Selective progesterone receptor modulators (SPRMs) for uterine fibroids

Ally Murji; Lucy Whitaker; Tiffany L Chow; Mara L Sobel

doi:10.1002/14651858.CD010770.pub2

. 2017 Apr 26;2017(4):CD010770. doi: 10.1002/14651858.CD010770.pub2

Selective progesterone receptor modulators (SPRMs) for uterine fibroids

Ally Murji ^1,^✉, Lucy Whitaker ², Tiffany L Chow ³, Mara L Sobel ¹

Editor: Cochrane Gynaecology and Fertility Group

PMCID: PMC6478099 PMID: 28444736

Abstract

Background

Uterine fibroids are smooth muscle tumours arising from the uterus. These tumours, although benign, are commonly associated with abnormal uterine bleeding, bulk symptoms and reproductive dysfunction. The importance of progesterone in fibroid pathogenesis supports selective progesterone receptor modulators (SPRMs) as effective treatment. Both biochemical and clinical evidence suggests that SPRMs may reduce fibroid growth and ameliorate symptoms. SPRMs can cause unique histological changes to the endometrium that are not related to cancer, are not precancerous and have been found to be benign and reversible. This review summarises randomised trials conducted to evaluate the effectiveness of SPRMs as a class of medication for treatment of individuals with fibroids.

Objectives

To evaluate the effectiveness and safety of SPRMs for treatment of premenopausal women with uterine fibroids.

Search methods

We searched the Specialised Register of the Cochrane Gynaecology and Fertility Group, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and clinical trials registries from database inception to May 2016. We handsearched the reference lists of relevant articles and contacted experts in the field to request additional data.

Selection criteria

Included studies were randomised controlled trials (RCTs) of premenopausal women with fibroids who were treated for at least three months with a SPRM.

Data collection and analysis

Two review authors independently reviewed all eligible studies identified by the search. We extracted data and assessed risk of bias independently using standard forms. We analysed data using mean differences (MDs) or standardised mean differences (SMDs) for continuous data and odds ratios (ORs) for dichotomous data. We performed meta‐analyses using the random‐effects model. Our primary outcome was change in fibroid‐related symptoms.

Main results

We included in the review 14 RCTs with a total of 1215 study participants. We could not extract complete data from three studies. We included in the meta‐analysis 11 studies involving 1021 study participants: 685 received SPRMs and 336 were given a control intervention (placebo or leuprolide). Investigators evaluated three SPRMs: mifepristone (five studies), ulipristal acetate (four studies) and asoprisnil (two studies). The primary outcome was change in fibroid‐related symptoms (symptom severity, health‐related quality of life, abnormal uterine bleeding, pelvic pain). Adverse event reporting in the included studies was limited to SPRM‐associated endometrial changes. More than half (8/14) of these studies were at low risk of bias in all domains. The most common limitation of the other studies was poor reporting of methods. The main limitation for the overall quality of evidence was potential publication bias.

SPRM versus placebo

SPRM treatment resulted in improvements in fibroid symptom severity (MD ‐20.04 points, 95% confidence interval (CI) ‐26.63 to ‐13.46; four RCTs, 171 women, I² = 0%; moderate‐quality evidence) and health‐related quality of life (MD 22.52 points, 95% CI 12.87 to 32.17; four RCTs, 200 women, I² = 63%; moderate‐quality evidence) on the Uterine Fibroid Symptom Quality of Life Scale (UFS‐QoL, scale 0 to 100). Women treated with an SPRM showed reduced menstrual blood loss on patient‐reported bleeding scales, although this effect was small (SMD ‐1.11, 95% CI ‐1.38 to ‐0.83; three RCTs, 310 women, I² = 0%; moderate‐quality evidence), along with higher rates of amenorrhoea (29 per 1000 in the placebo group vs 237 to 961 per 1000 in the SPRM group; OR 82.50, 95% CI 37.01 to 183.90; seven RCTs, 590 women, I² = 0%; moderate‐quality evidence), compared with those given placebo. We could draw no conclusions regarding changes in pelvic pain owing to variability in the estimates. With respect to adverse effects, SPRM‐associated endometrial changes were more common after SPRM therapy than after placebo (OR 15.12, 95% CI 6.45 to 35.47; five RCTs, 405 women, I² = 0%; low‐quality evidence).

SPRM versus leuprolide acetate

In comparing SPRM versus other treatments, two RCTs evaluated SPRM versus leuprolide acetate. One RCT reported primary outcomes. No evidence suggested a difference between SPRM and leuprolide groups for improvement in quality of life, as measured by UFS‐QoL fibroid symptom severity scores (MD ‐3.70 points, 95% CI ‐9.85 to 2.45; one RCT, 281 women; moderate‐quality evidence) and health‐related quality of life scores (MD 1.06 points, 95% CI ‐5.73 to 7.85; one RCT, 281 women; moderate‐quality evidence). It was unclear whether results showed a difference between SPRM and leuprolide groups for reduction in menstrual blood loss based on the pictorial blood loss assessment chart (PBAC), as confidence intervals were wide (MD 6 points, 95% CI ‐40.95 to 50.95; one RCT, 281 women; low‐quality evidence), or for rates of amenorrhoea (804 per 1000 in the placebo group vs 732 to 933 per 1000 in the SPRM group; OR 1.14, 95% CI 0.60 to 2.16; one RCT, 280 women; moderate‐quality evidence). No evidence revealed differences between groups in pelvic pain scores based on the McGill Pain Questionnaire (scale 0 to 45) (MD ‐0.01 points, 95% CI ‐2.14 to 2.12; 281 women; moderate‐quality evidence). With respect to adverse effects, SPRM‐associated endometrial changes were more common after SPRM therapy than after leuprolide treatment (OR 10.45, 95% CI 5.38 to 20.33; 301 women; moderate‐quality evidence).

Authors' conclusions

Short‐term use of SPRMs resulted in improved quality of life, reduced menstrual bleeding and higher rates of amenorrhoea than were seen with placebo. Thus, SPRMs may provide effective treatment for women with symptomatic fibroids. Evidence derived from one RCT showed no difference between leuprolide acetate and SPRM with respect to improved quality of life and bleeding symptoms. Evidence was insufficient to show whether effectiveness was different between SPRMs and leuprolide. Investigators more frequently observed SPRM‐associated endometrial changes in women treated with SPRMs than in those treated with placebo or leuprolide acetate. As noted above, SPRM‐associated endometrial changes are benign, are not related to cancer and are not precancerous. Reporting bias may impact the conclusion of this meta‐analysis. Well‐designed RCTs comparing SPRMs versus other treatments are needed.

Plain language summary

Drugs to treat fibroids

Review question

We reviewed the evidence on effectiveness and safety of a new class of medications called selective progesterone receptor modulators (SPRMs) for treating premenopausal women with uterine fibroids.

Background

Fibroids (non‐cancerous masses within the muscle layer of the womb) are a common condition. Fibroids can negatively impact a woman's health by causing heavy periods, creating symptoms related to their size (such as pressing on the bladder or rectum) and/or making it difficult to conceive.

A new class of medication called SPRMs has shown promise for treatment of women with fibroids. The class of SPRMs includes various drugs such as mifepristone, ulipristal acetate and asoprisnil. SPRMs can cause benign changes to the endometrium that are not related to cancer and are not precancerous.

Search date

We searched the literature up to May 2016.

Study characteristics

Review authors included 14 randomised controlled trials (RCTs) (1215 women) but could not obtain data from three studies. In addition, several completed registered trials had not yet reported findings. This review evaluated results of 11 RCTs that included 1021 women with fibroids. Investigators treated women with mifepristone (five studies), ulipristal acetate (four studies) or asoprisnil (two studies) and compared SPRMs with either placebo or leuprolide acetate. More than half of these studies were at low risk of bias in all domains. The most common limitation of the other studies was poor reporting of methods.

Key results

The main outcomes studied were changes in symptoms (fibroid‐related symptom severity, quality of life, menstrual bleeding, pelvic pain). When compared with placebo (identical "dummy" tablet that contains no active medication), SPRMs improved fibroid‐related symptoms (by an average effect of 20 points on a 100‐point scale), improved women's quality of life (by an average effect of 22 points on a 100‐point scale) and resulted in a small decrease in menstrual bleeding. Between 24% and 96% of women treated with SPRMs had no period at all (compared with 3% taking placebo). Review authors could draw no conclusions about changes in pelvic pain, as this was not consistently evaluated. Two studies compared SPRMs versus a gonadotropin‐releasing hormone agonist (leuprolide) and found that both drugs (SPRMs and leuprolide) were effective in improving symptoms related to fibroids (improving quality of life, reducing menstrual bleeding, causing cessation of periods, decreasing pelvic pain). However, we are not sure if researchers noted a difference in effectiveness between SPRMs and leuprolide.

Women treated with SPRMs were more likely to develop changes to the lining of the womb (endometrium) than women treated with placebo or leuprolide. These changes are benign and reversible once SPRMs are discontinued.

In summary, the studies included in this review show that SPRMs improve fibroid‐related symptoms, quality of life and menstrual bleeding. However, we need larger, well‐designed studies comparing SPRMs against other treatments currently available for the management of fibroids.

Quality of the evidence

In comparisons with placebo, moderate‐quality evidence showed improvements in quality of life, reduction in menstrual bleeding and cessation of periods with SPRMs. Low‐quality evidence suggested a higher rate of changes to the endometrium with SPRM treatment than with placebo. Comparisons with leuprolide were based on moderate‐quality evidence for changes in quality of life, cessation of periods, pelvic pain and endometrial changes. The main limitation in the overall quality of evidence was potential publication bias.

Summary of findings

Background

Description of the condition

Uterine fibroids are common smooth muscle tumours arising from the uterus. They are also known as leiomyomata or myomas. The prevalence of these tumours depends on the population’s ethnicity and the method of detection. More than 80% of black women and nearly 70% of white women will develop fibroids before the age of 50 years (Baird 2003). These tumours, although benign, can cause significant distortion of the uterus and result in symptoms in up to 50% of women (Baird 2003). Fibroids are frequently associated with abnormal uterine bleeding, bulk symptoms (pelvic pressure, urinary dysfunction, constipation, pain) and reproductive dysfunction (subfertility, miscarriage, pregnancy complications) (Stovall 2001).

In the United States alone, the direct cost of treatment for women with fibroids is estimated to be over four billion dollars annually (Cardozo 2012). Fibroid‐related symptoms can be treated with surgery (hysterectomy, myomectomy, endometrial ablation, myolysis), minimally invasive procedures (uterine artery embolisation, magnetic resonance‐guided focused ultrasound) or medical therapies (Wallach 2004). Despite these treatment options, hysterectomy is the second most frequently performed surgical procedure in the United States, with fibroids the most common indication (Merrill 2008); this has contributed to significant surgical morbidity and escalating healthcare costs. Thus, focus on more conservative options is needed.

Description of the intervention

Currently, no pharmacological agents have received global approval specifically for long‐term treatment of individuals with uterine fibroids. The mainstay of medical management has comprised use of gonadotropin‐releasing hormone analogues (GnRHa) for preoperative optimisation seen as decreased blood loss, corrected anaemia and reduced fibroid volume (Sabry 2012). Leuprolide acetate is one of the most frequently used GnRHa treatments for fibroids and is approved in the United States and Europe for this indication. Challenges associated with GnRHa therapy include decreased bone mineral density, development of vasomotor symptoms and an initial oestrogen flare that may exacerbate symptoms. Although medical therapies such as combined hormonal contraceptives, progestins, progestin‐releasing intrauterine systems and danazol may be used to decrease menstrual blood flow, their specific effects on fibroids and bulk symptoms are limited, and they often cause side effects that lead to discontinuation (Ke 2009; Sangkomkamhang 2013; Van Voorhis 2009).

Traditionally, oestrogen has been considered the most important hormone for stimulating fibroid growth. Recently, progesterone was found to be essential for the maintenance and growth of fibroids (Bulun 2013). For this reason, selective progesterone receptor modulators (SPRMs) have shown promise for the treatment of women with uterine fibroids (Chwalisz 2005). These molecules bind to the progesterone receptor and show varying levels of antagonistic activity. SPRMs were first discovered in 1980, and mifepristone, a powerful progesterone antagonist, was the pioneer drug. It has been used mainly for pregnancy termination but has also been evaluated as a therapeutic agent for fibroids. Meta‐analysis of three randomised trials showed that mifepristone is effective in reducing bleeding symptoms and improving fibroid‐related quality of life, with no effect on fibroid volume (Tristan 2012).

Other SPRMs were subsequently developed, each with different affinity for the progesterone receptor and showing varying degrees of antagonistic activity. The clinical activity of each SPRM class member reflects the subtlety of its spectrum of agonist and antagonist activity, along with tissue‐specific expression of progesterone receptor (PR) subtypes.

How the intervention might work

The ‘progesterone hypothesis’ suggests that progesterone acts as a key hormone in the development of fibroids by increasing mitotic rates and reducing apoptosis of fibroid smooth muscle cells (Bulun 2013). Data also suggest that signalling occurs between oestrogen and progesterone receptors, whereby oestrogen induces increased expression of the progesterone receptor in fibroid cells (Ishikawa 2010). The importance of progesterone in fibroid pathogenesis supports SPRMs as effective treatment for women with fibroids. Fibroid cells cultured with SPRMs demonstrate inhibited proliferation and increased apoptosis, without affecting normal myometrium (Bouchard 2011). SPRMs can also downregulate the number of growth factors while reducing collagen synthesis in cultured fibroid cells (Bouchard 2011). SPRMs act upon the uterine endometrium to provide relief of bleeding symptoms in women with fibroids (Wagenfeld 2016). SPRMs are known to cause unique changes to the endometrium. Histological endometrial changes have been labelled as progesterone receptor modulator‐associated endometrial changes (PAECs) on the basis of international consensus (Mutter 2008). These changes are benign and reversible.

SPRMs may be used to treat women with fibroids in several clinical scenarios. Currently, the only SPRM approved for medical management of fibroids is ulipristal acetate (Esmya, Gedeon‐Richter, Europe, February 2012; Fibristal, Watson Laboratories Inc, Canada, July 2013). This drug was approved to treat bleeding symptoms while decreasing fibroid size for up to three months before surgery. Recently, it was approved in Europe and Canada for ongoing intermittent use. Long‐term use of SPRMs for fibroid‐related symptoms may decrease the need for surgical intervention and associated morbidity and costs. Long‐term medical therapy may be particularly beneficial for bridging perimenopausal women until menopause, when fibroids would then spontaneously decrease. Although pregnancy is contraindicated with SPRMs, evidence shows that the decrease in fibroid size is sustained after the medication has been discontinued (Donnez 2012). This may cause fibroid‐related subfertility, for which medical management may reduce fibroid volume and facilitate pregnancy after discontinuation of SPRM treatment.

Why it is important to do this review

Despite the prevalence of uterine fibroids, only a few high‐quality studies have examined the effectiveness of medical therapies. With increasing demand for less invasive fibroid therapies, the benefits and risks of medical treatments must be critically evaluated. Furthermore, women are delaying childbearing, hence fertility‐sparing therapeutic options are needed. Biochemical and clinical evidence shows that SPRMs may decrease fibroid growth and ameliorate symptoms (Chwalisz 2005). Although a Cochrane review on mifepristone has been completed (Tristan 2012), the newer SPRMs require systematic evaluation of their benefits and harms.

Objectives

To evaluate the effectiveness and safety of selective progesterone receptor modulators (SPRMs) for treatment of premenopausal women with uterine fibroids.

Methods

Criteria for considering studies for this review

Types of studies

We included data from all published and unpublished randomised controlled trials (RCTs). For cross‐over studies, we included for meta‐analysis only data from the first phase of the trial.

Types of participants

Premenopausal women with uterine fibroids, with or without symptoms. The presence of fibroids was confirmed surgically (laparoscopy, laparotomy or hysteroscopy) or through at least one of the following imaging modalities: ultrasonography, computed tomography or magnetic resonance imaging (MRI).

Types of interventions

Treatment with any SPRM for at least three months versus:

placebo;
no treatment;
another medical therapy (another SPRM, a GnRHa or another class of medication);
surgery (myomectomy or hysterectomy); or
uterine artery embolisation (UAE).

Commercially available SPRMs included, but were not limited to, mifepristone, asoprisnil, telapristone acetate and ulipristal acetate. Additional interventions were permitted as long as they were uniformly used in all study arms. Leuprolide acetate is a GnRHa that is commonly used to treat fibroids. We searched for comparisons of SPRM versus leuprolide acetate or other medications in the GnRHa class.

Types of outcome measures

Primary outcomes

Change in fibroid‐related symptoms
- Quality of life assessed through standardised and validated measures. Examples of scales that measured health‐related quality of life for women with uterine fibroids (Williams 2006) included but were not limited to Uterine Fibroid Symptom Quality of Life Scale (UFS‐QoL) (Spies 2002), EuroQoL (Brooks 1996) and Short Form‐36 (SF‐36) (Ware 1992)
- Abnormal uterine bleeding measured objectively (e.g. haemoglobin levels, haematocrit, ferritin levels, alkaline haematin technique) or subjectively (e.g. pictorIal blood loss assessment)
- Pain and pelvic pressure measured subjectively (e.g. visual analogue scales, Likert scales)

Secondary outcomes

Change in fibroid or uterine size, or both, as measured by ultrasonography or MRI
SPRM‐related effects including, but not limited to, SPRM‐associated endometrial changes (Mutter 2008), endometrial hyperplasia, endometrial carcinoma, abnormal liver enzymes and prolactin levels, osteoporosis, breast discomfort, hot flushes, headache and nausea

Search methods for identification of studies

We searched for all published and unpublished RCTs of SPRMs used for treatment of uterine fibroids. We applied no language restrictions. We developed and executed the search strategy in consultation with the Cochrane Gynaecology and Fertility Group Information Specialist and a Mount Sinai Hospital librarian.

Electronic searches

We searched the following databases from inception until 15 May 2016.

Cochrane Gynaecology and Fertility Group Specialised Register (Appendix 1).
Cochrane Central Register of Controlled Trials (CENTRAL) (Appendix 2).
MEDLINE (Appendix 3).
Embase (Appendix 4).
PsycINFO (Appendix 5).
Cumulative Index to Nursing and Allied Health Literature (CINAHL)0 (Appendix 6).
Database of Abstracts of Reviews of Effects (DARE) (Appendix 7).
Other.

- Trial registers for ongoing and registered trials: www.clinicaltrials.gov.
- Web of Knowledge: http://wokinfo.com/.
- Clinical study results for clinical trials of marketed pharmaceuticals: www.clinicalstudyresults.org.
- World Health Organization (WHO) International Clinical Trials Registry Platform: www.who.int/trialsearch.
- OpenGrey for unpublished literature from Europe: www.opengrey.eu.
- Latin American Caribbean Health Sciences Literature (LILACS) for Portuguese and Spanish trials.

Searching other resources

We handsearched appropriate journals recommended by the Gynaecology and Fertility Group that were not captured in the above databases. We also handsearched reference lists of relevant articles and contacted experts in the field to obtain additional data.

Data collection and analysis

We performed statistical analysis according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We used Review Manager 5.3 (RevMan 2014) software for the analysis.

Selection of studies

Two review authors independently completed the initial title and abstract screening. We retrieved full texts when studies met the following criteria: used an SPRM as an intervention for treatment of uterine fibroids, and had a prospective design. If we had any doubts based on these screening criteria, we retrieved the full text. We excluded studies if full‐text articles did not mention randomisation. We resolved disagreements during the screening process by consulting a third review author. We documented the selection process in a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) flow diagram (Figure 1).

Data extraction and management

Two review authors independently extracted data from all eligible studies to be included in the review. We extracted data using forms that we had pilot‐tested. These forms included specifics of study characteristics and outcomes data. When data from a trial had been published more than once, review authors extracted data that were additional and were not repeated. We contacted trial authors for clarification when required. We resolved disagreements between review authors by consensus after involving an additional review author.

Assessment of risk of bias in included studies

Two review authors independently assessed bias for included studies using the Cochrane risk of bias tool (www.cochrane‐handbook.org). We assessed the following elements: selection bias (random sequence generation, allocation concealment); performance bias (blinding of participants and personnel); detection bias (blinding of outcome assessors); attrition bias (incomplete outcome data); reporting bias (selective reporting); and other biases. We paid special attention to within‐trial selective reporting when study authors failed to report obvious outcomes or reported them with insufficient detail. We compared studies against published protocols to determine whether planned outcome measures were indeed reported.

Measures of treatment effect

We analysed the various comparisons separately using RevMan 5.3. We reported dichotomous data as odds ratios (ORs) with 95% confidence intervals (CIs). We reported continuous data as mean differences (MDs) with 95% CIs. When outcomes were reported as continuous data on different scales, we reported standardised mean differences (SMDs) and 95% CIs.

We interpreted the SMD using the following rule‐of‐thumb guide: 0.2 represents a small effect, 0.5 a moderate effect and 0.8 a large effect (Cohen 1988).

Unit of analysis issues

We performed the primary analysis per woman randomised.

We prepared additional tables to briefly summarise data that did not allow valid analysis (e.g. 'per cycle' data) and did not meta‐analyse these data. This applied to "change in fibroid size data", which we analysed on the basis of number of fibroids tracked ‐ not number of participants (i.e. some participants contributed more fibroids to the analysis than others).

We included only first‐phase data from cross‐over trials.

Dealing with missing data

We contacted primary authors electronically to request missing data and clarification of any issues that arose. We analysed data on the basis of intention‐to‐treat analysis. When all randomised participants were not included in the analysis, we calculated and separately reported the percentage of participants lost to follow‐up. In these cases, we imputed values only for primary outcomes. For other outcomes, we analysed only available data.

When data were reported in a form unsuitable for analysis (e.g. did not report standard deviations or reported medians rather than means), we obtained statistical advice and imputed the data (see Appendix 12).

Assessment of heterogeneity

We evaluated included trials to determine whether studied participants, interventions and outcomes were similar enough that we could meta‐analyse them. If we determined that trials could be meta‐analysed to yield clinically relevant results, we assessed these trials for statistical heterogeneity. We performed tests for heterogeneity across studies by using the Q statistic and the I² statistic. We used the following criteria for heterogeneity: I² < 25% showed low, 25% to 50% moderate and > 50% high heterogeneity (Higgins 2011). When we found high heterogeneity across any of these criteria, we conducted subgroup and sensitivity analyses.

Assessment of reporting biases

We aimed to minimise reporting bias by completing a comprehensive search for eligible studies while staying conscious of data duplication. If we found a sufficient number of trials for inclusion (> 10), we used a funnel plot to assess for publication bias (under‐reporting of small negative studies).

Data synthesis

We pooled data for clinically similar studies using a random‐effects model for the meta‐analysis. When studies could not be pooled, we described outcomes in narrative form. We analysed different comparisons separately.

All SPRMs versus placebo or no treatment.
All SPRMs versus alternative active therapy, stratified by alternatives.
- SPRMs versus medical therapy (stratified by class of medical therapy).
- SPRMs versus surgical management (stratified by type of surgical management).
- SPRMs versus UAE.

Subgroup analysis and investigation of heterogeneity

We planned to perform the following subgroup analyses if sufficient data were available (i.e. more than five studies).

Individual types of SPRMs versus placebo, no treatment or each alternative active therapy.
Duration of therapy (< 6 months, 6 to 12 months, > 12 months).
SPRM dose (low, medium, high).
Fibroid location (submucous, intramural, subserosal).

When high heterogeneity was present, we planned to explore possible explanations including individual study risk of bias, participant population (age, ethnicity, types and sizes of fibroids), dose of SPRM, duration of treatment and follow‐up.

Sensitivity analysis

We planned to conduct sensitivity analyses for primary outcomes when data were sufficient (more than five studies) to determine whether conclusions were robust to arbitrary decisions made regarding eligibility and analysis. These planned analyses included consideration of whether review conclusions would have differed if:

eligibility had been restricted to studies without high risk of bias;
a fixed‐effect model had been adopted;
alternative imputation strategies had been implemented; or
the summary effect measure had been risk ratio rather than odds ratio.

Overall quality of the body of evidence: 'Summary of findings' table

We prepared a 'Summary of findings' table using GRADEpro (GRADEpro GDT 2014) and Cochrane methods (Higgins 2011). These tables evaluated the overall quality of the body of evidence for main review outcomes (symptom severity, health‐related quality of life, menstrual blood loss, rate of amenorrhoea, pelvic pain/pressure, SPRM‐associated endometrial changes) for main review comparisons (SPRM vs placebo and SPRM vs leuprolide acetate). We assessed the quality of the evidence using the following GRADE criteria: risk of bias, consistency of effect, imprecision, indirectness and publication bias. Two review authors independently judged evidence quality (high, moderate, low or very low) and resolved disagreements by discussion. We justified, documented and incorporated these judgements into reporting of results for each outcome.

Results

Description of studies

See Characteristics of included studies and Characteristics of excluded studies.

Results of the search

The electronic search of databases generated 476 records after we eliminated duplicates. We identified no additional records through handsearching and other sources. After screening titles and abstracts, we eliminated 437 records that did not meet review inclusion criteria. We retrieved 39 full‐text manuscripts and excluded 25 citations (15 were secondary publications/duplicated cohorts, 10 compared various doses of SPRM ‐ see Characteristics of excluded studies). We identified 10 ongoing trials (see Characteristics of ongoing studies) and included 14 studies in the review. Bigatti 2014 presented preliminary data on surgical outcomes after pretreatment with a variety of hormonal agents including ulipristal acetate. We could not extract data as no participants were treated with SPRM at the time of publication and investigators reported only surgery‐related outcomes. We did not include this study in further analyses in this review. Furthermore, we could not extract data from Liu 2015 and Prasad 2013, as the numbers of participants assigned to treatment and control groups were unclear. Our attempts to contact study authors were unsuccessful. Hence, we used 11 studies for meta‐analysis. Two publications reported on the same participant cohort but reported different clinical outcomes; Wilkens 2008 reported these details. We have outlined details of the study screening process in Figure 1. The search was current as of 15 May 2016.

Included studies

For more information on included studies, see Characteristics of included studies.

Methods and setting

All studies were RCTs. Four studies were multi‐centre trials: three from European centres (Donnez 2012; Donnez 2012a; Wilkens 2008) and one from a North American centre (Chwalisz 2007). Four single‐site studies were conducted in the United States (Fiscella 2006; Levens 2008; Nieman 2011; Reinsch 1994); two in India (Bagaria 2009; Prasad 2013) and the remainder in Cuba (Esteve 2013), China (Liu 2015), Sweden (Engman 2009) and Italy (Bigatti 2014).

Participants

Studies included a total of 1215 study participants: 685 received SPRM and 336 were given a control. For two studies, numbers of participants in SPRM and control groups were unclear (Liu 2015; Prasad 2013). All studies, with one exception, included only patients with symptomatic fibroids. In Chwalisz 2007, although participants were not expected to be symptomatic at baseline, most of them experienced symptoms (76% had abnormal uterine bleeding and 94% had bulk symptoms). Three studies scheduled participants for surgery for their symptomatic fibroids (Engman 2009; Esteve 2013; Wilkens 2008). Eight studies diagnosed uterine fibroids by ultrasonography, and three by MRI (Donnez 2012; Levens 2008; Nieman 2011).

Eight studies reported the following ethnicities for 931 participants (91% of participants were included in this analysis): 644 White/Caucasian (69%), 183 Black (20%), 31 Asian (3%), 29 Afro‐Cuban (3%), 4 Hispanic (< 1%) and 40 “other” (4%).

Interventions

The SPRM in seven studies was mifepristone (see Table 3). Five studies investigated ulipristal acetate (see Table 4), and two investigated asoprisnil. Chwalisz 2007 investigated three daily doses of asoprisnil (5 mg, 10 mg, 25 mg) and compared them with placebo over a three‐month period. Wilkens 2008 compared 10 mg and 25 mg daily of asoprisnil versus placebo over three months in a cohort of 33 participants (see Table 5).

1. Mifepristone studies.

Study	Participants	Daily dose	Control	Follow‐up (months)
Esteve 2013	124	5 mg	Placebo	3
Fiscella 2006	42	5 mg	Placebo	6
Bagaria 2009	40	10 mg	Placebo	3
Liu 2015	62	10 mg	Placebo	3
Prasad 2013	132	10 mg	Placebo	3
Reinsch 1994	14	25 mg	Leuprolide acetate	3
Engman 2009	30	50 mg	Vitamin B	3

SPRM vs placebo
Patient or population: women with uterine fibroids  Setting: outpatient clinic  Intervention: SPRM  Comparison: placebo
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with placebo	Risk with SPRM	Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Quality of life: change in symptom severity score measured with Uterine Fibroid Symptom Quality of Life Scale (UFS‐QoL): scale 0 to 100		Mean change in symptom severity score (QoL) in the intervention group was 20.04 points lower (26.63 lower to 13.46 lower), indicating improvement in symptom severity with SPRM treatment for 3 months	‐	171  (4 RCTs)	⊕⊕⊕⊝  MODERATE^a
Quality of life: change in health‐related quality of life score measured with UFS‐QoL: scale 0 to 100		Mean change in health‐related quality of life score in the intervention group was 22.52 points higher (12.87 higher to 32.17 higher), indicating improvement in quality of life with SPRM treatment for 3 to 6 months	‐	200  (4 RCTs)	⊕⊕⊕⊝  MODERATE^a	1 RCT (Fiscella 2006) reported outcomes at 6 months. Remaining studies had a 3‐month follow‐up period
Abnormal uterine bleeding: change in menstrual blood loss		Mean change in menstrual blood loss in the intervention group was 1.11 points lower (1.38 lower to 0.83 lower), indicating a decrease in menstrual blood loss with SPRM treatment for 3 months	‐	310  (3 RCTs)	⊕⊕⊕⊝  MODERATE^a	Measured by PBAC score or similar menstrual pictorial score. PBAC score ≥ 100 correlates with menorrhagia, which is defined as > 80 mL menstrual blood loss
Abnormal uterine bleeding: amenorrhoea	29 per 1000	477 per 1000  (237 to 961) with 3 to 6 months of SPRM treatment	OR 82.50  (37.10 to 183.90)	590  (7 RCTs)	⊕⊕⊕⊝  MODERATE^a	1 RCT (Fiscella 2006) reported outcomes at 6 months. Remaining studies had a 3‐month follow‐up period
Pelvic pain (measured subjectively)		No conclusions could be drawn owing to variability in estimates		629 (7 RCTs)
Adverse effects: SPRM‐associated endometrial changes	77 per 1000	351 per 1000  (176 to 697) with 3 months of SPRM treatment	OR 15.12  (6.45 to 35.47)	405  (5 RCTs)	⊕⊕⊝⊝  LOW^a,b
*Risk in the intervention group (and its 95% confidence interval) is based on mean risk in the comparison group and relative effect of the intervention (and its 95% CI)    CI: confidence interval; OR: odds ratio
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to the estimate of effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of effect but may be substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

SPRM versus leuprolide acetate for uterine fibroids
Patient or population: uterine fibroids  Setting: outpatient clinic  Intervention: SPRM  Comparison: leuprolide acetate
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with leuprolide acetate	Risk with SPRM	Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Quality of life: change in symptom severity score measured with Uterine Fibroid Symptom Quality of Life Scale (UFS‐QoL): scale 0 to 100		Mean change in symptom severity score (QoL) in the SPRM group was 3.7 points lower  (9.85 lower to 2.45 higher) compared with the leuprolide group at 3 months	‐	281  (1 RCT)	⊕⊕⊕⊝  MODERATE^a
Quality of life: change in health‐related quality of life score measured with UFS‐QoL: scale 0 to 100		Mean change in health‐related quality of life score in the SPRM group was 1.06 points higher  (5.73 lower to 7.85 higher) compared with the leuprolide group at 3 months	‐	281  (1 RCT)	⊕⊕⊕⊝  MODERATE^a
Abnormal uterine bleeding: change in menstrual blood loss (measured using PBAC score)		Mean change in menstrual blood loss in the SPRM group was 6 points higher  (40.95 lower to 52.95 higher) compared with the leuprolide group at 3 months	‐	281  (1 RCT)	⊕⊕⊝⊝  LOW^a,b	PBAC score ≥ 100 correlates with menorrhagia, which is defined as > 80 mL menstrual blood loss
Abnormal uterine bleeding: amenorrhoea	804 per 1000	828 per 1000  (732 to 933) at 3 months	OR 1.14  (0.60 to 2.16)	280  (1 RCT)	⊕⊕⊕⊝  MODERATE^a
Pelvic pain (measured using McGill Pain Questionnaire: range 0 to 45)		Mean change in pelvic pain in the SPRM group was 0.01 points lower (2.14 lower to 2.12 higher) than in the leuprolide group at 3 months	‐	281  (1 RCT)	⊕⊕⊕⊝  MODERATE^a
Adverse effects: SPRM‐associated endometrial changes	119 per 1000	585 per 1000  (340 to 1000) after 3 months of treatment	OR 10.45  (5.38 to 20.33)	301  (1 RCT)	⊕⊕⊕⊝  MODERATE^a
*Risk in the intervention group (and its 95% confidence interval) is based on mean risk in the comparison group and relative effect of the intervention (and its 95% CI)    CI: confidence interval; OR: odds ratio
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to the estimate of effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of effect but may be substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Study	SPRM type	SPRM			Placebo
		MD	SD	n	MD	SD	n	Finding
Bagaria 2009	Mifepristone	‐41.5 cc	220.59	19	0.6 cc	266.63 cc	16	No significant difference
Engman 2009	Mifepristone	‐10.0 cc	107.39	12	‐16.0 cc	98.54 cc	15	No significant difference
Esteve 2013	Mifepristone	‐37.0 cc	96.24	58	4.0 cc	99.1 cc	47	Favours SPRM
Donnez 2012	Ulipristal acetate	‐16.88%	31.34	165	3.0%	31.63	45	Favours SPRM
Nieman 2011	Ulipristal acetate	‐20.5%	20.6	26	7.0%	25.0	12	Favours SPRM

Study	SPRM			Leuprolide
	MD	SD	n	MD	SD	n	Finding
Donnez 2012a	‐39.03%	37.92	188	‐53.0%	24.44	93	Favours leuprolide

#	Query	Results
S35	S22 AND S34	23
S34	S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33	1,066,484
S33	TX allocat* random*	5,196
S32	(MH "Quantitative Studies")	14,755
S31	(MH "Placebos")	9,774
S30	TX placebo*	39,205
S29	TX random* allocat*	5,196
S28	(MH "Random Assignment")	41,421
S27	TX randomi* control* trial*	108,575
S26	TX ( (singl* n1 blind) or (singl n1 mask) ) or TX ( (doubl n1 blind) or (doubl n1 mask) ) or TX ( (tripl n1 blind) or (tripl n1 mask) ) or TX ( (trebl n1 blind) or (trebl n1 mask*) )	845,197
S25	TX clinic* n1 trial*	188,356
S24	PT Clinical trial	79,704
S23	(MH "Clinical Trials+")	201,384
S22	S7 AND S21	62
S21	S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20	970
S20	TX CDB‐4124	2
S19	TX Ulipristal	87
S18	TX Telapristone	3
S17	TX J867	1
S16	TX Asoprisnil	5
S15	TX ru‐486	163
S14	TX ru‐38486	7
S13	TX ru38486	7
S12	TX mifeprex	20
S11	TX Mifepristone	831
S10	(MM "Mifepristone")	397
S9	TX SPRM*	5
S8	TX selective progesterone receptor modulator*	22
S7	S1 OR S2 OR S3 OR S4 OR S5 OR S6	3,181
S6	TX fibromyoma	2
S5	TX (uter* N3 fibroma*)	5
S4	TX Leiomyoma*	2,594
S3	TX myoma*	404
S2	TX fibroid*	1,096
S1	(MM "Leiomyoma") OR (MH "Myoma+")	2,017

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in symptom severity score (QoL)	4	171	Mean Difference (IV, Random, 95% CI)	‐20.04 [‐26.63, ‐13.46]
2 Change in health‐related quality of life score	4	200	Mean Difference (IV, Random, 95% CI)	22.52 [12.87, 32.17]
3 Change in menstrual blood loss	3	310	Std. Mean Difference (IV, Random, 95% CI)	‐1.11 [‐1.38, ‐0.83]
4 Amenorrhoea	7	590	Odds Ratio (IV, Random, 95% CI)	82.50 [37.01, 183.90]
5 Change in uterine volume	4	419	Std. Mean Difference (IV, Random, 95% CI)	‐0.63 [‐0.91, ‐0.36]
6 SPRM‐associated endometrial changes	5	405	Odds Ratio (IV, Random, 95% CI)	15.12 [6.45, 35.47]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in symptom severity score (QoL)	1	281	Mean Difference (IV, Random, 95% CI)	‐3.70 [‐9.85, 2.45]
2 Change in health‐related quality of life score	1	281	Mean Difference (IV, Random, 95% CI)	1.06 [‐5.73, 7.85]
3 Change in menstrual blood loss	1	281	Mean Difference (IV, Random, 95% CI)	6.00 [‐40.95, 52.95]
4 Amenorrhoea	1	280	Odds Ratio (M‐H, Random, 95% CI)	1.14 [0.60, 2.16]
5 Change in pelvic pain	1	281	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐2.14, 2.12]
6 Percent change in uterine volume	2	295	Mean Difference (IV, Random, 95% CI)	25.94 [20.49, 31.39]
7 SPRM‐associated endometrial changes	1	301	Odds Ratio (M‐H, Random, 95% CI)	10.45 [5.38, 20.33]

Methods	Single‐center blinded placebo RCT
Participants	Participants randomised to 1 of 2 groups in a 1:1 ratio (n = 40) ‐ 20 mifepristone 10 mg: 1 withdrawn, 19 analysed ‐ 20 placebo: 4 withdrawn, 16 analysed Baseline demographics similar in each group Inclusion criteria ‐ Premenopausal ‐ Symptomatic fibroids (confirmed on ultrasonography) Exclusion criteria ‐ Pregnancy/lactation ‐ Ovarian/cervical/uterine malignancy ‐ Histopathological evidence of endometrial hyperplasia ‐ Hormonal treatment previous 3 months ‐ Liver, respiratory, renal, cardiac disease ‐ Pelvic inflammatory disease ‐ Need for early surgical intervention for fibroids Setting: Delhi, India
Interventions	Mifepristone 10 mg orally daily vs placebo Duration: 3 months starting on cycle day 1 to 3
Outcomes	Outcomes assessed monthly for 3 months in the post‐menstrual phase or on a fixed day if amenorrhoeic ‐ Uterine/fibroid ultrasound volumes ‣ Uterine (Viscomi formula) ‣ Average and largest fibroid (formula for sphere) ‐ Blood loss ‣ PBAC ‣ Mean Hgb level ‣ Amenorrhoea ‐ Fibroid symptoms (VAS) ‣ Dysmenorrhoea ‣ Pelvic pain ‣ Backache ‣ Urinary complaints ‣ Dyspareunia ‐ Serum haemoglobin, liver and renal function tests ‐ Side effects ‣ Nausea/vomiting ‣ Fatigue ‣ Diarrhoea ‣ Headache ‣ Weakness ‣ Hot flashes ‣ Loss of libido ‐ Endometrial biopsy for hyperplasia (only at end of study) but did not report on PAEC
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random tables were used to randomise packets to contain mifepristone or placebo
Allocation concealment (selection bias)	Low risk	As participants were enrolled, they were assigned numbers 1 to 40 and received the corresponding numbered drug packet prepared/dispensed by a third party
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Mifepristone and placebo capsules were identical in appearance and were prepared/dispensed by a third party
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Not stated Main outcomes objective (e.g. fibroid volume, Hgb), so less influenced by bias if present
Incomplete outcome data (attrition bias)   All outcomes	High risk	1 and 4 participants lost to follow‐up in mifepristone vs placebo group. This represents unequal loss of follow‐up between groups (5% vs 20%). No intention‐to‐treat analysis
Selective reporting (reporting bias)	Unclear risk	Protocol not found. Study authors emailed for protocol
Other bias	Unclear risk	Potential for dose variation in mifepristone group, as no specific detail regarding capsule derivation method from 200 mg tablets and associated quality control

Methods	Randomised prospective comparative study
Participants	Unclear but likely premenopausal women with submucosal fibroids undergoing hysteroscopic myomectomy
Interventions	‐ Group A: norethisterone acetate 10 mg 2 times per day  ‐ Group B: micronised progesterone 200 mg 1 time per day  ‐ Group C: dienogest 2 mg 1 time per day  ‐ Group D: ulipristal acetate 5 mg 1 time per day  ‐ Group E: control group with no treatment
Outcomes	Fluid balance, cervical canal dilatation time, resection and total operation time,  complications, second‐look procedures, conversion to bipolar resectoscopy
Notes	Conference proceeding. Irrelevant clinical outcomes reported in this conference proceeding. This trial included 5 arms (ulipristal acetate, dienogest, micronised progesterone, norethindrone acetate, placebo). Investigators reported on surgical outcomes at hysteroscopic myomectomy, including fluid balance, cervical canal dilatation time, resection and total operation time, complications, second‐look procedures and conversion to bipolar resectoscopy. Total of 7 participants were recruited at time of publication. None of these participants were treated with an SPRM
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Not stated
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not stated
Selective reporting (reporting bias)	Unclear risk	Not stated
Other bias	Unclear risk	Data in form of conference proceedings. No published follow‐up data

Methods	Multi‐centre blinded placebo RCT
Participants	Participants randomised to 1 of 4 groups in a 1:1:1:1 ratio (n = 129) ‐ 33 asoprisnil 5 mg: 1 withdrawn, 32 analysed ‐ 29 asoprisnil 10 mg: 2 withdrawn, 27 analysed ‐ 36 asoprisnil 25 mg: 4 withdrawn, 32 analysed ‐ 31 placebo: 2 withdrawn, 29 analysed Baseline demographics similar in each group Inclusion criteria ‐ 18 to 49 years old ‐ Good general health ‐ No history of uterine artery embolisation, cryomyolysis or electrical myolysis ‐ At least 1 fibroid ≥ 3 cm diameter or uterine volume > 200 cm³ caused by multiple small fibroids (ultrasonography) Exclusion criteria ‐ Pelvic pathology (e.g. endometriosis, ovarian cysts ‐ simple > 3 cm or complex) ‐ Adenomyosis on ultrasonography (confirmed on MRI) ‐ Endometrial polyp (confirmed on saline infusion sonography) Setting: 28 sites in United States and 1 site in Canada
Interventions	Asoprisnil 5, 10 and 25 mg orally daily vs placebo Duration: 12 weeks starting on cycle day 1 to 4 Participants previously on hormone preparations underwent washout period (3 months to 1 year, depending on agent)
Outcomes	Outcomes assessed at baseline and at 2, 4, 8 and 12 weeks Efficacy ‐ Bleeding (daily diaries) ‣ Suppression of bleeding ‣ Amenorrhoea ‣ Haemoglobin concentrations and iron parameters ‐ Uterine/largest fibroid ultrasound volumes (formula for ellipsoid) ‐ Patient‐reported symptoms (unvalidated questionnaire) ‣ Bulk symptoms (bloating, pressure, urinary frequency) ‣ Heavy uterine bleeding ‣ Pelvic pain ‣ Dyspareunia ‣ Dysmenorrhoea ‐ Global efficacy question (only at 12 weeks) Safety ‐ Endometrial changes (only at 12 weeks). To report on non‐physiological changes, investigators developed a new classification system for endometrial biopsies that included 2 additional subcategories: non‐physiological secretory effect and secretory pattern mixed‐type ‣ Thickness (ultrasonography) ‣ Histology (pipelle endometrial biopsy) ‐ Hormone parameters ‣ Serum oestradiol, estrone, progesterone, cortisol, FHS, LH, sex hormone binding globulin, androstenedione, DHEAS, prolactin, TSH, T4 ‣ Serum and urine N‐telopeptide ‐ Lipids ‣ Total cholesterol, HDL, LDL ‐ Physical examination ‣ Weight, blood pressure, pulse, breast and pelvic exams ‐ Ultrasound assessment of ovarian cysts ‐ Papanicolaou test ‐ Electrocardiography ‐ Adverse events
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“A computer generated central randomization schedule was used to assign each patient in a 1:1:1:1 ratio to the four treatment groups”
Allocation concealment (selection bias)	Low risk	From study author‐provided protocol: "Fisher US packaged and labelled all study drug. The study drug was then shipped to Fisher UK who were responsible for supplying study drug to the clinical sites... When the randomization number was assigned for each subject, the  duplicate label with the attached blinded label was removed from the subject kit and affixed to the appropriate CRF by study personnel. The identity of the contents of the blister card was not disclosed on the label"
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	“This study was…double‐blind…All asoprisnil and placebo tablets were identical in appearance” From study author‐provided protocol: "The investigator, clinical research coordinator, monitors, subject, and pathologist were blinded to  each subject’s treatment group throughout the study"
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Patient‐reported outcomes were blinded: “Representatives of TAP collected the data, and statisticians at TAP conducted all statistical analyses”
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Reasons for drop‐out given and plausible. Dropouts balanced between placebo (6.5%) and SPRM (7%) groups and unlikely “Nine of 129 randomized patients prematurely ... Among these nine patients, three terminated prematurely as a result of an adverse event" One drop‐out from AE in placebo group (3%) and 2 in SPRM group (2%). Drop‐outs for other reasons (less likely to affect outcomes) occurred in placebo group 1 (3%) and SPRM group 5 (5%)
Selective reporting (reporting bias)	Low risk	Protocol NCT00160459 reviewed
Other bias	Low risk	None identified

Methods	Multi‐centre blinded non‐inferiority active‐comparator RCT
Participants	Participants randomised to 1 of 3 groups in a 1:1:1 ratio (n = 307; 4 excluded): ‐ 98 ulipristal acetate (UA) 5 mg, 3 withdrawn, 95 analysed ‐ 104 ulipristal acetate 10 mg (UA), 4 withdrawn, 100 analysed ‐ 101 leuprolide acetate (LA) 3.75 IM, 6 withdrawn, 95 analysed Randomisation stratified according to ‐ Race (black or other) Baseline demographics similar in each group Inclusion criteria ‐ Premenopausal women 18 to 50 years old ‐ BMI 18 to 40 ‐ Heavy uterine bleeding caused by fibroids (PBAC > 100) ‐ At least 1 fibroid ≥ 3 cm and < 10 cm ‐ Uterine size ≤ 16 weeks ‐ Eligible for surgery Exclusion criteria ‐ History of uterine surgery (except for cesarean section or cervical conisation) ‐ Endometrial ablation or uterine artery embolisation ‐ History of concurrent gynaecological cancer ‐ Current endometrial hyperplasia ‐ Hgb ≤ 6 g/L or any condition requiring immediate blood transfusion ‐ Known haemoglobinopathy ‐ Known severe coagulation disorder ‐ Large uterine polyp (> 2 cm) ‐ 1 or more ovarian cyst ≥ 4 cm in diameter on ultrasound ‐ Previous or current fibroid treatment with an SPRM or GnRH agonist ‐ Treatment with agents known to affect hepatic cytochrome CYP3A4 ‐ Progestins, acetylsalicylic acid, mefenamic acid, anticoagulants, antifibrinolytic drugs or systemic glucocorticoid treatments Setting: 38 centres in 6 European countries
Interventions	Ulipristal acetate 5 mg or 10 mg orally daily vs leuprolide acetate 3.75 mg IM injection once monthly Duration: 13 weeks starting on cycle day 1 to 4 ‐ After 13 weeks, participants could undergo surgery ‐ No further pharmacological treatment of fibroids administered ‐ Iron supplementation left to the discretion of the treating physician
Outcomes	Outcomes assessed at baseline and at 13 weeks Primary efficacy endpoint ‐ Reduction in bleeding (PBAC < 75; non‐inferiority margin ‐20%) Secondary efficacy endpoints ‐ Bleeding pattern (PBAC scores) ‐ Amenorrhoea (PBAC score ≤ 2) ‐ Uterine/fibroid (3 largest) ultrasound volumes ‐ Global pain score (Short‐Form McGill Pain Questionnaire and VAS) ‐ Uterine Fibroid Symptom and Quality of Life (UFS‐QoL) questionnaire ‐ Haemoglobin, haematocrit and ferritin levels Co‐primary safety endpoints ‐ Serum oestradiol levels ‐ Moderate to severe hot flashes Secondary safety endpoints ‐ Adverse events ‐ Serum oestradiol, progesterone, corticotropin, thyrotropin, prolactin, lipids and glucose ‐ Endometrial thickness and ovaries on ultrasound ‐ Endometrial biopsy. Used the standard definition of SPRM‐associated endometrial changes (PAEC) provided by Mutter 2008
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“Patients were randomly assigned in a 1:1:1 ratio to receive either 5 mg or 10 mg of daily oral ulipristal acetate plus an intramuscular saline injection once monthly or a daily oral placebo plus an intramuscular injection of 3.75 mg of leuprolide acetate once monthly” From protocol: "a randomization list will be generated by a designated statistician from MDSL to be transmitted to the assigned clinical packaging organization for labelling"
Allocation concealment (selection bias)	Low risk	“A Web‐integrated voice‐response system transmitted the randomization to the packaging organization, which delivered the medications to the treatment centres”
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Study is described in the article as “double‐blind and double‐dummy”
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Participant outcomes were blinded “Endometrial biopsy samples were assessed by three independent pathologists who were unaware of the study‐group assignments, the visit sequence” “Data were collected by an independent contract research organization and handled and analyzed by an independent data‐management organization”
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing outcome data balanced in numbers across intervention groups: "The modified intention‐to‐treat analyses did not include five patients: two patients (one in each ulipristal‐acetate group) who never received the study drug and were not followed and three patients (one who was assigned to receive 10 mg of ulipristal acetate and two in the leuprolide acetate group) with missing efficacy data after baseline" Appropriate imputation of missing data: "Missing data for week 13 were imputed with the use of data for the last available 28 days during treatment. A sensitivity analysis in the modified intention‐to‐treat population (including three patients without any on treatment efficacy data) was performed with the use of baseline data carried forward"
Selective reporting (reporting bias)	Low risk	Protocol available on clinicaltrials.gov NCT00740831
Other bias	Low risk	None identified

Methods	Single‐center blinded placebo (vitamin B) RCT
Participants	Participants randomised to 1 of 2 groups in a 1:1 ratio (n = 30) ‐ 14 mifepristone, 14 analysed ‐ 16 placebo (vitamin B), 2 withdrawn, 14 analysed Baseline demographics similar in each group (except for free testosterone greater in mifepristone group) Inclusion criteria ‐ Healthy, non‐pregnant women ‐ Fibroid‐related problems indicating surgical intervention ‐ No steroid hormones within 3 months of recruitment Exclusion criteria ‐ Breast cancer or other malignancy ‐ Bleeding not controlled by tranexamic acid and iron ‐ Abnormal mammogram and breast biopsy at baseline ‐ Adnexal abnormality ‐ Suspicion of leiomyosarcoma ‐ Abnormal FSH or LH or any other hormonal dysfunction of clinical significance ‐ Labs: suspicion of blood, liver or renal dysfunction ‐ Abnormal Papanicolaou test at screening ‐ Contraindication to mifepristone Setting: Stockholm, Sweden
Interventions	Mifepristone 50 mg vs vitamin B (placebo) orally every other day Duration: 3 months starting on cycle day 1 until surgery
Outcomes	Outcomes assessed at baseline and monthly for 3 months ‐ Uterine/fibroid (largest and total) ultrasound volumes (formula for an ellipsoid) ‐ Uterine/fibroid blood flow (Doppler ultrasound of PI and peak flow) ‐ Uterine bleeding ‣ Number of bleeding days ‣ Amenorrhoea Safety ‐ Blood work (every 4 weeks) ‣ Haematological, renal and liver ‣ Hormone profile ‐ Endometrial biopsy (baseline and study end during surgery). To describe non‐physiological changes, they devised their own semiquantitative assessment of glandular architecture ‐ Mammogram (baseline) ‐ Breast biopsy (baseline and study end) Fibroid symptoms (Likert scale 0 to 4) ‐ Bleeding ‐ Pelvic pain or pressure ‐ Bladder pressure ‐ Micturition problems ‐ Low back pain ‐ Proctodynia ‐ Dyspareunia ‐ Flushes ‐ Headache ‐ Nausea ‐ Vomiting ‐ Diarrhoea ‐ Mood fluctuations ‐ Libido ‐ Weakness ‐ Fatigue Medication side effects
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation by third party
Allocation concealment (selection bias)	Low risk	Packed and coded by third party
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Identical pills prepared and distributed by third party
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Ultrasound blinding not specifically mentioned, but "Patients and staff were blinded to treatment groups", as were assessors of endometrial pathology
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Two in placebo arm excluded
Selective reporting (reporting bias)	Low risk	Protocol available and reviewed on clinicaltrials.gov NCT00579475
Other bias	Low risk	None identified

Methods	Single‐centre blinded placebo RCT
Participants	Participants randomised to 1 of 2 groups in a 1:1 ratio (n = 42) ‐ 22 mifepristone 5 mg, 2 withdrawn, 20 analysed ‐ 20 placebo, 3 withdrawn, 17 analysed Randomisation stratified according to ‐ Uterine Fibroid Symptom Quality of Life (UFS‐QoL) symptom severity (> 64 vs ≤ 63) Baseline demographics similar in each group except for ‐ BMI and baseline uterine volume (higher in treatment group) Inclusion criteria ‐ Age ≥ 18 years ‐ Premenopausal ‐ At least moderately severe fibroid‐related symptoms (> 39 on UFS‐QoL symptom severity subscale) ‐ Total uterine volume ≥ 160 mL ‐ At least 1 fibroid ≥ 2.5 cm ‐ Had not used short‐acting hormone analogues or other long‐acting hormone medications in past 6 months Exclusion criteria ‐ Pregnant or intending pregnancy during next 6 months ‐ Major medical morbidity ‐ Severe anaemia ‐ Active mental illness ‐ Elevated liver enzymes ‐ Substance abuse Setting: New York, USA
Interventions	Mifepristone 5 mg orally daily vs placebo Duration: 26 weeks ‐ Participants agreed to use barrier contraception and not to use hormonal or surgical treatments for fibroids during the study ‐ Participants were allowed to use analgesics and were asked to record use
Outcomes	Outcomes assessed at baseline and at 1, 3 and 6 months Primary outcome ‐ Fibroid‐specific overall QoL (UFS‐QoL) Secondary outcomes ‐ Global health status (Medical Outcomes 36‐item Short Form (SF‐36) survey) ‐ Global pain (McGill Pain Questionnaire) assessed monthly ‐ Bleeding (daily menstrual logs and pictorial charts) ‣ Amenorrhoea ‣ Mean monthly blood loss index ‣ Haemoglobin ‐ Uterine/fibroid (5 largest summed) ultrasound volumes (measured in 3 planes) ‐ Fibroid symptoms (5‐point Likert scale) assessed monthly ‣ Pelvic pain ‣ Pelvic pressure ‣ Bladder pressure ‣ Urinary frequency ‣ Low back pain ‣ Rectal pain ‣ Pain with intercourse ‐ Adverse effects (5‐point Likert scale) assessed monthly ‐ Liver function tests ‐ Endometrial biopsy assessed at baseline and at 6 months. Did not report on PAEC
Notes	19/20 women in the treatment group correctly guessed that they had been receiving mifepristone because of cessation of bleeding
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“Using random numbers generated with SAS 9, women were randomly assigned in blocks of four, stratified by Uterine Fibroid Symptom Quality of Life”
Allocation concealment (selection bias)	Low risk	“Study assignments were placed in opaque sealed envelopes that were opened by the study pharmacist once the participant was fully qualified”
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	“The study pharmacist prepared mifepristone 5 mg and placebo in capsules that were identical in appearance and weight” “None of the study personnel, with the exception of the pharmacist, were aware of treatment assignments”
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	"None of the study personnel, with the exception of the pharmacist, were aware of treatment assignments" However, blinding of outcome assessors was not specifically described
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing outcome data relatively balanced in numbers across intervention groups and unlikely to be related to the true outcome “3 [women] completed the intake measures and were randomised (two to treatment and one to placebo) but then declined to participate, and 39 began the trial and participated for at least one month” “Two other women (from placebo group) dropped out during the course of the study. Neither reported leaving due to adverse effects”
Selective reporting (reporting bias)	Low risk	Main outcomes reported. Protocol available at clinicaltrials.gov NCT00133705
Other bias	Low risk	None identified

Methods	Single‐centre blinded RCT
Participants	Participants randomised to 1 of 2 groups (n = 132) ‐ Mifepristone 10 mg ‐ Placebo Inclusion criteria ‐ Symptomatic fibroids No additional details available Setting: Beijing, China
Interventions	Mifepristone 10 mg orally daily vs placebo Duration: 3 months
Outcomes	Outcomes assessed at baseline and at 3 months ‐ Fibroid volume ‐ Hgb ‐ Liver function tests ‐ FSH
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomized" ‐ no details. Attempts to contact study authors unsuccessful
Allocation concealment (selection bias)	Unclear risk	Not stated. Attempts to contact study authors unsuccessful
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	"Double blind" ‐ no further details. Attempts to contact study authors unsuccessful
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	"Double blind" ‐ no further details. Attempts to contact study authors unsuccessful
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No details. Attempts to contact study authors unsuccessful
Selective reporting (reporting bias)	Unclear risk	No details. Attempts to contact study authors unsuccessful
Other bias	Unclear risk	Data in form of conference proceedings. No published follow‐up data. Protocol not found on clinicaltrials.gov

Methods	Single‐centre placebo RCT
Participants	Participants randomised to 1 of 2 groups (n = 62) ‐ Mifepristone 10 mg ‐ Placebo Inclusion criteria ‐ Symptomatic fibroids No additional details available Setting: Delhi, India
Interventions	Mifepristone 10 mg orally daily vs placebo Duration: 3 months
Outcomes	Outcomes assessed at baseline and at 3 months Primary outcome ‐ Fibroid volume Secondary outcomes ‐ Endometrial biopsy. Reported on 'cystic glandular hyperplasia' but pathology criteria not available ‐ Hormone profile ‐ Fibroid symptoms ‣ Bleeding/amenorrhoea ‣ Dysmenorrhoea
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomized" ‐ no details. Attempts to contact study authors unsuccessful
Allocation concealment (selection bias)	Unclear risk	Not stated. Attempts to contact study authors unsuccessful
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	"Single blind" ‐ no further details. Attempts to contact study authors unsuccessful
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	"Single blind" ‐ no further details. Attempts to contact study authors unsuccessful
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No details. Attempts to contact study authors unsuccessful
Selective reporting (reporting bias)	Unclear risk	No details. Attempts to contact study authors unsuccessful
Other bias	Unclear risk	Data in form of conference proceedings. No published follow‐up data. Protocol not found on clinicaltrials.gov

Methods	Single‐centre randomised prospective active‐comparator trial
Participants	Participants randomised to 1 of 2 groups (n = 14) ‐ 8 mifepristone 25 mg, 8 analysed ‐ 6 leuprolide acetate 3.75 mg, 6 analysed Baseline demographics similar in each group Inclusion criteria ‐ Women with uterine fibroids on ultrasound ‐ Scheduled to have myomectomy or hysterectomy Setting: California, USA
Interventions	Mifepristone 25 mg orally daily vs leuprolide acetate 3.75 mg IM monthly Duration ‐ 3 months ‐ Initiated in early follicular phase ‐ Study drug discontinued immediately before surgery
Outcomes	Outcomes assessed at baseline and at 3 months Primary outcomes ‐ Uterine ultrasound volume (formula for a sphere) ‐ Uterine artery blood flow (RI on Doppler ultrasound) Secocondary outcomes (for mifepristone group only) ‐ Side effects ‣ Nausea ‣ Hot flushes ‣ Night sweats ‣ Fatigue ‣ Vaginal dryness ‐ 24‐Hour urine‐free cortisol, creatinine, BUN, AST, ALT and LDH (baseline and monthly)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Details of randomisation are not provided: “They were randomly assigned to group A or group B”
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Not mentioned
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not mentioned
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No drop‐outs
Selective reporting (reporting bias)	High risk	No protocol provided. Chose not to measure/report fibroid volume
Other bias	Low risk	None identified

Study	Reason for exclusion
Carbonell 2008	Compared different doses, no placebo group
Carbonell 2012	Compared different doses, no placebo group
Carbonell 2013	Compared different doses, no placebo group
Carbonell 2013a	Compared different doses, no placebo group
Chwalisz 2003	Compared different doses, no placebo group
Donnez 2014	Compared different doses, no placebo group
Eisinger 2003	Compared different doses, no placebo group
Eisinger 2005	Compared different doses, no placebo group
Esteve 2012	Compared different doses, no placebo group
Kulshrestha 2013	Compared different doses, no placebo group

Methods	Randomised controlled trial
Participants	Premenopausal women with fibroids
Interventions	Ulipristal acetate 10 mg vs 25 mg vs placebo.
Outcomes	Unclear
Notes	Protocol NCT00044876 in clinicaltrials.gov of ulipristal acetate 10 mg vs 25 mg vs placebo. No results published in database nor in published literature. States trial was completed

Methods	Randomised phase 1 study
Participants	Healthy females
Interventions	Vilaprisan (0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg) vs placebo
Outcomes	Non‐bleeding rate (i.e. women without bleeding from treatment day 9 until the end of treatment)
Notes	Protocol NCT01816815 in clinicaltrials.gov of Vilaprisan vs placebo. No results in database nor in published literature. States trial was completed

Trial name or title	Bay1002670, Fibroids, Safety and Efficacy EU, US, Can, Jap (ASTEROID 1)
Methods	Randomised controlled trial
Participants	Premenopausal women with heavy menstrual bleeding and fibroid ≥ than 3 cm
Interventions	Vilaprisan 0.5 mg, 1 mg, 2 mg, 4 mg vs placebo
Outcomes	Amenorrhoea at 3 months
Starting date	May 2014
Contact information	Bayer
Notes

PERMALINK

Selective progesterone receptor modulators (SPRMs) for uterine fibroids

Ally Murji

Lucy Whitaker

Tiffany L Chow

Mara L Sobel

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

1.

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Overall quality of the body of evidence: 'Summary of findings' table

Results

Description of studies

Results of the search

Included studies

Methods and setting

Participants

Interventions

1. Mifepristone studies.

2. Ulipristal acetate studies.

3. Asoprisnil studies.

Outcomes

Excluded studies

Ongoing studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. SPRM versus placebo.

Summary of findings 2. SPRM versus leuprolide acetate for uterine fibroids.

Comparison of SPRM versus placebo

PRIMARY OUTCOMES

Fibroid‐related symptoms

Quality of life

1.1. Analysis.

4.

1.2. Analysis.

5.

Abnormal uterine bleeding

Trial name or title	A Study of the Safety and Efficacy of Intermittent Ulipristal Treatment of Abnormal Uterine Bleeding Associated With Leiomyomas
Methods	Randomised controlled trial
Participants	Cyclic abnormal uterine bleeding (heavy or prolonged)  Menstrual blood loss (MBL) ≥ 80 mL in the first 8 days of menses  Minimum of 1 discrete leiomyoma observable by transvaginal ultrasound
Interventions	Various permutations of ulipristal acetate 5 mg or 10 mg or placebo
Outcomes	Absence of bleeding (time frame: 12 weeks)  Time to absence of bleeding (time frame: 12 weeks)
Starting date	January 2014
Contact information	Watson Pharmaceuticals
Notes

Trial name or title	A Study of the Efficacy and Safety of a Single Ulipristal Treatment Course for the Treatment of Abnormal Uterine Bleeding Associated With Leiomyomas
Methods	Randomised controlled trial
Participants	Premenopausal women, 18 to 50 years of age, inclusive  Experienced cyclic abnormal uterine bleeding (heavy or prolonged)  Menstrual blood loss (MBL) ≥ 80 mL as measured once by the alkaline hematin method during screening over first 8 days of menses  Minimum of 1 discrete leiomyoma observable by transvaginal ultrasound at screening assessment
Interventions	Ulipristal acetate 5 mg vs 10 mg vs placebo
Outcomes	Absence of bleeding (time frame: 12 weeks)  Time to absence of bleeding (time frame: 12 weeks)
Starting date	April 2014
Contact information	Watson Pharmaceuticals
Notes	Expected completion date March 2016

Trial name or title	Ulipristal vs. GnRHa Prior to Laparoscopic Myomectomy (MYOMEX)
Methods	Randomised controlled trial
Participants	Premenopausal women eligible for laparoscopic myomectomy with fibroid size 5 to 12 cm
Interventions	Leuprolide 11.25 mg IM × 1 vs ulipristal acetate 5 mg daily × 3 months
Outcomes	Blood loss during surgery
Starting date	December 2014
Contact information	I. de Milliano, MD, VU University Medical Center
Notes

Trial name or title	A Phase 2 Study to Evaluate the Safety and Efficacy of Proellex (Telapristone Acetate) Administered Vaginally in the Treatment of Uterine Fibroids
Methods	Randomised controlled trial
Participants	Premenopausal women with symptomatic uterine fibroids
Interventions	Two vaginal doses of Proellex (6 mg vs 12 mg vs placebo) administered for up to 2 courses of treatment (18 weeks each), each separated by an off‐drug interval (ODI)
Outcomes	Percentage of participants who become amenorrhoeic after 1 course of treatment (6 months)
Starting date	December 2014
Contact information	Repros Therapeutics Inc
Notes

Trial name or title	Ulipristal Acetate Versus GnRH Analogue and Myometrial Preservation
Methods	Randomised controlled trial
Participants	Premenopausal women with G2 submucosal leiomyoma < 3 cm, symptoms of menometrorrhagia, menstrual disorder, infertility, pelvic pain
Interventions	Ulipristal acetate 5 mg/d for 2 courses of 3 months each vs IM on leuprolide acetate 11.25 in luteal phase repeated 3 months later
Outcomes	Proportion of restored uterine cavity 1 year after enrolment
Starting date	February 2015
Contact information	Fulvio Zullo, University Magna Graecia
Notes

Trial name or title	Ulipristal Acetate for the Preoperative Management of Hypoechoic Cellular Leiomyomas
Methods	Randomised controlled trial
Participants	Premenopausal women with hypoechoic uterine leiomyoma (echogenicity < 3), intramural leiomyomas with ultrasonographic size < 20 cm but > 4 cm, indication to surgery (symptoms of menometrorrhagia, menstrual disorder, infertility, pelvic pain or pelvic pressure)
Interventions	5 mg/d of oral ulipristal acetate for 3 months vs IM injection of leuprolide acetate 11.25 mg in luteal phase
Outcomes	Operative time (minutes) (time frame: at time of skin closure at the end of the myomectomy)
Starting date	February 2015
Contact information	Fulvio Zullo, University Magna Graecia
Notes

Trial name or title	Ulipristal Acetate 10 mg and Assisted Reproduction
Methods	Randomised controlled trial
Participants	Patients > 18 and < 50 years of age Patients who undergo first/second cycle OVD Patients who present with 1 to 3 intramural myomata > 2 cm and < 5 cm that do not distort the cavity, type 3 and 4 FIGO classification
Interventions	Ulipristal acetate 10 mg vs placebo
Outcomes	Increase in rate of clinical pregnancy at 12 weeks
Starting date	May 2015
Contact information	Instituto Valenciano de Infertilidad, IVI VALENCIA: Davinia Oltra, PhD ‐ Davinia.Oltra@ivi.es
Notes

Trial name or title	Assess Safety and Efficacy of Vilaprisan in Patients With Uterine Fibroids (ASTEROID 2)
Methods	Randomised controlled trial
Participants	Premenopausal women with heavy menstrual bleeding and fibroid ≥ 3 cm
Interventions	Vilaprisan 2 mg vs ulipristal 5 mg in varying regimens
Outcomes	Amenorrhoea at 3 months
Starting date	June 2015
Contact information	Bayer
Notes