In this trial involving women with symptomatic fibroids who were planning to undergo surgery, treatment with the selective progesterone-receptor modulator ulipristal acetate was effective in ...controlling excessive bleeding and reducing fibroid size at 13 weeks.
Uterine leiomyomas, or fibroids, are benign, hormone-sensitive, smooth-muscle tumors that occur in 20 to 40% of women of reproductive age.
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The most common symptoms are menorrhagia and iron-deficiency anemia, which may lead to chronic fatigue
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that may not be adequately controlled with iron supplementation alone.
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Other symptoms include pelvic pain, dysmenorrhea, and pressure effects, which may adversely affect quality of life and fertility.
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Many patients require intervention, and the choice of treatment is guided by the patient's age and desire to preserve fertility and avoid hysterectomy.
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Fibroids are the most common indication for hysterectomy.
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Other treatments include . . .
In this trial comparing oral ulipristal acetate (5 mg or 10 mg daily) with once-monthly leuprolide acetate in women with symptomatic uterine fibroids before planned surgery, both doses of ulipristal ...acetate were noninferior to leuprolide acetate in controlling uterine bleeding.
Uterine leiomyomas, or fibroids, are the most common benign uterine tumors in women of reproductive age. In addition to anemia caused by heavy bleeding, fibroids can cause pelvic pain, pressure, dysmenorrhea, reduced quality of life, and infertility. Current management strategies consist mainly of surgical or radiologic interventions; options for medical therapy are limited.
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The use of oral progestin has not been extensively investigated, but small studies report breakthrough bleeding
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and possible promotion of myoma growth.
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The use of a progestin-releasing intrauterine device controls menorrhagia in some patients, but trials have generally excluded patients with uteri distorted by submucosal myomas. . . .
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).
Objective To investigate the efficacy and safety of repeated 12-week courses of 5 or 10 mg daily of ulipristal acetate for intermittent treatment of symptomatic uterine fibroids. Design Double-blind, ...randomized administration of two 12-week courses of ulipristal acetate. Setting Gynecology centers. Patient(s) A total of 451 patients with symptomatic uterine fibroid(s) and heavy bleeding. Intervention(s) Two repeated 12-week treatment courses of daily 5 or 10 mg of ulipristal acetate. Main Outcome Measure(s) Amenorrhea, controlled bleeding, fibroid volume, quality of life (QoL), pain. Result(s) In the 5- and 10-mg treatment groups (62% and 73% of patients, respectively) achieved amenorrhea during both treatment courses. Proportions of patients achieving controlled bleeding during two treatment courses were >80%. Menstruation resumed after each treatment course and was diminished compared with baseline. After the second treatment course, median reductions from baseline in fibroid volume were 54% and 58% for the patients receiving 5 and 10 mg of ulipristal acetate, respectively. Pain and QoL improved in both groups. Ulipristal acetate was well tolerated with less than 5% of patients discontinuing treatment due to adverse events. Conclusion(s) Repeated 12-week courses of daily oral ulipristal acetate (5 and 10 mg) effectively control bleeding and pain, reduce fibroid volume, and restore QoL in patients with symptomatic fibroids. Clinical Trial Registration Number NCT01629563 (PEARL IV).
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. Design Double-blind, ...randomized administration of four 12-week courses of ulipristal acetate. Setting Gynecology centers. Patient(s) Four hundred fifty-one subjects with symptomatic uterine fibroid(s) and heavy menstrual bleeding. Intervention(s) Four repeated 12-week treatment courses of daily 5 or 10 mg ulipristal acetate. Main Outcome Measure(s) Endometrial safety and general safety, laboratory parameters, amenorrhea, controlled bleeding, fibroid 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 QoL showed marked improvements from screening, even during the off-treatment intervals. The safety profile of ulipristal acetate was confirmed, and repeated treatment courses did not increase the occurrence of adverse reactions. There were no significant changes in laboratory parameters during the study. The percentage of subjects with endometrial thickness ≥16 mm was 7.4% (all subjects) after the first treatment course and returned to below screening levels (4.9%) in subsequent treatment courses. As in previous studies, ulipristal acetate did not increase the occurrence of endometrial features of concern. The frequency of nonphysiological changes did not increase with repeated treatment. They were observed in 17.8% and 13.3% of biopsies after treatment courses 2 and 4, respectively, and were reversible after treatment cessation. 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 NCT01629563.
(1) Background: The aim of the present pilot study was to study the effect of a new oral gonadotropin-releasing hormone antagonist on adenomyosis. (2) Methods: Eight premenopausal women, aged between ...37 and 45 years, presenting with heavy menstrual bleeding, pelvic pain, and dysmenorrhea due to diffuse and disseminated uterine adenomyosis, confirmed by magnetic resonance imaging (MRI), received 200 mg linzagolix once daily for a period of 12 weeks, after which they were switched to 100 mg linzagolix once daily for another 12 weeks. The primary efficacy endpoint was the change in volume of the adenomyotic uterus from baseline to 24 weeks, evaluated by MRI. Secondary efficacy endpoints included the change in uterine volume from baseline to 12 and 36 weeks by MRI, and also weeks 12, 24, and 36 assessed by transvaginal ultrasound (TVUS). Other endpoints were overall pelvic pain, dysmenorrhea, non-menstrual pelvic pain, dyspareunia, amenorrhea, quality of life measures, bone mineral density (BMD), junctional zone thickness, and serum estradiol values. (3) Results: Median serum estradiol was suppressed below 20 pg/mL during the 12 weeks on linzagolix 200 mg, and maintained below 60 pg/mL during the second 12 weeks on linzagolix 100 mg. At baseline, the mean ± SD uterine volume was 333 ± 250 cm
. After 24 weeks of treatment, it was 204 ± 126 cm
, a reduction of 32% (
= 0.0057). After 12 weeks, the mean uterine volume was 159 ± 95 cm
, a reduction of 55% from baseline (
= 0.0001). A similar pattern was observed when uterine volume was assessed by TVUS. Improvements in overall pelvic pain, dysmenorrhea, non-menstrual pelvic pain, dyspareunia, and dyschezia, as well as quality of life measured using the EHP-30 were also observed. Mean percentage BMD loss at 24 weeks was, respectively, -2.4%, -1.3%, and -4.1% for the spine, femoral neck, and total hip. The most common adverse events were hot flushes, which occurred in 6/8 women during the first 12 weeks, and 1/8 women between 12 and 24 weeks. (4) Conclusions: Linzagolix at a dose of 200 mg/day reduced uterine volume, and improved clinically relevant symptoms. Treatment with 100 mg thereafter retains the therapeutic benefits of the starting dose while minimizing side effects. This 'hit hard first and then maintain' approach may be the optimal way to treat women with symptomatic adenomyosis.
In addition to the estrogen receptor, the progesterone receptor plays an important role in the growth of uterine fibroids. Several selective progesterone receptor modulators (SPRMs) have been ...evaluated for medical treatment of uterine fibroids and, because of safety issues, some molecules were stopped during clinical development. However, in 2012, ulipristal acetate received the approval for a pre-surgical treatment of uterine fibroids. Clinical trials with ulipristal acetate for long-term medical treatment of uterine fibroids are ongoing. This review article describes the action of SPRMs at the progesterone receptor level and the mechanism of action on the fibroid tissue. A review of the published clinical trials is performed, including the current evidence of efficacy on uterine fibroid symptom management, size reduction and tolerability. The therapeutic potential of SPRMs for uterine fibroids is discussed.
To study the effect of a new investigational oral gonadotropin-releasing hormone antagonist, linzagolix, on endometriosis-associated pain (EAP).
A multinational, parallel group, randomized, ...placebo-controlled, double-blind, dose-ranging trial.
Clinical centers.
Women aged 18–45 years with surgically confirmed endometriosis and moderate-to-severe EAP.
The interventions were 50, 75, 100, or 200 mg linzagolix (or matching placebo) administered once daily for 24 weeks.
The primary endpoint was the number of responders (≥30% reduction in overall pelvic pain) after 12 weeks. Other endpoints included dysmenorrhea, non-menstrual pelvic pain, serum estradiol, amenorrhea, quality of life (QoL) measures, and bone mineral density (BMD).
Compared with placebo, doses ≥ 75 mg resulted in a significantly greater proportion of responders for overall pelvic pain at 12 weeks (34.5%, 61.5%, 56.4%, and 56.3% for placebo, 75, 100, and 200 mg, respectively). A similar pattern was seen for dysmenorrhea and non-menstrual pelvic pain. The effects were maintained or increased at 24 weeks. Serum estradiol was suppressed, QoL improved, and the rate of amenorrhea increased in a dose-dependent fashion. Mean BMD loss (spine) at 24 weeks was <1% at doses of 50 and 75 mg and increased in a dose-dependent fashion up to 2.6% for 200 mg. BMD of femoral neck and total hip showed a similar pattern.
Linzagolix significantly reduced EAP and improved QoL at doses of 75–200 mg and decreased BMD dose-dependently.
NCT02778399
Tratamiento del dolor asociado a la endometriosis con linzagolix, un antagonista de la hormona liberadora de gonadotropina (GnRH) oral: un ensayo clínico aleatorizado
estudiar el efecto de un nuevo antagonista oral de la hormona liberadora de gonadotropina en investigación, linzagolix, en el dolor asociado a la endometriosis (EAP).
un ensayo multinacional, de grupos paralelos, aleatorizado, controlado con placebo, doble ciego y de rango de dosis.
centros clínicos.
Mujeres de 18 a 45 años con endometriosis confirmada quirúrgicamente y EAP moderado a severa.
las intervenciones fueron 50, 75, 100 o 200 mg de linzagolix (o placebo equivalente) administrado una vez al día durante 24 semanas.
El objetivo primario final fue el número de respondedores (reducción de >30% en el dolor pélvico general) después de 12 semanas. Otros objetivos incluyeron dismenorrea, dolor pélvico no menstrual, estradiol sérico, amenorrea, calidad de vida (QoL) medidas y densidad mineral ósea (DMO).
en comparación con placebo, las dosis de ≥75 mg dieron como resultado una proporción significativamente mayor de respondedores para el dolor pélvico general en 12 semanas (34.5%, 61.5%, 56.4% y 56.3% para placebo, 75, 100 y 200 mg, respectivamente). Se observó un patrón similar para la dismenorrea y el dolor pélvico no menstrual. Los efectos se mantuvieron o aumentaron a las 24 semanas. El estradiol sérico se suprimió, la calidad de vida mejoró, y la tasa de amenorrea aumentó de forma dependiente de la dosis. La pérdida media de DMO (columna vertebral) a las 24 semanas fue <1% a dosis de 50 y 75 mg y aumentó de forma dependiente de la dosis hasta 2.6% por 200 mg. La DMO del cuello femoral y la cadera total mostró un patrón similar.
Linzagolix redujo significativamente la EAP y mejoró la calidad de vida a dosis de 75–200 mg y disminuyó la DMO de forma dosis-dependiente.
INTRODUCTION:
We previously reported safety and efficacy results from the PRIMROSE 1 and 2 trials of linzagolix in the treatment of women with heavy menstrual bleeding associated with uterine ...fibroids (UFs), which showed maintenance of treatment effect for up to 52 weeks of dosing. Here we report post-treatment follow-up of key efficacy and safety results from weeks 64 and 76.
METHODS:
PRIMROSE1 and PRIMROSE2 were two randomized, double-blind, placebo-controlled phase 3 trials investigating the efficacy and safety of linzagolix 100 mg and 200 mg once daily, with or without hormonal add-back therapy (ABT) in the treatment of UFs for 52 weeks. Participants were followed for up to 6 months (week 76) after completion of treatment.
RESULTS:
At week 64, improvements in pain, hemoglobin, health-related quality of life, and uterine and fibroid volumes, observed at 24 and 52 weeks, were diminished but a beneficial difference from baseline was maintained. In patients with amenorrhea at week 52, the median (95% CI) time to first uterine bleeding was 30 (SD 27; SD 32) and 31 (SD 29; SD 32) days in PRIMROSE 1 and 2, respectively. At week 76, participants had full or partial recovery of lumbar spine bone mineral density (BMD): with 53%, 52% and 64% for 100 mg, 100 mg+ABT and 200 mg+ABT, respectively in PRIMROSE1 and 59%, 80% and 67% in PRIMROSE2.
CONCLUSION:
Linzagolix effects persisted following treatment discontinuation, although there was partial return to baseline for all measured efficacy endpoints. BMD also improved. The return to menstruation was rapid.
INTRODUCTION:
Although hair loss (alopecia) is a benign disorder, it can negatively affect patient's self-esteem, self-image, and overall quality of life. Linzagolix is an oral GnRH antagonist being ...developed at full and partial suppression doses with and without hormonal add-back therapy (ABT) for treatment of uterine fibroid-related symptoms. Alopecia was previously reported with other GnRH antagonists.
METHODS:
PRIMROSE 1 and 2 are two randomized, double-blind, placebo-controlled phase 3 trials investigating the efficacy and safety of linzagolix 100 mg and 200 mg once daily, +/- ABT in the treatment of uterine fibroids for 52 weeks.
RESULTS:
Up to week 24, alopecia was reported in total of five subjects (0.5%) in the pooled safety analysis set (N=1037). There was a similar incidence in the placebo (two subjects; 1.0%), 100 mg (one subject; 0.5%), and 200 mg+ABT groups (two subjects; 1.0%), and no reports in the 100 mg+ABT or 200 mg groups. Four of the cases resolved. For one subject (200 mg+ABT group) mild alopecia had not resolved. For this subject, the study drug was continued, and no concomitant therapy was administered for the alopecia. Up to week 52, one (0.1%) subject in the 200 mg+ABT group reported alopecia, which resolved. None of the cases led to treatment discontinuation. No subjects reported alopecia during the post-treatment follow-up.
CONCLUSION:
Hair loss (alopecia) was rarely observed in the PRIMROSE trials of linzagolix in the treatment of uterine fibroids.
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