Combined oral contraceptive with a favorable blood pressure profile

Abstract

The present invention relates to a combined oral contraceptive having a beneficial effect on blood pressure, to the associated compositions, dosage units, and packaging units thereof. Particularly, the present invention concerns the use of a composition comprising from about 1 mg to about 40 mg of estetrol and from about 0.5 mg to about 10 mg of drospirenone and which, during use, has a favorable effect on blood pressure.

Description

[0001] COMBINED ORAL CONTRACEPTIVE WITH A FAVORABLE BLOOD PRESSURE PROFILE

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to combined oral contraceptives. In particular, the invention relates to combined oral contraceptives comprising estetrol (E4) and a progestogenic component such as drospirenone (DRSP), which have a beneficial effect on the blood pressure profde. The invention also relates to contraceptive methods and uses thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] Combined Oral Contraceptives (COCs) comprising a progestogenic component and an estrogenic component are commonly used for contraception worldwide. The progestoenic component is primarily responsible for the contraceptive effect, while the main function of the estrogenic component is to balance the impact of the progestin on the endometrium. Historically, most COCs contain ethinyl estradiol (EE) as the estrogenic component, which is combined with a progestogenic component that may vary from product to product.

[0006] Despite their widespread use, COCs comprising an estrogenic component and a progestogenic component such as levonorgestrel have been known to increase the risk of hypertension in subjects taking the COC. In high normotensive or hypertensive subjects, taking a COC hence poses a potential risk. Consequently, for women with multiple cardiovascular risk factors the use of progestogen-only contraceptives (POCs) is usually recommended since POCs have been associated with substantially less risk of cardiovascular events when compared to standard ethinyl-estradiol-COCs since it has been reported that the ethinyl-estradiol (EE) in COCs is responsible for the increased cardiovascular risks and particularly the VTE events (Kaminski, P et al., Neuro Endocrinol Lett 2013;34:587-9). In addition, it was recently reported that a drospirenone (DRSP)-only contraceptive gives a slight decrease in blood pressure versus baseline (Kubba et al., Eur J Contracept Reprod Health Care (2023) Feb;28(l):36-43). The report also showed that the women with a baseline SBP value higher than 130 mmHg or a baseline DBP value higher than 85 mmHg (n= 130) had an average decrease of 7.0 mmHg with drospirenone- only at a daily dose of 4 mg for the systolic value and 5.5 mmHg for the diastolic value over time. For participants with average SPP (<130 mmHg) and DBP (<85 mmHg), the absolute mean change was 0.00 mmHg for both parameters.

[0007] Despite their advantages, POCs have the drawback of an unfavourable bleeding pattern and are hence not always preferred by premenopausal subjects. This suboptimal efficacy was even commented on and emphasized by the Food and Drug Administration (FDA) in a public letter to the manufacturer (FDA, Letter to Exeltis re NDA 211367 SLYND® (drospirenone) tablets, for oral use, 2023).

[0008] The increased risk of hypertension associated with the use of COCs was reported to be reduced when levonorgestrel is replaced with other progestins such as DRSP. In addition, several groups have reported on the effect of using a COC comprising ethinyl estradiol and progestins such as DRSP on blood pressure, and concluded that it slightly lowered (Oelkers, W et al. The Journal of clinical endocrinology and metabolism vol. 80,6 (1995): 1816-21) or did not significantly modify the systolic blood pressure (SBP) and diastolic blood pressure (DBP) of normotensive participants (Gaspard, U et al. Contraception vol. 67,6 (2003): 423-9). W02007081206A1 and WO03103683 Al disclose a method of treating an acute vascular disorder or for treating or preventing cardiovascular pathologies comprising orally administering, upon demand (W02007081206A1), an effective amount of E4 alone. There is no mentioning of contraception or a COC comprising a progestogenic such as drospirenone. A pre -menopausal population is not specified nor particularly envisaged throughout the documents.

[0009] WO2023174947A1 discloses a composition comprising E4 and DRSP for use in a subject diagnosed with, considered to have, or considered at risk to develop an endothelial vulnerability leading to an increase of cardiovascular risk. While a reference to blood pressure or hypertension is lacking, particular focus is on subjects who are at least in the perimenopausal stage of life.

[0010] Various reports have been published regarding the influence distinct COCs have on the risk of venous thromboembolism (VTE) risk. However, after investigation of a possible link between VTE and blood pressure, no evidence of a causal association between elevated SBP and VTE could be identified (Nazarzadeh, M et al., Journal of Hypertension 37:p e95, July (2019)). Therefore, any effect of a COC on thromboembolism does not indicate an effect on blood pressure.

[0011] In order to prevent the above mentioned risks, hypertensive subjects are today often recommended to use a progestin-only contraceptive such as a drospirenone-only pill. This however has the drawback of creating undesired bleeding profiles.

[0012] There hence remains a need in the art for a COC with a good bleeding profile and beneficial effect on blood pressure that can be used in subjects classified as at least pre-hypertensive..

[0013] SUMMARY OF THE INVENTION

[0014] By analysing the data of a Phase 3 clinical trial using a combined oral contraceptive (COC) comprising 15mg Estetrol (E4) monohydrate and 3mg Drospirenone (DRSP) - ESTELLE®, the inventors found that said COC can be considered as an alternative to progestogen-only pills, since E4 does not attenuate the antihypertensive effect of DRSP in high normotensive patients. More particular, in subjects that are pre-hypertensive (SBP > 120 to 139 mmHg and DBP > 80 to 89 mmHg), have normal baseline BP (SBP > 130 mmHg and / or DBP > 85 mmHg), have low range hypertension at baseline (SBP > 140 mmHg and / or DBP > 90 mmHg) or have stage 1 hypertension (SBP > 140 to 159 mmHg and DBP > 90 to 99 mmHg).

[0015] Indeed, the effects of E4 / DRSP on blood pressure in high normotensive participants were similar to that of the 4 mg DRSP alone study with an average decrease of 7.6 mmHg in SBP and 4.9 mmHg in DBP in the E4 / DRSP trial in the EU and 7.63 (± 9.72) mmHg for the SBP and 4.02 (± 7.71) mmHg in the DRSP alone study (the latter study being discussed extensively in Kubba et al., 2023 - The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception vol. 28,1 (2023): 36-43).

[0016] The present invention hence teaches that the presence of E4 in a DRSP-containing COC does not weaken the beneficial impact of DRSP on SBP and DBP. This is in contrast to reports on EE / DRSP, where the beneficial effect of DRSP seems to be reduced. This decrease in BP, which is limited to high-normotensive, low hypertensive, or even hypertensive subjects is to the patient's advantage and was unexpected. In fact, an unexpected synergistic effect can be assumed with the combination of E4 / DRSP: Although the concentration of DRSP in ESTELLE® is only 3 mg, comparable values are achieved as with said DRSP-alone pill, which, however, contains 4 mg of DRSP. E4 therefore enhances the blood pressure lowering effect of DRSP, resulting in an unexpected synergism between the two substances. COCs comprising estetrol and drospirenone may therefore be used as an alternative to POCs (such as but not limited to SLYND®), allowing for the concentration of DRSP to be decreased and the bleeding profile to be improved.

[0017] Unexpectedly, COCs different from E4 / DRSP, i.e. comprising another (non-estetrol) estrogen component, do not show synergism between the estrogen and the progestogen with regard to blood pressure effects. The present invention therefore shows for the first time that the effect of DRSP on blood pressure can be enhanced by combining DRSP with E4. The DRSP and E4 combination therefore results in a clear synergistic effect.

[0018] The invention therefore provides in the following aspects:

[0019] Aspect 1. A contraceptive method having a reduced risk of hypertension, comprising administering to a female subject an amount of estetrol and drospirenone, to reduce the risk of hypertension associated with the use of a combined oral contraceptive (COC) comprising an estrogenic and a progestogenic component, wherein the female subject is selected from subjects having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said COC.

[0020] Aspect 2. A combined oral contraceptive (COC) comprising estetrol and drospirenone for use in normalizing or reducing blood pressure in a female subject having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said COC.

[0021] Aspect 3. A combined oral contraceptive (COC) comprising estetrol and drospirenone for use in reducing the risk of hypertension in a female subject having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said COC.

[0022] Aspect 4. Use of a composition comprising estetrol and drospirenone for the manufacture of a medicament for use in normalizing or reducing blood pressure in a female subject, wherein said female subject is characterised by having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said composition.

[0023] Aspect 5. Use of a composition comprising estetrol and drospirenone for the manufacture of a medicament for reducing the risk of hypertension associated with the use of a combined oral contraceptive (COC) in a female subject, wherein said female subject is characterised by having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said COC.

[0024] Aspect 6. Use of a composition comprising estetrol and drospirenone for normalizing or reducing blood pressure in a female subject, wherein said female subject is characterised by having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said composition. Aspect 7. Use of a composition comprising estetrol and drospirenone for reducing the risk of hypertension associated with the use of a combined oral contraceptive (COC) in a female subject, wherein said female subject is characterised by having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said COC.

[0025] Aspect 8. A method of normalizing or reducing blood pressure in a female subject having a systolic blood pressure equal or higher than 120 mmHg and / or a diastolic blood pressure equal to or higher than 80 mmHg, comprising administering a COC comprising estetrol and drospirenone to said subject.

[0026] Aspect 9. A method of reducing the risk of hypertension associated with the use of a combined oral contraceptive (COC) in a female subject having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said COC, comprising administering a COC comprising estetrol and drospirenone to said subject.

[0027] Aspect 10. The contraceptive method according to aspect 1, the COC for use according to aspect 2 or 3, the use according to any one of aspects 4 to 7, or the method according to aspect 8 or 9, wherein the female subject is a pre-hypertensive, high normotensive (elevated) or low (stage 1) hypertensive subject.

[0028] Aspect 11. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the female subject is selected from subjects having a baseline systolic blood pressure equal to or higher than about 120 mmHg and / or a baseline diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said COC. In a preferred embodiment, the subject is pre-hypertensive (SBP > 120 to 139 mmHg and DBP > 80 to 89 mmHg), has high normal baseline BP (SBP > 130 mmHg and / or DBP > 85 mmHg), has low range hypertension at baseline (SBP > 140 mmHg and / or DBP > 90 mmHg) or has stage 1 hypertension (SBP > 140 to 159 mmHg and DBP > 90 to 99 mmHg).

[0029] Aspect 12. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the systolic and / or diastolic blood pressure is not increased versus the respective baseline blood pressure, preferably wherein the systolic and / or diastolic blood pressure is decreased by about 5% versus the respective baseline blood pressure, preferably wherein the baseline blood pressure is the blood pressure of the subject prior to the use of any COC or as measured while using a COC comprising as estrogenic component EE and as progestogenic component DRSP.

[0030] Aspect 13. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the systolic blood pressure is decreased to less than about 125 mmHg, preferably less than about 124 mmHg, preferably less than about 123 mmHg, preferably less than about 122 mmHg, preferably less than about 121 mmHg, or more preferably to less than about 120 mmHg.

[0031] Aspect 14. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the female subject is a subject of reproductive age, preferably a pre-menopausal subject.

[0032] Aspect 15. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the female subject is selected from subjects having an age of equal to or higher than about 30 years, preferably of equal to or higher than about 35 years, more preferably older than about 40 years. Aspect 16. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the female subject is selected from subjects having a body mass index (BMI) of equal to or higher than about 25 kg / m2, preferably equal to higher than about 30 kg / m2, more preferably equal to higher than about 30 kg / m2.

[0033] Aspect 17. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the female subject is selected from subjects that are smoking, preferably wherein the female subject is a subject that smokes at least one tobacco and / or nicotine-containing product or equivalent thereof per day.

[0034] Aspect 18. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the female subject is selected from subjects that are diabetic, preferably wherein the female subject is a subject diagnosed to have, or is considered to have diabetes mellitus, such as diabetes mellitus with vascular involvement (nephropathy, retinopathy, neuropathy, other) or diabetes mellitus of more than 20- year duration or diabetes mellitus without vascular involvement (nephropathy, retinopathy, neuropathy, other) or diabetes mellitus of more than 20-year duration, or is a subject diagnosed to have prediabetes (defined as having blood glucose levels that are higher than normal, but not yet at the point that defines diabetes.

[0035] Aspect 19. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the female subject has polycystic ovary syndrome (PCOS) and / or dysmenorrhea.

[0036] Aspect 20. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the female subject is selected from first-ever users and switchers / re-starters with a break of more than 4 weeks.

[0037] Aspect 21. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the estetrol is administered at a daily dose of from about 1 mg to about 40 mg.

[0038] Aspect 22. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the COC comprises from about 1 mg to about 40 mg of estetrol.

[0039] Aspect 23. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the estetrol is administered at a daily dose of from about 5 mg to about 25 mg, preferably at a daily dose of from about 10 mg to about 20 mg, more preferably at a daily dose of about 15 mg.

[0040] Aspect 24. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the COC comprises from about 5 mg to about 25 mg of estetrol, preferably from about 10 mg to about 20 mg of estetrol, more preferably about 15 mg of estetrol.

[0041] Aspect 25. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the drospirenone is administered at a daily dose of from about 0.5 mg to about 10 mg.

[0042] Aspect 26. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the COC comprises from about 0.5 mg to about 10 mg of drospirenone. Aspect 27. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the drospirenone is administered at a daily dose of from about 1 mg to about 4 mg.

[0043] Aspect 28. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the COC comprises from about 1 mg to about 4 mg of drospirenone.

[0044] Aspect 29. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the method is a combined administration method with an administration-free interval of about 7 days.

[0045] Aspect 30. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the method is a combined administration method with an administration-free interval of about 4 days.

[0046] Aspect 31. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the estetrol component is estetrol monohydrate.

[0047] Aspect 32. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the estetrol is administered at a daily dose of about 15 mg estetrol monohydrate.

[0048] Aspect 33. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the COC comprises about 15 mg of estetrol monohydrate.

[0049] Aspect 34. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the drospirenone is administered at a daily dose of about 3 mg.

[0050] Aspect 35. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the COC comprises about 3 mg of drospirenone.

[0051] Aspect 36. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the estetrol and drospirenone are formulated together in a single oral dosage unit.

[0052] Aspect 37. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the COC is formulated to provide a daily dose of the estetrol and drospirenone (i.e. formulated as a daily oral dosage unit).

[0053] Aspect 38. The contraceptive method, the COC for use, the use, or the method according to any one of aspects 1 to 35, wherein the estetrol is formulated in a first oral dosage unit and the drospirenone is formulated in a second oral dosage unit.

[0054] Aspect 39. The contraceptive method, the COC for use, the use, or the method according to aspect 38, wherein the first oral dosage unit is formulated to provide a daily dose of the estetrol and the second oral dosage unit is formulated to provide a daily dose of the drospirenone.

[0055] Aspect 40. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the subject has used the COC for at least one, two, three, or more cycles. Aspect 41. The contraceptive method, the COC for use, the use, or the method according to any one of the preceding aspects, wherein the systolic blood pressure is decreased at least about 1%, preferably at least about 2%, more preferably at least about 10% from prior to administration to after the second or third administration cycle.

[0056] Aspect 42. The contraceptive method, the COC for use, the use, or the method according to aspect 41, wherein said decrease is maintained substantially stable after the second or third administration cycle.

[0057] In any one of the aspects defined herein, said COC may be presented as a kit-of-parts containing a packaging unit, e.g. a blister pack, containing the daily oral dosage units comprising the estetrol and drospirenone. The skilled person will additionally know that, within the scope of the present invention, each packaging unit, e.g. blister pack, may be numbered or otherwise marked. In a particular embodiment of the kit-of-parts, the packaging unit comprises 28 containers or a multitude of 28 containers, such as 2 to 12 times 28 containers. In a preferred embodiment, the packaging unit comprises 3 or 6 times 28 containers. Within the scope of the invention, each packaging unit may be a sealed blister pack with a cardboard, paperboard, foil plastic backing and enclosed in a suitable cover.

[0058] A preferred embodiment is directed to a packaging unit comprising the COCs described herein. The packaging unit may comprise at least 14, preferably at least 21, even more preferably at least 28, containers for holding separately packaged and individually removable COCs, wherein each container comprises at least one COC as described herein. Optionally, each of the containers for holding one or more COCs is individually visually arranged to present a recommended order of administration. By means of illustration and not limitation, each packaging unit may be a sealed blister pack with a cardboard, paperboard, foil plastic backing and enclosed in a suitable cover. Each supplied plastic blister may contain 24 active (COC-containing) tablets, that may be coloured (e.g. pink) and 4 inactive (non-COC containing) tablets, that may be colourless or white.

[0059] The skilled person appreciates that within the scope of the present invention, each packaging unit, e.g. blister pack, may be numbered or otherwise marked. The packaging units may be provided in any suitable packaging means known in the art, non-limiting examples being troches, sachets, pouches, bottles, films, sprays, microcapsules, implants, rods or blister packs.

[0060] Also envisaged in any one of the aspects defined herein are packaging units such as bottles. The material of the bottle is not particularly limiting. In preferred embodiments, the bottle is a glass bottle characterized by a colour capable of reducing or preventing degradation of the contents of the bottle by e.g. UV light while maintaining a degree of transparency that allows for visual inspection of the contents of said bottle. Suitable colours include without limitation amber, cobalt, or vintage green.

[0061] The above and further aspects and preferred embodiments of the invention are described in the following sections and in the appended claims. The subject matter of the appended claims is hereby specifically incorporated in this specification. DETAILED DESCRIPTION

[0062] As used herein, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise.

[0063] The terms “comprising”, “comprises” and “comprised of’ as used herein are synonymous with “including”, “includes” or “containing”, “contains”, and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The terms also encompass “consisting of’ and “consisting essentially of’, which enjoy well-established meanings in patent terminology.

[0064] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints. This applies to numerical ranges irrespective of whether they are introduced by the expression “from ... to ...” or the expression “between... and ...” or another expression.

[0065] The terms “about” or “approximately” as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, are meant to encompass variations of and from the specified value, such as variations of + / -10% or less, preferably + / -5% or less, more preferably + / -!% or less, and still more preferably + / -0.1% or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier “about” or “approximately” refers is itself also specifically, and preferably, disclosed.

[0066] Whereas the terms “one or more” or “at least one”, such as one or more members or at least one member of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g. any >3, >4, >5, >6 or >7 etc. of said members, and up to all said members. In another example, “one or more” or “at least one” may refer to 1, 2, 3, 4, 5, 6, 7 or more.

[0067] The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known, or part of the common general knowledge in any country as of the priority date of any of the claims.

[0068] Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. All documents cited in the present specification are hereby incorporated by reference in their entirety. In particular, the teachings or sections of such documents herein specifically referred to are incorporated by reference.

[0069] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the invention. When specific terms are defined in connection with a particular aspect of the invention or a particular embodiment of the invention, such connotation or meaning is meant to apply throughout this specification, i.e. also in the context of other aspects or embodiments of the invention, unless otherwise defined. For example, embodiments directed to products are also applicable to corresponding features of methods and uses. In the following passages, different aspects or embodiments of the invention are defined in more detail. Each aspect or embodiment so defined may be combined with any other aspect(s) or embodiment(s) unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

[0070] Reference throughout this specification to “one embodiment”, “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the appended claims, alternative combinations of claimed embodiments are encompassed, as would be understood by those in the art.

[0071] Unless indicated otherwise, all methods, steps, techniques and manipulations that are not specifically described in detail can be performed and have been performed in a manner known per se, as will be clear to the skilled person. Reference is for example again made to standard handbooks as well as to the general background art referred to herein and to the further references cited therein.

[0072] The term "Combined Oral Contraceptives” (COCs), as used throughout the present specification, represent a class of pharmaceutical formulations aiming to provide a comprehensive and reliable method for preventing pregnancy through oral administration. The synergistic action of an estrogenic and a progestogenic component mimics the physiological intricacies of the menstrual cycle, exerting multifaceted contraceptive effects. Particularly, COCs suppress ovulation. In addition, COCs create cervical mucus alterations, hindering sperm penetration into the uterus, and induce modifications in the endometrial lining, rendering it less receptive to embryo implantation. COCs therefore provide a high degree of contraceptive efficacy and other benefits such as the regulation of menstrual cycles and reduction of menstmal pain.

[0073] The term “progestogen-only pill”, abbreviated herein and throughout the art as “POC” and interchangeably indicated by the name “mini-pill” refers to an oral contraceptive comprising a progestogenic component without any estrogenic component. Progestogenic components routinely used in POCs include without limitation norethindrone, desogestrel, levonorgestrel, norgestrel, drospirenone, etonogestrel, and norgestimate.

[0074] The term “estetrol” as used herein refers to 1,3,5 (10)-estratrien-3,15alpha,16alpha,17beta-tetrol or 15alpha- hydroxyestriol as well as hydrates of estetrol, e.g. estetrol monohydrate. “Estetrol”, or short “E4” is an estrogen steroid produced by the foetal human liver (PubChem CID: 27125). Estetrol may be described as a 3-hydroxy steroid corresponding to 17beta-estradiol wherein the 15a and 16a positions are substituted for two additional hydroxy groups. It is known that estetrol is an estrogen receptor agonist (Coelingh Bennink et al., Climacteric, 2008). The estetrol may be chemically synthetised, synthesised by the use of (mutant) recombinant enzymes, or synthesised by any combination thereof. It is therefore evident that the terms “estetrol” and “estetrol components” equally encompass further chemically modified estetrol. Estetrol may be indicated in the art by its molecular formula: C18H24O4, or by structural formula (I).

[0075] Formula (I)

[0076] It is understood that when estetrol is mentioned throughout any section of this specification, any estetrol- containing component (i.e. compound) and / or estetrol derivative (such as an estetrol ester) is also envisaged. More preferably, in the context of the present disclosure, a particularly preferred estetrol (component) is estetrol monohydrate. Estetrol monohydrate is a white to off-white crystalline solid that is poorly soluble in water and aqueous solutions. It is soluble in methanol, ethanol, sparingly soluble in acetone, and slightly soluble in ethyl acetate and acetonitrile. A skilled person appreciates that estetrol monohydrate corresponds to estetrol containing one molecule of water, and that the core structural formula of estetrol does not differ from Formula (I). By means of illustration and not limitation, the structural formula of estetrol monohydrate is indicated by Formula (II):

[0077] Formula (II)

[0078] “Drospirenone” (abbreviated as DRSP, PubChem CID: 68873) is an example of a progestogenic component and enjoys a widespread use in Combined Oral Contraceptives (commonly abbreviated as COCs) due to its antimineralocorticoid and antiandrogenic activity combined with a general low off-target activity. Drospirenone is a white to almost white or slightly yellow crystalline powder. It is a neutral molecule with slight solubility in water. In general, drospirenone-containing COCs are referred to as fourth generation COCs. Non-limiting examples of commercially available COCs comprising drospirenone are known as “Yaz™” and Yasmin™. An illustrative example of a drospirenone only progestogen pill is “Slynd™”, which is also commercially available. Additionally, hormone replacement therapy compositions comprising an estrogen such as estradiol and drospirenone are available such as “Angeliq™”. Drospirenone may alternatively be indicated in the art by its molecular formula C24H30O3, or by the structural formula (III):

[0079] Formula (III)

[0080] It is understood that when the term “drospirenone” is used herein, any drospirenone derivatives are also envisaged. The terms “progestogen”, “gestagen”, or“gestogen” and derived hereof “progestogenic components” as used both herein and in the art refer to any molecule that produces effects similar to those of the natural female sex hormone progesterone in the body of a subject. Progestogens are considered to be agonists of the progesterone receptors and their functions have been thoroughly examined in the art (inter alia discussed in Kuhl, Climacteric, 2005). Progestins are a subgroup of progestogens that comprise synthetic progestogens. While the above terms may be used interchangeably in the art, there is a general understanding that when progestin is mentioned, synthetic progestogens are meant.

[0081] The COCs, related compositions, uses, and methods described throughout the present disclosure are generally compared in terms of safety and efficacy to a fixed dose combination tablet comprising ethinylestradiol and drospirenone. “Ethinylestradiol” (abbreviated as EE, PubChem CID: 5991; molecular formula: C20H24O2), refers to an estrogen distinct from estetrol and estetrol monohydrate that is widely used in birth control pills in combination with a progestogenic component. Ethinylestradiol is a synthetic derivative of estradiol (the latter being a natural estrogen). The popularity of ethinylestradiol is partly due to its favourable properties when compared to estradiol including improved bioavailability and an increased resistance to metabolism. By means of illustration and not limitation, the structural formula of ethinylestradiol is indicated by Formula (IV):

[0082] Formula (IV)

[0083] Numerous references are made throughout the present specification to indicate that a certain condition in a subject is changed, i.e. treated. The terms “treatment” or “treat” are to be interpreted as both the therapeutic treatment of a symptom, disease or condition that has already developed, leading to (clinical) manifestations, as well as prophylactic or preventive measures, wherein the goal of the treatment is to prevent, lessen, or reduce the chances of incidence of an undesired affliction, such as to prevent occurrence, development and progression of blood pressure increases and / or hypertension, and (clinical) conditions that are a consequence thereof.

[0084] “Prevention” or “prevent” as used in the context of the invention refers to an aversion of manifestation of a condition or disease image in a subject, i.e. the establishment of preventive measures or prophylactic measures. Preventive treatment refers to treatments wherein the object is to avoid a subject’s body or an element thereof to show (worsening of) symptoms of an undesired physiological or psychological change, in the present context for example an increase of blood pressure. As used herein, the term “prevent” includes both preventing symptoms from occurring and preventing symptoms of worsening.

[0085] Unexpectedly, the inventors have found that a COC comprising E4 monohydrate and DRSP can be considered as an alternative to progestogen-only pills, since E4, in contrast to other estrogenic components such as EE, does not attenuate the antihypertensive effect of DRSP in high normotensive patients. Indeed, remarkably the effects of E4 / DRSP on blood pressure in high normotensive participants was similar to that of a POC based on DRSP alone. This decrease in BP is to the patient's advantage and is unexpected. The effect is seen particularly in prehypertension (pre-hypertension (SBP > 120 to 139 mmHg and DBP > 80 to 89 mmHg), high normal baseline BP (SBP > 130 mmHg and / or DBP > 85 mmHg), low range hypertension at baseline (SBP > 140 mmHg and / or DBP > 90 mmHg) and stage 1 hypertension (SBP > 140 to 159 mmHg and DBP > 90 to 99 mmHg)) subjects. COCs comprising estetrol and drospirenone can therefore be considered improved vis-a-vis commercially available POCs such as SLYND® given the improved bleeding profile that is achieved through the inclusion of an estrogen, and can also be considered improved vis-a-vis other COCs that rely on a combination different than E4 / DRSP such as “Yaz®” and Yasmin® and do not maintain the favourable effects of DRSP on blood pressure.

[0086] It is important to note that COCs different from E4 / DRSP, i.e. comprising another (non-estetrol) estrogen component, do not show synergism between the estrogen and the progestogen with regard to blood pressure effects. The present invention therefore shows for the first time that the effect of DRSP on blood pressure can be enhanced by combining DRSP with E4. The DRSP and E4 combination therefore results in a clear synergistic effect.

[0087] Accordingly, a first aspect of the invention is directed to a contraceptive method having a reduced risk of hypertension, comprising administering to a female subject an amount of estetrol and drospirenone, to reduce the risk of hypertension associated with the use of a combined oral contraceptive (COC) comprising an estrogenic and a progestogenic component, wherein the female subject is selected from subjects having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said COC. Alternatively worded, the invention provides a method of reducing the risk of hypertension associated with the use of a combined oral contraceptive (COC) in a female subject having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said COC, comprising administering a COC comprising estetrol and drospirenone to said subject. Equally envisaged is the use of a composition comprising estetrol and drospirenone for the manufacture of a medicament for reducing the risk of hypertension associated with the use of a combined oral contraceptive (COC) in a female subject, wherein said female subject is characterised by having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said COC.

[0088] Accordingly, also envisaged is a combined oral contraceptive (COC) comprising estetrol and drospirenone for use in normalizing or reducing blood pressure in a female subject having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said COC, as well as a combined oral contraceptive (COC) comprising estetrol and drospirenone for use in reducing the risk of hypertension in a female subject having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said COC.

[0089] "Hypertension”, as used herein and interchangeably used in the art with synonyms such as but not limited to “high blood pressure”, is a (chronic) medical condition marked by consistently elevated blood pressure levels, exceeding the established norm. Blood pressure is the force exerted by circulating blood on the walls of arteries, and hypertension results when this force is persistently higher than the recommended range. Hypertension places increased stress on the cardiovascular system and may lead to various health risks and complications if not effectively addressed. Non-limiting examples of said health risks and complications include without limitation cardiovascular diseases such as coronary artery disease and hearth failure, stroke, kidney damage, peripheral artery disease, vision problems, aneurysms, cognitive decline, and metabolic syndromes such as obesity, elevated blood sugar levels, and elevated cholesterol levels. The condition may manifest in various degrees of severity, ranging from mild to severe, and may be further categorized into primary (essential, without identifiable cause) and secondary hypertension (which is the result of an identifiable underlying cause). Hypertension is one of the primary indications for beta-blockers such as metoprolol. Although hypertension may in certain cases lead to cardiovascular dysfunction, it is in the context of the invention to be seen as a stand-alone (separate) indication that has many different underlying mechanisms which (de-)regulate blood pressure. Examples are Renal Parenchymal Disease, Endcrine disorders, Renovascular and Vascular disorders, obstructive sleep apnea, polycystic ovarian syndrome, preeclampsia, and also certain drugs may contribute to the etiology of secondary hypertension.

[0090] A skilled person understands that the commonly accepted meaning of the term “blood pressure” refers to the force exerted by circulating blood against the artery wall when pumped throughout the body by the heart. It is commonly denoted in the art by means of the unit millimetres of mercury (mmHg) and is expressed as two values: systolic pressure over diastolic pressure. Systolic (blood) pressure (abbreviated as SBP or SP) corresponds to the higher of the two numbers and indicates the pressure in the arteries upon contraction (i.e. beating) of the heart, pumping blood into the circulation. Diastolic (blood) pressure corresponds to the lower of the two numbers and represents the pressure in the arteries between heartbeats (i.e. during the relaxation phase). Generally, a SBP of less than!20 mmHg and a DBP of less than 80 mmHg are typically considered as normal blood pressure. According to the American Heart Association, blood pressure is defined as follows:

[0091] The present invention is preferably beneficial to subjects having high normal or elevated blood pressure or hypertension stage 1.

[0092] Methods to measure blood pressure have been described in the art and are well known to a skilled person. The method for measuring the blood pressure of the subject is not particular limiting for the invention and may therefore be any suitable means for the purpose. By means of illustration and not limitation, suitable methods for measuring the blood pressure of a subject include: use of a manual sphygmomanometer and stethoscope, use of an automated blood pressure monitor or device, wearing an ambulatory blood pressure monitor, arterial catheterization, by the use of oscillometric devices, use of mobile health apps, and / or the use of fitness trackers and smartwatches.

[0093] Optionally, the female subject may be a high normotensive or low hypertensive subject. High normotensive blood pressure as used throughout the present specification, refers to blood pressure levels that, while falling within the conventional normotensive range, exhibit an elevated threshold within that range. It is to be understood that unlike typical normotensive values, high normotensive blood pressure is characterized by systolic and / or diastolic readings that, although not meeting the criteria for hypertension, surpass the upper limits of the established normal range. Thus, in certain embodiments, the female subject is a subject selected from female subjects having an elevated blood pressure, such as a SBP of about 120 to about 129 mmHg and a DBP of about 80 to about 89 mmHg. In alternative embodiments, the female subject is a subject selected from female subjects having a SBP of about 125 mmHg or higher, preferably a SBP of about 130 mmHg or higher. In further embodiments, the female subject is a subject selected from female subjects having a DBP of about 82.5 mmHg or higher, preferably a DBP of about 85 mmHg or higher. In yet further embodiments, the female subject is a subject selected from female subjects having a SBP of about 125 mmHg or higher and a DBP of about 82.5 mmHg or higher, preferably wherein the subject is a female subject having a SBP of about 130 mmHg or higher and a DBP of about 85 mmHg or higher. In alternative embodiments, the female subject is a subject selected from female subjects having an elevated blood pressure, such as a SBP of about 130 mmHg to about 140 mmHg and a DBP of about 90 mmHg or more. In further embodiments, the female subject is a subject selected from female subjects having a SBP of about 130 mmHg or higher, preferably a SBP of about 140 mmHg or higher. In further embodiments, the female subject is a subject selected from female subjects having a DBP of about 85 mmHg or higher, preferably a DBP of about 90 mmHg or higher. In yet further embodiments, the female subject is a subject selected from female subjects having a SBP of about 140 mmHg or higher and a DBP of about 85 mmHg or higher, preferably wherein the subject is a female subject having a SBP of about 140 mmHg or higher and a DBP of about 90 mmHg or higher. In preferred embodiments, the above recited blood pressure values are the values measured prior to the use of the COC subject of the present invention.

[0094] In a preferred embodiment, the subject is pre-hypertensive (SBP > 120 to 139 mmHg and DBP > 80 to 89 mmHg), has high normal baseline BP (SBP > 130 mmHg and / or DBP > 85 mmHg), has low range hypertension at baseline (SBP > 140 mmHg and / or DBP > 90 mmHg) or has stage 1 hypertension (SBP > 140 to 159 mmHg and DBP > 90 to 99 mmHg).

[0095] In certain embodiments, the female subject is considered a pre-hypertensive, a high normotensive or low hypertensive subject prior to the onset of using the COC described herein, whose status changes to a normotensive subject due to the use thereof.

[0096] The COC described herein does not increase the SBP or the DBP of the subject when compared to the respectively the SBP and / or the DBP of said subject prior to the use of any COC. Preferably neither the SBP nor the DBP of the subject are increased when compared to the respectively the SBP and the DBP of said subject prior to the use of any COC. Preferably, the SBP of the subject is decreased by at least about 1%, preferably at least about 2%, preferably at least about 3%, preferably at least about 4%, preferably at least about 5%, most preferably more than about 5%, when compared to the respectively the SBP of said subject prior to the use of any COC. Preferably, the DBP of the subject is decreased by at least about 1%, preferably at least about 2%, preferably at least about 3%, preferably at least about 4%, preferably at least about 5%, most preferably more than about 5%, when compared to the respectively the DBP of said subject prior to the use of any COC. In further preferred embodiments, both the SBP and DBP are each independently decreased by at least about 1%, preferably at least about 2%, preferably at least about 3%, preferably at least about 4%, preferably at least about 5%, most preferably more than about 5%, when compared to the respectively the DBP of said subject prior to the use of any COC.

[0097] In certain embodiments, the COC described herein decreases the SBP and / or DBP of the subject when compared to the respectively SBP and / or DBP of said subject measured when said subject was using, or was administered a COC comprising as estrogenic component EE and as progestogenic component DRSP. Preferably, the SBP of the subject is decreased by at least about 1%, preferably at least about 2%, preferably at least about 3%, preferably at least about 4%, preferably at least about 5%, most preferably more than about 5%, when compared to the respectively the SBP of said subject measured when said subject was using, or was administered a COC comprising as estrogenic component EE and as progestogenic component DRSP. Preferably, the DBP of the subject is decreased by at least about 1%, preferably at least about 2%, preferably at least about 3%, preferably at least about 4%, preferably at least about 5%, most preferably more than about 5%, when compared to the respectively the DBP of said subject measured when said subject was using, or was administered a COC comprising as estrogenic component EE and as progestogenic component DRSP. In further preferred embodiments, both the SBP and DBP are each independently decreased by at least about 1%, preferably at least about 2%, preferably at least about 3%, preferably at least about 4%, preferably at least about 5%, most preferably more than about 5%, when compared to the respectively the DBP of said subject measured when said subject was using, or was administered a COC comprising as estrogenic component EE and as progestogenic component DRSP.

[0098] In certain embodiments, (use of) the COC subject of the present invention decreases the SBP to less than about 129 mmHg, preferably to less than about 128 mmHg, preferably to less than about 127 mmHg, preferably to less than about 126 mmHg, preferably to less than about 125 mmHg, preferably to less than about 124 mmHg, preferably to less than about 123 mmHg, preferably to less than about 122 mmHg, preferably to less than about 121 mmHg, preferably to less than about 120 mmHg. In certain embodiments, (use of) the COC subject of the present invention decreases the DBP to less than about 85 mmHg, preferably to less than about 84 mmHg, preferably to less than about 83 mmHg, preferably to less than about 82 mmHg, preferably to less than about 81 mmHg, preferably to less than about 80 mmHg.

[0099] In further embodiments, (use of) the COC subject of the present invention decreases the SBP and DBP to respectively less than about 129 mmHg and less than about 85 mmHg, preferably to respectively less than about 128 mmHg and less than about 85 mmHg, preferably to less than about 127 mmHg and less than about 84 mmHg, preferably to less than about 126 mmHg and less than about 84 mmHg, preferably to less than about 125 mmHg and less than about 83 mmHg, preferably to less than about 124 mmHg and less than about 83 mmHg, preferably to less than about 123 mmHg and less than about 82 mmHg, preferably to less than about 122 mmHg and less than about 82 mmHg, preferably to less than about 121 mmHg and less than about 81 mmHg, preferably to less than about 120 mmHg and less than about 80 mmHg.

[0100] The (female) subject referred to throughout the present specification is preferably a female subject of reproductive age, and hence preferably a pre-menopausal female subject. A woman of reproductive age, as defined within the context of this patent application, pertains to an individual who has reached the onset of puberty and has not yet entered menopause, typically spanning the age range from approximately 12 to 50 years. This demographic encompasses the reproductive phase of a woman's life, during which she is biologically capable of conceiving and bearing children. A skilled person appreciates that there is an inherent variability in the onset and duration of reproductive capacity among individuals and is thus also aware of the physiological changes associated with the menstrual cycle. It is to be understood that a pre-menopausal subject in the present context is a subject that has not experienced menopause. Optionally, the subject is a subject from about 12 to about 40 years, preferably from about 16 to about 38 years, more preferably from about 18 to about 36 years, more preferably from about 20 to about 35 years. Alternatively, the subject is a subject having an age of equal to or higher than about 30 years, preferably having an age of equal to or higher than about 35 years, more preferably having an age of equal to or higher than about 40 years. Optionally, the subject is a subject having an age of from about 40 years to about 60 years.

[0101] In certain embodiments, the female subject is an overweight or obese female subject. "Overweight" and "obesity" are commonly used terms to indicate excessive body weight. These classifications are generally based on the body mass index (BMI) of a subject, corresponding to a numerical value calculated from an individual's height and weight. BMI is calculated using the following formula: BMI= weight (kg) / height (m2) or in other words the formula for BMI is weight in kilograms divided by height in meters squared. While the boundaries of weight groups such as the overweight group and obese group may differ among populations, ages, and gender groups, general definitions are available for these groups. “Overweight” generally refers to an excess amount of body weight, without a de facto presence of an excessive amount of body fat. The overweight subject may be categorised as such due to other factors including but not limited to increased muscle mass, high bone density, and high water content. Nevertheless, overweight subject in general have a higher proportion of body fat than is considered healthy. The World Health Organization (WHO) defines an overweight subject as a subject having a BMI of at least 25 kg / m2 to less than 30 kg / m2. The WHO defines an obese subject as a subject having a BMI of at least 30 kg / m2. Obesity is a more severe condition when compared to overweight and is characterized by an excess of body fat that may have negative effects on the health of a subject. It is associated with an increased risk of various health problems, including cardiovascular disease, type 2 diabetes, and certain cancers. Throughout the art, obesity is routinely categorized into different classes based on distinct BMI ranges: Class 1 (moderate obesity): BMI of about 30 kg / m2 to about 34.9 kg / m2; Class 2 (severe obesity): BMI of about 35 kg / m2 to about 39.9 kg / m2; Class 3 (very severe or morbid obesity): BMI of about 40 kg / m2 or higher. In certain embodiments, the female subject is characterized by a BMI of about 25 kg / m2 or more, or even about 30 kg / m2 or more. In further embodiments, the female subject is characterised by a BMI of about 25 kg / m2 to about 40 kg / m2, preferably a BMI of about 27.5 kg / m2 to about 35 kg / m2, more preferably a BMI of about 30 kg / m2 to about 32.5 kg / m2.

[0102] Optionally, the female subject is a subject that is considered to be a smoker (i.e. a subject that is characterised by a smoking status). The term "smoker" is indicative of a subject that has smoked tobacco products in the past 5 years, preferably in the past 4 years, preferably in the past 3 years, preferably in the past 2 years, most preferably in the past year. Optionally, the smoker is a current smoker. Optionally, the smoker has smoked at least 100 tobacco products or more in his / her lifetime or even within the last year, and may optionally smoke tobacco every day or on some days (non-daily). Optionally, the subject is a smoker that smokes at least one tobacco product or equivalent thereof per day, optionally at least 2 tobacco products per day, optionally at least 5 tobacco products per day, optionally at least 10 tobacco products per day, or optionally at least 15 tobacco products per day or more. In certain embodiments, the subject is a consumer of nicotine-containing products, optionally tobacco-free nicotine-containing products. Alternatively, the female subject is a subject that is considered to be a non-smoker. The term "non-smoker" as used herein means a subject that has never been a smoker, or has previously been a smoker but has not smoked tobacco products in the past year, preferably in the past 2 years, preferably in the past 3 years, preferably in the past 4 years, most preferably in the past 5 years. The non-smoker will be deemed to have abstained from smoking. A non-smoker can be a never smoker or can be a former smoker.

[0103] In the test population in the examples section, 18,2% of subjects aged 18 to 35 and 15,8% of all subjects were currently smoking; 4.0% of subjects aged 18 to 35 and 4.6% of all subjects were former smokers; 77,8% of subjects aged 18 to 35 and 79,6% of all subjects were never smokers.

[0104] Optionally, the subject is a diabetic female subject. Hence, the subject may be a female subject diagnosed to have, or is considered to have diabetes mellitus. It is well established in the art that “diabetes mellitus” refers to a chronic metabolic disorder characterized by elevated blood glucose levels. Optionally the particular type of diabetes mellitus is selected from the group consisting of: Type 1 diabetes, Type 2 diabetes, gestational diabetes mellitus (GDM), maturity-onset diabetes of the young, or secondary diabetes. The diabetes may be characterised by an insulin dependence. Numerous methods have been described in the art that are suitable for diagnosing diabetes mellitus and include by means of illustration and not limitation: fasting plasma glucose test (FPG), oral glucose tolerance test (OGTT), haemoglobin Ale (HbAlc) test, random plasma glucose test, glycated albumin test, and a fructosamine test. In certain embodiments, the diabetes may be diabetes mellitus with or without vascular involvement. It has been described in the art that chronic hyperglycaemia can lead to the damaging of the small and large blood vessels resulting in various complications such as nephropathy (kidney disease), retinopathy (eye disease), neuropathy (nerve damage), and cardiovascular complications. By means of illustration and not limitation, exemplary nephropathies include microalbuminuria, macroalbuminuria, and end-stage renal disease. Exemplary retinopathies include microaneurysms, small haemorrhages, proliferative retinopathy, and diabetic macular oedema. Exemplary neuropathies include peripheral neuropathy (tingling, pain, and / or weakness of extremities) and autonomic neuropathies (gastrointestinal problems, cardiovascular problems, sexual dysfunction). Exemplary cardiovascular complications include coronary artery disease, stroke, peripheral artery disease, and atherosclerosis.

[0105] The terms “selected” or “selection”, “diagnosed” or “diagnosis, “predicted” or “prediction” and, “prognosticated” or “prognosis” may be used interchangeably herein and are commonplace and well-understood in medical and clinical practice. It shall be understood that the phrase “a method for the diagnosis, prediction and / or prognosis” a given disease or condition may also be interchanged with phrases such as “a method for diagnosing, predicting and / or prognosticating” of said disease or condition or “a method for making (or determining or establishing) the diagnosis, prediction and / or prognosis” of said disease or condition, or the like.

[0106] Without limitation, "predicting" or "prediction" generally refer to a statement, declaration, indication or foretelling of a disease or condition in a subject not (yet) showing any, or a limited, clinical manifestation of said disease or condition. A prediction of a disease or condition in a subject may indicate a probability, chance or risk that the subject will develop said disease or condition, for example within a certain time period or by a certain age. Said probability, chance or risk may be indicated as any suitable qualitative or quantitative expression, wherein nonlimiting examples of a quantitative expression include absolute values, ranges or statistics. Alternatively the probability, chance, or risk may be indicated relative to a suitable control subject or subject population (such as, e.g., relative to a general, normal or healthy subject or subject population). Hence, the probability, chance or risk that a subject will develop a disease or condition may be advantageously indicated as increased or decreased, or as fold-increased or fold-decreased relative to a suitable control subject or subject population. The term “prediction” of the conditions or diseases as taught herein in a subject may also particularly mean that the subject has a 'positive' prediction of such, i.e., that the subject is at risk of having such (e.g., the risk is significantly increased vis-a-vis a control subject or subject population).

[0107] The terms "diagnosing" or "diagnosis" are indicative for a process of recognizing, deciding on or concluding on a disease or condition in a subject on the basis of symptoms and signs and / or from results of various diagnostic procedures (such as, for example, from knowing the presence, absence and / or quantity of one or more biomarkers of or clinical symptoms characteristic for the diagnosed disease or condition). “Diagnosis of’ the diseases or conditions as taught herein in a subject may particularly mean that the subject has such disease or condition. A subject may be diagnosed as not having such despite displaying one or more conventional symptoms or signs reminiscent of such.

[0108] In certain embodiments, the female subject is a first-ever user, switcher, or re-starter with a break of more than 4 weeks. In the present context, a “first-ever user” refers to a female subject that is in her first year of ever using a hormonal contraceptive. As used herein, a “switcher” indicates a female subject that discontinues the use of one type of hormonal contraceptive to initiate the use of another type of hormonal contraceptive. Optionally, this switch comprises a break in use of hormonal contraceptives of 4 weeks or more. A female subject is typically considered to be a “switcher” if the previous hormonal contraceptive use took place within 3 months prior to E4 / DRSP use. Finally, in the present context a female subject is considered is a “starter” or “re-starter” when she has discontinued use of hormonal contraceptives for three months or longer prior to initiating the use of the COC subject of the present invention. More particularly, the female subject can be a “switcher” when she discontinues the use of one type of hormonal contraceptive to initiate the use of another type of hormonal contraceptive. Optionally, this switch comprises a break in use of hormonal contraceptives of 4 weeks or more. A female subject is typically considered as a "sw itcher" if previous hormonal contraceptive use took place within 3 months prior to E4 / DRSP use. As used herein a female subject is a "first-ever-user" or a “true new user” when she is in her first year of ever using a hormonal contraceptive (first ever user). As used herein a female subject is a “(re-)starter” when she has discontinued use of hormonal contraceptives for three months or longer.

[0109] In embodiments wherein the subject is a switcher switching from a POC to the COC subject of the present specification, the bleeding profile may be improved by a score of at least 1, preferably at least 2, preferably at least 3, preferably at least 4, preferably at least 5, preferably at least 6, preferably at least 7, preferably at least 8, preferably at least 9, or even 10 when evaluated by the subject using a self-reporting score from 0 to 10. In further embodiments wherein the subject is a switcher switching from a POC to the COC subject of the present specification, the regularity of the menstrual cycle is improved, reducing the median and / or mean variability in menstrual cycle as evaluated over a period of at least 3 months, preferably over a period of at least 6 months, preferably over a period of at least 12 months by at least about 25%, more preferably at least about 50%, more preferably at least about 75%, or even about 100%.

[0110] In embodiments wherein a group of subjects consists of switchers switching from a POC to the COC subject of the present specification, the number of pregnancies as a result of failure to provide a contraceptive effect by the contraceptive is reduced by at least about 5%, preferably by at least about 10%, more preferably by at least about 25%, more preferably by at least about 50%, more preferably by at least about 75%, most preferably by at least about 100%. Alternatively, this improvement may be expressed by the Method Failure Pearl Index, which is improved in the above described subjects. In certain embodiments, the Method Failure Pearl Index is improved by at least about 5%, preferably by at least about 10%, more preferably by at least about 25%, more preferably by at least about 50%, more preferably by at least about 75%, more preferably by more than about 75%.

[0111] The Method Failure Pearl Index corresponds to the number of pregnancies as a result of method failure per 100 women-years of treatment and is calculated according to the formula: Pearl Index = (1300*number of on-treatment pregnancies as a result of method failurej / number of women 28-day equivalent cycles of treatment. The method failure Pearl Index includes only pregnancies that were classified as method failure and not pregnancies due to user failure, i.e. incorrect intake of the investigational product. Only at-risk cycles are included in the denominator of the Pearl Index calculation. At-risk-cycles correspond to cycles in which no other methods of birth control (including condoms and optionally including emergency contraceptives) are used by the subject and during which sexual intercourse occurred.

[0112] The compositions (i.e. the COCs) described herein are formulated to administer a daily dose (i.e. a daily quantity) of estetrol and drospirenone to the subject. Both multiple administrations per day to arrive at said daily dose or a single administration per day to obtain said daily dose are envisaged. The term “daily” indicates that the recited amounts are the cumulative amount that is administered to a subject per day. A skilled person understands that if the estetrol and / or drospirenone is administered only once per day (i.e. daily), that the amount of estetrol and / or drospirenone administered in that single administration will be the daily dose. Alternatively, a skilled person appreciates that if the estetrol and / or drospirenone is administered more than once per day (e.g. 2 times or 3 times) the daily amount will correspond to the sum of respectively estetrol and drospirenone administered during each administration event within a total time window of about 24 hours. In embodiments where different estetrol components are comprised in the composition (e.g. estetrol monohydrate and an estetrol ester), it is within the capacities of a skilled person to verify the amount of estetrol each estetrol component corresponds to. Preferred embodiments within the context of the invention comprise the administration of a single estetrol component, such as but not limited to estetrol monohydrate. Yet alternatively, the composition may be administered to the subject in a once-a-day multiple dose regimen.

[0113] A skilled person is aware that terms such as “quantity”, “amount” and “level” are synonyms and have a well- defined meaning in the art. The terms as used herein may particularly refer to an absolute quantification of a molecule such as a steroid, in (a sample taken from) a subject, or to a relative quantification of a molecule or analyte in a sample, i.e., relative to another value such as relative to a reference value as taught herein, or to a range of values indicating a base-line of a certain parameter. These values or ranges of values may be obtained from one single subject or from a group of subjects (i.e. at least two subjects).

[0114] As detailed above, the composition (i.e. COC) which is subject of the present invention is administered at a daily amount of from about 1 mg to about 40 mg of estetrol, estetrol monohydrate, or an ester of estetrol. Evidently, this includes embodiments wherein the composition comprises from about 1 mg to about 40 mg of estetrol, estetrol monohydrate, or an ester of estetrol (a skilled person appreciates that this is encompassed by the definition of “equivalent to from about 1 mg to about 40 mg of estetrol”). In further embodiments, the composition is administered at a daily amount of from about 5 mg to about 25 mg of estetrol, estetrol monohydrate, or an ester of estetrol, or comprises from about 5 mg to about 25 mg of estetrol, estetrol monohydrate, or an ester of estetrol. Preferably the composition the composition is administered at a daily amount of from about 10 mg to about 20 mg of estetrol, estetrol monohydrate, or an ester of estetrol, or comprises from about 10 mg to about 20 mg of estetrol, estetrol monohydrate, or an ester of estetrol. In further embodiments, the composition is administered at a daily amount of about 15 mg of estetrol, estetrol monohydrate, or an ester of estetrol, or comprises about 15 mg of estetrol, estetrol monohydrate, or an ester of estetrol. In a preferred embodiment, the composition is administered at a daily amount of 14.2 mg of estetrol or comprises 14.2 mg of estetrol. In alternative embodiments, the composition is administered at a daily amount of about 20 mg of estetrol, estetrol monohydrate, or an ester of estetrol, or comprises about 20 mg of estetrol, estetrol monohydrate.

[0115] In preferred embodiments, the composition (i.e. COC) which is subject of the present invention is administered at a daily amount of from about 0.5 mg to about 10 mg of drospirenone. Evidently, this includes embodiments wherein the composition comprises from about 0.5 mg to about 10 mg of drospirenone (a skilled person appreciates that this is encompassed by the definition of “equivalent to from about 0.5 mg to about 10 mg of drospirenone”). In further embodiments, the composition is administered at a daily amount of from about 1 mg to about 4 mg of drospirenone, or comprises from about 1 mg to about 4 mg of drospirenone. In further embodiments, the composition is administered at a daily amount of about 3 mg of drospirenone, or comprises about 3 mg of drospirenone.

[0116] In yet further preferred embodiments, the composition (i.e. COC) which is subject of the present invention is administered at a daily amount of from about 1 mg to about 40 mg of estetrol, estetrol monohydrate, or an ester of estetrol and at a daily amount of from about 0.5 mg to about 10 mg of drospirenone. In further embodiments, the composition (i.e. COC) which is subject of the present invention comprises from about 1 mg to 40 mg of estetrol, estetrol monohydrate, or an ester of estetrol and from about 0.5 mg to about 10 mg of drospirenone. Preferably, the composition (i.e. COC) which is subject of the present invention is administered at a daily amount of from about 5 mg to about 25 mg of estetrol, estetrol monohydrate, or an ester of estetrol and at a daily amount of from about 1 mg to about 4 mg of drospirenone. In further embodiments, the composition (i.e. COC) which is subject of the present invention comprises from about 5 mg to 25 mg of estetrol, estetrol monohydrate, or an ester of estetrol and from about 1 mg to about 4 mg of drospirenone. Yet more preferably, the composition (i.e. COC) which is subject of the present invention is administered at a daily amount of from about 10 mg to about 20 mg of estetrol, estetrol monohydrate, or an ester of estetrol and at a daily amount of from about 1 mg to about 4 mg of drospirenone. In further embodiments, the composition (i.e. COC) which is subject of the present invention comprises from about 10 mg to 20 mg of estetrol, estetrol monohydrate, or an ester of estetrol and from about 1 mg to about 4 mg of drospirenone. Most preferably, the composition (i.e. COC) which is subject of the present invention is administered at a daily amount of about 15 mg of estetrol, estetrol monohydrate, or an ester of estetrol and at a daily amount of about 3 mg of drospirenone. In further embodiments, the composition (i.e. COC) which is subject of the present invention comprises about 15 mg of estetrol, estetrol monohydrate, or an ester of estetrol and about 3 mg of drospirenone. In preferred embodiments, the composition (i.e. COC) which is subject of the present invention comprises 14.2 mg of estetrol and 3 mg of drospirenone

[0117] Optionally, the composition comprises estetrol monohydrate administered in a daily amount of from about 1 mg to about 40 mg and drospirenone administered in a daily amount of from about 0.5 mg to about 10 mg. In further optional embodiments, the composition is administered in a daily amount of from about 5 mg to about 25 mg of estetrol monohydrate, and drospirenone administered in a daily amount of from about 1 mg to about 4 mg. In further optional embodiments, the composition is administered in a daily amount of from about 10 mg to about 20 mg of estetrol monohydrate, and drospirenone administered in a daily amount of from about 1 mg to about 4 mg. In yet further optional embodiments, the composition is administered in a daily amount of about 15 mg estetrol monohydrate, and drospirenone administered in a daily amount of about 3 mg. In preferred embodiments, the composition is administered in a daily amount of 14.2 mg estetrol, and drospirenone administered in a daily amount of about 3 mg.

[0118] Optionally, the composition comprises estetrol, preferably estetrol monohydrate, in an amount from about 1 mg to about 40 mg and drospirenone in an amount of from about 0.5 mg to about 10 mg. In further optional embodiments, the composition comprises from about 5 mg to about 25 mg of estetrol monohydrate, and from about 1 mg to about 4 mg drospirenone. In further optional embodiments, the composition comprises from about 10 mg to about 20 mg of estetrol monohydrate, and from about 1 mg to about 4 mg drospirenone. In yet further optional embodiments, the composition comprises about 15 mg estetrol monohydrate, and about 3 mg of drospirenone.

[0119] Preferably, the COC described herein is used in cycles of from 21 to 28 daily administrations (i.e. a cyclical administration schedule). The COC described herein may be used in cycles of 21, 22, 23, 24, 25, 26, 27, or 28 daily administrations by means of administration of a corresponding amount of daily active dosage units. The cycle preferably further comprises an administration-free interval of 7, 6, 5, or 4 days. Preferably, the cycle comprises an administration-free interval of 4 days. The number of cycles the COC subject of the invention may be used is not particularly limiting for the invention. Hence, the COC may be used for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more than 13 cycles. The favourable effect on the blood pressure of the subject may be apparent after using the COC for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more than 13 cycles. The favourable effect on the blood pressure of the subject may be apparent when comparing the blood pressure prior to administration to after the 1st, 2nd, 3rdadministration cycle and preferably includes a decrease in systolic blood pressure of at least about 1%, preferably at least about 2.5%, preferably at least about 5%, more preferably at least about 7.5%, more preferably at least about 10%. It has been observed that the obtained effect on blood pressure remains present and stable for a prolonged period of time, preferably wherein the effect on blood pressure is maintained about stable up to after the second or third administration cycle.

[0120] The COC may be comprised of a single dosage unit, i.e. a dosage unit wherein the estetrol and drospirenone are contained in the same dosage unit, said dosage unit corresponding to the COC that is to be administered to the subject. Alternatively, the COC may be comprised of at least two dosage units wherein one dosage unit comprises the estetrol and a second dosage unit comprises the drospirenone. In such embodiments, the COC may be a two- part COC comprising two separate dosage units conjoined to one another. In preferred embodiments, the COC is formulated to provide a daily dose of the estetrol and the drospirenone (i.e., the COC is formulated as a daily oral dosage unit). “Dosage unit”, interchangeably used with “dosage form” herein and in the art indicates a physical preparate that is suitable for administration to a subject, without the necessity to adapt the dmg product prior to administration, i.e. the final beneficial product. A dosage unit therefore indicates a ready-to-administer composition (in the present context a ready -to administer COC). The term is not limiting for any other particulars of the treatment, such as frequency of administration and / or any characteristic of the dosage unit (taste, appearance, size, etc.).

[0121] Optionally, the COC is formulated as a daily dosage unit. Optionally, the COC is formulated as an oral dosage unit. The composition (i.e. COC) subject of the present invention is particularly suited for formulation as an oral dosage unit with oral ingestion as the envisaged mode of administration. After oral ingestion, the active ingredient is subjected to the first-pass effect. However, equally envisaged are dosage units formulated towards alternative administration methods such as but not limited to sublingual, buccal, or sublabial dosage units, that are intended to avoid the first-pass effect. The (solid) COC may therefore be suitably or even specifically manufactured for sublingual, buccal, and / or sublabial administration. The dosage unit (COC) may be able to rapidly release the estetrol and drospirenone when contacted with an aqueous solvent such as saliva. Hence, in such embodiments the COC is an orodispersible COC which releases at least about 50%, preferably at least about 60%, more preferably at least about 70%, yet more preferably at least about 80%, most preferably more than about 80% of the estetrol and / or drospirenone within about 5 minutes, preferably within about 3 minutes, more preferably within about 2.5 minutes, more preferably within about 90 seconds, most preferably within about 90 seconds. In further embodiments, the COC rapidly disintegrates in the oral cavity when it comes into contact with saliva and disperses the estetrol and / or drospirenone into the saliva so it may be absorbed through the mucosal lining of the oral cavity. A skilled person is aware of methods to determine the release rate of a pharmaceutically active ingredient such as estetrol and drospirenone from a dosage unit (a COC in the present context). Non-limiting standardized tests generally accepted in the field include the disintegration test according to Ph. Eur. 2.9.1 (“Disintegration of tablets and capsules”) and USP <701> (“Disintegration”), for example using water as the disintegration medium.

[0122] The term “sublingual” as used herein refers to the pharmacological route of administration by which the estetrol and / or drospirenone (comprised in the COC) diffuse into the blood through tissues under the tongue.

[0123] The term “buccal” as used herein refers to the pharmacological route of administration by which the estetrol and / or drospirenone (comprised in the COC) diffuse into the blood through tissues of the buccal vestibule, the area inside the mouth between the lining of cheek (the buccal mucosa) and the teeth / gums.

[0124] The term “sublabial” as used herein refers to the pharmacological route of administration by which the estetrol and / or drospirenone (comprised in the COC) are placed between the lip and the gingiva.

[0125] Optionally, the dosage unit (COC) is administered to a subject by means of a continuous administration schedule. The terms "continuous" and ’’continuously” as used herein, means that the dosage units (COCs) are administered at relatively regular intervals, with no (therapeutically) significant interruptions. Naturally, minor interruptions may occur that do not affect the overall effectiveness of the present method, and indeed such aberrations are encompassed by the present invention. Preferably and more arithmetically, the administration regimen is deemed to be continuous if the longest interval between two subsequent administrations is not more than 3.5 times as long as the average interval. Even more preferably said longest interval is not more than 2.5 times, most preferably not more than 1.5 times as long as the average interval. By means of illustration and not limitation, the treatment strategies and method of treatments described herein preferably employ continuous administration of the estetrol and drospirenone during a period of at least 10 days, preferably of at least 20 days.

[0126] Alternatively, the dosage unit (COC) is administered to a subject by means of a sequential administration schedule. It is to be appreciated that the term “sequential” means an administration during, for example, 10 to 14 days each month or during 14 days every 3 months. Sequential administration schedules are particularly envisaged wherein a progestogenic component is part of the composition or treatment described herein.

[0127] It is evident that any of the COCs and dosage units described herein may suitably contain one or more pharmaceutically acceptable excipients. The term “pharmaceutically acceptable” as used herein is consistent with the art and means compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient thereof.

[0128] As described above, the COC, and hence the (oral) dosage unit may comprise one or more suitable excipients. The term “excipient” may be a “carrier” indicative for any solvent, diluent, buffer (including but not limited to neutral buffered saline, phosphate buffered saline, or optionally Tris-HCl, acetate or phosphate buffers), solubiliser (including but not limited to Tween 80 or Polysorbate 80), colloid, dispersion medium, vehicle, filler, chelating agent (including but not limited to EDTA or glutathione), amino acid, protein, disintegrant, binder, lubricant, wetting agent, stabiliser, emulsifier, sweetener, colorant, flavoring, aromatiser, thickener, any agent suitable to achieve a depot effect, coating, antifungal agent, any preservative (including but not limited to Thimerosal™ or thiomersal, benzalkonium chloride, or benzyl alcohol), antioxidant (including but not limited to ascorbic acid, sodium metabisulfite), tonicity controlling agent, absorption delaying agent, adjuvant, bulking agent (including but not limited to lactose, mannitol) and any other ingredient that may influence any parameter or characteristic of the oral dosage unit subject of the invention. A skilled person understands that one or more excipients may be used in the composition or oral dosage unit on condition that the one or more excipient is compatible with the pharmaceutical ingredients (i.e. in the context of the present disclosure at least estetrol and drospirenone) and that a pharmaceutically acceptable formulation is obtained.

[0129] In certain embodiments, the excipient may be an active pharmaceutical ingredient excipient, binder excipient, carrier excipient, co-processed excipient, coating system excipient, controlled release excipient, diluent excipient, disintegrant excipient, dry powder inhalation excipient, effervescent system excipient, emulsifier excipient, lipid excipient, lubricant excipient, modified release excipient, penetration enhancer excipient, permeation enhancer excipient, pH modifier excipient, plasticiser excipient, preservative excipient, preservative excipient, solubiliser excipient, solvent excipient, sustained release excipient, sweetener excipient, taste making excipient, thickener excipient, viscosity modifier excipient, filler excipient, compaction excipient, dry granulation excipient, hot melt extrusion excipient, wet granulation excipient, rapid release agent excipient, increased bioavailability excipient, dispersion excipient, solubility enhancement excipient, stabilizer excipient, capsule filling excipient, or any combination hereof. A skilled person is aware that use of such media and agents for pharmaceutical active substances is common practice and incorporation of these excipients is hence well known in the art. It is evident that all of the used ingredients should be non-toxic in the concentration contained in the final pharmaceutical composition and should not negatively interfere with the activity of the one or more pharmaceutically active ingredients, in this context at least the estetrol component.

[0130] The COC described herein may alternatively be described as a a solid or semi solid dosage unit such as a tablet, a capsule, a cachet, a pellet, a pill, powder, granules, or any combination thereof. For example, the COC subject of the invention may be a tablet comprising estetrol-containing granules and drospirenone or a capsule comprising estetrol-containing granules and drospirenone. Optionally, the drospirenone may be comprised in the estetrol- containing granules. Alternatively, the drospirenone may be comprised in distinct granules, i.e. granules that do not comprise estetrol. The term "solid or semi-solid dosage unit" also encompasses capsules that contain a liquid, e.g. an oil, in which estetrol and drospirenone are dissolved or dispersed.

[0131] Tablets and equivalent solid and semi-solid dosage units can suitably contain materials such as binders (e.g. hydroxypropylmethyl cellulose, polyvinyl pyrrolidone (povidone, PVP), other cellulosic materials and starch), diluents (e.g. lactose (monohydrate) and other sugars, starch (e.g. maize starch), dicalcium phosphate and cellulosic materials), disintegrating agents (e.g. starch polymers and cellulosic materials (e.g. sodium starch glycolate) and lubricating agents (e.g., (magnesium) stearates and talc). These tablets and equivalent solid dosage units may be prepared by any suitable means, which have been described in detail in the art (e.g. Kaur, Int Res J Pharm, 2012). Non-limiting examples of processing methods of the estetrol and drospirenone when manufacturing the dosage unit include wet granulation, e.g. using an aqueous solution or an organic solution, direct compression, 3D printing, or by coating carrier particles with the estetrol and optionally with the drospirenone (either on the same carrier particles or distinct particles) using an organic or inorganic solvent.

[0132] Optionally, the COC is formulated as a tablet comprising in addition to estetrol and drospirenone a filler, a superdisintegrant, a binder and disintegrant, a further binder, and a lubricant. In preferred embodiments, the composition is comprised in a tablet comprising estetrol and drospirenone, lactose, sodium starch glycolate, maize / com starch, povidone, and magnesium stearate. Preferably, the COC is formulated as a tablet comprising estetrol monohydrate, drospirenone, lactose monohydrate, sodium starch glycolate type A, maize starch, povidone K30, and magnesium stearate. Optionally, the tablet is coated with a coating agent. In further optional embodiments, the coating agent comprises hypromellose, hydroxypropylcellulose, titanium dioxide, red iron oxide, hydrogenated cottonseed oil, and talc. By means of illustration and not limitation, a suitable coating agent is AquaPolish Pink 044.08 MS. A skilled person further appreciates that any excipients present in any dosage unit such as an oral dosage unit should adhere to pharmaceutical grade industry quality standards such as Ph. Eur. and USP-NF.

[0133] By means of illustration and not limitation, an oral dosage unit comprising the composition subject of the present disclosure may be manufactured by a process involving wet granulation, e.g. using an aqueous solution or an organic solution, direct compression, 3D printing, or by coating carrier particles with the estetrol and drospirenone using an organic or inorganic solvent. A skilled person appreciates that a wet granulation process may suitable comprise the successive steps of: dispensing and sieving of the active ingredient(s) and excipients, blending the sieved materials in a processor, granulation, screening (i.e. further sieving) of the granules, and one or more blending steps of the sieved granules with one or more further excipients. Afterwards, if desired in view of the final dosage unit the granules may be compressed into for example a tablet, optionally involving a coating step of said tablet.

[0134] The estetrol may be comprised in the composition and final dosage unit as particles. Optionally, the estetrol particles have a D(10) from about 0.5 pm to about 10 pm, preferably from about 1 pm to about 5 pm, more preferably of from about 1.5 pm to about 2.5 pm. Optionally, the estetrol particles have a D(50) of less than 20 pm or preferably less than 12 pm, more preferably from about 5 pm to about 15 pm, preferably from about 6 pm to about 12 pm, more preferably from about 7 pm to about 11 pm, , most preferably from about 8 pm to about 12 pm. Optionally, the estetrol particles have a D(90) from about 15 pm to about 50 pm, preferably from about 20 pm to about 30 pm, more preferably from about 22 pm to about 28 pm. Optionally, the estetrol particles are further granulated into larger granulates. In certain embodiments, estetrol is comprised in the composition as a multitude of larger granulates that have a volume median diameter from about 100 pm to about 4000 pm, preferably from about 200 pm to about 1000 pm, more preferably from about 200 pm to about 600 pm.

[0135] A multitude of measurement techniques are available for determining particle-size distribution values and include sieve analysis, air elutriation analysis, photo analysis, optical counting, electro resistance counting, sedimentation, laser diffraction, laser obscuration, time of transition, acoustic spectroscopy, ultrasound attenuation microscopy, by means of a cascade impactor, or any combination thereof. Unless explicitly mentioned otherwise, the particlesize distribution values of the present disclosure are obtained by laser diffraction analysis. Laser diffraction analysis, interchangeably annotated in the art by laser diffraction spectroscopy, is a particle measurement technology based on interpretation of laser diffraction patterns passed through an object. Laser diffraction is capable to measure the geometrical dimensions of a particle. Laser diffraction protocols have been described in detail in the art on numerous occasions (e.g. as reviewed in detail in a context of particle analysis in Eshel et al., Soil Science Society of America Journal, 2004). As progestin, drospirenone is preferred, and particularly from 0.5 mg to 10 mg of drospirenone, more particularly 1 mg to 4 mg of drospirenone, more particularly about 3 mg of drospirenone is highly preferred in the context of the present invention.

[0136] A further aspect of the invention is directed to packaging units comprising the COCs described herein. The packaging units may comprise at least 14, preferably at least 21, even more preferably at least 28, containers for holding separately packaged and individually removable COCs, wherein each container comprises at least one COC as described herein. Optionally, each of the containers for holding one or more COCs is individually visually arranged to present a recommended order of administration.

[0137] The skilled person appreciates that within the scope of the present invention, each packaging unit, e.g. blister pack, may be numbered or otherwise marked. The packaging units may be provided in any suitable packaging means known in the art, non-limiting examples being troches, sachets, pouches, bottles, films, sprays, microcapsules, implants, rods or blister packs.

[0138] By means of illustration and not limitation, each packaging unit may be a sealed blister pack with a cardboard, paperboard, foil plastic backing and enclosed in a suitable cover. Each supplied plastic blister may contain 24 active tablets, that may be pink and 4 inactive tablets, that may be white.

[0139] Also envisaged in any one of the aspects defined herein are packaging units such as bottles. The material of the bottle is not particularly limiting. In preferred embodiments, the bottle is a glass bottle characterized by a color capable of reducing or preventing degradation of the contents of the bottle by e.g. UV light while maintaining a degree of transparency that allows for visual inspection of the contents of said bottle. Suitable colors include without limitation amber, cobalt, or vintage green.

[0140] In a particular embodiment of the invention the packaging unit comprises 28 containers or a multiple of 28 containers, such as 3 or six multiples of 28 containers. In a preferred embodiment, the COC of the invention can be supplied in (plastic) blister packs, each containing 24 active (comprising the COC - typically coloured) tablets and 4 inactive (non-COC containing - typically white or colourless) tablets. Both the pink and white tablets can have a drop-shaped logo on one side. In a preferred embodiment, the COC is supplied in cardboard cartons containing 1, 3 or up to 6 blister packs.

[0141] The packaging unit of the contraceptive kit disclosed herein may be a “compliance package”. As known from the art, “compliance packages” are packaging units of variable sizes and formats that, next to providing a suitable storage means for one or more medicaments, aim to provide assistance and / or guidance to a subject to comply with the intended periodical administration (Peck Gossel, Packaging the Pill, Manifesting Medicine: Bodies and Machines, New York: Taylor & Francis, 1999). As a non-limiting example, the packaging unit may be provided with numerical indications and / or symbols that allow the subject to keep track of for example said subject’s menstrual cycle. In an alternative non-limiting example, the packaging unit may comprise means to send an electronic signal to a subject when a predefined time of administration (i.e. a certain day) is reached and the dosage unit for that time point is still contained in the packaging unit. In those examples, the electronic signal may be sent to a data storage means and / or sent to a user-defined electronic device, smartphones and smart wear begin illustrative examples hereof. In certain embodiments, distinct portions of the packaging unit(s) provide a different sensory trigger to a subject, non-limiting examples being distinct colors or roughness. While the present specification envisages COCs, it is evident that estetrol-only tablets are equally envisaged. A skilled person appreciates that such estetrol-only tablets may be used in a combination treatment with a POC containing drospirenone, ultimately achieving the same technical effects as outlined above (i.e. improved bleeding pattern when compared to a POC, and improved blood pressure results when compared to other COCs such as but not limited to those comprising EE and DRSP). Hence, in certain embodiments a composition comprising estetrol is administered at a daily amount of from about 1 mg to about 40 mg of estetrol, estetrol monohydrate, or an ester of estetrol, or the composition comprises from about 1 mg to about 40 mg estetrol, estetrol monohydrate, or an ester of estetrol. In further embodiments, the composition is administered at a daily amount of from about 5 mg to about 25 mg of estetrol, estetrol monohydrate, or an ester of estetrol, or comprises from about 5 mg to about 25 mg of estetrol, estetrol monohydrate, or an ester of estetrol. Preferably the composition the composition is administered at a daily amount of from about 10 mg to about 20 mg of estetrol, estetrol monohydrate, or an ester of estetrol, or comprises from about 10 mg to about 20 mg of estetrol, estetrol monohydrate, or an ester of estetrol. In further embodiments, the composition is administered at a daily amount of about 15 mg of estetrol, estetrol monohydrate, or an ester of estetrol, or comprises about 15 mg of estetrol, estetrol monohydrate, or an ester of estetrol. In preferred embodiments, the composition is administered at a daily amount of 14.2 mg of estetrol, or comprises 14.2 mg of estetrol. In alternative embodiments, the composition is administered at a daily amount of about 20 mg of estetrol, estetrol monohydrate, or an ester of estetrol, or comprises about 20 mg of estetrol, estetrol monohydrate.

[0142] While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations as follows in the spirit and broad scope of the appended claims. The herein disclosed aspects and embodiments of the invention are further supported by the following non-limiting examples. The following specific experimental examples are provided in support of the claimed invention but are not to be seen as limiting the scope of the invention.

[0143] EXAMPLES OF THE INVENTION

[0144] Example 1: A multicenter, open-label, single-arm study to evaluate the contraceptive efficacy and safety of a combined oral contraceptive containing 15 mg estetrol monohydrate and 3 mg drospirenone

[0145] The objectives of this study were to evaluate the contraceptive efficacy, vaginal bleeding pattern (cycle control), and the general safety and acceptability of the 15 mg estetrol monohydrate (E4) / 3 mg drospirenone (DRSP) combination in healthy women aged 18 to 50 years (C301-EU / Russia Study) and 16 to 50 years (C302-United States / Canada Study). The latter corresponds to the safety analysis set.

[0146] Intervention:

[0147] Drug: 15 mg estetrol monohydrate / 3 mg DRSP

[0148] 15 mg estetrol monohydrate and 3 mg drospirenone tablets administered once daily for 13 consecutive cycles following a 24 / 4-day regimen, i.e. one 15 mg estetrol monohydrate / 3 mg DRSP active tablet per day for 24 consecutive days followed by one placebo tablet per day for 4 consecutive days. Study Arms:

[0149] Experimental: 15 mg estetrol monohydrate / 3 mg DRSP

[0150] 15 mg estetrol monohydrate / 3 mg drospirenone (DRSP) combined oral contraceptive

[0151] Primary Outcome Measures:

[0152] The number of on-treatment pregnancies (with+ 2-day window (C301) / + 7-day window (C302)) per 100 woman- years of exposure (Pearl Index) in subjects aged 18 to 35 years (C301) / 16 to 35 years (C302), inclusive, at the time of Screening [Time Frame: Up to 12 months (13 cycles with 1 cycle = 28 days)]

[0153] On-treatment pregnancies are defined as pregnancies with an estimated date of conception within the in-treatment period i.e. Day 1 to 2 days (C301) / i.e. Day 1 to 7 days (C302) after the last intake of investigational product (whether active or inactive tablet). The Pearl Index, defined as the number of pregnancies per 100 women-years of treatment was calculated as: Pearl Index = (1300*number of on-treatment pregnancies) / number of women 28-day equivalent cycles of treatment. Only at-risk cycles were included in the denominator of the Pearl Index calculation, in case of C302 unless a conception occurred during a cycle. At-risk-cycles were defined as cycles in which no other methods of birth control (including condoms and for C302- also emergency contraception) were used by the subject as confirmed in the subject diary and during which the subject confirmed that sexual intercourse had occurred.

[0154] Secondary Outcome Measures:

[0155] The number of on-treatment pregnancies (with 2-day window- C301 and +7-day window-C302) as assessed by the Method Failure Pearl Index in subjects aged 18 to 35 years (C301) / 16 to 35 years (C302), inclusive, at the time of screening [time frame: Up to 12 months (13 cycles with 1 cycle = 28 days)]

[0156] On-treatment pregnancies are defined as pregnancies with an estimated date of conception within the in-treatment period i.e. Day 1 to 2 days (C301) or Day 1 to 7 (C302) after the last intake of investigational product (whether active or inactive tablet). The method failure Pearl Index, defined as the number of pregnancies as a result of method failure per 100 women-years of treatment was calculated as follows: Pearl Index = (1300*number of on-treatment pregnancies as a result of method failure) / number of women 28-day equivalent cycles of treatment. The method failure Pearl Index includes only those pregnancies that were classified as method failure and not the pregnancies due to user failure, i.e. incorrect intake of the investigational product. Only at-risk cycles were included in the denominator of the Pearl Index calculation. At-risk-cycles were defined as cycles in which no other methods of birth control (including condoms and, in case of C302- emergency contraception) were used by the subject as confirmed in the subject diary and during which the subject confirmed that sexual intercourse had occurred. The number of on-treatment pregnancies (with + 2-day window(C301) or +7 -day window (C302)) per 100 woman-years of exposure (Pearl Index) in the overall study population (18-50 years (C301) and 16-50 years (C302)) [time frame: up to 12 months (13 cycles with 1 cycle = 28 days)]

[0157] On-treatment pregnancies are defined as pregnancies with an estimated date of conception within the in-treatment period i.e. Day 1 to 2 days (C301) or Day 1 to 7 days (C302) after the last intake of investigational product (whether active or inactive tablet). The Pearl Index, defined as the number of pregnancies per 100 women-years of treatment was calculated as: Pearl Index = (1300*number of on-treatment pregnancies) / number of women 28-day equivalent cycles of treatment. Only at-risk cycles were included in the denominator of the Pearl Index calculation. At-risk-cycles were defined as cycles in which no other methods of birth control (including condoms and, for C302- emergency contraception) were used by the subject as confirmed in the subject diary and during which the subject confirmed that sexual intercourse had occurred.

[0158] The number of on-treatment pregnancies as assessed by the Method Failure Pearl Index in the overall study population (18-50 years for C301 and 16-50 years for C302) [time frame: up to 12 months (13 cycles with 1 cycle = 28 days)]

[0159] On-treatment pregnancies are defined as pregnancies with an estimated date of conception within the in-treatment period i.e. Day 1 to 2 days (C301) or Day 1 to 7 days (C302) after the last intake of investigational product (whether active or inactive tablet). The Pearl Index, defined as the number of pregnancies per 100 women-years of treatment was calculated as: Pearl Index = (1300*number of on-treatment pregnancies) / number of women 28-day equivalent cycles of treatment. The method failure Pearl Index includes only those pregnancies that were classified as method failure and not the pregnancies due to user failure, i.e. incorrect intake of the investigational product. Only at-risk cycles were included in the denominator of the Pearl Index calculation. At-risk-cycles were defined as cycles in which no other methods of birth control (including condoms and for C302-emergency contraception) were used by the subject as confirmed in the subject diary and during which the subject confirmed that sexual intercourse had occurred.

[0160] C302 only:

[0161] Rate of pregnancy (life-table analysis) in participants aged 16 to 35 years [time frame: up to 12 months (13 cycles with 1 cycle = 28 days)]

[0162] The life-table analysis evaluates the cumulative probability of pregnancy over 13 cycles. Cumulative Rate and 95% CI are from Kaplan-Meier estimation. Only on-treatment pregnancies are included. On-treatment pregnancy is a pregnancy with an estimated date of conception after the date of the first dose of study medication to 7 days after the last dose of study medication (regardless of whether the last dose is an active or inactive tablet) inclusive. Rate of pregnancy (life-table analysis) in participants aged 16 to 50 years [time frame: up to 12 months (13 cycles with 1 cycle = 28 days)]

[0163] The life-table analysis evaluates the cumulative probability of pregnancy over 13 cycles. Cumulative Rate and 95% confidence interval (CI) are from Kaplan-Meier estimation. Only on-treatment pregnancies are included. On-treatment pregnancy is a pregnancy with an estimated date of conception after the date of the first dose of study medication to 7 days after the last dose of study medication (regardless of whether the last dose is an active or inactive tablet) inclusive.

[0164] Both C301 and C302:

[0165] Number of subjects with unscheduled bleeding / spotting [time frame: up to 11 months (12 cycles with 1 cycle = 28 days)]

[0166] Unscheduled bleeding / spotting is defined as any bleeding / spotting that occurs while taking active hormones that does not meet the criteria for scheduled bleeding.

[0167] Number of unscheduled bleeding days per cycle [Time Frame: up to 11 months (12 cycles with 1 cycle = 28 days)]

[0168] Unscheduled bleeding is defined as any bleeding that occurs while taking active hormones that does not meet the criteria for scheduled bleeding and / or spotting.

[0169] Number of unscheduled spotting days per cycle [time frame: up to 11 months (12 cycles with 1 cycle = 28 days)]

[0170] Unscheduled spotting is defined as any spotting that occurs while taking active hormones that does not meet the criteria for scheduled bleeding and / or spotting.

[0171] Number of subjects with absence of scheduled bleeding and / or spotting [time frame: up to 11 months (12 cycles with 1 cycle = 28 days)]

[0172] Scheduled bleeding / spotting is defined as any bleeding / spotting that occurs during the hormone-free interval (i.e. Days 25 - 28) and continues through days 1-3 of the subsequent active cycle.

[0173] Number of scheduled bleeding and / or spotting days per cycle [time frame: up to 11 months (12 cycles with 1 cycle = 28 days)]

[0174] Scheduled bleeding and / or spotting is defined as any bleeding and / or spotting that occurs during the hormone-free interval (i.e. days 25 - 28) and continues through days 1-3 of the subsequent active cycle.

[0175] C302 only: Number of subjects with bleeding and / or spotting episodes by reference period [Time Frame: Up to 12 months (13 cycles with 1 cycle = 28 days)]

[0176] Bleeding data were analysed by 91-day reference period. There were 4 RPs: Reference Period 1 = Day 1 to Day 91; Reference Period 2 = Day 92 to Day 182; Reference Period 3 = Day 183 to Day 273; and Reference Period 4 = Day 274 to Day 364.

[0177] Mean number of bleeding and spotting days by reference period [time frame: up to 12 months (13 cycles)]

[0178] Bleeding data were analysed by 91-day reference period (RP). There were 4 RPs: Reference Period 1 = Day 1 to Day 91; Reference Period 2 = Day 92 to Day 182; Reference Period 3 = Day 183 to Day 273; and Reference Period 4 = Day 274 to Day 364.

[0179] Number of subjects with treatment-emergent adverse events as a measure of safety and tolerability, [time frame: up to 12 months (13 cycles with 1 cycle = 28 days)]

[0180] A treatment-emergent adverse event (TEAE) was defined as any AE not present prior to the initiation of the treatment or any event already present that worsened in either intensity or frequency following exposure to the treatment. Since the starting point for adverse event (AE) collection was the signing of the informed consent, not the start of the investigational product, the AEs recorded prior to first investigational product administration were designated as AEs while those that occurred or worsened after the initiation of the investigational product were designated as TEAEs.

[0181] Both C301 and C302:

[0182] Number of subjects with clinically abnormal vital signs [time frame: up to 12 months (13 cycles with 1 cycle = 28 days)]

[0183] Vital signs included sitting systolic and diastolic blood pressures, and heart rate. All abnormal findings in vital signs that were considered by the Investigator to be clinically significant were recorded as adverse events.

[0184] Number of subjects with abnormal laboratory assessment results [time frame: from screening to end of treatment (12 months)]

[0185] Laboratory assessment included blood hematology, biochemistry, and lipids

[0186] Number of subjects with abnormal physical examination results [time frame: from screening to end of treatment (12 months)] Physical examinations included an evaluation of body as a whole, skin, head, eyes, ears, nose, and throat, neck, cardiovascular, respiratory, musculoskeletal, neurologic, lymphatic / thyroid, abdomen. When reporting the results of the physical examination, the use of the "Abnormal" category was reserved for findings that were considered clinically significant, in the opinion of the Investigator; the "Normal" category included "Abnormal" results that were not clinically significant, as well as no findings.

[0187] Number of subjects with abnormal gynaecological examination results [Time Frame: From screening to end of treatment (12 months)]

[0188] Gynaecological examinations included breast examination (performed by palpation) and assessment of the adnexa, cervix, uterus, vagina, and external genitalia. When reporting the results, the use of the "Abnormal" category was reserved for findings that were considered clinically significant, in the opinion of the Investigator; the "Normal" category included "Abnormal" results that were not clinically significant, as well as no findings.

[0189] C301 only:

[0190] Endometrial biopsy histology at screening and end of treatment [time frame: baseline and end of treatment (up to 13 cycles with 1 cycle = 28 days)]

[0191] Endometrial biopsies were obtained from a subset of subjects included in the endometrial safety substudy at the screening visit and at the end of treatment visit if the subject has completed at least 10 cycles.

[0192] Both C301 and C302:

[0193] Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) results at baseline and end of treatment - percentage maximum (sum of first 14 items) [Time Frame: Baseline and Cycle 13 (1 cycle = 28 days)]

[0194] The Q-LES-Q-SF is a self-report measure designed to assess the degree of enjoyment and satisfaction in daily functioning. Participants were asked to rate 16 different items on a 5 -point scale where score 1 = very poor and score 5 = very good. A raw total score is calculated by summing the first 14 items and ranges from 14 to 70 with a higher scores indicating higher life enjoyment and satisfaction. The raw total score is then transformed into a percentage maximum score using the following formula: (raw total score-minimum score) / (maximum possible raw score-minimum score). The minimum raw is 14 and maximum raw score is 70. Thus the formula for % maximum score can be written as (raw score - 14) / 56. A higher percentage maximum score indicates a higher life enjoyment and satisfaction. In addition, the last two items (15 and 16) are two global items that are scored individually. These items rate "satisfaction with medicine" and "overall life satisfaction over the past week". Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) results at baseline and End of treatment - satisfaction with medicine and overall life satisfaction over the past week [time frame: baseline and cycle 13 (1 cycle = 28 days)]

[0195] The Q-LES-Q-SF is a self-report measure designed to assess the degree of enjoyment and satisfaction in daily functioning. Participants were asked to rate 16 different items on a 5 -point scale where score 1 = very poor and score 5 = very good. A raw total score is calculated by summing the first 14 items and ranges from 14 to 70 with a higher scores indicating higher life enjoyment and satisfaction. The raw total score is then transformed into a percentage maximum score using the following formula: (raw total score-minimum score) / (maximum possible raw score-minimum score). In addition, the last two items (15 and 16) are two global items that are scored individually. These items rate "satisfaction with medicine" and "overall life satisfaction over the past week".

[0196] Change from baseline to end of treatment in the score of the Menstmal Distress Questionnaire (MDQ) [time frame: baseline and cycle 13 (1 cycle = 28 days)]

[0197] The MDQ is a standard method for measuring cyclical perimenstrual symptoms. The participants rated common symptoms and feelings associated with menstruation using the following scale: 0 (no experience of symptom), 1 (present, mild), 2 (present, moderate), 3 (present, strong), and 4 (present, severe) observed during pre-menstrual (4 days before menstruation), menstrual (most recent flow) and intermenstrual (remainder of the cycle) phases. Reported values are values at cycle 13 minus values at baseline. An overall positive change from baseline represents an increase in symptom or feeling severity.

[0198] Inclusion Criteria:

[0199] Heterosexually active female at risk for pregnancy and requesting contraception.

[0200] Negative serum pregnancy test at subject enrohnent / screening.

[0201] Willing to use the investigational product as the primary method of contraception for 13 consecutive cycles.

[0202] Good physical and mental health on the basis of medical, surgical and gynaecological history, physical examination, gynaecological examination, clinical laboratory, and vital signs.

[0203] Body mass index (BMI) below or equal to (<) 35.0 kg / m2.

[0204] Able to fulfil the requirements of the protocol and have indicated a willingness to participate in the study by providing written informed consent (IC).

[0205] Willing and able to complete the diaries and questionnaires.

[0206] Exclusion Criteria:

[0207] Known hypersensitivity to any of the investigational product ingredients.

[0208] Smoking nicotine-containing products if > 35 years old, at screening. Any condition associated with decreased fertility.

[0209] Dyslipoproteinemia requiring active treatment with antilipidemic agent.

[0210] Diabetes mellitus with vascular involvement (nephropathy, retinopathy, neuropathy, other) or diabetes mellitus of more than 20-year duration.

[0211] Arterial hypertension. Any arterial hypertension (controlled and uncontrolled) defined by blood pressure values of: a. systolic blood pressure > 140 mmHg and / or, b. diastolic blood pressure > 90 mmHg.

[0212] It is noted that the subjects with a systolic blood pressure of > 140 mmHg and diastolic blood pressure > 90 mmHg at baseline had lower values at screening and had no history or diagnosis of hypertension, and for this reason they were included in the study.

[0213] Any condition associated with an increased risk of venous thromboembolism and / or arterial thromboembolism.

[0214] Any condition associated with abnormal uterine / vaginal bleeding.

[0215] Abnormal Pap test based on current international recommendations.

[0216] Presence of an undiagnosed breast mass.

[0217] Current symptomatic gallbladder disease.

[0218] History of combined oral contraceptive (COC) related cholestasis.

[0219] Presence or history of severe hepatic disease.

[0220] Presence or history of pancreatitis if associated with hypertriglyceridemia.

[0221] Porphyria.

[0222] Presence or history of hepatocellular adenoma or malignant liver tumors.

[0223] Renal impairment.

[0224] Hyperkaliemia or presence of conditions that predispose to hyperkaliemia.

[0225] Presence or history of hormone-related malignancy.

[0226] History of non-hormone -related malignancy within 5 years before screening. Subjects with a nonmelanoma skin cancer are allowed in the study.

[0227] Use of drugs potentially triggering interactions with COCs.

[0228] History of alcohol or dmg abuse (including laxatives) within 12 months prior to screening.

[0229] Use of drugs potentially triggering interactions with COCs.

[0230] Any condition that could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the investigational product.

[0231] Uncontrolled thyroid disorders.

[0232] Participation in another investigational drug clinical study within 1 month (30 days) or have received an investigational drug within the last 3 months (90 days) prior to study entry. Subjects who participated in an oral contraceptive clinical study, using FDA / EU approved active ingredients, may be enrolled 2 months (60 days) after completing the preceding study.

[0233] Sponsor, CRO or Investigator's site personnel directly affiliated with this study.

[0234] Anyone that is judged by the Investigator to be unsuitable for any reason. Methods:

[0235] Data from two parallel, multicentre, phase 3 trials (C301 and C302). Both trials measured BP at baseline and end of treatment (EoT) by 13 cycles (dropouts included).

[0236] Sitting systolic and diastolic blood pressure measurements were performed using a sphygmomanometer with an appropriate cuff size for the individual subject. Measurements were taken while the subject was seated following a period of at least 5 minutes rest in the seated position.

[0237] Changes in BP in participants with normal baseline BP (systolic BP [SBP] < 130 mmHg and diastolic BP [DBP] < 85 mmHg) and participants with a high normal baseline BP (SBP > 130 mmHg and / or DBP > 85 mmHg) were evaluated. The changes from baseline by study and parameter were analyzed by t-test.

[0238] Patients: 3417 healthy participants aged 18-50 years (C301, n=1553) or aged 16-50 years (C302, n=1864) with body mass index of 18-35 kg / m2.

[0239] Main outcome measures: Mean population SBP and DBP and change from baseline to EoT in participants with normal (n=3042) and high normal (n=375) baseline BP.

[0240] Results:

[0241] In normotensive participants, mean (±SD) population BPs at baseline and EoT were similar (SBP: 111.7±9.0 mmHg and 112.8±10.1; DBP 71.0±6.9 mmHg and 72.1±7.4 mmHg; Table 1 and Table 2). In high normal baseline BP participants, mean population SBP decreased by 7.6±9.7 mmHg from 129.2±7.0 mmHg to 121.9±9.6 mmHg at EoT (pO.OOOl); mean population DBP decreased by 4.0±7.7 mmHg from 82.7±5.8 at baseline to 78.5±7.6 mmHg at EoT (pO.OOOl) (Tables 1 to 3). In addition, a switch of category from borderline hypertensive at baseline (SBP > 130 and / or DBP > 85 mmHg) to normal (SBP < 130 and DBP < 85 mmHg) was observed EoT (Table 4).

[0242] Table 1: Blood pressure observations at baseline in normotensive participants (systolic blood pressure (SBP) < 130 and diastolic blood pressure (DBP) < 85 mmHg) and in high normal (abnormal) baseline participants (SBP > 130 and / or DBP > 85 mmHg) per study (C301 or C302, respectively) or pooled (participants from both C301 and C302). The safety analysis set was taken into account. N= Number of patients, SD= Standard Deviation

[0243] Table 2: Blood pressure observations at the end of treatment in normotensive participants (systolic blood pressure (SBP) < 130 and diastolic blood pressure (DBP) < 85 mmHg) and in high normal (abnormal) baseline participants (SBP > 130 and / or DBP > 85 mmHg) per study (C301 or C302, respectively) or pooled (participants from both C301 and C302). The safety analysis set was taken into account. N= Number of patients, SD= Standard Deviation

[0244] Table 3: Changes from blood pressure at baseline in normotensive participants (systolic blood pressure (SBP) < 130 and diastolic blood pressure (DBP) < 85 mmHg) and in high normal (abnormal) baseline participants (SBP > 130 and / or DBP > 85 mmHg) per study (C301 or C302, respectively) or pooled (participants from both C301 and

[0245] C302). The safety analysis set was taken into account. N= Number of patients, SD= Standard Deviation, *= Clinical relevance: changes for SBP were close to normotensive BP thresholds (~ 120mmHg), DBP reached normotensive values (< 80 mmHg).

[0246] Table 4: Number of participants switching categories - from borderline hypertensive (systolic blood pressure (SBP) > 130 and / or diastolic blood pressure (DBP) > 85 mmHg at baseline) to normal (SBP < 130 and DBP < 85 mmHg) at end of treatment per study (C301 or C302, respectively) or pooled (participants from both C301 and C302). The safety analysis set was taken into account. N= Number of patients

[0247] Conclusion:

[0248] While E4 / DRSP did not modify BP in normotensive women, a clinically relevant decrease in BP was observed in women with a high normal BP, since the changes for SBP reached close to threshold values for normotensive BP (~ 120mmHg) and DBP reached normotensive values (< 80 mmHg). These findings suggest that this combination could be studied in patients with mild hypertension . Women benefit from the fact that the antihypertensive effect is surprisingly limited to patients with high normal baseline BP. In contrast, BP is not unnecessarily reduced in patients with normotensive values at baseline.

[0249] Example 2: A multicenter, randomized, double-blind, placebo-controlled study to evaluate the effect of a combined oral contraceptive containing 15 mg estetrol monohydrate and 3 mg drospirenone on blood pressure

[0250] A prospective study will be conducted to select patients with pre-hypertension (SBP > 120 to 139 mmHg and DBP > 80 to 89 mmHg) or with high normal baseline BP (SBP > 130 mmHg and / or DBP > 85 mmHg) or even low-range hypertension (SBP > 140 mmHg and / or DBP > 90 mmHg) or even stage 1 hypertension (SBP > 140 to 159 mmHg and DBP > 90 to 99 mmHg), confirming the diagnosis with at least two blood pressure readings taken on different occasions or preferably by 24-hour ambulatory blood pressure monitoring or by home measurement. BP measures will most preferably be conducted at the same time of the day and, most commonly in the morning, to account for natural fluctuations. Then a randomized, double-blind trial comparing E4 / DRSP with a placebo will be performed. This trial will involve monitoring BP at regular intervals, preferably over a few months, to evaluate any changes. Measurements will be performed in triplicate and the mean value will be taken into account. As for the prospective study, 24-hour ambulatory blood pressure monitoring or home measurement are preferred and BP measures will most preferably be conducted at the same time of the day and, most commonly in the morning, to account for natural fluctuations. Through this approach clinically relevant findings will be substantiated.

[0251] Intervention:

[0252] Drug: 15 mg estetrol monohydrate / 3 mg DRSP. 15 mg estetrol monohydrate and 3 mg drospirenone tablets administered once daily for 13 consecutive cycles following a 24 / 4-day regimen, i.e. one 15 mg estetrol monohydrate / 3 mg DRSP active tablet per day for 24 consecutive days followed by one placebo tablet per day for 4 consecutive days.

[0253] Placebo: Placebo tablets administered once daily for 13 consecutive cycles of 28 days each.

[0254] Study Arms:

[0255] Experimental: 15 mg estetrol monohydrate / 3 mg DRSP

[0256] 15 mg estetrol monohydrate / 3 mg drospirenone (DRSP) combined oral contraceptive Placebo tablets

[0257] Main Outcome Measures:

[0258] Mean population SBP and DBP and change from baseline to EoT in participants with pre-hypertension (SBP > 120 to 139 mmHg and DBP > 80 to 89 mmHg), high normal baseline BP (SBP > 130 mmHg and / or DBP > 85 mmHg), low range hypertension at baseline (SBP > 140 mmHg and / or DBP > 90 mmHg) and stage 1 hypertension (SBP > 140 to 159 mmHg and DBP > 90 to 99 mmHg) optionally presenting one or more risk factors selected from age >35 years, BMI >30, smoking, diabetes and prediabetes will be evaluated. The changes from baseline will be analyzed by t-test.

[0259] Inclusion and Exclusion Criteria:

[0260] Inclusion and Exclusion criteria will be in line with Example 1, while also subjects with SBP > 140 mmHg and / or diastolic blood pressure > 90 mmHg at screening will be enrolled. Preferably, patients will be enrolled presenting one or more cardiovascular risk factors selected from age >35 years, BMI >30, smoking, diabetes and prediabetes. The latter is defined as having blood glucose levels that are higher than normal, but not yet at the point that defines diabetes

[0261] Methods:

[0262] BP measurements will be performed as described in Example 1. So will BP be measured at baseline and end of treatment (EoT) by 13 cycles (dropouts included). Changes in BP from baseline in participants with pre-hypertension (SBP > 120 to 139 mmHg and DBP > 80 to 89 mmHg), high normal baseline BP (SBP > 130 mmHg and / or DBP > 85 mmHg), low range hypertension at baseline (SBP > 140 mmHg and / or DBP > 90 mmHg) and stage 1 hypertension (SBP > 140 to 159 mmHg and DBP > 90 to 99 mmHg) were evaluated. The changes from baseline will be analyzed by t-test.

[0263] Results:

[0264] A clinically relevant decrease in blood pressure from baseline will be observed in participants with prehypertension (SBP > 120 to 139 mmHg and DBP > 80 to 89 mmHg), high normal baseline BP (SBP > 130 mmHg and / or DBP > 85 mmHg), low range hypertension at baseline (SBP > 140 mmHg and / or DBP > 90 mmHg) or even stage 1 hypertension (SBP > 140 to 159 mmHg and DBP > 90 to 99 mmHg) at baseline reaching close-to- threshold values for normotensive BP such as SBP~ 120mmHg and / or DBP< 80 mmHg. There will be no evidence of the risk of an increase in blood pressure in participants who present one or more cardiovascular risk factors selected from age >35 years, BMI >30, smoking, diabetes and prediabetes. Preferably, said clinically relevant decrease in blood pressure from baseline will be more pronounced in these participants.

[0265] Conclusion:

[0266] The conclusion will be that E4 / DRSP can be considered as a safe alternative to progestin-only birth control pills, as high-risk patients can now benefit from the presence of an estrogen. The advantages include, for example, a controlled bleeding profde.

Claims

CLAIMS1. A combined oral contraceptive (COC) comprising estetrol and drospirenone for use in normalizing or reducing blood pressure in a female subject having a systolic blood pressure equal to or higher than 120 mmHg and / or a diastolic blood pressure equal to or higher than 80 mmHg prior to the use of said COC.

2. A combined oral contraceptive (COC) comprising estetrol and drospirenone for use in reducing the risk of hypertension in a female subject having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said COC.

3. Use of a composition comprising estetrol and drospirenone for the manufacture of a medicament for use in normalizing or reducing blood pressure in a female subject, wherein said female subject is characterised by having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said composition.

4. Use of a composition comprising estetrol and drospirenone for the manufacture of a medicament for reducing the risk of hypertension associated with the use of a combined oral contraceptive (COC) in a female subject, wherein said female subject is characterised by having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said composition.

5. A method of normalizing or reducing blood pressure in a female subject having a systolic blood pressure equal or higher than 120 mmHg and / or a diastolic blood pressure equal to or higher than 80 mmHg, comprising administering a COC comprising estetrol and drospirenone to said subject.

6. A method of reducing the risk of hypertension associated with the use of a combined oral contraceptive (COC) in a female subject having a systolic blood pressure equal to or higher than about 120 mmHg and / or a diastolic blood pressure equal to or higher than about 80 mmHg prior to the use of said COC, comprising administering a COC comprising estetrol and drospirenone to said subject.

7. A contraceptive method having a reduced risk of hypertension, comprising administering to a female subject an amount of estetrol and drospirenone, to reduce the risk of hypertension associated with the use of a combined oral contraceptive (COC) comprising an estrogenic and a progestogenic component, wherein the female subject is selected from subjects having a systolic blood pressure equal to or higher than 120 mmHg and / or a diastolic blood pressure equal to or higher than 80 mmHg prior to the use of said COC.

8. The COC for use according to claim 1 or 2, the use according to claim 3 or 4, the method according to claim 5 or 6, or the contraceptive method according to claim 7, wherein the female subject is selected from subjects that are pre-hypertensive (SBP > 120 to 139 mmHg and DBP > 80 to 89 mmHg), have high normal baseline BP (SBP > 130 mmHg and / or DBP > 85 mmHg), have low range hypertension at baseline (SBP > 140 mmHg and / or DBP > 90 mmHg) or have stage 1 hypertension (SBP > 140 to 159 mmHg and DBP > 90 to 99 mmHg).

9. The COC for use, the use, the method, or the contraceptive method according to any one of claims 1 to 8, wherein the systolic blood pressure is decreased to less than about 125 mmHg, preferably less than about 124 mmHg, preferably less than about 123 mmHg, preferably less than about 122 mmHg, preferably less than about 121 mmHg, more preferably to less than about 120 mmHg.

10. The COC for use, the use, the method, or the contraceptive method according to any one of claims 1 to 9, wherein the female subject is selected from pre-menopausal subjects, preferably wherein the female subject is selected from subjects having an age of equal to or higher than 30 years, preferably of equal to or higher than 35 years, more preferably older than 40 years.

11. The COC for use, the use, the method, or the contraceptive method according to any one of claims 1 to 10, wherein the female subject is selected from subjects having a body mass index (BMI) of equal to or higher than 30 kg / m212. The COC for use, the use, the method, or the contraceptive method according to any one of claims 1 to 11, wherein the female subject is selected from subjects that are smoking and / or subjects that are diabetic or have polycystic ovary syndrome (PCOS) and / or dysmenorrhea.

13. The COC for use, the use, the method, or the contraceptive method according to any one of claims 1 to 12, wherein the female subject is selected from first-ever users and switchers / re-starters with a break of more than 4 weeks.

14. The COC for use, the use, the method, or the contraceptive method according to any one of claims 1 to 13, wherein the estetrol is administered at a daily dose of from about 1 mg to about 40 mg, preferably at a daily dose of from about 5 mg to about 25 mg, more preferably at a daily dose of about 15 mg.

15. The COC for use, the use, the method, or the contraceptive method according to any one of claims 1 to 14, wherein the drospirenone is administered at a daily dose of from about 0.5 mg to about 10 mg, preferably at a daily dose of from about 1 mg to about 4 mg.

16. The COC for use, the use, the method, or the contraceptive method according to any one of claims 1 to 15, wherein the method is a combined administration method with an administration-free interval of about 7 days, preferably a combined administration method with an administration-free interval of about 4 days.

17. The COC for use, the use, the method, or the contraceptive method according to any one of claims 1 to 16, wherein the estetrol is estetrol monohydrate.

18. The COC for use, the use, the method, or the contraceptive method according to any one of claims 1 to 17, wherein the estetrol is administered at a daily dose of about 15 mg estetrol monohydrate.

19. The COC for use, the use, the method, or the contraceptive method according to any one of claims 1 to 18, wherein the drospirenone is administered at a daily dose of about 3 mg.

20. The COC for use, the use, the method, or the contraceptive method according to any one of claims 1 to 19, wherein the estetrol and drospirenone are formulated together in a single oral dosage unit, preferably wherein said single oral dosage unit is formulated to provide a daily dose of the estetrol and drospirenone.