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Grand Rounds

RCT Results; Does Relugolix Reduce Fibroid-Associated Heavy Menstrual Bleeding?

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BACKGROUND AND PURPOSE:

  • Relugolix is a GnRH-receptor antagonist
    • Suppresses ovarian estradiol and progesterone production
    • Used in combination with estradiol to minimize hypoestrogenic side effects and norethindrone acetate to prevent sequelae of unopposed estrogen
  • Al-Hendy et al. (NEJM, 2021) reports on two phase 3 trials to assess the efficacy and safety of once-daily relugolix combination therapy in women with fibroid-associated heavy menstrual bleeding

METHODS:

  • Two replicate international, double-blind, 24-week, phase 3 trials
    • LIBERTY 1 (L1)  and LIBERTY 2 (L2)
  • Participants
    • Women with fibroid-associated heavy menstrual bleeding
    • Heavy menstrual bleeding definition
      • Volume of menstrual blood loss of ≥80 ml per cycle for two cycles or
      • Volume of ≥160 ml during one cycle
  • Interventions (1:1:1 randomization)
    • Relugolix combination therapy
      • Once-daily 40 mg of relugolix | 1 mg of estradiol | 0.5 mg of norethindrone acetate
    • Delayed relugolix combination therapy
      • 12 weeks of 40 mg of relugolix monotherapy daily, followed by 12 weeks of relugolix combination therapy daily
    • Placebo
  • Primary outcomes
    • The percentage of participants with volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline
  • Secondary outcomes
    • Amenorrhea
    • Volume of menstrual blood loss
    • Distress from bleeding and pelvic discomfort
    • Distress from pain
    • Anemia
    • Fibroid and uterine volume
  • Statistical analysis
    • 90% power | two-sided alpha level of 0.05
    • Assumptions: 25% placebo response rate | 20% of participants would withdraw
    • Require approximately 390 participants in each trial to demonstrate a 30% difference in the primary outcome

RESULTS:

  • 388 women in L1 | 382 women in L2

Primary Outcome: Menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline

  • A significantly greater percentage of women using combination therapy achieved the primary endpoint vs placebo (P<0.001 for each trial)
    • L1
      • Combination therapy: 73% of participants
      • Placebo: 19% of participants
    • L2
      • Combination therapy: 71% of participants
      • Placebo: 15% of participants

Secondary Outcomes

  • Both combination therapy groups demonstrated significant improvements vs placebo for the following
    • Menstrual blood loss (including amenorrhea in approximately 50% of participants)
    • Pain
    • Distress from bleeding and pelvic discomfort
    • Anemia
    • Uterine volume
  • Vasomotor symptoms were increased in relugolix monotherapy group
  • Fibroid volume was not significantly different between groups

Adverse Events

  • The incidence of adverse events was similar between groups
  • Bone mineral density
    • Similar in the combination therapy and the placebo groups
    • Reduced in the relugolix monotherapy group

CONCLUSION:

  • For women with uterine fibroids, a daily combination relugolix therapy resulted in significantly reduced menstrual bleeding compared to placebo
  • The relugolix combination therapy had no effect on bone mineral density compared to placebo
  • Following these RCTs, participants were offered enrollment in a 28-week extension study to assess longer term outcomes | Results pending
  • The authors state

In these trials, once-daily relugolix combination therapy resulted in a substantial reduction in heavy menstrual bleeding in women with uterine fibroids, with resolution of anemia, a reduction in pain, and reduced distress related to bleeding and pelvic discomfort, while preserving bone density and minimizing the incidence of hot flashes associated with relugolix monotherapy

Learn More – Primary Sources:

Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy

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Related ObG Topics:

Managing Fibroids: Medical and Surgical Options
Ulipristal Acetate: A New Treatment for Symptomatic Uterine Fibroids?
What Uterine-Sparing Treatment for Fibroids Has the Best Outcomes?

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