Randomized placebo-controlled trial of CDB-2914 in new users of a levonorgestrel-releasing intrauterine system shows only short-lived amelioration of unscheduled bleeding

Warner, Pamela; Guttinger, Anja; Glasier, Anna; Lee, Robert; Nickerson, S.C.; Brenner, Robert; Critchley, Hilary O. D.

doi:10.1093/humrep/dep377

Cited by 27 publications

(25 citation statements)

References 15 publications

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“…Questionnaires are outlined in the footnotes to table 1—they are based on those used in previous studies 1328 29 The study doctors and in particular study nurses will develop excellent rapport with patients to maximise completeness of data collected.…”

Section: Design and Methodsmentioning

confidence: 99%

“…The Levonorgestrel intrauterine system (LNG-IUS), a hormonal contraceptive now licensed as treatment for HMB, is unsuitable for women seeking to become pregnant. LNG-IUS can cause amenorrhoea, or for other users there is ongoing and unpredictable unscheduled bleeding, and these consequences can be unacceptable to women 13. The audit reported that in the first year after attendance for HMB, oral medication and IUS were received by 29% and 33%, respectively, but these were the ‘final’ treatment for only 12% (over half switched from oral medication) and 22% (one third switched from IUS) 11.…”

Section: Introductionmentioning

confidence: 99%

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Low-dose dexamethasone as a treatment for women with heavy menstrual bleeding: protocol for response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM)

et al. 2015

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IntroductionHeavy menstrual bleeding (HMB) diminishes individual quality-of-life and poses substantial societal burden. In HMB endometrium, inactivation of cortisol (by enzyme 11β hydroxysteroid dehydrogenase type 2 (11βHSD2)), may cause local endometrial glucocorticoid deficiency and hence increased angiogenesis and impaired vasoconstriction. We propose that ‘rescue’ of luteal phase endometrial glucocorticoid deficiency could reduce menstrual bleeding.Methods and analysisDexFEM is a double-blind response-adaptive parallel-group placebo-controlled trial in women with HMB (108 to be randomised), with active treatment the potent oral synthetic glucocorticoid dexamethasone, which is relatively resistant to 11βHSD2 inactivation. Participants will be aged over 18 years, with mean measured menstrual blood loss (MBL) for two screening cycles ≥50 mL. The primary outcome is reduction in MBL from screening. Secondary end points are questionnaire assessments of treatment effect and acceptability. Treatment will be for 5 days in the mid-luteal phases of three treatment menstrual cycles. Six doses of low-dose dexamethasone (ranging from 0.2 to 0.9 mg twice daily) will be compared with placebo, to ascertain optimal dose, and whether this has advantage over placebo. Statistical efficiency is maximised by allowing randomisation probabilities to ‘adapt’ at five points during enrolment phase, based on the response data available so far, to favour doses expected to provide greatest additional information on the dose–response. Bayesian Normal Dynamic Linear Modelling, with baseline MBL included as covariate, will determine optimal dose (re reduction in MBL). Secondary end points will be analysed using generalised dynamic linear models. For each dose for all end points, a 95% credible interval will be calculated for effect versus placebo.Ethics and disseminationDexamethasone is widely used and hence well-characterised safety-wise. Ethical approval has been obtained from Scotland A Research Ethics Committee (12/SS/0147). Trial findings will be disseminated via open-access peer-reviewed publications, conferences, clinical networks, public lectures, and our websites.Trial registration numberClinicalTrials.gov NCT01769820; EudractCT 2012-003405-98.

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Section: Design and Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Low-dose dexamethasone as a treatment for women with heavy menstrual bleeding: protocol for response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM)

et al. 2015

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“…With ongoing treatment, the placebo group appeared to have a more favourable bleeding pattern, even though there were no significant differences in acceptability measures. 79 This study highlighted the important difference between prevention and treatment of an undesired side effect and concluded that there is possibly more potential for PRMs to improve than to prevent unscheduled bleeding in users of POC. 79…”

Section: Contraceptionmentioning

confidence: 96%

“…78 However, suppression of unscheduled bleeding has not been consistently demonstrated, and the implications for contraceptive efficacy also remain to be clarified. 79,80 One study administering CDB-2914 to new LNG-IUS users in an attempt to prevent breakthrough bleeding found that the initial beneficial effect was temporary. With ongoing treatment, the placebo group appeared to have a more favourable bleeding pattern, even though there were no significant differences in acceptability measures.…”

Section: Contraceptionmentioning

confidence: 99%

Progesterone receptor modulators in gynaecological practice

Wilkens¹,

Critchley²

2010

j fam plann reprod health care

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IntroductionThe sex steroid progesterone plays a major role in the regulation of female reproductive activity. Circulating levels of progesterone are maximal in the secretory phase of the menstrual cycle, its main source being the corpus luteum. The effects of progesterone are mediated via the progesterone receptor (PR), which is essential not only for the co-ordination of ovulation, implantation and the maintenance of pregnancy but also for breast development and sexual behaviour. Within the uterus, progesterone predominantly contributes to the regulation of endometrial function. Progesterone is crucial in preparation for implantation by decidualisation, during pregnancy and during the process of menstruation, which occurs when progesterone levels fall in the absence of a conceptus. Since the discovery of natural progesterone in the mid-1930s, 1 many synthetic progestogens have been developed and introduced into clinical practice. As contraceptive agents, these compounds have revolutionised fertility control. Progestogens also have an established role in the management of benign gynaecological conditions such as menstrual disturbances and endometriosis, as well as in hormone replacement therapy and assisted reproductive technology.The discovery of the progesterone receptor 2,3 enabled the development of synthetic compounds binding to the PR with agonistic but also with antagonistic properties. The first of these to be described in 1981 was mifepristone (RU 486), a PR and glucocorticoid receptor (GR) antagonist. 4 Reports soon followed on its effect on menstruation, 5 highlighting its potential for cycle regulation and birth control. 6 It was established that mifepristone could induce menstruation by interrupting the luteal phase of the menstrual cycle. Its potency to disrupt early pregnancy was then recognised, leading to its clinical application in the termination of pregnancy. 7 Various related compounds exerting their effect via the PR have subsequently been developed and are reviewed here. Development of PRMsThe initial aim in developing progesterone receptor modulators (PRMs) was to find compounds with more profound P antagonistic potency but less antiglucocorticoid activity than mifepristone. The applications envisaged in the early stages were fertility control and the treatment of breast cancer. 8,9 The major therapeutic potential of PRMs for the management of benign gynaecological conditions became apparent when their endometrial antiproliferative effect inducing endometrial atrophy and amenorrhoea was 10,11 Unfortunately, the significant abortifacient activity of progesterone receptor antagonists (PAs) led to the delay and obstruction of development of mifepristone and similar compounds with progesterone antagonistic properties for other clinical applications. Large pharmaceutical companies distanced themselves from the perceived negative image of a drug that was capable of terminating a pregnancy. Further introduction of PRMs into clinical practice was also precluded by concerns regarding safety...

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“…By the third cycle, ulipristal treatment was associated with an increase in bleeding and spotting days, equivalent to 6 extra days. 22 …”

Section: Selective Progesterone Receptor Modulatorsmentioning

confidence: 99%

Therapeutic Options for Unscheduled Bleeding Associated with Long-Acting Reversible Contraception

Friedländer

Kaneshiro

2015

Obstetrics and Gynecology Clinics of North America

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Randomized placebo-controlled trial of CDB-2914 in new users of a levonorgestrel-releasing intrauterine system shows only short-lived amelioration of unscheduled bleeding

Cited by 27 publications

References 15 publications

Low-dose dexamethasone as a treatment for women with heavy menstrual bleeding: protocol for response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM)

Low-dose dexamethasone as a treatment for women with heavy menstrual bleeding: protocol for response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM)

Progesterone receptor modulators in gynaecological practice

Therapeutic Options for Unscheduled Bleeding Associated with Long-Acting Reversible Contraception

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