cyproterone acetate, levonorgestrel, dl-norgestrel, d-17aacetoxy-13e-ethyl-17a-ethynyl-gon-4-en-3-one oxime, cyproterone acetate, gestiondene, desogestrel, and norgestimate. The

ES 2 561 491 T3 preferred progestin is levonorgestrel.

The weight ratio of the active ingredients, eg, ethinyl estradiol and levonorgestrel, is at least 1:45 and preferably at least 1:50. The preferable amount of ethinyl estradiol is about 10-50 pg and the preferable amount of levonorgestrel is about 0.15-1.5 mg. Other estrogens differ in the potency of ethinyl estradiol. For example, 30 pg of ethinyl estradiol is roughly equivalent to 60 pg of mestranol or 2 g of 17e-estradiol. Also, other progestins differ in the potency of levonorgestrel. Therefore, 1 mg of levonorgestrel is approximately equivalent to approximately 3.5 mg of norethindrone acetate, or to 1 mg of desogestrel and 3-ketodesogestrel, or to approximately 0.7 mg of gestiondene. The values ​​given above are for ethinyl estradiol and levonorgestrel and if a different estrogen or progestin is used, an adjustment should be made in the amount based on relative potency. The potency correlations between the different estrogens and progestins are known. See for example European patent application No. 0 253 607.

The described regimen will prevent pregnancy.

Other usable estrogens include estradiol, estrone, and ethinyl estradiol esters such as acetate, sulfate, valerate, or benzoate, conjugated to equine estrogens, agnostic anti-estrogens, and selective estrogen receptor modulators. The formulations of the invention are administered orally, preferably in the form of tablets.

Pharmaceutical formulations or preparations containing the formulations of the invention and a pharmaceutically acceptable carrier can be solid dosage forms including tablets, dragees, capsules, wafers, pellets, pills, powders or granules.

It is known in the art that active ingredients can be contained in such formulations in addition to diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and similar, pharmaceutically acceptable. The means and methods for administration are known in the art and one of skill can turn to various drug references for guidance. For example, see "Modern Pharmaceutics", Banker &amp; Rhodes, Marcel Dekker, Inc. (1979); "Goodman &amp; Gilman's The Pharmaceutical Basis of Therapeutics", 6th Edition, MacMillan Publishing Co., New York (1980), or Remington's Pharmaceutical Sciences, Osol, A., ed., Mack Publishing Company, Easton, Pa. (1980).

Generally speaking, the formulations are prepared according to conventionally known procedures according to the method of administration. Therefore, the active ingredients are prepared according to known methods in a pharmaceutically acceptable form for administration. These ingredients, in their required amounts, are combined with appropriate pharmaceutical excipients such as additives, vehicles and / or flavor enhancing substances. These substances can be identified as diluents, binders and lubricants. Gums, starches, and sugars are also common terms. Typical of these types of substances or excipients are the pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, saccharin sodium, talc, cellulose, glucose, sucrose, magnesium carbonate and the like. The active ingredient (s) may comprise from about 0.01% by weight to about 99.99% by weight of the total formulation and the balance comprises the pharmaceutically acceptable excipient. The percentage of active ingredient (s) may vary according to the system or method of administration and is chosen according to conventional methods known in the art.

For the oral form of the formulation, the contraceptive preparations are preferably produced in the form of a kit or pack, with daily dosages ordered for appropriate sequential administration. Therefore, in another aspect, the present invention also provides a pharmaceutical package containing combination-type contraceptives in multiple unit doses in a fixed, synchronized sequence, wherein the sequence or ordering of the unit doses corresponds to the steps of daily administration.

For example, the pharmaceutical formulations may be provided in the form of a kit containing for the 28 day regimen at least about 18, and preferably at least about 21 tablets, and up to 26 tablets, intended to be ingested on successive days. Preferably administration is daily for at least 21 days using tablets containing both estrogen and progestin and then for at least 7 days using tablets containing only estrogen.

In order to further illustrate the present invention, specific examples are included below. It will be appreciated, however, that these examples are illustrative only and are not intended to limit the scope of the invention.

EXAMPLES

Example 1 Phase III, randomized, multicenter clinical trial to evaluate two continuous regimens of

ES 2 561 491 T3 oral contraceptives in women diagnosed with premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD)

Clinical and summary design

In a multicenter, randomized clinical trial, the efficacy and safety of three combination oral contraceptive regimens in preventing pregnancy in sexually active women, aged 18 to 40 years, are evaluated. Patients will be randomly assigned on a 1: 1: 1 basis to one of the following regimens:

· Levonorgestrel 150 pg / ethinyl estradiol (EE) 30 pg administered once daily for 84 days as a combination oral tablet followed by ethinylestradiol 30 pg administered once daily for 7 days (DP3-84 / 30);

· Levonorgestrel 150 pg / ethinyl estradiol 30 pg administered once daily for 84 days as a combination oral tablet followed by ethinyl estradiol 10 pg administered once daily for 7 days (DP3-84 / 10); or · Levonorgestrel 150 pg / ethinyl estradiol 30 pg administered once daily for 25 days as an oral combination tablet followed by ethinylestradiol 30 pg administered once daily for 3 days (DP3-25 / 30).

Patients randomly assigned to DP3-84 / 30 or DP3-84 / 10 receive 4 cycles of study drug. Patients randomized to DP3-25 / 30 receive 13 cycles of study drug. All patients receive approximately 1 year of therapy.

The study coordinator or designated staff enrolls the patient. Patients will be randomly assigned to one of the treatment regimens. The assignment of the treatment group will not be revealed to the patient before signing the informed consent.

All patients, regardless of randomization, will begin study oral contraceptive therapy on the first Sunday after the start of their menstrual period (“Sunday Beginners”) and will remain Sunday Beginners throughout the study. Each of the dose packs will be dispensed with a summary patient information sheet and a more detailed patient information leaflet (PPI).

All patients will complete and upload the information entered into an electronic diary. Evaluations will include adherence to study drug use, use of additional forms of contraception, characteristics of bleeding, weight, evaluation of frequency and severity of related menstrual symptoms, and medication taken to alleviate these symptoms. The information will be self-recorded in the electronic journal through a series of pre-programmed questions.

Two hundred (200) patients in each treatment regimen are chosen to complete the study. The pregnancy rate will be calculated using data from patients aged 18 to 35 years. Patients ages 36 to 40 will be enrolled as well.

Patient eligibility

Inclusion criteria

Patients must meet the following criteria to be included in the study:

1. Sexually active adult women (age 18 to 40 years), of potential fertility, in a heterosexual relationship, at risk of pregnancy, who are in good health and who have a history of oral contraceptive use during an interval of at least three successive cycles with regular withdrawal bleeding (bleeding during the pill-free interval or during the first three days of the subsequent cycle) prior to study enrollment (Continuous Users) or

Do not have a history of oral contraceptive use (New Participants) or

Have no history of oral contraceptive use in the 6 months prior to enrollment (Previous users)

two. Negative urine pregnancy test.

3. Signed informed consent.

Four. Agree to use the study's oral contraceptive therapy as your primary method of birth control (BCM).

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Exclusion criteria

Patients will be excluded from the study if any of the following criteria are met:

1. History of hypersensitivity to the estrogen or progestin components of oral contraceptives.

two. History of alcohol or drug abuse that, in the opinion of the investigator, renders the patient incapable of participation in the study.

3. Active smoker&gt; 34 years.

Four. Chronic use of any medication that may interfere with the effectiveness of oral contraceptives.

5. History of being HIV positive or Hepatitis C positive.

6. History of persistent non-compliance with any chronic medication.

7. History of having received injectable hormonal therapy (eg, Depo-Provera® (Pharmacia and Upjohn)) in the 10 months prior to enrollment or having had a progestin-releasing intrauterine device (IUD) in the past 3 months upon enrollment or who has had a contraceptive implant removed less than a month prior to enrollment or who has received any other form of hormonal contraception in the 3 months prior to enrollment.

8. Routine concomitant use of additional forms of contraception (IUD, diaphragm, contraceptive sponge) with the exception of condoms.

9. Patients who have recently had a surgical or medical abortion, miscarriage, or vaginal or cesarean delivery must have had at least two normal menstrual cycles prior to enrollment.

10. History of abnormal bleeding (breakthrough or withdrawal bleeding lasting&gt; 10 consecutive days or excessive spotting lasting&gt; 10 consecutive days) with conventional oral contraceptives.

eleven. History of thromboembolic disorder, vascular disease, cerebrovascular disease, or coronary artery disease.

12. Uncontrolled or untreated hypertension (systolic blood pressure&gt; 140 mm Hg and diastolic blood pressure&gt; 90 mm Hg on more than two occasions).

13. Known or suspected breast carcinoma, endometrial carcinoma, or known or suspected estrogen-dependent neoplasia.

14. Undiagnosed abnormal genital bleeding.

fifteen. History of liver adenomas or carcinomas.

16. History of cholestatic jaundice of pregnancy or jaundice with previous use of oral contraceptives.

17. Known or suspected pregnancy or simultaneous breastfeeding.

18. Hyperlipidemia requiring active treatment with antihyperlipidemic agents.

19. History of diabetes mellitus, glucose intolerance, or gestational diabetes.

twenty. History of abnormal results of clinical tests in the selection process.

twenty-one. Any clinically significant finding or abnormal condition in the history, screening, physical examination, pelvic examination, or any finding in clinical tests that contraindicates the use of oral contraceptives.

22. You have participated in any clinical research in the 30 days prior to enrollment in the study.

2. 3. You have donated or lost more than 500 cc of blood in the 30 days prior to enrollment in the study.

Treatment regimen

Description of study medication

DP3-84 / 30

All tablets of the DP3-84 / 30 regimen; 84 tablets each containing 150 pg of levonorgestrel / 30 pg of EE (ethinylestradiol) and 7 tablets each containing 30 pg of EE, will be white non-etched tablets. One combination tablet will be taken each day for 84 days followed by 7 days of EE tablets in cycles of 91 days repeated consecutively for approximately one year (4 cycles). Each DP3-84 / 30 dose kit will be packaged in 3 thermoformed white blister platelet packs, where each of the first two blister packs has 28 active tablets and the third blister pack has 28 active tablets and 7 active tablets. Ethinylestradiol (35 tablets total) for each 91-day cycle.

Each platelet blister pack will be sealed in an aluminum pouch, which will be labeled with a specific label for the patient. Each foil bag will contain an oxygen absorber. At each clinic visit, an aluminum bag, a patient information sheet, a more detailed patient leaflet (PPI), and a child-resistant bag will be dispensed.

DP3-84 / 10

All tablets of the DP3-84 / 10 regimen; 84 tablets each containing 150-pg levonorgestrel / 30-pg EE (ethinyl estradiol) and 7 tablets each containing 10 pg EE, will be white unengraved tablets. One combination tablet will be taken each day for 84 days followed by 7 days of

ES 2 561 491 T3 EE tablets in cycles of 91 days repeated consecutively for approximately one year (4 cycles). Each DP3-84 / 10 dose kit will be packaged in 3 packs of thermoformed white blister platelets, where each of the first two blister packs has 28 active tablets and the third blister pack has 28 active tablets and 7 tablets of Ethinylestradiol (35 tablets total) for each 91-day cycle.

Each platelet blister pack will be sealed in an aluminum pouch, which will be labeled with a specific label for the patient. Each foil bag will contain an oxygen absorber. At each clinic visit, an aluminum bag, a patient information sheet, a more detailed patient leaflet (PPI), and a child-resistant bag will be dispensed.

DP3-25 / 30

All tablets of the DP3-25 / 30 regimen; 25 tablets each containing 150-pg of levonorgestrel / 30-pg of EE and 3 tablets each containing 30 pg of EE, will be white non-etched tablets. One combination tablet will be taken each day for 25 days followed by 3 days of EE tablets in cycles of 28 days repeated consecutively for approximately one year (13 cycles). Each DP3-25 / 30 blister plate will contain 25 active tablets followed by 3 ethinyl estradiol tablets (28 tablets total) for each 28 day cycle.

Each blister plate will be sealed in an aluminum bag, which will be labeled with a specific label for the patient. Each foil bag will contain an oxygen absorber. At clinic visits one to three, 3 foil pouches, a patient information sheet, a more detailed patient leaflet (PPI), and a child-resistant bag will be dispensed. At the fourth clinic visit, 4 foil bags, a patient information sheet, a more detailed patient leaflet (PPI), and a child-resistant bag will be dispensed.

All patients, regardless of randomization, will be instructed to start oral contraceptive therapy on the first Sunday after the start of their menstrual period ("Sunday Beginners"). Patients will be instructed to take their study medication at the same time each day. Study day 1 will be defined as the first study medication day.

Administration

Designated staff will dispense all study drugs. All study medications must be kept in a safe area and at a temperature ranging from approximately 15-25 ° C. All patients will be instructed to take one tablet a day at approximately the same time each day. All patients will be "Sunday Beginners"; that is, all patients will begin study drug therapy the first Sunday after the start of their previous menstrual cycle or the termination of previous oral contraceptive regimens. All patients enrolled in the study will remain Sunday Beginners for each successive cycle.

The end-of-study evaluation will take place 1 week after the completion of withdrawal periods after the last cycle of study oral contraceptive therapy. At the clinic visit in which patients receive the final supply of study medication, they will be guided to use an alternative method of birth control during the interval from when they have finished the study medication until they have completed the visit. end of study.

Patients randomized to DP3-84 / 30 or DP3-84 / 10 will receive a 13-week supply (single cycle) of study drug at each clinic visit during weeks 13, 26, and 39. Patients randomized to DP3- 25/30 will receive a 12-week supply (three cycles) of study drug at study start and at clinic visits during weeks 12 and 24. During the 36 week clinic visit, patients randomly assigned to DP3-25 / 30 will receive a 16-week supply (four cycles) of study medication.

Exams / Tests

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Table 5. Study program

<td>Parameter</td><td>Screening</td><td>Visit 1</td><td>Visit 2-4^to</td><td>Termination of therapy</td>

<td>Informed consent</td><td>X</td><td></td><td></td><td></td>

<td>Medical and contraceptive history</td><td>X</td><td></td><td></td><td></td>

<td>Physical exam including pelvic exam</td><td>X</td><td></td><td></td><td>X</td>

<td>Weight, vital signs</td><td>X</td><td>X</td><td>X</td><td>X</td>

<td>Pap test</td><td>X</td><td></td><td></td><td>X</td>

<td>Randomization</td><td></td><td>X</td><td></td><td></td>

<td>Clinical analysis^b</td><td>X</td><td></td><td></td><td>X</td>

<td>Urine pregnancy test^c</td><td>X</td><td>X</td><td>X</td><td>X</td>

<td>Study drug distribution^d</td><td></td><td>X</td><td>X</td><td></td>

<td>Electronic journal distribution</td><td></td><td>X</td><td></td><td></td>

<td>Measure of compliance with the use of the study drug</td><td></td><td></td><td>X</td><td>X</td>

<td>Adverse event log</td><td></td><td></td><td>X</td><td>X</td>

^toPatients randomized to DP3-84 / 30 or DP3-84 / 10 will be seen at weeks 13, 26, and 39. Patients randomized to DP3-25 / 30 will be seen at weeks 12, 24, and 40.

^bClinical tests include complete blood test (CBC), serum chemistry, lipid profile, urinalysis ^cRepeated at visit 1 if screening was completed more than 2 weeks prior to study enrollment. ^dFor patients randomized to DP3 25/30, a three (3) cycle supply will be dispensed at weeks 12 and 24; A supply of four (4) cycles will be dispensed in week 40.

Study procedures per visit

Selection and registration

The patients will sign an informed consent. Prior to enrollment, in the four weeks prior to the start of study therapy, all patients will undergo a screening evaluation that will include prior medical and contraceptive history, smoking history, physical examination including pelvic exam and blood pressure test. Pap smear, vital signs and weight, and clinical tests including complete blood test (CBC), serum chemistry, lipid profile, urinalysis, and urine pregnancy test.

All clinical analysis evaluations (blood and urine) will be performed by a central laboratory. All researchers will be provided with a laboratory manual that explains the sampling and transport procedures.

If screening evaluation is completed more than two weeks prior to the start of study therapy, the urine pregnancy test must be repeated at Visit 1. Patients with a report of a Pap smear abnormality will be disqualified from enrollment unless the investigator decides that the results are not clinically significant and do not interfere with the conduct of the study. The investigator's decision must be documented. Patients who have had a normal Pap test in the three months prior to enrollment in the study will not need to repeat the test. A copy of the results should be available in the patient's medical record. For any patient with an insufficient cell report the test must be repeated and documented as normal prior to enrollment. The patients will then be enrolled in the study.

Visit 1

Visit 1 will take place during the final week of the menstrual cycle before starting study therapy (that is, during menstruation for those patients not taking oral contraceptives or during week 4 for those taking oral contraceptives). During Visit 1, patients will be randomly assigned to one of the following treatment groups:

DP3-84 / 30; levonorgestrel 150 pg / EE 30 pg for 84 days + EE 30 pg for 7 days or

· DP3-84 / 10; levonorgestrel 150 pg / EE 30 pg for 84 days + EE 10 pg for 7 days or

DP3-25 / 3; levonorgestrel 150 pg / EE 30 pg for 25 days + EE 30 pg for 3 days

The assignment of the treatment regimen will be carried out randomly through the Interactive Voice Response System (IVRS). The treatment group assignment will not be disclosed to the patient before she signs the informed consent.

ES 2 561 491 T3

Women who were screened more than two weeks prior to visit 1 will be given a urine pregnancy test again. Study medication will be dispensed with instructions to the patient. An electronic diary will be given to each patient. Each patient will be trained regarding the use and care of the electronic diary. Patients will be instructed to take each dose of study medication and to complete all diary entries at approximately the same time each day.

Visits 2-4

All visits must take place within seven days prior to the completion of study medication for that cycle. Any visit that takes place before the final week of the cycle will be recorded as a deviation from the protocol. Any visit that takes place after the final week of the cycle that results in a failure to take the study medication will be recorded as a protocol violation and will cause the patient to be withdrawn from the study. Any visit that occurs after the final week of the cycle but does not result in a failure to take the study medication (e.g., the patient received an emergency supply of study medication) will be recorded as a protocol deviation.

Patients randomized to DP3-84 / 30 or DP3-84 / 10 will be seen at weeks 13, 26, and 39. Patients randomized to DP3-25 / 30 will be seen at weeks 12, 24, and 36. During these weeks visits, patients will be questioned regarding adverse effects, concomitant medications, change in smoking history, and compliance with instructions. Vital signs and weight will be recorded. A urine pregnancy test will be done. Used study medication will be returned and counted by the study pharmacist or designated staff.

Termination of therapy

The end-of-study evaluation will take place 1 week after the completion of the last cycle of study drug. Patients will be guided to use birth control during the interval from the completion of the study medication to the completion of the final study visit. Patients will undergo a physical exam including a pelvic exam and a Pap smear. Vital signs and weight will be recorded. Blood and urine samples will be obtained for clinical analysis including complete blood test (CBC), serum chemistry, lipid profile, urinalysis, and urine pregnancy test. Used study medication will be returned and counted by the study pharmacist or designated staff. Patients will be questioned regarding adverse effects, concomitant medications, change in smoking history, and compliance with instructions. The electronic journal must be returned.

Post-study visit

After termination / withdrawal from the study, patients will be followed up with phone calls to check for the onset of pregnancy and until the menstrual cycle returns to normal. The patient, based on the characteristics of the cycle before entering the study, will determine the return to the normal menstrual cycle. The minimum follow-up period will be 3 months. Patients who decide to use a contraceptive method that regulates / alters the menstrual cycle after termination / withdrawal from the study will be followed up for 3 months by phone calls.

Only those patients who are experiencing a severe adverse event that has not been resolved or those who have become pregnant during the course of the study will be followed up by clinical visits after the completion of the study. Patients who are experiencing severe adverse events will be followed up until the event has been satisfactorily controlled or resolved. Patients who are pregnant will be followed for eight weeks after delivery or termination of pregnancy. The children's health assessment will be followed for eight weeks after delivery. This follow-up can be in the form of a written report by a family doctor, obstetrician, or pediatrician. All severe adverse events occurring within three months after discontinuation of therapy will be recorded. Severe adverse events occurring at any time after study termination / discontinuation will be recorded if the investigator determines that they are drug related.

Anticipated termination

Any patient who withdraws or is withdrawn from the study must return the investigational medication and electronic journal and will be asked to complete all procedures for the final visit. All patients will be followed by phone calls for 3 months to check for pregnancy and until the menstrual cycle returns to normal. All patients will be followed by phone calls for three months to check for severe adverse events.

Exams and Procedures

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Physical exam, medical and gynecological history

A complete physical and gynecological examination, including Pap smear, will be performed at screening and termination of therapy or after early withdrawal from the study. Any patient with an abnormal Pap smear will be disqualified from enrollment unless the investigator decides that the results are not clinically significant and that they do not interfere with the conduct of the study. The investigator's decision must be documented. Patients who have had a Pap test recorded as within normal limits in the three months prior to enrollment in the study will not need to repeat the test. A copy of the results should be available in the patient's medical record. Any patient with a low cell report must repeat the test and the test must be documented by the investigator as within normal limits prior to enrollment.

Clinical safety analysis

Clinical tests will be performed at selection and termination of therapy or after early withdrawal. All clinical analyzes will be performed in a central laboratory. Clinical tests include complete blood test (CBC), serum chemistry, lipid profile, urinalysis, and urine pregnancy test. In addition, urine pregnancy tests will be performed at each clinic visit and upon completion of therapy or after early withdrawal from the study. All urine pregnancy tests will be performed using the Sure Step® Pregnancy Test Kit (Applied Biotech, Inc.).

Pregnancy

All patients will be followed for onset of pregnancy for three months after study completion. This follow-up can be in the form of a phone call. All pregnancies that appear throughout the study or in the three months after study completion will be dated using ultrasound to establish the gestational age of the fetus. Patients who have become pregnant due to method failure will be followed throughout the study for eight weeks after delivery or termination of pregnancy. The children's health assessment will be followed for eight weeks after delivery. This follow-up can be in the form of a documented telephone conversation with the associate pediatrician or a written report from the associate pediatrician.

Electronic diaries

Patients will be asked to complete electronic diaries. The electronic diary will be programmed to ask specific questions related to compliance with study instructions, characteristics of bleeding, and the appearance of symptoms that are commonly associated with hormonal fluctuation during the menstrual cycle. Questions will address dose, compliance, bleeding characteristics, and hormone-related symptoms on the 0-3 scale or using the 10-cm visual analog scale (VAS).

Manual data acquisition devices will be used to collect the patient's responses. The electronic diary will provide patients with a graphical, menu-driven interface to enter diary information (as well as objective data) using a manual stylus. Data entry will be electronic and key fields must be completed appropriately before allowing the patient to complete the registration. Each record will be uploaded via telephone network connection.

The electronic diary will incorporate an alarm to remind the patient when to complete her records. The alarm times will be set by the site and can be specific to the patient's preference. The patient will be instructed to complete a diary each day. Retrospective data entry will not be allowed; registrations cannot be completed the previous days. Once each question has been completed the patient will confirm the answer and will not be allowed to return to that question to modify it.

The information to be collected on hormone-related symptoms comes from the Calendar of Premenstrual Experiences (COPE) and the Diagnostic and Statistical Manual of Mental Disorders Forth Edition (DSM-IV).

The validity and reliability of the COPE instrument was evaluated by Mortola, et al., Obstet. Gynecol. 89: 179-83 (1990), who administered 36 strictly selected women with PMS and 18 controls over two consecutive ovulatory cycles. The validity of the visual analog scales applied to the psychological symptoms associated with PMDD has been previously documented.

Treatment modifications based on toxicity

No significant toxicity is expected from the study medication. However, if the patient develops any symptoms or any abnormal clinical analysis parameter attributed to the drug, let it be

ES 2 561 491 T3 considered by the patient and / or by the physician of unacceptable severity, then the study medication should be discontinued.

Concomitant medications

Patients will be asked about concomitant medication use in monthly phone calls and quarterly clinic visits. The use of all concomitant medications (both prescription and non-prescription (OTC), including herbal medicines and nutritional supplements) must be reported during the study, and recorded in the patient case record format (CRF).

Patients requiring the initiation of chronic therapy with drugs known to interact with oral contraceptives will be withdrawn from the study. Patients requiring intermittent therapy with drugs known to interact with oral contraceptives (eg, antibiotic therapy) will remain in the study and receive guidance regarding the need for additional contraceptive protection throughout the cycle. Patients will receive the list of medications known to interact with oral contraceptives and will be instructed to notify the study coordinator as soon as the medication is prescribed to receive appropriate guidance. Notification and guidance can be done over the phone and must be documented in the patient's CRF. Those cycles in which drugs that are known to interact with oral contraceptive therapy are taken will not be used in calculating the pregnancy rate.

The use of emergency contraceptive pills (“the morning after pills”) is prohibited in the study. Data from any patient using birth control pills other than those provided for the study will not be included in the calculation of the pregnancy rate for that cycle.

Adverse Event Report

An adverse event (AE) is any reaction, side effect, or other undesirable event that occurs in conjunction with the use of a drug, biological product, or diagnostic agent in humans, whether or not the event is considered drug-related. .

A severe adverse event (SAE) is one that meets any one of the following criteria:

Is fatal or life threatening Needs or prolongs a patient's hospitalization Produces persistent or significant disability / incapacity Congenital abnormality

The term "life threatening" in the definition of "severe" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event that hypothetically could have caused death if it were more severe. Medical and scientific judgment must be used to decide whether a major medical event is severe. Although the event may not be immediately life threatening, fatal, or result in hospitalization, it should be considered serious when it endangers the patient, or requires intervention to avoid a serious outcome as defined above.

The adverse event reporting period for this study begins at the enrollment visit and ends at the final clinic visit. The reporting period for severe adverse events will continue for 3 months after the final clinic visit. All severe adverse events will be followed until resolution or until the investigator evaluates the severe adverse event as chronic or stable.

A pre-existing condition (that is, a condition that was present before the adverse event reporting period began and noted on the pretreatment medical history and physical form) should not be recorded as an adverse event unless the condition worsens or increases the condition. frequency of episodes during the adverse event reporting period.

During the study, adverse events will be reported through monthly phone calls and quarterly clinic visits. A phone number should be provided to patients who wish to report an adverse event between phone calls and scheduled clinic visits.