LE + CC vs. LE for Ovulation Induction

Официальное название

The Combination of Letrozole (LE) and Clomiphene Citrate (CC) or LE Alone for Ovulation Induction in Women With WHO Group II/IV Ovulatory Disorders: A Randomized Controlled Trial

Обзор

This randomized controlled trial (RCT) aims to evaluate whether, in infertile women with WHO II/IV ovulatory disorders, a combination of letrozole (LE) and clomiphene citrate (CC) compared to LE alone, result in higher live birth rates. The study is designed as an open-label, multicenter RCT across six fertility clinics in Vietnam. Participants will be randomized into two groups: (1) LE + CC , (2) LE alone. The primary outcome measure is the live birth rate after one treatment cycle. Based on prior data, the live birth rate for IUI in letrozole cycles is estimated at 12%. To detect a 10% increase in live birth rates with CC, 436 couples are needed (α = 0.05, power = 80%). Additionally, the live birth rate after IUI with LE-induced ovulation is approximately 18.7% (Diamond et al., 2015). To detect a 10% increase with CC, 560 couples are required (α = 0.05, power = 80%). Considering a 5% loss to follow-up and protocol deviations, the study plans to recruit 600 participants (150 per arm).

Подробное описание

Letrozole (LE) has been suggested as a first-line treatment for ovulation induction in PCOS. Clomiphene citrate (CC) is another widely used drug to induce ovulation in women with PCOS. Due to the different mechanisms of action of CC and letrozole, it is possible that taking these drugs together may increase the ovulation rate by having a synergistic effect with their own mechanisms and resulting to increase the pregnancy outcome of patients undergoing ovulation induction (OI).

Mejia et al. conducted a randomized controlled trial (RCT) and reported the ovulation rate was significantly higher in the combination group than in the LE-alone group (N=70, 77% vs. 42.9%, respectively; RR 1.80 95%. CI. 1.18 to 2.75, P=0.007). This finding is confirmed by another RCT but not in a third more recent RCT, with larger sample size. Live birth rate was only reported as secondary endpoint in two studies, with a non-significant difference between the two groups \[12% vs. 7%, RR 1.68, 95% CI 0.19 to 14.66) and 16.4% vs. 18.6%, RR 0.92, 95% CI 0.57 to 1.50)\]. Therefore, the investigators plan an RCT to evaluate whether a combination of LE and CC results in higher live birth rates than LE alone in women with WHO II/IV ovulatory disorders.

This is a open-label, multicenter, randomized controlled trial across six fertility clinics in Vietnam. Potentially eligible participants will be given a study information sheet during their first consultation, at least 2 weeks before the start of the menstrual cycle, whether spontaneous or induced. In case the women present to the clinic during their menstrual cycle and wish to start treatment straightaway, they will be given the information sheet to read while waiting for the clinicians. Screening for eligibility will be performed by treating physicians on the day OI starts. Eligible participants will be invited to a full discussion with investigators about the study. Women who fulfil the eligibility criteria and who have been counselled before will be formally invited to participate in the study. If the women agree to participate, they will be asked to sign the informed consent form. After informed consent, a fasting blood sample will be obtained for hormone and biochemical analysis.

Participants will be randomized in a 1:1 ratio to receive the combination of LE and CC (LE+CC) and LE alone. The computer-generated random list will be prepared by an independent statistician who has no other involvement in the study. Assignment to treatment allocation will be done via a web portal hosted by HOPE Research Center, Vietnam. The randomization schedule will be computer-generated at HOPE Research Center, with a permuted random block size of 4 and 8.

Combination of LE and CC group: 5 milligrams LE per day (Femara® 2.5 milligrams, Novartis, Switzerland) and 50 milligrams CC (Duinum 50 milligrams, Medochemie, Cyprus) per day, starting on the second to the fourth day of the cycle, for five consecutive days.

LE alone group: 5 milligrams LE per day (Femara® 2.5 milligrams, Novartis, Switzerland), starting on the second to the fourth day of cycle, for five consecutive days.

IUI or natural intercourse will be indicated based on the physicians and patients.

The primary endpoint will be live birth after one treatment cycle.

Вмешательства

• Процедура IUI or intercourse
  5 milligrams LE per day (Femara® 2.5 milligrams, Novartis, Switzerland) and 50 milligrams CC (Duinum 50 milligrams, Medochemie, Cyprus) or 5 milligrams LE per day (Femara® 2.5 milligrams, Novartis, Switzerland) will be started on the second to the fourth day of the cycle, for five consecutive days. An ultrasound will be carried out three days after the last dose of medicine (day 8 of OI) to evaluate ovarian follicles' growth and the endometrium's thickness. If the follicular diameter reach ≥14 m

Первичные конечные точки

• Live birth after one treatment cycle [Срок оценки: At 22 weeks of gestation]

Вторичные конечные точки (12)

• Duration of stimulation [Срок оценки: During the intervention]
• Number of follicles ≥14mm on day of hCG [Срок оценки: During the intervention]
• Endometrial thickness on day of hCG [Срок оценки: During the intervention]
• Cycle cancellation [Срок оценки: At 21 day of the ovulation induction cycle]
• Ovulation [Срок оценки: At day 7 after the hCG injection]
• Positive pregnancy test [Срок оценки: At day 15 after IUI or timed intercourse]
• Clinical pregnancy [Срок оценки: After 6 weeks of gestation]
• Ongoing pregnancy [Срок оценки: After 12 weeks of gestation]
• Multiple pregnancies [Срок оценки: At 6-9 weeks of gestation]
• Multiple birth [Срок оценки: At 22 weeks of gestation]
• Ectopic pregnancy [Срок оценки: At 7 weeks of gestation]
• Miscarriage <22 weeks [Срок оценки: Before 22 completed weeks of gestation]

Критерии участия

Критерии включения

• Women 18-40 years of age
• Having ovulation disorder (length of cycle < 21 or > 35 days or having < 8 cycles per year)
• FSH ≥5 IU/L and ≤25 IU/L, or LH ≥5 IU/L and AMH ≥1.2 ng/mL
• Progressive motility (PR) ≥ 32% OR total progressive motility sperm count > 5 million; and sperm concentration ≥ 5 million/ml, (World Health Organization, 2021)
• Agreeing to take part in study.
• Not participating in other studies.

Критерии исключения

• Untreated thyroid disease; Thyroid disease is suspected if patients have one of these (Bednarczuk et al., 2021); TSH ≥4 mIU/L or TSH ≥2.5mIU/L and TPOAb (+) or TSH <0.1mIU/L
• Untreated hyper-prolactinemia; Hyperprolactinemia is suspected if patients have prolactinemia concentration >50 ng/mL (The sample is collected after an overnight fast, at least 2 hours after waking up, ensuring that venipuncture does not cause excessive stress.)
• Allergy or having contraindications to LE or CC;
• Unilateral or Bilateral fallopian tube blockage (HSG, HyFoSy or surgery confirmation)
• Untreated endometrial abnormalities include endometrial hyperplasia, intrauterine adhesions, endometrial polyp, or chronic endometritis.
• Uterine abnormalities include leiomyomas L0, L1, or L2; severe adenomyosis; congenital uterine abnormalities, include didelphus, arcuate, unicornuate, bicornuate, septate.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Вьетнам · 1 центр

• My Duc Hospital — Ho Chi Minh City

Публикации

• Teede HJ, Tay CT, Laven JJE, Dokras A, Moran LJ, Piltonen TT, Costello MF, Boivin J, Redman LM, Boyle JA, Norman RJ, Mousa A, Joham AE. Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2023 Sep 18;108(10):2447-2469. doi: 10.1210/clinem/dgad463. PMID 37580314
• Weiss NS, Nahuis MJ, Bordewijk E, Oosterhuis JE, Smeenk JM, Hoek A, Broekmans FJ, Fleischer K, de Bruin JP, Kaaijk EM, Laven JS, Hendriks DJ, Gerards MH, van Rooij IA, Bourdrez P, Gianotten J, Koks C, Lambalk CB, Hompes PG, van der Veen F, Mol BWJ, van Wely M. Gonadotrophins versus clomifene citrate with or without intrauterine insemination in women with normogonadotropic anovulation and clomifene PMID 29273245
• Mejia RB, Summers KM, Kresowik JD, Van Voorhis BJ. A randomized controlled trial of combination letrozole and clomiphene citrate or letrozole alone for ovulation induction in women with polycystic ovary syndrome. Fertil Steril. 2019 Mar;111(3):571-578.e1. doi: 10.1016/j.fertnstert.2018.11.030. Epub 2019 Jan 22. PMID 30683591
• Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, Christman GM, Ager J, Huang H, Hansen KR, Baker V, Usadi R, Seungdamrong A, Bates GW, Rosen RM, Haisenleder D, Krawetz SA, Barnhart K, Trussell JC, Ohl D, Jin Y, Santoro N, Eisenberg E, Zhang H; NICHD Reproductive Medicine Network. Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility. N Engl J Med. 2015 Sep 24;373(1 PMID 26398071

Идентификаторы

NCT: NCT06934785 · 02/25/DD/BVMD

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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