Hum. Reprod. Advance Access published online on November 7, 2009
Human Reproduction, doi:10.1093/humrep/dep377
Randomized placebo-controlled trial of CDB-2914 in new users of a levonorgestrel-releasing intrauterine system shows only short-lived amelioration of unscheduled bleeding
1 Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK 2 Centre for Reproductive Biology, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK 3 NHS Lothian Family Planning & Well Woman Service, Edinburgh EH4 1NL, UK 4 Oregon Health & Sciences University, Oregon National Primate Research Center, Beaverton, OR 97006, USA
5 Correspondence address. Tel: +44-131-242-6858; Fax: +44-131-242-6441; E-mail: hilary.critchley{at}ed.ac.uk
BACKGROUND: The levonorgestrel-releasing intrauterine system (LNG-IUS) is a highly effective contraceptive. However, during early months of use unscheduled vaginal bleeding is common, sometimes leading to discontinuation. This study aimed to determine whether intermittent administration of progesterone receptor modulator CDB-2914 would suppress unscheduled bleeding during the first 4 months after insertion of the LNG-IUS.
METHODS: CDB-2914 150 mg, in divided doses, or placebo tablets, were administered over three consecutive days starting on Days 21, 49 and 77 after LNG-IUS insertion, in a double-blind randomized controlled trial of women aged 19–49 years, newly starting use of LNG-IUS. Daily bleeding diaries were completed for 6 months, and summarized across blocks as percentage days bleeding/spotting (BS%).
RESULTS: Of 69 women randomized to receive CDB-2914, and 67 placebo, 61 and 55, respectively, completed the trial. BS% decreased with time in both arms, but showed a much steeper treatment-phase gradient in the placebo arm (P < 0.0001), so that a benefit of CDB-2914 in the 28 days after first treatment (–11% points, 95% CI –19 to –2), converted to a disadvantage by 64 days after the third treatment (+10% points, 95% CI 1–18).
CONCLUSIONS: The effect of CDB-2914 on BS% was initially beneficial but then by third treatment was disadvantageous. Nevertheless, only 3% (4/136) of all women discontinued LNG-IUS. These findings give insight into possible mechanisms and suggest future research directions. ISRCTN Trial no. ISRCTN58283041 [controlled-trials.com] ; EudraCT no. 2006-006511-72.
Key words: CDB-2914/LNG-IUS/endometrium/unscheduled bleeding
These authors contributed equally. Submitted on June 18, 2009; resubmitted on September 29, 2009; accepted on October 1, 2009.