Use of combined oral contraceptives containing nomegestrol acetate and estradiol

Abstract

Use of a composition comprising nomegestrol acetate and estradiol or one of its esters for reducing the risk of venous thromboembolism associated with the use of combined oral contraceptives; wherein the risk of venous thromboembolism associated with the use of the composition is not higher than the risk of venous thromboembolism associated with the use of a combined oral contraceptive containing levonorgestrel.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to the use of compositions containing nomegestrol acetate (NOMAC) and estradiol or one of its esters. The compositions are intended for use in reducing the risk of venous thromboembolism (VTE) associated with the use of combined oral contraceptives (COCs). The compositions can be used in contraceptive methods and / or treatment methods in women with menstrual and / or fertility-related disorders. BACKGROUND TO THE INVENTION

[0002] Combined oral contraceptives (COCs), also known as combined hormonal contraceptives (CHCs), are used to control women's menstrual cycles. Taking COCs by women typically prevents ovulation and is therefore a means of preventing pregnancy. COCs are a popular form of contraception and are taken by over 100 million women worldwide. COCs are also used in a clinical setting to treat a number of disorders or conditions related to menstruation and fertility. Examples include reducing heavy menstrual bleeding, regulating the menstrual cycle, relieving dysmenorrhea, treating polycystic ovary syndrome, treating hirsutism, and treating premenstrual syndrome (Carey and Allen, The Obstetrician & Gynaecologist 2012; 14: 223-228).

[0003] COCs typically contain an estrogen and a progestin. Different COCs use different combinations of estrogens and progestins. Examples of different progestins used in currently marketed COCs include levonorgestrel, norethisterone, desogestrel, gestodene, cyproterone acetate, drospirenone, dienogest, and nomegestrol acetate. Examples of different estrogens used in currently marketed COCs include ethinylestradiol, mestranol, estradiol valerate, and estradiol.

[0004] A significant problem associated with the use of COCs is the increased risk of venous thromboembolism (VTE); VTE is one of the most serious adverse events (AEs) associated with the use of COCs (World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception, The Lancet. (1995) 346: 1575-82; Practice Committee of the American Society for Reproductive Medicine, Fertility and Sterility. (2016) 107(1): 43-51; Dragoman et al., Int. J. Gynaecol Obstet. (2018) 141(3): 287-294; see also: https: / / www.ema.europa.eu / en / human-regulatory / post-authorisation / referralprocedures / combined-hormonal-contraceptives).

[0005] A VTE is characterized by a series of events in which a blood clot, or "thrombus," forms in a vein, a piece of the clot breaks off, and is carried in the bloodstream to a distal site, where it lodges and causes a blockage in a blood vessel. A pulmonary embolism describes a blockage in one of the pulmonary arteries in the lungs caused by a blood clot that has traveled from a vein at a distal site, typically a deep vein in the leg.

[0006] Considering the above, there is a clear need to identify compositions capable of reducing the risk of VTE associated with the use of COCs in women. The present invention addresses this need, as further explained below. OVERVIEW OF THE INVENTION

[0007] An example of a COC already in clinical use is "NOMAC-E2," a COC marketed by Theramex HQ UK Limited as ZOELY®. NOMAC-E2 is a monophasic oral contraceptive containing a fixed dose of nomegestrol acetate (2.5 mg) and 17β-estradiol (1.5 mg). NOMAC-E2 pills are typically taken by women for 24 days, followed by 4 days of placebo.

[0008] The progestin contained in NOMAC-E2, nomegestrol acetate or "NOMAC," is a derivative of 19-norprogesterone and is therefore structurally very similar to the naturally occurring progesterone produced by the human body. It has a strong affinity for the progesterone receptor and potent antigonadotropic activity, as well as progesterone receptor-mediated antiestrogenic activity. It also has moderate antiandrogenic activity and is free of estrogenic, androgenic, glucocorticoid, or mineralocorticoid activity.

[0009] The estrogen contained in NOMAC-E2 is 17β-estradiol, or "E2." E2 is a synthetically produced estrogen, but it is identical to the natural estrogen—17β-estradiol—produced by the human body; it is classified as a "bioidentical" hormone.

[0010] This application relates to the results of a study that found that NOMAC-E2 reduced the risk of VTE when tested with comparable COCs. The comparable COCs contained the synthetic progesterone levonorgestrel (LNG) and the synthetic estrogen ethinylestradiol. NOMAC-E2 has been used clinically for some time without serious health concerns. However, this application demonstrates for the first time the possibility of using COCs containing NOMAC and estradiol to reduce the risk of VTE in women prescribed COC medications for contraception or otherwise.

[0011] In a first aspect, the present invention provides a composition for use in reducing the risk of venous thromboembolism (VTE) associated with the use of combined oral contraceptives, the composition comprising nomegestrol acetate and estradiol or one of its esters.

[0012] The invention also provides a method for reducing the risk of venous thromboembolism (VTE) associated with the use of combined oral contraceptives, the method comprising administering to a woman a composition comprising nomegestrol acetate (NOMAC) and estradiol or one of its esters.

[0013] In a further aspect, the invention provides the use of a composition comprising nomegestrol acetate and estradiol or one of its esters as a contraceptive, thereby reducing the risk of venous thromboembolism (VTE) associated with the use of combined oral contraceptives.

[0014] The invention also provides a method of contraception, the method comprising administering to a woman a composition comprising nomegestrol acetate and estradiol or one of its esters, whereby the risk of venous thromboembolism (VTE) associated with the use of combined oral contraceptives is reduced in the woman to whom the composition is administered.

[0015] In another aspect, the invention provides a method for treating any of the following conditions: painful menstrual bleeding, heavy and / or prolonged menstrual bleeding, acne, ovarian cysts, polycystic ovary syndrome (PCOS), premenstrual syndrome (PMS), endometriosis, and premenstrual dysphoric disorder (PMDD), the method comprising administering to a woman a composition comprising nomegestrol acetate and estradiol or one of its esters, whereby the risk of venous thromboembolism (VTE) associated with the use of combined oral contraceptives is reduced in the woman to whom the composition is administered.

[0016] The invention also encompasses a composition for use in a method of treating any of the following conditions: painful menstrual bleeding; heavy and / or prolonged menstrual bleeding; acne; ovarian cysts; polycystic ovary syndrome; premenstrual syndrome; endometriosis and premenstrual dysphoric disorder, wherein the composition comprises nomegestrol acetate and estradiol or one of its esters and wherein the risk of venous thromboembolism associated with the use of combined oral contraceptives is reduced.

[0017] In preferred embodiments of all aspects of the invention described herein, the composition comprises nomegestrol acetate and 17β-estradiol. BRIEF DESCRIPTION OF THE DRAWINGS Fig. Figure 1 shows an overview of the cohorts included in the clinical study, categorized by age groups. Fig.Figure 2 shows the incidence of serious adverse events (SAEs) observed in the study, by COC or contraceptive used. Fig. Figure 3 shows the incidence of deep vein thrombosis (DVT) of the lower extremities and pulmonary embolism (PE). The incidence rates per 10,000 WY and 95% confidence intervals per (sub)cohort are shown. Fig. Figure 4 shows lower extremity deep vein thrombosis (DVT) and pulmonary embolism (PE) in women without known predefined risk factors at baseline. The incidence rates per 10,000 WY and 95% confidence intervals per (sub)cohort are presented. Fig. Figure 5 shows lower extremity deep vein thrombosis (DVT) and pulmonary embolism (PE) in women using a combined oral contraceptive (COC) exclusively for contraceptive purposes. Incidence rates per 10,000 women and 95% confidence intervals per (sub)cohort are given. Fig.Figure 6 shows lower extremity deep vein thrombosis (DVT) and pulmonary embolism (PE) excluding the Russian women included in the study. The incidence rates per 10,000 WY and 95% confidence intervals per (sub)cohort are shown. Fig. Figure 7 shows all cases of venous thromboembolism (VTE), with incidence rates per 10,000 WY and 95% confidence intervals per (sub-)cohort. DETAILED DESCRIPTION A. Definitions

[0018] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.

[0019] Venous thromboembolism (VTE) - as used here, the term “venous thromboembolism” or “VTE” is used to describe a series of events in which: - a blood clot (also called a thrombus) forms in a vein; - the blood clot or a fragment of it detaches from the original site of formation; - the blood clot or fragment of it is transported via the circulatory system to another blood vessel - the blood clot or fragment thereof becomes lodged in the other blood vessel, thereby causing a partial or complete blockage of blood flow in the affected vessel.

[0020] There are several risk factors associated with the development of VTE. Taking hormonal medications is associated with an increased risk of VTE. Examples of hormonal medications include oral contraceptives and hormone replacement therapy for women.

[0021] "Deep vein thrombosis" - As used here, the term "deep vein thrombosis" or "DVT" is used to describe a thrombus that forms in the deep veins of the legs, groin, or arms. Symptoms associated with DVT include pain or tenderness in the arms or legs (typically the thigh or calf), swollen legs or arms, skin that is red or warm to the touch, red streaks on the skin, or a change in skin color.

[0022] "Pulmonary embolism" - as used here, the term "pulmonary embolism" or "PE" refers to a blood clot or thrombus that has traveled from a distal location in the bloodstream to the lungs and blocks or partially blocks a blood vessel in the lungs. Symptoms of a pulmonary embolism include sudden unexplained shortness of breath, rapid breathing, sudden unexplained cough, sharp chest pain, rapid or irregular heartbeat, dizziness, and severe stomach pain.

[0023] "Combined oral contraceptives" (COC) - as used herein, a "combined oral contraceptive" or "COC" refers to a combination hormonal treatment for women containing an estrogen and a progestin. Combined oral contraceptives are also referred to in the literature as "combined hormonal contraceptives" or "CHCs." A variety of different combinations of estrogens and progestins are known to be used in various forms of COCs. The COCs for use according to the present invention comprise nomegestrol acetate (NOMAC) as the progestin and estradiol or one of its esters as the estrogen.

[0024] "Progestogens" - as used here, the term "progestogens" refers to a class of synthetic steroid hormones that produce similar or equivalent effects to progesterone, the naturally occurring progestogen. Progestogens are also referred to as "gestagens." Progestogens possess antiestrogenic and antigonadotropic properties. Many examples of progestogens are derivatives or metabolites of naturally occurring progesterone.

[0025] “Nomegestrol acetate” - as used here - "Nomegestrol acetate" or "NOMAC" or "NOMAc" refers to a type of progestin represented by the following formula: NOMAC is also known as 17α-acetoxy-6-methyl-δ6-19-norprogesterone or 17α-acetoxy-6-methyl-19-norpregna-4,6-diene-3,20-dione. It is a progesterone derivative belonging to the 19-norprogesterone and 17α-hydroxyprogesterone groups.

[0026] "Estrogens" - as used here, the term "estrogens" (also spelled "oestrogens") refers to a class of steroid hormones whose endogenous, or naturally occurring, forms are estrone (E1), estradiol (E2), estriol (E3), and otetrol (E4). Estrogens perform a variety of functions in the human body, including the regulation of the menstrual cycle, ovulation, and fertility.

[0027] “Estradiol” - as used here, the term “estradiol” or “E2” refers to the estrogen represented by the following formula:

[0028] This compound is also known as "17β-estradiol" or "beta-estradiol." Estradiol is the predominant estrogen produced by the human body during a woman's reproductive years.

[0029] "Woman of childbearing potential" - as used herein, this term refers to a woman after puberty and before menopause. A woman of childbearing potential is a woman who is most likely to use the compositions described here as a contraceptive.

[0030] “Contraceptive” - as used herein, this term refers to the use of a composition as described herein to prevent pregnancy.

[0031] “Non-contraceptive use” - as used herein, refers to the use of a composition as described herein for a purpose other than preventing pregnancy.

[0032] “Woman at increased risk of VTE” - as used here, this term refers to a woman who is considered to be at increased risk of VTE due to one or more risk factors known to predispose women to VTE.

[0033] “Body Mass Index” (BMI) - as used here, this term refers to a person’s body weight divided by the square of their height and is generally expressed in kg / m 2 According to the World Health Organization (WHO), a person with a BMI of over 30 (>30) is considered obese. Obesity is a condition in which a person's excess body fat has accumulated to such an extent that it can negatively impact the person's health.

[0034] Hazard Ratio (HR) - As used herein, the hazard ratio or HR is the ratio of the risk of VTE in a first group of subjects to the risk of VTE in a second group of subjects. The HR, as described here, typically represents the risk of VTE associated with women receiving the compositions described here (consisting of NOMAC and estradiol or one of its esters) compared to the risk of VTE associated with women receiving another COC. HRs can be calculated and expressed in crude form by simply comparing the incidence of VTE between two groups of subjects. HRs can also be calculated and expressed in adjusted form, with the HR adjusted to account for other known VTE risk factors such as age, body mass index (BMI) at baseline, duration of COC use, and family history of VTE in the two groups of subjects.

[0035] As used herein, the term “tablet” refers to a solid composition that is compressed or otherwise formed into a defined shape and quantity.

[0036] "Film-coated tablet" - as used herein, the term "film-coated tablet" refers to a tablet coated with a polymer-based coating. The coating may be used to prevent the tablet from disintegrating in the stomach.

[0037] "Sugar-coated tablet" - as used here, the term "sugar-coated tablet" refers to a tablet coated with a mono-, di-, oligo-, or polysaccharide. The coating can be used to mask the taste of particularly unpleasant medications. The coating can also be used to prevent light or moisture from penetrating the tablet, which could prevent premature degradation of the medication.

[0038] "Soft gelatin capsule" - as used herein, the term "soft gelatin capsule" refers to a dosage form in which a liquid or semi-solid core (inner filling) is enclosed within a solid capsule (outer shell). The outer shell may, for example, consist of a combination of gelatin, water, an opacifier, and a plasticizer such as glycerin and / or sorbitol(s).

[0039] "Cachets" or "wafer capsules" - as used here, these terms refer to a sealed capsule or wafer made of flour used to enclose powders with an unpleasant taste. The sealed dosage form is moistened and swallowed.

[0040] “Pill” – as used here, this term refers to any solid form of medication.

[0041] “Powder” - as used here, this term refers to a mixture of solid, uncompressed, active drug (e.g., NOMAC-E2) and excipients.

[0042] "Excipient" - as used herein, this term refers to a compound that is generally safe, nontoxic, and neither biologically nor otherwise undesirable. The excipient is essentially inert.

[0043] “Oral administration” – as used here, this term means that the dosage form is taken orally and thereby delivered into the gastrointestinal tract.

[0044] "Monophasic" - as used herein, this term means that a fixed amount or dosage of the estrogen and / or progestogen in the COC is administered during a treatment cycle. For example, if a treatment cycle consists of 24 daily doses of the COC, the woman is administered a fixed amount or dosage of the estrogen and / or progestogen on each day of the 24-day period. The NOMAC-E2 compositions described here can be administered as monophasic oral contraceptives. For example, a fixed dosage of 2.5 mg and 1.5 mg of E2 can be administered daily for a period of 24 days.

[0045] "Multiphasic" - as used here - means that the amount or dosage of estrogen and / or progestogen varies throughout a treatment cycle. For example, if a treatment cycle consists of daily doses of a COC over a period of several days, the amount of estrogen and / or progestogen administered to the woman may vary on different days of the treatment cycle.

[0046] "Acne" - as used here - refers to a long-term skin condition that occurs when dead skin cells and sebum clog hair follicles. Typical features of the condition include blackheads or pimples, spots, oily skin, and possible scarring.

[0047] "Ovarian cysts" - as used here, this term refers to fluid-filled sacs that develop in or on the ovaries. Typically, an ovarian cyst only causes symptoms if it ruptures, is very large, or blocks the blood supply to the ovaries. Symptoms associated with ovarian cysts include abdominal pain, pain during sex, difficulty having bowel movements, frequent urination, heavy periods, irregular periods, lighter periods than normal, bloating or a swollen abdomen, feeling extremely full after eating very little, and difficulty getting pregnant.

[0048] Polycystic ovary syndrome (PCOS) – as used here, this term refers to a condition in which the ovaries contain a large number of follicles. The follicles are underdeveloped sacs in which eggs develop, meaning these sacs are often unable to release an egg. PCOS can lead to a lack of ovulation and problems with fertility. Symptoms of PCOS include irregular or no periods, difficulty getting pregnant, excessive hair growth (hirsutism), particularly on the face, chest, back, or buttocks, weight gain, thinning hair and scalp, oily skin, or acne.

[0049] "Premenstrual syndrome" (PMS) - as used here, this term refers to a recurrent, cyclical disorder characterized by behavioral, emotional, social, and physical symptoms (Steiner et al., Annu. Rev. Med. (1997) 48: 447-455). Symptoms may include irritability, mood swings, depression, hostility, and social withdrawal. Physical symptoms include bloating, breast tenderness, myalgia, migraines, headaches, or fatigue.

[0050] "Endometriosis" - as used here - refers to a condition in which tissue similar to the lining of the uterus begins to grow elsewhere in the reproductive system, such as the ovaries and fallopian tubes. Symptoms may include one or more of the following: abdominal pain, back pain, period pain, pain during or after sex, pain during bowel movements or urination, nausea, constipation, diarrhea, bloody stools, difficulty getting pregnant, heavy periods, or depression.

[0051] Premenstrual dysphoric disorder (PMDD) – as used here, this term refers to a disorder that occurs in a subset of women with PMS. PMDD is considered a severe form of PMS. Symptoms may include one or more of the following: mood swings, sadness or tearfulness, anger or irritability, feelings of anxiety, hopelessness, tension or nervousness, difficulty concentrating, feeling overwhelmed, lack of energy, decreased interest in normally enjoyable activities, suicidal thoughts, breast tenderness or swelling, muscle and joint pain, headaches, bloating, changes in appetite, or trouble sleeping.

[0052] "Menstrual cycle regulation" - as used here, this term refers to the regulation of the menstrual cycle through hormone therapy. Hormone treatments can be used to regulate the menstrual cycle in women experiencing problems, including, but not limited to, uneven menstrual cycle lengths, painful periods, and very heavy bleeding during menstruation.

[0053] “Placebo” – as used here – refers to a dosage form that does not contain any active ingredient. B. Compositions and methods to reduce the risk of venous thromboembolism (VTE)

[0054] As explained below, the use of COCs is associated with an increased risk of blood clots in the veins or “venous thrombosis” and consequently with an increased risk of VTE.

[0055] Typically, about 2 out of 10,000 women not taking a COC and not pregnant will develop a blood clot in a vein within a year. In contrast, about 5-7 out of 10,000 women taking a COC containing levonorgestrel, norethisterone, or norgestimate will develop a blood clot in a vein within a year. The incidence increases to about 6-12 out of 10,000 women taking a COC containing etonogestrel or norelgestromin, and about 9-12 out of 10,000 women taking a COC containing drospirenone, gestodene, or desogestrel (see https: / / www.ema.europa.eu / en / humanregulatory / post-authorisation / referral-procedures / combined-hormonal-contraceptives).

[0056] As described here, it was unexpectedly found that women taking a COC containing NOMAC and estradiol have a lower risk of VTE. This risk reduction was observed compared to women taking other COCs containing other forms of progestogen and estrogen. In women taking a COC containing NOMAC and estradiol, VTE, measured as a combination of lower extremity DVT and PE, occurred at a rate of 1.5 per 10,000 women-years. In contrast, women taking a COC containing levonorgestrel (COC LNG ) developed VTE, measured by a combination of lower extremity DVT and PE, at a rate of 2.6 per 10,000 women-years. In addition, women taking other forms of COCs containing different estrogens and / or progestogens developed VTE at a rate of 6.7 per 10,000 women-years.

[0057] Taking the above into account, the invention provides, in a first aspect, a composition for use in reducing the risk of venous thromboembolism (VTE) associated with the use of combined oral contraceptives (COCs), the composition comprising NOMAC and estradiol or one of its esters.

[0058] The invention provides, in a further aspect, a method for reducing the risk of venous thromboembolism (VTE) associated with the use of combined oral contraceptives (COCs), the method comprising administering to a woman or women a composition comprising NOMAC and estradiol or one of its esters.

[0059] All embodiments described below are equally applicable to the compositions for use and methods for reducing the risk of VTE according to these aspects of the invention. (i) Reducing the risk of VTE

[0060] The compositions for use and methods according to these aspects of the invention aim to reduce the risk of VTE associated with the use of COCs. As described herein, a significant decrease in the incidence of VTE was observed in women taking a COC containing NOMAC and estradiol compared to women taking other forms of COC. The risk of VTE associated with the use of COCs is therefore significantly reduced in women taking compositions containing NOMAC and estradiol or its esters.

[0061] In some embodiments, a reduced VTE risk manifests as a reduced incidence or risk of "idiopathic VTE." Idiopathic VTE is also referred to as "unprovoked VTE" or "spontaneous VTE." Idiopathic VTE includes all forms of VTE not associated with temporary risk factors; temporary risk factors include, but are not limited to, pregnancy, childbirth, trauma, immobilization, long-distance travel, surgery, and chemotherapy.

[0062] In some embodiments, a reduced VTE risk manifests as a reduced incidence or risk of deep vein thrombosis (DVT). In some embodiments, a reduced VTE risk manifests as a reduced incidence or risk of pulmonary embolism (PE). In some embodiments, a reduced VTE risk manifests as a reduced incidence or risk of DVT and PE. As described above, DVT and PE are common events in the chain of events associated with VTE, and thus, a reduction in the incidence or risk of one or both of these events is directly associated with a reduced VTE risk.

[0063] The invention provides compositions for use and methods for reducing the risk of VTE associated with the use of COCs. As noted above, the use of COCs in women results in an increased risk of VTE compared to the risk of VTE in women not taking COCs. For example, the risk of DVT in women taking COCs increases from approximately 2 in 10,000 women per year to 5 to 12 in 10,000 women per year (depending on the active ingredient).

[0064] The risk of VTE associated with the compositions used according to the invention is reduced compared to the increased risk observed in women taking COCs, i.e., the risk generally associated with the use of COCs. In certain embodiments, the risk is reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to the risk observed in women taking COCs (of any type).

[0065] In some embodiments, the risk of VTE associated with the compositions of the invention is reduced compared to the risk of VTE associated with the use of a particular COC, particularly a different COC. In this regard, a different COC means a COC that is not a composition for use according to the invention as defined herein. A different COC does not contain NOMAC and estradiol or one of its esters.

[0066] In some embodiments, the risk of VTE is reduced compared to the risk associated with the use of another COC containing other forms of estrogen and / or progestin compared to the compositions described herein. The other COC may contain a synthetic estrogen selected from the group including, but not limited to, ethinyl estradiol or mestranol. Alternatively or additionally, the other COC may contain a synthetic progestogen selected from the group including, but not limited to, levonorgestrel, norethisterone, desogestrel, gestodene, cyproterone acetate, drospirenone, or dienogest.

[0067] In some embodiments, the risk of VTE is reduced compared to the risk associated with the use of a COC containing a progestogen selected from norethisterone, levonorgestrel, or desogestrel. As referenced in the Committee on Practice of the American Society for Reproductive Medicine, Fertility and Sterility (2016) 107(1): 43-51 (the contents of which are incorporated herein in their entirety), the relative risks in women taking COCs containing norethisterone, levonorgestrel, or desogestrel are 3.2, 2.8, and 3.8, respectively. This relative risk is expressed relative to the risk of VTE in non-pregnant women not receiving hormone therapy.The relative risk of VTE associated with compositions used according to the invention can be reduced by at least 10%, at least 20%, at least 30%, at least 40% or at least 50% compared to the relative risk observed in women using COCs containing norethisterone, levonorgestrel and / or desogestrel.

[0068] In some embodiments, the risk of VTE associated with the compositions of the invention is lower than the risk associated with the use of a COC containing the progestogen levonorgestrel - also referred to herein as a COC LNG - reduced. In some embodiments, the risk of VTE is reduced compared to the risk associated with the use of a COC containing levonorgestrel and ethinylestradiol.

[0069] In some embodiments, the risk of VTE is reduced compared to a monophasic COC containing levonorgestrel. In some embodiments, the risk of VTE is reduced compared to a monophasic COC containing levonorgestrel and 20-30 µg ethinyl estradiol. In some embodiments, the risk of VTE is reduced compared to a monophasic COC containing levonorgestrel and 20 µg ethinyl estradiol. In some embodiments, the risk of VTE is reduced compared to a multiphasic COC containing levonorgestrel. In other embodiments, the risk of VTE is reduced compared to a multiphasic COC containing levonorgestrel and 40 µg ethinyl estradiol. The dose of levonorgestrel in the COC can range from 100 µg to 250 µg. In certain embodiments, the dose of levonorgestrel in the COC is 150 µg.The reduction in the risk of VTE associated with the compositions of the invention can be expressed as a hazard ratio (HR). In some embodiments, the HR associated with the use of the compositions described herein is 0.3-0.6. In some embodiments, the HR associated with the use of the compositions described herein is 0.5-0.7. In some embodiments, the HR is 0.5-0.6. In some embodiments, the HR is 0.5. In some embodiments, the crude HR (HR crude ) 0.5. In other embodiments, the adjusted HR (HR adj ) 0.5. In other embodiments, the HR is 0.6. In some embodiments, the raw HR (HR crude ) 0.6. In other embodiments, the adjusted HR (HR adj ) 0.6.

[0070] As described herein, the crude HR may be adjusted to account for other known VTE risk factors. These risk factors include, for example, baseline BMI in the two subject groups. In some embodiments, the adjusted HR accounts for the actual baseline BMI. In other embodiments, the adjusted HR accounts for an imputed baseline BMI (i.e., where missing BMI values ​​have been imputed). In these embodiments, the adjusted HR is 0.5.

[0071] In some embodiments, the risk of VTE is reduced compared to a monophasic combined oral contraceptive containing levonorgestrel and 20 µg ethinylestradiol, and the HR crude is 0.4. In other embodiments, the risk of VTE is reduced compared to a monophasic combined oral contraceptive containing levonorgestrel and 20 µg ethinylestradiol, and the HR adjis 0.3. In some embodiments, the risk of VTE is reduced compared to a multiphasic combined oral contraceptive containing levonorgestrel and 40 µg ethinylestradiol, and the HR crude is 0.5. In other embodiments, the risk of VTE is reduced compared to a multiphasic combined oral contraceptive containing levonorgestrel and 40 µg ethinylestradiol, and the HR adj is 0.4.

[0072] In some embodiments, the VTE risk associated with the compositions of the invention is at least 10%, at least 20%, at least 25%, at least 30%, or at least 40% lower than the risk associated with the use of combined oral contraceptives in women.

[0073] In some embodiments, the risk of VTE is at least 20% lower in women administered compositions containing NOMAC and estradiol or one of its esters than in women receiving COC LNG In some embodiments, the risk of VTE is at least 25% lower in women administered compositions containing NOMAC and estradiol or one of its esters than in women taking COC LNG In some embodiments, the risk of VTE is at least 30% lower in women administered compositions comprising NOMAC and estradiol or one of its esters than in women taking COC LNG In some embodiments, the risk of VTE is at least 35% lower in women administered compositions comprising NOMAC and estradiol or one of its esters than in women taking COC LNG take.

[0074] In preferred embodiments, the risk of VTE in women administered compositions comprising NOMAC and estradiol or one of its esters is lower compared to women receiving COC LNG by at least 40%. In further preferred embodiments, the risk of VTE in women administered compositions comprising NOMAC and estradiol or one of its esters is reduced compared to women taking COC LNG take, reduced by 50% or halved. (ii) Administration to women

[0075] VTE can affect men and women of all ages, races, and ethnicities. The current invention is directed to the use of compositions containing NOMAC and estradiol or one of its esters to reduce the risk of VTE associated with the use of COCs. As described herein, COCs are used for both contraceptive and non-contraceptive use in women, and therefore, the compositions containing NOMAC and estradiol or one of its esters as described herein are typically administered to a woman or women to reduce the increased risk of VTE associated with the use of COCs.

[0076] In some embodiments, the compositions described herein are administered to a woman or women of childbearing age. Accordingly, in some embodiments, the compositions are administered to a woman or women aged 12 to 55 years. In some embodiments, the woman or women are aged 15 to 55 years. In some embodiments, the woman or women are aged 15 to 50 years. In some embodiments, the woman or women are aged 15 to 45 years.

[0077] In certain embodiments, the compositions described herein are administered as contraceptives.

[0078] While the majority of women take COCs for contraceptive purposes, COCs can also be prescribed for non-contraceptive purposes. Accordingly, in certain embodiments, a composition described herein is administered to a woman or women for non-contraceptive use.

[0079] Non-contraceptive use may be to prevent or treat any of the following conditions: painful menstrual bleeding; heavy and / or prolonged menstrual bleeding; acne; ovarian cysts; polycystic ovary syndrome (PCOS); premenstrual syndrome (PMS); endometriosis; and premenstrual dysphoric disorder (PMDD).

[0080] In some embodiments, a composition as described herein is administered to a woman or women to prevent or treat one or more, two or more, three or more, four or more, five or more conditions selected from: painful menstrual bleeding; heavy and / or prolonged menstrual bleeding; acne; ovarian cysts; polycystic ovary syndrome (PCOS); premenstrual syndrome (PMS); endometriosis; and premenstrual dysphoric disorder (PMDD).

[0081] In some embodiments, a composition as described herein is administered to a woman or women for the purpose of regulating the menstrual cycle. The composition can be administered to normalize the duration of the menstrual cycle in a woman or women with irregular menstrual cycle lengths.

[0082] Alternatively or additionally, the composition may be administered to normalize the frequency of ovulation in a woman or women with irregular ovulation patterns.

[0083] Because the compositions described herein are associated with a reduced risk of VTE compared to the increased risk in women taking other forms of COCs, they are particularly effective in women who may have an increased risk of VTE associated with COC use. Certain groups of women are also known to have an increased risk of developing VTE compared to the general population or the general risk of women per se. Accordingly, in certain embodiments, a composition as described herein is administered to a woman or women classified as being at increased risk of VTE. A woman or women classified as being at increased risk of VTE may have an increased risk of VTE that is independent of the increased risk of VTE associated with COC use.

[0084] In some embodiments, a composition as described herein is administered to a woman or women aged 35 years or older; optionally 36 years or older; optionally 37 years or older; optionally 38 years or older; optionally 39 years or older; optionally 40 years or older. The composition may be administered to a woman or women between the ages of 35 and 45.

[0085] In some embodiments, a composition as described herein is administered to an overweight woman or women. In some embodiments, a composition as described herein is administered to an obese woman or women. In some embodiments, a composition as described herein is administered to a woman or women with a BMI of >23 kg / m 2In some embodiments, a composition as described herein is administered to a woman or women with a BMI of >25 kg / m 2 In some embodiments, a composition as described herein is administered to a woman or women with a body mass index (BMI) of >30 kg / m 2 In some embodiments, a composition as described herein is administered to a woman or women with a BMI of >35 kg / m 2 In some embodiments, a composition as described herein is administered to a woman or women with a BMI > 40 kg / m 2 In some embodiments, a composition as described herein is administered to a woman or women with a BMI of 30 kg / m 2 up to 35 kg / m 2 administered.

[0086] In some embodiments, a composition as described herein is administered to a woman or women who are classified as overweight or obese according to one or more measures used in clinical practice.

[0087] In some embodiments, a composition as described herein is administered to a woman or women who suffer from hypertension or have suffered from hypertension in the past (e.g., during pregnancy).

[0088] In some embodiments, a composition as described herein is administered to a woman or women who are smokers.

[0089] In some embodiments, a composition as described herein is administered to a woman or women with diabetes.

[0090] In some embodiments, a composition as described herein is administered to a woman or women suffering from any of the following conditions: cancer; systemic lupus erythematosus (SLE); hemolytic uremic syndrome; inflammatory bowel diseases (such as Crohn's disease or ulcerative colitis); and sickle cell disease.

[0091] In some embodiments, the composition is administered to a woman or women with cancer. The cancer may be selected from breast cancer or cervical cancer.

[0092] In some embodiments, the composition is administered to a woman or women after childbirth. The risk of VTE is significantly increased in pregnant and postpartum women. For example, incidence rates typically increase to 5-20 / 10,000 women-years in pregnancy and to 40-65 / 10,000 women-years after childbirth (see Practice Committee of the American Society for Reproductive Medicine, Fertility and Sterility. (2016) 107(1): 43-51). In some embodiments, the composition is administered to a woman or women who are breastfeeding for 6 weeks to 6 months after childbirth. In some embodiments, the composition is administered to a woman or women who are not breastfeeding for 3 weeks to 6 weeks after childbirth.

[0093] In certain embodiments, a composition such as that described herein is administered to a woman or women with a family history of VTE (particularly VTE in a parent or sibling). Alternatively or additionally, a woman or women administered a composition such as that described herein may have an acquired predisposition to VTE, for example, due to a condition that affects blood clotting. Examples of conditions that affect blood clotting include protein C deficiency, antithrombin III deficiency, Factor V Leiden thrombophilia, and antiphospholipid syndrome (APS).

[0094] In further embodiments, a composition such as that described herein is administered to a woman or women who have undergone major surgery. This may include, but is not limited to, leg or pelvic surgery, neurosurgical procedures, or severe trauma.

[0095] In further embodiments, a composition as described herein is administered to a woman or women who have long-term immobility, for example due to the use of a wheelchair.

[0096] In further embodiments, a composition such as that described herein is administered to a woman or women who have had one or more prior cases of deep vein thrombosis (DVT) and / or pulmonary embolism (PE). In other words, the woman or women may have a clinical history suggesting an increased risk of VTE.

[0097] In some embodiments, a composition such as that described herein is administered to a woman or women who have a variety of risk factors associated with an increased risk of developing VTE.

[0098] In some embodiments, a composition such as that described herein is administered to a woman or women who have not previously received a COC. In alternative embodiments, a composition such as that described herein is administered to a woman or women who have previously received a COC regimen in their lifetime. Such women may be classified as “restarters.” Such women may have taken a break from COC regimen for a period of 2 months or more, 3 months or more, 4 months or more, 5 months or more, 6 months or more, 12 months or more. As reported herein, the risk of VTE, as measured by lower extremity DVT and PE, may be particularly high in women who resume COC regimen—see Table 7, which refers to an incidence of 4.8 in women who discontinued COC use. LNGresume, compared to an incidence of 2.6 in the total population of women receiving COC LNG Significantly, this increase in VTE risk was not observed among the women who resumed treatment with NOMAC-E2—an incidence of 1.7 was observed among women who resumed treatment with NOMAC-E2, compared with an incidence of 1.5 among the overall population of women who received NOMAC-E2. This suggests that the compositions for use as described here are particularly effective in reducing the risk of VTE in women who have previously received COC treatment.

[0099] In some embodiments, a composition as described herein is administered to a woman or women who have previously received a COC that does not contain NOMAC and estradiol or one of its esters. (iii) Compositions containing NOMAC and estradiol or one of its esters

[0100] The compositions described herein for use according to the invention comprise NOMAC and estradiol or one of its esters. The compositions for use according to the invention are thus themselves COCs in which the progestogen active ingredient is NOMAC and the estrogen active ingredient is estradiol or one of its esters. As described elsewhere herein, these compositions are associated with a reduced risk of VTE and can therefore be used in place of other COCs to reduce the risk of VTE associated with the use of COCs in women.

[0101] In some embodiments, NOMAC and estradiol or one of its esters are present in a weight ratio of 5 to 0.5. In some embodiments, NOMAC and estradiol or one of its esters are present in a weight ratio of 3 to 1. In a preferred embodiment, NOMAC and estradiol or one of its esters are present in a weight ratio of 1.67 to 1.

[0102] In some embodiments, the NOMAC is present in an amount ranging from 1.5 mg to 3.75 mg. In some embodiments, the estradiol or one of its esters is present in an amount ranging from 0.5 mg to 3 mg. In some embodiments, the NOMAC is present in an amount of about 2.5 mg and the estradiol or one of its esters is present in an amount of about 1.5 mg.

[0103] In a preferred embodiment, the NOMAC is present in an amount of 2.5 mg and the estradiol or its ester is present in an amount of 1.5 mg.

[0104] In some embodiments, the compositions for use comprise NOMAC in combination with an estradiol ester. Such estradiol esters include, but are not limited to, estradiol valerate, estradiol benzoate, estradiol phenylpropionate, estradiol enzinate, estradiol acetate, estradiol cypionate, estradiol dipropionate, estradiol undecylate, and polyestradiol phosphate (an estradiol ester in polymer form).

[0105] In preferred embodiments, the composition comprises NOMAC in combination with 17β-estradiol (also referred to herein as E2). In a particularly preferred embodiment, the 17β-estradiol is in hemihydrate form. In preferred embodiments, the composition comprises 2.5 mg of NOMAC and 1.5 mg of 17β-estradiol.

[0106] Without wishing to be bound by any theory, it is believed that compositions containing NOMAC and 17β-estradiol may be associated with a reduced risk of VTE because the progestogens and estrogens contained in these compositions are structurally very similar (in the case of NOMAC) and identical (in the case of 17β-estradiol) to the naturally occurring forms of these hormones found in women.

[0107] The compositions for use according to the invention may be formulated to include one or more pharmaceutically acceptable carriers or excipients. Alternatively or additionally, the compositions for use according to the invention may be formulated to include one or more additional agents selected from, but not limited to, binders, disintegrants, lubricants, glidants, fillers, and / or diluents.

[0108] In some embodiments, the composition comprises one or more additional agents selected from: lactose monohydrate, anhydrous lactose, spray-dried lactose, sieved / screened / milled lactose, crystalline lactose, sucrose, trehalose, dextrose, fructose, dextrates, dextrin, anhydrous dextrose, sorbitol, mannitol, xylitol, maltitol solution, liquid glucose, and polydextrose.

[0109] Alternatively or additionally, the composition may contain one or more additional agents selected from: microcrystalline cellulose; cellulose powder or derivatives thereof of different molecular weights, including other forms such as gel, gum, crystal, cotton, sugar, alpha grade, paste, guar gum; pregelatinized corn starch; croscarmellose sodium; alginic acid; acacia; calcium phosphate (dibasic anhydrous / dihydrate, tribasic); sodium carboxymethylcellulose; carrageenan; silicified microcrystalline cellulose; cellulose acetate; cellulose acetate phthalate; carbomer; hydroxypropylcellulose (or low substituted); hydroxypropyl starch; hypromellose (and acetate succinate and phthalate); hydroxyethylcellulose; hydroxyethylmethylcellulose; hydroxypropylcellulose; sodium phosphate (dibasic or monobasic); sodium starch glycolate; corn starch; sucralose; povidone;Polyoxyethylene (including alkyl ethers, castor oil derivatives, sorbitan fatty acid esters, stearate, glycerides); shellac; sodium alginate; vitamin E polyethylene glycol succinate; calcium sulfate; carbomer (polyacrylic acid, carboxyvinyl polymer, carbopol); carrageenan; chitosan; hydroxypropyl starch; corn starch; pregelatinized starch; dextrates; dextrin; dextrose; glycerol behenate; Novagel® / Avicel® (such as PH 101, 102, 301, 302); Vivapur®; Emcocel®; Comprecel® and Microcel®.;

[0110] Alternatively or additionally, the composition may contain one or more additional agents selected from: crospovidone; PVP; polyvinyl-N-pyrrolidone; povidone, plasdone; polypasdone (including its XL / XL-10 / INF-10) with different particle size distribution (standard, fine, superfine, micronized); guar gum; hydroxypropylbetadex, hydroxypropyl starch, sodium starch glycolate, Kollidon® (with the full K value spectrum - PVP K12, PVP K15, PVP K17, PVP K30, PVP K60, PVP K90, bulk density, hydration capacity and peroxide content) and croscarmellose sodium.

[0111] Alternatively or additionally, the composition may comprise one or more additional agents selected from talc, magnesium silicate (monoclinic or triclinic), aluminum magnesium silicate, corn starch, kaolin, saponite, montmorillonite and titanium dioxide.

[0112] Alternatively or additionally, the composition may contain one or more additional agents selected from the group consisting of magnesium stearate (generally a mixture of crystalline forms - anhydrate, monohydrate, dihydrate and trihydrate containing Mg, Ca, Na), stearic acid, a composition of magnesium stearate to palmitate and other fatty acid esters such as palmitic acid, myristic acid, glyceride esters (glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate or Compritol 888) and sugar esters (sorbitan monostearate and sucrose monopalmitate); sodium stearyl fumarate; hydrogenated vegetable oil; hydrogenated castor oil; Sterotex; talc; waxes (such as anionic emulsifiers, carnauba, cetyl esters, microcrystalline, non-ionic emulsifiers, white or yellow); Stear-O-Wet; boric acid; Carbowax (PEG) 4000 / 6000; sodium oleate; Sodium benzoate; sodium acetate; sodium lauryl sulfate; and magnesium lauryl sulfate

[0113] Alternatively or additionally, the composition may contain one or more additional agents selected from the following: colloidal anhydrous silica or colloidal silicon dioxide; Aerosil; Cab-O-Sil; fumed silica; anhydrous silica; silicic anhydride; fumed silica; amorphous silica; magnesium trisilicate; magnesium silicate; and magnesium aluminum silicate.

[0114] In some embodiments, the composition comprises at least one additional agent selected from lactose monohydrate, microcrystalline cellulose, crospovidone, talc, magnesium stearate, and colloidal anhydrous silicon dioxide, or any combination thereof.

[0115] In some embodiments, the composition comprises the additional active ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, talc, magnesium stearate, and colloidal anhydrous silicon dioxide.

[0116] In some embodiments, the composition comprises or consists of: ingredient Amount (mg) NOMAC 1,5-3,5 17β-Estradiol 0,5-2,5 Lactose monohydrate 15-98 microcrystalline cellulose 5-90 Crospovidone 1-5 talc 0,2-2 Magnesium stearate 0,2-2 colloidal anhydrous silicon dioxide 0,2-2

[0117] In preferred embodiments, the composition comprises or consists of: ingredient Amount (mg) NOMAC 2,5 17ß-Estradiol 1,5 Lactose monohydrate 57,7 microcrystalline cellulose 14 Crospovidone 2,4 talc 0,7 Magnesium stearate 0,7 colloidal anhydrous silicon dioxide 0,44

[0118] In preferred embodiments, the composition comprises or consists of: ingredient Amount (mg) NOMAC 2,5 17β-Estradiol 1,55* Lactose monohydrate 57,7 microcrystalline cellulose 14 Crospovidone 2,4 talc 0,7 Magnesium stearate 0,7 colloidal anhydrous silicon dioxide 0,44 *Equivalent to 1.5 mg estradiol

[0119] In some embodiments, the composition is formulated for oral administration.

[0120] In some embodiments, the composition is in the form of uncoated or film-coated tablets, sugar-coated tablets, soft gelatin capsules, wafer capsules, pills, cachets, or powders.

[0121] In preferred embodiments, the composition is in the form of a film-coated tablet. In some embodiments, the film coating comprises one or more of the following: poly(vinyl alcohol), titanium dioxide, Macrogol 3350, and / or talc. (iv) Administration plan

[0122] The compositions for use according to the invention are, in some embodiments, administered at a frequency of once per day, i.e., daily. In some embodiments, the compositions are administered daily for a period of 21 to 28 days. In some embodiments, the compositions are administered daily for a period of 21 to 28 days per treatment cycle. In some embodiments, the compositions are administered for a period of 21 to 28 consecutive days per treatment cycle. In other embodiments, the compositions are administered for a period of 21 to 28 days with interruptions per treatment cycle. In a preferred embodiment, the compositions are administered once daily for a period of 24 consecutive days per treatment cycle.

[0123] The compositions may be administered once daily for a period of 24 consecutive days, followed by a hormone-free period of 4 consecutive days. The compositions may be administered once daily for a period of 24 consecutive days, followed by the administration of a placebo tablet once daily for a period of 4 consecutive days. The administration of 24 consecutive daily doses of the composition followed by 4 consecutive daily doses of placebo may constitute a treatment cycle. A treatment cycle may be immediately followed by one or more consecutive treatment cycles.

[0124] In preferred embodiments, the composition is administered as a monophasic composition for the duration of the administration period. (v) Medicine kits

[0125] In some embodiments, the compositions described herein are provided for use in the form of pharmaceutical kits, which kits optionally include instructions for use.

[0126] A pharmaceutical kit may comprise a plurality of dosage units of compositions such as those described herein. The pharmaceutical kit may optionally further comprise at least one placebo dosage unit.

[0127] In preferred embodiments, the pharmaceutical kits comprise or consist of 24 dosage units of a composition as described herein and 4 dosage units of a placebo. C. Contraceptive methods and practices

[0128] In another aspect, the invention provides the use of a composition comprising NOMAC and estradiol or one of its esters as a contraceptive, reducing the risk of venous thromboembolism (VTE) associated with the use of combined oral contraceptives (COCs).

[0129] In a further aspect, the invention also provides a method of contraception, the method comprising administering to a woman a composition comprising NOMAC and estradiol or one of its esters; and wherein the risk of VTE associated with the use of combined oral contraceptives (COCs) is reduced in the woman to whom the composition is administered.

[0130] All embodiments described herein relating to the composition for use according to the above aspects of the invention (see in particular Section B) are equally applicable to these further aspects of the invention. D. Treatment methods

[0131] Another aspect of the invention relates to a method of treating a condition which is one of the following: painful menstrual bleeding; heavy and / or prolonged menstrual bleeding; acne; ovarian cysts; polycystic ovary syndrome (PCOS); premenstrual syndrome (PMS); endometriosis; and premenstrual dysphoric disorder (PMDD), the method comprising administering to a woman a composition comprising nomegestrol acetate (NOMAC) and estradiol or one of its esters, wherein the risk of VTE associated with the use of combined oral contraceptives (COCs) is reduced in the woman to whom the composition is administered.

[0132] In a further aspect, the invention provides a composition for use in a method of treating any of the following conditions: painful menstrual bleeding; heavy and / or prolonged menstrual bleeding; acne; ovarian cysts; polycystic ovary syndrome (PCOS); premenstrual syndrome (PMS); endometriosis and premenstrual dysphoric disorder (PMDD), wherein the composition comprises nomegestrol acetate (NOMAC) and estradiol or one of its esters; and wherein the risk of VTE associated with the use of combined oral contraceptives (COCs) is reduced.

[0133] In some embodiments, the condition is a menstrual disorder. In some embodiments, the condition is painful menstrual bleeding. In some embodiments, the condition is dysmenorrhea.

[0134] In some embodiments, the condition is heavy and / or prolonged menstrual bleeding. In some embodiments, the condition is metrorrhagia. In some embodiments, the condition is polymenorrhea. In some embodiments, the condition is ovarian cysts. In some embodiments, the condition is polycystic ovary syndrome (PCOS). In some embodiments, the condition is premenstrual syndrome (PMS). In some embodiments, the condition is endometriosis.

[0135] In some embodiments, the disorder is premenstrual dysphoric disorder (PMDD). In some embodiments, the disorder is acne. In some embodiments, the disorder is hirsutism.

[0136] All embodiments described herein relating to compositions for use according to the above aspects of the invention (see in particular Section B) are equally applicable to these further aspects of the invention. Incorporation by reference

[0137] In the above description and the following example, various publications are cited, each of which is incorporated by reference in its entirety. EXAMPLE

[0138] The invention is explained in more detail with reference to the following non-limiting example. Prospective, controlled cohort study of the safety of a monophasic oral contraceptive containing nomegestrol acetate (2.5 mg) and 17β-estradiol (1.5 mg) (the PRO-E2 study)1. Summary

[0139] A large clinical trial was conducted to evaluate the safety of a monophasic combined oral contraceptive (COC) containing nomegestrol acetate (NOMAC) and 17β-estradiol. This COC—referred to here as NOMAC-E2—has been on the market for some time without any serious health concerns. However, this multinational, non-randomized, controlled, prospective, active surveillance study was conducted to compare the risk of rare serious adverse events in a large cohort of women taking NOMAC-E2 compared to a large cohort of women taking another COC—referred to here as COC LNG The COCs used in this study LNG -Comparator products are considered to be one of the CHCs with the lowest VTE risk in patients and are therefore usually used as first-choice CHCs.

[0140] The main clinical outcome of interest was venous thromboembolism (VTE), particularly deep vein thrombosis (DVT) of the lower extremities and pulmonary embolism (PE).

[0141] The results presented here are based on 91,313 women (44,559 NOMAC-E2 users and 46,754 COC LNG users) who were enrolled in the study between August 2014 and September 2019. 62.6% of NOMAC-E2 users and 64.4% of COC LNG -Users were first-time users (i.e., women who had not previously received COC treatment). A total of 37.4% of NOMAC-E2 users and 35.6% of COC LNG -Users were re-users (i.e., women who had previously received COC treatment). During the follow-up period, subcohorts emerged as women switched to other COCs or discontinued use of hormonal contraceptives. These subcohorts included: COC ,andere(i.e. users of COCs other than NOMAC-E2 or COC LNG ), other hormonal contraceptives (OHC) (e.g., users of progestin-only OCs, vaginal rings, intrauterine devices, or implants), and ex-users (i.e., women who do not use hormonal contraception).

[0142] The NOMAC-E2 cohort had a higher mean age than the COC LNG cohort and the difference was statistically significant (NOMAC-E2: 31.0 years; COC LNG : 29.3 years). NOMAC-E2 users and COC LNG -Users had a similar average weight (NOMAC-E2: 63.3 kg; COC LNG : 63.1 kg) and a similar BMI (NOMAC-E2: 23.2; COC LNG : 23.3). Gynecological history and baseline risk factors differed little between the cohorts.

[0143] Data were collected from 144,901 female observation years (WY), including 48,846 WY from NOMAC-E2 users and 54,037 WY from COC LNG -users. The remaining observation time was contributed by the subcohorts that formed during the follow-up: COC Other (8,300 WY), OHC (2,364 WY) and former users (31,354 WY).

[0144] In total, there were 30 deaths: 10 due to accidents (3 in NOMAC-E2 users, 3 in COC LNG -users, 1 in an OHC user and 3 in former users), 7 due to cancer (2 in NOMAC-E2 users and 5 in former users), 5 of unknown cause (1 in a NOMAC-E2 user, 1 in a COC LNG -user and 3 in former users), 3 due to infectious diseases (1 in a NOMAC-E2 user, 1 in a COC LNGuser and 1 in a former user), 2 due to acute myocardial infarction (1 in a COC user LNG and 1 in a COC user Other ), 1 due to a stroke (in a former user), 1 due to cerebral edema (in a user of COC LNG ) and 1 due to accidental poisoning and exposure to harmful substances (in a former user). An independent Safety Monitoring and Advisory Council (SMAC) assessed the deaths without knowing the exposure status to hormonal contraceptives and concluded that the deaths were not related to the use of hormonal contraceptives (19 deaths), a relationship was unlikely (4 deaths), or possible (3 deaths). Four further deaths (2 users of COC LNGand 2 former users) were classified as undetermined because there was insufficient information to allow the SMAC to adequately assess the association between death and hormonal contraceptive use.

[0145] In total, there were 34 VTEs in the main analysis of the primary outcome (lower extremity DVT and PE): 9 NOMAC-E2 (2.0 per 10,000 WY; 95% CI, 0.9-3.7), 15 COC LNG (3.0 per 10,000 WY; 95% CI, 1.7-5.0), 4 COC other OHC (4.8 per 10,000 WY; 95% CI, 0.1-26.8), and 5 former users (1.8 per 10,000 WY; 95% CI, 0.6-4.1). The Cox proportional hazards model a priori (complete case analysis) yielded a crude hazard ratio (HR crude ) for NOMAC-E2 versus COC LNG of 0.65 (95% CI, 0.28-1.48). After adjusting for age, BMI, family history of VTE, and current duration of HC use, the adjusted hazard ratio (HR adj ) 0.59 (95% CI, 0.25 - 1.35).

[0146] A total of 46 VTEs were included in the analysis of the secondary outcome of all VTE (i.e., not limited to lower extremity DVT and PE): 12 NOMAC-E2 (2.5 per 10,000 WY; 95% CI, 1.3-4.3), 20 COC LNG (3.7 per 10,000 WY; 95% CI, 2.3-5.7), 5 COC Other (6.0 per 10,000 WY; 95% CI, 2.0-14.1), 1 OHC (4.2 per 10,000 WY; 95% CI, 0.1-23.5), and 8 former users (2.6 per 10,000 WY; 95% CI, 1.1-5.0).

[0147] A total of 35 of the 46 confirmed VTEs were classified as idiopathic VTEs. The numbers and incidence rates for each (sub)cohort were as follows: NOMAC-E2 10 VTEs (2.0 per 10,000 WY; 95% CI, 1.0-3.8), COC LNG 15 VTEs (2.8 per 10,000 WY; 95% CI, 1.6-4.6), COC Other 5 VTEs (6.0 per 10,000 WY; 95% CI, 2.0-14.1), OHC 1 VTE (4.2 per 10,000 WY, 95% CI, 0.1-23.5) and former users 4 VTEs (1.3 per 10,000 WY; 95% CI, 0.35-3.3).

[0148] There were 16 confirmed ATEs: 4 NOMAC-E2 (0.8 per 10,000 WY; 95% CI, 0.2-2.1), 7 COC LNG (1.3 per 10,000 WY; 95% CI, 0.5-2.7), 1 COC anderer Art (1.2 per 10,000 WY; 95% CI, 0.0-6.7) and 4 former users (1.3 per 10,000 WY; 95% CI, 0.35-3.3).

[0149] In total, there were 62 thrombolic events (VTE and ATE): 16 in users of NOMAC-E2 (3.3 per 10,000 WY; 95% CI, 1.9-5.3), 27 in users of COC LNG (5.0 per 10,000 WY; 95% CI, 3.3-7.3), 6 in COC users Other (7.2 per 10,000 WY; 95% CI, 2.7-15.7), one in an OHC user (4.2 per 10,000 WY; 95% CI, 0.1-23.5), and 12 in former users (3.8 per 10,000 WY; 95% CI, 2.0-6.7). A Cox regression analysis was performed to compare the risk in NOMAC-E2 users with that in COC LNG -users. The a priori expert model resulted in an HR crudeof 0.68 (95% CI, 0.36 - 1.27) and after adjustment for age, BMI, current duration of HC use, family history of VTE and family history of ATE, an HR adj of 0.64 (95% CI, 0.34 - 1.20).

[0150] There were 289 unintended pregnancies among users of hormonal contraceptives: 64 NOMAC-E2 (0.15 per 100 WY; 95% CI, 0.11-0.19), 200 COC LNG (0.41 per 100 WY; 95% CI, 0.35-0.4 7), 19 COC Other (0.26 per 100 WY; 95% CI, 0.16-0.40) and 6 OHC (0.28 per 100 WY; 95% CI, 0.10-0.61). Unintended pregnancies were statistically significantly less likely in NOMAC-E2 users than in COC users. LNG (p<0.0001).

[0151] There were 261 cases of cholelithiasis (18.0 per 10,000 WY; 95% CI, 15.9-20.3): 84 NOMAC-E2 (17.2 per 10,000 WY; 95% CI, 13.7-21.3), 92 COC LNG (17.0 per 10,000 WY; 95% CI, 13.7 - 20.9), 21 COC Other(25.3 per 10,000 WY; 95% CI, 15.7-38.6), 8 OHC (33.8 per 10,000 WY; 95% CI, 14.6-66.6) and 56 former users (17.9 per 10,000 WY; 95% CI, 13.5-23.2) There were 24 cases of inflammatory bowel disease: 4 NOMAC-E2 (0.8 per 10,000 WY; 95% CI, 0.2-2.1), 13 COC LNG (2.4 per 10,000 WY; 95% CI, 1.3-4.1), 3 COC Other (3.6 per 10,000 WY; 95% CI, 0.75-10.6) and 4 former users (1.3 per 10,000 WY; 95% CI, 0.35-3.3).

[0152] Of the 191 cases of general hepatobiliary disorders, 65 occurred in users of NOMAC-E2 (13.3 per 10,000 WY; 95% CI, 10.3-17.0), 63 in users of COC LNG (11.7 per 10,000 WY; 95% CI, 9.0-14.9), 12 in COC users Other (14.5 per 10,000 WY; 95% CI, 7.5-25.2), 6 in users of OHC (2 5.4 per 10,000 WY; 95% CI, 9.3-55.2) and 45 in former users (14.4 per 10,000 WY; 95% CI, 10.5-19.2).

[0153] There were 188 cases of new depression or worsening of existing depression: 46 cases in NOMAC-E2 users (9.4 per 10,000 WY; 95% CI, 6.9-12.6), 80 in COC LNG -users (14.8 per 10,000 WY; 95% CI, 11.7-18.4), 13 in users of COC Other (15.7 per 10,000 WY; 95% CI, 8.3-26.8), 8 in users of OHC (33.8 per 10,000 WY; 95% CI, 14.6-66.6), and 41 in former users (13.1 per 10,000 WY; 95% CI, 9.4-17.7).

[0154] There was a trend towards a slight increase in mean body weight between study entry and follow-up for NOMAC-E2 and COC LNG -Users.

[0155] In general, NOMAC-E2 users appeared to experience greater improvement in their acne during follow-up (compared to baseline) than COC LNG -Users.

[0156] Further details about this clinical trial can be found below. 2. List of abbreviations 3. Basic principle and background

[0157] NOMAC-E2 is a monophasic OC containing a fixed dose of 2.5 mg nomegestrol acetate and 1.5 mg 17β-estradiol, taken for 24 days, followed by 4 days of placebo. Nomegestrol acetate has a strong affinity for the progesterone receptor and exhibits potent antigonadotropic activity and progesterone receptor-mediated antiestrogenic activity, as well as moderate antiandrogenic activity. It has no estrogenic, androgenic, glucocorticoid, or mineralocorticoid activity. The estrogen contained in NOMAC-E2 is 17β-estradiol, an estrogen identical to endogenous human 17β-estradiol.

[0158] Clinical experience with NOMAC-E2 and established COCs suggests that serious clinical outcomes may occur with the use of NOMAC-E2 and other COCs (including COCs containing levonorgestrel (COC LNG ) are rare. One of the most serious adverse events (AEs) associated with the use of COCs is VTE. The European Active Surveillance Study (EURAS) comprehensively investigated the risk of VTE and other serious cardiovascular events that might be associated with OC use (see Dinger JC et al., Contraception. (2007) 75: 344-354). However, for NOMAC-E2, there have been no similarly comprehensive data from large, controlled, prospective studies with defined follow-up measures for rare SAEs and low failure rates.

[0159] Data from randomized clinical trials have not revealed any serious health concerns related to NOMAC-E2. However, the statistical power to detect rare adverse events in these earlier studies was limited. Due to general public concerns about the safety of COCs, the prospective controlled cohort study on the safety of a monophasic oral contraceptive containing nomegestrol acetate (2.5 mg) and 17β-estradiol (1.5 mg) (PRO-E2) focused not only on VTE, but also on ATE, depressive disorders, cholelithiasis, general hepatobiliary disorders, inflammatory bowel disease, effects on fertility, pregnancy outcomes, weight changes, and the effects on acne.

[0160] The PRO-E2 study was conducted as a required post-authorisation safety study under Article 10a of EU Regulation 726 / 2004. The aim of the PRO-E2 study was to evaluate the cardiovascular and other health risks associated with the use of NOMAC-E2 compared with the use of COC LNG in standard clinical practice. The study included women who had received NOMAC-E2 or COC LNG was newly prescribed (either as first-time users or as re-users with at least a two-month break from COC use). During the follow-up period, subcohorts were formed if women switched to other COCs (formation of a COC Othersubcohort), switched to other hormonal contraceptives such as progestogen methods, injections, implants, levonorgestrel-releasing intrauterine devices and contraceptive patches (formation of an OHC subcohort) or discontinued the use of hormonal contraceptives (formation of a subcohort for former users).

[0161] As specified in the study protocol dated February 5, 2014, the following countries participated: Australia, Austria, France, Germany, Hungary, Italy, Poland, Russia, and Spain. Following protocol approval in April 2014, three additional countries (Mexico, Colombia, and Sweden) were enrolled in the study (as detailed in the final version of Addendum 1 to the study protocol dated June 20, 2019).

[0162] Patient recruitment began in Germany in August 2014. Recruitment subsequently began in Australia, Austria, Colombia, France, Hungary, Italy, Mexico, Poland, Russia, Spain, and Sweden after country-specific requirements were met. 4. Research questions and objectives

[0163] The main objective of the study was to compare the risks of using NOMAC-E2 with the use of COC LNG to characterize and compare in a study population representative of actual users of each drug. This included an estimate of the absolute risk of rare serious adverse events.

[0164] The main clinical outcomes of interest were VTE, specifically: - DVT of the lower extremities - PE

[0165] Secondary objectives of the study were the measurement / description for NOMAC-E2 users and the comparison with users of COC LNG during standard clinical practice: - All VTE, including thrombosis of the renal, mesenteric, portal and retinal veins - ATE incidence rate. ATE includes acute myocardial infarction (AMI) and cerebrovascular accidents (CVA) - Incidence rate of depressive disorders (based on assessment by treating psychiatrists and the Three Item Mental Health Inventory) - Incidence rate of cholelithiasis - Incidence rate of inflammatory bowel diseases - Effects on fertility - Drug use patterns and baseline risk for primary and secondary clinical outcomes - particularly cardiovascular outcomes - Pregnancy outcomes

[0166] Further secondary objectives were to measure / describe the following factors for NOMAC-E2 users and to compare them with users of COC LNG during standard clinical practice: - Weight change - General hepatobiliary disorders - Effects on acne 5. Research methodsStudy design

[0167] The study was a large, multinational, controlled, prospective, active observational study that followed two cohorts. The cohorts consisted of new users (beginners and re-users) of two different groups of hormonal contraceptives: NOMAC-E2 and COC. LNG. Novices were first-time users of a COC. Re-users were users who resumed using hormonal contraception with a COC (the same COC as before or a new COC) after a break of at least two months. This observational study provides standardized, comprehensive, and reliable information on these treatments in a routine clinical practice setting.

[0168] Study participants were recruited through an international network of COC-prescribing healthcare professionals (e.g., gynecologists, general practitioners, midwives). After study entry, study participants were followed for rare serious safety events over a period of 12 to 24 months. Regular, active contact with study participants provided the necessary information about health-related events or changes in health status. Additional follow-up procedures were used to validate participant-related events.

[0169] During the follow-up period, direct contact with study participants allowed us to capture almost all relevant clinical outcomes. However, laypeople often misclassify adverse events (e.g., pneumonia as "pulmonary embolism" or migraine attacks as "stroke," even when modern imaging techniques provide no clue to the perceived event). This type of inaccuracy in patient reports required careful validation of reported events. This was achieved by contacting the relevant physicians (i.e., treating physicians) and by reviewing source documents. Under routine medical conditions, clinical outcomes were not always confirmed by diagnostic procedures with high specificity.Therefore, the reported serious clinical outcomes were classified as "confirmed" or "not confirmed" by the physicians supervising this study according to a predefined algorithm. At the end of the study, this classification was verified by a blinded independent review. Setting

[0170] The PRO-E2 study was divided into two phases: a baseline survey completed by patients, which included an initial consultation at baseline by a participating physician during routine clinical practice, and a follow-up phase, which included two follow-up appointments with the patient during the first year and a follow-up visit 24 months after study entry. Subjects and study scope, including dropouts

[0171] The overall recruitment goal was to recruit 101,000 study participants (50,500 NOMAC-E2 users and 50,500 COC LNGusers) recruited by participating physicians. This should yield approximately 150,000 WY per month, assuming a dropout rate of approximately 0.7%.

[0172] Participating women were considered for inclusion in the PRO-E2 study after the participating physician and the woman had decided that taking NOMAC-E2 or COC LNG was appropriate. There were no specific medical inclusion / exclusion criteria and no age restrictions (to meet the requirements of the Pediatric Investigation Plan (PIP) in the EU). However, women who 1) were pregnant within 3 months of treatment initiation or 2) had a history of cancer / chemotherapy or an increased genetic risk for VTE at baseline were excluded from the VTE analysis.

[0173] After enrollment in the study, participants could stop (and restart) taking hormonal contraceptives or switch to a different hormonal contraceptive at any time. However, participants continued to be monitored regardless of whether they continued to use the prescribed contraceptive, provided they did not withdraw their consent. variables

[0174] The following variables were collected at baseline: ID number; date of birth; age at menarche; problems related to menstruation (e.g., irregular bleeding / spotting); hormonal contraceptive use (duration, brand name of last hormonal contraceptive used, hormonal contraceptive use in the past two months); reason(s) for prescription; previous pregnancies; pregnancy in the past three months; number of live births; number of miscarriages, stillbirths, abortions; family history of VTE and ATE; mood in the past four weeks; acne; impact of severe acne on self-esteem;Medical history (including DVT, PE, myocardial infarction, stroke, thrombophilia or hereditary increased risk of blood clots, depression requiring treatment, liver disease, gallbladder or bile duct disease, inflammatory bowel disease, cancer, diabetes, high blood pressure, other serious illnesses, surgeries); regular use of concomitant medications; height; weight; smoking status and number of cigarettes smoked daily; educational level; date of graduation.;

[0175] The following variables were recorded at follow-up: ID number; new SAEs / AEs; hospital stay (planned / unplanned, reason, surgery performed); use of hormonal contraceptives since last contact (discontinued / switched / unchanged, reason for discontinuation / switch); concomitant medication; pregnancy (occurrence, planned / unplanned, time to conception, pregnant despite use of OC, possible reasons for contraceptive failure); delivery; serious health problems of the newborn; mood in the last four weeks; acne; impact of severe acne on self-esteem; smoking status and number of cigarettes smoked daily; weight; date of completion; change in personal contact information; name of the treating physician in case of an SAE / AE. Exposure Cohort 1: NOMAC-E2 Cohort 2: Levonorgestrel-containing COCs: 1) Monophasic preparations containing 20-30 µg ethinylestradiol; 2) Multiphasic preparations containing up to 40 µg ethinylestradiol Result

[0176] The primary endpoint was VTE. Specific VTEs—lower extremity DVT and PE—were the primary outcomes of interest. Inferential statistics are based on VTE HR for NOMAC-E2 vs. COC. LNG This study provides data sufficiently robust to support a 1.5-fold VTE risk for NOMAC-E2 compared to COC LNG to exclude.

[0177] The secondary endpoints also investigated are described above in the “Research questions and objectives” section. Covariates

[0178] Regarding VTE risk, covariates include age, BMI, duration of current use, and family history of VTE. Data sources and measurement

[0179] Study participants documented their exposure to hormonal contraceptives and concomitant medications, the occurrence of primary and secondary endpoints, and the presence of potential confounders and potential effect modifiers in questionnaires. Where relevant, recruiting and treating physicians provided further information on supplementary documentation forms. Follow-up examinations for each study participant were scheduled for 6 months, 12 months, and 24 months after study entry. Questionnaires were administered to the participating women. In some cases, the events reported related to the time between regular follow-up examinations and concerned the participants themselves or their relatives, friends, or treating physicians. All reports (regardless of the source of information) were validated according to a standardized procedure.

[0180] The follow-up questionnaires addressed the occurrence of adverse events (especially SAEs). Reasons for discontinuing COCs or switching to another hormonal contraceptive were also explored, if applicable. Study procedures

[0181] Under routine medical conditions, the diagnosis of an SAE is not always confirmed by a diagnostic method with high specificity. Therefore, SAEs were classified as "confirmed" or "unconfirmed" according to the following predefined algorithm: - Definitive event: Confirmed by diagnostic measures with high specificity (e.g. phlebography in DVT, spiral CT in PE, cerebral MRI in cerebrovascular accidents, ECG with typical ST-segment elevation in acute myocardial infarction, histology in gynecological cancer, bilateral blood pressure measurement with diastolic blood pressure of more than 120 mmHg in hypertensive crisis). - Probable event: Lack of confirmation by a diagnostic measure with high specificity, but clinical diagnosis confirmed by a physician or supported by diagnostic tests with low specificity (e.g., D-dimer for VTE or typical ECG / blood gas tests for PE). These cases are typically characterized by subsequent specific therapy (e.g., fibrinolysis or long-term anticoagulant therapy). However, if the treating physician confirms that the diagnosis is correct, the event has been classified as a probable event, even if no specific treatment was provided. - Event not confirmed: - The diagnosis reported by the patient is excluded by diagnostic procedures. - The treating physician diagnoses another illness. - The participant did not consult a physician to clarify her symptoms, and no diagnostic measures were performed that could have clarified the diagnosis.

[0182] The exposure data referred to by the patients were validated through the prescribing physicians. Definite and probable events were classified as "confirmed events."

[0183] For VTE, the definition of “definite,” “probable,” and “unconfirmed” is further specified: - Definite VTE: Confirmed by imaging - DVT: phlebography, duplex sonography or magnetic resonance imaging (MRI). - PE: Pulmonary angiography, ventilation-perfusion scan, spiral computed tomography (CT), MRI or transesophageal echocardiography. - Probable VTE: No confirmation by imaging test, but a clinical diagnosis has been confirmed by a healthcare professional or is supported by a non-imaging test (such as ultrasound Doppler, plethysmography, D-dimer for VTE, or typical ECG / blood gas testing for PE). These cases are typically characterized by subsequent specific therapy (e.g., fibrinolysis or long-term anticoagulant therapy). However, if the treating physician has confirmed that the diagnosis is correct, the event has been classified as probable VTE, even if no specific treatment was provided. - VTE not confirmed: - VTE was ruled out by a doctor. - The treating physician diagnosed another illness. - The participant did not contact a doctor to clarify her symptoms, and no diagnostic measures were performed that could have clarified the diagnosis.

[0184] For the final analysis, this classification was verified by an independent blinded decision procedure. Scope of study

[0185] Sample size considerations were based on the expected VTE incidence for COC LNG . Sample size calculations were based on an incidence rate of 10 VTE per 10,000 WY 1 ("idiopathic" PE and DVT of the lower extremities) for COC LNG .

[0186] The study was designed to demonstrate the non-inferiority of NOMAC-E2 treatment with respect to VTE risk compared to the use of COC LNG The study was sufficiently powered to detect a 1.5-fold increased risk of VTE for NOMAC-E2 users compared to COC LNG -users if the actual VTE risk in NOMAC-E2 users is not higher than in COC LNG -Users.

[0187] The sample size required to investigate VTE risk was also sufficient for the evaluation of secondary endpoints (except for ATE). Acute myocardial infarction and stroke are very rare in women of childbearing age. The study was powered to detect a 2.5-fold increased risk of ATE in NOMAC-E2 users compared to COC users. LNG This was sufficient to search for safety signals and significant impacts. Statistical MethodsMain Summary Measures

[0188] Incidence rates, crude HRs, and adjusted HRs were calculated. Main statistical methods

[0189] The study used a non-inferiority design to investigate the VTE risk of NOMAC-E2. The a priori assumption was that the use of NOMAC-E2 compared to COC LNGis not associated with an increased risk of VTE (i.e. a statistical comparison of NOMAC-E2 and COC LNG should not show any difference). 6. ResultsParticipants

[0190] A total of 103,463 women participated in the study after being recruited by 2,413 physicians in Australia, Austria, Colombia, France, Germany, Hungary, Italy, Mexico, Poland, Russia, Spain, and Sweden. The results of the analyses presented here are based on 102,330 women. Descriptive data

[0191] Of the 91,313 women in the AT population, a total of 44,559 were users of NOMAC-E2 and 46,754 were users of COC LNG (48.8% and 51.2% of the study population, respectively). Of the 46,754 COC users LNG20,181 (22.1% of the total sample) were users of a monophasic preparation containing 20 µg EE, 17,469 (19.1% of the total sample) were users of a monophasic preparation containing 30 µg EE and 9,104 (10% of the total sample) were users of multiphasic preparations.

[0192] At study entry, the average age of NOMAC-E2 users was higher (31.0 years) than that of COC LNG -users (29.3 years), and this difference was statistically significant (p<0.0001). There were no significant differences in mean weight (NOMAC-E2: 63.3 kg; COC LNG : 63.1 kg) or the average BMI (NOMAC-E2: 23.2; COC LNG : 23.3). The distribution of cohorts by age category is shown in Fig. 1. Almost 33% of NOMAC-E2 users and 27% of COC LNG -Users were 35 years or older.

[0193] As mentioned above, beginners and returnees of COCs are included in the study population. Beginners accounted for 62.2% of NOMAC-E2 users and 64.4% of COC LNG -users. Returning users accounted for 37.8% and 35.6% of the NOMAC-E2 and COC LNG -users.

[0194] The distribution of cohorts by age category is shown in Fig. 1. Both cohorts of users had a similar weight (NOMAC-E2: 63.3 kg; COC LNG : 63.0 kg) and an average BMI indicating a healthy weight (NOMAC-E2: 23.2; COC LNG : 23.3).

[0195] Characteristics related to gynecological history were largely similar in both cohorts at baseline. These included the mean age at menarche (12.8 years for each cohort), the mean age at first delivery in parity women (NOMAC-E2: 24.3 years; COCLNG : 23.7 years), the mean number of live births (if ever pregnant) (1.0 in each cohort), and the mean number of miscarriages / stillbirths / abortion (if ever pregnant) (1.0 in each cohort). A larger proportion of NOMAC-E2 users reported ever having been pregnant (NOMAC-E2: 57.0%; COC LNG : 54.9%).

[0196] In this real-world observational study, women were asked about the reason(s) for their contraceptive prescription. Regarding motivating factors for COC use, 54.9% of NOMAC-E2 users reported that they wanted a COC prescribed solely for contraceptive purposes, compared to 57.1% of COC users. LNG The proportion of women who referred to both contraceptive and non-contraceptive reasons was 33.9% and 33.1% for NOMAC-E2 and COC, respectively. LNG-users. Meanwhile, 9.5% of NOMAC-E2 users and 8.6% of COC LNG -Users are advised to use COCs exclusively for non-contraceptive reasons (such as cycle control, acne, painful and / or prolonged / heavy bleeding).

[0197] The reasons other than contraception reported by study participants are listed in Table 1. Sometimes women reported more than one reason other than contraception. Table 1: Non-contraceptive reasons for prescribing COCs related to patients at study entry, by cohort Reason given by patient NOMAC-E2 (N = 50,187) COC LNG (N = 52,143) Total (N = 102,330) n % n % n % Cycle regulation 9,360 42.1 10,263 46.7 19,623 44.4 Painful menstrual bleeding 8,624 38.8 8,753 39.9 17,377 39.3 Heavy and / or prolonged menstrual bleeding 5,943 26.8 5,105 23.2 11,048 25.0 acne 2,178 9.8 1,875 8.5 4,053 9.2 Ovarian cysts 1,784 8.0 1,838 8.4 3,622 8.2 Polycystic Ovary Syndrome (PCOS) 1,328 6.0 1,334 6.1 2,662 6.0 Premenstrual syndrome (PMS) 1,293 5.8 1,047 4.8 2,340 5.3 Endometriosis 1,335 6.0 863 3.9 2,198 5.0 Spontaneous bleeding 551 2.5 617 2.8 1,168 2.6 Premenstrual dysphoric disorder (PMDD) 217 1.0 143 0.7 360 0.8 Other reasons 1,572 7.1 1,338 6.1 2,910 6.6 Note: Women could give multiple reasons.

[0198] At study entry, the women were also asked about (i) previously treated depression and (ii) previously treated acne. There were no significant differences between the cohorts. The women were also asked about their personal medical history and regular medication use. Outcome dataFatal consequences

[0199] A total of 30 study participants died during the study. Seven deaths involved NOMAC-E2 users: three were due to accidents, two were due to cancer (one woman died from late-stage lymphoma with liver metastases and the other from vulvar cancer with widespread metastases), one from a systemic herpes infection, and one from an unknown cause.

[0200] Without considering hormonal contraceptive exposure status, SMAC concluded that 19 of the deaths were not related to hormonal contraceptive use. One case, involving a NOMAC-E2 user with a history of heart disease who died of unknown causes, was assessed by SMAC as possibly related to hormonal contraceptive use because the cause of death was unknown. One case, involving a former user who died of unknown causes, was considered unlikely to be related to hormonal contraceptive use.In another case involving a former user who died for unknown reasons, the SMAC classified the relationship with the use of hormonal contraceptives as “undetermined” because there was insufficient information to assess a causal relationship. SAEs

[0201] There were a total of 3,388 SAEs. An SAE is defined in this study as an adverse event that results in death, a life-threatening experience, an inpatient hospitalization, persistent or significant disability / incapacity, or requires medical / surgical intervention to prevent any of these outcomes.

[0202] The incidence of SAEs was significantly lower in NOMAC-E2 users than in COC LNG -users. Of 3,388 SAEs, 983 occurred in NOMAC-E2 users, 1,225 in COC LNG -Users, 224 at COC Otherusers, 40 in OHC users, and 916 in former users. The corresponding incidence rates per 10,000 WY (and 95% confidence intervals) for each user cohort were as follows: 201.2 (189.0–214.1) for NOMAC-E2, 226.7 (214.3–239.6) for COC LNG , 269.9 (236.1 - 307.0) for COC Other , 169.2 (121.2 - 229.7) for OHC and 292.1 (273.8 - 311.4) for former users. In Fig. Incidence rates and 95% confidence intervals are shown graphically in Figure 2. Malignant neoplasm

[0203] A comparison of the user and (sub)cohorts showed no relevant difference: 41 NOMAC-E2 (8.4 per 10,000 WY; 95% CI, 6.0-11.4), 43 COC LNG (8.0 per 10,000 WY; 95% CI, 5.8-10.7), 5 COC Other(6.0 per 10,000 WY; 95% CI, 2.0-14.1), 1 OHC (4.2 per 10,000 WY; 95% CI, 0.1-23.5), and 40 former users (12.8 per 10,000 WY; 95% CI, 9.1-17.4). The most common cases were breast cancer: 11 NOMAC-E2 (2.3 per 10,000 WY; 95% CI, 1.1-4.0), 13 COC LNG (2.4 per 10,000 WY; 95% CI, 1.3-4.1), 4 COC Other (4.8 per 10,000 WY; 95% CI, 1.3-12.3), 1 OHC (4.2 per 10,000 WY; 95% CI, 0.1-23.5), and 19 former users (6.1 per 10,000 WY; 95% CI, 3.6-9.5). Main results

[0204] During the reporting period, data were collected from a total of 144,901 WY of observation. In addition to the cohorts at study entry (NOMAC-E2 and COC LNG ), several additional cohorts developed during the follow-up period as women switched to other forms of contraception or discontinued contraception use altogether. Table 2 shows the number of WY in each of the user cohorts. Table 2: Number of WY observations within each (sub)cohort (Sub-)cohort of users Female observation years Percentage of observation time NOMAC-E2 48,846 33.7 COC LNG 54,037 37.3 COC Other 8,300 5.7 Other hormonal contraceptives (OHC)* 2,364 1.6 Ex-users (no hormonal contraception) 31,354 21.6 Total 144,901 100** * Progestin-only OC, vaginal ring, injection, intrauterine device, contraceptive patch or implant. ** Rounding errors. Primary outcome measure of interest: DVT of the lower extremities and PE

[0205] In total, there were 38 confirmed VTEs, including the primary endpoint of interest (lower extremity DVT and PE): 10 in NOMAC-E2 users (2.0 per 10,000 WY; 95% CI, 1.0-3.8), 17 in COC users LNG (3.1 per 10,000 WY; 95% CI, 1.8-5.0), 4 in COC users Other (4.8 per 10,000 WY; 95% CI, 1.3-12.3), 1 in users of OHC (4.2 per 10,000 WY; 95% CI, 0.1-23.5) and 6 in former users (1.9 per 10,000 WY; 95% CI, 0.7-4.2) ( Fig. 3). Five women (2 users of COC LNG and 3 users of COC Other) experienced both lower extremity DVT and PE. The point estimates and 95% confidence intervals per user (sub)cohort are presented in Table 3. Table 3: DVT of the lower extremities and PE: Numbers, incidence rates per 10,000 WY and 95% confidence intervals per (sub)cohort category NOMAC-E2 (48,846 WY) COC LNG (54.037 WY) COC Other {8,300 WY} OHC (2,364 WY) Ex-user (31,354 WY) Total (144,901 WY) n Incidence** (95% CI) n Incidence** (95% CI) n Incidence** (95% CI) n Incidence** (95% CI) n Incidence** (95% CI) n Incidence** (95% CI) DVT of the lower extremities 10 2.0 (10-38) 17 3.1 (1.8-5.0) 4 4.8 (13-123) 1 n 4.2 (0.1-23.5) 6 1.9 (0.74.2) 38 2.6 (1.9-3.6) Of that: DVT 7 14 (0.6-3.0) 12 22 (1.1-3.9) 4 48 (1.3-12.3) 0 0.0 (0.0.15.6) 2 0.6 (0.1-2.3) 25 1.7 (1.1.2.5) PE 3 0.6 (0.1-1.8) 7 13 (0.5-2.7) 3 3.6 (0.75-10.6) 4.2 (0.1-1.235) 4 1.3 (0.35-3.3) 10 12 (0.7-2.0) *Pregnant within 3 months before starting treatment, history of cancer / chemotherapy, or increased genetic risk for VTE (e.g., Factor V Leiden, Protein S or Protein C deficiency). **Incidence rate per 10,000 WY Note: In five women (2 users of COC LNG and 3 users of COC other ) both DVT and PE occurred. DVT of the lower extremities and PE after exclusion of women with pre-defined risk factors at study entry

[0206] VTE risk estimates may be influenced by women who are pregnant within 3 months of treatment initiation, have a history of cancer / chemotherapy, or have an increased genetic risk for VTE (e.g., Factor V Leiden, protein S or C deficiency). Therefore, an analysis was planned that excluded all women who met these pre-defined risk factors at study entry. This resulted in 4 VTE participants being excluded from the analysis: 2 COC users. LNG and 1 former user who had been pregnant within 3 months of study entry, as well as 1 NOMAC-E2 user with a history of cancer / chemotherapy. Therefore, this analysis was based on 34 confirmed VTEs that included the primary outcome of interest (lower extremity DVT and PE): 9 in NOMAC-E2 users (2.0 per 10,000 WY; 95% CI, 0.9-3.7), 15 in COC users LNG(3.0 per 10,000 WY; 95% CI, 1.7-5.0), 4 in COC users Other (5.2 per 10,000 WY; 95% CI, 1.4-13.4), 1 in users of OHC (4.8 per 10,000 WY; 95% CI, 0.1-26.8) and 5 in former users (1.8 per 10,000 WY; 95% CI, 0.6-4.1) ( Fig. 4). The number of (primary endpoints) VTE, point estimates, and 95% confidence intervals for the (sub-)cohorts are presented in Table 4. Table 4: Lower extremity DVT and PE in women without known predefined risk factors at baseline: Number, incidence rates per 10,000 WY and 95% confidence intervals per (sub-)cohort category NOMAC-E2 (45,750 WY) COC LNG (49,729 WY) COC Other 7.320 WY) OHC (2,375 WY) Former users (28,375) Total (133,544 WY) n Incidence** (95% CI) n Incidence** (95% CI) n Incidence** (95% CI) n Incidence** (95% CI) N Incidence** n Incidence** (95% CI) DVT of the lower extremities 9 2.0 (0.9.3.7) 15 3.0 n (1.7-5.0) 4 5.2 (1.4-13.4) l 4.8 (0.1-26.8) 5 1.8 (0.6-4.1) 34 2.5 (1 8-3.6) Of that: DVT 6 1.3 (0.5-2.9) 11 2.2 (1.1-4.0) 4 5.2 1.4-13.4) 0 (0.0-17.8) 1 0.35 (0.01-2.0) 22 1.6 (1.0-2.5) PE 3 3.7 (0.1-1.9) 6 1.2 (0.4-2.6) 3 3.9 (0.8-11.5) 1 4.3 (0.1-26.8) 4 1.4 (0.4-3.6) 17 1.3 (0.7-2.0) * Women who were pregnant within 3 months prior to treatment initiation, had a history of cancer / chemotherapy, or had an increased genetic risk for VTE (e.g., Factor V Leiden, Protein S or Protein C deficiency). ** Incidence rate per 10,000 WY Note: In five women (2 users of COC LNG and 3 users of COC other ) both DVT and PE occurred.

[0207] The use of NOMAC-E2 does not appear to be associated with a higher risk of VTE than the use of other COCs. The HR crude for NOMAC-E2 vs. COC LNGof 0.65 with a 95% confidence interval of 0.28 - 1.48. After adjusting for age, BMI, family history of VTE and current duration of HC use, the HR was adj 0.59 (95% CI, 0.25 - 1.35).

[0208] The multiple imputation analysis resulted in an HR crude for NOMAC-E2 vs. COC LNG of 0.65 (95% CI, 0.28-1.48). After adjusting for age, BMI (multiple imputation), family history of VTE, and current duration of HC use, the HR was adj 0.59 (95% CI, 0.25 - 1.35). Lower extremity DVT and PE restricted to women using COCs for contraceptive purposes only

[0209] An analysis was conducted that was limited to women who reported that their prescription at study entry was solely for contraceptive purposes.

[0210] There were a total of 17 VTEs (2.4 per 10,000 WY; 95% CI, 1.4-3.9) among women who reported that their motivation for using the COC was solely for contraceptive reasons: 4 VTEs among NOMAC-E2 users (1.6 per 10,000 WY; 95% CI, 0.45-4.2), 10 VTEs among COC users LNG (3.6 per 10,000 WY; 95% CI, 1.7-6.7), 1 VTE in a COC user Other (2.8 per 10,000 WY; 95% CI, 0.1-15.7) and 2 VTE in former users (1.5 per 10,000 WY; 95% CI, 0.2-5.5) ( Fig. ). Table 5 shows the number of VTEs, point estimates, and 95% confidence intervals for the (sub)cohorts. Table 5: Lower extremity DVT and PE in women who were using NOMAC-E2 or COCLNG solely for contraceptive purposes at study entry: numbers, incidence rates per 10,000 WY, and 95% confidence intervals per (sub-)cohort category NOMAC-E2 (24,354 WY) COC LNG (27,443 WY) COC Other (3.554 OUT) OHC (1,043 WY) Ex-user (13,020 WY) Total (69,414 WY) n Incidence*** (95% CI) n Incidence*** (95% CI) n Incidence*** (95% CI) n Incidence*** (95% CI) n Incidence*** (95% CI) n Incidence*** (95% CI) DVT of the lower extremities 4 16 (0.45-4.2) 10 36 (1.7-6.7) 1 28 (0.1-15.7) 0 0.0 (0.0-35.3) 2 1.5 (0.2-5.5) 17 2.4 (1.4-3.9) Of that: DVT 2 0.8 (0.1-3.0) 6 22 (0.8-4.8) 1 2.8 (0.1-15.7) 0 0.0 (0.0-35.3) 1 0.8 (0.043) 10 1.4 (0.7-2.6) PE 2 0.8 (0.1-3.0) 6 2.2 (0.8-4.8) 1 2.8 (0.1-15.7) 0 0.0 (0.0-35.3) 1 0.8 (0.0-4.3) 10 1.4 (0.7-2.6) *Pregnant within 3 months of starting treatment, history of cancer / chemotherapy, or increased genetic risk for VTE (e.g., Factor V Leiden, Protein S or Protein C deficiency). ** Reasons for contraceptive use were recorded only at study entry and were not necessarily relevant at the time of the event. ***Incidence rate per 10,000 WY Note: In three women (2 users of COC LNG and 1 user of COC Other ) both DVT and PE occurred. Lower extremity DVT and PE by geographical region excluding Russia

[0211] The low overall incidence rate of lower extremity DVT and PE observed in this study (2.5 per 10,000 WY; 95% CI, 1.8-3.6) can be mainly explained by the particularly low VTE rate observed in Russian study participants, who constitute a large proportion (39.5%) of the PRO-E2 study population.

[0212] If Russia is excluded from the VTE analysis, incidence rates of 3.3 per 10,000 WY (95% CI, 1.4-6.5) for NOMAC-E2 and 4.7 per 10,000 WY (95% CI, 2.6-7.8) for COC are obtained. LNG ( Fig. 6). Except Australia, Colombia and Mexico

[0213] The analysis of the primary endpoint, which excluded data from Australia, Colombia, and Mexico, resulted in the calculation of risk estimates based on 33 VTE: 9 in NOMAC-E2 users (2.0 per 10,000 WY; 95% CI, 0.9-3.9), 14 in COC users LNG (3.0 per 10,000 WY; 95% CI, 1.7-5.1), 4 in users of COC Other (5.4 per 10,000 WY; 95% CI, 1.5-13.7) and 5 in former users (1.8 per 10,000 WY; 95% CI, 0.6-4.3). DVT of the lower extremities and PE according to user status (beginners vs. returning users)

[0214] A stratified analysis of VTE by user status (first-time, repeat) revealed no higher VTE risk for NOMAC-E2. There were 16 VTEs (lower extremity DVT and PE) among starters: 5 among NOMAC-E2 users (1.7 per 10,000 WY; 95% CI, 0.6–4.0), 6 among COC users LNG-users (1.9 per 10,000 WY; 95% CI, 0.7 - 4.1), 3 in users of COC Other (7.4 per 10,000 WY; 95% CI, 1.5-21.7) and 2 in former users (1.3 per 10,000 WY; 95% CI, 0.15-4.6). Among returners, 18 VTEs (lower extremity DVT and PE) occurred: 4 in NOMAC-E2 users (2.4 per 10,000 WY; 95% CI, 0.6-6.1), 9 in COC users LNG (5.0 per 10,000 WY; 95% CI, 2.3-9.5), 1 in COC users Other (2.8 per 10,000 WY; 95% CI, 0.1-15.5), 1 in users of OHC (9.4 per 10,000 WY; 95% CI, 0.2-52.4), and 3 in former users (2.4 per 10,000 WY; 95% CI, 0.5-6.9). Lower extremity DVT and PE by preparation type (monophasic vs. multiphasic)

[0215] The VTE risk in users of NOMAC-E2 was compared with the risk in users of monophasic COC LNG -Preparations with 20 µg EE (COC LNGMono / 20mcg ), COC LNG-Preparations with 30 µg EE (COC LNGMono / 30mcg ) and in users of multiphasic COC LNG -preparations (COC LNGMulti ). There were 9 VTEs in users of NOMAC-E2 (2.0 per 10,000 WY; 95% CI 0.9-3.7), 11 in users of COC LNGMono / 20mcg (4.9 per 10,000 WY; 95% CI, 2.4 - 8.7), 1 in COC users LNGMono / 30mcg (0.6 per 10,000 WY; 95% CI, 0.0 - 3.2) and 3 in COC users LNGMulti (3.2 per 10,000 WY; 95% CI, 0.7-9.3).

[0216] Hazard ratios (gross and after adjustment for age, BMI, family history of VTE, and current duration of use) were calculated. A comparison of NOMAC-E2 with monophasic COC LNG Preparations containing 20 mcg EE resulted in an HR crude of 0.4 (95% Cl, 0.1 - 1.1) and the HR adj was 0.3 (95% Cl, 0.1 - 1.0). The HR crude for NOMAC-E2 vs. COC LNGMono / 30mcg was 2.5 (95% CI, 0.3-20.6) and the HR adj was 2.6 (95% CI, 0.3-21.4). The HR crudefor NOMAC-E2 vs. COC LNGMulti was 0.5 (95% CI, 0.1-1.8) and the HR adj was 0.4 (95% CI, 0.1-1.6). Secondary endpoints of interest All VTE

[0217] A total of 46 VTEs were confirmed. In addition to the 38 VTEs that included lower extremity DVT or PE (the primary endpoint of interest) referenced in Table 33, there were 8 additional DVTs: 2 in NOMAC-E2 users (1 in the arm and 1 in the portal vein), 3 in COC users LNG (2 in the arm and 1 in the sinus vein), 1 in a COC user Other (in the arm) and 2 in former users (both in the subclavian vein). The numbers and incidence rates for each (sub)cohort were as follows: NOMAC-E2 12 VTEs (2.5 per 10,000 WY; 95% CI, 1.3-4.3), COC LNG 20 VTEs (3.7 per 10,000 WY; 95% CI, 2.3-5.7), COC Other5 VTEs (6.0 per 10,000 WY; 95% CI, 2.0-14.1), OHC 1 VTE (4.2 per 10,000 WY; 95% CI, 0.1-23.5) and former users 8 VTE (2.6 per 10,000 WY; 95% CI, 1.1-5.0) ( Fig. 7). Table 6: Number of VTE, point estimates and 95% confidence intervals for the (sub)cohorts. category NOMAC-E2 (48,846 WY) COC ING (54,037 WY) COC Other (8,300 WY) OHC (2,364 WY) Ex-user (31,354 WY) Total (144,901 WY) n Incidence* (95% CI) n Incidence* (95% CI) n Incidence* (95% CI) n Incidence* (95% CI) n Incidence* (95% CI) n Incidence* (95% CI) All VTE 12 25 (1343) 20 37 (2357) 5 6.0 (2.0-14.1) 1 4.2 (0.1-23.5) 8 2.6 1.1-5.0) 46 32 (234.2) Of that: DVT of the lower extremities and PE 10 2.0 (1.0-3.8) 17 3.1 (1.8-5.0) 4 : 48 (1.3-12.3) 1 : 42 (0.1-23.5) 6 19 (0.7-4.2) 38 2.6 (1.9-3.6) All other DVT 2 0.4 (0.0515) 3 0.56 (0116) 1 1.2 (0.0-6.7) 0 0.0 (0.0-15.6) 2 0.6 (0.1-2.3) 0 0.55 (021.1) * Incidence rate per 10,000 WY Idiopathic VTE

[0218] A total of 35 of the 46 confirmed VTEs were classified as idiopathic VTEs. The numbers and incidence rates for each (sub)cohort are as follows: NOMAC-E2 10 VTEs (2.0 per 10,000 WY; 95% CI, 1.0-3.8), COC LNG 15 VTEs (2.8 per 10,000 WY; 95% CI, 1.6-4.6), COC Other 5 VTEs (6.0 per 10,000 WY; 95% CI, 2.0-14.1), OHC 1 VTE (4.2 per 10,000 WY, 95% CI, 0.1-23.5) and former users 4 VTE (1.3 per 10,000 WY; 95% CI, 0.35-3.3). Summary of VTE results

[0219] A summary of the results of the numerous analyses conducted to assess the VTE risk in NOMAC-E2 users compared to COC users LNG to be evaluated is shown in Table 7. Table 7: Summary of results of VTE analyses: numbers, events, incidence rates per 10,000 WY and 95% confidence intervals in users of NOMAC-E2 and COCLNG category NOMAC-E2 COC LNG n Incidence* (95% CI) n Incidence* (95% CI) Primary outcome parameters (DVT of the lower extremities and PE) Main analysis (excluding women with pre-defined risk factors** at study entry) 9 2.0 (09-3.7) 15 3.0 (1.7-5.0) Only young people 0 0.0 (0.0-21.3) 2 5.9 (0.7-21.4) Without Russia 8 3.3 (1.4-5.5) 15 4.7 (2.6-7.8) Excluding Australia and Latin America 9 2.0 (0.9-3.9) 14 3.0 (1.7-5.1) Including Mexico 9 1.9 (0.9-3.7) 15 3.0 (1.7-5.0) Beginners only 5 1.7 (0.56-4.0) 6 1.9 (0.7-4.1) Only returning women 4 2.4 (0.6-6.1) 9 5.0 (2.3-8.5) Including ICD-10 code 180.3*** 10 2.2 (1.0-4.0) 16 3.2 (1.8-5.2) Assignment of a VTE to COC Other instead of NOMAC-E2 8 1.7 (0.75-3.4) 15 3.0 (1.75-5.0) COC use only for contraceptive purposes 4 1.6 (0.46-4.2) 10 3.6 (1.7-6.7) Monophasic COC LNG with 2.0 (0.9–3.9) mcg EE 9 2.0 (0.9-3.7) 11 4.9 (2.4-8.7) Monophasic COC LNG with 30 mcg EE 9 2.0 (0.9-3.7) 1 0.6 (0.01-3.2) Multiphasische COC LNG 9 2.0 (0.9-3.7) 3 3.2 (0.66-9.3) Including women with pre-defined risk factors** at study entry 10 2.0 (0.98-3.8) 17 3.1 (1.8-5.0) Secondary endpoint (all VTE) 12 2.5 (0.9-3.9) 20 3.7 (2.3-5.7) Confirmed and possible VTE 14 2.9 (1.6-4.8) 21 3.9 (2.4-5.9) Confirmed, possible and potential VTE 20 4.1 (2.5-6.3) 28 5.2 (3.4-7.5) Secondary outcome parameter (idiopathic VTE) 10 2.0 (0.98-3.8) 15 2.8 (1.6-4.8) *Incidence rate per 10,000 WY **Pregnant within 3 months of starting treatment, history of cancer / chemotherapy or increased genetic risk for VTE (e.g., factor V Leiden, protein S or protein C deficiency) at baseline. ***Phlebitis and thrombophlebitis of the lower extremities, unspecified. Further secondary results

[0220] There were 289 unintended pregnancies among users of hormonal contraceptives: 64 NOMAC-E2 (0.15 per 100 WY; 95% CI, 0.11-0.19), 200 COC LNG (0.41 per 100 WY; 95% CI, 0.35-0.4 7), 19 COC Other (0.26 per 100 WY; 95% CI, 0.16-0.40) and 6 OHC (0.28 per 100 WY; 95% CI, 0.10-0.61). Unintended pregnancies were statistically significantly less likely in NOMAC-E2 users than in COC users. LNG (p<0.0001).

[0221] A total of 16 ATEs were confirmed: 4 ATEs (2 ischemic strokes, 1 TIA and 1 myocardial infarction) in NOMAC-E2 users (0.8 per 10,000 WY; 95% CI, 0.2-2.1), 7 ATEs (4 ischemic strokes and 3 AMIs) in COC users LNG (1.3 per 10,000 WY; 95% CI, 0.5-2.7), 1 ATE (one AMI) in a COC user Other (1.2 per 10,000 WY; 95% CI, 0.0-6.7) and 4 ATEs (3 ischemic strokes and 1 AMI) in former users (1.3 per 10,000 WY; 95% CI, 0.35-3.3).

[0222] There were 24 cases of inflammatory bowel disease. The numbers and incidences per (sub)cohort were as follows: 4 in NOMAC-E2 users (0.8 per 10,000 WY; 95% CI, 0.2-2.1), 13 in COC users LNG (2.4 per 10,000 WY; 95% CI, 1.3-4.1), 3 in COC users Other (3.6 per 10,000 WY; 95% CI, 0.75-10.6) and 4 in former users (1.3 per 10,000 WY; 95% CI, 0.35-3.3).

[0223] There were 261 cases of cholelithiasis (18.0 per 10,000 WY; 95% CI, 15.9-20.3): 84 NOMAC-E2 (17.2 per 10,000 WY; 95% CI, 13.7-21.3), 92 COC LNG (17.0 per 10,000 WY; 95% CI, 13.7 - 20.9), 21 COC Other (25.3 per 10,000 WY; 95% CI, 15.7-38.6), 8 OHC (33.8 per 10,000 WY; 95% CI, 14.6-66.6) and 56 former users (17.9 per 10,000 WY; 95% CI, 13.5-23.2)

[0224] There were 24 cases of inflammatory bowel disease: 4 NOMAC-E2 (0.8 per 10,000 WY; 95% CI, 0.2-2.1), 13 COC LNG (2.4 per 10,000 WY; 95% CI, 1.3-4.1), 3 COC Other Users (3.6 per 10,000 WY; 95% CI, 0.75-10.6) and 4 former users (1.3 per 10,000 WY; 95% CI, 0.35-3.3).

[0225] Of the 191 cases of general hepatobiliary disorders, 65 occurred in users of NOMAC-E2 (13.3 per 10,000 WY; 95% CI, 10.3-17.0), 63 in users of COC LNG(11.7 per 10,000 WY; 95% CI, 9.0-14.9), 12 in COC users Other (14.5 per 10,000 WY; 95% CI, 7.5-25.2), 6 in OHC users (25.4 per 10,000 WY; 95% CI, 9.3-55.2), and 45 in former users (14.4 per 10,000 WY; 95% CI, 10.5-19.2).

[0226] There were 188 cases of new depression or worsening of existing depression: 46 cases in NOMAC-E2 users (9.4 per 10,000 WY; 95% CI, 6.9-12.6), 80 in COC LNG -users (14.8 per 10,000 WY; 95% CI, 11.7-18.4), 13 in users of COC Other (15.7 per 10,000 WY; 95% CI, 8.3-26.8), 8 in OHC users (33.8 per 10,000 WY; 95% CI, 14.6-66.6), and 41 in former users (13.1 per 10,000 WY; 95% CI, 9.4-17.7).

[0227] Mean body weight increased between follow-up points (6, 12, and 24 months after study entry) compared to baseline in both NOMAC-E2 and COC LNG -users slightly. In general, acne appeared to improve more in NOMAC-E2 users during follow-up (compared to baseline) than in COC LNG -Users. Review of projections

[0228] The sample size calculations provided in the study protocol were based on an incidence of 10 VTE per 10,000 WY for COC LNGSample size calculations for a non-inferiority test of two exponential survival curves showed that an expected number of 150 VTE cases would be sufficient to achieve this goal. These calculations were based on the following assumptions: 1) a one-sided α of 0.05; 2) a power (1-β) of 0.80; and 3) a non-inferiority margin at an HR of 1.5. Given an incidence rate of 10 / 10,000 WY, a total of 150 VTE cases could be expected within 150,000 WY.

[0229] The results presented here suggest that the VTE risk in users of NOMAC-E2 and COC LNG is currently not equally high. Regarding the primary outcome of interest (lower extremity DVT and PE) in women without predefined risk factors at study entry, the rohe HR for NOMAC-E2 vs. COC LNG0.6 with a 95% confidence interval of 0.2 to 1.5. After adjusting for age, BMI, family history of VTE, and current duration of use, the HR remained adj for NOMAC-E2 vs. COC LNG at 0.6 (0.2-1.5). interpretation

[0230] These results show that users of NOMAC-E2 compared to users of COC LNG are not at higher risk for VTE, ATE, death, SAE, cholelithiasis, inflammatory bowel disease, general hepatobiliary disorders, depressive disorders, mood swings, weight changes, or acne. They also show that NOMAC-E2 users, compared to COC users, LNG have a lower risk of unwanted pregnancies. generalization

[0231] The study was designed to reflect the routine clinical use of COCs. Study participants were recruited from COC-prescribing healthcare professionals (e.g., gynecologists, general practitioners, midwives), and all new users of COCs were eligible to participate. Participation was not restricted by medical inclusion or exclusion criteria. Therefore, the potential for generalizing the results of this study is high. 7. SummaryInitial characteristics - NOMAC-E2 users had a higher average age at study entry than COC LNG -Users. Other baseline characteristics (including cardiovascular risk factors) were similar across the user cohorts. The similarities between cohorts suggest that confounding should be minimal. Primary endpoint of interest - The risk of lower extremity DVT and PE (VTE) was significantly lower in the NOMAC-E2 cohort (2.0 per 10,000 WY; 95% CI, 0.9-3.7) compared to the COC LNG cohort (3.0 per 10,000 WY; 95% CI, 1.7-5.0) lower. - The HR crude for NOMAC-E2 compared to COC LNG was 0.65 with a 95% confidence interval of 0.28 to 1.48. After adjustment for age, BMI, family history of VTE and current duration of use, the adjustierte HR at 0.6 (95% CI, 0.25-1.35). - COC LNG are considered to be one of the CHCs with the lowest VTE risk in patients and are therefore used as first-line CHCs. This study is the first to refer to NOMAC-E2, which, compared to COC LNG is associated with a lower risk of VTE. Therefore, this study supports the use of NOMAC-E2 as a first-line CHC. Secondary outcomes of interest - The risk for all VTE was lower in the NOMAC-E2 cohort (2.5 per 10,000 WY; 95% CI, 1.3-4.3) than in the COC LNG cohort (3.7 per 10,000 WY; 95% CI, 2.3-5.7). - The risk of idiopathic VTE was lower in NOMAC-E2 users (2.0 per 10,000 WY; 95% CI, 1.0-3.8) than in COC users s LNG (2.8 per 10,000 WY; 95% CI, 1.6-4.6). - There were no statistically significant differences between NOMAC-E2 users and COC LNG -Users regarding the risk of ATE, cholelithiasis, inflammatory bowel disease, general hepatobiliary disorders, depressive disorders, mood swings, weight or acne. - The risk of unintended pregnancy was statistically significantly lower in the NOMAC-E2 cohort (0.15 per 100 WY; 95% CI, 0.11-0.19) than in the COC LNG-Cohort (0.41 per 100 WY; 95% CI, 0.35 - 0.47) (p<0.0001) In general, NOMAC-E2 users appeared to experience greater improvement in their acne during follow-up (compared to baseline) than COC LNG -Users.

[0232] The invention can also be understood taking into account the numbered clauses below. 1. A composition for use in reducing the risk of venous thromboembolism associated with the use of combined oral contraceptives, the composition comprising nomegestrol acetate and estradiol or one of its esters. 2. Composition for use according to clause 1, whereby the risk of deep vein thrombosis is reduced. 3. A composition for use according to clause 1 or 2, wherein the risk of pulmonary embolism is reduced. 4. A composition for use according to any of the preceding clauses, wherein the risk of venous thromboembolism is reduced compared to a combined oral contraceptive containing levonorgestrel and optionally ethinylestradiol. 5. A composition for use according to any of the preceding clauses, wherein the risk of venous thromboembolism is reduced by at least 40%. 6. Composition for use according to any of the preceding clauses, wherein the hazard ratio is 0.5-0.6. 7. A composition for use according to any of the preceding clauses, wherein the composition is administered to a woman or women of childbearing potential as a means of contraception. 8. A composition for use according to any of the preceding clauses, wherein the composition is administered to a woman or women for a non-contraceptive purpose. 9. A composition for use according to clause 8, wherein the non-contraceptive use is selected from (i) the treatment of any of the following conditions: painful menstrual bleeding, heavy and / or prolonged menstrual bleeding, acne, ovarian cysts, polycystic ovary syndrome, premenstrual syndrome, endometriosis, or premenstrual dysphoric disorder; and / or (ii) the regulation of the menstrual cycle. 10. A composition for use according to any of the preceding clauses, wherein the composition is administered to a woman or women identified as being at increased risk of venous thromboembolism. 11. A composition for use according to any of the preceding clauses, wherein the composition is administered to a woman or women whose age is 35 years or more. 12. A composition for use according to any of the preceding clauses, wherein the composition is intended for a woman or women with a body mass index of more than 30 kg / m 2 and / or is administered to a woman or women with diabetes. 13. A composition for use according to any of the preceding clauses, wherein the composition is administered to a woman or women suffering from any of the following conditions: cancer, systemic lupus erythematosus, hemolytic uremic syndrome, inflammatory bowel disease, optionally Crohn's disease or ulcerative colitis, and sickle cell disease. 14. A composition for use according to any of the preceding clauses, wherein the composition is administered to a woman or women who have not previously received treatment with a combined oral contraceptive. 15. A composition for use according to any one of clauses 1-13, wherein the composition is administered to a woman or women who have previously received treatment with a combined oral contraceptive. 16. A composition for use according to any one of the preceding clauses, wherein the nomegestrol acetate and estradiol or one of its esters are present in the composition in a weight ratio of about 1.67 to 1. 17. A composition for use according to any one of the preceding clauses, wherein the nomegestrol acetate is present in an amount ranging from about 1.5 mg to about 3.75 mg. 18. A composition for use according to any one of the preceding clauses, wherein the estradiol or one of its esters is present in an amount ranging from about 0.5 mg to about 3 mg. 19. A composition for use according to any one of the preceding clauses, wherein the estradiol is 17β-estradiol; optionally, wherein the 17β-estradiol is in hemihydrate form. 20. A composition for use according to any one of the preceding clauses, wherein the nomegestrol acetate is present in an amount of about 2.5 mg and the estradiol is present in an amount of about 1.5 mg. 21. A composition for use according to any of the preceding clauses, wherein the composition is administered daily for a period of 21 to 28 days; optionally for a period of 24 consecutive days. 22. A composition for use according to any of the preceding clauses, wherein the composition is in the form of plain or film-coated tablets, sugar-coated tablets, soft gelatin capsules, wafer capsules, pills, wafers or powders. 23. A composition for use according to any one of the preceding clauses, wherein the composition further comprises at least one excipient selected from: lactose monohydrate; microcrystalline cellulose (E460); crospovidone (E1201); talc (E553b); magnesium stearate (E572); and colloidal anhydrous silicon dioxide; or any combination thereof. 24. A composition for use according to any one of the preceding clauses, the composition comprising: 2.5 mg nomegestrol acetate; 1.5 mg 17β-estradiol; 57.7 mg lactose monohydrate, 14 mg microcrystalline cellulose, 2.4 mg crospovidone, 0.7 mg talc, 0.7 mg magnesium stearate and 0.44 mg colloidal anhydrous silicon dioxide. 25. A composition for use according to any one of the preceding clauses, wherein the composition is provided as a pharmaceutical kit comprising a plurality of dosage units and optionally at least one placebo. 26. Use of a composition comprising nomegestrol acetate and estradiol or one of its esters as a contraceptive; whereby the risk of venous thromboembolism associated with the use of combined oral contraceptives is reduced. 27. A method of contraception, the method comprising administering to a woman a composition comprising nomegestrol acetate and estradiol or one of its esters, wherein the risk of venous thromboembolism associated with the use of combined oral contraceptives is reduced in the woman to whom the composition is administered. 28. A composition for use in a method of treating any of the following conditions: painful menstrual bleeding; heavy and / or prolonged menstrual bleeding; acne; ovarian cysts; polycystic ovary syndrome; premenstrual syndrome; endometriosis; and premenstrual dysphoric disorder, wherein the composition comprises nomegestrol acetate and estradiol or one of its esters; and reducing the risk of venous thromboembolism associated with the use of combined oral contraceptives. 29. A method for reducing the risk of venous thromboembolism associated with the use of combined oral contraceptives, the method comprising administering to a woman a composition comprising nomegestrol acetate and estradiol or one of its esters. QUOTES CONTAINED IN THE DESCRIPTION

[0000] This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions. Cited non-patent literature

[0000] Carey and Allen, The Obstetrician & Gynecologist 2012; 14: 223-228

[0002] World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception, The Lancet. (1995) 346: 1575-82

[0004] Practice Committee of the American Society for Reproductive Medicine, Fertility and Sterility. (2016) 107(1): 43-51 [0004, 0092] Dragoman et al., Int. J. Gynaecol Obstet. (2018) 141(3): 287-294

[0004] Steiner et al., Annu. Rev. Med. (1997) 48: 447-455

[0049] 10,000 women per year to 5 to 12 out of 10,000 women per year (depending on the active ingredient

[0063] Practice of the American Society for Reproductive Medicine, Fertility and Sterility. (2016) 107(1): 43-51

[0067] Dinger JC et al., Contraception. (2007) 75: 344-354

[0158] Study protocol of 5 February 2014, the following countries participated: Australia, Austria, France, Germany, Hungary, Italy, Poland, Russia and Spain

[0161] After approval of the study protocol in April 2014

[0161] Mexico, Colombia and Sweden) were included in the study (as outlined in the final version of Addendum 1 to the study protocol dated June 20, 2019

[0161]

Claims

[1] Use of a composition comprising nomegestrol acetate and estradiol or one of its esters for reducing the risk of venous thromboembolism associated with the use of combined oral contraceptives; wherein the risk of venous thromboembolism associated with the use of the composition is not greater than the risk of venous thromboembolism associated with the use of a combined oral contraceptive containing levonorgestrel. [2] Use of a composition comprising nomegestrol acetate and estradiol or one of its esters for reducing the risk of venous thromboembolism associated with the use of combined oral contraceptives; wherein the risk of venous thromboembolism associated with the use of the composition is reduced compared to a combined oral contraceptive containing levonorgestrel. [3] Use of the composition according to claim 1 or 2, wherein the risk of deep vein thrombosis and / or the risk of pulmonary embolism is reduced. [4] Use of the composition according to any one of the preceding claims, wherein: (i) the risk of venous thromboembolism is reduced compared to a combined oral contraceptive containing levonorgestrel and ethinylestradiol; and / or (ii) the risk of venous thromboembolism is reduced by at least 40%; and / or (ii) the hazard ratio is 0.5-0.6; and / or (iii) the composition is administered to a woman or women of childbearing potential as a contraceptive. [5] Use of the composition according to any one of the preceding claims, wherein the composition is administered to a woman or women for non-contraceptive use; and wherein the non-contraceptive use is optionally one of the following: (i) the treatment of one of the following conditions: painful menstrual bleeding, heavy and / or prolonged menstrual bleeding, acne, ovarian cysts, polycystic ovary syndrome, premenstrual syndrome, endometriosis or premenstrual dysphoric disorder; and / or (ii) regulation of the menstrual cycle. [6] Use of the composition according to any one of the preceding claims, wherein: (i) the composition is administered to a woman or women identified as being at increased risk of venous thromboembolism; and / or (ii) the composition is administered to a woman or women aged 35 years or older; and / or (iii) the composition of a woman or women with a body mass index of over 30 kg / m 2 and / or is administered to a woman or women with diabetes; and / or (iv) the composition is administered to a woman or women suffering from any of the following conditions: cancer, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease, optionally Crohn's disease or ulcerative colitis, and sickle cell disease. [7] Use of the composition according to any one of the preceding claims, wherein the composition is administered to a woman or women who have not previously received treatment with combined oral contraceptives. [8] Use of the composition according to any one of claims 1 to 6, wherein the composition is administered to a woman or women who have previously received treatment with combined oral contraceptives. [9] Use of the composition according to any one of the preceding claims, wherein (i) the nomegestrol acetate and estradiol or one of its esters are present in the composition in a weight ratio of about 1.67 to 1; and / or (ii) the nomegestrol acetate is present in an amount ranging from about 1.5 mg to about 3.75 mg; and / or (iii) the estradiol or one of its esters is in an amount ranging from about 0.5 mg to about 3 mg; and / or (iv) the estradiol is 17ß-estradiol; optionally, wherein the 17ß-estradiol is in hemihydrate form; and / or (v) the nomegestrol acetate is present in an amount of about 2.5 mg and the estradiol is present in an amount of about 1.5 mg. [10] Use of the composition according to any one of the preceding claims, wherein the composition is administered daily for a period of 21 to 28 days; optionally for a period of 24 consecutive days. [11] Use of the composition according to any one of the preceding claims, wherein the composition is in the form of tablets, film-coated tablets, sugar-coated tablets, soft gelatin capsules, wafer capsules, pills, cachets or powders. [12] Use of the composition according to any one of the preceding claims, wherein (i) the composition further comprises at least one excipient selected from: Lactose monohydrate; microcrystalline cellulose (E460); crospovidone (E1201); talc (E553b); magnesium stearate (E572); and colloidal anhydrous silicon dioxide; or any combination thereof; and / or (ii) the composition contains: 2.5 mg nomegestrol acetate; 1.5 mg 17ß-estradiol; 57.7 mg lactose monohydrate; 14 mg microcrystalline cellulose; 2.4 mg crospovidone; 0.7 mg talc; 0.7 mg magnesium stearate and 0.44 mg colloidal anhydrous silicon dioxide. [13] Use of the composition according to any one of the preceding claims, wherein the composition is provided as a pharmaceutical kit comprising a plurality of dosage units and optionally at least one placebo. [14] Use of a composition comprising nomegestrol acetate and estradiol or one of its esters for treating a condition selected from: painful menstrual bleeding; heavy and / or prolonged menstrual bleeding; acne; ovarian cysts; polycystic ovary syndrome; premenstrual syndrome; endometriosis; and premenstrual dysphoric disorder; and wherein the risk of venous thromboembolism associated with the use of combined oral contraceptives is reduced; and wherein the risk of venous thromboembolism associated with the use of the composition comprising nomegestrol acetate and estradiol or one of its esters is not higher than the risk of venous thromboembolism associated with the use of a combined oral contraceptive composition containing levonorgestrel. [15] Use of the composition according to claim 14, wherein the risk of venous thromboembolism is reduced compared to a combined oral contraceptive containing levonorgestrel. [16] A composition for use in reducing the risk of venous thromboembolism associated with the use of combined oral contraceptives, the composition comprising nomegestrol acetate and estradiol or one of its esters; and wherein the risk of venous thromboembolism associated with the use of the composition comprising nomegestrol acetate and estradiol or one of its esters is not higher than the risk of venous thromboembolism associated with the use of a combined oral contraceptive containing levonorgestrel. [17] A composition for use according to claim 16, wherein the risk of venous thromboembolism is reduced compared to a combined oral contraceptive containing levonorgestrel. [18] A composition for use according to claim 16 or 17, wherein the risk of deep vein thrombosis and / or the risk of pulmonary embolism is reduced. [19] Composition for use according to any one of claims 16 to 18, wherein: (i) the risk of venous thromboembolism is reduced compared to a combined oral contraceptive containing levonorgestrel and ethinylestradiol; and / or (ii) the risk of venous thromboembolism is reduced by at least 40%; and / or (ii) the hazard ratio is 0.5-0.6; and / or (iii) the composition is administered to a woman or women of childbearing potential as a contraceptive. [20] A composition for use according to any one of claims 16 to 19, wherein the composition is administered to a woman or women for non-contraceptive use; and wherein the non-contraceptive use is optionally one of the following: (i) the treatment of one of the following conditions: painful menstrual bleeding, heavy and / or prolonged menstrual bleeding, acne, ovarian cysts, polycystic ovary syndrome, premenstrual syndrome, endometriosis or premenstrual dysphoric disorder; and / or (ii) regulation of the menstrual cycle. [21] Composition for use according to any one of claims 16 to 20, wherein: (i) the composition is administered to a woman or women identified as being at increased risk of venous thromboembolism; and / or (ii) the composition is administered to a woman or women aged 35 years or older; and / or (iii) the composition of a woman or women with a body mass index of over 30 kg / m 2 and / or is administered to a woman or women with diabetes; and / or (iv) the composition is administered to a woman or women suffering from any of the following conditions: cancer, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease, optionally Crohn's disease or ulcerative colitis, and sickle cell disease. [22] A composition for use according to any one of claims 16 to 21, wherein the composition is administered to a woman or women who have not previously received treatment with combined oral contraceptives. [23] A composition for use according to any one of claims 16 to 22, wherein the composition is administered to a woman or women who have previously received treatment with combined oral contraceptives. [24] Composition for use according to any one of claims 16 to 23, wherein (i) the nomegestrol acetate and estradiol or one of its esters are present in the composition in a weight ratio of about 1.67 to 1; and / or (ii) the nomegestrol acetate is present in an amount ranging from about 1.5 mg to about 3.75 mg; and / or (iii) the estradiol or one of its esters is in an amount ranging from about 0.5 mg to about 3 mg; and / or (iv) the estradiol is 17ß-estradiol; optionally, wherein the 17ß-estradiol is in hemihydrate form; and / or (v) the nomegestrol acetate is present in an amount of about 2.5 mg and the estradiol is present in an amount of about 1.5 mg. [25] A composition for use according to any one of claims 16 to 24, wherein the composition is administered daily for a period of 21 to 28 days; optionally for a period of 24 consecutive days. [26] The composition for use according to any one of claims 16 to 25, wherein the composition is in the form of tablets, film-coated tablets, sugar-coated tablets, soft gelatin capsules, wafer capsules, pills, cachets or powders. [27] A composition for use according to any one of claims 16 to 26, wherein (i) the composition further comprises at least one excipient selected from: Lactose monohydrate; microcrystalline cellulose (E460); crospovidone (E1201); talc (E553b); magnesium stearate (E572); and colloidal anhydrous silicon dioxide; or any combination thereof; and / or (ii) the composition contains: 2.5 mg nomegestrol acetate; 1.5 mg 17β-estradiol; 57.7 mg lactose monohydrate; 14 mg microcrystalline cellulose; 2.4 mg crospovidone; 0.7 mg talc; 0.7 mg magnesium stearate and 0.44 mg colloidal anhydrous silicon dioxide. [28] A composition for use according to any one of claims 16 to 27, wherein the composition is provided as a pharmaceutical kit comprising a plurality of dosage units and optionally at least one placebo. [29] A composition for use in a method of treating any of the following conditions: painful menstrual bleeding; heavy and / or prolonged menstrual bleeding; acne; ovarian cysts; polycystic ovary syndrome; premenstrual syndrome; endometriosis; and premenstrual dysphoric disorder, wherein the composition comprises nomegestrol acetate and estradiol or one of its esters; and wherein the risk of venous thromboembolism associated with the use of combined oral contraceptives is reduced; and wherein the risk of venous thromboembolism associated with the use of the composition comprising nomegestrol acetate and estradiol or one of its esters is not higher than the risk of venous thromboembolism associated with the use of a combined oral contraceptive composition containing levonorgestrel. [30] A composition for use according to claim 29, wherein the risk of venous thromboembolism is reduced compared to a combined oral contraceptive containing levonorgestrel. [31] A composition for use in reducing the risk of venous thromboembolism associated with the use of combined oral contraceptives, the composition comprising nomegestrol acetate and estradiol or one of its esters. [32] A composition for use according to claim 31, wherein the risk of deep vein thrombosis is reduced. [33] A composition for use according to claim 31 or 32, wherein the risk of pulmonary embolism is reduced. [34] A composition for use according to any one of claims 31 to 33, wherein the risk of venous thromboembolism is reduced compared to a combined oral contraceptive containing levonorgestrel and optionally ethinylestradiol. [35] A composition for use according to any one of claims 31 to 34, wherein the risk of venous thromboembolism is reduced by at least 40%. [36] Composition for use according to any one of the preceding claims 31 to 35, wherein the hazard ratio is 0.5-0.

6. [37] A composition for use according to any one of claims 31 to 36, wherein the composition is administered to a woman or women of childbearing age as a contraceptive. [38] A composition for use according to any one of claims 31 to 37, wherein the composition is administered to a woman or women for a non-contraceptive purpose. [39] A composition for use according to claim 38, wherein the non-contraceptive use is selected from (i) the treatment of any of the following conditions: painful menstrual bleeding, heavy and / or prolonged menstrual bleeding, acne, ovarian cysts, polycystic ovary syndrome, premenstrual syndrome, endometriosis, or premenstrual dysphoric disorder; and / or (ii) the regulation of the menstrual cycle. [40] A composition for use according to any one of claims 31 to 39, wherein the composition is administered to a woman or women identified as being at increased risk of venous thromboembolism. [41] A composition for use according to any one of claims 31 to 40, wherein the composition is administered to a woman or women whose age is 35 years or more. [42] A composition for use according to any one of claims 31 to 41, wherein the composition is addressed to a woman or women having a body mass index of more than 30 kg / m 2 and / or is administered to a woman or women with diabetes. [43] A composition for use according to any one of claims 31 to 42, wherein the composition is administered to a woman or women suffering from any of the following diseases: cancer, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease, optionally Crohn's disease or ulcerative colitis, and sickle cell disease. [44] A composition for use according to any one of claims 31 to 43, wherein the composition is administered to a woman or women who have not previously received treatment with a combined oral contraceptive. [45] A composition for use according to any one of claims 31 to 43, wherein the composition is administered to a woman or women who have previously received treatment with a combined oral contraceptive. [46] A composition for use according to any one of claims 31 to 45, wherein the nomegestrol acetate and estradiol or an ester thereof are present in the composition in a weight ratio of about 1.67 to 1. [47] A composition for use according to any one of claims 31 to 46, wherein the nomegestrol acetate is present in an amount ranging from about 1.5 mg to about 3.75 mg. [48] ​​A composition for use according to any one of claims 31 to 47, wherein the estradiol or an ester thereof is present in an amount ranging from about 0.5 mg to about 3 mg. [49] A composition for use according to any one of claims 31 to 48, wherein the estradiol is 17ß-estradiol; optionally, wherein the 17ß-estradiol is in hemihydrate form. [50] A composition for use according to any one of claims 31 to 49, wherein the nomegestrol acetate is present in an amount of about 2.5 mg and the estradiol is present in an amount of about 1.5 mg. [51] A composition for use according to any one of claims 31 to 50, wherein the composition is administered daily for a period of 21 to 28 days; optionally for a period of 24 consecutive days. [52] A composition for use according to any one of claims 31 to 51, wherein the composition is in the form of plain or film-coated tablets, sugar-coated tablets, soft gelatin capsules, wafer capsules, pills, wafers or powders. [53] A composition for use according to any one of claims 31 to 52, wherein the composition further comprises at least one excipient selected from: lactose monohydrate; microcrystalline cellulose (E460); crospovidone (E1201); talc (E553b); magnesium stearate (E572); and colloidal anhydrous silicon dioxide; or any combination thereof. [54] A composition for use according to any one of claims 31 to 53, wherein the composition comprises: 2.5 mg nomegestrol acetate; 1.5 mg 17β-estradiol; 57.7 mg lactose monohydrate, 14 mg microcrystalline cellulose, 2.4 mg crospovidone, 0.7 mg talc, 0.7 mg magnesium stearate and 0.44 mg colloidal anhydrous silicon dioxide. [55] A composition for use according to any one of claims 31 to 54, wherein the composition is provided as a pharmaceutical kit comprising a plurality of dosage units and optionally at least one placebo. [56] Use of a composition comprising nomegestrol acetate and estradiol or one of its esters as a contraceptive; whereby the risk of venous thromboembolism associated with the use of combined oral contraceptives is reduced. [57] A composition for use in a method of treating any of the following conditions: painful menstrual bleeding; heavy and / or prolonged menstrual bleeding; acne; ovarian cysts; polycystic ovary syndrome; premenstrual syndrome; endometriosis; and premenstrual dysphoric disorder, wherein the composition comprises nomegestrol acetate and estradiol or one of its esters; and reducing the risk of venous thromboembolism associated with the use of combined oral contraceptives.

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