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
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 600
- 试验地点
- 2
- 主要终点
- Live birth after one treatment cycle
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: IUI or intercourse (Procedure)
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.
干预措施: IUI or intercourse (Procedure)
结局指标
主要结局
Live birth after one treatment cycle
时间窗: At 22 weeks of gestation
Live birth will be defined as the complete expulsion or extraction from a woman of a product of fertilization, after 22 completed weeks of gestational age; which, after such separation, breathes or shows any other evidence of life, such as heart beat, umbilical cord pulsation or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut or the placenta is attached.
次要结局
- Duration of stimulation(During the intervention)
- Number of follicles ≥14mm on day of hCG(During the intervention)
- Endometrial thickness on day of hCG(During the intervention)
- Cycle cancellation(At 21 day of the ovulation induction cycle)
- Ovulation(At day 7 after the hCG injection)
- Positive pregnancy test(At day 15 after IUI or timed intercourse)
- Clinical pregnancy(After 6 weeks of gestation)
- Ongoing pregnancy(After 12 weeks of gestation)
- Mode of delivery(At the time of delivery)
- Birth weight(At the time of delivery)
- Multiple pregnancies(At 6-9 weeks of gestation)
- Multiple birth(At 22 weeks of gestation)
- Ectopic pregnancy(At 7 weeks of gestation)
- Miscarriage <22 weeks(Before 22 completed weeks of gestation)
- Gestational age at delivery(At the time of delivery)
- Growth restriction(At the time of delivery)
- Stillbirth(After 20 completed weeks of gestational age)
- Premature birth(At 22, 28, 32 weeks and 37 weeks of gestation)
- Onset of labour(At the time of delivery)
- Low birth weight(At the time of delivery)
- Very low birth weight(At the time of delivery)
- High birth weight(At the time of delivery)
- Very high birth weight(At the time of delivery)
- Gestational diabetes mellitus(At 24 to 28 weeks of gestation)
- Hypertension in pregnancy(after 20 weeks of gestation or beyond)
- Congenital abnormalities(At birth)
- Neonatal mortality(within 28 days of birth)
- NICU admission(At birth)
- Reported side-effects(During the intervention)
- Hospitalized or seek any additional care during the ovulation induction cycle(During the intervention)
- Incidence of Ovarian hyperstimulation syndrome (OHSS)(10 days after the intervention)