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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