Efficacy in Suppressing Ovulation and Safety of a Low dose Oral Contraceptive in a Continuous Regimen (84+7) With Continuous Ethinyl Estradiol Instead of a Hormone-Free Interval: An Evaluation of Ovulation Suppression and Ovarian Activity
Abstract
Background: This study aimed to evaluate the efficacy of a low dose oral contraceptive in a continuous regimen (84+7) with continuous ethinyl estradiol (EE) instead of a hormone-free interval (HFI) (84 tablets containing 100 mcg levonorgestrel (LNG) + 20 mcg EE, and 7 tablets containing 10 mcg EE; MODELLE® LIBERA, Teva) in suppression of ovulation and ovarian activity.
Methods: A multicenter, open-label, single-treatment, Phase 3 study that evaluated 52 healthy non-pregnant females aged 18 through 35 years, of whom 47 (90%) participants completed the entire 91-day treatment. Evaluation of the efficacy of the formulation in suppressing ovulation was achieved by performing transvaginal ultrasound examinations and determining the serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone.
Results: Overall, 88% of the participants presented with a lack of ovarian activity during all three 28-day intervals corresponding to a standard cycle. Ovarian suppression was reported in 99% of all cycles. The serum levels of sex hormones corresponded to the predicted values with allowance for the relevant extended mode of administration of the combined oral contraceptives (COCs). During the post-therapeutic follow-up visit, the restoration of ovulation on the post-therapeutic follow-up visit (the 20th week of the study) was reported in 45 females (87%, 95% binomial CI: 74.2%, 94.4%), 13% did not return to ovulation.
Conclusions: The efficacy of the study drug in suppressing ovulation was confirmed by the absence of ovarian activity reported in the majority of the participants over the 91-day course of treatment. Ovarian activity was detected in 2 participants (grade 4 according to the Hoogland and Skouby scale, luteinized unruptured follicle), and in each, the relevant activity was observed during the 3rd interval within the 91-day cycle during the 7-day period when only low doses of EE were administered. The underlying basis of the ovarian activity observed during the 7-day EE-only period has not been fully elucidated. The results of the study demonstrate that a low dose oral contraceptive in a continuous regimen (84+7) with continuous EE instead of a hormone-free interval is safe and can be an additional contraceptive option for healthy women seeking decreased menstrual bleeding.
Trial registration: Grls.rosminzdrav.ru (RCT №37 (28.01.2014).
Keywords: Continuous regimen; Oral contraception; Low dose; Hormone-free interval; Modelle ® Libera; LoSeasonique
Introduction
Combined oral contraceptives are effective and one of the most popular methods of contraception. Since their appearance, these medications composition and regimen have undergone changes. The traditional regimens simulate a 28-day menstrual cycle. However 91-day prolonged regimens without hormonal free intervals have already been developed. This prolonged regimen allows to decrease the frequency of menstrual-like scheduled bleeding episodes and can meet women’s social and cultural reasons.
In this study, the efficacy in suppressing ovulation and safety of low dose oral contraceptive in a continuous regimen without hormonal free intervals were evaluated. The efficacy was evaluated with the help of ultrasound examinations of the ovaries and the serum concentrations of sex hormones measurements: follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone.
52 healthy non-pregnant women have participated in the study. Suppression of ovarian function and, consequently, the effectiveness of contraceptives was observed in 99% of all cycles. No pregnancies were detected during the treatment period. The safety profile was also within the expected values. Ovarian function restoration was recorded in 87% of participants on the 20th week of the study during the follow-up period.
In conclusion, these results have demonstrated that the low dose combined oral contraceptives in a continuous regimen are effective and safe for healthy women.
Introduction
COCs are the most used reversible method of birth control and have remained the most popular form of contraception for decades, despite the introduction of other methods of contraception such as parenteral methods [1]. Approximately 9% of women globally aged 15 to 49 years prefer COCs over other methods of contraception, and this figure reaches 18% in developed countries [2], while the frequency of use of modern contraceptive methods in developed countries is generally higher. Over the years, the composition of COCs has undergone significant changes: the dose of the estrogen component has been significantly reduced, and new progestogens have been developed and included. The current practice includes administration of multiphase drugs and extended administration regimens with shorter hormone-free intervals (24/4) [1,3-6] in order to increase the efficacy, safety, and acceptability of COCs [7- 11].
Since their initial development over 50 years ago, COCs have been most administered in accordance with the standard regimen that simulates a natural 28-day cycle (21 active pills + 7-day break) [3]. This regimen was developed to mimic natural menstrual cycles. It was not designed out of medical necessity but due to cultural and social practices [12]. COCs represented a revolutionary method of controlling fertility at the time of their creation, which was supposed to be convenient for both women and physicians. The absence of the scheduled bleeding episodes raised doubts regarding the efficacy of the method and could lead to refusals to use this method of birth control, as amenorrhea was clearly associated with the onset of pregnancy some years ago [4]. Today, as there is no longer any doubt regarding the efficacy of COCs, the diagnosis of early pregnancy is relatively easy, and the use of prolonged regimens is a routine practice, the question of the expediency of the administration of COCs in the traditional cyclic regimens remains debatable.
The administration of COCs over prolonged periods of time accompanied by a predictable decrease in the frequency of menstrual-like scheduled bleeding episodes may be desirable for many women. Women express a desire to reduce the frequency of menstruation, including for social and cultural reasons [5,6,13]. Reductions in the number of menses per year contribute to improvements in the quality of life by reducing the frequency of menstrual and premenstrual symptoms. The use of prolonged administration regimens leads to a reduction in the incidence of side effects and generally increases the efficacy of contraception [3].
The development of the drugs characterized by continuous administration regimens gained popularity in the early 2000s, while studies on the use of COCs over prolonged periods of time began as far back as the 1970s. In 2003, the FDA approved a new administration regimen for COCs (84/7) [14].
The administration of extended-cycle COCs does not lead to complete suppression of ovarian function. At the beginning of the 7-day hormone-free interval, the activity of the ovaries is minimal [15]. However, due to the lack of active components during the HFI, the activity of the hypothalamic-pituitary-ovarian system axis is slowly restored as the estrogens and progestogens are metabolized. The reduction or modification of the HFI may contribute to an additional decrease in the functional activity of the ovaries [3].
In 2003, the first drug that replaced the HFI with the administration of tablets containing ultra-low doses of EE of 10 mcg/day was created [3]. The stabilizing period associated with the administration of tablets containing 10 mcg EE instead of placebo suppresses the levels of endogenous estradiol, FSH, and Inhibin-B and leads to increased suppression of ovarian follicular development, reduction in follicular growth and reduction in the risk of ovulation and, accordingly, the risk of unplanned pregnancy [16].
The study drug (MODELLE® LIBERA, Teva LLC Russia; also registered in the USA as LoSeasonique, Teva) is a low dose combined estrogen-progestogen oral contraceptive in a 91-day continuous regimen (84+7) with continuous 10 mcg EE instead of an HFI. The drug suppresses the secretion of gonadotropic hormones. The contraceptive effect is achieved in several ways, the most important of which is through the suppression of ovulation. A single package contains 84 tablets containing 100 mcg LNG and 20 mcg EE each and 7 tablets containing 10 mcg EE each. Administration of this COC reduces the number of menstrual-like bleeding episodes to just four per year. Over the last 7 days of the prolonged use of the drug (on days 85-91), the administration of 10 mcg of EE instead of placebo is associated with an increase in the suppression of the ovarian follicular apparatus and a decrease in the risk of ovulation. Menstrual-like bleeding after discontinuation of the active tablets of the drug is attributed to the absence of the progestin-mediated effect exerted on the endometrium. Meanwhile, residual suppression of the hypothalamic-pituitary-ovarian system and functional activity of the ovaries is retained during this period due to the administration of a small dose of EE [17].
The purpose of this study was to evaluate the efficacy of a low dose oral contraceptive in a continuous regimen (84+7) with continuous EE instead of an HFI in suppressing ovulation and ovarian activity. For this purpose, the following indicators were evaluated:
• Ripening of follicles in the ovaries using transvaginal ultrasound (transvaginal sonography, TVS);
• Determination of serum concentrations of FSH, LH, estradiol, and progesterone.
Additionally, restoration of ovulation function, the frequency and severity of adverse events and the frequency of pregnancies were evaluated.
Materials and Methods
Design of the study and population
The efficacy in suppression of ovulation and safety of a low dose oral contraceptive in a continuous regimen (84+7) was evaluated in an open-label multicenter (6 trial sites) study with a single group of female volunteers on the basis of the assessment of the ovarian function and the level of sex hormones (Study DR-101-WH-30007). It was planned to include 60 women in the study with a minimum of 30 women completing the 91-day treatment period. The size of the sample was calculated for the main variable of the study which was the efficacy in suppressing ovulation assessed by the ovarian activity (Hoogland & Skouby scale). It was assumed that the trial power would be 80% (β = 0.2, zβ = 0.84), the significance level α = 0.05 (zα = 1.64). It was also assumed that the efficacy of the treatment in suppressing ovulation would be established after the drug administration in 75% of volunteers (p = 0.75). The reference value of this indicator was considered equal to 50% (p0 = 0.5). It was also assumed that a difference more than 10% (d = 0.1) would indicate clinical importance. Thus, for the final analysis at least 51 female volunteers were required. Considering the possible exclusion of the participants during the treatment period up to 20%, it was necessary to screen at least 60 women for enrollment. One cohort of the participants was analyzed. The baseline characteristics, the frequency of efficacy in suppressing ovulation and safety were assessed and summarized. The significance levels and confidence intervals were calculated as two-sided; the statistical significance of the differences was also two-sided and related to the significance level of 0.05.
66 healthy females were screened for enrollment into the study. Of these women, 52 sexually active healthy females aged 18 to 35 (with the median age of 26.5 years) who agreed to use COCs as their main method of contraception throughout the entire study period of 91 days and use a double barrier method of contraception (e.g., a condom and spermicide or a diaphragm and spermicide) to prevent pregnancy were included. Of the 14 females who were not enrolled, 8 were not enrolled due to low baseline progesterone levels (<15.9 mmol/L), 2 were excluded on the basis of inclusion criteria, 2 were excluded on the basis of exclusion criteria, 1 revoked patient informed consent and 1 was lost to follow-up. Regular spontaneous menstruation occurring approximately once a month or every 23- 33 days before the screening visit, determining that the subject was ovulating, was among the inclusion criteria. The patients with contraindications to COCs and/or a history of significant adverse events associated with the administration of oral contraceptives were excluded from the study. The exclusion criteria also included the use of injectable hormonal contraceptives over a period of 6 months prior to the screening visit or the presence of a contraceptive implant/hormonal intrauterine device at the time of the screening visit. All participants were instructed during visit 1a to the study site on the regimen of taking1 tablet once a day at the same time (84 tablets of 100 mcg LNG + 20 mcg EE and 7 tablets of 10 mcg EE) during the 91 days of the treatment period.
The study included 4 stages, during which the patients were obliged to visit their study sites a total of 9 times (visits 1a-9a), corresponding to the relevant weeks of the study (Table 1).
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