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Long-term medical management of uterine fibroids with ulipristal acetate
ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE 1 2 3 4 5 6 7 a b Dace Matule, M.D.,c Hans-Joachim Ahrendt, M.D.,d 8 Q9 Jacques Donnez, M.D., e Olivier Donnez, M.D., f Robert Hudecek, M.D., Janos Zatik, M.D., Zaneta Kasilovskiene, M.D.,g Mihai Cristian Dumitrascu, M.D.,h 9 i Fernandez, M.D., David H. Barlow, F.R.C.O.G.,j Philippe Bouchard, M.D.,k Bart C. J. M. Fauser, M.D.,l Herve 10 Elke Bestel, M.D.,m and Ernest Loumaye, M.D.n 11 a te de Recherche pour l'Infertilite ; and b Institut de Recherche Expe rimentale et Clinique, Universite Catholique de Socie 12 €r Louvain, Brussels, Belgium; c Medical Company ARS Gynaecology Department No. 5, Riga, Latvia; d Praxis fu 13 Frauenheilkunde, Klinische Forschung und Weiterbildung, Magdeburg, Germany; e Department of Obstetrics and 14 Gynaecology, Masaryk University and University Hospital Brno, Brno, Czech Republic; f Szent Anna Szuleszeti, Nogyogyaszati es Ultrahang Maganrendelo, Debrecen, Hungary; g Private Clinic Maxmeda, Vilnius, Lithuania; h Centrul 15 ^ pital Bice ^tre-APHP, Service de Gyne cologieMedical EUROMED SRL, Obstetrica-Ginecologie, Bucuresti, Romania; i Ho 16 trique, Bice ^tre cedex, France; j Hamad Medical Corporation, Qatar and University of Glasgow, Glasgow, United Obste 17 ^ pital Saint-Antoine, Paris, France; l Department of Reproductive Medicine and Kingdom; k Service d'Endocrinologie, Ho Gynecology, University Medical Center Utrecht, Utrecht, The Netherlands; and m PregLem S.A., and n ObsEva S.A, Plan18 19 Q8 Les-Ouates, Geneva, Switzerland 20 21 22 23 Objective: To investigate the efficacy and safety of repeated 12-week courses of 5 or 10 mg daily ulipristal acetate for intermittent treatment of symptomatic uterine fibroids. 24 Design: Double-blind, randomized administration of four 12-week courses of ulipristal acetate. 25 Setting: XXX. 26 Q1 Patient(s): Four hundred fifty-one subjects with symptomatic uterine fibroid(s) and heavy menstrual bleeding. 27 Intervention(s): Four repeated 12-week treatment courses of daily 5 or 10 mg ulipristal acetate. 28 Main Outcome Measure(s): Endometrial safety and general safety, laboratory parameters, amenorrhea, controlled bleeding, fibroid 29 volume, quality of life (QoL), and pain. Result(s): Efficacy results, such as bleeding control and fibroid volume reduction, were in line with previously published data. Pain and 30 QoL showed marked improvements from screening, even during the off-treatment intervals. The safety profile of ulipristal acetate was 31 confirmed, and repeated treatment courses did not increase the occurrence of adverse reactions. There were no significant changes in 32 laboratory parameters during the study. The percentage of subjects with endometrial thickness R16 mm was 7.4% (all subjects) after the 33 first treatment course and returned to below screening levels (4.9%) in subsequent treatment courses. As in previous studies, ulipristal 34 acetate did not increase the occurrence of endometrial features of concern. The frequency of nonphysiological changes did not increase 35 with repeated treatment. They were observed in 17.8% and 13.3% of biopsies after treatment courses 2 and 4, respectively, and were 36 reversible after treatment cessation. 37 38 39 40 Received June 25, 2015; revised September 18, 2015; accepted September 21, 2015. 41 J.D. has been a member of the Scientific Advisory Board (SAB) of PregLem S.A. since 2007. He held PregLem stocks related to SAB activities that he sold in 42 October 2010 at PregLem's full acquisition by the Gedeon Richter Group. There is no relationship between stock payment value and future commercial performance of the study drug. O.D. and his institution received a grant for this study and support for travel to the investigator meetings. D.M. and her 43 institution received a grant for this study. H.-J.A. and his institution received a grant for this study, study equipment, and support for travel to the 44 investigator meetings for PEARL IV. R.H. and his institution received a grant for this study, study equipment, and support for travel to the investigator meetings for PEARL IV. J.Z. and his institution received a grant for this study, study equipment, and support for travel to the investigator meetings for 45 PEARL IV. Z.K. and her institution received a grant for this study and support for travel to the investigator meetings for PEARL IV. M.C.D. and his insti46 tution received a grant for this study and support for travel to the investigator meetings for PEARL IV. H.F. and his institution received a grant for this 47 study. D.H.B has been a member of the SAB of PregLem S.A. since 2007. He held PregLem stocks related to SAB activities that he sold in October 2010 at PregLem's full acquisition by the Gedeon Richter Group. There is no relationship between stock payment value and future commercial performance of 48 the study drug. P.B. is a member of PregLem's SAB. He held PregLem stocks related to SAB activities that he sold in October 2010 at PregLem's full 49 acquisition by the Gedeon Richter Group. There is no relationship between stock payment value and future commercial performance of the study drug. B.C.J.M.F. is a member of PregLem's SAB. He held PregLem stocks related to SAB activities that he sold in October 2010 at PregLem's full acqui50 sition by the Gedeon Richter Group. There is no relationship between stock payment value and future commercial performance of the study drug. E.B. 51 is an employee of PregLem S.A. She held PregLem stocks related to her employment that she sold in October 2010 at PregLem's full acquisition by the Gedeon Richter Group. There is no relationship between stock payment value and future commercial performance of the study drug. E.L. is a member 52 of PregLem's SAB. He received payment for consultancy and held PregLem stocks that he sold in October 2010 at PregLem's full acquisition by the 53 Gedeon Richter Group. There is no relationship between stock payment value and future commercial performance of the study drug. The clinical trial supporting this work was funded by PregLem S.A., Geneva, Switzerland. 54 Q7 te de Recherches pour l'Infertilite , 143, Avenue Grandchamp, B-1150 Brussels, Belgium (E-mail: jacques. Reprint requests: Jacques Donnez, M.D., Socie 55 [email protected]). 56 Fertility and Sterility® Vol. -, No. -, - 2015 0015-0282 57 Copyright ©2015 The Authors, Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ 58 by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.fertnstert.2015.09.032 59
Long-term medical management of uterine fibroids with ulipristal acetate
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Conclusion(s): The results of this study demonstrate the efficacy and further support the safety profile of repeated intermittent treatment of symptomatic fibroids with ulipristal acetate. Clinical Trial Registration Number: ClinicalTrials.gov (www.clinicaltrials.gov) registration number NCT01629563 (PEARL IV). (Fertil SterilÒ 2015;-:-–-. Ó2015 by American Society Use your smartphone for Reproductive Medicine.) to scan this QR code Key Words: Ulipristal acetate, uterine fibroid, pain, bleeding, fibroid volume, long-term and connect to the treatment Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/donnezj-ulipristal-acetate-uterine-fibroids-management/
terine fibroids are benign smooth muscle tumors of the uterus (1). When symptomatic, they are frequently responsible for heavy menstrual bleeding (2), infertility (2), and a decreased quality of life (3) (QoL). Ulipristal acetate (UPA) is a possible option for medical therapy. UPA is a steroid compound with the main pharmacodynamic property of reversibly blocking the P receptor in its target tissue, acting as a potent orally active P receptor modulator. It belongs to the class of selective P receptor modulators (SPRMs). UPA is indicated for preoperative and intermittent treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age. In the two short-term phase III studies for European registration PEARL I (4) (comparator: placebo) and PEARL II (5) (active comparator: leuprorelin acetate; a GnRH agonist authorized for preoperative treatment of fibroids), UPA was shown to be effective to control uterine bleeding related to myomas, to reduce myoma size, and to have a good safety profile. In clinical studies, SPRM administration has been associated with a pattern of benign, nonphysiological, nonproliferative, histologic features of the endometrium termed P receptor modulator associated endometrial changes (PAEC). These changes are characterized by cystic glandular dilatation, apoptosis, low mitotic activity in the glands and stroma, absence of stromal breakdown, and glandular crowding as clearly described by Williams et al. (6). The previous clinical studies illustrated the reversibility of PAEC on endometrial biopsies taken 6 months after UPA treatment completion. Two additional studies were initiated to assess the efficacy and safety of long-term, repeated, intermittent administration of UPA in patients with symptomatic fibroids. PEARL III and its extension (7) (long-term, intermittent, 10 mg/day for 3 months with drug-free intervals) demonstrated that this dosing regimen provided an effective and well-tolerated treatment of the symptoms of uterine myomas with efficient bleeding control accompanied by a reduction in fibroid volume. The PEARL IV study, reported here, was the second pivotal study to investigate the use of UPA for long-term intermittent use and the first one reporting results with the authorized dose of UPA 5 mg. The main objective was to assess the sustained efficacy and safety of up to four intermittent treatment courses with UPA 5 or 10 mg doses for uterine bleeding, myoma volume, pain, QoL, and safety. The results
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from the first two treatment courses have previously been published (8). The primary null hypothesis was that there would be no difference in the percentage of subjects who are in amenorrhea at the end of all four treatment courses for UPA 10 mg compared with UPA 5 mg. The data reported herein focus on the new findings from treatment courses 3 and 4 as well as the four treatment courses combined. With the recently registered indication of intermittent treatment with UPA, the absence of endometrial and laboratory safety findings associated with long-term therapy is of special interest to clinicians.
MATERIALS AND METHODS Study Design and Oversight The study design and oversight of the phase III double-blind, randomized PEARL IV study have been published elsewhere (7). PEARL IV was conducted in 46 centers in 11 European countries from June 2012 to December 2014. The study was approved by the independent ethics committees at each participating site and was conducted in accordance with the International Conference on Harmonization-Good Clinical Practice Guidelines. The study was designed by the sponsor (PregLem S.A.) with the involvement of academic investigators and a contract study statistician (CROS NT). Data were collected by an independent Contract Research Organization (ICON Clinical Research) and handled and analyzed by an independent Data Management organization (CROS NT). The first author vouches for the data accuracy and analysis and the fidelity of the study to the protocol.
Study Population Subjects enrolled in the study were premenopausal women with at least one fibroid R3 cm in diameter and none >12 cm (as assessed by ultrasound), heavy menstrual bleeding >100 (pictorial blood-loss assessment chart [PBAC]), and uterine size <16 weeks of gestation. Eligible subjects were aged between 18 and 50 years inclusive, with body mass index 18–40 (kg/m2) and regular menstrual cycles of 22–35 days with FSH %20 IU/L. Written informed consent was obtained from all subjects. The main exclusion criteria are listed in Supplemental Table 1. Q2 VOL. - NO. - / - 2015
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Randomization and Treatment Subjects were allocated randomly by a web-integrated voice response system in a 1:1 ratio to receive either 5 or 10 mg of daily oral UPA and matching placebos for four 12-week courses. UPA was started during the first 4 days of menstruation. Treatment courses were separated by a drug-free interval. Subsequent courses started with the second menstruation in the off-treatment period. Final follow-up was performed after a 3-month drug-free period following the fourth treatment course. The sequence of treatments and biopsies is illustrated in the Supplemental Figure 1.
Assessment of Uterine Bleeding Subjects recorded their bleeding intensity in a diary using an 8-day PBAC (Supplemental Fig. 2) at screening and during the first menstruation after treatment courses 1, 2, and 4. A PBAC score >100 indicates menorrhagia. Outside this timeframe, bleeding was recorded using a simplified semiquantitative questionnaire containing four categories defined as ‘‘no bleeding’’, ‘‘spotting’’, ‘‘bleeding’’, or ‘‘heavy bleeding’’.
Assessment of Endometrial Histology Endometrial biopsies were obtained at screening and posttreatment courses 2 and 4 and at 3 months post-treatment follow-up. Evaluation of all biopsies was performed by three independent pathologists who were blinded to visit sequence, study-group assignment, each other's assessments, and whether or not the subject had already received UPA treatment. The sample collection of endometrial tissue was performed by a gynecologist using a Pipelle de Cornier. To allow collection of sufficient biopsy material, the biopsy was performed in the late proliferative or early secretory phase of the menstrual cycle (i.e., at least 10–18 days after the start of menstruation).
Assessment of Fibroid Size and Endometrial Thickness Fibroid size and endometrial thickness measurements were carried out by transvaginal ultrasound at screening, at the end of treatment courses, and at follow-up. The ultrasonographer was blinded to the subject's treatment, and the same operator performed each subject's ultrasound assessments. At each visit, the three largest myomas and the endometrial thickness were measured. For consistent myoma volume evaluation, the ultrasonographer was requested to record the myomas in three dimensions as well as the type of myoma (submucosal, intramural, subserosal, pedunculated) and to photo-document the measurements.
Assessment of Pain and QoL Pain and QoL assessments were carried out at screening, at the start and end of each treatment course, and at post-treatment follow-up. Pain was assessed using a visual analogue scale ranging from 0 to 100, with higher scores indicating more severe pain. QoL was assessed using a validated questionnaire
measuring uterine fibroid symptom severity (UFS-QoL), where lower scores indicate fewer symptoms and where a level of 23 has been reported for healthy subjects (3).
Endpoints The primary efficacy endpoint for this study was the percentage of subjects in amenorrhea at the end of all four treatment courses, where amenorrhea was classified as no more than 1 day of spotting in a 35-day period. Secondary efficacy endpoints included amenorrhea at the end of each individual treatment course (1, 2, 3, and 4); controlled bleeding in the last 56 days of each individual treatment course (defined as no episodes of heavy bleeding and a maximum of 8 days of bleeding during the last 56 days of a treatment course); time to amenorrhea during treatment courses 1, 2, 3, and 4; volume of three largest fibroids; and pain and QoL. The results for treatment courses 1 and 2 have previously been published (8). The safety endpoints included the number and proportion of subjects withdrawing from treatment early for safety reasons and the number and proportion of subjects experiencing adverse events (AEs), including clinically significant changes in gynecological or breast examination, ovarian ultrasound, electrocardiogram (ECG), laboratory parameters, vital signs, and endometrial thickness and histology.
Statistical Analysis Efficacy analyses were carried out on both the full analysis set (FAS) and the per protocol set (PP). The population of primary interest was the FAS, which was defined as all randomized and treated patients. The PP set was defined as all subjects who had completed all four treatment courses with no major deviation in any treatment course. All statistical tests were two-sided, with a 5% level of significance. No adjustments were made for the multiple testing of secondary endpoints. In general, missing values were not imputed before analysis. However, if only 3 consecutive days or fewer of the daily bleeding pattern were missing, the missing values were imputed with the greatest strength of bleeding immediately before or after the period of missing days. The results for binary endpoints (including the primary efficacy endpoint) for UPA 10 mg versus UPA 5 mg were compared using c2-tests, with confidence intervals of the difference calculated using the Newcombe-Wilson score method (9). The change in total fibroid volume and uterine volume was analyzed via repeated-measures analysis of covariance after a log-transformation, with the results backtransformed before presentation. The change from baseline in PBAC scores was analyzed via the Wilcoxon rank-sum test with the Hodges-Lehmann estimator (and corresponding Moses confidence interval) used for the differences in medians (10). Assuming a drop-out rate of approximately 10%, 444 subjects were to be randomized for the study to have >85% power to detect an absolute difference in the primary endpoint of R14%. This level of absolute difference was
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based on the results of the previous registration studies and was therefore of clinical relevance (5).
RESULTS Patients Demographic and baseline characteristics were comparable across the two treatment groups. All patients had moderate to severe bleeding, and many had considerable pain as well as impaired QoL (Supplemental Table 2). Seventy-five percent of patients completed all four treatment courses. Treatment compliance across both groups was high (R80%), and the intertreatment intervals were on average 51–56 days between each treatment course for both groups.
Efficacy All efficacy results are presented for the FAS1 population, where subjects had to have started at least the first treatment course, unless other indicated. The percentages of subjects identified as being in amenorrhea for individual treatment courses 1, 2, 3, and 4 were 71.8%, 74.1%, 73.3%, and 69.6% in the 5 mg group and 82.6%, 82.2%, 78.3%, and 74.5% in the 10 mg group, respectively. A statistically significant difference was detected between the two treatment groups at the end of course 1 (P¼ .011) but not at the end of treatment courses 2, 3, and 4 (Table 1 and Supplemental Table 3). Of all subjects having started treatment, 48.7% in the 5 mg group and 60.5% in the 10 mg group were in amenorrhea in all four treatment courses (1, 2, 3, and 4 combined).
A statistically significant difference was found between the two treatment groups (P¼ .027). To avoid the impact of dropouts, the same analysis was also performed on the FAS4, where subjects had to have started the fourth treatment course, and the PP set 4 (PP4), where subjects had to be at least 80% compliant in each of the four courses with no major protocol deviations. For FAS 4 and for PP4, the percentage of subjects assessed as being in amenorrhea at the end of all four treatment courses was 62.7% and 63.1% in the 5 mg and 72.1% and 73.2% in the 10 mg groups, respectively. No statistically significant difference was found between the two treatment groups for either of these populations (Table 1 and Supplemental Table 3). The percentage of patients with controlled bleeding in the last 56 days for individual treatment courses ranged from 73.3% to 93.4% across both treatment groups, with corresponding median times to amenorrhea of 4–6 days in all groups for each treatment course. No statistically significant differences were detected between the two treatment groups at any of the time points (Table 1 and Supplemental Table 3). PBAC was measured at screening and after courses 1, 2, and 4 to assess the level of menstrual bleeding. In the 5-mg group, the mean (median) levels at screening were 300.2 (224.0), and these decreased with each subsequent course to levels of 139.7 (77.5) after course 4. The same pattern was also seen in the 10-mg group (screening, 304.0 [214.5]; after course 4, 128.2 [76.0]). No statistically significant differences were detected between the two treatment groups at any of the time points (Table 1 and Supplemental Table 3).
TABLE 1 Key efficacy outcomes (FAS 1 unless otherwise specified). UPA 5 mg (n [ 228)
UPA 10 mg (n [ 223)
Primary endpoint: amenorrhea at the end of all four treatment courses, n/N (%) 95/195 (48.7) 112/185 (60.5) FAS 1a 94/150 (62.7) 106/147 (72.1) FAS 4b c 94/149 (63.1) 104/142 (73.2) PP set 4 Secondary endpoints Controlled bleeding 106/158 (67.1) 105/146 (71.9) Controlled bleedingd at the end of all four treatment courses, n/N (%) 144/192 (75.0) Controlled bleedingd at the end of treatment 148/202 (73.3) course 4, n/N (%) PBAC PBAC scores, first menses postscreening, 300.2 (224.0) 304.0 (214.5) baseline actual, mean (median) PBAC scores, first menses post-treatment 139.7 (77.5) 128.2 (76.0) course 4, mean (median) 3 Total volume of three largest fibroids, cm End of treatment course 4 %CFB, median (IQR) 71.8 (87.6 to 32.6) 72.7 (87.5 to 47.0) Follow-up %CFB, median (IQR) 65.0 (85.1 to 28.4) 67.4 (87.4 to 44.6) Fibroid volume reduction R25%: end of treatment 135/166 (81.3) 150/170 (88.2) course 4, n/N (%)
Difference (95% CI) P (UPA 10 mg vs. UPA 5 mg) value 11.8 (1.9–21.8) 9.4 (1.2 to 20.0) 10.2 (0.5 to 20.8)
.027 .107 .084
4.8 (5.5 to 15.2)
.430
1.7 (6.9 to 10.4)
.781
NA
NA
11.0 (49.0 to 26.0)
.563
0.88 (0.69–1.13)e 0.87 (0.67–1.14)e NA
.314 .314 NA
Note: If a woman had more than 3 consecutive missing days in the last 35 d of a treatment course, the amenorrhea assessment was left as missing, unless the women had reported bleeding during these last 35 d (subject is not in amenorrhea). Sensitivity analyses for this endpoint are reported in the Supplemental Material (available online). Results of additional time points and other secondary endpoints can be found in Supplemental Table 3. IQR ¼ interquartile range; CFB ¼ change from baseline; %CFB ¼ percent change from baseline; NA ¼ no formal statistical analysis. a FAS 1 is defined as all subjects who received study treatment at least once for treatment course 1. b FAS 4 is defined as all subjects who received study medication in the fourth treatment course at least once. c PP set 4 is defined as all subjects who received study medication in the fourth treatment course for at least for 56 d. d Controlled bleeding was defined as no episodes of heavy bleeding and a maximum of 8 d of bleeding during the last 56 d of a course of treatment. e Ratio of UPA 10 mg ratio to baseline to UPA 5 mg ratio to baseline (95% CI). Donnez. Ulipristal acetate in uterine fibroids. Fertil Steril 2015.
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Clinically significant reduction of R25% volume of the three largest fibroids was reported after each treatment course. In both groups, the percentage of subjects with a clinically significant reduction increased from course 1 to course 4. In the 5-mg group, the percentages increased from 62.3% after course 1 to 78.1% after course 4. Similarly, in the 10mg group, the percentages increased from 66.5% to 80.5%. (Table 1 and Supplemental Table 3). Further examination showed that at the end of four treatment courses, 73.5% of all subjects had a fibroid volume reduction of R25% and were in amenorrhea (Supplemental Fig. 4). In addition, the percentage of subjects with a clinically significant volume reduction R50% increased from course 1 to course 4 in both treatment groups (Supplemental Table 3). Pain scores improved in both groups during treatment; the median overall pain scores in the 5- and 10-mg groups at screening were 39 and 43, respectively, and ranged from 5 to 7 during treatment. Even during the off-treatment periods, including follow-up, the median pain ranged from 9.0 to 22.5. No statistically significant differences were detected between the two treatment groups at any of the time points (Supplemental Tables 4A and 4B). Similarly, median UFS-QoL symptom severity scores of 50 at screening corresponded well to published symptom severity scores for fibroid patients (3). During treatment, median scores from 12.5 to 15.6 (which are scores comparable to those of healthy subjects [3]) indicated the important reduction of symptom severity in both groups. Even during the off-treatment periods, including follow-up, the median symptom severity score ranged from 18.8 to 31.3. No statistically significant differences were detected between the two treatment groups at any of the time points (Supplemental Tables 4A and 4B).
Endometrial Safety At screening for study eligibility, endometrial biopsies for a total of 493 subjects were reviewed by the central laboratory. Of these, nine (1.8%) subjects were not eligible for the study owing to abnormal findings (8 [1.6%] diagnoses of simple nonatypical hyperplasia and one diagnosis of complex nonatypical hyperplasia). A consensus diagnosis (at least two out of three pathologists in agreement) of benign endometrium was reached by the independent pathologists for all subjects accepted into the study. Benign polyps were reported in seven (1.7%) subjects. One subject from the 5-mg group had a diagnosis of complex atypical hyperplasia during the study. At follow-up and without any further medical or surgical intervention, this subject had a consensus diagnosis of benign endometrium. Four other subjects were reported to have benign polyps, and one subject from the 5-mg group was reported to have a hyperplasic polyp. All cases of hyperplasia observed after treatment (including the cases previously reported [7]) returned to benign endometrium under continued treatment (four courses) and/or during the follow-up period. One case of hyperplasia was reported in the follow-up biopsy (3 months after
treatment course 4). For this subject, all previous biopsies (including after treatment course 4) had been diagnosed as benign endometrium by the three independent pathologists. The occurrence of nonphysiological endometrial changes was observed in 7.8% of the 5-mg group and 8.4% of the 10mg group at screening. As expected, after treatment with UPA nonphysiological changes increased, but this increase was independent of the dose and the number of treatment courses. After treatment course 2, nonphysiological endometrial changes were observed in 16.3% and 19.2% of the biopsies for the 5- and 10-mg groups, respectively, decreasing to 16.2% and 10.3% after treatment course 4 (Table 2). At follow-up, in 286 biopsies adequate for review, nonphysiological changes were observed in 9.0% and 6.3% of the biopsies for the 5- and 10-mg groups, respectively, which compares to the observed values at screening. During the study, the median endometrial thickness remained between 7 and 8 mm. The percentage of subjects with endometrial thickness R16 mm was 7.4% (all subjects) after the first treatment course and returned to below screening levels (4.9%) in subsequent treatment courses. (Fig. 1 and Supplemental Table 3).
Laboratory Parameters The median Hb value at screening was 12.55 and 12.40 g/dL for subjects from the 5- and 10-mg groups, respectively. From treatment course 1 to treatment course 4, Hb levels increased compared with screening values, reaching a peak at the end of treatment course 4, with median levels for the 5- and 10-mg groups of 13.10 and 13.35 g/dL, respectively (Supplemental Table 5). The median Hct values at screening were 0.40 for both the 5- and 10-mg groups. During the study, Hct levels increased to reach a peak at the end of treatment course 2 for both treatment groups, median 0.42 (Supplemental Table 5). E2 levels remained stable in both treatment groups across the study period (Supplemental Table 5). At screening, four (1.8%) and seven (3.2%), subjects had high values (>ULN) for aspartate aminotransferase (AST) in Q3 the 5- and 10-mg groups, respectively. At the follow-up assessment, approximately 3 months after end of study treatment, four (2.4%) and six (3.6%) had high values in the two respective groups. For alanine aminotransferase (ALT), at screening four (1.8%) and two (0.9%) had high values, with two (1.2%) and four (2.4%) of patients also reporting high values at the follow-up assessment in the 5- and 10-mg groups, respectively. The number of subjects with high gamma glutamyl transferase (GGT) levels at screening were 14 (6.1%) and 10 (4.5%) for the 5- and 10-mg groups, respectively, with 12 (7.1%) and 15 (9.0%) also reporting high levels at follow-up (Supplemental Table 6). For all lipid parameters, the levels for subjects from the 5and 10-mg groups were comparable during the study. At screening, the median levels of total cholesterol for the two groups were 4.93 and 5.03 mmol/L. The levels remained stable at each subsequent assessment, with medians ranging from 5.21 to 5.48. The median levels of low-density lipoprotein cholesterol for the two groups were 2.90 and 2.97 mmol/L
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ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649
TABLE 2 Summary of endometrium biopsy results (safety population). Visits Category
Classification
Screening
After treatment 2
After treatment 4
Follow-up
Endometrium biopsy performed Specimen adequatea Primary diagnosisb
Yes Yes Benign endometrium Hyperplasia Simple, nonatypical Complex, nonatypical Simple, atypical Complex, atypical Malignant neoplasm Endometrial adenocarcinomac Other malignant neoplasm Absent Present: benign Present: hyperplasic Present: carcinomatous Nonphysiological changes observed by two or three pathologistsb Yes Yes Benign endometrium Hyperplasia Simple, nonatypical Complex, nonatypical Simple, atypical Complex, atypical Malignant neoplasm Endometrial adenocarcinoma Other malignant neoplasm Absent Present: benign Present: hyperplasic Present: carcinomatous Nonphysiological changes observed by two or three pathologistsb
230 219 (95.2) 219 (100.0) 0 0 0 0 0 0 0
193 178 (92.2) 176 (98.9) 1 (0.6) 1 (0.6) 0 0 0 1 (0.6) 1 (0.6)
168 148 (88.1) 147 (99.3) 1 (0.7) 0 0 0 1 (0.7) 0 0
164 144 (87.8) 143 (99.3) 1 (0.7) 0 0 0 1 0 0
0 216 (98.6) 3 (1.4) 0 0 17 (7.8)
0 176 (98.9) 2 (1.1) 0 0 29 (16.3)
0 146 (98.6) 1 (0.7) 1 (0.7) 0 24 (16.2)
0 143 (99.3) 1 (0.7) 0 0 13 (9.0)
220 203 (92.3) 203 (100.0) 0 0 0 0 0 0 0 0 199 (98.0) 4 (2.0) 0 0 17 (8.4)
194 182 (93.8) 180 (98.9) 2 (1.1) 1 (0.5) 0 1 (0.5) 0 0 0 0 180 (98.9) 2 (1.1) 0 0 35 (19.2)
163 145 (89.0) 145 (100.0) 0 0 0 0 0 0 0 0 142 (97.9) 3 (2.1) 0 0 15 (10.3)
160 142 (88.8) 142 (100.0) 0 0 0 0 0 0 0 0 142 (100) 0 0 0 9 (6.3)
Treatment group UPA 5 mg (n ¼ 230)
Polypsb
Of those with Benign endometrium UPA 10 mg (n ¼ 221)
Endometrium Biopsy performed Specimen adequatea Primary Diagnosisb
Polypsb
Of those with benign endometrium
Note: Numbers in parentheses are percents. In addition to cases of hyperplasia captured at nominated protocol visits, one consensus diagnosis of simple atypical hyperplasia was reported after the unscheduled histology review of material taken by curettage after the SAE of menorrhagia after treatment course 1. At early termination visit approximately 1 mo later, this subject had a consensus diagnosis of benign endometrium. a Denominator of percentage is the number of subjects that have an endometrium biopsy performed. b Denominator of percentage is the number of subjects with an adequate specimen. c Preexisting condition. Donnez. Ulipristal acetate in uterine fibroids. Fertil Steril 2015.
at screening, and these remained stable at each subsequent assessment, with medians ranging from 2.99 to 3.23. Following the same pattern, at screening, the median levels of high-density lipoprotein cholesterol for the two groups were 1.61 and 1.55 mmol/L. The levels remained stable at each subsequent assessment across the treatment groups, with medians ranging from 1.64 to 1.71. Levels of triglycerides increased slightly during the study. At screening, the medians in the 5- and 10-mg groups were 0.87 and 0.91 mmol/L, respectively, increasing to median levels of 0.97 and 1.08 at the follow-up assessment (Supplemental Table 5). Furthermore, at screening, 27 (11.8%) and 30 (13.7%) subjects had high values (>ULN) for triglycerides in the 5- and 10-mg groups, respectively. Similarly at the follow-up assessment, 27 (16.0%) and 26 (15.6%) had high values in the two respective groups (Supplemental Table 6).
General Safety The numbers (percentages) of subjects who reported AEs during treatment courses 1, 2, 3, and 4 were 102 (44.3%), 59 (27.4%), 32 (16.6%), and 43 (23.9%), respectively, for the 5mg group and 98 (44.3%), 60 (29.3%), 38 (20.2%), and 33 (19.0%), respectively, for the 10-mg group (Supplemental Table 7). The numbers (percentages) of subjects who reported AEs considered as treatment related by the investigator during treatment courses 1, 2, 3, and 4 were 47 (20.4%), 28 (13.0%), 9 (4.7%), and 11 (6.1%), respectively, for the 5-mg group and 43 (19.5%), 22 (10.7%), 12 (6.4%), and 14 (8.0%), respectively, for the 10-mg group. The vast majority of AEs (97.6%) were of mild or moderate severity in both groups. Headaches and hot flushes were the most frequently reported AEs (%11% of subjects in any treatment course), VOL. - NO. - / - 2015
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Percentage of patients
709 FIGURE 1 710 711 Patients with endometrial thickness >16mm (Safety population) 712 713 10 714 UPA 5 mg 715 UPA 10 mg 8.7 8 716 717 718 6 6.1 719 720 4.9 5.0 4 721 3.8 3.6 722 3.1 723 2 2.4 724 1.7 1.2 725 0.6 0.6 0 726 Baseline After course After course After course After course Follow Up 727 1* 2* 3* 4* 728 N=225 N=214 N=192 N=182 N=170 N=166 729 N=220 N=207 N=193 N=180 N=164 N=168 730 * After treatment course + 1 bleed 731 N, number of patients in whom endometrial thickness was measured 732 UPA, ulipristal acetate 733 Percentage of patients with endometrial thickness >16 mm. 734 Donnez. Ulipristal acetate in uterine fibroids. Fertil Steril 2015. 735 736 737 738 739 although the frequency of these events decreased with each could be used only for a limited period owing to the AE profile 740 Q4 successive treatment course (Supplemental Table 7). Breast and rapid fibroid regrowth after treatment cessation (5). 741 pain/discomfort was observed in %3% of subjects, with a Among the latest possible therapeutic options (11), UPA has 742 decrease in frequency for each successive treatment course proved to be a suitable alternative for the medical manage743 (%1% by treatment course 4). In total, 114 (25.3%) patients ment of fibroids. 744 discontinued the study at any time and for any reason. Of Out of the 451 subjects with symptomatic uterine fibroids 745 those, 32 patients discontinued due to AEs, of which 21 and confirmed menorrhagia recruited, 75% of subjects re746 were considered related to study drug. No difference between mained in the study on average a total of 20 months, demon747 Q5 treatment groups was observed. Overall 34 SAEs were restrating a good compliance with the protocol considering the 748 ported; 21 in the 5-mg group and 13 in the 10-mg group. duration of the study. 749 Of these, 13 were classified by the investigator as related to Investigation of the rate of amenorrhea during each treat750 study medication: nine in the 5 mg-group (five menorrhagia, ment course showed that both UPA 5 and 10 mg led to amen751 one bipolar disorder, one spontaneous myoma expulsion, one orrhea in a high percentage of subjects (R70%). Amenorrhea 752 abdominal pain, one back pain) and four in the 10-mg group was reached on average within 1 week, and post-treatment 753 (one partial expulsion, one spontaneous myoma expulsion, menstrual bleeding was markedly reduced compared with 754 one myoma necrosis, one endometriosis). pretreatment bleeding. 755 No safety concerns were identified from physical examiA high percentage of subjects were in amenorrhea for all 756 nation, vital signs, ovarian ultrasound, and ECGs. treatment courses combined. The small observed difference 757 between the treatment groups was within the predefined 758 acceptable difference of 14% and was therefore not deemed DISCUSSION 759 to be clinically relevant. This was confirmed by the analysis 760 The PEARL IV study was designed to investigate the safety of the group of subjects who had started all four courses, 761 and efficacy of long-term, repeated intermittent treatment which found no statistically significant difference between 762 with four 12-week treatment courses of daily oral administrathe groups. 763 tion of either 5 or 10 mg of UPA in subjects with uterine fiAn additional secondary endpoint of importance in as764 broids. This is the first full clinical trial reporting the use of sessing the efficacy of UPA is the evaluation of bleeding con765 UPA 5 mg in a long-term repeated intermittent manner. trol. No difference between the treatment groups was seen, 766 Alternative treatment options previously available for the with both groups showing R73% of subjects having bleeding 767 medical management of fibroids, such as GnRH agonists, control during each independent treatment course. This data VOL. - NO. - / - 2015
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ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885
confirm previously known data (4, 5, 7, 8) regarding the efficacy of UPA with regards to controlling bleeding symptoms in subjects with symptomatic uterine fibroids. Furthermore, assessment of the blood loss during the first menstrual bleed after the treatment courses using the PBAC showed a marked progressive reduction from baseline with no difference between the two treatment groups. Hb levels and associated hematology parameters increased over the first two treatment courses and were sustained until follow-up. The total volume of the three largest myomas was shown to decrease after the first treatment course and was seen to further decrease after each subsequent treatment course. The reduction in volume was maintained thereafter until the end of study follow-up. A similar level of response was seen from both treatment groups with no statistically significant differences between them at any visit during the study. Furthermore, over 73% of all subjects had both fibroid volume reduction R25% at the end of four treatment courses in combination with being in amenorrhea (Supplemental Fig. 4). For pain and QoL, an important improvement was recorded during treatment in these assessments, reaching scores reported for healthy individuals, in both treatment groups (3). The changes in these measurements were of a similar level between the two treatment groups. The results therefore show that the use of UPA results in an improvement in QoL and control of pain, in comparison to baseline, even during the off-treatment intervals. After a transient increase in endometrial thickness in the first treatment course, fewer subjects had endometrial thickness >16 mm after each successive treatment course. No important differences with regards to endometrial thickness were observed between the 5- and 10-mg groups. Over the entire observation period, six cases of hyperplasia were observed. All cases of hyperplasia observed after treatment returned to benign endometrium under continued treatment and/or during the follow-up period. The occurrence of hyperplasia in a follow-up biopsy in a subject having been exposed to four courses of UPA and for whom all previous biopsies (including the one taken after the end of treatment course 4) had been diagnosed as benign endometrium by all pathologists illustrates that hyperplasia can occur spontaneously in this population. Overall, the occurrence of nonphysiological changes of the endometrium was not increased with repetition of treatment courses and returned to pretreatment levels within 3 months of completion of treatment. Levels of E2 remained well above postmenopausal levels, suggesting that bone mineral density will not be adversely impacted by repeated intermittent use of UPA. Mean levels of AST and ALT did not alter during the study; however, some sporadic increases were seen in individual subjects. In no subject were increases in transaminases associated with increases in bilirubin. There were mild increases in mean cholesterol and triglyceride values during the study. At screening, 41.4% of all subjects had total cholesterol >ULN, and, as expected in such a long-term study recruiting women predominantly in their 40s, a number of subjects showed modest increases in
cholesterol over the duration of the study (approximately 20 months). However, the median ratio of total cholesterol/ high-density lipoprotein cholesterol remained virtually unchanged and below the level at which the risk of cardiovascular disease is considered to be increased. More on-treatment AEs were reported during treatment course 1 than during subsequent treatment courses, and the most frequently reported on-treatment AEs were headache and hot flush. No other AE occurred at a frequency of >4% of subjects, and over 97% of all reported on-treatment AEs were rated as being of mild or moderate severity. Overall, there were no differences between the 5- and 10-mg dosing groups with respect to the type, frequency, and severity of AEs.
Conclusions The current manuscript summarizes the full efficacy and safety results of the first randomized controlled trial using the approved dose of 5 mg UPA in a repeated, intermittent therapy setting (four courses) for the management of uterine fibroids. The administration of four 12-week treatment courses of UPA at doses of 5 and 10 mg was well tolerated, with a high level of treatment compliance. No differences between the 5 and 10 mg dosing groups were recorded in terms of safety evaluations, which include a comprehensive evaluation of the endometrial characteristics and laboratory parameters observed with the long-term use of UPA. In terms of efficacy, both doses provided efficient bleeding control leading to amenorrhea in the majority of subjects in each of the four treatment courses. This bleeding control was achieved very rapidly and was accompanied by a reduction in fibroid volume and a reduction of pain associated with a clinically significant improvement in QoL with both doses. Furthermore, even during off-treatment periods, the level of bleeding, pain, and QoL were still improved compared with baseline. Myoma reduction was largely maintained during the off-treatment periods, and these effects were sustained until the end of study follow-up, approximately 3 months after completion of the four treatment courses. The results of this study therefore demonstrate the efficacy and further verify the safety profile associated with repeated intermittent treatment of symptomatic fibroids with UPA. Acknowledgments: The authors thank Kerry Ferrero of PregLem S.A. for assistance with the preparation of the manuscript with the support of Pablo Arriagada and Helen Saunders of PregLem S.A.
REFERENCES 1. 2. 3.
Parker WH. Etiology, symptomatology and diagnosis of uterine myoma. Fertil Steril 2007;87:726–36. Gupta S, Jose J, Manyonda I. Clinical presentation of fibroids. Best Pract Res Clin Obstet Gynaecol 2008;22:615–26. Spies JB, Coyne K, Guaou GN, Boyle D, Skyrnarz-Murphy K, Gonzalves SM. The UFS-QOL, a new disease-specific symptom and health-related quality of life questionnaire for leiomyomata. Obstet Gynecol 2002;99:290–300. VOL. - NO. - / - 2015
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Fertility and Sterility® 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003
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5.
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7.
Donnez J, Tatarchuk TF, Bouchard P, Puscasiu L, Zakharenko NF, Ivanova T, et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med 2012;366:409–20. Donnez J, Tomaszewski J, Vazquez F, Bouchard P, Lemiezczuk B, Baro F, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012;366:421–32. Williams AR, Bergeron C, Barlow DH, Ferenczy A. Endometrial morphology after treatment of uterine fibroids with the selective progesterone receptor modulator, ulipristal acetate. Int J Gynecol Pathol 2012;31:556–69. Donnez J, Vazquez F, Tomaszewski J, Nouri K, Bouchard P, Bauser BC, et al. Long-term treatment of uterine fibroids with ulipristal acetate. Fertil Steril 2014;101:1565–73.
8.
Donnez J, Hudecek R, Donnez O, Matule D, Ahrendt HJ, Zatik J, et al. Efficacy and safety of repeated use of ulipristal acetate in uterine fibroids. Fertil Steril 2015;103:519–27. 9. Newcombe RB. Interval estimation for the difference between independent proportions: comparison of eleven methods. Stat Med 1998;17:873–90 [Erratum, Stat Med 1999;18:1293]. 10. Hollander M, Wolfe DA. Nonparametric statistical methods. 1st ed. New York: John Wiley & Sons; 1973:75–82. 11. Islam MS, Protic O, Giannubilo SR, Toti P, Tranquilli AL, Petraglia F, et al. Uterine leiomyoma: available medical treatments and new possible therapeutic options. J Clin Endocrinol Metab 2013;98: 921–34.
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ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121
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SUPPLEMENTAL FIGURE 1
Schedule of treatments and visits. Donnez. Ulipristal acetate in uterine fibroids. Fertil Steril 2015.
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Fertility and Sterility®
SUPPLEMENTAL FIGURE 2 Day 1
Day 1 of menstruation:
2
3
4
5
6
7
2 0 D D
Score
M M
Y Y Y Y
No bleeding
Towels
1 5 20 Tampons 1 5 10 Small clots/flooding
1
web 4C=FPO
1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239
2cm
Large clots/flooding
5
3cm
PBAC, one of the current standard methods used to objectively estimate menstrual blood loss and diagnose menorrhagia. The method that was Q6 developed and validated by Higham and Janssen defines excessive bleeding as a PBAC score >100. Donnez. Ulipristal acetate in uterine fibroids. Fertil Steril 2015.
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ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357
SUPPLEMENTAL FIGURE 3 Screened N=555
Patient disposition. Withdrawals are presented according to the timeframes in which they occurred, either during treatment or after treatment completion for each course. Two subjects randomized to the UPA 10 mg group received UPA 5 mg treatment in error; these subjects are included in the FAS sets according to randomization and in the safety set according to treatment received. Donnez. Ulipristal acetate in uterine fibroids. Fertil Steril 2015.
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SUPPLEMENTAL FIGURE 4
Yes
No
Yes
73.5%
7.8%
No
Subjects in Amenorrhoea
Clinically significant reduction in fibroid volume (>25%)
1417 1418 1419 1420 1421 1422 1423 1424 1425 1426 1427 1428 1429 1430 1431 1432 1433 1434 1435 1436 1437 1438 1439 1440 1441 1442 1443 1444 1445 1446 1447 1448 1449 1450 1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 1462 1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1475
13.9%
4.8%
Amenorrhea and/or fibroid volume reduction. Percentage of subjects with amenorrhea and/or a clinically significant reduction in fibroid volume (>25%). Donnez. Ulipristal acetate in uterine fibroids. Fertil Steril 2015.
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Long-term medical management of uterine fibroids with ulipristal acetate
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Conclusion(s): The results of this study demonstrate the efficacy and further support the safety profile of repeated intermittent treatment of symptomatic fibroids with ulipristal acetate. Clinical Trial Registration Number: ClinicalTrials.gov (www.clinicaltrials.gov) registration number NCT01629563 (PEARL IV). (Fertil SterilÒ 2015;-:-–-. Ó2015 by American Society Use your smartphone for Reproductive Medicine.) to scan this QR code Key Words: Ulipristal acetate, uterine fibroid, pain, bleeding, fibroid volume, long-term and connect to the treatment Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/donnezj-ulipristal-acetate-uterine-fibroids-management/
terine fibroids are benign smooth muscle tumors of the uterus (1). When symptomatic, they are frequently responsible for heavy menstrual bleeding (2), infertility (2), and a decreased quality of life (3) (QoL). Ulipristal acetate (UPA) is a possible option for medical therapy. UPA is a steroid compound with the main pharmacodynamic property of reversibly blocking the P receptor in its target tissue, acting as a potent orally active P receptor modulator. It belongs to the class of selective P receptor modulators (SPRMs). UPA is indicated for preoperative and intermittent treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age. In the two short-term phase III studies for European registration PEARL I (4) (comparator: placebo) and PEARL II (5) (active comparator: leuprorelin acetate; a GnRH agonist authorized for preoperative treatment of fibroids), UPA was shown to be effective to control uterine bleeding related to myomas, to reduce myoma size, and to have a good safety profile. In clinical studies, SPRM administration has been associated with a pattern of benign, nonphysiological, nonproliferative, histologic features of the endometrium termed P receptor modulator associated endometrial changes (PAEC). These changes are characterized by cystic glandular dilatation, apoptosis, low mitotic activity in the glands and stroma, absence of stromal breakdown, and glandular crowding as clearly described by Williams et al. (6). The previous clinical studies illustrated the reversibility of PAEC on endometrial biopsies taken 6 months after UPA treatment completion. Two additional studies were initiated to assess the efficacy and safety of long-term, repeated, intermittent administration of UPA in patients with symptomatic fibroids. PEARL III and its extension (7) (long-term, intermittent, 10 mg/day for 3 months with drug-free intervals) demonstrated that this dosing regimen provided an effective and well-tolerated treatment of the symptoms of uterine myomas with efficient bleeding control accompanied by a reduction in fibroid volume. The PEARL IV study, reported here, was the second pivotal study to investigate the use of UPA for long-term intermittent use and the first one reporting results with the authorized dose of UPA 5 mg. The main objective was to assess the sustained efficacy and safety of up to four intermittent treatment courses with UPA 5 or 10 mg doses for uterine bleeding, myoma volume, pain, QoL, and safety. The results
U
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from the first two treatment courses have previously been published (8). The primary null hypothesis was that there would be no difference in the percentage of subjects who are in amenorrhea at the end of all four treatment courses for UPA 10 mg compared with UPA 5 mg. The data reported herein focus on the new findings from treatment courses 3 and 4 as well as the four treatment courses combined. With the recently registered indication of intermittent treatment with UPA, the absence of endometrial and laboratory safety findings associated with long-term therapy is of special interest to clinicians.
MATERIALS AND METHODS Study Design and Oversight The study design and oversight of the phase III double-blind, randomized PEARL IV study have been published elsewhere (7). PEARL IV was conducted in 46 centers in 11 European countries from June 2012 to December 2014. The study was approved by the independent ethics committees at each participating site and was conducted in accordance with the International Conference on Harmonization-Good Clinical Practice Guidelines. The study was designed by the sponsor (PregLem S.A.) with the involvement of academic investigators and a contract study statistician (CROS NT). Data were collected by an independent Contract Research Organization (ICON Clinical Research) and handled and analyzed by an independent Data Management organization (CROS NT). The first author vouches for the data accuracy and analysis and the fidelity of the study to the protocol.
Study Population Subjects enrolled in the study were premenopausal women with at least one fibroid R3 cm in diameter and none >12 cm (as assessed by ultrasound), heavy menstrual bleeding >100 (pictorial blood-loss assessment chart [PBAC]), and uterine size <16 weeks of gestation. Eligible subjects were aged between 18 and 50 years inclusive, with body mass index 18–40 (kg/m2) and regular menstrual cycles of 22–35 days with FSH %20 IU/L. Written informed consent was obtained from all subjects. The main exclusion criteria are listed in Supplemental Table 1. Q2 VOL. - NO. - / - 2015
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Randomization and Treatment Subjects were allocated randomly by a web-integrated voice response system in a 1:1 ratio to receive either 5 or 10 mg of daily oral UPA and matching placebos for four 12-week courses. UPA was started during the first 4 days of menstruation. Treatment courses were separated by a drug-free interval. Subsequent courses started with the second menstruation in the off-treatment period. Final follow-up was performed after a 3-month drug-free period following the fourth treatment course. The sequence of treatments and biopsies is illustrated in the Supplemental Figure 1.
Assessment of Uterine Bleeding Subjects recorded their bleeding intensity in a diary using an 8-day PBAC (Supplemental Fig. 2) at screening and during the first menstruation after treatment courses 1, 2, and 4. A PBAC score >100 indicates menorrhagia. Outside this timeframe, bleeding was recorded using a simplified semiquantitative questionnaire containing four categories defined as ‘‘no bleeding’’, ‘‘spotting’’, ‘‘bleeding’’, or ‘‘heavy bleeding’’.
Assessment of Endometrial Histology Endometrial biopsies were obtained at screening and posttreatment courses 2 and 4 and at 3 months post-treatment follow-up. Evaluation of all biopsies was performed by three independent pathologists who were blinded to visit sequence, study-group assignment, each other's assessments, and whether or not the subject had already received UPA treatment. The sample collection of endometrial tissue was performed by a gynecologist using a Pipelle de Cornier. To allow collection of sufficient biopsy material, the biopsy was performed in the late proliferative or early secretory phase of the menstrual cycle (i.e., at least 10–18 days after the start of menstruation).
Assessment of Fibroid Size and Endometrial Thickness Fibroid size and endometrial thickness measurements were carried out by transvaginal ultrasound at screening, at the end of treatment courses, and at follow-up. The ultrasonographer was blinded to the subject's treatment, and the same operator performed each subject's ultrasound assessments. At each visit, the three largest myomas and the endometrial thickness were measured. For consistent myoma volume evaluation, the ultrasonographer was requested to record the myomas in three dimensions as well as the type of myoma (submucosal, intramural, subserosal, pedunculated) and to photo-document the measurements.
Assessment of Pain and QoL Pain and QoL assessments were carried out at screening, at the start and end of each treatment course, and at post-treatment follow-up. Pain was assessed using a visual analogue scale ranging from 0 to 100, with higher scores indicating more severe pain. QoL was assessed using a validated questionnaire
measuring uterine fibroid symptom severity (UFS-QoL), where lower scores indicate fewer symptoms and where a level of 23 has been reported for healthy subjects (3).
Endpoints The primary efficacy endpoint for this study was the percentage of subjects in amenorrhea at the end of all four treatment courses, where amenorrhea was classified as no more than 1 day of spotting in a 35-day period. Secondary efficacy endpoints included amenorrhea at the end of each individual treatment course (1, 2, 3, and 4); controlled bleeding in the last 56 days of each individual treatment course (defined as no episodes of heavy bleeding and a maximum of 8 days of bleeding during the last 56 days of a treatment course); time to amenorrhea during treatment courses 1, 2, 3, and 4; volume of three largest fibroids; and pain and QoL. The results for treatment courses 1 and 2 have previously been published (8). The safety endpoints included the number and proportion of subjects withdrawing from treatment early for safety reasons and the number and proportion of subjects experiencing adverse events (AEs), including clinically significant changes in gynecological or breast examination, ovarian ultrasound, electrocardiogram (ECG), laboratory parameters, vital signs, and endometrial thickness and histology.
Statistical Analysis Efficacy analyses were carried out on both the full analysis set (FAS) and the per protocol set (PP). The population of primary interest was the FAS, which was defined as all randomized and treated patients. The PP set was defined as all subjects who had completed all four treatment courses with no major deviation in any treatment course. All statistical tests were two-sided, with a 5% level of significance. No adjustments were made for the multiple testing of secondary endpoints. In general, missing values were not imputed before analysis. However, if only 3 consecutive days or fewer of the daily bleeding pattern were missing, the missing values were imputed with the greatest strength of bleeding immediately before or after the period of missing days. The results for binary endpoints (including the primary efficacy endpoint) for UPA 10 mg versus UPA 5 mg were compared using c2-tests, with confidence intervals of the difference calculated using the Newcombe-Wilson score method (9). The change in total fibroid volume and uterine volume was analyzed via repeated-measures analysis of covariance after a log-transformation, with the results backtransformed before presentation. The change from baseline in PBAC scores was analyzed via the Wilcoxon rank-sum test with the Hodges-Lehmann estimator (and corresponding Moses confidence interval) used for the differences in medians (10). Assuming a drop-out rate of approximately 10%, 444 subjects were to be randomized for the study to have >85% power to detect an absolute difference in the primary endpoint of R14%. This level of absolute difference was
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based on the results of the previous registration studies and was therefore of clinical relevance (5).
RESULTS Patients Demographic and baseline characteristics were comparable across the two treatment groups. All patients had moderate to severe bleeding, and many had considerable pain as well as impaired QoL (Supplemental Table 2). Seventy-five percent of patients completed all four treatment courses. Treatment compliance across both groups was high (R80%), and the intertreatment intervals were on average 51–56 days between each treatment course for both groups.
Efficacy All efficacy results are presented for the FAS1 population, where subjects had to have started at least the first treatment course, unless other indicated. The percentages of subjects identified as being in amenorrhea for individual treatment courses 1, 2, 3, and 4 were 71.8%, 74.1%, 73.3%, and 69.6% in the 5 mg group and 82.6%, 82.2%, 78.3%, and 74.5% in the 10 mg group, respectively. A statistically significant difference was detected between the two treatment groups at the end of course 1 (P¼ .011) but not at the end of treatment courses 2, 3, and 4 (Table 1 and Supplemental Table 3). Of all subjects having started treatment, 48.7% in the 5 mg group and 60.5% in the 10 mg group were in amenorrhea in all four treatment courses (1, 2, 3, and 4 combined).
A statistically significant difference was found between the two treatment groups (P¼ .027). To avoid the impact of dropouts, the same analysis was also performed on the FAS4, where subjects had to have started the fourth treatment course, and the PP set 4 (PP4), where subjects had to be at least 80% compliant in each of the four courses with no major protocol deviations. For FAS 4 and for PP4, the percentage of subjects assessed as being in amenorrhea at the end of all four treatment courses was 62.7% and 63.1% in the 5 mg and 72.1% and 73.2% in the 10 mg groups, respectively. No statistically significant difference was found between the two treatment groups for either of these populations (Table 1 and Supplemental Table 3). The percentage of patients with controlled bleeding in the last 56 days for individual treatment courses ranged from 73.3% to 93.4% across both treatment groups, with corresponding median times to amenorrhea of 4–6 days in all groups for each treatment course. No statistically significant differences were detected between the two treatment groups at any of the time points (Table 1 and Supplemental Table 3). PBAC was measured at screening and after courses 1, 2, and 4 to assess the level of menstrual bleeding. In the 5-mg group, the mean (median) levels at screening were 300.2 (224.0), and these decreased with each subsequent course to levels of 139.7 (77.5) after course 4. The same pattern was also seen in the 10-mg group (screening, 304.0 [214.5]; after course 4, 128.2 [76.0]). No statistically significant differences were detected between the two treatment groups at any of the time points (Table 1 and Supplemental Table 3).
TABLE 1 Key efficacy outcomes (FAS 1 unless otherwise specified). UPA 5 mg (n [ 228)
UPA 10 mg (n [ 223)
Primary endpoint: amenorrhea at the end of all four treatment courses, n/N (%) 95/195 (48.7) 112/185 (60.5) FAS 1a 94/150 (62.7) 106/147 (72.1) FAS 4b c 94/149 (63.1) 104/142 (73.2) PP set 4 Secondary endpoints Controlled bleeding 106/158 (67.1) 105/146 (71.9) Controlled bleedingd at the end of all four treatment courses, n/N (%) 144/192 (75.0) Controlled bleedingd at the end of treatment 148/202 (73.3) course 4, n/N (%) PBAC PBAC scores, first menses postscreening, 300.2 (224.0) 304.0 (214.5) baseline actual, mean (median) PBAC scores, first menses post-treatment 139.7 (77.5) 128.2 (76.0) course 4, mean (median) 3 Total volume of three largest fibroids, cm End of treatment course 4 %CFB, median (IQR) 71.8 (87.6 to 32.6) 72.7 (87.5 to 47.0) Follow-up %CFB, median (IQR) 65.0 (85.1 to 28.4) 67.4 (87.4 to 44.6) Fibroid volume reduction R25%: end of treatment 135/166 (81.3) 150/170 (88.2) course 4, n/N (%)
Difference (95% CI) P (UPA 10 mg vs. UPA 5 mg) value 11.8 (1.9–21.8) 9.4 (1.2 to 20.0) 10.2 (0.5 to 20.8)
.027 .107 .084
4.8 (5.5 to 15.2)
.430
1.7 (6.9 to 10.4)
.781
NA
NA
11.0 (49.0 to 26.0)
.563
0.88 (0.69–1.13)e 0.87 (0.67–1.14)e NA
.314 .314 NA
Note: If a woman had more than 3 consecutive missing days in the last 35 d of a treatment course, the amenorrhea assessment was left as missing, unless the women had reported bleeding during these last 35 d (subject is not in amenorrhea). Sensitivity analyses for this endpoint are reported in the Supplemental Material (available online). Results of additional time points and other secondary endpoints can be found in Supplemental Table 3. IQR ¼ interquartile range; CFB ¼ change from baseline; %CFB ¼ percent change from baseline; NA ¼ no formal statistical analysis. a FAS 1 is defined as all subjects who received study treatment at least once for treatment course 1. b FAS 4 is defined as all subjects who received study medication in the fourth treatment course at least once. c PP set 4 is defined as all subjects who received study medication in the fourth treatment course for at least for 56 d. d Controlled bleeding was defined as no episodes of heavy bleeding and a maximum of 8 d of bleeding during the last 56 d of a course of treatment. e Ratio of UPA 10 mg ratio to baseline to UPA 5 mg ratio to baseline (95% CI). Donnez. Ulipristal acetate in uterine fibroids. Fertil Steril 2015.
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Clinically significant reduction of R25% volume of the three largest fibroids was reported after each treatment course. In both groups, the percentage of subjects with a clinically significant reduction increased from course 1 to course 4. In the 5-mg group, the percentages increased from 62.3% after course 1 to 78.1% after course 4. Similarly, in the 10mg group, the percentages increased from 66.5% to 80.5%. (Table 1 and Supplemental Table 3). Further examination showed that at the end of four treatment courses, 73.5% of all subjects had a fibroid volume reduction of R25% and were in amenorrhea (Supplemental Fig. 4). In addition, the percentage of subjects with a clinically significant volume reduction R50% increased from course 1 to course 4 in both treatment groups (Supplemental Table 3). Pain scores improved in both groups during treatment; the median overall pain scores in the 5- and 10-mg groups at screening were 39 and 43, respectively, and ranged from 5 to 7 during treatment. Even during the off-treatment periods, including follow-up, the median pain ranged from 9.0 to 22.5. No statistically significant differences were detected between the two treatment groups at any of the time points (Supplemental Tables 4A and 4B). Similarly, median UFS-QoL symptom severity scores of 50 at screening corresponded well to published symptom severity scores for fibroid patients (3). During treatment, median scores from 12.5 to 15.6 (which are scores comparable to those of healthy subjects [3]) indicated the important reduction of symptom severity in both groups. Even during the off-treatment periods, including follow-up, the median symptom severity score ranged from 18.8 to 31.3. No statistically significant differences were detected between the two treatment groups at any of the time points (Supplemental Tables 4A and 4B).
Endometrial Safety At screening for study eligibility, endometrial biopsies for a total of 493 subjects were reviewed by the central laboratory. Of these, nine (1.8%) subjects were not eligible for the study owing to abnormal findings (8 [1.6%] diagnoses of simple nonatypical hyperplasia and one diagnosis of complex nonatypical hyperplasia). A consensus diagnosis (at least two out of three pathologists in agreement) of benign endometrium was reached by the independent pathologists for all subjects accepted into the study. Benign polyps were reported in seven (1.7%) subjects. One subject from the 5-mg group had a diagnosis of complex atypical hyperplasia during the study. At follow-up and without any further medical or surgical intervention, this subject had a consensus diagnosis of benign endometrium. Four other subjects were reported to have benign polyps, and one subject from the 5-mg group was reported to have a hyperplasic polyp. All cases of hyperplasia observed after treatment (including the cases previously reported [7]) returned to benign endometrium under continued treatment (four courses) and/or during the follow-up period. One case of hyperplasia was reported in the follow-up biopsy (3 months after
treatment course 4). For this subject, all previous biopsies (including after treatment course 4) had been diagnosed as benign endometrium by the three independent pathologists. The occurrence of nonphysiological endometrial changes was observed in 7.8% of the 5-mg group and 8.4% of the 10mg group at screening. As expected, after treatment with UPA nonphysiological changes increased, but this increase was independent of the dose and the number of treatment courses. After treatment course 2, nonphysiological endometrial changes were observed in 16.3% and 19.2% of the biopsies for the 5- and 10-mg groups, respectively, decreasing to 16.2% and 10.3% after treatment course 4 (Table 2). At follow-up, in 286 biopsies adequate for review, nonphysiological changes were observed in 9.0% and 6.3% of the biopsies for the 5- and 10-mg groups, respectively, which compares to the observed values at screening. During the study, the median endometrial thickness remained between 7 and 8 mm. The percentage of subjects with endometrial thickness R16 mm was 7.4% (all subjects) after the first treatment course and returned to below screening levels (4.9%) in subsequent treatment courses. (Fig. 1 and Supplemental Table 3).
Laboratory Parameters The median Hb value at screening was 12.55 and 12.40 g/dL for subjects from the 5- and 10-mg groups, respectively. From treatment course 1 to treatment course 4, Hb levels increased compared with screening values, reaching a peak at the end of treatment course 4, with median levels for the 5- and 10-mg groups of 13.10 and 13.35 g/dL, respectively (Supplemental Table 5). The median Hct values at screening were 0.40 for both the 5- and 10-mg groups. During the study, Hct levels increased to reach a peak at the end of treatment course 2 for both treatment groups, median 0.42 (Supplemental Table 5). E2 levels remained stable in both treatment groups across the study period (Supplemental Table 5). At screening, four (1.8%) and seven (3.2%), subjects had high values (>ULN) for aspartate aminotransferase (AST) in Q3 the 5- and 10-mg groups, respectively. At the follow-up assessment, approximately 3 months after end of study treatment, four (2.4%) and six (3.6%) had high values in the two respective groups. For alanine aminotransferase (ALT), at screening four (1.8%) and two (0.9%) had high values, with two (1.2%) and four (2.4%) of patients also reporting high values at the follow-up assessment in the 5- and 10-mg groups, respectively. The number of subjects with high gamma glutamyl transferase (GGT) levels at screening were 14 (6.1%) and 10 (4.5%) for the 5- and 10-mg groups, respectively, with 12 (7.1%) and 15 (9.0%) also reporting high levels at follow-up (Supplemental Table 6). For all lipid parameters, the levels for subjects from the 5and 10-mg groups were comparable during the study. At screening, the median levels of total cholesterol for the two groups were 4.93 and 5.03 mmol/L. The levels remained stable at each subsequent assessment, with medians ranging from 5.21 to 5.48. The median levels of low-density lipoprotein cholesterol for the two groups were 2.90 and 2.97 mmol/L
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ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649
TABLE 2 Summary of endometrium biopsy results (safety population). Visits Category
Classification
Screening
After treatment 2
After treatment 4
Follow-up
Endometrium biopsy performed Specimen adequatea Primary diagnosisb
Yes Yes Benign endometrium Hyperplasia Simple, nonatypical Complex, nonatypical Simple, atypical Complex, atypical Malignant neoplasm Endometrial adenocarcinomac Other malignant neoplasm Absent Present: benign Present: hyperplasic Present: carcinomatous Nonphysiological changes observed by two or three pathologistsb Yes Yes Benign endometrium Hyperplasia Simple, nonatypical Complex, nonatypical Simple, atypical Complex, atypical Malignant neoplasm Endometrial adenocarcinoma Other malignant neoplasm Absent Present: benign Present: hyperplasic Present: carcinomatous Nonphysiological changes observed by two or three pathologistsb
230 219 (95.2) 219 (100.0) 0 0 0 0 0 0 0
193 178 (92.2) 176 (98.9) 1 (0.6) 1 (0.6) 0 0 0 1 (0.6) 1 (0.6)
168 148 (88.1) 147 (99.3) 1 (0.7) 0 0 0 1 (0.7) 0 0
164 144 (87.8) 143 (99.3) 1 (0.7) 0 0 0 1 0 0
0 216 (98.6) 3 (1.4) 0 0 17 (7.8)
0 176 (98.9) 2 (1.1) 0 0 29 (16.3)
0 146 (98.6) 1 (0.7) 1 (0.7) 0 24 (16.2)
0 143 (99.3) 1 (0.7) 0 0 13 (9.0)
220 203 (92.3) 203 (100.0) 0 0 0 0 0 0 0 0 199 (98.0) 4 (2.0) 0 0 17 (8.4)
194 182 (93.8) 180 (98.9) 2 (1.1) 1 (0.5) 0 1 (0.5) 0 0 0 0 180 (98.9) 2 (1.1) 0 0 35 (19.2)
163 145 (89.0) 145 (100.0) 0 0 0 0 0 0 0 0 142 (97.9) 3 (2.1) 0 0 15 (10.3)
160 142 (88.8) 142 (100.0) 0 0 0 0 0 0 0 0 142 (100) 0 0 0 9 (6.3)
Treatment group UPA 5 mg (n ¼ 230)
Polypsb
Of those with Benign endometrium UPA 10 mg (n ¼ 221)
Endometrium Biopsy performed Specimen adequatea Primary Diagnosisb
Polypsb
Of those with benign endometrium
Note: Numbers in parentheses are percents. In addition to cases of hyperplasia captured at nominated protocol visits, one consensus diagnosis of simple atypical hyperplasia was reported after the unscheduled histology review of material taken by curettage after the SAE of menorrhagia after treatment course 1. At early termination visit approximately 1 mo later, this subject had a consensus diagnosis of benign endometrium. a Denominator of percentage is the number of subjects that have an endometrium biopsy performed. b Denominator of percentage is the number of subjects with an adequate specimen. c Preexisting condition. Donnez. Ulipristal acetate in uterine fibroids. Fertil Steril 2015.
at screening, and these remained stable at each subsequent assessment, with medians ranging from 2.99 to 3.23. Following the same pattern, at screening, the median levels of high-density lipoprotein cholesterol for the two groups were 1.61 and 1.55 mmol/L. The levels remained stable at each subsequent assessment across the treatment groups, with medians ranging from 1.64 to 1.71. Levels of triglycerides increased slightly during the study. At screening, the medians in the 5- and 10-mg groups were 0.87 and 0.91 mmol/L, respectively, increasing to median levels of 0.97 and 1.08 at the follow-up assessment (Supplemental Table 5). Furthermore, at screening, 27 (11.8%) and 30 (13.7%) subjects had high values (>ULN) for triglycerides in the 5- and 10-mg groups, respectively. Similarly at the follow-up assessment, 27 (16.0%) and 26 (15.6%) had high values in the two respective groups (Supplemental Table 6).
General Safety The numbers (percentages) of subjects who reported AEs during treatment courses 1, 2, 3, and 4 were 102 (44.3%), 59 (27.4%), 32 (16.6%), and 43 (23.9%), respectively, for the 5mg group and 98 (44.3%), 60 (29.3%), 38 (20.2%), and 33 (19.0%), respectively, for the 10-mg group (Supplemental Table 7). The numbers (percentages) of subjects who reported AEs considered as treatment related by the investigator during treatment courses 1, 2, 3, and 4 were 47 (20.4%), 28 (13.0%), 9 (4.7%), and 11 (6.1%), respectively, for the 5-mg group and 43 (19.5%), 22 (10.7%), 12 (6.4%), and 14 (8.0%), respectively, for the 10-mg group. The vast majority of AEs (97.6%) were of mild or moderate severity in both groups. Headaches and hot flushes were the most frequently reported AEs (%11% of subjects in any treatment course), VOL. - NO. - / - 2015
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Fertility and Sterility®
Percentage of patients
709 FIGURE 1 710 711 Patients with endometrial thickness >16mm (Safety population) 712 713 10 714 UPA 5 mg 715 UPA 10 mg 8.7 8 716 717 718 6 6.1 719 720 4.9 5.0 4 721 3.8 3.6 722 3.1 723 2 2.4 724 1.7 1.2 725 0.6 0.6 0 726 Baseline After course After course After course After course Follow Up 727 1* 2* 3* 4* 728 N=225 N=214 N=192 N=182 N=170 N=166 729 N=220 N=207 N=193 N=180 N=164 N=168 730 * After treatment course + 1 bleed 731 N, number of patients in whom endometrial thickness was measured 732 UPA, ulipristal acetate 733 Percentage of patients with endometrial thickness >16 mm. 734 Donnez. Ulipristal acetate in uterine fibroids. Fertil Steril 2015. 735 736 737 738 739 although the frequency of these events decreased with each could be used only for a limited period owing to the AE profile 740 Q4 successive treatment course (Supplemental Table 7). Breast and rapid fibroid regrowth after treatment cessation (5). 741 pain/discomfort was observed in %3% of subjects, with a Among the latest possible therapeutic options (11), UPA has 742 decrease in frequency for each successive treatment course proved to be a suitable alternative for the medical manage743 (%1% by treatment course 4). In total, 114 (25.3%) patients ment of fibroids. 744 discontinued the study at any time and for any reason. Of Out of the 451 subjects with symptomatic uterine fibroids 745 those, 32 patients discontinued due to AEs, of which 21 and confirmed menorrhagia recruited, 75% of subjects re746 were considered related to study drug. No difference between mained in the study on average a total of 20 months, demon747 Q5 treatment groups was observed. Overall 34 SAEs were restrating a good compliance with the protocol considering the 748 ported; 21 in the 5-mg group and 13 in the 10-mg group. duration of the study. 749 Of these, 13 were classified by the investigator as related to Investigation of the rate of amenorrhea during each treat750 study medication: nine in the 5 mg-group (five menorrhagia, ment course showed that both UPA 5 and 10 mg led to amen751 one bipolar disorder, one spontaneous myoma expulsion, one orrhea in a high percentage of subjects (R70%). Amenorrhea 752 abdominal pain, one back pain) and four in the 10-mg group was reached on average within 1 week, and post-treatment 753 (one partial expulsion, one spontaneous myoma expulsion, menstrual bleeding was markedly reduced compared with 754 one myoma necrosis, one endometriosis). pretreatment bleeding. 755 No safety concerns were identified from physical examiA high percentage of subjects were in amenorrhea for all 756 nation, vital signs, ovarian ultrasound, and ECGs. treatment courses combined. The small observed difference 757 between the treatment groups was within the predefined 758 acceptable difference of 14% and was therefore not deemed DISCUSSION 759 to be clinically relevant. This was confirmed by the analysis 760 The PEARL IV study was designed to investigate the safety of the group of subjects who had started all four courses, 761 and efficacy of long-term, repeated intermittent treatment which found no statistically significant difference between 762 with four 12-week treatment courses of daily oral administrathe groups. 763 tion of either 5 or 10 mg of UPA in subjects with uterine fiAn additional secondary endpoint of importance in as764 broids. This is the first full clinical trial reporting the use of sessing the efficacy of UPA is the evaluation of bleeding con765 UPA 5 mg in a long-term repeated intermittent manner. trol. No difference between the treatment groups was seen, 766 Alternative treatment options previously available for the with both groups showing R73% of subjects having bleeding 767 medical management of fibroids, such as GnRH agonists, control during each independent treatment course. This data VOL. - NO. - / - 2015
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ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885
confirm previously known data (4, 5, 7, 8) regarding the efficacy of UPA with regards to controlling bleeding symptoms in subjects with symptomatic uterine fibroids. Furthermore, assessment of the blood loss during the first menstrual bleed after the treatment courses using the PBAC showed a marked progressive reduction from baseline with no difference between the two treatment groups. Hb levels and associated hematology parameters increased over the first two treatment courses and were sustained until follow-up. The total volume of the three largest myomas was shown to decrease after the first treatment course and was seen to further decrease after each subsequent treatment course. The reduction in volume was maintained thereafter until the end of study follow-up. A similar level of response was seen from both treatment groups with no statistically significant differences between them at any visit during the study. Furthermore, over 73% of all subjects had both fibroid volume reduction R25% at the end of four treatment courses in combination with being in amenorrhea (Supplemental Fig. 4). For pain and QoL, an important improvement was recorded during treatment in these assessments, reaching scores reported for healthy individuals, in both treatment groups (3). The changes in these measurements were of a similar level between the two treatment groups. The results therefore show that the use of UPA results in an improvement in QoL and control of pain, in comparison to baseline, even during the off-treatment intervals. After a transient increase in endometrial thickness in the first treatment course, fewer subjects had endometrial thickness >16 mm after each successive treatment course. No important differences with regards to endometrial thickness were observed between the 5- and 10-mg groups. Over the entire observation period, six cases of hyperplasia were observed. All cases of hyperplasia observed after treatment returned to benign endometrium under continued treatment and/or during the follow-up period. The occurrence of hyperplasia in a follow-up biopsy in a subject having been exposed to four courses of UPA and for whom all previous biopsies (including the one taken after the end of treatment course 4) had been diagnosed as benign endometrium by all pathologists illustrates that hyperplasia can occur spontaneously in this population. Overall, the occurrence of nonphysiological changes of the endometrium was not increased with repetition of treatment courses and returned to pretreatment levels within 3 months of completion of treatment. Levels of E2 remained well above postmenopausal levels, suggesting that bone mineral density will not be adversely impacted by repeated intermittent use of UPA. Mean levels of AST and ALT did not alter during the study; however, some sporadic increases were seen in individual subjects. In no subject were increases in transaminases associated with increases in bilirubin. There were mild increases in mean cholesterol and triglyceride values during the study. At screening, 41.4% of all subjects had total cholesterol >ULN, and, as expected in such a long-term study recruiting women predominantly in their 40s, a number of subjects showed modest increases in
cholesterol over the duration of the study (approximately 20 months). However, the median ratio of total cholesterol/ high-density lipoprotein cholesterol remained virtually unchanged and below the level at which the risk of cardiovascular disease is considered to be increased. More on-treatment AEs were reported during treatment course 1 than during subsequent treatment courses, and the most frequently reported on-treatment AEs were headache and hot flush. No other AE occurred at a frequency of >4% of subjects, and over 97% of all reported on-treatment AEs were rated as being of mild or moderate severity. Overall, there were no differences between the 5- and 10-mg dosing groups with respect to the type, frequency, and severity of AEs.
Conclusions The current manuscript summarizes the full efficacy and safety results of the first randomized controlled trial using the approved dose of 5 mg UPA in a repeated, intermittent therapy setting (four courses) for the management of uterine fibroids. The administration of four 12-week treatment courses of UPA at doses of 5 and 10 mg was well tolerated, with a high level of treatment compliance. No differences between the 5 and 10 mg dosing groups were recorded in terms of safety evaluations, which include a comprehensive evaluation of the endometrial characteristics and laboratory parameters observed with the long-term use of UPA. In terms of efficacy, both doses provided efficient bleeding control leading to amenorrhea in the majority of subjects in each of the four treatment courses. This bleeding control was achieved very rapidly and was accompanied by a reduction in fibroid volume and a reduction of pain associated with a clinically significant improvement in QoL with both doses. Furthermore, even during off-treatment periods, the level of bleeding, pain, and QoL were still improved compared with baseline. Myoma reduction was largely maintained during the off-treatment periods, and these effects were sustained until the end of study follow-up, approximately 3 months after completion of the four treatment courses. The results of this study therefore demonstrate the efficacy and further verify the safety profile associated with repeated intermittent treatment of symptomatic fibroids with UPA. Acknowledgments: The authors thank Kerry Ferrero of PregLem S.A. for assistance with the preparation of the manuscript with the support of Pablo Arriagada and Helen Saunders of PregLem S.A.
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Fertility and Sterility® 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003
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ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121
1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180
SUPPLEMENTAL FIGURE 1
Schedule of treatments and visits. Donnez. Ulipristal acetate in uterine fibroids. Fertil Steril 2015.
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Fertility and Sterility®
SUPPLEMENTAL FIGURE 2 Day 1
Day 1 of menstruation:
2
3
4
5
6
7
2 0 D D
Score
M M
Y Y Y Y
No bleeding
Towels
1 5 20 Tampons 1 5 10 Small clots/flooding
1
web 4C=FPO
1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239
2cm
Large clots/flooding
5
3cm
PBAC, one of the current standard methods used to objectively estimate menstrual blood loss and diagnose menorrhagia. The method that was Q6 developed and validated by Higham and Janssen defines excessive bleeding as a PBAC score >100. Donnez. Ulipristal acetate in uterine fibroids. Fertil Steril 2015.
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ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357
SUPPLEMENTAL FIGURE 3 Screened N=555
Patient disposition. Withdrawals are presented according to the timeframes in which they occurred, either during treatment or after treatment completion for each course. Two subjects randomized to the UPA 10 mg group received UPA 5 mg treatment in error; these subjects are included in the FAS sets according to randomization and in the safety set according to treatment received. Donnez. Ulipristal acetate in uterine fibroids. Fertil Steril 2015.
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Fertility and Sterility® 1476 1477 1478 1479 1480 1481 1482 1483 1484 1485 1486 1487 1488 1489 1490 1491 1492 1493 1494 1495 1496 1497 1498 1499 1500 1501 1502 1503 1504 1505 1506 1507 1508 1509 1510 1511 1512 1513 1514 1515 1516 1517 1518 1519 1520 1521 1522 1523 1524 1525 1526 1527 1528 1529 1530 1531 1532 1533 1534
SUPPLEMENTAL FIGURE 4
Yes
No
Yes
73.5%
7.8%
No
Subjects in Amenorrhoea
Clinically significant reduction in fibroid volume (>25%)
1417 1418 1419 1420 1421 1422 1423 1424 1425 1426 1427 1428 1429 1430 1431 1432 1433 1434 1435 1436 1437 1438 1439 1440 1441 1442 1443 1444 1445 1446 1447 1448 1449 1450 1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 1462 1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1475
13.9%
4.8%
Amenorrhea and/or fibroid volume reduction. Percentage of subjects with amenorrhea and/or a clinically significant reduction in fibroid volume (>25%). Donnez. Ulipristal acetate in uterine fibroids. Fertil Steril 2015.
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