Scholarly article on topic 'Long-term treatment of uterine fibroids with ulipristal acetate☆'

Long-term treatment of uterine fibroids with ulipristal acetate☆ Academic research paper on "Health sciences"

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{"Long-term treatment" / "ulipristal acetate" / "uterine fibroid"}

Abstract of research paper on Health sciences, author of scientific article — Jacques Donnez, Francisco Vázquez, Janusz Tomaszewski, Kazem Nouri, Philippe Bouchard, et al.

Objective To investigate the efficacy and safety of ulipristal acetate (UPA) for long-term treatment of symptomatic uterine fibroids. Design Repeated intermittent open-label UPA courses, each followed by randomized double-blind norethisterone acetate (NETA) or placebo. Setting European clinical gynecology centers. Patient(s) Two hundred and nine women with symptomatic fibroids including heavy menstrual bleeding. Intervention(s) Patients received up to four 3-month courses of UPA 10 mg daily, immediately followed by 10-day double-blind treatment with NETA (10 mg daily) or placebo. Main Outcome Measure(s) Amenorrhea, fibroid volume, endometrial histology. Result(s) After the first UPA course, amenorrhea occurred in 79% of women, with median onset (from treatment start) of 4 days (interquartile range, 2–6 days). Median fibroid volume change was −45% (interquartile range, −66%; −25%). Amenorrhea rates were 89%, 88%, and 90% for the 131, 119, and 107 women who received treatment courses 2, 3, and 4, respectively. Median times to amenorrhea were 2, 3, and 3 days for treatment courses 2, 3, and 4, respectively. Median fibroid volume changes from baseline were −63%, −67%, and −72% after treatment courses 2, 3, and 4, respectively. All endometrial biopsies showed benign histology without hyperplasia; NETA did not affect fibroid volume or endometrial histology. Conclusion(s) Repeated 3-month UPA courses effectively control bleeding and shrink fibroids in patients with symptomatic fibroids. Clinical trial registration ClinicalTrials.gov (www.clinicaltrials.gov) registration numbers NCT01156857 (PEARL III) and NCT01252069 (PEARL III extension).

Academic research paper on topic "Long-term treatment of uterine fibroids with ulipristal acetate☆"

Long-term treatment of uterine fibroids with ulipristal acetate*

Jacques Donnez, M.D.,a Francisco Vázquez, M.D.,b Janusz Tomaszewski, M.D.,c Kazem Nouri, M.D.,d Philippe Bouchard, M.D.,e Bart C. J. M. Fauser, M.D.,f David H. Barlow, F.R.C.O.G.,9 Santiago Palacios, M.D.,h Olivier Donnez, M.D.,i Elke Bestel, M.D.,j Ian Osterloh, M.R.C.P.,k and Ernest Loumaye, M.D.,1 for the PEARL III and PEARL III Extension Study Group

a Sociátá de Recherche pour l'Infertilitá, Brussels, Belgium; b Centro de Estudios de Obstetricia y Ginecología Asociado, Lugo, Spain; c Prywatna Klinika Polozniczo-Ginekologiczna, Bialystok, Poland; d Department of Gynecological Endocrinology and Reproductive Medicine, Medical School of Vienna, Vienna, Austria; e Endocrinology Unit, AP-HP Hospital Saint-Antoine, Paris, France; f Department of Reproductive Medicine and Gynecology, University Medical Center Utrecht, Utrecht, the Netherlands; g College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland; h Palacios' Institute of Women's Health, Madrid, Spain; i Centre Hospitalier Universitaire Université Catholique de Louvain Mont-Godinne Dinant, Yvoir, Belgium; j PregLem S.A., Geneva, Switzerland; k OsterMed Ltd., Birmingham, United Kingdom; and l ObsEva S.A. Geneva, Switzerland

Objective: To investigate the efficacy and safety of ulipristal acetate (UPA) for long-term treatment of symptomatic uterine fibroids. Design: Repeated intermittent open-label UPA courses, each followed by randomized double-blind norethisterone acetate (NETA) or placebo.

Setting: European clinical gynecology centers.

Patient(s): Two hundred and nine women with symptomatic fibroids including heavy menstrual bleeding.

Intervention(s): Patients received up to four 3-month courses of UPA 10 mg daily, immediately followed by 10-day double-blind treatment with NETA (10 mg daily) or placebo.

Main Outcome Measure(s): Amenorrhea, fibroid volume, endometrial histology.

Result(s): After the first UPA course, amenorrhea occurred in 79% of women, with median onset (from treatment start) of 4 days (interquartile range, 2-6 days). Median fibroid volume change was —45% (interquartile range, —66%; —25%). Amenorrhea rates were 89%, 88%, and 90% for the 131, 119, and 107 women who received treatment courses 2, 3, and 4, respectively. Median times to amenorrhea were 2, 3, and 3 days for treatment courses 2, 3, and 4, respectively. Median fibroid volume changes from baseline were —63%,

Received January 22, 2014; revised and accepted February 6, 2014.

* This is an open access article under the CC BY-NC-ND license (http://creativecommons.Org/licenses/by-nc-nd/3.0/).

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 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. F.V. and his institution received a grant for this study and support for travel to the investigator meetings of the PEARL III and PEARL III extension study. J.T. and his institution received a grant for this study and support for travel to the investigator meetings. K.N. and his institution received a grant for this study and support for travel to the investigator meetings. He was also paid by Gedeon Richter Austria for holding lectures. 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 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 received payment for consultancy and was supported for travel to meetings. 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 the study drug. D.H.B. is a member of PregLem's SAB. He received payment for consultancy and data review activities and was supported for travel to meetings. 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 the study drug. S.P. and his institution received a grant for this study and support for travel to the investigator meetings. He was also paid by PregLem for his consultancy. O.D. and his institution received a grant for this study. E.B. 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. I.O. and his company Ostermed received payment for consultancy and support for travel to meetings. E.L. is a member 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 Gedeon Richter Group. There is no relationship between stock payment value and future commercial performance of the study drug.

Members of the PEARL III and PEARL III extension study group are Wlodzimierz Baranowski, David H. Barlow, Francesco Baro, Pedro N. Barri, Christine Bergeron, Elke Bestel, Philippe Bouchard, Sarah Brittain, Maria Jesus Cancelo Hidalgo, Francisco Carmona, Annie Dacquin, Jacques Donnez, Olivier Donnez, Bart C.J.M. Fauser, Alex Ferenczy, Albrecht Giuliani, Javier Haya, Johannes Huber, Artur Jakimiuk, Florence S. Jean, Jesus S. Jimenez, Jan Kotarski, Boguslaw Lemieszczuk, Ernest Loumaye, Michelle Nisolle, Kazem Nouri, Ian Osterloh, Santiago Palacios, Anna Pawlaczyk, Krzysztof Sodowski, Rafal Sozanski, Jacek Suzin, Paul Terrill, Janusz Tomaszewski, Francisco Vazquez, Emilia Villegas, and Alistair R.W. Williams.

The clinical trial supporting this work was funded by PregLem S.A., Geneva, Switzerland.

Reprint requests: Jacques Donnez, M.D., Societe de Recherche pour l'Infertilite, Av. Grandchamp, 143, 1150 Brussels, Belgium (E-mail: jacques.donnez@ gmail.com).

Fertility and Sterility® Vol. ■, No. ■, ■ 2014 0015-0282/S36.00 Copyright ©2014 The Authors. Published by Elsevier Inc. http://dx.doi.Org/10.1016/j.fertnstert.2014.02.008

—67%, and —72% after treatment courses 2, 3, and 4, respectively. All endometrial biopsies showed benign histology without hyperplasia; NETA did not affect fibroid volume or endometrial histology. Conclusion(s): Repeated 3-month UPA courses effectively control bleeding and shrink fibroids in patients with symptomatic fibroids.

Clinical trial registration: ClinicalTrials.gov (www.clinicaltrials.gov) registration numbers NCT01156857 (PEARL III) and NCT01252069 (PEARL III extension). (Fertil Steril® 2014; ■ :■-■. ©2014 by American Society for Reproductive Medicine.) Key Words: Long-term treatment, ulipristal acetate, uterine fibroid

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Leiomyomas or fibroids are benign hormone-sensitive tumors of uterine smooth-muscle cells, frequently involving point mutations and/or complex chromosomal rearrangements (1). They occur in about 20%-40% of women of reproductive age (2). Heavy menstrual bleeding (HMB), pelvic pressure and pain, and reproductive dysfunction are common symptoms that impair women's health and quality of life (QoL) (3, 4). Surgical interventions, especially hysterectomy, still predominate the treatment strategy (5). Options for medical therapy are currently limited to preoperative reduction of symptoms related to uterine bleeding and fibroid size; GnRH agonists are licensed but only for short-term therapy owing to safety concerns (loss of bone mass) and adverse reactions (hot flashes) (6, 7). The levonorgestrel-releasing intrauterine device, while not approved for this indication, has been found to reduce menstrual blood loss in women with uterine fibroids, but its efficacy is reduced in patients with a distorted uterus (8). Since February 2012, ulipristal acetate (UPA) is also approved in Europe for preoperative fibroid treatment (9). For the many women wishing to avoid surgery, there remains a substantial need for effective long-term medical therapy.

UPA is a selective P receptor modulator (SPRM) that potently modulates P-receptor activity (10) with proapopto-tic/antiproliferative effects on fibroid cells (11) and with phar-macokinetic properties supporting once daily dosing (12). Two short-term (3 months) randomized clinical trials showed that UPA effectively controls HMB and shrinks fibroids (13, 14). After treatment cessation, menstruation usually returns within 4-5 weeks, but fibroid volume reduction can be sustained for up to 6 months. In addition, treatment with UPA reduced fibroid-associated pain, improved QoL, and revealed no safety concerns (13, 14). Clinical trials have also shown that SPRM administration can lead to a pattern of benign, nonphysiological, nonproliferative, histological features of the endometrium termed P receptor modulator associated endometrial changes (PAEC) (15-17). These changes spontaneously reverse over a few weeks to months after cessation of the 3-month UPA treatment (13, 14, 18). Hence, intermittent courses of 3-month UPA treatment with off-treatment intervals are a potential option for the long-term medical management of fibroids (9).

In these two studies, the PGL4001 (UPA) Efficacy Assessment in Reduction of Symptoms due to Uterine Leiomyomata (PEARL) III trial and its extension, we evaluated the sustained

effects of UPA on menstrual bleeding, fibroid volume, pain, QoL, and safety during one to four 3-month UPA treatment courses.

Owing to the long-term treatment, no suitable active comparator to UPA was available. However, since UPA exerts mainly antiprogestagenic effects on the endometrium, we randomized women to receive 10 days of treatment with the progestin norethisterone acetate (NETA) or placebo (administered immediately after each completed UPA treatment) to explore any effect on the reversibility of PAEC or timing and magnitude of the next menstruation off treatment. The off-treatment period between each UPA course included one menstrual bleed and the beginning of a second bleed.

MATERIALS AND METHODS

Study Design and Oversight

PEARL III and its extension were long-term, open-label, phase III trials of UPA, which were double-blinded and placebo-controlled toward the administration of progestin after the end of each UPA treatment course. PEARL III was conducted at 21 investigation centers in four countries from July 2010 through November 2011, with 18 centers also participating in the extension protocol until January 2013. The trial and extension were approved by the independent ethics committee of each participating site and were conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines.

Study Population

PEARL III enrolled premenopausal women with at least one fibroid > 3cmindiameterand none >10 cm, HMB, and uterine size <16 weeks of gestation who were eligible for fibroid surgery. Eligible women were aged 18-48 years, with body mass index 18-40 (kg/m2) and regular menstrual cycles of 2235 days with FSH % 20IU/L. Written informed consent was obtained from all women. The main exclusion criteria are listed in Supplemental Table 1, available atwww.fertstert.org.

Randomization and Intervention

Women received a 3-month open-label course of UPA (10 mg) once daily immediately followed by double-blind oral NETA (10 mg) once daily or matching placebo for 10 days allocated randomly in a 1:1 ratio.

UPA was started during the first 4 days of menstruation. After the first UPA (and NETA/placebo) treatment course and the return of menstruation, women could either leave the study and attend a final follow-up visit 12 weeks later (PEARL III) or, if they wished to be assessed for a further 18 months, enroll in the PEARL III extension study to obtain up to three further courses of UPA (and NETA/placebo), each separated by an off-treatment period including a full menstrual cycle up to the start of the second menstruation. Follow-up visits in the extension study were conducted approximately 3 months after the final treatment course. The sequence of treatments is illustrated in Supplemental Figure 1.

safety endpoints comprised changes from baseline in hematology, coagulation, biochemistry, lipids, ACTH, TSH, and PRL, as well as serum levels of E2.

Endometrial Histology

Endometrial biopsy samples were obtained 10-18 days after menstruation start during screening, after treatment courses 1 and 4, and 3 months after the end of course 4 in women with PAEC observed after course 4. All samples were assessed in a blinded manner by three independent pathologists experienced in PAEC.

Efficacy endpoints

We evaluated efficacy and safety endpoints after the first treatment course (PEARL III), after each of up to three more treatment courses (PEARL III extension), and approximately 3 months after completion of the final treatment course. The primary efficacy endpoint was the occurrence of amenor-rhea at the end of each UPA course. In accordance with previously published data, amenorrhea was defined as no bleeding for a continuous period of at least 35 days (1 day of spotting was allowed within any 35-day interval) to accurately describe the degree of bleeding control during UPA treatment under the conditions of this study (13, 14). This differs from the general definition of amenorrhea, which is three menstrual cycle lengths of no bleeding. Bleeding was assessed using a semiquantitative bleeding scale. For an exploratory endpoint, the Pictorial Blood-Loss Assessment Chart (PBAC) (19) was used to assess the magnitude of menstrual bleeding over 8 days at baseline (start of the first treatment course) and for the first menstruation after the end of each treatment course. A score greater than 100 indicates HMB.

Secondary efficacy endpoints included the reduction of the three largest fibroids identified at screening on the basis of ultrasound performed at each center. Further secondary endpoints were pain, measured with the Short-Form McGill Pain questionnaire (20) and QoL, measured by the general EQ-5D questionnaire (21) and by the specific Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QoL) questionnaire (22). Additional details are presented in the Supplemental Material.

Assessment of Safety Endpoints

Safety endpoints included the number and proportion of women experiencing treatment-emergent adverse events (TEAEs), including clinically significant changes in vital signs, physical examination, gynecological and/or breast examination, electrocardiogram (ECG), ovarian ultrasound, changes from baseline in endometrial thickness, and clinically significant changes in endometrial biopsy. The frequency and severity of adverse events (spontaneously reported or elicited by the investigators with the use of non-leading questions) were recorded on standard forms at every visit. Serious adverse events were recorded up to the last visit approximately 3 months after treatment cessation. Other

Statistical Analysis

This study included open-label UPA treatment phases and placebo-controlled double-blinded NETA phases where assessments were considered exploratory. We planned to enroll 200 women, with approximately 80% of participants expected to fulfill the efficacy endpoint of amenorrhea at the end of the first UPA treatment course and allowing for a dropout rate of 10% during the first course of treatment. The planned sample size would provide an estimate of this percentage, with the corresponding 95% confidence interval (CI) being less than ±6%. We considered 90 evaluable participants per treatment group to be sufficient to enable a reliable exploration of any differences between NETA and placebo treatment. We conducted efficacy and safety analyses using all women who started treatment course 1 (PEARL III open-label set) and two (PEARL III extension full analysis set). Endpoints were summarized using descriptive statistics. A 95% CI for the percentage of amenorrheic women was produced using the Wilson score method. The time from the start of dosing to amenorrhea was summarized as a continuous variable and presented using the Kaplan Meier probability estimates. The Wilcoxon rank sum test was performed to compare the placebo versus NETA treatment groups for the time to return to menstruation.

RESULTS Patients

The baseline characteristics of the 209 participants who entered the study, the 132 who entered the extension study, and the 107 who received four treatment courses were very similar; most women were in their late 30s or early 40s with moderate to severe bleeding (the overall median PBAC was >200), and self-reported pain or discomfort and/or anxiety or depression (Table 1). Adverse events (eight women) and lack of efficacy (four women) were infrequent causes of study discontinuation (Supplemental Figs. 2 and 3).

Efficacy

Menstrual bleeding. At the end of the first treatment course, 164 women (78.5%) were amenorrheic (95% CI, 72.4%-83.5%; Supplemental Table 2). The median time to amenor-rhea from treatment start was 3.5 days (interquartile range [IQR], 2-6 days).

For the 132 women who entered the extension study to receive multiple treatment courses, 88.5%, 88.2%, and

TABLE 1

Baseline (pretreatment course 1) characteristics for participants entering PEARL III and extension studies.

PEARL III and extension study: PEARL III only: open-label set full analysis set (baseline data (baseline data for women who Characteristic started course 1), n = 209

for women who started at least two courses), n = 132

Age, mean ± SD Race, n (%)a White Black Other

Body mass index, kg/m2, mean ± SD Median (IQR) PBAC (days 1-8) scoreb Median (IQR) total volume of three

largest fibroids, cm3 Median (IQR) uterine volume, cm3 Hemoglobin, g/dL, mean ± SD Short-Form McGill Pain questionnaire0

assessment of pain, median (IQR) Visual analog scale (VAS),d median (IQR) UFS-QoL questionnaire6 Symptom severity, mean ± SD Health-related QoL total score, mean ± SD EQ-5D questionnaire Mobility (women with problems), n (%) Self-care (women with problems), n (%) Usual activities (women with problems), n (%)

Pain/discomfort (women with moderate

or extreme symptoms), n (%) Anxiety/depression (women with moderate or extreme symptoms), n (%)

VAS (health state),h mean ± SD

40.1 ± 6.0

179(85.6) 19(9.1) 11 (5.3) 25.4 ± 4.4 216(126, 401) 53.9(24.0, 128.7) (n = 207)

199.6(125.2, 291.3) (n = 209) 12.5 ± 1.8 (n = 199) 8.0 (3.0, 17.0) (n = 207)

38.0(17.0, 63.0) (n = 209)

47.7 ± 17.7 (n = 207) 57.1 ± 20.9 (n = 208)

40.5 ± 5.8

121 (91.7) 8(6.1) 3(2.3) 25.4 ± 4.7 235 (142, 397) 56.2 (25.7, 128.8) (n = 132)

200.7 (121.5, 303.1) (n = 132) 12.4 ± 1.8 (n = 127) 8.0(4.0, 19.0) (n = 131)

36.0(17.0, 63.5) (n = 132)

49.2 ± 17.7 (n = 131) 54.9 ± 20.6 (n = 132)

PEARL III and extension study: (baseline data for women who started all four courses), n = 107

40.8 ± 5.5

99 (92.5) 5 (4.7) 3 (2.8) 25.1 ± 4.6 234(132, 368) 49.8(26.9, 112.8) (n = 107)

178.6(116.6, 278.7) (n = 107) 12.5 ± 1.7 (n = 105) 8.0(4.0, 19.0) (n = 106)

37.0(16.0, 63.0) (n = 107)

49.0 ± 16.6 (n = 107) 55.3 ± 19.9 (n = 107)

n = 209 n = 132 n = 107

34(16.3) 19(14.4) 15 (14.0)

5 (2.4) 2(1.5) 1 (0.9)

50(23.9) 26(19.7) 22 (20.6)

54(73.7) 102 (77.3) 84 (78.5)

29 (62.0f) 85 (64.9g) 74 (69.2)

67.5 18.6

67.9 18.5

68.2 17.6

Note: n = Number of women with nonmissing observations.

a Race or ethnic group was reported by the investigator.

b PBAC, measured during days 1-8 at the start of the UPA treatment (course 1).

c Scores on the Short-Form McGill Pain questionnaire range from 0 to 45, with higher scores indicating more severe pain. d Scores on VAS range from 0 to 100, with higher scores indicating more severe pain.

e On the UFS-QoL questionnaire, scores for symptom severity range from 0 to 100, with higher scores indicating increased severity. Total scores for health-related QoL range from 0 to 100, with higher scores indicating a better QoL. f n = 208. g n = 131.

h Scores on VAS range from 0 to 100, with higher scores indicating a better health state. Donnez. Long-term treatment of uterine fibroids. Fertil Steril 2014.

89.7% were in amenorrhea at the end of courses 2, 3, and 4, respectively (Table 2). The median times to amenorrhea after the start of each course were 2, 3, and 3 days for courses 2, 3, and 4, respectively (Fig. 1A). The percentages of women with only spotting or no bleeding were 93.9%, 94.1%, and 93.5% at the end of courses 2, 3, and 4, respectively.

After the end of each treatment course, menstruation resumed. Menstrual bleeding (PBAC days 1-8) progressively reduced from medians of 228 and 257 at the start of the first course to 55 and 13 after the end of the fourth UPA course for women randomized to placebo or NETA, respectively (P= .02; Supplemental Table 3). Thus, 10-day progestin courses reduced the magnitude of menstrual bleeding during the off-treatment periods and also brought forward menstruation return (e.g., median of 15 days instead of 30 days for women receiving placebo after the end of the fourth UPA treatment course; P< .001).

Fibroid volume. The median change from baseline to end of the first UPA treatment course in the combined volume of

the three largest fibroids was —45.1% (IQR, —66.1 to — 24.9%; Supplemental Table 2). For women receiving multiple treatment courses, fibroids continued to shrink, reaching a median volume reduction of —72.1% after four treatment courses (Table 2, Fig. 1B). This volume reduction was mostly maintained (median —58.8%) at follow-up 3 months after the end of the fourth treatment course. Of women completing four treatment courses, 82.3% and 69.8%, respectively, had > 25% and > 50% reductions in volume of the three largest fibroids.

Pain and QoL. During the first treatment course, improvements in pain were apparent from the fifth week onward and were generally maintained for all UPA treatment periods (Table 2, Supplemental Table 2). UFS-QoL scores indicated substantially reduced QoL at baseline, but mean scores were within the range of healthy participants at the end of each treatment course and the improvement was largely maintained at 3-month follow-up after the final treatment course. The EQ-5D questionnaire showed that most women had

TABLE 2

Efficacy results for participants entering PEARL III extension study (PEARL III extension full analysis set).a

Course 1 Course 2 Course 3 Course 4 3 Month follow-up

Amenorrhea, n/N (%) 105/132 (79.5) 116/131 (88.5) 105/119(88.2) 96/107 (89.7) -

95% CI, % 71.9, 85.5 82.0, 92.9 81.2,92.9 82.5, 94.2 -

Spotting or no bleeding, n/N (%) 117/132 (88.6) 123/131 (93.9) 112/119(94.1) 100/107 (93.5) -

% Change in total volume of three largest -49.9 (-69.0, -27.2) (n = 130) -63.2 (-76.4, -38.3) (n = 119) -67.0 (-79.9, -33.5) (n = 106) -72.1 (-86.6, -35.7) (n = 96) -58.8 (79.2, -21.0) (n = 97)

fibroidsb from baseline, median (IQR)

Total reduction >25%, n (%) 101 (77.7) 95 (79.8) 83 (78.3) 79 (82.3) 70 (72.2)

Total reduction >50%, n (%) 65 (50.0) 77 (64.7) 66 (62.3) 67 (69.8) 56 (57.7)

% Change in uterine volume from baseline, -29.8 (-45.2, -10.5) (n = 132) -32.3 (-47.1,0.7) (n = 121) -29.9 (-47.5, -1.8) (n = 107) -40.2 (-55.6,-15.3) (n = 96) -22.3 (-46.2,5.5) (n = 99)

median (IQR)

Reduction >25%, n (%) 73 (55.3) 73 (60.3) 61 (57.0) 64 (66.7) 45 (45.5)

Assessment of pain

Short-Form McGill Pain questionnaire n = 131 n = 119 n = 108 n = 96 n = 96

Actual, median (IQR) 1.0(0.0,3.0) 1.0 (0.0, 4.0) 1.0(0.0, 6.0) 1.0(0.0,2.0) 2.0 (0.0, 7.0)

Change from baseline, median (IQR) -7.0 (-15.0, -2.0) -6.0 (-14.0, -2.0) -5.0 (-13.5, 0.0) -6.0 (-16.0, -2.0) -4.0 (-11.0,0.0)

VASc n = 132 n = 120 n = 109 n = 96 n = 98

Actual, median (IQR) 1.0(0.0, 11.0) 3.0 (0.0, 13.5) 2.0(0.0, 13.0) 1.5 (0.0, 8.5) 7.0 (1.0, 29.0)

Change from Baseline, median (IQR) -23.5 (-58.0, -6.5) -27.5 (-54.0, -7.0) -25.0, (-49.0, -6.0) -30.5 (-54.0, -10.0) -17.0 (-42.0, -2.0)

UFS-QoL questionnaired

Symptom severity n = 129 n=117 n = 104 n = 91 n = 98

Actual, mean ± SD 13.4 ± 15.3 18.4 ± 16.8 20.5 ± 19.5 17.9 ± 17.1 27.1 ± 21.1

Change from baseline, mean ± SD -35.8 ± 21.2 -30.5 ± 21.9 -27.7 ± 23.3 -30.0 ± 20.3 -21.2 ± 22.1

Health-related QoL total score n = 131 n=117 n = 108 n = 96 n = 99

Actual, mean ± SD 87.8 ± 14.8 85.2 ± 16.4 85.2 ± 18.1 87.5 ± 16.2 79.2 ± 22.9

Change from baseline, mean ± SD 32.8 ± 21.9 29.6 ± 22.4 29.4 ± 23.4 31.4 ± 21.6 22.7 ± 22.5

EQ-5D questionnaire n = 132 n = 121 n = 109 n = 96 n = 99

Mobility (women with problems), n (%) 6(4.5) 3(2.5) 5 (4.6) 4 (4.2) 3 (3.0)

Self-care (women with problems), n (%) 0 0 1 (0.9) 0 0

Usual activities (women with problems), n (%) 6(4.5) 3(2.5) 4(3.7) 3(3.1) 7(7.1)

Pain/discomfort (women with moderate or 33 (25.2e) 31 (25.6) 26 (24.1f) 23 (24.0) 37 (37.4)

extreme symptoms), n (%)

Anxiety/depression (women with moderate or 49 (37.1) 27 (22.3) 33 (30.3) 29 (30.2) 37 (37.4)

extreme symptoms), n (%)

VAS (health state)9 n = 132 n = 120 n = 109 n = 95 n = 99

Actual, mean ± SD 78.1 ± 18.0 81.2 ± 14.9 83.4 ± 13.5 84.4 ± 15.5 84.1 ± 14.9

Change from baseline, mean ± SD 10.2 ± 23.8 13.3 ± 21.3 15.6 ± 20.2 15.2 ± 20.3 14.8 ± 18.9

Note: n = Number of women with nonmissing observations.

a Amenorrhea (and spotting or no bleeding) assessed while under UPA treatment. For remaining results, courses 1 and 4 data were collected at the end of UPA treatment; courses 2 and 3 data were collected after the first menstrual bleed after UPA treatment and subsequent NETA/placebo treatment.

b The same three fibroids identified at screening were followed throughout the study. c Scores on VAS range from 0 to 100, with higher scores indicating more severe pain.

d On the UFS-QoL questionnaire, scores for symptom severity range from 0 to 100, with higher scores indicating increased severity. Total scores for health-related QoL range from 0 to 100, with higher scores indicating a better QoL.

= 131.

g Scores on VAS range from 0 to 100, with higher scores indicating a better health state. Donnez. Long-term treatment of uterine fibroids. Fertil Steril 2014.

FIGURE 1

(A) Time to no bleeding (persistent amenorrhea; PEARL III extension full analysis set). Time to amenorrhea was defined as the first day for which there was subsequently no bleeding for longer than 35 days to the end of UPA treatment within each treatment course, assessed using the patient diary data from the date of the first dose of UPA (day 0, which was to be within the first 4 days of the start of menstruation for treatment courses 1 and 2 and on the first day of menstruation for treatment courses 3 and 4). One day of spotting in any 35-day interval was accepted. Circles denote censored observation (i.e., a participant had a subsequent interval of 35 days or less up to the end of UPA treatment for which no more than 1 day of spotting was observed). (B) Percent change from baseline in total volume of the three largest fibroids (PEARL III extension full analysis set). N = number of women with nonmissing observations. The same three fibroids identified at screening were followed throughout the study. Box extends to 25th and 75th percentiles (IQR) and shows median value. Mean values are also plotted. Whiskers extend to 10th and 90th percentiles. Courses 1 and 4 data were collected at the end of UPA treatment; courses 2 and 3 data were collected after the first menstrual bleed after UPA treatment and subsequent NETA/placebo treatment.

Donnez. Long-term treatment of uterine fibroids. Fertil Steril 2014.

discomfort or pain and/or anxiety and depression at baseline, but few women reported these conditions at the end of each UPA treatment course and at 3-month follow-up (Tables 1 and 2).

Surgery and enrollment in extension study. A total of 132/ 209 patients consented and proceeded to the extension phase of the study. Among them were 64/91 women for whom surgery was planned at baseline (Supplemental Fig. 2). There were no significant differences in baseline disease severity between women who entered the extension study and those who did not.

After one course of treatment, UPA exerted similar control over bleeding and pain for patients entering the extension

study (compared with those who did not). Women entering the extension study had a somewhat greater reduction in median fibroid volume (—49.9% vs. —38.5%) and greater improvement in UFS-QoL (least square mean change, 31.2 vs. 25.3) after one course of UPA compared with those who did not enter the second study (Supplemental Table 4).

Safety

General safety. There were no serious adverse events (SAEs) reported during the first course of UPA treatment, but two women had three post-treatment SAEs (two episodes of uterine bleeding and one breast cancer) that were considered not related to study medication. Seven women who entered the extension study (and received multiple courses of treatment) reported SAEs (five cases of uterine bleeding, one thyroid cyst, and one chlamydia infection; Table 3).

During the first course of UPA treatment, TEAEs occurred in 120 women (57.4%; Supplemental Table 5), but only eight women (3.8%) had severe AEs. Only one TEAE (headache) led to treatment withdrawal. TEAEs occurring in >5% of women were headache (16.3%), nasopharyngitis (6.7%), and abdominal pain (5.3%). In women receiving multiple treatment courses, headaches, nasopharyngitis, abdominal pain, and hot flashes were the most frequent TEAEs, but the incidence did not increase over time and only five women discontinued UPA because of TEAEs (Table 3).

There were no safety signals arising from physical examination, vital signs, liver function, and other laboratory safety tests, hormone levels, ovarian ultrasound, and ECGs (see Supplemental Table 6).

Endometrial safety. Transient increases in endometrial thickness occurred in less than 10% of women after each UPA course (Supplemental Table 6). No cases of endometrial hyperplasia or adenocarcinoma were reported at any time point for any woman.

Nonphysiological features were reported by at least two pathologists for 18/171 (11%), 45/176 (26%), and 22/87 (25%) women biopsied at screening and at approximately 6 weeks after courses 1 and 4, respectively (Supplemental Table 7). Fifteen women with PAEC diagnosed after the fourth UPA course were rebiopsied 3 months later; only three had some nonphysiological features. Ten days of NETA did not have a significant impact on the incidence of nonphysiolog-ical changes induced by UPA.

DISCUSSION

In these sequential studies of women with fibroids and excessive menstrual bleeding, we administered intermittent courses of UPA. Women had the option of surgery after one course, but for many women the goal is to avoid surgery and most decided to enroll into the extension study where they could receive up to three additional courses even if surgery was planned at baseline. Intermittent UPA (administered over an 18-month period) induced high rates of amenorrhea (nearly 90% during repeat treatment courses), confirming its ability to control for the long term the most troublesome symptom

Adverse events (PEARL III extension safety set).a

Overall Course 1 Course 2 Course 3 Course 4

Adverse event, no. of women (%) (n = 132) (n = 132) (n = 131) (n = 119) (n = 107)

At least one SAE 7 (5.3) 0 2(1.5) 2(1.7) 3 (2.8)

Any SAE during UPA treatment 6 (4.5) 0 2(1.5) 2(1.7) 2(1.9)

HMB 2(1.5) 0 1 (0.8) 0 1 (0.9)

Uterine hemorrhage 2(1.5) 0 1 (0.8) 0 1 (0.9)

Metrorrhagia 1 (0.8) 0 0 1 (0.8) 0

Thyroid cyst 1 (0.8) 0 0 1 (0.8) 0

Any SAE during NETA/placebo treatment 0 0 0 0 0

Any SAE off treatment 1 (0.8) 0 0 0 1 (0.9)

Chlamydial infection 1 (0.8) 0 0 0 1 (0.9)b

Adverse eventsc

Leading to study withdrawal 5 (3.8) 0 1 (0.8) 2(1.7) 2(1.9)

At least one event 91 (68.9) 73 (55.3) 27 (20.6) 35 (29.4) 37 (34.6)

Headache 26 (19.7) 19(14.4) 4(3.1) 6 (5.0) 7 (6.5)

Nasopharyngitis 18 (13.6) 10(7.6) 3 (2.3) 1 (0.8) 6(5.6)

Abdominal pain (including upper/lower) 12 (9.1) 7(5.3) 3 (2.3) 1 (0.8) 2(1.9)

Hot flashes 12 (9.1) 7 (5.3) 1 (0.8) 5(4.2) 1 (0.9)

Back pain 8(6.1) 2(1.5) 0 4(3.4) 2(1.9)

Fatigue 8(6.1) 4 (3.0) 0 3(2.5) 3 (2.8)

Nausea 8(6.1) 4 (3.0) 2(1.5) 1 (0.8) 1 (0.9)

Vertigo 7 (5.3) 6 (4.5) 0 1 (0.8) 1 (0.9)

Hair loss 6 (4.5) 5 (3.8) 1 (0.8) 2(1.7) 0

Breast discomfort/breast pain/breast tenderness 6 (4.5) 4 (3.0) 0 1 (0.8) 1 (0.9)

a All SAEs and all adverse events that occurred during UPA treatment in at least 4% of women overall are included.

b SAE was diagnosed 3 months after treatment course 4.

c Adverse events with onset on or after the first dose of UPA and before the first dose of NETA/placebo within each treatment course or up to and including 7 days after the last dose of UPA if NETA/

placebo was never started.

d In addition, another adverse event that occurred when a woman was not receiving UPA led to study withdrawal.

Donnez. Long-term treatment of uterine fibroids. Fertil Steril 2014.

of fibroids for most women. The previously reported efficacy of UPA in shrinking fibroids was also confirmed, and there was further fibroid shrinkage with successive treatment courses with no evidence of rapid rebound growth. However, even in women with little or no fibroid shrinkage, UPA still induced high rates of bleeding control (Supplemental Table 8). Women also reported substantial improvements in pain, anxiety and depression, and QoL during treatment. The UFS-QoL scores at baseline were slightly less severe than reported in some previous studies of patients undergoing invasive treatments; however, at the end of each UPA course, symptom severity and QoL scores were similar to those reported at follow-up for patients who underwent hysterectomy, myomectomy, uterine artery embolization, high-intensity focused ultrasound, or experimental treatment with mifepristone (23-26).

It might have been expected that fibroid-related symptoms would partially return during off-treatment periods, but the magnitude of menstrual bleeding (after the end of each treatment course) progressively diminished. Moreover, at 3 months after the last treatment course, the reduction in fibroid volume and the improvements in pain and QoL were largely maintained. These findings, together with previous observations (11) that UPA can induce apoptosis and decrease proliferation in fibroid cells, suggest that long-term intermittent SPRM therapy could result in disease regression.

Most adverse events were mild or moderate and did not increase in frequency with successive treatment courses.

The most frequently reported SAE was excessive uterine bleeding, but considering that women were monitored for over 18 months, the incidence of this finding is not greater than that reported in previous studies of UPA, placebo, and comparator agents in women with fibroid-related HMB (13, 14).

Some of the nonphysiological features of PAEC can be observed in women of reproductive age in the absence of pharmacotherapy (>10% incidence at screening in this study) (18). Donnez et al. previously reported that 3-month courses of UPA induce PAEC in approximately 60% of women and that this is fully reversible 6 months after the end of the treatment (13, 14). In this study, the endometrium was biopsied approximately 6 weeks after the end of the first and fourth courses of UPA treatment, and PAEC was diagnosed in approximately 25% of women at both time points. Similar incidences of PAEC after one and four courses of treatment indicate that treatment duration and cumulative dose do not affect occurrence of PAEC during prolonged, intermittent UPA administration. In the small subgroup of women with PAEC diagnosed after the fourth UPA course, the PAEC diagnosis rate at 3 months follow-up was the same as at screening, confirming that PAEC is rapidly reversible in most women after successive on/off administration. No cases of endometrial hyperplasia or adenocarcinoma were observed.

A 10-day course of progestin, administered immediately after each UPA treatment course, did not affect PAEC but was associated with a significantly reduced and

an earlier occurrence of menstrual bleeding during the off-treatment periods. However, these findings are probably insufficient to suggest that progestins should be routinely used in conjunction with UPA treatment unless there is a need to control the timing or amount of menstrual bleeding, for example, before a planned invasive procedure.

Currently, there are no approved long-term medical treatment options for the management of women with symptomatic fibroids. Some clinicians have attempted to use GnRH agonists with hormonal add-back therapy, but women still have menopausal symptoms, rates of bone mass loss may not be entirely mitigated, and fibroids rapidly enlarge after treatment is stopped (7). There are abundant P receptors in fibroids, and oral progestins (alone) have been used but without evidence that they shrink fibroids and with risk of breakthrough bleeding (27, 28). Intrauterine levonorgestrel does not consistently reduce fibroid volume, and its efficacy in women with submucous fibroids or a distorted uterus is controversial (8). Thus our results suggest that intermittent UPA could become the first long-term medical management option for many women with symptomatic fibroids.

There are some limitations to our study. We could not use an active or placebo control for long-term UPA treatment. However, it was previously demonstrated that a 3-month course of UPA was superior to placebo and noninferior to a GnRH agonist for control of HMB (13, 14). The dose (10 mg) and duration of each UPA course (3 months) were based on previous experience, but it is unknown whether longer periods of continuous treatment could also be safe and effective. We also recruited relatively few black participants, but previous studies reported efficacy in these women (13, 14, 29, 30). We also restricted fibroid size to a maximum diameter of 10 cm, but we note that the median diameter of the largest fibroid in a series of patients undergoing hysterectomy, myomectomy, or uterine artery embolization was 6 cm (24). Approximately one-third of women (some of whom had surgery) did not enroll in the extension study, and so we cannot be certain how this subset of patients would have responded to repeated UPA treatment courses. Women who received only one UPA treatment course achieved similar levels of bleeding control to those participating in the extension study, although improvements in QoL and fibroid volume reduction were slightly less substantial.

In conclusion, repeated 3-month courses of oral UPA 10 mg once daily effectively control bleeding and pain, reduce fibroid volume, and restore QoL over the long term in many women with symptomatic fibroids, providing an effective and well-tolerated long-term medical treatment for fibroids.

Acknowledgments: The authors thank Paul Terrill of MDSL International for statistical consultancy during the PEARL III and PEARL III extension studies and the preparation of tables and figures of this manuscript. The authors also thank Oliver Pohl (freelance medical writer, formerly PregLem S.A.) for

coordinating the manuscript writing and editorial assistance (funded by PregLem S.A.) with the support of Sarah Brittain of MDSL International and Florence S. Jean and Annie Dac-quin of PregLem S.A.

REFERENCES

1. Mehine M, Kaasinen E, Mäkinen N, Katainen R, Kämpjärvi K, Pitkänen E, et al. Characterization of uterine leiomyomas by whole-genome sequencing. N Engl J Med 2013;369:43-53.

2. Wallach EE, Vlahos NF. Uterine myomas: an overview of development, clinical features, and management. Obstet Gynecol 2004;104:393-406.

3. Stewart EA. Uterine fibroids. Lancet 2001;357:293-8.

4. Donnez J, Jadoul P. What are the implications of myomas on fertility? A need for a debate? Hum Reprod 2002;17:1424-30.

5. Stewart EA. Uterine fibroids and evidence-based medicine—not an oxymoron. N Engl J Med 2012;366:471-3.

6. Donnez J, Schrurs B, Gillerot S, Sandow J, Clerckx F. Treatment of uterine fibroids with implants of gonadotropin-releasing hormone agonist: assessment by hysterography. Fertil Steril 1989;51:947-50.

7. Lethaby A, Vollenhoven B. Fibroids (uterine myomatosis, leiomyomas). Clin Evid (Online) 2011;2011:0814.

8. Zapata LB, Whiteman MK, Tepper NK, Jamieson DJ, Marchbanks PA, Curtis KM. Intrauterine device use among women with uterine fibroids: a systematic review. Contraception 2010;82:41-55.

9. Melis GB, Piras B, Marotto MF, Orrü MM, Maricosu G, Pilloni M, et al. Pharmacokinetic evaluation of ulipristal acetate for uterine leiomyoma treatment. Expert Opin Drug Metab Toxicol 2012;8:901-8.

10. Gainer EE, Ulmann A. Pharmacologic properties of CDB(VA)-2914. Steroids 2003;68:1005-11.

11. Horak P, Mara M, Dundr P, Kubinova K, Kuzel D, Hudecek R, et al. Effect of a selective progesterone receptor modulator on induction of apoptosis in uterine fibroids in vivo. Int J Endocrinol 2012;2012:436174.

12. Pohl O, Osterloh I, Gotteland JP. Ulipristal acetate—safety and pharmacokinetics following multiple doses of 10-50 mg per day. J Clin Pharm Ther 2013;38:314-20.

13. 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.

14. Donnez J, Tomaszewski J, Vazquez F, Bouchard P, Lemieszczuk B, Baro F, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012;366:421-32.

15. Mutter GL, Bergeron C, Deligdisch L, Ferenczy A, Glant M, Merino M, et al. The spectrum of endometrial pathology induced by progesterone receptor modulators. Mod Pathol 2008;21:591-8.

16. Fiscella J, Bonfiglio T, Winters P, Eisinger SH, Fiscella K. Distinguishing features of endometrial pathology after exposure to the progesterone receptor modulator mifepristone. Hum Pathol 2011;42:947-53.

17. Ioffe OB, Zaino RJ, Mutter GL. Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator. Mod Pathol 2009;22:450-9.

18. 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.

19. Higham JM, O'Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol 1990;97:734-9.

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22. 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 Gyne-col 2002;99:290-300.

23. Fiscella K, Eisinger SH, Meldrum S, Feng C, Fisher SG, Guzick DS. Effect of mifepristone for symptomatic leiomyomata on quality of life and

uterine size: a randomized controlled trial. Obstet Gynecol 2006;108: 1381-7.

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25. Takeda T, Osuga K, Miyake A, Wakabayashi A, Morishige K, Kimura T. Elevated level of plasma vascular endothelial growth factor after gonadotropin-releasing hormone agonist treatment for leiomyomata. Gynecol Endocrinol 2008;24:724-6.

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30. Nieman LK, Blocker W, Nansel T, Mahoney S, Reynolds J, Blithe D, et al. Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebo-controlled, phase IIb study. Fertil Steril 2011;95:767-72.

SUPPLEMENTAL MATERIALS

Donnez. Long-term treatment of uterine fibroids. Fertil Steril 2014.

This appendix has been provided by the authors to give readers additional information about their work. The full protocols of the clinical trials are available on request to Dr Elke Bestel, M.D., Chief Medical Officer, PregLem S.A., Switzerland (E-mail: elke.bestel@preglem.com).

Contributors: Wlodzimierz Baranowski, David H. Barlow, Francesco Baro, Pedro N. Barri, Christine Bergeron, Elke Bestel, Philippe Bouchard, Sarah Brittain, Maria Jesus Cancelo Hidalgo, Francisco Carmona, Annie Dacquin, Jacques Donnez, Olivier Donnez, Bart C.J.M. Fauser, Alex Ferenczy, Albrecht Giuliani, Javier Haya, Johannes Huber, Artur Jakimiuk, Florence S. Jean, Jesus S. Jimenez, Jan Kotarski, Boguslaw Lemieszczuk, Ernest Loumaye, Michelle Nisolle, Kazem Nouri, Ian Osterloh, Santiago Palacios, Anna Pawlac-zyk, Krzysztof Sodowski, Rafal Sozanski, Jacek Suzin, Paul Terrill, Janusz Tomaszewski, Francisco Vázquez, Emilia Villegas, and Alistair R.W. Williams.

MATERIALS AND METHODS Study Population

Dates of the study period. PEARL III only: July 13, 2010, to November 10, 2011.

PEARL III + PEARL III extension: July 13, 2010 to January 24, 2013.

The study ended after the last follow-up of the last patient as foreseen in the protocol.

Principal exclusion criteria. The principal exclusion criteria for the study are listed in Supplemental Table 1. The body mass index was calculated using the body weight in kilograms divided by the height in meters squared.

Randomization and masking. All women received open-label treatment with UPA. UPA treatment courses were equal to 90 days of UPA treatment. Women consented to participate to one treatment course (PEARL III study). Approximately 8 weeks into treatment course 1, women were randomized to receive double-blind treatment with either NETA or matching placebo after a predefined order and according to a predefined randomization list that had been established by the designated unblinded statistician at MDSL International with the corresponding treatment supplied at the end of the first course of UPA. The NETA or placebo were packaged in blisters of identical appearance. The treatment packs were assigned within each site by the investigator to the subjects in sequential order starting from the lowest number to the highest number.

After completion of the first treatment period, patients were proposed to participate in an extension study (PEARL III extension) with three further UPA treatment courses. The women received the same double-blind treatment of NETA or placebo throughout all treatment courses. Double-blinding was maintained for women and investigators throughout the entire study. At the end of the PEARL III study, the blind was broken for selected sponsor members to fulfill regulatory reporting requirements.

Efficacy Endpoints

Assessment of menstrual bleeding. The proportion of women in amenorrhea at the end of each UPA treatment course and the time to onset of amenorrhea for each treatment course were evaluated. Amenorrhea was defined as no bleeding for a continuous period of at least 35 days. Within any 35-day interval, 1 day of spotting was accepted. To assess this endpoint, we used a simplified semiquantitative bleeding scale, which included four categories: "no bleeding,'' "spotting," "bleeding," or "heavy bleeding.'' During the first treatment course the diary was completed daily with four categories available, whereas during subsequent treatment courses, women only reported spotting, bleeding, or heavy bleeding on days when these occurred (Supplemental Fig. 4A and B show sample charts). The proportion of women with ''spotting"/"no bleeding'' (that is, no "bleeding" or "heavy bleeding'') and the time to onset of "spotting"/"no bleeding'' for each treatment course was also evaluated.

The PBAC (1-4), an instrument that estimates menstrual blood loss in a semiquantitative measure, was used to evaluate the magnitude of menstrual bleeding at the start of the first treatment cycle and during the off-treatment period after each treatment course. PBAC has been widely used for evaluating drugs or devices interfering with menstrual bleeding such as desmopressin (5), tranexamic acid (6), orme-loxifene (7), levonorgestrel intrauterine device (8), and devices for endometrial ablation (9). The possible score ranges from 0 to more than 500 (with no defined upper limit), with higher scores indicating a greater severity of bleeding. Scores greater than 100 indicate HMB (1). Standardized sanitary materials were provided, and women recorded the number of tampons or pads used and the extent of soiling with blood. A sample chart is presented in Supplemental Figure 4C. The PBAC was completed by women during the first 8 days of their menstrual cycle at the start of treatment course 1 to have an objective assessment of the bleeding intensity and during the first 8 days of the first menstrual cycle after each NETA/placebo treatment.

Secondary efficacy endpoints. The volume of the three largest fibroids was assessed using transvaginal ultrasound (TVUS). The same three fibroids identified during screening were followed throughout the study. TVUS also included an assessment of the ovaries, uterine volume, endometrial thickness, and deformation of the uterine cavity and was performed at baseline, at the end of UPA treatment for course 1, and for subjects continuing in the extension study: 2 weeks after the start of first menses after treatment courses 2 and 3, at the end of UPA treatment course 4, and approximately 3 months after the end of the final treatment course.

Pain was measured with the Short-Form McGill Pain questionnaire (SF-MPQ) (10). The SF-MPQ part A consists of 15 descriptors that are ranked on an intensity scale of 0 = none to 3 = severe. Descriptors 1-11 represent the sensory (S) dimension of the pain experience, and 12-15 represent the affective (A) dimension. The total score for S is obtained by adding the ranks from descriptors 1-11. The total score for A is obtained by adding the ranks from descriptors

12-15. The overall total score is then obtained by adding the scores for S and A. If either the score for A or S is missing, then the overall total score will also be missing. Scores for SF-MPQ part A range from 0 (no pain) to 45 (severe pain for every S and A descriptor). SF-MPQ part B consists of a visual analog scale (VAS), with the resulting score between 0 mm and 100 mm; scores range from 0 (no pain) to 100 (worst possible pain). The SF-MPQ was assessed at baseline, at the end of weeks 4 and 8, and at the end of UPA treatment for the first treatment course, as well as for subjects continuing in the extension study 2 weeks after the start of first menses after treatment courses 2 and 3, at the end of UPA treatment for course 4, and approximately 3 months after the end of the final treatment course.

QoL was assessed using the Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QoL) questionnaire (11). The UFS-QoL is a validated, disease-specific questionnaire that consists of two parts; [1] a symptom severity score that includes bleeding, abdominal pressure, urination frequency, and fatigue (range, 0-100) with high symptom severity scores indicating increased symptom severity; and [2] a health-related quality of life (HRQL) total score. The HRQL total score (range, 0-100) is composed of six domains: Concern, Activities, Energy/Mood, Control, Self-Conscious, and Sexual Function. High HRQL scores indicate better QoL. Furthermore, another measure of QoL was assessed using the EQ-5D questionnaire, a standardized instrument for use as a measure of health outcome that consists of five dimensions of health status: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, all with a three-level scale. It also includes a VAS ranging from zero to 100, with lower scores indicating a worse health state. QoL assessments were recorded at the same time points as the volume of fibroids.

Safety Endpoints

All biopsy samples were processed at a central location and were assessed by three independent pathologists who were unaware of the study group assignments, the visit sequence, and one another's assessment. All pathologists have participated in previous UPA studies (12). Assessments were made according to standard diagnostic criteria and terminology for nonphysiological endometrial changes (p-receptor modulator-associated endometrial changes or PAEC), as described elsewhere by Mutter and colleagues (13). A consensus diagnosis of PAEC was made if two or more pa-thologists observed nonphysiological changes in an endo-metrial biopsy specimen. The timing of endometrial biopsies is presented in Supplemental Figure 1. Additional samples could be taken if endometrial thickness was >18 mm or if judged necessary by the investigator.

Clinical laboratory testing (hematology, biochemistry, and coagulation) was performed in a central laboratory (ICON Central Laboratories Ltd.) using validated assays. Laboratory investigations and vital signs were assessed at all visits. Serum E2, ACTH TSH and PRL levels were measured at screening, at the end of UPA treatment for courses 1 and 4, 2 weeks after the start of first menses after treatment

course 2, and approximately 3 months after the end of the final treatment course. The FSH level was measured at screening.

Statistical Analyses

Data management and statistical analysis were conducted using SAS 9.2 and governed by a comprehensive quality assurance system following International Conference on Harmonisation (14) and other applicable regulatory guidelines.

RESULTS

Supplemental Table 2 presents efficacy results for the first treatment course in the PEARL III open-label set.

The individual decisions on whether to have surgery or enter the extension study and to continue successive treatment courses may depend on many factors including advice of the investigator or surgeon, the response to treatment, and the patient's own preference for continued treatment and to adhere to all the study visits and procedures. The women's baseline characteristics and the overall response to course 1 (amenorrhea, fibroid volume reduction, pain, and QoL) were similar for women who continued into the extension study compared with all women who started PEARL III. Only four women discontinued PEARL III extension owing to lack of efficacy, and an analysis (not shown) of women who completed all four courses of treatment indicates that there were improvements in amenorrhea rates and fibroid volume reduction with successive treatment courses.

Supplemental Table 3 presents a summary ofvolume and timing of first menstruations during off-treatment periods for the PEARL III double-blind set (all women who received NETA or placebo at the end of UPA treatment for treatment course 1) and the PEARL III extension full analysis set), split by the NETA and placebo treatment groups and overall.

Supplemental Table 8 presents the proportion of women in amenorrhea at the end of each treatment course according to whether the total volume of the three largest fibroids was reduced by > 25%.

Supplemental Table 4 presents a summary of relevant efficacy results after the first UPA treatment course comparing women not entering the PEARL III extension study with those who decided to participate in an extension study with up to three additional treatment courses. Both subgroups had similar disease severity at baseline and efficacy response to one course of UPA.

Supplemental Table 5 presents a summary of adverse events in the PEARL III safety set (for the first treatment course).

Five women discontinued the extension study owing to adverse events. These were women with heavy uterine bleeding (n = 1) after the end of course 2, metrorrhagia (n = 1) during course 3, vertigo/dyspepsia/abdominal cramps and constipation during course 3, high blood pressure (n = 1) during course 4, and heavy uterine bleeding (n = 1) during course 4. Another woman discontinued the study due to leg pain that started 2 months after the end of course 2.

Supplemental Table 7 shows a summary of pathologist consensus of nonphysiological histological features in the endometrium.

Supplemental Tables 6 and 9 present summaries of other safety assessments in the PEARL III safety set and the PEARL III extension safety set.

Supplemental Figure 5 presents the time to spotting/no bleeding for each treatment course for the PEARL III extension full analysis set.

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prospective crossover study of intranasal desmopressin and oral tranexamic acid. Br J Haematol 2009;145:212-20.

7. Kriplani A, Kulshrestha V, Agarwal N. Efficacy and safety of ormeloxifene in management of menorrhagia: a pilot study. J Obstet Gynaecol Res 2009; 35:746-52.

8. Reid PC, Virtanen-Kari S. Randomised comparative trial of the levonorgestrel intrauterine system and mefenamic acid for the treatment of idiopathic menorrhagia: a multiple analysis using total menstrual fluid loss, menstrual blood loss and pictorial blood loss assessment charts. Br J Obstet Gynaecol 2005;112:1121-5.

9. Busfield RA, Farquhar CM, Sowter MC, Lethaby A, Sprecher M, Yu Y, et al. A randomized trial comparing the levonorgestrel intrauterine system and thermal balloon ablation for heavy menstrual bleeding. Obstet Gynecol Surv 2006;61:444-5.

10. Melzack R. The Short-Form McGill Pain Questionnaire. Pain 1987;30: 191-7.

11. 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.

12. 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.

13. Mutter GL, Bergeron C, Deligdisch L, Ferenczy A, Glant M, Merino M, et al. The spectrum of endometrial pathology induced by progesterone receptor modulators. Mod Pathol 2008;21:591-8.

14. Brown D, Day S, Hemmings R, Wright D. Assessing the impact of ICH E9. Pharm Stat 2008;7:77-87.

SUPPLEMENTAL FIGURE 1

UPA 10 mg 3-month (open-label) Progestin or Placebo 10 d (double-blind) Menses • Biopsy (required)

H Timeline (weeks) O Biopsy (if clinically indicated)

Pictorial flow diagram of treatments and biopsies for PEARL III and extension study.

Donnez. Long-term treatment of uterine fibroids. Fertil Steril 2014.

Patient disposition for participants entering PEARL III and PEARL III extension. aIncludes one woman who was withdrawn owing to an adverse event occurring in an off-treatment period. bOne woman was treated correctly for treatment course 1 but received only placebo medication (no UPA) in error for treatment course 2.

Donnez. Long-term treatment of uterine fibroids. Fertil Steril 2014.

Patient disposition for participants entering PEARL III and PEARL III extension, including details for NETA/placebo treatment groups. aOne woman was treated correctly for treatment course 1 but received only placebo medication (no UPA) in error for treatment course 2. bIncludes one woman who was withdrawn owing to an adverse event occurring in an off-treatment period.

Donnez. Long-term treatment of uterine fibroids. Fertil Steril 2014.

SUPPLEMENTAL FIGURE 4

Please complete your uterine bleeding pattern and the table recording the study medication you have taken every day during treatment with PGL4001.

LLII I I llilol I

DO U M M Y Y Y Y

9 10 11 12 13 14 15

No Bleeding: □ □ □ □ □ □ □

Spotting: □ □ □ □ □ □ □

Bleeding: □ □ □ □ □ □ □

Heavy Bleeding: □ □ □ □ □ □ □

UTERINE BLEEDING PATTERN

If you have had any Spotting. Bleeding or Heavy Bleeding dunng treatment with study medication, please complete the date and severity of bleeding below.

0«t* SpOttWVQ Blinding Heavy Bie«J no

I I II I I II2I0I I □ □ □

DD M M M Y Y Y Y

Assessment of uterine bleeding. (A) Semiquantitative bleeding scale used in PEARL III. (B) Semiquantitative bleeding scale used in PEARL III extension. (C) Example of a completed PBAC showing a score of 320 (equivalent to a menstrual blood loss of approximately 250 mL).

Donnez. Long-term treatment of uterine fibroids. Fertii Sterii 2014.

SUPPLEMENTAL FIGURE 4 Continued

Day 1 of Menstruation:

Likl H°H?I

DO MMM Y Y Y Y

1 2 3 4 5 6 7 8

Score Towels No bleeding □ No bieeong □ No bleeding □ No bleeding □ No bfe«ding □ No bleeding S No bleeding 0

1 s \ // //

5 /

20 /// //

1 / //

5 / /

10 m // // ///

1 Small Clots /Flooding ///

5 Large Clots /Flooding // / //

Score (Investigator use only) j? 93 SO S J? 0 o

Sum Score for first 8 days (investigator use only) 320

Large clots/flooding ^^^ Small clots/flooding ^ ^ "-1 l 1 3.0 cm 20 cm

Donnez. Long-term treatment of uterine fibroids. Fertii Sterii 2014.

SUPPLEMENTAL FIGURE 5

0 10 20 30 40 50 60 70 SO 90 100 Days

Time to spotting/no bleeding (PEARL III extension full analysis set). Time to spotting/no bleeding was defined as the first day for which there was subsequently only spotting or no bleeding for longer than 35 days to the end of UPA treatment within each treatment course, assessed using the patient diary data from the date of the first dose of UPA (day 0, which was to be within the first 4 days of the start of menstruation for treatment courses 1 and 2 and on the first day of menstruation for treatment courses 3 and 4). Circles denote censored observation (i.e., a woman had a subsequent interval of 35 days or less up to the end of UPA treatment for which only spotting or no bleeding was observed).

Donnez. Long-term treatment of uterine fibroids. Fertii Sterii 2014.

Key exclusion criteria.

Previous uterine surgery including endometrial ablation or uterine artery embolization.

History of or current uterus, cervix, ovarian, or breast cancer.

Significant finding on Papanikolaou test (PAP) smear within the past 12 months.

Endometrium hyperplasia or adenocarcinoma within the past 6 months or similar lesions in the screening biopsy. In case of biopsies older than 6 months, these had to be repeated.

Large uterine polyp (>2 cm).

Calcified fibroids and/or a calcified uterus.

Severe coagulation disorder.

One or more ovarian cysts >4 cm diagnosed by ultrasound.

History of treatment for fibroid with an SPRM, including UPA.

Treatments with progestins (systemic or progestin-releasing intrauterine system), oral contraceptive, acetylsalicylic acid, mefenamic acid,

anticoagulants such as cumarins and/or antifibrinolytic drugs such as tranexamic acid, P antagonists, systemic glucocorticoid treatments and/or systemic depot glucocorticoid, treatments that contain PgP substrate (digoxin, fexofenadine) or contain moderate or potent inhibitors or inducers of CYP3A4.

Donnez. Long-term treatment of uterine fibroids. Fertii Sterii 2014.

SUPPLEMENTAL TABLE 2

Efficacy results for first treatment course (PEARL III open-label set;

n = 209).

Assessment n Result3

Amenorrhea

No. of women in 209 164 (78.5)

amenorrhea (%)

95% CI, % 209 72.4, 83.5

Spotting/no bleeding

No. of women with 209 181 (86.6)

spotting or no

bleeding (%)

95% CI 209 81.3, 90.6

Total volume of three largest

fibroidsb

% Change from baseline, 194 -45.1 (-66.1, -24.9)

median (IQR)

Total reduction >25%, n 194 145 (74.7)

Total reduction >50%, n 194 86 (44.3)

Uterine volume

% Change from baseline, 201 -28.9 (-45.5, -8.4)

median (IQR)

Reduction >25%, n (%) 201 109(54.2)

Assessment of pain

SF-MPQc

End of week 4 actual, 204 2.0(0.0, 4.0)

median (IQR)

End of week 4 change 202 -5.0 (-12.0, -1.0)

from baseline, median

End of week 8 actual, 198 0.0(0.0, 2.0)

median (IQR)

End of week 8 change 196 -6.0 (-14.0, -1.6)

from baseline, median

End of course 1 actual, 200 1.0(0.0, 3.0)

median (IQR)

Course 1 change from 198 -6.0 (-14.0, -2.0)

baseline, median (IQR)

Visual analog scale (VAS)d

End of week 4 actual, 204 8.0(0.0, 28.0)

median (IQR)

End of week 4 change 204 -21.0 (-39.0, -2.0)

from baseline, median

End of week 8 actual, 202 2.0(0.0, 12.0)

median (IQR)

End of week 8 change 202 -26.0 (-54.0, -7.0)

from baseline, median

Course 1 actual, median 200 1.0(0.0, 12.0)

Course 1 change from 200 -24.5 (-54.0, -6.0)

baseline, median (IQR)

UFS-QoL questionnairee

Symptom severity

Actual, mean ± SD 196 14.5 ± 15.5

Change from baseline, 194 -33.3 ± 21.5

mean ± SD

Health-Related QoL total

Actual, mean ± SD 201 86.2 ± 15.6

Change from baseline, 200 29.2 ± 22.4

mean ± SD

EQ-5D questionnaire

Mobility (women with 201 10 (5.0)

problems), n (%)

Donnez. Long-term treatment of uterine fibroids. Fertii Sterii 2014.

Continued.

Assessment n Result3

Self-care (women with 201 0 (0.0)

problems), n (%)

Usual activities (women 200 12 (6.0)

with problems), n (%)

Pain/discomfort (women 200 60 (30.0)

with moderate/

extreme symptoms), n (%)

Anxiety/depression 201 84 (41.8)

(women with moderate/extreme symptoms), n (%) VAS (health state)f Actual, mean ± SD 200 76.8 ± 17.6

Change from baseline, 200 9.6 ± 23.3 mean ± SD

Note: n = Number of women with nonmissing observations.

a Assessments were made at end of a 13-week treatment course of UPA and before 10-day treatment course of NETA/placebo, except for the SF-MPQ, which was also assessed after 4 and 8 weeks of treatment.

b The same three fibroids identified at screening were followed throughout the study. c Scores on the SF-MPQ range from 0 to 45, with higher scores indicating more severe pain. d Scores on the VAS of the SF-MPQ range from 0 to 100, with higher scores indicating more severe pain.

e Scores on the VAS of the EQ-5D range from 0 to 100, with higher scores indicating a better health state.

f On the UFS-QoL questionnaire, scores for symptom severity range from 0 to 100, with higher scores indicating increased severity. Total scores for health-related QoL range from 0 to 100, with higher scores indicating a better QoL.

Donnez. Long-term treatment of uterine fibroids. Fertii Sterii 2014.

I / ■ 2014

Summary of PBAC at the start of treatment course 1 and PBAC and timing of first menstruation after each treatment course.

Total UPA then placebo UPA then NETA P value3

PEARL III (double-blind set) n = 201 n = 103 n = 98

PBAC score (days 1-8 of first menses)b

Postscreening, median 216(126, 376) 218(126, 344) 206(131,422)

Post-treatment course 1 n = 194 n = 99 n = 95

Actual, median (IQR) 98 (36,211) 123 (51, 248) 75 (27, 179)

Change, median (IQR) -92 (-220, 23) -69 (-167, 40) -122 (-299, -9) .01

Time to return to menstruation, daysc

Post-treatment course 1 n = 196 n = 101 n = 95

Median (IQR) 18(14, 26) 25 (20, 29) 14(13, 15) < .0001

PEARL III extension (full n = 132 n = 69 n = 63

analysis set)

PBAC score (days 1-8 of first menses)b

Post-screening, median 235 (142, 397) 228(142, 139) 257 (140, 498)

Post-treatment course 1 n = 131 n = 69 n = 62

Actual, median (IQR) 94 (31, 210) 123 (53, 233) 59(21, 155)

Change, median (IQR) -120 (-264, 5) -92 (-171, 25) -144 (-367, -42) .006

Post-treatment course 2 n = 123 n = 65 n = 58

Actual, median (IQR) 64(20, 168) 84(18, 226) 54(21, 103)

Change, median (IQR) -150 (-255, -55) -127 (-211, -14) -171 (-372, -71) .01

Post-treatment course 3 n = 114 n = 58 n = 56

Actual, median (IQR) 42 (14, 138) 75 (22, 191) 28 (9, 66)

Change, median (IQR) -131 (-311, -59) -103 (-186, -36) -224 (-461, -104) < .0003

Post-treatment course 4 n = 89 n = 49 n = 40

Actual, median (IQR) 31 (11, 100) 55 (22, 136) 13 (6, 48)

Change, median (IQR) -120 (-255, -45) -97 (-184, -31) -166 (-356, -74) .02

Time to return to menstruation, daysc

Post-treatment course 1 n = 131 n = 69 n = 62

Median (IQR) 18(14, 27) 25 (20, 30) 14(13, 15) < .0001

Post-treatment course 2 n = 125 n = 66 n = 59

Median (IQR) 18(14, 27) 26(21, 34) 14(13, 17) < .0001

Post-treatment course 3 n = 116 n = 60 n = 56

Median (IQR) 21 (14, 31) 30 (24, 36) 14(13, 17) < .0001

Post-treatment course 4 n = 99 n = 53 n = 46

Median (IQR) 22 (15, 34) 30 (23, 35) 15(14, 18) < .0001

a Tests comparing NETA to placebo were conducted using the Wilcoxon rank sum test.

b PBAC score postscreening assessment measured during days 1-8 at start of UPA treatment course 1. Score post-treatment course assessments measured during days 1 — 3 of first menstruation

after the end of the respective treatment course.

c Excludes women in whom surgery was performed before return of menstruation or women discontinued before return of menstruation.

Donnez. Long-term treatment of uterine fibroids. Fértil Steril 2014.

SUPPLEMENTAL TABLE 4

Selected efficacy results for participants not entering/entering the PEARL III extension study.

Did not enter extension Entered extension Difference Statistics3

Amenorrhea, n/N (%)b 59/77 (76.6) 105/132 (79.5) (2.9) .73

95% CI, % 66.0, 84.7 71.9, 85.5 -8.8, 14.6

Spotting or no bleeding, n/N 64/77 (83.1) 117/132(88.6) (5.5) .30

95% CI, % 73.2, 89.9 82.1, 93.0 -4.4, 15.5

Total volume of three largest n = 64 n = 130

fibroids0

% Change from baseline -38.5 -49.9 -12.1 .01

95% CI, % -47.8, -29.0 -56.7, -42.5 -22.2, -2.7

Uterine volume n = 69 n = 132

% Change from baseline -27.0 -29.8 -1.4 .79

95% CI, % -33.9, -14.5 -35.3, -22.6 -10.1, 7.5

Assessment of pain

VASd n = 68 n = 132

Change from baseline -27.5 -23.5 -3.0 .53

95% CI, % -36.0, -13.0 -34.0, -17.0 -12.0, 6.0

UFS-QoL questionnaire6

Symptom severity n = 65 n = 129

Change from baseline -28.4 -35.8

Least square mean -30.6 -34.7 -4.1 .08

95% CI, % -34.3, -26.8 -37.3, -32.0 -8.7, 0.5

Health-related QoL total n = 69 n = 131

Change from baseline 22.2 32.8

Least square mean 25.3 31.2 5.9 .009

95% CI, % 21.7, 28.8 28.6, 33.8 1.5, 10.3

a Fisher's exact test was used for amenorrhea and spotting or no bleeding; Wilcoxon rank sum test was used for total volume of three largest fibroids, uterine volume, assessment of pain (medians

reported), and analysis of covariance for the UFS-QoL questionnaire (means reported).

b Amenorrhea (and spotting or no bleeding) assessed while under UPA treatment. For remaining results, data were collected at the end of UPA treatment.

c The same three fibroids identified at screening were followed throughout the study.

d Scores on VAS range from 0 to 100, with higher scores indicating more severe pain.

e On the UFS-QoL questionnaire, scores for symptom severity range from 0 to 100, with higher scores indicating increased severity. Total scores for health-related QoL range from 0 to 100, with

higher scores indicating a better QoL.

Donnez. Long-term treatment of uterine fibroids. Fértil Steril 2014.

Adverse events (PEARL III safety set; n = 209).

Adverse event No. of women (%)

At least one SAE 2(1.0)

Any SAE during UPA treatment 0

Any SAE during NETA/Placebo 0

treatment 2 (1.0)b

Any SAE off treatment

Menometrorrhagia 1 (0.5)

Uterine hemorrhage 1 (0.5)

Breast cancer 1 (0.5)c

Adverse eventsd

Leading to study withdrawal6 1 (0.5)

At least one event 120 (57.4)

Headache 34(16.3)

Nasopharyngitis 14(6.7)

Abdominal pain (including upper/ 11 (5.3)

lower)

Hot flashes 10 (4.8)

Fatigue 9 (4.3)

Nausea 8 (3.8)

Vertigo 8 (3.8)

Breast discomfort/breast pain/breast 8 (3.8)

tenderness

Pelvic pain 8 (3.8)

a All adverse events that occurred during UPA treatment in at least 3% of women overall and

all SAEs are included.

b One woman had two off-treatment SAEs.

c A 46-year-old woman was diagnosed with a lobular breast cancer 2 months after the end of

treatment (T1, grade II).

d Adverse events with onset on or after the first dose of UPA and before the first dose of

NETA/placebo within each treatment course or up to and including 7 days after the last

dose of UPA if NETA/placebo was never started.

e In addition, another adverse event that occurred when a woman was not receiving UPA led

to study withdrawal.

Donnez. Long-term treatment of uterine fibroids. Fertii Sterii 2014.

SUPPLEMENTAL TABLE 6

Summary of other safety assessments (PEARL III safety set;

n = 209).

Assessmenta n Result

Serum E2, pg/mL

Screening, median (IQR) 205 120.0(77, 184)

Course 1, median (IQR) 180 55.0(41, 84)

ACTH, pg/mL

Screening, median (IQR) 196 13.3 (9.3, 19.8)

Course 1, median (IQR) 177 13.2 (9.2, 17.1)

TSH, mIU/L

Screening, median (IQR) 205 1.36(0.96, 1.96)

Course 1, median (IQR) 181 1.49(1.00, 2.00)

PRL, ng/mL

Screening, median (IQR) 205 11.4 (8.2, 18.2)

Course 1, median (IQR) 180 7.9(5.5, 11.7)

Total cholesterol, mmol/L

Screening, median (IQR) 205 5.06 (4.48, 5.60)

Course 1, median (IQR) 180 5.25 (4.71, 5.82)

Second menstrual bleed 123 4.89 (4.41, 5.47)

post-treatment,

median (IQR)

3-Month follow-up, 56 5.16 (4.44, 5.93)

median (IQR)

HDL, mmol/L

Screening, median (IQR) 205 1.61 (1.43, 1.91)

Course 1, median (IQR) 180 1.64(1.44, 1.89)

Second menstrual bleed 123 1.56 (1.31, 1.81)

post-treatment,

median (IQR)

3-Month follow-up, 56 1.72(1.46, 1.92)

median (IQR)

LDL, mmol/L

Screening, median (IQR) 203 2.81 (2.40, 3.39)

Course 1, median (IQR) 178 2.97 (2.55, 3.54)

Second menstrual bleed 121 2.72 (2.30, 3.07)

post-treatment,

median (IQR)

3-Month follow-up, 56 2.73 (2.19, 3.53)

median (IQR)

Endometrial thickness, mm

Screening, mean ± SD 202 8.7 ± 3.7

<4 mm, n (%) 14 (6.9)

>4 to < 16 mm, n (%) 185 (91.6)

>16 mm, n (%) 3(1.5)

Course 1, mean ± SD 198 9.2 ± 4.6

<4 mm, n (%) 23 (11.6)

>4 to < 16 mm, n (%) 157 (79.3)

>16 mm, n (%) 18(9.1)

2 Weeks after first 181 8.9 ± 4.1

menstrual bleed post-

treatment, mean ± SD

<4 mm, n (%) 19(10.5)

>4 to < 16 mm, n (%) 150(82.9)

>16 mm, n (%) 12 (6.6)

3-Month follow-up, 48 7.6 ± 3.4

mean ± SD

<4 mm, n (%) 9(18.8)

>4 to < 16 mm, n (%) 39(81.3)

>16 mm, n (%) 0

Systolic blood pressure, mmHg

Baseline, mean ± SD 209 121.4 ± 13.8

End of week 4, mean ± SD 207 119.7 ± 13.1

End of week 8, mean ± SD 203 119.7 ± 13.7

Course 1, mean ± SD 202 120.2 ± 13.7

2 Weeks after first 191 121.9 ± 12.3

menstrual bleed post-

treatment, mean ± SD

Donnez. Long-term treatment of uterine fibroids. Fértil Steril 2014.

SUPPLEMENTAL TABLE 6

Continued.

Assessment3 n Result

Second menstrual bleed 132 119.8 ± 13.2

post-treatment,

mean ± SD

3-Month follow-up, 57 120.4 ± 13.6

mean ± SD

Diastolic blood pressure, mmHg

Baseline, mean ± SD 209 74.4 ± 9.8

End of week 4, mean ± SD 207 73.4 ± 9.9

End of week 8, mean ± SD 203 74.0 ± 10.0

Course 1, mean ± SD 202 74.2 ± 9.9

2 Weeks after first 191 74.9 ± 9.5

menstrual bleed post-

treatment, mean ± SD

Second menstrual bleed 132 73.6 ± 9.4

post-treatment,

mean ± SD

3-Month follow-up, 57 74.5 ± 10.8

mean ± SD

Pulse rate, bpm

Baseline, mean ± SD 209 73.9 ± 10.7

End of week 4, mean ± SD 207 72.6 ± 9.3

End of week 8, mean ± SD 203 72.7 ± 9.3

Course 1, mean ± SD 201 72.1 ± 9.4

2 Weeks after first 191 72.8 ± 9.5

menstrual bleed post-

treatment, mean ± SD

Second menstrual bleed 132 72.4 ± 10.4

post-treatment,

mean ± SD

3-Month follow-up, 56 72.2 ± 10.8

mean ± SD

Weight, kg

Baseline, mean ± SD 209 69.0 ± 12.8

Course 1, mean ± SD 202 68.5 ± 12.8

Second menstrual bleed 132 68.2 ± 13.2

post-treatment,

mean ± SD

3-Month follow-up, 58 70.2 ± 11.7

mean ± SD

Mnte- n — Mi imhpr nf wnmen with nnnmksinn nhcprv/a+innc

a Course 1 data were collected at the end of UPA treatment. Second menstrual bleed post-treatment data were collected for those entering the extension; 3-month follow-up data were collected for those not entering the extension. Donnez. Long-term treatment of uterine fibroids. Fertil Steril 2014.

Summary of pathologist consensus of nonphysiological histological

features in the endometrium. UPAthen UPAthen

Total Placebo NETA

PEARL III n = 209 n = 103 n = 98

Screening n = 171 n = 85 n = 80

No. of women (%) 18 (10.5) 7 (8.2) 11 (13.8)

2 Weeks after first menstrual n = 176 n = 92 n = 84

bleed post-treatment

No. of women (%) 45 (25.6) 26 (28.3) 19 (22.6)

PEARL III extension n = 132 n = 69 n = 63

Screening n = 105 n = 56 n = 49

No. of women (%) 11 (10.5) 4(7.1) 7 (14.3)

2 Weeks after first menstrual n = 122 n = 65 n = 57

bleed post-treatment

course 1

No. of women (%) 35 (28.7) 20 (30.8) 15 (26.3)

2 Weeks after first menstrual n = 87 n = 47 n = 40

bleed post-treatment

course 4

No. of women (%) 22 (25.3)a 11 (23.4) 11 (27.5)

Note: n = Number of women with nonmissing observations

a Of the 22 women diagnosed with a consensus of nonphysiological histological features

2 weeks after first menstrual bleed post-treatment course 4,15 (7 placebo, 8 NETA) women

had biopsies at 3-month follow-up. Of these, three (1 placebo and 2 NETA) women were

diagnosed with nonphysiological histological features at this follow-up visit.

Donnez. Long-term treatment of uterine fibroids. Fertii Sterii 2014.

SUPPLEMENTAL TABLE 8

Women in amenorrhea at the end of each treatment course by total volume of a reduction R 25% of the three largest fibroids.

Fibroid volume Amenorrhea,

Treatment course reduction R25%a Total n (%)

Course 1 Yes 101 82 (81.2)

No 29 22 (75.9)

Totalb 130 104 (80.0)

Course 2 Yes 95 88 (92.6)

No 24 19(79.2)

Totalb 119 107 (89.9)

Course 3 Yes 83 74 (89.2)

No 23 21 (91.3)

Totalb 106 95 (89.6)

Course 4 Yes 79 75 (94.9)

No 17 14(82.4)

Totalb 96 89 (92.7)

a Fibroid volume reduction assessed using total volume of the three largest fibroids assessed during the screening period before the first treatment course. The same three fibroids identified at screening were followed throughout the study. Course 1 and 4 data were collected at the end of UPA treatment; course 2 and 3 data were collected after first menstrual bleed after UPA treatment and subsequent NETA/placebo treatment.

b Overall totals for each treatment course are the number of women receiving UPA in each treatment course who did not have surgery performed during or before the end of each treatment course and who have a nonmissing amenorrhea assessment and nonmissing fibroid volume reduction assessment for the treatment course in question.

Donnez. Long-term treatment of uterine fibroids. Fertii Sterii 2014.

Summary of other safety assessments (PEARL III extension safety

set; n = 132)

Assessment3 n Result

Serum E2, pg/mL

Screening, median (IQR) 131 120.0(76.0, 185.0)

Course 1, median (IQR) 112 54.0(38.5,81.0)

Course 2, median (IQR) 119 129.0(62.0, 194.0)

Course 4, median (IQR) 95 43.0(27.0,61.0)

3-Month follow-up, 96 96.5 (66.5, 173.0)

median (IQR)

ACTH, pg/mL

Screening, median (IQR) 126 13.0 (9.3, 19.3)

Course 1, median (IQR) 117 12.7 (9.7, 16.9)

Course 2, median (IQR) 103 12.6 (8.3, 17.3)

Course 4, median (IQR) 86 12.5 (8.1, 16.3)

3-Month follow-up, 89 13.2 (8.9, 20.9)

median (IQR)

TSH, mIU/L

Screening, median (IQR) 131 1.31 (0.94, 1.83)

Course 1, median (IQR) 113 1.41 (0.93, 2.00)

Course 2, median (IQR) 119 1.35 (0.92, 1.88)

Course 4, median (IQR) 95 1.39 (0.84, 2.16)

3-Month follow-up, 96 1.33 (0.90, 1.85)

median (IQR)

PRL, ng/mL

Screening, median (IQR) 131 11.3 (8.9, 18.5)

Course 1, median (IQR) 112 7.55 (5.45, 11.35)

Course 2, median (IQR) 118 8.85 (6.30, 12.90)

Course 4, median (IQR) 95 6.90 (5.10, 11.60)

3-Month follow-up, 96 9.35 (7.35, 15.35)

median (IQR)

Total cholesterol, mmol/L

Screening, median (IQR) 131 5.00 (4.50, 5.58)

Course 1, median (IQR) 112 5.25 (4.93, 5.78)

Course 2, median (IQR) 119 4.97 (4.57, 5.49)

Course 4, median (IQR) 94 5.33 (4.93, 5.85)

3-Month follow-up, 96 5.17 (4.73, 5.69)

median (IQR)

HDL, mmol/L

Screening, median (IQR) 131 1.61 (1.43, 1.88)

Course 1, median (IQR) 112 1.65 (1.41, 1.92)

Course 2, median (IQR) 119 1.59 (1.40, 1.90)

Course 4, median (IQR) 94 1.60 (1.40, 1.87)

3-Month follow-up, 96 1.62 (1.41, 1.92)

median (IQR)

LDL, mmol/L

Screening, median (IQR) 129 2.81 (2.40, 3.38)

Course 1, median (IQR) 110 3.01 (2.60, 3.50)

Course 2, median (IQR) 117 2.77 (2.41, 3.26)

Course 4, median (IQR) 94 3.04 (2.58, 3.62)

3-Month follow-up, 96 2.95 (2.52, 3.56)

median (IQR)

Endometrial thickness, mm

Screening, mean ± SD 129 9.3 ± 4.0

<4 mm, n (%) 7 (5.4)

>4 to < 16 mm, n (%) 119(92.2)

>16 mm, n (%) 3 (2.3)

Course 1, mean ± SD 130 9.4 ± 4.5

<4 mm, n (%) 13 (10.0)

>4 to < 16 mm, n (%) 107 (82.3)

>16 mm, n (%) 10 (7.7)

Course 2, mean ± SD 120 8.8 ± 3.8

<4 mm, n (%) 15 (12.5)

>4 to < 16 mm, n (%) 101 (84.2)

>16 mm, n (%) 4(3.3)

Course 3, mean ± SD 107 8.0 ± 3.4

<4 mm, n (%) 15 (14.0)

>4 to < 16 mm, n (%) 91 (85.0)

>16 mm, n (%) 1 (0.9)

Donnez. Long-term treatment of uterine fibroids. Fértil Steril 2014.

SUPPLEMENTAL TABLE 9

Continued.

Assessment3 n Result

Course 4, mean ± SD 95 7.5 ± 3.4

<4 mm, n (%) 17 (17.9)

>4 to <16 mm, n (%) 77 (81.1 )

>16 mm, n (%) 1 (1.1)

3-Month follow-up, 97 8.9 ± 3.2

mean ± SD

<4 mm, n (%) 6 (6.2)

>4 to <16 mm, n (%) 89 (91.8 )

>16 mm, n (%) 2(2.1)

Systolic blood pressure, mmHg

Baseline, mean ± SD 132 122.2 ± 14.1

Course 1, mean ± SD 132 120.5 ± 13.6

Course 2, mean ± SD 121 120.4 ± 13.7

Course 3, mean ± SD 109 120.3 ± 11.4

Course 4, mean ± SD 96 120.7 ± 13.3

3-Month follow-up, 99 119.5 ± 11.0

mean ± SD

Diastolic blood pressure, mmHg

Baseline, mean ± SD 132 74.2 ± 9.3

Course 1, mean ± SD 132 74.4 ± 9.7

Course 2, mean ± SD 121 .7 4. 7 0.3

Course 3, mean ± SD 109 73.6 ± 8.8

Course 4, mean ± SD 96 74.4 ± 8.1

3-Month follow-up, 99 73.5 ± 9.2

mean ± SD

Pulse rate, bpm

Baseline, mean ± SD 132 73.8 ± 0.7

Course 1, mean ± SD 132 72.5 ± 9.5

Course 2, mean ± SD 121 73.8 ± 0.5

Course 3, mean ± SD 109 73.3 ± 9.5

Course 4, mean ± SD 96 72.2 ± 8.7

3-Month follow-up, 99 72.9 ± 9.5

mean ± SD

Weight, kg

Baseline, mean ± SD 132 68.7 ± 3.6

Course 1, mean ± SD 132 67.8 ± 3.3

Course 2, mean ± SD 121 67.3 ± 2.6

Course 3, mean ± SD 109 67.5 ± 2.7

Course 4, mean ± SD 96 67.4 ± 2.6

3-Month follow-up, 99 67.8 ± 3.3

mean ± SD

Mnto- n — Mumhor rvf imrmn .' i+h nmmitdnn r\ l->c o n/at in n c

a Course 1 and 4 data were collected at the end of UPA treatment; course 2 and 3 data were

collected after first menstrual bleed after UPA treatment and subsequent NETA/placebo

treatment.

Donnez. Long-term treatment of uterine fibroids. Fertil Steril 2014.