Clomiphene Citrate, Letrozole, Ovulation Disorder, Ovulation Induction
Conditions
Brief summary
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).
Detailed description
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.
Interventions
PROCEDUREIUI 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 millimetres, check-up will be planned every two days until it reaches 18 millimetres. If there is the appearance of at least one follicle reaching 18 millimetres or more, a human chorionic gonadotropin (hCG) injection (IVF-C 5000 IU, LG Life Science, Korea) will be administered on the same day of the ultrasound in order to induce ovulation. IUI will be scheduled 36 - 38 hours after hCG injection or intercourse will be scheduled in the next day.
Sponsors
Mỹ Đức Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
* 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.
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Live birth after one treatment cycle | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of stimulation | During the intervention | Duration of stimulation |
| Number of follicles ≥14mm on day of hCG | During the intervention | Number of follicles ≥14mm on day of hCG |
| Endometrial thickness on day of hCG | During the intervention | Endometrial thickness on day of hCG |
| Cycle cancellation | At 21 day of the ovulation induction cycle | The cycle will be cancelled if (1) there is no follicle reaches ≥18 millimetres) on day 21 of the OI; (2) there are ≥ 3 follicles with diameter ≥16 millimetres or (3) ≥ 4 ovarian follicles with diameter ≥10 millimetres |
| Ovulation | At day 7 after the hCG injection | A serum midluteal progesterone (17-OH-progesterone) will be measured on day 7 after the hCG injection. A level of \>3 ng/mL (\>9.5 nmol/L) will be used as evidence of ovulation. |
| Positive pregnancy test | At day 15 after IUI or timed intercourse | Serum human chorionic gonadotropin level greater than 25 mIU/mL at day 15 after IUI or timed intercourse |
| Clinical pregnancy | After 6 weeks of gestation | Diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy at 6 weeks or more. In addition to intra-uterine pregnancy, it includes a clinically documented ectopic pregnancy |
| Ongoing pregnancy | After 12 weeks of gestation | Pregnancy with a detectable heart rate at 12 weeks gestation or beyond |
| Multiple pregnancies | At 6-9 weeks of gestation | The presence of more than one sac at early pregnancy ultrasound (6-9 weeks gestation) |
| Multiple birth | At 22 weeks of gestation | The complete expulsion or extraction from a woman of more than one fetus, after 22 completed weeks of gestational age, irrespective of whether it is a live birth or stillbirth |
| Ectopic pregnancy | At 7 weeks of gestation | A pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualization or histopathology |
| Miscarriage <22 weeks | Before 22 completed weeks of gestation | Spontaneous loss of pregnancy up to 22 weeks of gestation |
| Gestational age at delivery | At the time of delivery | Gestational age at delivery |
| Growth restriction | At the time of delivery | a birth weight \< 10th percentile |
| Stillbirth | After 20 completed weeks of gestational age | The death of a fetus prior to the complete expulsion or extraction from its mother after 20 completed weeks of gestational age. The death is determined by the fact that, after such separation, the fetus does not breathe or show any other. |
| Premature birth | At 22, 28, 32 weeks and 37 weeks of gestation | Multiple definitions, defined as delivery at \<24, \<28, \<32, \<37 completed weeks |
| Onset of labour | At the time of delivery | Onset of labour |
| Mode of delivery | At the time of delivery | Mode of delivery |
| Birth weight | At the time of delivery | Weight of singletons and twins |
| Low birth weight | At the time of delivery | Weight \< 2500 gm at birth |
| Very low birth weight | At the time of delivery | Weight \< 1500 gm at birth |
| High birth weight | At the time of delivery | Weight 4000 gm or 4500 gm at birth |
| Very high birth weight | At the time of delivery | Weight over than 4.500 g for women with diabetes, and a threshold of 5000 g for women without diabetes |
| Gestational diabetes mellitus | At 24 to 28 weeks of gestation | GDM is diagnosed using a 75g oral glucose tolerance test |
| Hypertension in pregnancy | after 20 weeks of gestation or beyond | Pregnancy-induced hypertension, pre-eclampsia, eclampsia and HELLP syndrome |
| Congenital abnormalities | At birth | Structural or functional disorders that occur during intra-uterine life and can be identified prenatally, at birth or later in life. Congenital anomalies can be caused by single gene defects, chromosomal disorders, multifactorial inheritance, environmental teratogens, and micronutrient deficiencies. The time of identification should be reported |
| Neonatal mortality | within 28 days of birth | Death of a live-born baby within 28 days of birth |
| NICU admission | At birth | The admittance of the newborn to NICU |
| Reported side-effects | During the intervention | included headache, hot flashes, abdominal bloating, abdominal pain including cramps, nausea, mood changes, fatigue, back pain, dizziness, breast discomfort, diarrhoea, night sweats, sleep disturbances |
| Hospitalized or seek any additional care during the ovulation induction cycle | During the intervention | Hospitalized or seek any additional care during the ovulation induction cycle |
| Incidence of Ovarian hyperstimulation syndrome (OHSS) | 10 days after the intervention | A potentially lethal iatrogenic complication of the early luteal phase or/and early pregnancy after OI or ovarian stimulation. OHSS was evaluated if symptoms were reported by the patient. OHSS was classified using the flow diagram |
Countries
Vietnam
Contacts
CONTACTVan TT Tran, MD
CONTACTVinh Q Dang, MSc,MD
PRINCIPAL_INVESTIGATORLan N Vuong, PhD,MD
University of Medicine and Pharmacy at Ho Chi Minh City
Outcome results
None listed