Continuous LNG/EE, a Low-dose Continuous-use Oral Contraceptive, Provides Similar Efficacy and Safety to a Monthly Cyclic Oral Contraceptive Alexander Teichmann, MD, PhD11Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany. On behalf of:Cornelis Kluft, PhD2; Gary Grubb, MD, MPH3; Ginger Constantine, MD3; Daniele Spielmann, MD, MSc4 2Gaubius Laboratory, TNO Quality of Life, Biomedical Research, Leiden, The Netherlands; 3Research Headquarters, Wyeth Research, Collegeville, PA, USA; 4Wyeth Research, Paris, France. Study funded by Wyeth Research, Collegeville, PA, USA.
Continuous LNG/EE • Continuous levonorgestrel (LNG)/ethinyl estradiol (EE) is taken every day, 365 days a year, without a hormone-free interval • Elimination of the hormone-free interval may reduce the total number of bleeding days • Contains LNG (90 µg) and EE (20 µg) at the lowest combination of doses currently available in the United States • Because of the low dose, the yearly cumulative hormone exposure is lower than that for many cyclic or extended-use oral contraceptives (OCs)
Study Objectives • Primary objective • To evaluate the contraceptive efficacy of continuous LNG/EE • Secondary objective • To compare continuous LNG/EE to a similarly formulated 21/7 cyclic OC (LNG 100 µg/EE 20 µg) with respect to vaginal bleeding, safety, and metabolic effects
Study Design • Phase III, randomized, open-label, 1-year study conducted at 44 sites in Europe • Czech Republic, Finland, Germany, Hungary, Italy, The Netherlands, Norway, Poland • Women were randomly assigned to take 13 pill packs of either continuous LNG/EE or the LNG 100/EE 20, cyclic 21/7-day OC
Key Inclusion Criteria • Healthy women aged 18 to 49 years who were sexually active and willing to rely on a combination OC as their only means of contraception • Regular (21- to 35-day) menstrual cycles in the previous 3 months
Key Exclusion Criteria • Standard OC contraindications • 34 years of age and smoking 15 cigarettes per day • Use of Depo-Provera within 10 months of screening • Use of any of the following within 60 days of screening: • Intrauterine device, implantable contraceptive, or Lunelle • Hepatic enzyme-inducing drugs • Experimental drugs • Noncontraceptive estrogens, progestins, or androgens
Study Procedures • Women were instructed to begin taking the study drug on the first day of their menstrual bleeding • Women recorded vaginal bleeding and adverse events (AEs) on daily diary cards • Bleeding terms were defined according to the World Health Organization • Bleeding: required sanitary protection • Spotting: bleeding that did not require sanitary protection • Amenorrhea: no bleeding or spotting • A subset of women who met predetermined criteria were also screened for 4 metabolic panels • Included carbohydrate, fasting lipid, hemostasis, and bone maker panels
Subject Disposition Subjects randomly assigned to a treatment group N = 651 Continuous LNG/EE n = 328 LNG 100/EE 20 cyclic 21/7-day OC n = 323 No drug taken n = 5 No drug taken n = 5 Took 1 dose of study drug n = 641 Continuous LNG/EE n = 323 LNG 100/EE 20 cyclic 21/7-day OC n = 318 Discontinuations n = 69 Discontinuations n = 107 Completed continuous LNG/EE arm n = 216 Completed LNG 100/EE 20 cyclic 21/7-day OC arm n = 249
Contraceptive Efficacy • There were no on-treatment pregnancies among women in the continuous LNG/EE group • Women in the LNG 100/EE 20, cyclic 21/7-day OC group had 3 on-treatment pregnancies
Bleeding Summary • For continuous LNG/EE, the percentage of women achieving amenorrhea generally increased with each pill pack to 53% at pill pack 13 • The median number of bleeding/spotting days decreased over time for both study groups • The median number of unscheduled bleeding days was 0 for pill pack 2 to 13 for continuous LNG/EE • Median number of spotting days was 0 for pill packs 8 to 13 for continuous LNG/EE
Most Common Treatment Emergent AEs (5% of Patients) * P <0.05 * *
Differences in Treatment Emergent AEs Based on Mid-point Analyses *Vaginal bleeding is a combination of COSTART terms metrorrhagia, menorrhagia, and vaginal and uterine hemorrhage.
Mean Change in Body Weight *P <0.01 vs. baseline.
Mean Change From Baseline in Blood Pressure *P <0.05 vs baseline. All pairwise P values not significant.
Cervical Smear Results ASCUS, atypical squamous cells of undetermined significance; SIL, squamous intraepithelial lesions.
Safety Summary • There was no statistical difference in the total number of AEs reported by each study group • Significantly more women reported metrorrhagia (P <0.001) and vaginal hemorrhage (P = 0.011) in the continuous LNG/EE group • The bleeding-related treatment-emergent AEs that were initially significantly higher for continuous LNG/EE in pill packs 1 to 6 were no longer different by pill packs 7 to 13 • During pill packs 7 to 13, women in the continuous LNG/EE group reported significantly less breast pain and nausea than the LNG 100/EE 20 cyclic 21/7-day OC group
Summary of Metabolic Substudy • Twenty-nine metabolic parameters were assessed and 20 were not significantly different between study groups • Those that were statistically significantly different were not deemed clinically important • These results have been presented elsewhere
Summary and Conclusions • Continuous LNG/EE demonstrated a similar safety profile to an established 21/7-day cyclic OC • Over time, continuous LNG/EE offered women the ability to achieve amenorrhea and reduce the number of bleeding days • Continuous LNG/EE did not demonstrate clinically important differences compared to the LNG 100/EE 20 cyclic 21/7-day OC in metabolic parameters commonly affected by OCs • There were no on-treatment pregnancies in the continuous LNG/EE group and 3 in the LNG 100/EE 20 cyclic 21/7-day OC group