{"paper_id":"94470001-e137-41e5-a738-e35d45acb48e","body_text":"Page 1 of 10\nEfficacy in Suppressing Ovulation and Safety of a Low \ndose Oral Contraceptive in a Continuous Regimen \n(84+7) With Continuous Ethinyl Estradiol Instead of \na Hormone-Free Interval: An Evaluation of Ovulation \nSuppression and Ovarian Activity\nInna Apolikhina1,2*, Andrey Kuzemin1, Victoria Odinokova1, Victor Radzinsky3, Alexandra Gardner4* and \nGennady Sukhikh1,2\n1National Medical Research Center of Obstetrics, Gynecology, and Perinatology named after Academician VI Kulakov, Ministry of Health of Russia, Russia\n2Department of Obstetrics, Gynecology, Perinatology, and Reproductology, Institute of Professional Education, IM Sechenov First Moscow State Medical \nUniversity, Russia\n3Department of Obstetrics and Gynecology with the course of perinatology of the Peoples’ Friendship University of Russia, Russia\n4Teva LLC, Moscow, Russia\n*Corresponding author:  Inna Apolikhina, Professor, Obstetrician-Gynecologist, \nNational Medical Research Center of Obstetrics, Gynecology, and Perinatology \nnamed after Academician VI Kulakov, Ministry of Health of Russia, Moscow, Russia.\nReceived Date: January 12, 2020\nPublished Date: January 29, 2020\nISSN: 2641-6247                                                                                                                           DOI: 10.33552/WJGWH.2020.03.000559\nWorld Journal of \nGynecology & Women’s Health\nResearch Article Copyright © All rights are reserved by Inna Apolikhina\nThis work is licensed under Creative Commons Attribution 4.0 License  WJGWH.MS.ID.000559.\nSummary\nCombined oral contraceptives are effective and one of the most \npopular methods of contraception. Since their appearance, these  \n \nmedications composition and regimen have undergone changes. The \ntraditional regimens simulate a 28-day menstrual cycle. However, \nAbstract \nBackground: This study aimed to evaluate the efficacy of a low dose oral contraceptive in a continuous regimen (84+7) with continuous ethinyl \nestradiol (EE) instead of a hormone-free interval (HFI) (84 tablets containing 100 mcg levonorgestrel (LNG) + 20 mcg EE, and 7 tablets containing \n10 mcg EE; MODELLE® LIBERA, Teva) in suppression of ovulation and ovarian activity.\nMethods: A multicenter, open-label, single-treatment, Phase 3 study that evaluated 52 healthy non-pregnant females aged 18 through 35 years, \nof whom 47 (90%) participants completed the entire 91-day treatment. Evaluation of the efficacy of the formulation in suppressing ovulation was \nachieved by performing transvaginal ultrasound examinations and determining the serum concentrations of follicle-stimulating hormone (FSH), \nluteinizing hormone (LH), estradiol, and progesterone. \nResults: Overall, 88% of the participants presented with a lack of ovarian activity during all three 28-day intervals corresponding to a standard \ncycle. Ovarian suppression was reported in 99% of all cycles. The serum levels of sex hormones corresponded to the predicted values with allowance \nfor the relevant extended mode of administration of the combined oral contraceptives (COCs). During the post-therapeutic follow-up visit, the \nrestoration of ovulation on the post-therapeutic follow-up visit (the 20th week of the study) was reported in 45 females (87%, 95% binomial CI: \n74.2%, 94.4%), 13% did not return to ovulation. \nConclusions: The efficacy of the study drug in suppressing ovulation was confirmed by the absence of ovarian activity reported in the majority of \nthe participants over the 91-day course of treatment. Ovarian activity was detected in 2 participants (grade 4 according to the Hoogland and Skouby \nscale, luteinized unruptured follicle), and in each, the relevant activity was observed during the 3rd interval within the 91-day cycle during the 7-day \nperiod 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 \nbeen fully elucidated. The results of the study demonstrate that a low dose oral contraceptive in a continuous regimen (84+7) with continuous EE \ninstead of a hormone-free interval is safe and can be an additional contraceptive option for healthy women seeking decreased menstrual bleeding.\nTrial registration: Grls.rosminzdrav.ru (RCT №37 (28.01.2014).\nKeywords: Continuous regimen; Oral contraception; Low dose; Hormone-free interval; Modelle ® Libera; LoSeasonique\n\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 3-Issue 2\nCitation: Inna Apolikhina, Andrey Kuzemin, Victoria Odinokova, Victor Radzinsky, Alexandra Gardner, Gennady Sukhikh. Efficacy in \nSuppressing Ovulation and Safety of a Low dose Oral Contraceptive in a Continuous Regimen (84+7) With Continuous Ethinyl Estradiol \nInstead of a Hormone-Free Interval: An Evaluation of Ovulation Suppression and Ovarian Activity. W J Gynecol Women’s Health. 3(2): 2020. \nWJGWH.MS.ID.000559. DOI: 10.33552/WJGWH.2020.03.000559.\nPage 2 of 10\n91-day prolonged regimens without hormonal free intervals have \nalready been developed. This prolonged regimen allows to decrease \nthe frequency of menstrual-like scheduled bleeding episodes and \ncan meet women’s social and cultural reasons.\nIn this study, the efficacy in suppressing ovulation and \nsafety of low dose oral contraceptive in a continuous regimen \nwithout hormonal free intervals were evaluated. The efficacy was \nevaluated with the help of ultrasound examinations of the ovaries \nand the serum concentrations of sex hormones measurements: \nfollicle-stimulating hormone, luteinizing hormone, estradiol, and \nprogesterone. \n52 healthy non-pregnant women have participated in the \nstudy. Suppression of ovarian function and, consequently, the \neffectiveness of contraceptives was observed in 99% of all cycles. \nNo pregnancies were detected during the treatment period. The \nsafety profile was also within the expected values. Ovarian function \nrestoration was recorded in 87% of participants on the 20th week \nof the study during the follow-up period.\nIn conclusion, these results have demonstrated that the low \ndose combined oral contraceptives in a continuous regimen are \neffective and safe for healthy women.\nIntroduction\nCOCs are the most used reversible method of birth control and \nhave remained the most popular form of contraception for decades, \ndespite the introduction of other methods of contraception such as \nparenteral methods [1]. Approximately 9% of women globally aged \n15 to 49 years prefer COCs over other methods of contraception, \nand this figure reaches 18% in developed countries [2], while the \nfrequency of use of modern contraceptive methods in developed \ncountries is generally higher. Over the years, the composition of \nCOCs has undergone significant changes: the dose of the estrogen \ncomponent has been significantly reduced, and new progestogens \nhave been developed and included. The current practice includes \nadministration of multiphase drugs and extended administration \nregimens with shorter hormone-free intervals (24/4) [1,3-6] in \norder to increase the efficacy, safety, and acceptability of COCs [7-\n11].\nSince their initial development over 50 years ago, COCs have \nbeen most administered in accordance with the standard regimen \nthat simulates a natural 28-day cycle (21 active pills + 7-day break) \n[3]. This regimen was developed to mimic natural menstrual cycles. \nIt was not designed out of medical necessity but due to cultural and \nsocial practices [12]. COCs represented a revolutionary method \nof controlling fertility at the time of their creation, which was \nsupposed to be convenient for both women and physicians. The \nabsence of the scheduled bleeding episodes raised doubts regarding \nthe efficacy of the method and could lead to refusals to use this \nmethod of birth control, as amenorrhea was clearly associated \nwith the onset of pregnancy some years ago [4]. Today, as there is \nno longer any doubt regarding the efficacy of COCs, the diagnosis \nof early pregnancy is relatively easy, and the use of prolonged \nregimens is a routine practice, the question of the expediency of the \nadministration of COCs in the traditional cyclic regimens remains \ndebatable.\nThe administration of COCs over prolonged periods of time \naccompanied by a predictable decrease in the frequency of \nmenstrual-like scheduled bleeding episodes may be desirable for \nmany women. Women express a desire to reduce the frequency of \nmenstruation, including for social and cultural reasons [5,6,13]. \nReductions in the number of menses per year contribute to \nimprovements in the quality of life by reducing the frequency of \nmenstrual and premenstrual symptoms. The use of prolonged \nadministration regimens leads to a reduction in the incidence of \nside effects and generally increases the efficacy of contraception \n[3].\nThe development of the drugs characterized by continuous \nadministration regimens gained popularity in the early 2000s, \nwhile studies on the use of COCs over prolonged periods of time \nbegan as far back as the 1970s. In 2003, the FDA approved a new \nadministration regimen for COCs (84/7) [14].\nThe administration of extended-cycle COCs does not lead to \ncomplete suppression of ovarian function. At the beginning of the \n7-day hormone-free interval, the activity of the ovaries is minimal \n[15]. However, due to the lack of active components during the HFI, \nthe activity of the hypothalamic-pituitary-ovarian system axis is \nslowly restored as the estrogens and progestogens are metabolized. \nThe reduction or modification of the HFI may contribute to an \nadditional decrease in the functional activity of the ovaries [3].\nIn 2003, the first drug that replaced the HFI with the \nadministration of tablets containing ultra-low doses of EE of 10 \nmcg/day was created [3]. The stabilizing period associated with \nthe administration of tablets containing 10 mcg EE instead of \nplacebo suppresses the levels of endogenous estradiol, FSH, and \nInhibin-B and leads to increased suppression of ovarian follicular \ndevelopment, reduction in follicular growth and reduction in the \nrisk of ovulation and, accordingly, the risk of unplanned pregnancy \n[16].\nThe study drug (MODELLE® LIBERA, Teva LLC Russia; \nalso registered in the USA as LoSeasonique, Teva) is a low dose \ncombined estrogen-progestogen oral contraceptive in a 91-day \ncontinuous regimen (84+7) with continuous 10 mcg EE instead \nof an HFI. The drug suppresses the secretion of gonadotropic \nhormones. The contraceptive effect is achieved in several ways, the \nmost important of which is through the suppression of ovulation. \nA single package contains 84 tablets containing 100 mcg LNG \nand 20 mcg EE each and 7 tablets containing 10 mcg EE each. \nAdministration of this COC reduces the number of menstrual-like \nbleeding episodes to just four per year. Over the last 7 days of the \nprolonged use of the drug (on days 85-91), the administration of 10 \nmcg of EE instead of placebo is associated with an increase in the \nsuppression of the ovarian follicular apparatus and a decrease in \nthe risk of ovulation. Menstrual-like bleeding after discontinuation \n\nCitation: Inna Apolikhina, Andrey Kuzemin, Victoria Odinokova, Victor Radzinsky, Alexandra Gardner, Gennady Sukhikh. Efficacy in \nSuppressing Ovulation and Safety of a Low dose Oral Contraceptive in a Continuous Regimen (84+7) With Continuous Ethinyl Estradiol \nInstead of a Hormone-Free Interval: An Evaluation of Ovulation Suppression and Ovarian Activity. W J Gynecol Women’s Health. 3(2): 2020. \nWJGWH.MS.ID.000559. DOI: 10.33552/WJGWH.2020.03.000559.\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 3-Issue 2\nPage 3 of 10\nof the active tablets of the drug is attributed to the absence of the \nprogestin-mediated effect exerted on the endometrium. Meanwhile, \nresidual suppression of the hypothalamic-pituitary-ovarian system \nand functional activity of the ovaries is retained during this period \ndue to the administration of a small dose of EE [17].\nThe purpose of this study was to evaluate the efficacy of a \nlow dose oral contraceptive in a continuous regimen (84+7) with \ncontinuous EE instead of an HFI in suppressing ovulation and \novarian activity. For this purpose, the following indicators were \nevaluated:\n• Ripening of follicles in the ovaries using transvaginal \nultrasound (transvaginal sonography, TVS);\n• Determination of serum concentrations of FSH, LH, \nestradiol, and progesterone.\nAdditionally, restoration of ovulation function, the frequency \nand severity of adverse events and the frequency of pregnancies \nwere evaluated.\nMaterials and Methods\nDesign of the study and population\nThe efficacy in suppression of ovulation and safety of a low dose \noral contraceptive in a continuous regimen (84+7) was evaluated in \nan open-label multicenter (6 trial sites) study with a single group \nof female volunteers on the basis of the assessment of the ovarian \nfunction and the level of sex hormones (Study DR-101-WH-30007). \nIt was planned to include 60 women in the study with a minimum \nof 30 women completing the 91-day treatment period. The size of \nthe sample was calculated for the main variable of the study which \nwas the efficacy in suppressing ovulation assessed by the ovarian \nactivity (Hoogland & Skouby scale). It was assumed that the trial \npower would be 80% (β = 0.2, zβ = 0.84), the significance level \nα = 0.05 (zα = 1.64). It was also assumed that the efficacy of the \ntreatment in suppressing ovulation would be established after the \ndrug administration in 75% of volunteers (p = 0.75). The reference \nvalue of this indicator was considered equal to 50% (p0 = 0.5). It \nwas also assumed that a difference more than 10% (d = 0.1) would \nindicate clinical importance. Thus, for the final analysis at least 51 \nfemale volunteers were required. Considering the possible exclusion \nof the participants during the treatment period up to 20%, it was \nnecessary to screen at least 60 women for enrollment. One cohort \nof the participants was analyzed. The baseline characteristics, the \nfrequency of efficacy in suppressing ovulation and safety were \nassessed and summarized. The significance levels and confidence \nintervals were calculated as two-sided; the statistical significance \nof the differences was also two-sided and related to the significance \nlevel of 0.05. \n66 healthy females were screened for enrollment into the study. \nOf these women, 52 sexually active healthy females aged 18 to 35 \n(with the median age of 26.5 years) who agreed to use COCs as their \nmain method of contraception throughout the entire study period \nof 91 days and use a double barrier method of contraception (e.g., a \ncondom and spermicide or a diaphragm and spermicide) to prevent \npregnancy were included. Of the 14 females who were not enrolled, \n8 were not enrolled due to low baseline progesterone levels (<15.9 \nmmol/L), 2 were excluded on the basis of inclusion criteria, 2 \nwere excluded on the basis of exclusion criteria, 1 revoked patient \ninformed consent and 1 was lost to follow-up. Regular spontaneous \nmenstruation occurring approximately once a month or every 23-\n33 days before the screening visit, determining that the subject \nwas ovulating, was among the inclusion criteria. The patients with \ncontraindications to COCs and/or a history of significant adverse \nevents associated with the administration of oral contraceptives \nwere excluded from the study. The exclusion criteria also included \nthe use of injectable hormonal contraceptives over a period of 6 \nmonths prior to the screening visit or the presence of a contraceptive \nimplant/hormonal intrauterine device at the time of the screening \nvisit. All participants were instructed during visit 1a to the study \nsite on the regimen of taking1 tablet once a day at the same time \n(84 tablets of 100 mcg LNG + 20 mcg EE and 7 tablets of 10 mcg EE) \nduring the 91 days of the treatment period. \nThe study included 4 stages, during which the patients were \nobliged to visit their study sites a total of 9 times (visits 1a-9a), \ncorresponding to the relevant weeks of the study (Table 1).\nTable 1: Designation of the visits with allowance for the weeks of the \nstudy.\nWeek Visit\n3 1a\n5 2a and 3a\n6 4a\n10 5a\n15 6a\n16 7a\n17 8a\n20 9a\nStudy procedures\nDuring the screening phase, the participants underwent \ngynecological examinations, their medical histories were reviewed, \nand the date of the onset of the last menstruation was determined \nfor each patient. The first TVS examination was also performed \nduring the specified stage to confirm the normal anatomy of both \novaries and to determine the feasibility of their visualization. Prior \nto the administration of the drug, the levels of sex hormones were \ndetermined, and the participants were assessed for their eligibility \nfor participation through the inclusion/exclusion criteria. Visit \n1а was organized on day 18-20 of the menstrual cycle. During \nthat stage, the levels of FSH, LH, estradiol, and progesterone \nwere evaluated (Figure 1). The relevant values were recorded \nas the baseline values. Spontaneous ovulation was assessed by \ndetermining the serum level of progesterone. The participants were \nalso subjected to TVS examinations to assess the initial activity of \nthe ovarian follicles. During the subsequent visits, the study drug \nwas administered. The ovarian activity was evaluated using TVS and \nthe Hoogland and Skouby scale [18]; the levels of FSH, LH, estradiol, \n\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 3-Issue 2\nCitation: Inna Apolikhina, Andrey Kuzemin, Victoria Odinokova, Victor Radzinsky, Alexandra Gardner, Gennady Sukhikh. Efficacy in \nSuppressing Ovulation and Safety of a Low dose Oral Contraceptive in a Continuous Regimen (84+7) With Continuous Ethinyl Estradiol \nInstead of a Hormone-Free Interval: An Evaluation of Ovulation Suppression and Ovarian Activity. W J Gynecol Women’s Health. 3(2): 2020. \nWJGWH.MS.ID.000559. DOI: 10.33552/WJGWH.2020.03.000559.\nPage 4 of 10\nand progesterone were also determined. Throughout the entirety \nof the study, the participants-maintained diaries recording their \nintake of medications and any health-related changes. After the \ncompletion of the treatment cycle, the restoration of ovulation was \nevaluated by measuring the serum level of progesterone (Figure 2).\nFigure 1: Changes in the FSH, LH, and estradiol levels.\nFigure 2: Blood serum level of progesterone.\nEvaluation of efficacy in suppressing ovulation\nThe ovarian follicular activity evaluation indicators provided \nby the Hoogland and Skouby scale represented the primary \nefficacy criteria (percentage of patients with ovarian activity at \neach TVS examination visit within the active treatment phase). \nFor each participant, a rating from 0 (absence of ovarian activity) \nto 5 (ovulation with follicle rupture) was determined. Ovarian \nactivity was confirmed at grade 4 (luteinized unruptured follicle) \nor 5 (ovulation). Furthermore, the suppression of ovulation was \nevaluated, and the serum contents of the sex hormones (FSH, \nLH, estradiol, and progesterone) were determined within the \nframework of the study. During the post-therapeutic follow-up \nperiod, the restoration of ovulation was evaluated on the basis of \nthe serum level of progesterone; the relevant tests were repeated \nuntil the level of progesterone reached at least 15.9 nmol/L (but \nnot more than on 6 separate occasions). The incidence of pregnancy \nwas determined on the basis of urinary tests during all visits for all \nparticipants throughout the study.\nSafety\nThe safety analysis was conducted on the basis of the reported \nadverse events, laboratory test results, vital signs, physical \nexamination data, and information regarding concomitant drug \ntreatment.\n\nCitation: Inna Apolikhina, Andrey Kuzemin, Victoria Odinokova, Victor Radzinsky, Alexandra Gardner, Gennady Sukhikh. Efficacy in \nSuppressing Ovulation and Safety of a Low dose Oral Contraceptive in a Continuous Regimen (84+7) With Continuous Ethinyl Estradiol \nInstead of a Hormone-Free Interval: An Evaluation of Ovulation Suppression and Ovarian Activity. W J Gynecol Women’s Health. 3(2): 2020. \nWJGWH.MS.ID.000559. DOI: 10.33552/WJGWH.2020.03.000559.\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 3-Issue 2\nPage 5 of 10\nThe evaluation of laboratory parameters, including the \nbiochemical analyses, complete blood counts, coagulograms, and \ndeterminations of the levels of hormones, were performed by the \ncentral laboratory.\nThe biochemical assay included serum levels of glucose, \npotassium, calcium, creatinine, urea nitrogen, chloride, total \nbilirubin, alkaline phosphatase, alanine aminotransferase (ALT), \naspartate aminotransferase (AST), total protein, inorganic \nphosphorus, triglycerides and cholesterol (including high-density \nlipoproteins (HDL), low-density lipoproteins (LDL), and total \ncholesterol). The creatinine clearance was calculated using the \nmethod developed by Cockcroft-Gault.\nStatistical analysis\nData were processed using SAS®, version 9.1.3. The laboratory \ndata, as well as the data regarding the efficacy in suppressing \novulation and safety, were evaluated using descriptive statistical \nmethods. The patient population receiving treatment (intent-to-\ntreat population, ITT) was represented by all the participants \nreceiving treatment who had undergone at least one TVS procedure \nduring the treatment period. The patient population that observed \nthe protocol conditions (modified per protocol population, mPP) \nwas represented by all the participants from the ITT population \nexcept for the participants who were excluded from the study for \nthe following reasons:\n• Completed less than 82 days of treatment;\n• Failed to ingest a total of 3 tablets of study drug \nconsecutively;\n• Failed to ingest a total of 9 tablets of study drug over the \nentire study period;\n• Failed to appear for successive TVS procedures during \nvisits 2a to 4a or visits 5a to 7a.\nSummaries of the efficacy data were provided for the ITT and \nmPP populations. Comparative analysis was not carried out, as the \nstudy was conducted in the same group of patients.\nTreatment adherence was calculated using the following \nformula:\nTreatment adherence (%) = (actual number of ingested tablets \n/ number of tablets to be ingested*) × 100\nTreatment adherence was not calculated for the participants \nwho failed to return the relevant empty blister cards.\nAll adverse events were encoded using MedDRA, version 17.0.\nResults\nStudy participants\nThe study included 52 healthy females. All participants received \nat least 1 dose of the study drug and were suitable for evaluation of \nthe safety and efficacy in suppressing ovulation (ITT population); \namong the specified number of participants, 47 (90%) of the \nparticipants completed the study by participating in all phases of \nthe 91-day treatment period. The majority of the participants were \nCaucasian (51 participants [98%], and one participant was of Asian \ndescent [2%]). The median age was 26.5 years. The study was \nconducted at 6 study sites located within the Russian Federation.\nThe treatment of 5 (10%) participants was terminated \nprematurely, of whom 3 (6%) withdrew because of an adverse \nevent and 2 (4%) due to protocol violations.\nThe data regarding the participants enrolled in the study are \npresented in Tables 2&3.\nTable 2: Baseline characteristics of the patients.\nParameter Value\nAge, years (mean ± SD) 26.6 ±4.8\nRace, n (%)\nCaucasians 51 (98)\nAsians 1 (2)\nBody weight, kg (mean ± SD) 61.2 ± 9.8\nHeight, cm (mean ± SD) 165.4 ± 7.7\nBMI, kg/m2 (mean ± SD)  22.4 ± 3.4\nAverage volume of menstruum, n (%)\nScanty 0\nModerate 51 (98)\nHeavy 1 (2)\nDuration of bleeding in days, n (%)\n1 0 (0)\n2 0 (0)\n3 0 (0)\n4 8 (15)\n5 23 (44)\n6 12 (23)\n7 9 (17)\n8 0 (0)\n9 0 (0)\n10 and more 0 (0)\nHistory of use of hormonal contraceptives, n (%)\nPrevious experience 17 (33)\nFirst experience 35 (67)\nTable 3: The percentage of the participants among the ITT population \nwith ovarian activity according to the Hoogland and Skouby scale at \ncertain point in time during the 91-day period.\nGrade according to \nthe Hoogland and \nSkouby scale\nNumber, n (%) 95 % binomial \nconfidence intervals\n0: Lack of activity 39 (75)  \n1: Potentially active 11 (21)  \n2: Inactive follicles 0 (0)  \n3: Active follicles 0 (0)  \n4: Luteinized \nunruptured follicle 2 (4)  \n5: Ovulation 0 (0)  \nParticipants with \novarian activity 2 (4) 0.5%; 13.2%\n\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 3-Issue 2\nCitation: Inna Apolikhina, Andrey Kuzemin, Victoria Odinokova, Victor Radzinsky, Alexandra Gardner, Gennady Sukhikh. Efficacy in \nSuppressing Ovulation and Safety of a Low dose Oral Contraceptive in a Continuous Regimen (84+7) With Continuous Ethinyl Estradiol \nInstead of a Hormone-Free Interval: An Evaluation of Ovulation Suppression and Ovarian Activity. W J Gynecol Women’s Health. 3(2): 2020. \nWJGWH.MS.ID.000559. DOI: 10.33552/WJGWH.2020.03.000559.\nPage 6 of 10\nResults of efficacy in suppressing ovulation evaluation\nThe majority of the participants who took the study drug \nand returned the empty blister cards in accordance with the \nprotocol followed the treatment regimen instructions precisely \n(50 participants [96%]). None of the participants who returned \nthe blister cards miss the pill during the treatment period. One \nparticipant (2%) did not return blister cards and was classified as \nhaving failed to follow the instructions of the treatment regimen, \nthe adherence of this participant was not included in the final \nanalysis. Another participant (2%) ceased to be a participant of the \nstudy and was classified as an “absentee” . \nEvaluation of the state of ovarian follicles using the \nHoogland and Skouby scale\nThe summary data regarding the proportion of the participants \npresenting with ovarian activity at a certain point in time during \nthe 91-day treatment period are presented in Table 4. In the ITT \npopulation, 39 females (75%) presented with no ovarian activity \nat all times during the treatment period. Potential ovarian activity \nwas reported in 11 women (21%), and 2 participants (4%; 95% CI: \n0.5%, 13.2%) presented with confirmed ovarian activity (grade 4 \naccording to the Hoogland and Skouby scale, luteinized unruptured \nfollicle).\nThe results for the mPP population were comparable: the \novarian activity at a certain point in time during the treatment \nperiod was reported in two participants (4%; 95% CI: 0.5%, \n14.5%); 11 participants (23%) presented with potential ovarian \nactivity, and 34 females (72%) presented with no ovarian activity \nthroughout the treatment period.\nThe 91-day extended treatment cycle was divided into 3 \nintervals (i.e., the initial 28 days of the treatment, the subsequent 28 \ndays of the treatment, and the final 35 days of the treatment; these \ndata are presented in Table 4) to determine the number of patient-\ncycles with signs of ovulation. The 91-day period of treatment was \ndivided into such intervals to compare them with the traditional 28-\nday cycle of the oral contraceptive treatment. In the similar studies \non the evaluation of the ovarian activity with oral contraceptive \ntreatment in the 21+7 regimen, the 7-day interval was included in \nthe study period. Thereby the duration of the last interval (28 days \nof taking 100 mcg LNG + 20 mcg EE + 7 days of taking 10 mcg EE) \nwas 35 days.\nTable 4: The prevalence of the ovarian activity among the ITT population according to the Hoogland and Skouby scale during the 91-day period of \ntreatment.\nGrade according to the Hoogland and Skouby scale Number, n (%) 95% CI\nFirst interval (the initial 28-day interval of the treatment)\nNumber of cycles n = 52\n0: Lack of activity 49 (94)  \n1: Potentially active 3 (6)  \n2: Inactive follicles 0 (0)  \n3: Active follicles 0 (0)  \n4: Luteinized unruptured follicle 0 (0)  \n5: Ovulation 0 (0)  \nCycles with ovarian activity during the interval 0 (0) 0.0%, 6.8%\nSecond interval (the subsequent 28-day interval of the treatment)\nNumber of cycles n = 47\n0: Lack of activity 42 (89)  \n1: Potentially active 5 (11)  \n2: Inactive follicles 0 (0)  \n3: Active follicles 0 (0)  \n4: Luteinized unruptured follicle 0 (0)  \n5: Ovulation 0 (0)  \nCycles with ovarian activity during the interval 0 0.0%, 7.5%\nThird interval (the final 35-day interval of the treatment)\nNumber of cycles n = 47\n0: Lack of activity 37 (79)  \n1: Potentially active 8 (17)  \n2: Inactive follicles 0 (0)  \n3: Active follicles 0 (0)  \n4: Luteinized unruptured follicle 2 (4)  \n5: Ovulation 0 (0)  \nCycles with ovarian activity during the interval 2 (4) 0.5%, 14.5%\nTotal (91 days)\n\nCitation: Inna Apolikhina, Andrey Kuzemin, Victoria Odinokova, Victor Radzinsky, Alexandra Gardner, Gennady Sukhikh. Efficacy in \nSuppressing Ovulation and Safety of a Low dose Oral Contraceptive in a Continuous Regimen (84+7) With Continuous Ethinyl Estradiol \nInstead of a Hormone-Free Interval: An Evaluation of Ovulation Suppression and Ovarian Activity. W J Gynecol Women’s Health. 3(2): 2020. \nWJGWH.MS.ID.000559. DOI: 10.33552/WJGWH.2020.03.000559.\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 3-Issue 2\nPage 7 of 10\nNumber of cycles over the therapeutic period n = 146\n0: Lack of activity 128 (88)  \n1: Potentially active 16 (11)  \n2: Inactive follicles 0 (0)  \n3: Active follicles 0 (0)  \n4: Luteinized unruptured follicle 2 (1)  \n5: Ovulation 0 (0)  \nCycles with ovarian activity during the interval 2 (1) 0.2%, 4.9%\nDuring the 1 st interval, the cycles were reported in 52 \nparticipants, and during intervals 2 and 3, the cycles were reported \nin 47 participants, which was an expected outcome with allowance \nfor the fact that 5 participants left the study prior to completion of \ninterval 2 (day 56). Overall, the lack of ovarian activity was reported \nin 88% of the participants during all intervals (91 days) (grade 0 \naccording to the Hoogland and Skouby scale). The number of cycles \naccompanied by potential ovarian activity (grade 1 according to the \nHoogland and Skouby scale) increased during each interval: from 3 \ncycles (6%) during interval 1 to 5 (11%) and 8 cycles (17%) during \nintervals 2 and 3, respectively. Ovarian activity (grade 4 according \nto the Hoogland and Skouby scale) was reported in 2 cycles (4%; \nbinomial CI: 0.5%, 14.5%) during interval 3 (i.e., during the last 35 \ndays of the 91-day period of treatment).\nThe analysis of the study results obtained for the patient \npopulation that completed the study modified per protocol (mPP) \nrevealed comparable results: ovarian activity (grade 4 according \nto the Hoogland and Skouby scale) was reported in 2 cycles (4%; \nCI: 0.5%, 14.5%) during interval 3 (i.e., during the final 35 days of \nthe 91-day therapy treatment period). The number of participants \nwith cycles characterized by potential ovarian activity (grade 1 \naccording to the Hoogland and Skouby scale) increased during each \nsuccessive interval from 3 cycles (6%) during interval 1 to 5 (11%) \nand 8 cycles (17%) during intervals 2 and 3, respectively. Overall, \nthe majority of the participants (not less than 87%) presented with \na lack of ovarian activity (grade 0 according to the Hoogland and \nSkouby scale) over the entire period (91 days).\nEvaluation of ovulation suppression \nOver the entire period of the treatment, 96% of the participants \n(50 females) from the ITT population presented with ovarian \nsuppression (below grade 4 according to the Hoogland and Skouby \nscale, with a 95% binomial CI of 86.8%, 99.5%). The results for \nthe mPP population were comparable: 96% of the participants \n(45 females) presented with ovarian suppression (below grade \n4 according to the Hoogland and Skouby scale; 95% CI: 85.5%, \n99.5%).\nOvarian suppression was reported in 99% of all cycles during \nthe treatment period. During interval 3, ovarian suppression \nwas reported in all but 2 cycles (45 cycles [96%; 95% CI: 85.5%, \n99.5%]). Analysis of the ovarian suppression observed during all \nintervals simulating a standard cycle each (i.e., the initial 28 days \nof the treatment, the subsequent 28 days of the treatment, and the \nfinal 35 days of the treatment) demonstrated that all cycles were \ncharacterized by ovarian suppression during intervals 1 and 2 (52 \ncycles [100%; 95% CI: 93.2%, 100%] and 47 cycles [100%; 95% CI: \n92.5%, 100%], respectively).\nSerum levels of sex hormones\nOver the observation period, the mean FSH concentrations \ndecreased from 6.7±9.4 mIU/mL to 5.90±2.59 at the final \nexamination. The mean LH concentrations decreased more than \n2.5-fold from 12.62±19.59 mIU/mL (baseline) to 4.730±2.796 \nmIU/mL at the final visit. The mean concentrations of estradiol \ndecreased from 0.6±0.3 nmol/L (baseline) to 0.17±0.06 nmol/L at \nvisit 2a, with an over 4-fold increase relative to the baseline level \nto 2.63±16.09 nmol/L at visit 8a and with a mean final value of \n2.35±15.14 nmol/L at the end of the study.\nThe mean progesterone concentrations decreased more \nthan 20-fold from 29.19±10.29 nmol/L at baseline to 1.30±0.82 \nnmol/L at visit 2a and 0.93±0.38 nmol/L at visit 3a. Despite the \nincrease in progesterone concentrations at visit 8a, they remained \napproximately 2-fold lower in comparison to the baseline values: \n13.68±81.37 nmol/L and 12.23±76.54 nmol/L at the endpoint \nvisit prior to increasing to approximately the baseline values of \n28.64±15.02 nmol/L at the post-therapeutic follow-up visit. \nFrequency of resumption of ovulation\nAt the post-therapeutic follow-up visit, the majority of \nthe participants (45 females [87%]; 95% CI: 74.2%, 94.4%) \npresented with resumption of ovulation (i.e., the progesterone \nconcentrations reached or exceeded 15.9 nmol/L), 13% did not \nreturn to ovulation. The concentrations of progesterone at visit \n9a were below 15.9 nmol/L in 23 participants (44%). It was \nexpected that the progesterone levels in these participants would \nbe additionally measured up to 5 times after visit 9a in accordance \nwith the protocol (i.e., during 6 visits in total, visits 9a-f) until the \nrelevant values would reach or exceed 15.9 nmol/L. Among these \n23 participants, 16 patients returned for additional visits, and the \nrelevant progesterone concentrations reached or exceeded 15.9 \nnmol/L. Five females either did not return for additional visits \nor returned for fewer than 5 additional visits, and the relevant \nprogesterone concentrations did not reach or exceed 15.9 nmol/L, \nwhile the progesterone concentrations in 2 participants remained \nbelow 15.9 nmol/L after 5 additional visits (after 6 measurements \nin total). Since the primary aim of the study was to assess the \nsuppression of ovulation, not the resumption of it, additional data \nindicating the return to ovulation were not documented.\n\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 3-Issue 2\nCitation: Inna Apolikhina, Andrey Kuzemin, Victoria Odinokova, Victor Radzinsky, Alexandra Gardner, Gennady Sukhikh. Efficacy in \nSuppressing Ovulation and Safety of a Low dose Oral Contraceptive in a Continuous Regimen (84+7) With Continuous Ethinyl Estradiol \nInstead of a Hormone-Free Interval: An Evaluation of Ovulation Suppression and Ovarian Activity. W J Gynecol Women’s Health. 3(2): 2020. \nWJGWH.MS.ID.000559. DOI: 10.33552/WJGWH.2020.03.000559.\nPage 8 of 10\nIncidence of pregnancy\nNo pregnancy cases were reported among the participants \nduring the study.\nSafety evaluation results\nIncidence of adverse events (AE):  The majority of the \nparticipants (45 females [87%]) reported at least 1 adverse \nevent. No lethal outcomes were reported during the study. Two \nparticipants (4%) reported at least 1 adverse event with severe \nintensity, and 3 participants (6%) experienced adverse events \nthat led to the termination of their participation in the study. One \nevent was recognized as a serious adverse event, and two events \nwere found to be related to the treatment. Expect for the related \nirregular bleeding (metrorrhagia) reported by the majority of the \nparticipants (31 females [60%], Table 5), all treatment-related \nadverse events were reported in no more than 2 participants (4%). \nOne subject with the registered metrorrhagia was a 22-year old \nfemale who experienced this adverse event starting on day 11 that \nwas considered resolved on day 42. As a result of the event, study \ntreatment was withdrawn, and the subject discontinued from the \nstudy on day 58. Expect for 1 adverse event with severe intensity in \nthe form of an unrelated toothache reported in 1 participant (2%), \nall adverse events were mild (28 participants [54%]) or moderate \n(16 participants [31%]) in severity.\nTable 5: All adverse events associated with the treatment.\nOrgan system class Number, n (%)\nParticipants with at least 1 AE associated with \ntreatment 34 (65)\nDisorders of the reproductive system and \nmammary glands 31 (60)\nMetrorrhagia 31 (60)\nOvarian cyst 1 (2)\nDisorders of the gastrointestinal tract 2 (4)\nNausea 2 (4)\nMental disorders 2 (4)\nAnxiety 1 (2)\nTearfulness 1 (2)\nDisorders of the skin and subcutaneous tissue 1 (2)\nDrug-induced rash 1 (2)\nTwo participants discontinued the treatment because of \nthe protocol violation. One subject was a 20-year old female \nwho experienced a serious adverse event (hospitalization with \nthe suspected appendicitis) of nontreatment-related moderate \novulation pain starting on day 24 that was considered resolved on \nday 27. As a result of the event, the treatment was withdrawn, and \nthe subject was discontinued from the study on day 41. Another \nparticipant who discontinued from the study on day 13 was a \n35-year old female. The subject experienced an adverse event of \nmoderate study drug induced dermatitis starting on day 9. The \nevent was considered as resolved on day 18.\nNo clinically significant changes in the clinical laboratory \nindicators, blood serum biochemical indicators, complete blood \ncount indicators, blood clotting indicators or other changes \nin vital signs were observed. None of the results of the clinical \nlaboratory studies and physical examination data collected \nduring the observation period demonstrated clinically significant \nabnormalities.\nDiscussion\nThis multicenter, open-label, non-randomized study involving \none group of patients was conducted to evaluate the efficacy in \nsuppression of ovulation and safety of a low dose oral contraceptive \nin a continuous regim en (84+7) on the basis of evaluation of the \novarian function and sex hormone levels in females aged 18-35 in \nthe Russian Federation.\nPrevious studies have demonstrated that a COC regimen that \nentails administration of 10 mcg LNG and 20 mcg EE over a period \nof 84 days followed by subsequent administration of 10 mcg EE \nover 7 additional days is safe and effective throughout the 91-day \ntreatment period [15].\nWhen used in accordance with the recommendations, a 91-\nday regimen of a low dose oral contraceptive is over 99% effective \nat pregnancy prevention and demonstrates a Pearl index value of \n2.74 (including typical use in females failing to observe the relevant \nrecommendations). Among compliant subjects 18–35 years old, the \nPearl Index was 1.73 [15].\nAlthough the Pearl index was not determined within the \nframework of the present study, the efficacy of the MODELLE® \nLIBERA preparation in suppressing ovulation was clearly \ndemonstrated by the fact that 75% of the participants presented \nwith a lack of ovarian activity over the 91-day period of treatment, \nas demonstrated by the analysis of the results of TVS and the \nHoogland and Skouby scale scores. Potential ovarian activity was \nobserved in approximately 1/5 of the patients (11 participants \n[21%]), although no active follicles were observed in any of the \nparticipants. Analysis of the ovarian activity observed during 3 \nintervals simulating a standard cycle each and lasting from 28 to \n35 days (the score according to the Hoogland and Skouby scale) \ndemonstrated a slight increase in the ovarian activity over time, \nmanifesting the fact that the number of potentially active cycles \n(grade 1 according to the Hoogland and Skouby scale) increased \nwith each subsequent interval, from 3 cycles (6%) during interval 1 \nto 5 (11%) and 8 cycles (17%) during intervals 2 and 3, respectively.\nThe sustainability of the efficacy of the MODELLE® LIBERA \npreparation in suppression of ovulation is further demonstrated by \nthe fact that the results collected within the framework of this study \nwere comparable for the ITT and mPP populations.\nOvarian activity was reported in 2 participants (grade 4 \naccording to the Hoogland and Skouby scale, luteinized unruptured \nfollicle), and in both cases, this activity was observed during \ninterval 3 of the 91-day cycle, over the 7-day period when 10 mcg \nEE doses were administered. The cause of the ovarian activity in \nthese 2 patients during the 7-day period when low EE doses were \nadministered has not been determined. It was reported within the \nframework of a study conducted by Baerwald and Pierson that the \n\nCitation: Inna Apolikhina, Andrey Kuzemin, Victoria Odinokova, Victor Radzinsky, Alexandra Gardner, Gennady Sukhikh. Efficacy in \nSuppressing Ovulation and Safety of a Low dose Oral Contraceptive in a Continuous Regimen (84+7) With Continuous Ethinyl Estradiol \nInstead of a Hormone-Free Interval: An Evaluation of Ovulation Suppression and Ovarian Activity. W J Gynecol Women’s Health. 3(2): 2020. \nWJGWH.MS.ID.000559. DOI: 10.33552/WJGWH.2020.03.000559.\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 3-Issue 2\nPage 9 of 10\nonset of ovarian activity and the stability of ovarian suppression \nfluctuated over several cycles of COCs. The growth of follicles was \nalso demonstrated to be highest during the hormone-free interval \n[17].\nOverall, the changes in sex hormone levels in the ITT population \nin response to the 91-day treatment with the study drug were \nexpected for prolonged COC usage [19]. Prolonged suppression of \nserum levels of FSH, estradiol, and LH were also indicative of ovarian \nsuppression. The return to ovulation was documented on the post-\ntherapeutic visit (on the 20th week) in 87% of women; 13% did not \nreturn to ovulation. The latter is likely attributable to the fact that \ncertain participants did not return for follow-up measurements of \nprogesterone concentrations according to the protocol.\nOverall, the safety results obtained within the framework of \nthis study convincingly demonstrated that MODELLE® LIBERA \ncan safely be administered for contraceptive purpose to healthy \nfemales. The frequency and the profile of the reported adverse \nevents corresponded to the predicted values for the study drug \nand the specified treatment regimen. The AEs associated with the \ntreatment were mostly mild in severity, and the frequency of their \noccurrence aligned with the expectations. The study limitations \ninclude cases of metrorrhagia and ovarian cyst, since the study \nof these issues was not the aim of the present trial. Overall, none \nof the potentially clinically significant changes in the results of \nclinical laboratory studies (serum biochemical assay, complete \nblood count, and blood coagulation analysis), vital signs (heart rate, \ndiastolic blood pressure and systolic blood pressure), body weight \nor physical examination results (including body weight) were \nattributed to the treatment with the study drug.\nConclusion\nThe results of the study demonstrate that a low dose oral \ncontraceptive in a continuous extended regimen (84+7) with \ncontinuous EE instead of an HFI is safe in accordance with the \nprescribed regimen. The study drug can be an additional extended \ncycle COC option that offers effective suppression of ovulation and \npregnancy prevention in healthy females while decreasing the \nnumber of menstruations to only four per year. The results obtained \ncorrespond to the data of previous clinical studies of low dose oral \ncontraceptives in 91-day regimens (84 tablets of 100 mcg LNG + 20 \nmcg EE and 7 tablets of 10 mcg EE).\nDeclarations\nEthics approval and consent to participate\nThe study was approved by Council on Ethics of Russian Ministry \nof Health, and the local ethics committees of all participating sites \nand conducted in accordance with the protocol and amendments \nthereto of the ethical principles of the Helsinki Declaration of \nthe World Medical Association (Seoul, 2008), ICH GCP , and in \ncompliance with the relevant regulatory documents and legislation \nof the Russian Federation. All participants were required to provide \ninformed consent. \nConsent for publication\nNot applicable.\nAvailability of data and material\nThe datasets generated and analysed during the current study \navailable from the corresponding author on reasonable request. \nFunding\nThe study was funded by Teva LLC Russia.\nAcknowledgement\nThe authors acknowledge Yakov Pakhomov and Irina Bode of \nMedical Adviser’s Group, part of CRA-club LLC, for their assistance \nand provision of medical writing support in the development of \nthis manuscript. Medical writing support was funded by Teva LLC, \nMoscow, Russia.\nThe authors acknowledge all the investigators who took part \nin this project: Petrova V, Parsadanyan S, Gurskaya T , Manko M, \nChernyshova L, Razmakhnina N, Shpachenko Ya, Baranova N, Rybak \nO, Guseva E, Kovalev V, Kudryavtseva E, Islamidi D, Majorchik \nE, Khasanov A, Abdrakhmanova A, Tagirova L, Garifullova Yu, \nGrigoryan F, Plotnikov A, Osmanova S, and Kabilova L.\nCompeting Interests\nInna Apolikhina, Andrey Kuzemin, Victoria Odinokova, Viktor \nRadzinsky, and Gennady Sukhih have participated as investigators \nin studies conducted by Teva LLC Russia. Viktor Radzinsky is a \nmember of the Teva advisory board. Alexandra Gardner is a full-\ntime employee of Teva LLC Russia.\nAuthors’ Contributions\nAll authors contributed to the data interpretation, reviewed \ndrafts of the manuscript and approved the final draft for submission.\nConflict of Interest\nAuthors declare no conflict of interest.\nReferences\n1. 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