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Mifepristone 2.5, 5, 10 mg versus placebo in the treatment of endometriosis
Accepted Manuscript Title: Mifepristone 2.5, 5, 10 mg versus placebo in the treatment of endometriosis Author: Josep Lluis Carbonell Ana M. River´on Yara Leonard Jes´us Gonz´alez Braulio Heredia Carlos S´anchez PII: DOI: Reference:
S2214-420X(15)00042-X http://dx.doi.org/doi:10.1016/j.jrhm.2015.09.001 JRHM 19
To appear in: Received date: Revised date: Accepted date:
8-4-2015 31-8-2015 1-9-2015
Please cite this article as: Josep Lluis CarbonellAna M. River´onYara LeonardJes´us Gonz´alezBraulio HerediaCarlos S´anchez Mifepristone 2.5, 5, 10 mg versus placebo in the treatment of endometriosis (2015), http://dx.doi.org/10.1016/j.jrhm.2015.09.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Mifepristone 2.5, 5, 10 mg versus placebo in the treatment of endometriosis Josep Lluis Carbonell,+ Ana M. Riverón,* Yara Leonard,* Jesús González,* Braulio
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Heredia,* Carlos Sánchez* +Outpatients Major Surgery Centre, Mediterránea Médica Clinic, Valencia, Spain.
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*“Eusebio Hernández” Gynecologic-Obstetric Teaching Hospital, Havana, Cuba.
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Name and address of corresponding author:
Dr. Josep Lluis Carbonell Esteve; Mediterránea Médica Clinic; C/ Salvador Guinot, 14;
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Valencia 46017, Spain; Tel: 34 96 358 6020.
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Fax: 34 96-3785485; e-mail: [email protected]; [email protected]
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Summary Objectives: to evaluate the effectiveness and safety of 2.5, 5 and 10 mg doses of mifepristone against a placebo in women with laparoscopic diagnostic of endometriosis. Methods: double-blind, placebo-controlled study of 360 subjects randomly assigned to
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receive orally one daily tablet of 2.5, 5 or 10 mg mifepristone for 6 month, or 1 daily tablet of mifepristone placebo for 3 months, (90 in each treatment group), carried out at “Eusebio Hernández” Hospital, Havana, Cuba. Efficacy was assessed by measuring changes in
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prevalence of dysmenorrhea and changes in scores according to AFS. Safety was evaluated by the incidence of hot flushes, nausea, dizzy spells, vomiting, fatigue/tiredness, raised
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hepatic transaminases, histological alterations of the endometrium.
Results: in the mifepristone groups, the prevalence of symptoms was significantly inferior to
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those at the beginning of treatment with no significant differences between the groups of 5 and 10 mg, unlike in 2,5 mg of mifepristone and the placebo group. The scores of the AFS were significantly differents at the end of the treatment in the mifepristone groups. In the
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mifepristone groups there were 9/264 (3.4%) subjects with raised hepatic transaminases up to 99 IU. doses and placebo.
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Conclusions: mifepristone 5 mg was safer and more effective than the others mifepristone
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ClinicalTrials.gov Identifier: NCT02271958
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Introduction Endometriosis, characterized by the ectopic presence of endometrial-like glands and stroma, is a common gynecological condition with an enigmatic pathogenesis.1 There is currently no cure for endometriosis and reported recurrence rates after surgical therapy are high.2
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Approved treatments for endometriosis include hormonal therapies.3, These methods of treatment are relatively effective but their side-effects limit their effectiveness and impeding their continued use.4-6
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The progestagen dienogest has shown to be more efficacious than placebo in relieving pain associated to endometriosis and also showed a similar efficacy to GnRh in alleviating
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endometriosis main symptom.7
Bouchard et al reported that selective progesterone receptors modulators (SPRM), as mifepristone and progestagens, could reduce the growth of endometrial tissue and also
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diminish endometriosis associated pain. 8
In contrast, Brown et al, they concluded that only be present a limited evidence to support
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that the use of progestagens and antiprogestagens (gestrinone) relieves endometriosis associated pain. But, they warned that the reviewed studies are few with a scarce number of subjects, and then, that conclusion is not definitive.9
Brown et al, only analyse the
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antiprogestagen gestrinone, in their revision, they did not make any reference to the studies
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by Kettel et al, Murphy et al, where they treated endometriosis with mifepristone. 10-13 Agreeing with Bouchard et al, Prentice et al concluded that also progestagens and the
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antiprogestagens gestrinone ameliorate the pain symptoms associated to endometriosis.3 SPRMs, in general, owns an antiproliferative effect, as that has been pointed out that happens in the endometrium of primates,14 and in rodent mammary tumors.15 Mifepristone is a practically pure SPRM which its strong antiprogestagenic action is only overtaken by onapristone. Mifepristone acts being coupled to the progesterone receptors at uterine cervix level, in the endometrium, miometrio, mammary tissue, and in every site where progesterone receptors exist.
Endometriosis is considered an estrogen-dependent condition influenced by the levels of aromatase activity, whose production is markedly increased in the ectopic endometriosis implants compared with eutopic endometrium and this leads to an increase in the production of estradiol.16 Mifepristone blocks medroxyprogesterone acetate induced aromatase action in the endometrial cells.17 A study on Wistar rats using a mifepristone implant proved to be effective on endometriotic lesions.18 Several studies published by Kettel et al using 100, 50 and 5 mg mifepristone to
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treat endometriosis obtained significant reductions of pain (intensity and prevalence) and also in the dimensions of the endometriotic lesions according to the mifepristone dose used.10-13 In 2010, we carried out a pilot study using mifepristone 5 and 25 mg doses for the treatment of endometriosis. The 5 mg dose had a similar to the 25 mg regarding clinical improvement: reducing pain in 95% of cases and reducing in more than 50% the volumes of the
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endometriotic lesions according to AFS scores.19
In China, during the past decade, more than a hundred clinical trials were carried out
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including several thousands of patients using mifepristone for the treatment of endometriosis, though Sun-Wei Guo questions their results because of inappropriate protocol designs. 20
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The fact that our results confirmed, or were better than the ones reported by Kettel et al, using 5 mg-mifepristone doses led us to design a clinical study trying to get a more definitely result
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on the use of mifepristone to treat endometriosis.
The objective of this study was to evaluate the effectiveness and safety of doses of 2.5, 5 and
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10 mg mifepristone versus a placebo for the treatment of endometriosis.
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Material and methods This is a double-blind randomized clinical trial, with 3 mifepristone treatment groups and one placebo group to evaluate efficacy and safety in the treatment of endometriosis. The study was approved by the Ethics and Science Committee at the “Eusebio Hernández” teaching
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hospital in Havana, Cuba and carried out in accordance with the Declaration of the XVIII and XLI World Medical Assembly of Helsinki (1964) and last modified by the Tokyo Assembly (2004). At the recruitment visit, subjects were informed the pros and cons and possible side-
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effects of the treatment. Examinations undertaken
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Before treatment, for all patients, thorough gynecological and pelvic ultrasound examinations for endometrioma and diagnostic laparoscopy were performed to determine localization, extent and severity of the endometriotic lesions; a score was assigned according to the revised
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American Fertility Society (AFS) classification.21 Blood samples were taken for hematological tests and hepatic function. Before treatment, endometrial biopsy was
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performed if endometrial thickness, measured at any moment of the menstrual cycle, by ultrasound was >8 mm or if an abnormal bleeding had occurred in the past 3 months. At 90 and 180 days of treatment ultrasound examination for endometrioma of the pelvis was
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undertaken; when treatment ended a diagnostic-therapeutic laparoscopy and endometrial
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biopsy were performed. All our operators are more than sufficiently trained in gynecological investigation, both on ultrasonography or surgical techniques; they were blinded to the
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experimental protocol. Subjects
Women with laparoscopic confirmed endometriosis who volunteered to take part in the study. Inclusion criteria: a) age 18 to 45, b) patients with dysmenorrhea or pelvic pain not attributable to other gynecological illness and c) acceptance of using barrier contraceptive methods during treatment. Exclusion criteria: a) breastfeeding, b) hormonal or surgical therapies less than 4 months previous to study, c) diabetes, d) severe arterial hypertension, e) hepatopathy, renal malfunction, endocrinopathy, and f) any contraindication about the use of antiprogestins. Products used The mifepristone was supplied by Zizu Pharma Laboratories, Beijing, China for the first 91 subjects, and by Litaphar Laboratories, Azpeitía, (Guipúzcoa, Basque Country), Spain for patients 92 to 360 .
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Treatment Group I: 2.5 mg mifepristone per day for 6 months; Group II: 5 mg mifepristone per day for 6 months; Group III: 10 mg mifepristone per day for 6 months, Group IV: a mifepristone placebo daily for 3 months. The mifepristone was prepared in tablets containing 2.5, 5, 10 mg
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or a mifepristone placebo. All tablets had the same shape, size and color and were taken orally. There were evaluation visits every 30 days until the end of the study.
The main variables in evaluating efficacy were the changes in prevalence of dysmenorrhea and
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the average reduction in its intensity. Other variables used were: a) changes in AFS scores, b) changes in AFS stages, c) changes in the dimensions of the endometriotic lesions detectable by
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ultrasound and d) change in prevalence and intensity of symptoms of endometriosis. The intensity of each symptom was evaluated by means of a visual scale from 0 to 10 where 0
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represented absence of symptoms and 10 their maximum intensity being indicated by the subject herself. The endometriotic lesions volume was calculated, approximately, by the formula 0.524xAxBxC where A, B, C, represent the diameters of a spheroid in each of the three
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dimensions.
The variables to evaluate safety were incidences of: a) hot flushes, b) nausea, c) dizziness, d) vomiting, e) fatigue/tiredness, f) raised hepatic transaminases (ASAT and ALAT, with reference
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values 46 and 49 IU, respectively) evaluated at the beginning, after 3 months and at the end of
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treatment, h) changes in endometrial thickness measured at the beginning, at 90 days and at the end of treatment, and i) presence of PAEC (progesterone associated endometrial changes),
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evaluated by means of an endometrial biopsy. Amenorrhea was considered to be absent when spotting lasted more than 5 days or when light bleeding lasted more than 1 day. The methodology undertaken to diagnose PAEC in the current study was as follows: between 3 and 10 days after treatment cessation, an sample of endometrium tissue was taken and the histological obtained images were interpreted according to the criteria referred by Mutter et al
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and Horn and Blithe
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, who consider that a PAEC is present when the
following histological sings are observed: cystic dilation of the endometrial glands, thickened vessels, and an existing alteration of the proportion between the parenchyma and stroma in a way that may be interpreted as a simple endometrial hyperplasia. The differences between PAEC and simple endometrial hyperplasia have been widely described by Mutter et al and Horn and Blithe.
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Women were asked, prior and after treatment, with a visual scale with the following questions: “How do you think endometriosis affects your quality of life?” and “How do you
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think endometriosis affected your quality of life during treatment” on a scale of 0 to 10 where “0” symbolized “nothing” and “10” “the highest value for her”. Assignation to treatment Subjects were assigned to each treatment group according to a random list obtained from the
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MEDSTAT 2.1 program, Jan 1989, Copenhagen, Denmark, DOS Software. Staff unrelated to the study prepared opaque sealed envelopes containing a card indicating the treatment group to which the patient was assigned: 1) “mifepristone A” or 2) “mifepristone B” or 3)
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“mifepristone C” or 4) “mifepristone D”. Each of these groups corresponded to mifepristone doses of 2.5, 5, 10 mg or the placebo, respectively. Neither doctor nor subject knew which
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treatment had been chosen. After 90 days of treatment, the monitor informed the researchers which women had finished their part in the study because they belonged to the placebo group,
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and the established end of treatment procedure was activated for them. Determination of the number of subjects to be included
The intensity of pre-treatment dysmenorrhea was the variable which determined the number
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of subjects to be included. We assumed that by administrating 2.5 mg of mifepristone an average reduction of 4 points in dysmenorrhea intensity would be obtained and a 2 point reduction in the case of the placebo, taking an average intensity value of 8 points as starting
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point, this being taken from our previous study. According to G*Power,24 and based on the
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previous projections, with four treatment groups, to guarantee a power of 90% in a two-tailed, 0.05 significance level test, with a 25% average effect size, a minimum sample size of 232
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subjects was required for the complete study, 58 in each treatment group. The total size of the sample was increased in 35% (360 subjects totally, 90 in each group) in order to offset subject dropout. As it was a typical ANOVA clinical trial we calculate on the basis of a minimum power of 0.90, because for values below 0.90 a greater risk of not detecting the statistical differences desired had to be accepted. The results are shown as frequencies, percentages, means and 95% confidence intervals, standard deviations and maximum and minimum values in each variable when it was the case. We used Pearson’s Chi-square test and the one-way ANOVA to assess differences among the treatment groups and the Bonferroni correction as post hoc test. The Student’s ttest for paired samples was used to evaluate changes in intensity of symptoms of endometriosis and scores according to the AFS in each treatment group. The changes of stages according to the AFS were analyzed by McNemar’s test. In all cases p<0.05 was significant and all statistical tests were two-tailed.
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Results Inclusion and compliance with protocol The study began on November 30th 2011; the last subject was included in March 2014 and completed treatment in October 2014. In all, 373 women were referred to the clinical trial
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consultancy. Laparoscopy failed to discover endometriosis in two of them, 1 had adenomyosis and the other had several fibroids. Eleven subjects previously treated for infertility due to endometriosis were not included because 8 of them were pregnant and the
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other 3 had recently give birth. In total, we included 360/373 (96.5%) subjects out of the possible candidates. In total, there were 68/360 (18.9%) infertile women included in the study
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with not significant differences among the treatment groups. After 3 months treatment, as planned, the participation of the placebo group came to an end.
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All told, 15 subjects had received hysterectomies as part of their treatment for endometriosis, but the initial laparoscopy before inclusion confirmed the persistence of the condition and the doctors decided to include them. Five subjects also presented endometriosis in the scar of
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previous episiotomies and in the rectal and pararrectal region.
Of the subjects who completed the study protocol in the 2.5, 5, 10 mg and placebo groups, 4/86 (4.7%), 4/90 (4.4%), 5/88 (5.7%) and 17/89 (19.1%), respectively, refused to undergo
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final post-treatment laparoscopy.
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the final laparoscopy (“second look”). In total 29/360 (8.1%) subjects refused to undergo the
Homogeneity of the treatment groups
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Table 1 shows the general characteristics of the subjects by treatment groups. The distribution of the AFS stages of endometriosis before treatment by group showed no significant differences between them, p = 0.924. The average scores in the subject’s perception of how endometriosis affected her quality of life were: 8.2 points in the 5 mg mifepristone group; 8.1 points in the 2.5 and 10 mg groups, respectively, and 7.8 points in the placebo group, p = 0. 613.
All told, dysmenorrhea, dyspareunia and inter-menstrual pelvic pain occurred in 341/360 (96.7%), 233/360 (64.7%) 217/360 (60.3%) of all subjects included, respectively. Other symptoms were the voiding syndrome 69/360 (19.2%) and intestinal upsets experienced by 117/360 (32.5%) subjects, respectively. In no case there were significant differences between treatment groups. Nor did average intensities in pelvic pain, urinary disorders, dysmenorrhea, dyspareunia and intestinal upsets present significant differences between treatment groups. The average pre-treatment hemoglobin levels did not register significant differences between treatment groups and distribution of the two hepatic transaminases studied (ASAT and
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ALAT) did not differ significantly between groups. We performed 38/360 (10.6%) endometrial biopsies prior to treatment. All in all, 22/38 (57.9%) cases of secretory endometrium were diagnosed, 10/38 (26.3%) cases of proliferative endometrium, 4/38 (10.5%) cases of physiological disorders in endometrial maturity, and 2/38 (5.3%) cases
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which were not useful diagnostically, with no significant differences between the groups, p = 0.1.
Table 2 shows the prevalence of symptoms of endometriosis before, at 3 months and at the
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end of treatment by groups. Prevalence of pelvic pain was significantly greater in the 2.5 mg group than in the 5 and 10 mg groups, p = 0.007. Dyspareunia and intestinal upsets were
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significantly more frequent in the 2.5 group than in the 5 mg group, p = 0.023 and p = 0.013, respectively. Amongst the subjects who took mifepristone, symptom intensity, in those
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subjects still suffering them, was slightly inferior to those at the beginning but there were no significant differences between groups. Amongst those taking the placebo, symptom intensity was the same to those of pre-treatment.
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Incidence of treatment side effects reported by subjects after 3 and 6 months by groups is shown in table 3. There were significant differences in frequency of tiredness and fatigue between the 5 and 10 mg mifepristone groups, p = 0.009.
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In total, in the groups that received mifepristone there were 9/264 (3.4%) subjects with raised
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hepatic transaminases; the highest values registered were 81 and 99 IU for ASAT and ALAT, respectively. In the placebo group, at the end of treatment, there were 3/89 (3.4%) subjects IU.
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with raised ASAT (maximum value 53 IU) and 1/89 (1.1%) subjects with ALAT rose to 53 In the placebo group there were no differences between the average values, before and after treatment, in the volumes of the endometriomas, p = 0.376; the endometrial thickness was significantly greater than before treatment: 6.0 ± 1.6 vs 11.2 ± 5.0 mm, respectively, p < 0.001. The measurements of endometrial thickness and endometriomas at the end of treatment in the mifepristone groups were significantly different between the 2.5 and 10 mg mifepristone groups, p = 0.045.
Focal points of endometriosis were observed in the second look laparoscopy in all subjects in the placebo group. Before treatment started, 15/72 (20.8%) subjects were at stage I and at the end 19/72 (26.4%) subjects had reached this point. All told, at the end of treatment, we observed percentage distributions of the stage similar to those at the beginning. In the 2.5 mg group no focal points of endometriosis were observed in 3/82 (3.7%) in the second look laparoscopy. In general, there were significant changes towards less advanced
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stages of endometriosis, p = 0.002. Before treatment there were 17/82 (20.7%) subjects at stage 1 and on termination there were 19/82 (23.2%) subjects. In 1/86 (1.2%) subject who received 5 mg mifepristone, focal points of endometriosis were not detected in the second look laparoscopy.
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Regarding final scores by AFS, a significant difference was only observed between the 2.5 and 5 mg groups, p = 0.023. In every treatment groups, but the 2.5 mg dose (p=0.761), the final AFS scores were significantly lower than before, p<0.001(5 mg), p<0.001 (10 mg) and
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p=0.003 (placebo), respectively.
Changes in stage with respect to the beginning were significant and tended towards earlier
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ones, p < 0.001. At the beginning of treatment there were 19/86 (22.1%) subjects at stage 1 and at the end this figure increased to 35/86 (40.7%) subjects. In 9/83 (10.8%) subjects
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treated with 10 mg mifepristone, focal points of endometriosis were not detected in the second look laparoscopy. Changes towards less advanced stages of the condition with respect to the beginning of treatment were significant, p < 0.001. At the beginning of treatment there
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were 18/83 (21.7%) subjects at stage 1 and at the end this had increased to 21/83 (25.3%) subjects.
Concerning the issue on how each subject evaluated the way in which endometriosis affected
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her quality of life it was obtained very significant differences, p < 0.001, between all
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mifepristone groups compared with the placebo group. There were also significant differences between the 2.5 and 5 mg groups, p < 0.001, and between the 2.5 and 10 mg
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groups, p < 0.001; between the 5 and 10 mg groups there were no significant differences, p = 1.000.
We performed 57/86 (66.3%) endometrial biopsies at the end of treatment in the placebo group; in 3/57 (5.3%) the presence of cystic glands was diagnosed; the remaining diagnoses were secretory endometrium in 33/57 (57.9%) or proliferative endometrium in 21/57 (36.8%) subjects. Table 4 shows 225 endometrial biopsies at the end of treatment with known results in the mifepristone groups; PAEC was diagnosed in 13/66 (19.7%), 8/82 (9.7%) and 10/77 (13.0%) subjects in the 2.5, 5 and 10 mg mifepristone groups, respectively, p > 0.05.
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DISCUSSION It was a positive fact that it was possible to include 360/373 (96.5%) subjects of those available to participate that is an indicator of a high external validity. The fact that no violations of the random list occurred and that all treatment groups were homogenous
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guaranties a good internal validity. This is the first study on the use of mifepristone versus placebo to treat endometriosis. A negative matter was that it was not mandatory to perform biopsies on the endometrial lesions, it is known that a third of endometrial lesions are not
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histologically confirmed.25. Another negative point was not implementing post-treatment follow-up periods and thus not evaluating the possible rates of recurrence and pregnancies.
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The test on the subject’s perception of quality of life revealed an interesting practical soundness and the scores obtained in all treatment groups coincide with the average high
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intensities of dysmenorrhea, displaying a distinct drop in post-treatment scores in the 3 mifepristone groups with a clear statistical significance with respect to the placebo group where the opposite result was found.
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Regarding pre-treatment prevalence of symptoms, there were no differences between the groups nor in the intensity of these symptoms except in dyspareunia in favor of the 5 mg group with respect to the placebo group and in intestinal upsets in favor of group 1 with
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respect to group 3 and group 2 with respect to group 4.
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The conclusions achieved by Brown et al in their systematic revision on the use on progestagens and antiprogestagens to treat endometriosis are not valid for mifepristone
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because the only progestagen analyzed in 4 papers is the gestrinone, and even more, doing a careful lecture of such articles, 2 of them concluded that the gestrinone had a similar efficacy to danazol and to GnRH analogues regarding improvement of endometriosis associated pain and/or dysmenorrhea.26,
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Mifepristone was not studied in such papers, then their
conclusions are not pertinent to the same. Furthermore, such studies did not analyze the efficacy of dienogest in deep, there is included only one article on its use. Dienogest is already approved, in several countries, as a specific treatment for endometriosis achieving a higher efficacy than other antiprogestagens marketed. 7, Up to date, the continued usage, or not, of oral contraceptives is one of the most therapeutics options used for endometriosis, and the combination most used is dienogest + etinilestradiol, only in those countries where are available such commercial presentation. Nowadays, we are carrying out a clinical trial on the use of mifepristone versus dienogest + etinilestradiol to treat endometriosis.
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Guo SW et al, did a wide revision of 104 out of 160 clinical trials carried out in China, in the past decade, using mifepristone to treat endometriosis. They cannot conclude that mifepristone is a valid treatment for endometriosis, mainly due to the low quality of the methodological design of those high number of trials which included 10 003 subjects who
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received mifepristone for endometriosis. Many of such studies administered mifepristone, before or after surgery with no control group in every case being impossible to determine if the improvement was due to mifepristone, surgery or both.
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Nevertheless, two of those studies performed by Li Dan and by Li Xiao et al, administered 12.5 and 10 mg mifepristone dose during 6 months, respectively, after surgery contrasting to
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a control group whose patients only received surgery without administering mifepristone afterwards and the results were significantly higher in both mifepristone groups regarding
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clinic improvement and lower rates of recurrence. 28, 29
In our opinion, it is hardly difficult to assume that mifepristone is not efficient as a treatment for endometriosis after being carried out 160 clinical trials in a 15 years period counting 15
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000 women. Other issue to allow for is that Chinese researches lack from knowledge on research methodology; in fact Guo himself his doubts on this matter in his paper. The results achieved in the 5 and 10 mifepristone groups widely agreed and confirmed the
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ones obtained in our first study using mifepristone 5 and 25 mg as well as for the decrease of
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dysmenorrhea and the sizes of the endometriotic lesions according to AFS scores. That agree is also valid regarding side effects as hot-flushes, liver enzymes, etc. 19
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Although in lesser extension, our results partially are alike with those obtained by Kettel et al in the study where they used only mifepristone 5 mg for endometriosis during 6 months; in it 6/7 (85.7%) women had significant improvement of pelvic pain; we obtained a 90% of improvement/eradication of such pain. 12 With respect to diminish of the AFS score comparing with the pretreatment values, there were a reduction of 2 scores (10 ± 3.2 to 8 ± 1.2 ) in the study by Kettel et al that presumably was not significant due to the scarce number of subjects included; analyzing them separately, it could be observed that half of them experienced 45% and 32% in the values of the AFS scores. 10-13 Apparently, the results of the studies by Kettel et al are contrary to ours, but this is relative. For example, in their first study using a high dose of mifepristone (100 mg) one subject had a complete disappearance of the endometriotic lesions at the second-look laparoscopy. 10 Nonetheless, the criterion used in this study to evaluate the decreasing of the endometriotic lesions was the change of AFS stage, nevertheless this criterion could be inaccurate because a
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subject starting treatment with a score of 39 (AFS stage III) and after treatment cessation has a score of 17, remains in the same stage of AFS but had diminished the severity of her illness in 16 points indicating an improvement in endometriosis. We feel that the criterion to evaluate improve should be the score and not the stage.
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By last, in the study of Kettel et al, where they use 50 mg of mifepristone they obtained a 55% reduction in endometriotic lesions. Besides, in studies by Kettel they obtained significant decreases of pain, independently of the mifepristone dose used. 11
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Effectiveness
All mifepristone treatment groups were more effective than the placebo group. After 90 and
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180 days of treatment there were no differences between 5 and 10 mg doses which behave similarly with regard to clinical improvement. There is, however, a statistically significant
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difference in favor of groups 2 and 3 with respect to the 2.5 mg group 1, regarding the improvement of all symptoms.. This difference concurs with the significantly greater use of
Amenorrhea and bleeding pattern
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analgesics sustained by the subjects in group 1.
Amenorrhea in the 2.5 mg group was significantly inferior than in groups 2 and 3, therefore those subjects present longer and more intense bleeding and the percentage of subjects who
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do not bleed at all was significantly inferior in the 5 and 10 mg groups. This is less
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comfortable for the subjects in group 1. Since amenorrhea set in slower in group 1 and attained percentages inferior to those in groups 2 and 3, bleeding was heavier both in
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frequency and duration. The same applies to clinical improvement, which took longer and was less intense than in the other groups. Scores and AFS stages
Aside from the placebo group, all groups experienced significant improvements, both in the average AFS score as well as in a change of stage with respect to that of pre-treatment; the 2.5 mg dose was less effective than the 5 and 10 mg groups. The fact that there is no change in stage does not mean mifepristone was not effective; e.g., a subject scoring 130 AFS, who on termination of treatment got a score of 46 points, has improved by 84 points, yet continues to be in stage IV as before treatment.. In the 10 mg group, out of 19 cases starting off in stage 3 only 1 experienced a change in stage, the other 18 remaining in it, having a significant reduction in AFS score dropping from 28.4 at start to 19.5 points at the end. Summarizing, the 5 and 10 mg groups behave very similarly.
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Hepatic Toxicity Elevated transaminase levels were similar in the three mifepristone groups and of neither little clinical importance, never rising above 100 IU nor 5% in frequency of appearance. However, in any treatment with mifepristone it is always necessary to monitor them.
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Hot Flushes In this study we saw significant differences between the mifepristone groups concerning hot flushes brought on by the 10 mg dose being more numerous than in the 5 and 2.5 mg groups.
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In the 2.5 and 5 mg groups the hot flushes, when they appeared, were of low intensity (1 to 4 points, visual analogue scale of 1 to 10), short duration (< l.5 minute), once a day, and usually
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at night. In the 10 mg group the hot flushes were more frequent, longer (≥ 1.5 minute), of greater intensity (5 to 9 points, visual analogue scale) and occurring several times within 24
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hours. Other side effects
Nausea, vomiting, etc., are similar in the 3 mifepristone treatment groups and compatible
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with publications to date, their scores always low and compatible with an orally-administered medicine. Fatigue and tiredness, even with low absolute scores, are significantly superior in
Endometrial thickness
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the 10 mg group, p < 0.001 and p = 0.024, after 3 and 6 months, respectively.
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With respect to endometrial thickness there are no significant differences at the end of treatment between the 4 groups, including the placebo group, probably because the timing of
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the ultrasound examination in this last group coincides with the perimenstrual period. The difference between the mean endometrial thickness before and after treatment is due to the mifepristone effect in groups 1, 2 and 3 and to menstruation in the placebo group. Summarizing, our results, improvement of illness and low incidence of side effects, are similar to those obtained in our previous study, and partially compatible with those of Kettel et al, with the exception of one case of the study of Kettel et al when they used mifepristone 50 mg where the liver transaminases rise from 21 and 28 IU to 199 and 499 IU, respectively16 In our studies on the use with the same dose of 5 mg of mifepristone to treat uterine fibroids we have obtained similar results regarding nausea, vomiting, hot-flushes, tiredness, alterations of liver enzymes, endometrial thickness, PAECs, etc. 30-35 It is remarkable and contradictory that mifepristone causes the shrinking of endometrial foci and eutopic endometrium is thickened in a significant percentage of cases. This is probably due to histological, metabolic differences, , etc., at cellular level. Endometrial histology
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No case of endometrial hyperplasia was diagnosed and PAEC22, 23 ,36 (progesterone associated endometrial changes) percentages did not present any statistical significance between groups. Conclusions The three mifepristone treatment groups display a noticeable therapeutic superiority over the
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placebo group. The 5 and 10 mg doses present a similar therapeutic efficacy but the 5 mg group has less side effects. The 2.5 mg group presents significantly lower percentages of amenorrhea and clinical improvement than the 5 and 10 mg groups. The 5 mg dose proved to
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be efficacious and safe and should be the studied in future trials on endometriosis in which mifepristone should contrasted with another medications approved to treat endometriosis
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such as: dienogest, GnRh analogues, oral contraceptives, etc.
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Bibliography 1. Giudice LC, Kao LC. Endometriosis. Lancet 2004;64:24-35. 2. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update 2009;15:441– 61. with endometriosis. Cochrane Database Syst Rev 2000;2:CD002122.
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3. Prentice A, Deary AJ, Bland E. Progestagens and anti-progestagens for pain associated 4. Winkel CA, Scialli AR. Medical and surgical therapies for pain associated with
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endometriosis. J Womens Health Gend Based Med 2001;10:137–62.
5. Mounsey AL, Wilgus A, Slawson DC. Diagnosis and management of endometriosis. Am
us
Fam Physician 2006;74:594–600.
6. Selak V, Farquhar C, Prentice A, Singla AA. Danazol for pelvic pain associated with
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endometriosis. Cochrane Database of Syst Rev 2007;Issue 4. Art. No.: CD000068. DOI: 10.1002/14651858.CD000068.pub2.
7. Strowitzki T, Faustmann T, Gerlinger C, Seitz C. Dienogest in the treatment of
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endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebocontrolled study. Eur J Obstet Gynecol Reprod Biol. 2010 Aug;151(2):193-8. 8. Bouchard P, Chabbert-Buffet N, Fauser BC. Selective progesterone receptor modulators
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2011;96(5):1175-89.
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in reproductive medicine: pharmacology, clinical efficacy and safety. Fertil Steril. 9. Brown J, Kives S, Akhtar M. Progestagens and anti-progestagens for pain associated with
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endometriosis. Cochrane Database Syst Rev. 2012 Mar14;3:CD002122. 10. Kettel LM, Murphy AA, Mortola JF, Liu JH, Ulmann A, Yen SS. Endocrine responses to long-term administration of the antiprogesterone RU486 in patients with pelvic endometriosis. Fertil Steril. 1991 Sep;56(3):402-7. 11 Kettel LM, Kettel M, Murphy AA, Morales AJ, Ulmann A, Baulieu EE, Yen SSC. Treatment of endometriosis with the antiprogesterone mifepristone (RU 486). Fertil Steril 1996;65:23-8.
12. Kettel LM, Murphy AA, Morales AJ, Yen SSC, Adamson RGD, Powers TW. Preliminary report on the treatment of endometriosis with low-dose mifepristone (RU 486). Am J Obstet Gynecol 1998;178:1151-6. 13. Álvarez-Murphy A, Castellano PZ. RU 486: pharmacology and potential use in the treatment of endometriosis and leiomyomata uteri. Curr Opin Obstet Gynecol 1994;6:269-78. 14.
Spitz IM. Progesterone
receptor antagonists. Curr Opin Investig Drugs.
2006;Oct;7(10):882-90. Review.
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15 Wiehle RD, Christov K, Mehta R. Anti-progestins suppress the growth of established tumors induced by 7,12-dimethylbenz(a)anthracene: comparison between RU486 and a new 21-substituted-19-nor-progestin. Oncol Rep. 2007;18(1):167-74. 16. Arici A. Endometriosis. Semin Reprod Med 2003;21(2).
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17. Tseng L, Mazella J, Sun B. Modulation of aromatase activity in human endometrial stromal cells by steroids, tamoxifen and RU 486. Endocrinology. 1986;118(4):1312-8.
18. Mei L, Bao J, Tang L, Zhang C, Wang H, Sun L, et al. A novel mifepristone-loaded
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implant for long term treatment of endometriosis: In vitro and in vivo studies. Eur J Pharm Scie 2010;39:421-7.
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19. Carbonell JL, Perera O, Riverón AM, González J, Tomasi G. Treatment of endometriosis using 5 mg or 25 mg daily dosage of mifepristone over 6 months. Double-blind random
an
clinical trial. Prog Obstet Gynecol 2012;55(2):51-9.
20. Guo SW, Liu M, Shen F, Liu X. Use of mifepristone to treat endometriosis: a review of clinical trials and trial-like studies conducted in China. Women Health 2011;7(1):51-70.
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21. Revised American Fertility Society for Reproductive Medicine Classification of Endometriosis: 1996. Fertil Steril 1996;67(5):817-21.
22. Mutter G, Bergeron C, Deligdisch, Ferenczy A, Glant M, Merino M, Williams ARW,
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Blithe DL. The spectrum of endometrial pathology induced by progesterone receptor
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modulators. Mod Pathol 2008;21:591-8.
23. Horne FM, Blithe DL . Progesterone receptor modulators and the endometrium: changes
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and consequences Hum Reprod Update 2007;13:567-80. 24. Faul F. G*Power [computer program]. Version 3.0.10. Kiel: Universitat Kiel. Germany. 25. Stegmann BJ, Sinaii N, Liu S, Segars J, Merino M, Nieman LK, Stratton P. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertil Steril 2008;89:1632-6 26. Bromham DR, Booker MW, Rose GL, Wardle PG, Newton JR. A multicentre comparative study of gestrinone and danazol in the treatment of endometriosis. Journal of Obstetrics and Gynaecology 1995;15:188–94. 27. The Gestrinone Italian Study Group. Gestrinone versus a gonadotropin releasing hormone agonist for the treatment of pelvic pain associated with endometriosis: a multicenter, randomised, double-blind study. Fertility and Sterility 1996; 66:911–9. 28. Li X, Liu WM. Efficacy of the combined laparoscopy and mifepristone in the treatment of endometriosis. J. Med. Forum 2006; 27, 89-90.
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29. Li D, The clinical investigation on the effects of mifepristone for endometriosis after surgery. Chin. J. Mod. Drug Appl. 2009;3,84 30. Carbonell J. LL. Et al. Mifepristone for the treatment of uterine leiomyomatas. A ramdom controlled trial. Obstetrics & Gynecology. Voll 112,nº 5, Novemver 2008
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31. Carbonell JL, Acosta R, Pérez Y, Campos R, Valle A, Sánchez C. Treatment of uterine myoma with 5 or 10 mg mifepristone daily during 6 months, post-treatment evolution over 12 months. Double blind randomized clinical trial. Eur J Obstet Gynecol Reprod Biol. 2012
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Apr;161(2):202-8
32. Carbonell JL, Riverón AM, Cano M, Ortiz AI, Valle A, CS Texidó, Tomasi G.
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Mifepristone 2.5 mg versus 5 mg daily in the treatment of leiomyoma before surgery. Randomized clinical trial. Internat J Women Health 2012;4:75-84.
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33. Carbonell JL, Acosta R, Pérez Y, Campos R, Valle A, Sánchez C Safety and effectiveness of different dosage of mifepristone for the treatment of uterine fibroids: a double-blind randomized clinical trial. International J. of Women’s Health 2012;4:1–10.
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34. Carbonell JL, Acosta R, Pérez Y, et al. 5 mg mifepristone daily versus placebo for 3 months to treat uterine myomas. Double blind randomized clinical trial. International Journal of Women’s Health 2013:5
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35. Carbonell JL, et al. Treatment of uterine myoma with 2.5 or 5 mg mifepristone daily
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during 3 months with 9 months post-treatment follow-up. Randomized clinical trial. ISRN Obstetrics and Gynecology. Volume 2013
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36. Baird DT, Brown A, Critchley HOD, Williams AR, Ling S, Cheng L. Effect of long-term treatment with low-dose mifepristone on the endometrium. Hum Reprod 2003;18:61-8.
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Table 1 General characteristics and gyneco-obstetric history of subjects included by treatment group Group
N
Average
SD
CI 95%
Min
Max
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Characteristics
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2.5 mg 90 31.6 7.0 30.1 - 33.1 19 49 5 mg 90 31.4 6.3 30.0 - 32.7 20 46 Age(years) 10 mg 90 33.4 7.0 31.9 - 34.9 19 47 Placebo 90 31.9 7.1 30.4 - 33.4 20 48 2.5 mg 90 61.3 10.8 59.1 - 63.6 46.0 97.0 5 mg 90 61.3 9.9 59.2 - 63.4 40.0 97.0 Weight (kg) 10 mg 90 61.1 11.5 58.6 - 63.5 46.0 97.0 Placebo 90 60.3 11.4 57.9 - 62.7 40.0 110.0 2.5 mg 90 1.61 .1 1.60 - 1.62 1.50 1.75 5 mg 90 1.62 .1 1.61 - 1.63 1.51 1.75 Height (m) 10 mg 90 1.62 .1 1.60 - 1.63 1.45 1.85 Placebo 90 1.61 .1 1.60 - 1.62 1.48 1.81 2.5 mg 90 23.6 3.8 22.8 - 24.4 17.3 34.9 5 mg 90 23.4 3.5 22.7 - 24.2 16.2 35.8 BMI+ 10 mg 90 23.4 4.1 22.5 - 24.3 15.5 36.1 Placebo 90 23.3 4.0 22.4 - 24.1 16.2 41.4 2.5 mg 90 1.4 1.7 1.8 - 1.8 0 8 5 mg 90 1.8 2.0 1.3 – 2.2 0 9 Pregnancies 10 mg 90 1.7 2.2 1.3 - 2.2 0 12 Placebo 90 2.1 2.3 1.6 - 2.6 0 10 2.5 mg 90 .3 .52 .2 - .4 0 2 5 mg 90 .3 .6 .2 - .4 0 2 Deliveries 10 mg 90 .5 .7 .3 - .6 0 3 Placebo 90 .4 .7 .3 - .6 0 3 2.5 mg 90 .8 1.2 .5 - 1.0 0 5 5 mg 90 1.1 1.6 .7 - 1.4 0 8 Abortions 10 mg 90 1.0 1.6 .7 - 1.3 0 10 Placebo 90 1.0 1.5 .7 - 1.4 0 8 2.5 mg 19 41 48 17 - 65 7 228 Endometriomas 5 mg 14 50 45 24 - 77 4 187 (cc)* 10 mg 17 51 59 21 - 81 4 203 Placebo 16 42 48 15 - 68 3 187 2.5 mg 82 7.2 2.0 6.7 - 7.6 3 11 Endometrial 5 mg 88 5.8 1.7 5.5 - 6.8 3 14 thickness 10 mg 88 6.8 2.4 6.3 7.3 3 20 (mm) Placebo 87 6.0 1.6 5.7 - 6.4 1 11 2.5 mg 90 28.1 29.0 22.0 - 34.3 1 128 5 mg 90 29.3 30.0 23.0 - 35.5 1 131 AFS score 10 mg 90 29.3 31.2 22.8 - 35.9 1 134 Placebo 90 26.1 25.4 20.7 - 31.3 1 105 *cc= cubic centimeters, measured and detected by ultrasound; + Body mass index; SD= standard deviation
Page 19 of 22
Table 2
Prevalence of symptoms of endometriosis before, after 3 months and at the end of treatment by groups. Data are presented as n(%)
2.5 mg
97 (96.8) 35 (39.3)
59 (65.6) 17 (19.1)
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Dysmenorrhea 82 (91.1) 88 (97.8) 85 (94.4) Before 9 (10.2) 1 (1.1) 1 (1.1) 3 months 4 (4.6) 5 (5.6) 4 (4.7) 6 months Dyspareunia 55 (61.1) 53 (70.0) 56 (62.2) Before 10 (10.4) 1 (1.1) 3 (3.4) 3 months 6 (7.0) 1 (1.1) 2 (2.3) 6 months Pelvic pain 51 (56.7) 59 (65.6) 61 (67.8) Before 14 (15.9) 1 (1.1) 3 (3.4) 3 months 10 (11.6) 7 (7.8) 2 (2.3) 6 months Urinary (urinary retention, neurogenic dysfunction, etc.) 18 (20.0) 16 (17.8) 19 (21.1) Before 3 (3.4) 0 (0.0) 1 (1.1) 3 months 3 (3.5) 1 (1.1) 0 (0.0) 6 months
p
Placebo
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Treatment groups 5 mg 10 mg
d
0.717 <0.001 0.089
46 (51.1) 36 (40.4)
0.259 <0.001 <0.001
16 (17.8) 4 (5.0)
0.822 0.150 0.202
Intestinal (diarrhea, constipation, etc) 23 (25.6) 30 (33.3) 35 (38.9) 29 (32.2) Before 5 (5.7) 0 (0.0) 2 (2.3) 3 (3.4) 3 months 7 (8.1) 1 (1.1) 0 (0.0) 6 months % calculated over the number of subjects completing each treatment period
0.276 0.074 0.005
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0.644 <0.001 0.867
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Symptoms
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Table 3 Incidence of mifepristone side effects after 3 months and 6 months treatment by groups p <0.001 0.868
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Symptoms 2.5 mg 5 mg 10 mg Placebo Amenorrhea 63 (78.7) 88 (97.8) 88 (98.9) 1.1 3 months 67 (85.9) 78 (88.6) 77 (87.5) 6 months Hot flushes 16 (18.9) 19 (21.1) 31 (34.8) 1 (1.1) 3 months 13 (15.1) 15 (16.7) 19 (21.6) 6 months Nausea 0 (0.0) 1 (1.1) 3 (3.4) 0 (0.0) 3 months 2 (2.3) 1 (1.1) 1 (1.1) 6 months Vomiting 1 (1.1) 0 (0.0) 1 (1.1) 0 (0.0) 3 months 1 (1.2) 0 (0.0) 1 (1.1) 6 months Fatigue / Tiredness 5 (5.7) 0 (0.0) 9 (10.1) 0 (0.0) 3 months 6 (7.0) 0 (0.0) 13 (14.8) 6 months % calculated over the number of subjects completing each treatment period
0.109 0.755 0.383 0.894
<0.001 <0.001
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<0.001 0.505
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Table 4
Proliferative endometrium PAEC Secretory endometrium
10 mg 4 4.7 37 43.0 10 11.6 30 34.9 5 5.8 86
100.0
100.0
100.0
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Useless for diagnosis
N % N % N % N % N % N %
Treatment groups 5 mg 2 2.3 27 30.7 8 9.1 47 53.4 4 4.5 88
14 5.6 91 36.1 31 12.3 103 40.9 13 5.2 252
100.0
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Total
Total
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Subjects refused to undergo endometrial biopsy
2.5 mg 8 10.2 27 34.7 13 16.7 26 33.3 4 5.1 78
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Results of the endometrial biopsy
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Results of the biopsy of the endometrium after treatment cessation
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S2214-420X(15)00042-X http://dx.doi.org/doi:10.1016/j.jrhm.2015.09.001 JRHM 19
To appear in: Received date: Revised date: Accepted date:
8-4-2015 31-8-2015 1-9-2015
Please cite this article as: Josep Lluis CarbonellAna M. River´onYara LeonardJes´us Gonz´alezBraulio HerediaCarlos S´anchez Mifepristone 2.5, 5, 10 mg versus placebo in the treatment of endometriosis (2015), http://dx.doi.org/10.1016/j.jrhm.2015.09.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Mifepristone 2.5, 5, 10 mg versus placebo in the treatment of endometriosis Josep Lluis Carbonell,+ Ana M. Riverón,* Yara Leonard,* Jesús González,* Braulio
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Heredia,* Carlos Sánchez* +Outpatients Major Surgery Centre, Mediterránea Médica Clinic, Valencia, Spain.
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*“Eusebio Hernández” Gynecologic-Obstetric Teaching Hospital, Havana, Cuba.
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Name and address of corresponding author:
Dr. Josep Lluis Carbonell Esteve; Mediterránea Médica Clinic; C/ Salvador Guinot, 14;
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Valencia 46017, Spain; Tel: 34 96 358 6020.
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Fax: 34 96-3785485; e-mail: [email protected]; [email protected]
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Summary Objectives: to evaluate the effectiveness and safety of 2.5, 5 and 10 mg doses of mifepristone against a placebo in women with laparoscopic diagnostic of endometriosis. Methods: double-blind, placebo-controlled study of 360 subjects randomly assigned to
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receive orally one daily tablet of 2.5, 5 or 10 mg mifepristone for 6 month, or 1 daily tablet of mifepristone placebo for 3 months, (90 in each treatment group), carried out at “Eusebio Hernández” Hospital, Havana, Cuba. Efficacy was assessed by measuring changes in
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prevalence of dysmenorrhea and changes in scores according to AFS. Safety was evaluated by the incidence of hot flushes, nausea, dizzy spells, vomiting, fatigue/tiredness, raised
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hepatic transaminases, histological alterations of the endometrium.
Results: in the mifepristone groups, the prevalence of symptoms was significantly inferior to
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those at the beginning of treatment with no significant differences between the groups of 5 and 10 mg, unlike in 2,5 mg of mifepristone and the placebo group. The scores of the AFS were significantly differents at the end of the treatment in the mifepristone groups. In the
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mifepristone groups there were 9/264 (3.4%) subjects with raised hepatic transaminases up to 99 IU. doses and placebo.
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Conclusions: mifepristone 5 mg was safer and more effective than the others mifepristone
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ClinicalTrials.gov Identifier: NCT02271958
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Introduction Endometriosis, characterized by the ectopic presence of endometrial-like glands and stroma, is a common gynecological condition with an enigmatic pathogenesis.1 There is currently no cure for endometriosis and reported recurrence rates after surgical therapy are high.2
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Approved treatments for endometriosis include hormonal therapies.3, These methods of treatment are relatively effective but their side-effects limit their effectiveness and impeding their continued use.4-6
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The progestagen dienogest has shown to be more efficacious than placebo in relieving pain associated to endometriosis and also showed a similar efficacy to GnRh in alleviating
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endometriosis main symptom.7
Bouchard et al reported that selective progesterone receptors modulators (SPRM), as mifepristone and progestagens, could reduce the growth of endometrial tissue and also
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diminish endometriosis associated pain. 8
In contrast, Brown et al, they concluded that only be present a limited evidence to support
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that the use of progestagens and antiprogestagens (gestrinone) relieves endometriosis associated pain. But, they warned that the reviewed studies are few with a scarce number of subjects, and then, that conclusion is not definitive.9
Brown et al, only analyse the
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antiprogestagen gestrinone, in their revision, they did not make any reference to the studies
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by Kettel et al, Murphy et al, where they treated endometriosis with mifepristone. 10-13 Agreeing with Bouchard et al, Prentice et al concluded that also progestagens and the
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antiprogestagens gestrinone ameliorate the pain symptoms associated to endometriosis.3 SPRMs, in general, owns an antiproliferative effect, as that has been pointed out that happens in the endometrium of primates,14 and in rodent mammary tumors.15 Mifepristone is a practically pure SPRM which its strong antiprogestagenic action is only overtaken by onapristone. Mifepristone acts being coupled to the progesterone receptors at uterine cervix level, in the endometrium, miometrio, mammary tissue, and in every site where progesterone receptors exist.
Endometriosis is considered an estrogen-dependent condition influenced by the levels of aromatase activity, whose production is markedly increased in the ectopic endometriosis implants compared with eutopic endometrium and this leads to an increase in the production of estradiol.16 Mifepristone blocks medroxyprogesterone acetate induced aromatase action in the endometrial cells.17 A study on Wistar rats using a mifepristone implant proved to be effective on endometriotic lesions.18 Several studies published by Kettel et al using 100, 50 and 5 mg mifepristone to
Page 3 of 22
treat endometriosis obtained significant reductions of pain (intensity and prevalence) and also in the dimensions of the endometriotic lesions according to the mifepristone dose used.10-13 In 2010, we carried out a pilot study using mifepristone 5 and 25 mg doses for the treatment of endometriosis. The 5 mg dose had a similar to the 25 mg regarding clinical improvement: reducing pain in 95% of cases and reducing in more than 50% the volumes of the
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endometriotic lesions according to AFS scores.19
In China, during the past decade, more than a hundred clinical trials were carried out
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including several thousands of patients using mifepristone for the treatment of endometriosis, though Sun-Wei Guo questions their results because of inappropriate protocol designs. 20
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The fact that our results confirmed, or were better than the ones reported by Kettel et al, using 5 mg-mifepristone doses led us to design a clinical study trying to get a more definitely result
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on the use of mifepristone to treat endometriosis.
The objective of this study was to evaluate the effectiveness and safety of doses of 2.5, 5 and
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10 mg mifepristone versus a placebo for the treatment of endometriosis.
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Material and methods This is a double-blind randomized clinical trial, with 3 mifepristone treatment groups and one placebo group to evaluate efficacy and safety in the treatment of endometriosis. The study was approved by the Ethics and Science Committee at the “Eusebio Hernández” teaching
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hospital in Havana, Cuba and carried out in accordance with the Declaration of the XVIII and XLI World Medical Assembly of Helsinki (1964) and last modified by the Tokyo Assembly (2004). At the recruitment visit, subjects were informed the pros and cons and possible side-
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effects of the treatment. Examinations undertaken
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Before treatment, for all patients, thorough gynecological and pelvic ultrasound examinations for endometrioma and diagnostic laparoscopy were performed to determine localization, extent and severity of the endometriotic lesions; a score was assigned according to the revised
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American Fertility Society (AFS) classification.21 Blood samples were taken for hematological tests and hepatic function. Before treatment, endometrial biopsy was
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performed if endometrial thickness, measured at any moment of the menstrual cycle, by ultrasound was >8 mm or if an abnormal bleeding had occurred in the past 3 months. At 90 and 180 days of treatment ultrasound examination for endometrioma of the pelvis was
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undertaken; when treatment ended a diagnostic-therapeutic laparoscopy and endometrial
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biopsy were performed. All our operators are more than sufficiently trained in gynecological investigation, both on ultrasonography or surgical techniques; they were blinded to the
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experimental protocol. Subjects
Women with laparoscopic confirmed endometriosis who volunteered to take part in the study. Inclusion criteria: a) age 18 to 45, b) patients with dysmenorrhea or pelvic pain not attributable to other gynecological illness and c) acceptance of using barrier contraceptive methods during treatment. Exclusion criteria: a) breastfeeding, b) hormonal or surgical therapies less than 4 months previous to study, c) diabetes, d) severe arterial hypertension, e) hepatopathy, renal malfunction, endocrinopathy, and f) any contraindication about the use of antiprogestins. Products used The mifepristone was supplied by Zizu Pharma Laboratories, Beijing, China for the first 91 subjects, and by Litaphar Laboratories, Azpeitía, (Guipúzcoa, Basque Country), Spain for patients 92 to 360 .
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Treatment Group I: 2.5 mg mifepristone per day for 6 months; Group II: 5 mg mifepristone per day for 6 months; Group III: 10 mg mifepristone per day for 6 months, Group IV: a mifepristone placebo daily for 3 months. The mifepristone was prepared in tablets containing 2.5, 5, 10 mg
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or a mifepristone placebo. All tablets had the same shape, size and color and were taken orally. There were evaluation visits every 30 days until the end of the study.
The main variables in evaluating efficacy were the changes in prevalence of dysmenorrhea and
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the average reduction in its intensity. Other variables used were: a) changes in AFS scores, b) changes in AFS stages, c) changes in the dimensions of the endometriotic lesions detectable by
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ultrasound and d) change in prevalence and intensity of symptoms of endometriosis. The intensity of each symptom was evaluated by means of a visual scale from 0 to 10 where 0
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represented absence of symptoms and 10 their maximum intensity being indicated by the subject herself. The endometriotic lesions volume was calculated, approximately, by the formula 0.524xAxBxC where A, B, C, represent the diameters of a spheroid in each of the three
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dimensions.
The variables to evaluate safety were incidences of: a) hot flushes, b) nausea, c) dizziness, d) vomiting, e) fatigue/tiredness, f) raised hepatic transaminases (ASAT and ALAT, with reference
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values 46 and 49 IU, respectively) evaluated at the beginning, after 3 months and at the end of
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treatment, h) changes in endometrial thickness measured at the beginning, at 90 days and at the end of treatment, and i) presence of PAEC (progesterone associated endometrial changes),
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evaluated by means of an endometrial biopsy. Amenorrhea was considered to be absent when spotting lasted more than 5 days or when light bleeding lasted more than 1 day. The methodology undertaken to diagnose PAEC in the current study was as follows: between 3 and 10 days after treatment cessation, an sample of endometrium tissue was taken and the histological obtained images were interpreted according to the criteria referred by Mutter et al
22
and Horn and Blithe
23
, who consider that a PAEC is present when the
following histological sings are observed: cystic dilation of the endometrial glands, thickened vessels, and an existing alteration of the proportion between the parenchyma and stroma in a way that may be interpreted as a simple endometrial hyperplasia. The differences between PAEC and simple endometrial hyperplasia have been widely described by Mutter et al and Horn and Blithe.
22
23
Women were asked, prior and after treatment, with a visual scale with the following questions: “How do you think endometriosis affects your quality of life?” and “How do you
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think endometriosis affected your quality of life during treatment” on a scale of 0 to 10 where “0” symbolized “nothing” and “10” “the highest value for her”. Assignation to treatment Subjects were assigned to each treatment group according to a random list obtained from the
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MEDSTAT 2.1 program, Jan 1989, Copenhagen, Denmark, DOS Software. Staff unrelated to the study prepared opaque sealed envelopes containing a card indicating the treatment group to which the patient was assigned: 1) “mifepristone A” or 2) “mifepristone B” or 3)
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“mifepristone C” or 4) “mifepristone D”. Each of these groups corresponded to mifepristone doses of 2.5, 5, 10 mg or the placebo, respectively. Neither doctor nor subject knew which
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treatment had been chosen. After 90 days of treatment, the monitor informed the researchers which women had finished their part in the study because they belonged to the placebo group,
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and the established end of treatment procedure was activated for them. Determination of the number of subjects to be included
The intensity of pre-treatment dysmenorrhea was the variable which determined the number
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of subjects to be included. We assumed that by administrating 2.5 mg of mifepristone an average reduction of 4 points in dysmenorrhea intensity would be obtained and a 2 point reduction in the case of the placebo, taking an average intensity value of 8 points as starting
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point, this being taken from our previous study. According to G*Power,24 and based on the
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previous projections, with four treatment groups, to guarantee a power of 90% in a two-tailed, 0.05 significance level test, with a 25% average effect size, a minimum sample size of 232
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subjects was required for the complete study, 58 in each treatment group. The total size of the sample was increased in 35% (360 subjects totally, 90 in each group) in order to offset subject dropout. As it was a typical ANOVA clinical trial we calculate on the basis of a minimum power of 0.90, because for values below 0.90 a greater risk of not detecting the statistical differences desired had to be accepted. The results are shown as frequencies, percentages, means and 95% confidence intervals, standard deviations and maximum and minimum values in each variable when it was the case. We used Pearson’s Chi-square test and the one-way ANOVA to assess differences among the treatment groups and the Bonferroni correction as post hoc test. The Student’s ttest for paired samples was used to evaluate changes in intensity of symptoms of endometriosis and scores according to the AFS in each treatment group. The changes of stages according to the AFS were analyzed by McNemar’s test. In all cases p<0.05 was significant and all statistical tests were two-tailed.
Page 7 of 22
Results Inclusion and compliance with protocol The study began on November 30th 2011; the last subject was included in March 2014 and completed treatment in October 2014. In all, 373 women were referred to the clinical trial
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consultancy. Laparoscopy failed to discover endometriosis in two of them, 1 had adenomyosis and the other had several fibroids. Eleven subjects previously treated for infertility due to endometriosis were not included because 8 of them were pregnant and the
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other 3 had recently give birth. In total, we included 360/373 (96.5%) subjects out of the possible candidates. In total, there were 68/360 (18.9%) infertile women included in the study
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with not significant differences among the treatment groups. After 3 months treatment, as planned, the participation of the placebo group came to an end.
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All told, 15 subjects had received hysterectomies as part of their treatment for endometriosis, but the initial laparoscopy before inclusion confirmed the persistence of the condition and the doctors decided to include them. Five subjects also presented endometriosis in the scar of
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previous episiotomies and in the rectal and pararrectal region.
Of the subjects who completed the study protocol in the 2.5, 5, 10 mg and placebo groups, 4/86 (4.7%), 4/90 (4.4%), 5/88 (5.7%) and 17/89 (19.1%), respectively, refused to undergo
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final post-treatment laparoscopy.
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the final laparoscopy (“second look”). In total 29/360 (8.1%) subjects refused to undergo the
Homogeneity of the treatment groups
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Table 1 shows the general characteristics of the subjects by treatment groups. The distribution of the AFS stages of endometriosis before treatment by group showed no significant differences between them, p = 0.924. The average scores in the subject’s perception of how endometriosis affected her quality of life were: 8.2 points in the 5 mg mifepristone group; 8.1 points in the 2.5 and 10 mg groups, respectively, and 7.8 points in the placebo group, p = 0. 613.
All told, dysmenorrhea, dyspareunia and inter-menstrual pelvic pain occurred in 341/360 (96.7%), 233/360 (64.7%) 217/360 (60.3%) of all subjects included, respectively. Other symptoms were the voiding syndrome 69/360 (19.2%) and intestinal upsets experienced by 117/360 (32.5%) subjects, respectively. In no case there were significant differences between treatment groups. Nor did average intensities in pelvic pain, urinary disorders, dysmenorrhea, dyspareunia and intestinal upsets present significant differences between treatment groups. The average pre-treatment hemoglobin levels did not register significant differences between treatment groups and distribution of the two hepatic transaminases studied (ASAT and
Page 8 of 22
ALAT) did not differ significantly between groups. We performed 38/360 (10.6%) endometrial biopsies prior to treatment. All in all, 22/38 (57.9%) cases of secretory endometrium were diagnosed, 10/38 (26.3%) cases of proliferative endometrium, 4/38 (10.5%) cases of physiological disorders in endometrial maturity, and 2/38 (5.3%) cases
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which were not useful diagnostically, with no significant differences between the groups, p = 0.1.
Table 2 shows the prevalence of symptoms of endometriosis before, at 3 months and at the
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end of treatment by groups. Prevalence of pelvic pain was significantly greater in the 2.5 mg group than in the 5 and 10 mg groups, p = 0.007. Dyspareunia and intestinal upsets were
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significantly more frequent in the 2.5 group than in the 5 mg group, p = 0.023 and p = 0.013, respectively. Amongst the subjects who took mifepristone, symptom intensity, in those
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subjects still suffering them, was slightly inferior to those at the beginning but there were no significant differences between groups. Amongst those taking the placebo, symptom intensity was the same to those of pre-treatment.
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Incidence of treatment side effects reported by subjects after 3 and 6 months by groups is shown in table 3. There were significant differences in frequency of tiredness and fatigue between the 5 and 10 mg mifepristone groups, p = 0.009.
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In total, in the groups that received mifepristone there were 9/264 (3.4%) subjects with raised
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hepatic transaminases; the highest values registered were 81 and 99 IU for ASAT and ALAT, respectively. In the placebo group, at the end of treatment, there were 3/89 (3.4%) subjects IU.
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with raised ASAT (maximum value 53 IU) and 1/89 (1.1%) subjects with ALAT rose to 53 In the placebo group there were no differences between the average values, before and after treatment, in the volumes of the endometriomas, p = 0.376; the endometrial thickness was significantly greater than before treatment: 6.0 ± 1.6 vs 11.2 ± 5.0 mm, respectively, p < 0.001. The measurements of endometrial thickness and endometriomas at the end of treatment in the mifepristone groups were significantly different between the 2.5 and 10 mg mifepristone groups, p = 0.045.
Focal points of endometriosis were observed in the second look laparoscopy in all subjects in the placebo group. Before treatment started, 15/72 (20.8%) subjects were at stage I and at the end 19/72 (26.4%) subjects had reached this point. All told, at the end of treatment, we observed percentage distributions of the stage similar to those at the beginning. In the 2.5 mg group no focal points of endometriosis were observed in 3/82 (3.7%) in the second look laparoscopy. In general, there were significant changes towards less advanced
Page 9 of 22
stages of endometriosis, p = 0.002. Before treatment there were 17/82 (20.7%) subjects at stage 1 and on termination there were 19/82 (23.2%) subjects. In 1/86 (1.2%) subject who received 5 mg mifepristone, focal points of endometriosis were not detected in the second look laparoscopy.
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Regarding final scores by AFS, a significant difference was only observed between the 2.5 and 5 mg groups, p = 0.023. In every treatment groups, but the 2.5 mg dose (p=0.761), the final AFS scores were significantly lower than before, p<0.001(5 mg), p<0.001 (10 mg) and
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p=0.003 (placebo), respectively.
Changes in stage with respect to the beginning were significant and tended towards earlier
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ones, p < 0.001. At the beginning of treatment there were 19/86 (22.1%) subjects at stage 1 and at the end this figure increased to 35/86 (40.7%) subjects. In 9/83 (10.8%) subjects
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treated with 10 mg mifepristone, focal points of endometriosis were not detected in the second look laparoscopy. Changes towards less advanced stages of the condition with respect to the beginning of treatment were significant, p < 0.001. At the beginning of treatment there
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were 18/83 (21.7%) subjects at stage 1 and at the end this had increased to 21/83 (25.3%) subjects.
Concerning the issue on how each subject evaluated the way in which endometriosis affected
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her quality of life it was obtained very significant differences, p < 0.001, between all
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mifepristone groups compared with the placebo group. There were also significant differences between the 2.5 and 5 mg groups, p < 0.001, and between the 2.5 and 10 mg
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groups, p < 0.001; between the 5 and 10 mg groups there were no significant differences, p = 1.000.
We performed 57/86 (66.3%) endometrial biopsies at the end of treatment in the placebo group; in 3/57 (5.3%) the presence of cystic glands was diagnosed; the remaining diagnoses were secretory endometrium in 33/57 (57.9%) or proliferative endometrium in 21/57 (36.8%) subjects. Table 4 shows 225 endometrial biopsies at the end of treatment with known results in the mifepristone groups; PAEC was diagnosed in 13/66 (19.7%), 8/82 (9.7%) and 10/77 (13.0%) subjects in the 2.5, 5 and 10 mg mifepristone groups, respectively, p > 0.05.
Page 10 of 22
DISCUSSION It was a positive fact that it was possible to include 360/373 (96.5%) subjects of those available to participate that is an indicator of a high external validity. The fact that no violations of the random list occurred and that all treatment groups were homogenous
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guaranties a good internal validity. This is the first study on the use of mifepristone versus placebo to treat endometriosis. A negative matter was that it was not mandatory to perform biopsies on the endometrial lesions, it is known that a third of endometrial lesions are not
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histologically confirmed.25. Another negative point was not implementing post-treatment follow-up periods and thus not evaluating the possible rates of recurrence and pregnancies.
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The test on the subject’s perception of quality of life revealed an interesting practical soundness and the scores obtained in all treatment groups coincide with the average high
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intensities of dysmenorrhea, displaying a distinct drop in post-treatment scores in the 3 mifepristone groups with a clear statistical significance with respect to the placebo group where the opposite result was found.
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Regarding pre-treatment prevalence of symptoms, there were no differences between the groups nor in the intensity of these symptoms except in dyspareunia in favor of the 5 mg group with respect to the placebo group and in intestinal upsets in favor of group 1 with
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respect to group 3 and group 2 with respect to group 4.
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The conclusions achieved by Brown et al in their systematic revision on the use on progestagens and antiprogestagens to treat endometriosis are not valid for mifepristone
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because the only progestagen analyzed in 4 papers is the gestrinone, and even more, doing a careful lecture of such articles, 2 of them concluded that the gestrinone had a similar efficacy to danazol and to GnRH analogues regarding improvement of endometriosis associated pain and/or dysmenorrhea.26,
27
Mifepristone was not studied in such papers, then their
conclusions are not pertinent to the same. Furthermore, such studies did not analyze the efficacy of dienogest in deep, there is included only one article on its use. Dienogest is already approved, in several countries, as a specific treatment for endometriosis achieving a higher efficacy than other antiprogestagens marketed. 7, Up to date, the continued usage, or not, of oral contraceptives is one of the most therapeutics options used for endometriosis, and the combination most used is dienogest + etinilestradiol, only in those countries where are available such commercial presentation. Nowadays, we are carrying out a clinical trial on the use of mifepristone versus dienogest + etinilestradiol to treat endometriosis.
Page 11 of 22
Guo SW et al, did a wide revision of 104 out of 160 clinical trials carried out in China, in the past decade, using mifepristone to treat endometriosis. They cannot conclude that mifepristone is a valid treatment for endometriosis, mainly due to the low quality of the methodological design of those high number of trials which included 10 003 subjects who
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received mifepristone for endometriosis. Many of such studies administered mifepristone, before or after surgery with no control group in every case being impossible to determine if the improvement was due to mifepristone, surgery or both.
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Nevertheless, two of those studies performed by Li Dan and by Li Xiao et al, administered 12.5 and 10 mg mifepristone dose during 6 months, respectively, after surgery contrasting to
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a control group whose patients only received surgery without administering mifepristone afterwards and the results were significantly higher in both mifepristone groups regarding
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clinic improvement and lower rates of recurrence. 28, 29
In our opinion, it is hardly difficult to assume that mifepristone is not efficient as a treatment for endometriosis after being carried out 160 clinical trials in a 15 years period counting 15
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000 women. Other issue to allow for is that Chinese researches lack from knowledge on research methodology; in fact Guo himself his doubts on this matter in his paper. The results achieved in the 5 and 10 mifepristone groups widely agreed and confirmed the
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ones obtained in our first study using mifepristone 5 and 25 mg as well as for the decrease of
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dysmenorrhea and the sizes of the endometriotic lesions according to AFS scores. That agree is also valid regarding side effects as hot-flushes, liver enzymes, etc. 19
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Although in lesser extension, our results partially are alike with those obtained by Kettel et al in the study where they used only mifepristone 5 mg for endometriosis during 6 months; in it 6/7 (85.7%) women had significant improvement of pelvic pain; we obtained a 90% of improvement/eradication of such pain. 12 With respect to diminish of the AFS score comparing with the pretreatment values, there were a reduction of 2 scores (10 ± 3.2 to 8 ± 1.2 ) in the study by Kettel et al that presumably was not significant due to the scarce number of subjects included; analyzing them separately, it could be observed that half of them experienced 45% and 32% in the values of the AFS scores. 10-13 Apparently, the results of the studies by Kettel et al are contrary to ours, but this is relative. For example, in their first study using a high dose of mifepristone (100 mg) one subject had a complete disappearance of the endometriotic lesions at the second-look laparoscopy. 10 Nonetheless, the criterion used in this study to evaluate the decreasing of the endometriotic lesions was the change of AFS stage, nevertheless this criterion could be inaccurate because a
Page 12 of 22
subject starting treatment with a score of 39 (AFS stage III) and after treatment cessation has a score of 17, remains in the same stage of AFS but had diminished the severity of her illness in 16 points indicating an improvement in endometriosis. We feel that the criterion to evaluate improve should be the score and not the stage.
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By last, in the study of Kettel et al, where they use 50 mg of mifepristone they obtained a 55% reduction in endometriotic lesions. Besides, in studies by Kettel they obtained significant decreases of pain, independently of the mifepristone dose used. 11
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Effectiveness
All mifepristone treatment groups were more effective than the placebo group. After 90 and
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180 days of treatment there were no differences between 5 and 10 mg doses which behave similarly with regard to clinical improvement. There is, however, a statistically significant
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difference in favor of groups 2 and 3 with respect to the 2.5 mg group 1, regarding the improvement of all symptoms.. This difference concurs with the significantly greater use of
Amenorrhea and bleeding pattern
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analgesics sustained by the subjects in group 1.
Amenorrhea in the 2.5 mg group was significantly inferior than in groups 2 and 3, therefore those subjects present longer and more intense bleeding and the percentage of subjects who
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do not bleed at all was significantly inferior in the 5 and 10 mg groups. This is less
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comfortable for the subjects in group 1. Since amenorrhea set in slower in group 1 and attained percentages inferior to those in groups 2 and 3, bleeding was heavier both in
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frequency and duration. The same applies to clinical improvement, which took longer and was less intense than in the other groups. Scores and AFS stages
Aside from the placebo group, all groups experienced significant improvements, both in the average AFS score as well as in a change of stage with respect to that of pre-treatment; the 2.5 mg dose was less effective than the 5 and 10 mg groups. The fact that there is no change in stage does not mean mifepristone was not effective; e.g., a subject scoring 130 AFS, who on termination of treatment got a score of 46 points, has improved by 84 points, yet continues to be in stage IV as before treatment.. In the 10 mg group, out of 19 cases starting off in stage 3 only 1 experienced a change in stage, the other 18 remaining in it, having a significant reduction in AFS score dropping from 28.4 at start to 19.5 points at the end. Summarizing, the 5 and 10 mg groups behave very similarly.
Page 13 of 22
Hepatic Toxicity Elevated transaminase levels were similar in the three mifepristone groups and of neither little clinical importance, never rising above 100 IU nor 5% in frequency of appearance. However, in any treatment with mifepristone it is always necessary to monitor them.
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Hot Flushes In this study we saw significant differences between the mifepristone groups concerning hot flushes brought on by the 10 mg dose being more numerous than in the 5 and 2.5 mg groups.
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In the 2.5 and 5 mg groups the hot flushes, when they appeared, were of low intensity (1 to 4 points, visual analogue scale of 1 to 10), short duration (< l.5 minute), once a day, and usually
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at night. In the 10 mg group the hot flushes were more frequent, longer (≥ 1.5 minute), of greater intensity (5 to 9 points, visual analogue scale) and occurring several times within 24
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hours. Other side effects
Nausea, vomiting, etc., are similar in the 3 mifepristone treatment groups and compatible
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with publications to date, their scores always low and compatible with an orally-administered medicine. Fatigue and tiredness, even with low absolute scores, are significantly superior in
Endometrial thickness
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the 10 mg group, p < 0.001 and p = 0.024, after 3 and 6 months, respectively.
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With respect to endometrial thickness there are no significant differences at the end of treatment between the 4 groups, including the placebo group, probably because the timing of
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the ultrasound examination in this last group coincides with the perimenstrual period. The difference between the mean endometrial thickness before and after treatment is due to the mifepristone effect in groups 1, 2 and 3 and to menstruation in the placebo group. Summarizing, our results, improvement of illness and low incidence of side effects, are similar to those obtained in our previous study, and partially compatible with those of Kettel et al, with the exception of one case of the study of Kettel et al when they used mifepristone 50 mg where the liver transaminases rise from 21 and 28 IU to 199 and 499 IU, respectively16 In our studies on the use with the same dose of 5 mg of mifepristone to treat uterine fibroids we have obtained similar results regarding nausea, vomiting, hot-flushes, tiredness, alterations of liver enzymes, endometrial thickness, PAECs, etc. 30-35 It is remarkable and contradictory that mifepristone causes the shrinking of endometrial foci and eutopic endometrium is thickened in a significant percentage of cases. This is probably due to histological, metabolic differences, , etc., at cellular level. Endometrial histology
Page 14 of 22
No case of endometrial hyperplasia was diagnosed and PAEC22, 23 ,36 (progesterone associated endometrial changes) percentages did not present any statistical significance between groups. Conclusions The three mifepristone treatment groups display a noticeable therapeutic superiority over the
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placebo group. The 5 and 10 mg doses present a similar therapeutic efficacy but the 5 mg group has less side effects. The 2.5 mg group presents significantly lower percentages of amenorrhea and clinical improvement than the 5 and 10 mg groups. The 5 mg dose proved to
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be efficacious and safe and should be the studied in future trials on endometriosis in which mifepristone should contrasted with another medications approved to treat endometriosis
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such as: dienogest, GnRh analogues, oral contraceptives, etc.
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Bibliography 1. Giudice LC, Kao LC. Endometriosis. Lancet 2004;64:24-35. 2. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update 2009;15:441– 61. with endometriosis. Cochrane Database Syst Rev 2000;2:CD002122.
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3. Prentice A, Deary AJ, Bland E. Progestagens and anti-progestagens for pain associated 4. Winkel CA, Scialli AR. Medical and surgical therapies for pain associated with
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endometriosis. J Womens Health Gend Based Med 2001;10:137–62.
5. Mounsey AL, Wilgus A, Slawson DC. Diagnosis and management of endometriosis. Am
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Fam Physician 2006;74:594–600.
6. Selak V, Farquhar C, Prentice A, Singla AA. Danazol for pelvic pain associated with
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endometriosis. Cochrane Database of Syst Rev 2007;Issue 4. Art. No.: CD000068. DOI: 10.1002/14651858.CD000068.pub2.
7. Strowitzki T, Faustmann T, Gerlinger C, Seitz C. Dienogest in the treatment of
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endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebocontrolled study. Eur J Obstet Gynecol Reprod Biol. 2010 Aug;151(2):193-8. 8. Bouchard P, Chabbert-Buffet N, Fauser BC. Selective progesterone receptor modulators
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2011;96(5):1175-89.
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in reproductive medicine: pharmacology, clinical efficacy and safety. Fertil Steril. 9. Brown J, Kives S, Akhtar M. Progestagens and anti-progestagens for pain associated with
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endometriosis. Cochrane Database Syst Rev. 2012 Mar14;3:CD002122. 10. Kettel LM, Murphy AA, Mortola JF, Liu JH, Ulmann A, Yen SS. Endocrine responses to long-term administration of the antiprogesterone RU486 in patients with pelvic endometriosis. Fertil Steril. 1991 Sep;56(3):402-7. 11 Kettel LM, Kettel M, Murphy AA, Morales AJ, Ulmann A, Baulieu EE, Yen SSC. Treatment of endometriosis with the antiprogesterone mifepristone (RU 486). Fertil Steril 1996;65:23-8.
12. Kettel LM, Murphy AA, Morales AJ, Yen SSC, Adamson RGD, Powers TW. Preliminary report on the treatment of endometriosis with low-dose mifepristone (RU 486). Am J Obstet Gynecol 1998;178:1151-6. 13. Álvarez-Murphy A, Castellano PZ. RU 486: pharmacology and potential use in the treatment of endometriosis and leiomyomata uteri. Curr Opin Obstet Gynecol 1994;6:269-78. 14.
Spitz IM. Progesterone
receptor antagonists. Curr Opin Investig Drugs.
2006;Oct;7(10):882-90. Review.
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15 Wiehle RD, Christov K, Mehta R. Anti-progestins suppress the growth of established tumors induced by 7,12-dimethylbenz(a)anthracene: comparison between RU486 and a new 21-substituted-19-nor-progestin. Oncol Rep. 2007;18(1):167-74. 16. Arici A. Endometriosis. Semin Reprod Med 2003;21(2).
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17. Tseng L, Mazella J, Sun B. Modulation of aromatase activity in human endometrial stromal cells by steroids, tamoxifen and RU 486. Endocrinology. 1986;118(4):1312-8.
18. Mei L, Bao J, Tang L, Zhang C, Wang H, Sun L, et al. A novel mifepristone-loaded
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implant for long term treatment of endometriosis: In vitro and in vivo studies. Eur J Pharm Scie 2010;39:421-7.
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19. Carbonell JL, Perera O, Riverón AM, González J, Tomasi G. Treatment of endometriosis using 5 mg or 25 mg daily dosage of mifepristone over 6 months. Double-blind random
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clinical trial. Prog Obstet Gynecol 2012;55(2):51-9.
20. Guo SW, Liu M, Shen F, Liu X. Use of mifepristone to treat endometriosis: a review of clinical trials and trial-like studies conducted in China. Women Health 2011;7(1):51-70.
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21. Revised American Fertility Society for Reproductive Medicine Classification of Endometriosis: 1996. Fertil Steril 1996;67(5):817-21.
22. Mutter G, Bergeron C, Deligdisch, Ferenczy A, Glant M, Merino M, Williams ARW,
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Blithe DL. The spectrum of endometrial pathology induced by progesterone receptor
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modulators. Mod Pathol 2008;21:591-8.
23. Horne FM, Blithe DL . Progesterone receptor modulators and the endometrium: changes
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and consequences Hum Reprod Update 2007;13:567-80. 24. Faul F. G*Power [computer program]. Version 3.0.10. Kiel: Universitat Kiel. Germany. 25. Stegmann BJ, Sinaii N, Liu S, Segars J, Merino M, Nieman LK, Stratton P. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertil Steril 2008;89:1632-6 26. Bromham DR, Booker MW, Rose GL, Wardle PG, Newton JR. A multicentre comparative study of gestrinone and danazol in the treatment of endometriosis. Journal of Obstetrics and Gynaecology 1995;15:188–94. 27. The Gestrinone Italian Study Group. Gestrinone versus a gonadotropin releasing hormone agonist for the treatment of pelvic pain associated with endometriosis: a multicenter, randomised, double-blind study. Fertility and Sterility 1996; 66:911–9. 28. Li X, Liu WM. Efficacy of the combined laparoscopy and mifepristone in the treatment of endometriosis. J. Med. Forum 2006; 27, 89-90.
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29. Li D, The clinical investigation on the effects of mifepristone for endometriosis after surgery. Chin. J. Mod. Drug Appl. 2009;3,84 30. Carbonell J. LL. Et al. Mifepristone for the treatment of uterine leiomyomatas. A ramdom controlled trial. Obstetrics & Gynecology. Voll 112,nº 5, Novemver 2008
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31. Carbonell JL, Acosta R, Pérez Y, Campos R, Valle A, Sánchez C. Treatment of uterine myoma with 5 or 10 mg mifepristone daily during 6 months, post-treatment evolution over 12 months. Double blind randomized clinical trial. Eur J Obstet Gynecol Reprod Biol. 2012
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Apr;161(2):202-8
32. Carbonell JL, Riverón AM, Cano M, Ortiz AI, Valle A, CS Texidó, Tomasi G.
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Mifepristone 2.5 mg versus 5 mg daily in the treatment of leiomyoma before surgery. Randomized clinical trial. Internat J Women Health 2012;4:75-84.
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33. Carbonell JL, Acosta R, Pérez Y, Campos R, Valle A, Sánchez C Safety and effectiveness of different dosage of mifepristone for the treatment of uterine fibroids: a double-blind randomized clinical trial. International J. of Women’s Health 2012;4:1–10.
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34. Carbonell JL, Acosta R, Pérez Y, et al. 5 mg mifepristone daily versus placebo for 3 months to treat uterine myomas. Double blind randomized clinical trial. International Journal of Women’s Health 2013:5
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35. Carbonell JL, et al. Treatment of uterine myoma with 2.5 or 5 mg mifepristone daily
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during 3 months with 9 months post-treatment follow-up. Randomized clinical trial. ISRN Obstetrics and Gynecology. Volume 2013
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36. Baird DT, Brown A, Critchley HOD, Williams AR, Ling S, Cheng L. Effect of long-term treatment with low-dose mifepristone on the endometrium. Hum Reprod 2003;18:61-8.
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Table 1 General characteristics and gyneco-obstetric history of subjects included by treatment group Group
N
Average
SD
CI 95%
Min
Max
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Characteristics
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M
an
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2.5 mg 90 31.6 7.0 30.1 - 33.1 19 49 5 mg 90 31.4 6.3 30.0 - 32.7 20 46 Age(years) 10 mg 90 33.4 7.0 31.9 - 34.9 19 47 Placebo 90 31.9 7.1 30.4 - 33.4 20 48 2.5 mg 90 61.3 10.8 59.1 - 63.6 46.0 97.0 5 mg 90 61.3 9.9 59.2 - 63.4 40.0 97.0 Weight (kg) 10 mg 90 61.1 11.5 58.6 - 63.5 46.0 97.0 Placebo 90 60.3 11.4 57.9 - 62.7 40.0 110.0 2.5 mg 90 1.61 .1 1.60 - 1.62 1.50 1.75 5 mg 90 1.62 .1 1.61 - 1.63 1.51 1.75 Height (m) 10 mg 90 1.62 .1 1.60 - 1.63 1.45 1.85 Placebo 90 1.61 .1 1.60 - 1.62 1.48 1.81 2.5 mg 90 23.6 3.8 22.8 - 24.4 17.3 34.9 5 mg 90 23.4 3.5 22.7 - 24.2 16.2 35.8 BMI+ 10 mg 90 23.4 4.1 22.5 - 24.3 15.5 36.1 Placebo 90 23.3 4.0 22.4 - 24.1 16.2 41.4 2.5 mg 90 1.4 1.7 1.8 - 1.8 0 8 5 mg 90 1.8 2.0 1.3 – 2.2 0 9 Pregnancies 10 mg 90 1.7 2.2 1.3 - 2.2 0 12 Placebo 90 2.1 2.3 1.6 - 2.6 0 10 2.5 mg 90 .3 .52 .2 - .4 0 2 5 mg 90 .3 .6 .2 - .4 0 2 Deliveries 10 mg 90 .5 .7 .3 - .6 0 3 Placebo 90 .4 .7 .3 - .6 0 3 2.5 mg 90 .8 1.2 .5 - 1.0 0 5 5 mg 90 1.1 1.6 .7 - 1.4 0 8 Abortions 10 mg 90 1.0 1.6 .7 - 1.3 0 10 Placebo 90 1.0 1.5 .7 - 1.4 0 8 2.5 mg 19 41 48 17 - 65 7 228 Endometriomas 5 mg 14 50 45 24 - 77 4 187 (cc)* 10 mg 17 51 59 21 - 81 4 203 Placebo 16 42 48 15 - 68 3 187 2.5 mg 82 7.2 2.0 6.7 - 7.6 3 11 Endometrial 5 mg 88 5.8 1.7 5.5 - 6.8 3 14 thickness 10 mg 88 6.8 2.4 6.3 7.3 3 20 (mm) Placebo 87 6.0 1.6 5.7 - 6.4 1 11 2.5 mg 90 28.1 29.0 22.0 - 34.3 1 128 5 mg 90 29.3 30.0 23.0 - 35.5 1 131 AFS score 10 mg 90 29.3 31.2 22.8 - 35.9 1 134 Placebo 90 26.1 25.4 20.7 - 31.3 1 105 *cc= cubic centimeters, measured and detected by ultrasound; + Body mass index; SD= standard deviation
Page 19 of 22
Table 2
Prevalence of symptoms of endometriosis before, after 3 months and at the end of treatment by groups. Data are presented as n(%)
2.5 mg
97 (96.8) 35 (39.3)
59 (65.6) 17 (19.1)
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an
us
Dysmenorrhea 82 (91.1) 88 (97.8) 85 (94.4) Before 9 (10.2) 1 (1.1) 1 (1.1) 3 months 4 (4.6) 5 (5.6) 4 (4.7) 6 months Dyspareunia 55 (61.1) 53 (70.0) 56 (62.2) Before 10 (10.4) 1 (1.1) 3 (3.4) 3 months 6 (7.0) 1 (1.1) 2 (2.3) 6 months Pelvic pain 51 (56.7) 59 (65.6) 61 (67.8) Before 14 (15.9) 1 (1.1) 3 (3.4) 3 months 10 (11.6) 7 (7.8) 2 (2.3) 6 months Urinary (urinary retention, neurogenic dysfunction, etc.) 18 (20.0) 16 (17.8) 19 (21.1) Before 3 (3.4) 0 (0.0) 1 (1.1) 3 months 3 (3.5) 1 (1.1) 0 (0.0) 6 months
p
Placebo
ip t
Treatment groups 5 mg 10 mg
d
0.717 <0.001 0.089
46 (51.1) 36 (40.4)
0.259 <0.001 <0.001
16 (17.8) 4 (5.0)
0.822 0.150 0.202
Intestinal (diarrhea, constipation, etc) 23 (25.6) 30 (33.3) 35 (38.9) 29 (32.2) Before 5 (5.7) 0 (0.0) 2 (2.3) 3 (3.4) 3 months 7 (8.1) 1 (1.1) 0 (0.0) 6 months % calculated over the number of subjects completing each treatment period
0.276 0.074 0.005
Ac ce p
te
0.644 <0.001 0.867
cr
Symptoms
Page 20 of 22
Table 3 Incidence of mifepristone side effects after 3 months and 6 months treatment by groups p <0.001 0.868
ip t
Symptoms 2.5 mg 5 mg 10 mg Placebo Amenorrhea 63 (78.7) 88 (97.8) 88 (98.9) 1.1 3 months 67 (85.9) 78 (88.6) 77 (87.5) 6 months Hot flushes 16 (18.9) 19 (21.1) 31 (34.8) 1 (1.1) 3 months 13 (15.1) 15 (16.7) 19 (21.6) 6 months Nausea 0 (0.0) 1 (1.1) 3 (3.4) 0 (0.0) 3 months 2 (2.3) 1 (1.1) 1 (1.1) 6 months Vomiting 1 (1.1) 0 (0.0) 1 (1.1) 0 (0.0) 3 months 1 (1.2) 0 (0.0) 1 (1.1) 6 months Fatigue / Tiredness 5 (5.7) 0 (0.0) 9 (10.1) 0 (0.0) 3 months 6 (7.0) 0 (0.0) 13 (14.8) 6 months % calculated over the number of subjects completing each treatment period
0.109 0.755 0.383 0.894
<0.001 <0.001
Ac ce p
te
d
M
an
us
cr
<0.001 0.505
Page 21 of 22
Table 4
Proliferative endometrium PAEC Secretory endometrium
10 mg 4 4.7 37 43.0 10 11.6 30 34.9 5 5.8 86
100.0
100.0
100.0
an
Useless for diagnosis
N % N % N % N % N % N %
Treatment groups 5 mg 2 2.3 27 30.7 8 9.1 47 53.4 4 4.5 88
14 5.6 91 36.1 31 12.3 103 40.9 13 5.2 252
100.0
Ac ce p
te
d
M
Total
Total
ip t
Subjects refused to undergo endometrial biopsy
2.5 mg 8 10.2 27 34.7 13 16.7 26 33.3 4 5.1 78
cr
Results of the endometrial biopsy
us
Results of the biopsy of the endometrium after treatment cessation
Page 22 of 22