A 12-month extension study to evaluate the safety and efficacy of asoprisnil in women with heavy menstrual bleeding and uterine fibroids

Abstract

Study question: What is the safety and efficacy profile during long-term (12-24 months) uninterrupted treatment with the selective progesterone receptor modulator asoprisnil, 10 and 25 mg in women with heavy menstrual bleeding (HMB) associated with uterine fibroids?

Summary answer: Uninterrupted treatment with asoprisnil should be avoided due to endometrial safety concerns and unknown potential long-term consequences.

What is known already: Asoprisnil was well tolerated in shorter-term studies and effectively suppressed HMB and reduced fibroid volume.

Study design size duration: Women with uterine fibroids who had previously received placebo (n = 87) or asoprisnil 10 mg (n = 221) or 25 mg (n = 215) for 12 months in two double-blind studies entered this randomized uncontrolled extension study and received up to 12 additional months of treatment followed by 6 months of post-treatment follow-up. Women who previously received placebo were re-randomized to either asoprisnil 10 or 25 mg for the extension study. This report focuses on the 436 women who received asoprisnil in the double-blind studies and this extension study. Results for women who previously received placebo in the double-blind studies are not described.

Participants/materials setting methods: Women ≥18 years of age who completed a 12-month, double-blind, placebo-controlled study, had estradiol levels indicating that they were not menopausal and had no endometrial hyperplasia or other significant endometrial pathology were eligible. The safety endpoints were focused on endometrial assessments. The composite primary efficacy endpoint was the proportion of women who demonstrated a response to treatment by meeting all three of the following criteria at the final month for participants who prematurely discontinued or at month 12 for those who completed the study: a reduction from initial baseline to final visit of ≥50% in the menstrual pictogram score, hemoglobin concentration ≥11 g/dl or an increase of ≥1 g/dl from initial baseline at the final visit, and no surgical or invasive intervention for uterine fibroids. Other efficacy endpoints included rates for amenorrhea and suppression of bleeding, changes in fibroid and uterine volume and changes in hematologic parameters. No statistical tests were planned or performed for this uncontrolled study.

Main results and role of chance: Imaging studies revealed a progressive increase in endometrial thickness and cystic changes that frequently prompted invasive diagnostic procedures. Endometrial biopsy results were consistent with antiproliferative effects of asoprisnil. Two cases of endometrial cancer were diagnosed. At the final month of this extension study (total duration of uninterrupted treatment up to 24 months), the primary efficacy endpoint was achieved in 86 and 92% of women in the asoprisnil 10- and 25-mg groups, respectively. During each month of treatment, amenorrhea was observed in the majority of women (up to 77 and 94% at 10 and 25 mg, respectively). There was a progressive, dose-dependent decrease in the volume of the primary fibroid with asoprisnil 10 and 25 mg (-55.7 and -75.2% median decrease, respectively, from baseline [i.e. the beginning of the placebo-controlled study] to month 12 [cumulative months 12-24] of this extension study). These effects were associated with improvements in quality of life measures.

Limitations reasons for caution: This study was uncontrolled, which limits the interpretation of safety and efficacy findings. The study also had multiple protocol amendments with the addition of diagnostic procedures and, because no active comparator was included, the potential place of asoprisnil in comparison to therapies such as GnRH agonists and surgery cannot be determined.

Wider implications of the findings: Long-term, uninterrupted treatment with asoprisnil leads to prominent cystic endometrial changes that are consistent with the 'late progesterone receptor modulator' effects, which prompted invasive diagnostic procedures, although treatment efficacy is maintained. Although endometrial cancers were uncommon during both treatment and follow-up, these findings raise concerns regarding endometrial safety during uninterrupted long-term treatment with asoprisnil. This study shows that uninterrupted treatment with asoprisnil should be avoided due to safety concerns and unknown potential long-term consequences.

Study funding/competing interests: AbbVie Inc. (prior sponsor, TAP Pharmaceutical Products Inc.) sponsored the study and contributed to the design and conduct of the study, data management, data analysis, interpretation of the data and the preparation and approval of the manuscript. Financial support for medical writing and editorial assistance was provided by AbbVie Inc. M. P. Diamond received research funding for the conduct of the study paid to the institution and is a consultant to AbbVie. He is a stockholder and board and director member of Advanced Reproductive Care. He has also received funding for study conduct paid to the institution for Bayer and ObsEva. E. A. Stewart participated as a site investigator in the phase 2 study of asoprisnil and served as a consultant to TAP Pharmaceuticals during the time of design and conduct of the studies while on the faculty of Harvard Medical School and Brigham and Women's Hospital, Boston, MA. In the last 3 years, she has received support from National Institutes of Health grants HD063312, HS023418 and HD074711. She has served as a consultant for AbbVie Inc., Allergan, Bayer HealthCare AG and Myovant for consulting related to uterine leiomyoma and to Welltwigs for consulting related to infertility. She has received royalties from UpToDate and the Med Learning Group. A.R.W. Williams has acted as a consultant for TAP Pharmaceutical Products Inc. and Repros Therapeutics Inc. He has current consultancies with PregLem SA, Gedeon Richter, HRA Pharma and Bayer. B.R. Carr has served as consultant and received research funding from AbbVie Inc. and Synteract (Medicines360). E.R. Myers has served as consultant for AbbVie Inc., Allergan and Bayer. R.A. Feldman received compensation for serving as a principal investigator and participating in the conduct of the trial. W. Elger was a co-inventor of several patents related to asoprisnil.C. Mattia-Goldberg is a former employee of AbbVie Inc. and owns AbbVie stock or stock options. B.M. Schwefel and K. Chwalisz are employees of AbbVie Inc. and own AbbVie stock or stock options.

Trial registration number: NCT00156195 at clinicaltrials.gov.

Keywords: J867; asoprisnil; selective progesterone receptor modulator; uterine fibroids; uterine leiomyoma; uterine leiomyomata.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Figures

Figure 1

Design of a 12-month extension study to evaluate the safety and efficacy of asoprisnil in women with heavy menstrual bleeding and uterine fibroids. The dashed box indicates the population that is the primary focus of this report.

Figure 2

Study disposition (N = 523) showing the number of women who entered the extension study, completed the study, prematurely discontinued from the treatment period, entered the follow-up periods and the reasons for premature discontinuation. Women from the two placebo-controlled studies continued treatment with their initial asoprisnil dosage of 10 (n = 221) or 25 (n = 215) mg (asoprisnil/asoprisnil participants; n = 436). Women who previously received placebo were randomized to asoprisnil 10 (n = 43) or 25 (n = 44) mg (placebo/asoprisnil participants; n = 87). This report focuses on the asoprisnil/asoprisnil participants.

Figure 3

Endometrial thickness during the extension study (safety analysis population). (A) Mean (SD) values at study visits. (B) Mean (SD) changes from baseline (start of the placebo-controlled, phase 3 studies) at study visits. (C) Proportion of women with endometrial thickness ≥19 mm at study visits and at any time during the treatment period. An absence of data indicates that the diagnostic procedure was not performed at that time point. TVU = transvaginal ultrasound.

Figure 4

Endometrial thickness for women with post-treatment follow-up data (safety analysis population). (A) Mean (SD) values at study visits. (B) Mean (SD) changes from baseline (start of the placebo-controlled, phase 3 studies) at study visits. (C) Proportion of women with endometrial thickness ≥19 mm at study visits and at any time during the treatment period. An absence of data indicates that the diagnostic procedure was not performed at that time point.

Figure 5

Responder rate (primary efficacy endpoint) at month 6 and month 12 of treatment in the extension study (18 and 24 months total treatment mITT population; asoprisnil/asoprisnil groups only). DB = double-blind; mITT = modified intent-to-treat. Women started with >80 ml of blood loss during screening menstrual cycle of the DB study or hemoglobin ≤10.5 g/dl during screening or at day-1 of the DB study. Response to treatment was the percentage of women who met all of the following criteria: ≥50% decrease in blood loss during month 12 or final visit if they discontinued prematurely; hemoglobin ≥11 g/dl or an increase ≥1 g/dl from baseline to month 12 or final visit if they discontinued prematurely and no surgery or withdrawal with a plan to have surgery for leiomyomata. aOr final visit if they discontinued prematurely. bWomen who qualified for the primary analysis were those in the mITT population who had baseline and on-treatment data for the primary endpoint, unless they prematurely discontinued to have surgery or invasive intervention for leiomyomata.

Figure 6

Percentage of women with monthly amenorrhea rates during each month of treatment in the extension study. The percentage of women with no bleeding during each 30-day treatment period was assessed for women who had ≥20 days of diary data for any month or who had bleeding during any month.