A prospective, open-label, single arm, multicentre study to evaluate efficacy, safety and acceptability of pericoital oral contraception using levonorgestrel 1.5 mg

Abstract

Study question: Will the use of levonorgestrel (LNG) 1.5 mg taken at each day of coitus by women who have relatively infrequent sex be an efficacious, safe and acceptable contraceptive method?

Summary answer: Typical use of LNG 1.5 mg taken pericoitally, before or within 24 h of sexual intercourse, provides contraceptive efficacy of up to 11.0 pregnancies per 100 women-years (W-Y) in the primary evaluable population and 7.1 pregnancies per 100 W-Y in the evaluable population.

What is known already: LNG 1.5 mg is an effective emergency contraception following unprotected intercourse. Some users take it repeatedly, as their means of regular contraception.

Study design, size, duration: This was a prospective, open-label, single-arm, multicentre Phase III trial study with women who have infrequent coitus (on up to 6 days a month). Each woman had a follow-up visit at 2.5, 4.5 and 6.5 months after admission or until pregnancy occurs if sooner, or she decided to interrupt participation. The study was conducted between 10 January 2012 and 15 November 2014.

Participants/materials, setting, methods: A total of 330 healthy fertile women aged 18-45 years at risk of pregnancy who reported sexual intercourse on up to 6 days a month, were recruited from four university centres located in Bangkok, Thailand; Campinas, Brazil; Singapore and Szeged, Hungary to use LNG 1.5 mg pericoitally (24 h before or after coitus) as their primary method of contraception. The participants were instructed to take one tablet every day she had sex, without taking more than one tablet in any 24-h period, and to maintain a paper diary for recording date and time for every coital act and ingestion of the study tablet, use of other contraceptive methods and vaginal bleeding patterns. Anaemia was assessed by haemoglobin evaluation. Pregnancy tests were performed monthly and pregnancies occurring during product use were assessed by ultrasound. At the 2.5-month and final visit at 6.5 months, acceptability questions were administered.

Main results and the role of chance: There were 321 women included in the evaluable population (which includes all eligible women enrolled), with 141.9 woman-years (W-Y) of observation and with a rate (95% confidence interval [CI]) of 7.1 (3.8; 13.1) pregnancies per 100 W-Y of typical use (which reflects use of the study drug as main contraceptive method, but also includes possible use of other contraceptives from admission to end of study) and 7.5 (4.0; 13.9) pregnancies per 100 W-Y of sole use. In the primary evaluable population (which includes only eligible enrolled women <35 years old), the rate was 10.3 (5.4; 19.9) pregnancies per 100 W-Y of typical use, and 11.0 (5.7; 13.1) pregnancies per 100 W-Y of sole use. There were three reported severe adverse events and 102 other mild adverse events (most common were headache, nausea, abdominal and pelvic pain), with high recovery rate. The vaginal bleeding patterns showed a slight decrease in volume of bleeding and the number of bleeding-free days increased over time. There was only one case of severe anaemia, found at the final visit (0.4%). The method was considered acceptable, as over 90% of participants would choose to use it in the future or would recommend it to others.

Limitations, reasons for caution: This was a single-arm study with small sample size, without a control group, designed as a proof of concept study to explore the feasibility of this type of contraception.

Wider implications of the findings: A larger clinical study evaluating pericoital contraception with LNG is feasible and our data show that this method would be acceptable to many women.

Study funding/competing interests: This study received partial financial support from the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR) and the World Health Organization. Gynuity and the Bill and Melinda Gates Foundation (BMGF) provided financial support for project monitoring. HRA Pharma donated the LNG product. N.K. was the initial project manager when she was with WHO/HRP and was employed by HRA Pharma, which distributes LNG for emergency contraception. The other authors declare no conflicts of interest.

Trial registration number: This study was registered on ANZCTR, Trial ID ACTRN12611001037998.

Trial registration date: 4 October 2011.

Date of first patient's enrolment: 10 January 2012.

Keywords: anaemia; contraception; effectiveness; oral levonorgestrel; pericoital.

Figure 1

Participant flowchart for the study. *Two participants with pregnancy conception dated prior to enrolment (Singapore ID 3048, Brazil ID 4305). ^†Use of prohibited contraception (n = 2: Hungary, Brazil), stopped study pill (n = 2: Hungary, Thailand), health reasons (n = 1: Hungary). ITT Popn, intention to treat population; EV Popn, evaluable populations; Primary EV, primary evaluable population; User Popn, population.

Figure 2

Frequency of irregular bleeding patterns per 90 day study period based on number of tablets taken: (A) prolonged vaginal bleeding (at least one bleeding episode lasting 14 days or more during the reference period of 90 days); (B) frequent vaginal bleeding episodes (defined as having more than five bleeding episodes throughout the reference period of 90 days); (C) light vaginal bleeding episodes; (D) medium vaginal bleeding episodes (at least 1 day of medium with any number of light bleeding days recorded during the episode, and no days of heavy bleeding); (E) heavy vaginal bleeding episodes (at least 1 or 2 days of heavy bleeding recorded, with any number of light and medium days, during the episode) and (F) very heavy vaginal bleeding episodes (three or more days of heavy bleeding recorded during the episode, with any number of light and medium days).

Figure 2

Continued.