LE + CC vs. LE for Ovulation Induction With and Without IUI

This randomized controlled trial (RCT) aims to evaluate whether, in infertile women with WHO II/IV ovulatory disorders, (I) a combination of letrozole (LE) and clomiphene citrate (CC) compared to LE alone, and (II) adding intrauterine insemination (IUI) compared to timed intercourse, result in higher live birth rates.

The study is designed as an open-label, multicenter, two-by-two factorial RCT across six fertility clinics in Vietnam. Participants will be randomized into four groups: (1) LE + CC + IUI, (2) LE alone + IUI, (3) LE + CC + intercourse, and (4) LE alone + intercourse. 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).

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 \[12% vs. 7%, RR 1.68, 95% CI 0.19 to 14.66) and 16.4% vs. 18.6%, RR 0.92, 95% CI 0.57 to 1.50)\]. In addition, it is unclear if the addition of intrauterine insemination (IUI) to OI in case of normal sperm would be effective.

Another unanswered question is whether adding intrauterine insemination (IUI) to ovulation induction in case of normal sperm is an effective treatment. One could argue that in absence of a male factor, normal intercourse should be sufficient. In 2018, Weiss et al. reported the cumulative live birth rate of addition IUI to 6 cycles OI with CC in women with WHO class II anovulation was 49% vs 43% for 6 cycles of CC-OI without II (RR 1.14 (95% CI 0.97 to 1.35)).

In view of this lack of definite evidence on both questions, we 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, with and without IUI.

This is a open-label, multicenter, two-by-two factorial 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 1:1:1:1 ratio to receive the combination of LE and CC plus IUI (LE+CC and IUI), LE alone plus IUI (LE and IUI), the combination of LE and CC plus timed intercourse (LE+CC and intercourse) or LE alone plus timed intercourse (LE and intercourse). 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.

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

Eligibility Criteria:
Inclusion Criteria:

* Women 18-40 years of age
* Having WHO II/IV ovulatory disorders (length of cycle \< 21 or \> 35 days or having \< 8 cycles per year)
* Progressive motility (PR) ≥ 32%, sperm concentration ≥ 5 million/ml, total progressive motility sperm count \> 5 million (World Health Organization, 2021)
* Written informed consent.
* Not participating in other studies.

Exclusion Criteria:

* 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.

  * Patients were unable to have intercourse and will be indicated for IUI