LE + CC vs. LE for Ovulation Induction (COLA)

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

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).

Study Overview

• Status: Recruiting
• Conditions: Ovulation Induction; Letrozole; Ovulation Disorder; Clomiphene Citrate
• Intervention / Treatment: Procedure: IUI or intercourse

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, 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.

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.

• Study Type: Interventional
• Enrollment (Estimated): 600
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Van TT Tran, MD; Phone Number: +84353345020; Email: bsvan.ttt@myduchospital.vn
• Study Contact Backup: Name: Vinh Q Dang, MSc,MD; Email: vinh.dang@monash.edu

Study Locations

• Vietnam
  • Ho Chi Minh City
    • Ho Chi Minh City, Ho Chi Minh City, Vietnam, 70000
      • Recruiting
      • My Duc Hospital
      • Contact: Tuong M Ho, MSc,MD; Phone Number: +84 90 3633377; Email: tuongho.ivfmd@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Procedure: 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 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.
Active Comparator: 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.	Procedure: 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 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Live birth after one treatment cycle	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.	At 22 weeks of gestation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Birth weight	Weight of singletons and twins	At the time of delivery
Gestational diabetes mellitus	GDM is diagnosed using a 75g oral glucose tolerance test	At 24 to 28 weeks of gestation
Hypertension in pregnancy	Pregnancy-induced hypertension, pre-eclampsia, eclampsia and HELLP syndrome	after 20 weeks of gestation or beyond
Low birth weight	Weight < 2500 gm at birth	At the time of delivery
Very low birth weight	Weight < 1500 gm at birth	At the time of delivery
High birth weight	Weight 4000 gm or 4500 gm at birth	At the time of delivery
Very high birth weight	Weight over than 4.500 g for women with diabetes, and a threshold of 5000 g for women without diabetes	At the time of delivery
Duration of stimulation	Duration of stimulation	During the intervention
Number of follicles ≥14mm on day of hCG	Number of follicles ≥14mm on day of hCG	During the intervention
Endometrial thickness on day of hCG	Endometrial thickness on day of hCG	During the intervention
Cycle cancellation	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	At 21 day of the ovulation induction cycle
Ovulation	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.	At day 7 after the hCG injection
Positive pregnancy test	Serum human chorionic gonadotropin level greater than 25 mIU/mL at day 15 after IUI or timed intercourse	At day 15 after IUI or timed intercourse
Clinical pregnancy	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	After 6 weeks of gestation
Ongoing pregnancy	Pregnancy with a detectable heart rate at 12 weeks gestation or beyond	After 12 weeks of gestation
Multiple pregnancies	The presence of more than one sac at early pregnancy ultrasound (6-9 weeks gestation)	At 6-9 weeks of gestation
Multiple birth	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	At 22 weeks of gestation
Ectopic pregnancy	A pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualization or histopathology	At 7 weeks of gestation
Miscarriage <22 weeks	Spontaneous loss of pregnancy up to 22 weeks of gestation	Before 22 completed weeks of gestation
Gestational age at delivery	Gestational age at delivery	At the time of delivery
Growth restriction	a birth weight < 10th percentile	At the time of delivery
Stillbirth	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.	After 20 completed weeks of gestational age
Premature birth	Multiple definitions, defined as delivery at <24, <28, <32, <37 completed weeks	At 22, 28, 32 weeks and 37 weeks of gestation
Onset of labour	Onset of labour	At the time of delivery
Mode of delivery	Mode of delivery	At the time of delivery
Congenital abnormalities	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	At birth
Neonatal mortality	Death of a live-born baby within 28 days of birth	within 28 days of birth
NICU admission	The admittance of the newborn to NICU	At birth
Reported side-effects	included headache, hot flashes, abdominal bloating, abdominal pain including cramps, nausea, mood changes, fatigue, back pain, dizziness, breast discomfort, diarrhoea, night sweats, sleep disturbances	During the intervention
Hospitalized or seek any additional care during the ovulation induction cycle	Hospitalized or seek any additional care during the ovulation induction cycle	During the intervention
Incidence of Ovarian hyperstimulation syndrome (OHSS)	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	10 days after the intervention

Collaborators and Investigators

• Sponsor: Mỹ Đức Hospital
• Investigators: Principal Investigator: Lan N Vuong, PhD,MD, University of Medicine and Pharmacy at Ho Chi Minh City

Publications and helpful links

General Publications

• 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.
• 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 failure (M-OVIN): a randomised, two-by-two factorial trial. Lancet. 2018 Feb 24;391(10122):758-765. doi: 10.1016/S0140-6736(17)33308-1. Epub 2017 Dec 19.
• 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.
• 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(13):1230-40. doi: 10.1056/NEJMoa1414827.

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2025
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: April 7, 2025
• First Submitted That Met QC Criteria: April 12, 2025
• First Posted (Actual): April 18, 2025

Study Record Updates

• Last Update Posted (Estimated): September 11, 2025
• Last Update Submitted That Met QC Criteria: September 4, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Reproductive Physiological Phenomena; Reproductive and Urinary Physiological Phenomena; Sex
• Other Study ID Numbers: 02/25/DD/BVMD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No