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Esmya

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  • 1. ESMYA O N CH3 H3C OCH3 OCCH3 O 1.Chabbert-Buffet et al. J Clin Endocrinol Metab 2007;92:3582–3589 Dr. Francisco Vázquez Fernández
  • 2. Introduction to ESMYA • ESMYA (ulipristal acetate; CDB-2914) is a selective progesterone receptor modulator (SPRM) N CH3 H3C OCH3 OCCH3 • Induces amenorrhoea and inhibits ovulation in normal women1 O OCCH3 O 1.Chabbert-Buffet et al. J Clin Endocrinol Metab 2007;92:3582–3589
  • 3. Phase IIa study treatment Placebo 3 cycles / 90–102 days B A S E L I H Y S T E R R A N D ESMYA 10 mg daily ESMYA 20 mg daily I N E C Y C L E R E C T O M Y D O M I S E
  • 4. Phase IIb study treatment Patient choice: • Surgery Placebo 3 cycles / 90–102 days B A S E L I R A N D • Surgery • No surgery • Further ESMYA treatment ESMYA 10 mg daily ESMYA 20 mg daily I N E C Y C L E D O M I S E
  • 5. Endpoints in both studies • Primary endpoint – Change in fibroid size, assessed by magnetic resonance imaging (MRI) • Secondary endpoints – Effect on ovulation and folliculogenesis– Effect on ovulation and folliculogenesis – Change in size of the largest fibroid – Changes in fibroid-related symptoms – Effect on quality of life – Change in adrenal function – Adverse events
  • 6. ESMYA reduces fibroid size compared with placebo 7,3 11 0 5 10 15 Changeinfibroidvolume(%) Placebo ESMYA 10 mg Mean percentage change in total fibroid volume from baseline Phase IIa (n=19) Phase IIb (n=38) -18,7 -15,5-16,5 -19,1 -20 -15 -10 -5 Changeinfibroidvolume(%) ESMYA 10 mg ESMYA 20 mg p=0.0151 1Combined ESMYA arms vs placebo p=0.00581 • More patients achieve a reduction in fibroid size with ESMYA than with placebo
  • 7. PEARL I: Randomised, double-blind Phase III trial of ESMYA vs placebo R A N D S U RPatients with 3 months Once-daily oral ESMYA 5 mg + concomitant iron D O M I S E R G E R Y Patients with uterine fibroids http://www.clinicaltrials.gov/ct2/show/NCT00755755?term=NCT00755755&rank=1 Once-daily oral ESMYA 10 mg + concomitant iron Placebo + concomitant iron ClinicalTrials.gov Identifier: NCT00755755
  • 8. PEARL I: Study objectives Primary objectives • Demonstrate superior efficacy of ESMYA + iron versus placebo + iron for: – Reducing excessive uterine bleeding prior to surgery – Reducing total fibroid volume prior to surgery • Assess overall safety of ESMYA in subjects with uterine fibroids Secondary objectives • Demonstrate superior efficacy of ESMYA + iron versus placebo + iron at correcting anaemia caused by uterine fibroidscorrecting anaemia caused by uterine fibroids • Demonstrate improvements in fibroid-related symptoms, such as pain • Assess the capacity of ESMYA to decrease uterine volume Exploratory objectives • Proportion of subjects switched to less invasive surgery or for whom surgery is cancelled due to improved condition at treatment completion • Proportion of subjects undergoing blood transfusion, the number of transfusions and volume transfused per subject
  • 9. PEARL II: Randomised, double-blind Phase III trial of ESMYA vs GnRHa R A N D S U RPatients with 3 months Once-daily oral ESMYA 5 mg http://www.clinicaltrials.gov/ct2/show/NCT007408 31?term=NCT00740831&rank=1GnRHa, gonadotrophin-releasing hormone agonist D O M I S E R G E R Y Patients with uterine fibroids Once-daily oral ESMYA 10 mg Intramuscular leuprorelin 3.75 mg once every 4 weeks ClinicalTrials.gov Identifier: NCT00740831
  • 10. PEARL II: Study objectives Primary objective • Demonstrate non-inferior efficacy of ESMYA versus GnRHa for reducing excessive uterine bleeding prior to surgery • Demonstrate superior safety and tolerability of ESMYA versus GnRHa for castration-related symptoms and their consequences Secondary objectives • Demonstrate improvements in fibroid-related symptoms, such as QOL and pain• Demonstrate improvements in fibroid-related symptoms, such as QOL and pain • Assess the capacity of ESMYA to: – Decrease uterine volume – Decrease the volume of the 3 largest fibroids Exploratory objectives • Proportion of subjects switched to less invasive surgery or for whom surgery is cancelled due to improved condition at treatment completion • Proportion of subjects undergoing blood transfusion, the number of transfusions and volume transfused per subject GnRHa, gonadotrophin-releasing hormone agonist; QOL, quality of life
  • 11. PEARL II: Patients screened and randomised, by country 157 126 100 125 150 175 Numbersubjects Screened Randomised 36 51 21 33 93 28 41 20 71 9 7 12 0 25 50 75 100 Austria Belgium Germany Israel Italy Poland Spain Numbersubjects
  • 12. PEARL II Study - Spanish Participants 20 25 30 35 40 Treatment completed Early termination 2 4 19 14 8 5 2 6 3 8 0 5 10 15
  • 13. 3 months ESMYA (open-label) followed by 10 days progestin (Primolut Nor® 10mg) or placebo (double blind) EFFICACY • To investigate the efficacy of ESMYA on – Uterine bleeding – Myoma size – Pain – Quality of life PEARL III: Study objectives – Quality of life SAFETY • To assess safety of ESMYA • To extend the existing safety database EXPLORATORY • Uterine bleeding characteristics upon return of menses • Histology of the endometrium • Time to return of menstruation after ESMYA treatment EXTENSION • Investigate efficacy and safety of long-term on-off use up to a total of 4 times 3 months ESMYA
  • 14. Esmya Primolut Nor Menstruation Day14 Hysterec -tomy End of study Follow-up visit 50% N=200 Uterus- PEARL III: Design Esmya 10 mg 3 months Nor 10mg Placebo 10d Menstruation Day14–Biopsy No surgery PGL09-027 Extension 50% Double blindOpen label Optional extension sparing surgery
  • 15. PEARL III: Design PGL 4001´S EFFICACY ASSESMENT IN REDUCTION OF SYMPTOMS DUE TO UTERINE LEIOMYOMATA PEARL III VisitA–Extensionstart VisitB VisitC VisitE VisitF–F-up (VE+3mths) VisitD–EndofESMYA TA TB TC ESMYA ESMYA ESMYAESMYA PEARL III Extension Visit1-Screening Visit2-Baseline Visit6–end.Biopsy Visit4–OpenLabel Visit3-Open-label Visit5–EndofESMYA Visit7a–Followup ESMYA ESMYA open-label treatment Progestin/placebo double-blind treatment Menses Telephone call from investigator Visit7b–Followupif noextension