Selective progesterone receptor modulators (SPRMs) for uterine fibroids

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the effectiveness and safety of selective progesterone receptor modulators (SPRMs) in the treatment of pre-menopausal women with uterine fibroids. 

Background

Description of the condition

Uterine fibroids are common, benign, 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 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 commonly 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 for treatment of fibroids is estimated to be over four billion dollars annually (Cardozo 2012). Treatment of fibroid-related symptoms can include surgery (hysterectomy, myomectomy, endometrial ablation, myolysis), minimally-invasive procedures (uterine artery embolization, 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 being the most common indication (Wallach 2004).  This has contributed to significant surgical morbidity and escalating healthcare costs. As such, a focus on more conservative options is required.  

Description of the intervention

Currently, there are no pharmacological agents approved specifically for the long-term treatment of uterine fibroids. The mainstay of medical management has been the use of gonadotropin-releasing hormone analogues (GnRHa) for pre-operative optimization by decreasing blood loss, correcting anaemia and reducing fibroid volume (Sabry 2012). However, the challenges with GnRHa therapy include decreased bone mineral density, vasomotor symptoms and an initial estrogen flare that may exacerbate symptoms. Although medical therapies such as combined hormonal contraceptives, oral 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. They often cause side effects sufficient to discontinue use (Ke 2009; Sangkomkamhang 2013; Van Voorhis 2009).

Traditionally estrogen has been known to be the most important hormone in stimulating fibroid growth. More recently, progesterone has also been shown to be essential in the maintenance and growth of fibroids (Ishikawa 2010). For this reason, selective progesterone receptor modulators (SPRMs) have shown promise in the treatment of uterine fibroids (Chwalisz 2005). These molecules bind to the progesterone receptor and have varying levels of antagonistic activity. SPRMs were first discovered in 1980 and mifepristone, a powerful progesterone antagonist, was the pioneer drug. Its main use has been for pregnancy termination but it has also been evaluated as a therapeutic agent for fibroids. Meta-analysis of three randomized trials showed that mifepristone is effective in reducing bleeding symptoms and improving fibroid-related quality of life, without any effect on fibroid volume (Tristan 2012).  

Other SPRMs have been subsequently developed, each with different affinity for the progesterone receptor and with varying amounts of antagonistic activity. The clinical activity of each SPRM class member reflects the subtlety of the SPRM’s spectrum of agonist and antagonist activity, along with the tissue specific expression of progesterone receptor (PR) subtypes. Asoprisnil, telapristone acetate and ulipristal acetate are SPRMs that have shown clinical effectiveness for fibroids (Donnez 2012; Sabry 2012; Wilkens 2008). 

How the intervention might work

The ‘progesterone hypothesis’ suggests that progesterone is a key hormone in the development of fibroids, by increasing the mitotic rates and reducing apoptosis of fibroid smooth muscle cells (Rein 1995). Data also suggest signalling between estrogen and progesterone receptors, where estrogen induces increased expression of the progesterone receptor in fibroid cells (Ishikawa 2010). The importance of progesterone in fibroid pathogenesis supports SPRMs as effective treatment. Fibroid cells cultured with SPRMs demonstrate inhibited proliferation and increased apoptosis, without affecting normal myometrium (Bouchard 2011). SPRMs can also down-regulate the number of growth factors and reduce collagen synthesis in cultured fibroid cells (Bouchard 2011). SPRMs act upon the uterine endometrium to provide relief of bleeding symptoms in women with fibroids.

SPRMs may be used to treat fibroids in a number of clinical scenarios. Currently, the only SPRM approved for fibroids is ulipristal acetate (Esmya®, Gedeon-Richter, Europe February 2012; Fibristal®, Watson Laboratories Inc, Canada July 2013). It was approved to treat bleeding symptoms and decrease fibroid size for up to three months prior to surgical management. Future applications may include the use of SPRMs as a long-term medical treatment of fibroid-related symptoms. This would decrease surgical intervention and the associated morbidity and costs. Long-term medical therapy would be particularly beneficial in peri-menopausal women to bridge them until menopause, when fibroids would then spontaneously decrease. Although pregnancy is contraindicated with SPRMs, there is evidence that the decrease in fibroid size is sustained after the medication has been discontinued (Donnez 2012). This may have a potential impact on fibroid-related subfertility, where medical management may reduce fibroid volume and facilitate pregnancy after SPRM discontinuation.

Why it is important to do this review

Despite the prevalence of uterine fibroids, only few high quality studies examine the effectiveness of medical therapies. With an increasing demand for less invasive fibroid therapies, the benefits and risks of medical treatments must be critically evaluated. Furthermore, women are delaying child-bearing and hence there is a need for fertility sparing therapeutic options. There is both biochemical and clinical evidence that SPRMs may decrease fibroid growth and ameliorate symptoms (Chwalisz 2005). Although a Cochrane review on mifepristone has recently been completed (Tristan 2012), the newer SPRMs still require systematic evaluation of their benefits and harms. 

Objectives

To evaluate the effectiveness and safety of selective progesterone receptor modulators (SPRMs) in the treatment of pre-menopausal women with uterine fibroids. 

Methods

Criteria for considering studies for this review

Types of studies

Data from all published and unpublished randomized controlled trials (RCTs) will be included. For cross-over studies, only data from the first phase of the trial will be included for meta-analysis. 

Types of participants

Pre-menopausal women with uterine fibroids, either with or without symptoms. The presence of fibroids must be confirmed either surgically (laparoscopy, laparotomy, or hysteroscopy) or with at least one of the following imaging modalities: ultrasound, computed tomography, magnetic resonance imaging (MRI). 

Types of interventions

Treatment with any SPRM for at least three months versus:

  • placebo;

  • no treatment;

  • another medical therapy (either another SPRM or another class of medication);

  • surgery (myomectomy or hysterectomy);

  • uterine artery embolization (UAE).

Commercially available SPRMs include, but are not limited to, mifepristone, asoprisnil, telapristone acetate (Progenta) and ulipristal acetate (Esmya, Fibristal). Additional interventions will be permitted as long as they are uniformly used in all study arms. 

Types of outcome measures

Primary outcomes

Change in fibroid-related symptoms:

  • abnormal uterine bleeding measured objectively (eg. haemoglobin, haematocrit, ferritin levels, or alkaline haematin technique) or subjectively (eg. pictorIal blood loss assessment);

  • pain and pelvic pressure measured subjectively (eg. visual analogue or Likert scales);

  • quality of life assessed with standardized and validated measures. Examples of scales that measure health-related quality of life including for women with uterine fibroids (Williams 2006) include but are not limited to: Uterine Fibroid Symptom Quality of Life Scale (Spies 2002), EuroQoL (Brooks 1996), Short Form-36 (Ware 1992).

Secondary outcomes
  • Change in fibroid or uterine size, or both, as measured by ultrasonography or magnetic resonance imaging (MRI)

  • For fibroids that completely resolved during the treatment period, the recurrence rate over time will be assessed

  • 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, nausea

Search methods for identification of studies

We will search for all published and unpublished RCTs of SPRMs used for the treatment of uterine fibroids. There will be no language restriction. The search strategy will be developed and executed in consultation with the Menstrual Disorders and Subfertility Group (MDSG) trials search co-ordinator.

Electronic searches

Since the first SPRM (mifepristone) was discovered in 1980, the literature will be searched only as far back as that date. See Appendix 1 for the detailed search strategy. We will search the following databases:

  • Cochrane MDSG Specialized Register;

  • Cochrane Central Register of Controlled Trials (CENTRAL);

  • MEDLINE;

  • EMBASE;

  • PsycINFO;

  • CINAHL;

  • other,

    • trial registers for ongoing and registered trials: www.clinicaltrials.gov,

    • in The Cochrane Library the Database of Abstracts of Reviews of Effects (DARE),

    • the Web of Knowledge http://wokinfo.com/ (another source of trials and conference abstracts),

    • 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,

    • LILACS for Portuguese and Spanish trials.

Searching other resources

We will handsearch appropriate journals recommended by the MDSG that are not captured in the above databases. We will also handsearch reference lists of relevant articles and contact experts in the field to obtain additional data. In consultation with the trials search co-ordinator, we will handsearch relevant journals and conference proceedings that are not covered in the above resources.

Data collection and analysis

Statistical analysis will be performed according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Review Manager 5.2 (RevMan 5.2) will be the software used for analysis. 

Selection of studies

Two review authors will complete the initial title and abstract screening independently. Full texts will be retrieved when studies meet the following criteria: a) use a SPRM as an intervention for the treatment of uterine fibroids, and b) have a prospective design. If any doubts exist based on these screening criteria, the full text will be retrieved. Full text articles will be excluded if there is no mention of randomization. Any disagreements in the screening process will be resolved by a third review author. The selection process will be documented in a PRISMA flow diagram.

Data extraction and management

Two authors will independently extract data from all eligible studies to be included in the review. Data will be extracted using forms that have been pilot tested by the authors. The forms will include specifics of study characteristics and outcomes data. When data from a trial have been published more than once, the authors will extract data that are additional and not repeated. Trial authors will be contacted for further clarification when required.

Assessment of risk of bias in included studies

Two authors will independently assess bias for the included studies using the Cochrane risk of bias tool (www.cochrane-handbook.org). The elements that will be assessed include: 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 will pay special attention to within-trial selective reporting where authors fail to report obvious outcomes or report with insufficient detail. Comparisons will be made to the published protocols to determine if planned outcome measures were indeed reported.  

Measures of treatment effect

The various comparisons will be analysed separately using RevMan 5.2. Dichotomous data will be reported as odds ratios (OR) with 95% confidence intervals (CI). Continuous data will be reported as mean difference (MD) with 95% CI. When outcomes are reported as continuous data on different scales, we will report a standardized mean difference (SMD) and 95% CI. 

Unit of analysis issues

The primary analysis will be per woman randomised. Change in fibroid size data will be analysed based on the number of fibroids tracked and not the number of patients (that is some patients will contribute more fibroids to the analysis than others). Data that do not allow valid analysis (for example 'per cycle' data) will be briefly summarised in an additional table and will not be meta-analysed. Only first-phase data from cross-over trials will be included.

Dealing with missing data

We will contact primary authors electronically for missing data and for clarification of any issues that may arise. Data will be analysed based on intention-to-treat analysis. When randomized patients are not all included in the analysis, we will calculate and separately report the percentage of patients lost to follow-up. In these cases, we will impute values only for the primary outcomes. For other outcomes, we will analyse only the available data.

Assessment of heterogeneity

Included trials will be evaluated to determine if the studied patients, interventions and outcomes are similar enough for us to meta-analyse them. If it is determined that the trials can be meta-analysed to yield clinically relevant results, we will then assess the trials for statistical heterogeneity. Tests for heterogeneity across studies will be performed using the Q statistic and I2 statistic. The following criteria for heterogeneity will be used: I2 < 25% is low, 25% to 50% is moderate, and > 50% is high heterogeneity (Higgins 2011). When high heterogeneity is found across any of these criteria, subgroup and sensitivity analyses will be conducted.

Assessment of reporting biases

We will aim to minimize reporting bias by completing a comprehensive search for eligible studies and by being conscious of data duplication. If we have a sufficient number of included trials (> 10), we will use a funnel plot to assess for publication bias (under-reporting of small negative studies).

Data synthesis

Data for clinically similar studies will be pooled using a random-effects model for the meta-analysis. When studies cannot be pooled, the outcomes will be described in narrative form. Different comparisons will be analysed separately:

  • all SPRMs versus placebo or no treatment;

  • all SPRMs versus alternative active therapy, stratified by the alternatives,

    • class of medical therapy,

    • type of surgical management,

    • UAE.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses may be performed based on the following.

  • 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 substantial heterogeneity is present, we will explore possible explanations including individual study risk of bias, patient population (age, ethnicity, types and sizes of fibroids), dose of SPRM, duration of treatment and follow-up.  

Sensitivity analysis

When more than five studies are included in the meta-analysis, we will perform sensitivity analysis for the primary outcomes to test the stability of our results with respect to the following:

  • exclusion of studies with high risk of bias;

  • applying a fixed-effect model;

  • exclusion of unpublished studies;

  • exclusion of trials where data were imputed for the primary outcomes;

  • exclusion of studies using unpublished rating scales or scales that have not been validated to assess for symptom relief.

Overall quality of the body of evidence: summary of findings table

A summary of findings table will be generated using GRADEpro software. The table will evaluate the overall quality of the body of evidence using GRADE criteria for the main review outcomes.  Judgments about evidence quality (high, moderate, low) will be justified, documented, and incorporated into reporting of results for each outcome. 

Acknowledgements

Many thanks to Marian Showell, Trials Search Co-ordinator with the Cochrane Menstrual Disorders and Subfertility Group, for her help in devising our literature search strategy.

Appendices

Appendix 1. Search strategy

Menstrual Disorders and Subfertility Group (MDSG) Specialized Register

Keywords CONTAINS "Leiomyoma" or "leiomyomata" or "fibroids" or "uterine leiomyomas" or "uterine myoma" or "uterine myomas" or "uterine fibroids" or "myoma"  or "myomas" or Title CONTAINS "Leiomyoma" or "leiomyomata" or "fibroids" or "uterine leiomyomas" or "uterine myoma" or "uterine myomas" or "uterine fibroids" or "myoma"  or "myomas"

AND

Keywords CONTAINS "mifepristone" or "RU486" or "selective progesterone receptor modulator" or "CDB-2914" or "asoprisnil"or "Ulipristal"or Title CONTAINS "mifepristone" or "RU486" or "selective progesterone receptor modulator" or "CDB-2914" or "asoprisnil"or "Ulipristal"

 

Cochrane Central Register of Controlled Trials (CENTRAL)

1     exp Leiomyoma/

2     fibroid$.tw.

3     fibromyoma$.tw.

4     myoma$.tw.

5     hysteromyoma$.tw.

6     Leiomyom$.tw.

7     (uter$ adj3 fibroma$).tw.

8     or/1-7

9     exp Receptors, Progesterone/

10     selective progesterone receptor modulator$.tw.

11     SPRM$.tw.

11a PRM$.tw.

12     exp Mifepristone/

13     Mifepristone.tw.

14     mifegyne.tw.

15     mifeprex.tw.

16     r38486.tw.

17     ru-38486.tw.

18     ru-486.tw.

19     Asoprisnil.tw.

20     J867.tw.

21     Telapristone.tw.

22     Progenta.tw.

23     Ulipristal.tw.

24     Ella.tw.

25     Proellex.tw.

26     CDB-4124.tw.

27     or/9-26

28     8 and 27

 

MEDLINE

1     exp Leiomyoma/

2     fibroid$.tw.

3     fibromyoma$.tw.

4     myoma$.tw.

5     hysteromyoma$.tw.

6     Leiomyom$.tw.

7     (uter$ adj3 fibroma$).tw.

8     or/1-7

9     exp Receptors, Progesterone/

10     selective progesterone receptor modulator$.tw.

11     SPRM$.tw.

11a PRM$.tw.

12     exp Mifepristone/

13     Mifepristone.tw.

14     mifegyne.tw.

15     mifeprex.tw.

16     r38486.tw.

17     ru-38486.tw.

18     ru-486.tw.

19     Asoprisnil.tw.

20     J867.tw.

21     Telapristone.tw.

22     Progenta.tw.

23     Ulipristal.tw.

24     Ella.tw.

25     Proellex.tw.

26     CDB-4124.tw.

27     or/9-26

28     8 and 27

29     randomized controlled trial.pt.

30     controlled clinical trial.pt.

31     randomized.ab.

32     randomised.ab.

33     placebo.tw.

34     clinical trials as topic.sh.

35     randomly.ab.

36     trial.ti.

37     (crossover or cross-over or cross over).tw.

38     or/29-37

39     exp animals/ not humans.sh.

40     38 not 39

41     28 and 40

 

EMBASE

1     exp leiomyoma/

2     fibroid$.tw.

3     fibromyoma$.tw.

4     myoma$.tw.

5     hysteromyoma$.tw.

6     Leiomyom$.tw.

7     (uter$ adj3 fibroma$).tw.

8     or/1-7

9     exp progesterone receptor modulator/

10     selective progesterone receptor modulator$.tw.

11     SPRM$.tw.

11a PRM$.tw.

12     exp mifepristone/

13     Mifepristone.tw.

14     mifegyne.tw.

15     mifeprex.tw.

16     r38486.tw.

17     ru-38486.tw.

18     ru-486.tw.

19     Asoprisnil.tw.

20     J867.tw.

21     Telapristone.tw.

22     Progenta.tw.

23     Ulipristal.tw.

24     Ella.tw.

25     Proellex.tw.

26     CDB-4124.tw.

27     or/9-26

28     8 and 27

29     Clinical Trial/

30     Randomized Controlled Trial/

31     exp randomization/

32     Single Blind Procedure/

33     Double Blind Procedure/

34     Crossover Procedure/

35     Placebo/

36     Randomi?ed controlled trial$.tw.

37     Rct.tw.

38     random allocation.tw.

39     randomly allocated.tw.

40     allocated randomly.tw.

41     (allocated adj2 random).tw.

42     Single blind$.tw.

43     Double blind$.tw.

44     ((treble or triple) adj blind$).tw.

45     placebo$.tw.

46     prospective study/

47     or/29-46

48     case study/

49     case report.tw.

50     abstract report/ or letter/

51     or/48-50

52     47 not 51

53     28 and 52

 

PsycINFO

1     fibroid$.tw.

2     myoma$.tw.

3     fibromyoma$.tw.

4     hysteromyoma$.tw.

5     Leiomyom$.tw.

6     (uter$ adj3 fibroma$).tw.

7     or/1-6

8     selective progesterone receptor modulator$.tw.

9     SPRM$.tw.

9a PRM@$.tw.

10     Mifepristone.tw.

11     Mifegyne.tw.

12     mifeprex.tw.

13     r38486.tw.

14     ru-38486.tw.

15     ru-486.tw.

16     Ulipristal.tw.

17     CDB-4124.tw.

18     or/8-17

19     7 and 18

Contributions of authors

All authors contributed equally in drafting and reviewing the protocol.

Declarations of interest

The authors have no commercial interests to disclose.

Sources of support

Internal sources

  • None, Not specified.

External sources

  • None, Not specified.

Ancillary