Combined Letrozole and Clomid in Women With Infertility and PCOS

Combined Letrozole and Clomid in Polycystic Ovary Syndrome: a Randomized Control Trial of Combination of Letrozole and Clomiphene Citrate or Letrozole Alone for the Treatment of Infertility in Women With Polycystic Ovary Syndrome

This study evaluates the addition of clomid to letrozole for the treatment of infertility in women with polycystic ovary syndrome. Half of the participants will receive letrozole and clomid in combination, while the other half will receive letrozole alone.

Study Overview

• Status: Completed
• Conditions: Polycystic Ovary Syndrome; Infertility
• Intervention / Treatment: Drug: Letrozole; Drug: Clomiphene

Detailed Description

Letrozole and Clomid are both used for ovulation induction, but they have different mechanisms of action. Letrozole has been shown to be superior to clomid in achieving live birth rates in women with infertility and polycystic ovary syndrome. However, the combination of these medications has not been studied. This is a pilot study to evaluate if the combination treatment has improved efficacy as measured by ovulation rate.

This is a randomized controlled trial of letrozole versus letrozole and clomiphene citrate (CC) for one menstrual cycle. Women will be randomized in a 1:1 ratio to receive letrozole 2.5 mg or combination of letrozole 2.5 mg and clomiphene 50 mg for 5 days on days 3-7 of menstrual cycle. The women and their partners will be instructed to have regular intercourse with the intent to conceive during the cycle. Patients will have an transvaginal ultrasound mid cycle and to evaluate number of follicles (>15 mm), follicle size, endometrial thickness and pattern. Patients will have mid- luteal phase progesterone level drawn to evaluate ovulation. Side effect profile will also be monitored.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Willing to comply with all study procedures and be available for the duration of the study
2. Diagnosis of infertility: Inability of couple to achieve successful pregnancy after 12 months of regular timed unprotected intercourse in women less than 35 years of age; and after 6 months of regular intercourse without use of contraception in women 35 years and older
3. Diagnosis of polycystic ovary syndrome based on Revised Rotterdam criteria
4. Ability to have regular intercourse during the ovulation induction phase of the study
5. Normal sperm concentration of 15 million/mL and with normal motility of > 40% according to World Health Organization cutoff points, in at least one ejaculate during the previous year

Exclusion Criteria:

1. Current pregnancy
2. Current use of hormonal contraception; use of any type of combined contraceptive or oral progestins within the past month; or use of hormonal implants or depo progestins within the past 3 months
3. Other known cause of infertility: endometriosis, tubal factor, uterine abnormalities
4. Uncorrected thyroid disease
5. Untreated hyperprolactinemia.
6. Medical conditions in which avoiding pregnancy is recommended until under improved control: poorly controlled Type 1 or Type 2 diabetes, poorly controlled hypertension
7. Contraindications to clomiphene citrate: hypersensitivity to CC or any of its components, history of liver disease or known liver disease, unknown cause of abnormal uterine bleeding, or intracranial lesion
8. Contraindications to letrozole: hypersensitivity to letrozole or any of its components.
9. Use of medications known to affect reproductive function or metabolism or that are an absolute contraindication during pregnancy within the past month.
10. If patients are suspected based on clinical findings for other etiologies that mimic PCOS, work up must be completed to exclude other etiologies prior to enrollment (i.e. Cushing's syndrome, androgen-secreting tumor).

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: Letrozole; Letrozole 2.5 mg orally for 5 days on cycle days 3-7	Drug: Letrozole; Other Names: femara
Experimental: Letrozole + Clomiphene; Letrozole 2.5 mg orally for 5 days on cycle days 3-7 AND Clomid 50 mg orally for 5 days on cycle days 3-7	Drug: Letrozole; Other Names: femara; Drug: Clomiphene; Other Names: clomid; clomiphene citrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Achieving Ovulation Measured by Mid-luteal Progesterone Level	Ovulation: mid-luteal progesterone > /=3 ng/mL. No ovulation: mid-luteal progesterone <3ng/mL.	7 days following LH surge or at cycle day 21 if no LH surge was detected

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Developing Follicles	Number of follicles measuring > 10mm on ultrasound	Cycle day 12-14
Size of Largest Developing Follicle	Size of largest follicle on ultrasound	Cycle day 12-14
Endometrial Thickness	Thickness of endometrial lining assessed by ultrasound	Cycle day 12-14
Conception	Conception: a positive serum or urinary test of hCG; No conception: Neither a positive serum or urinary test of hCG	5 weeks after treatment
Clinical Pregnancy	Clinical Pregnancy: an intrauterine pregnancy with fetal heart motion determined by ultrasonography; No Clinical Pregnancy: no intrauterine pregnancy with fetal heart motion determined by ultrasonography	6-7 weeks after treatment
Multiple Gestation	Multiple Gestation: an intrauterine pregnancy with multiple fetal heart rates determined by ultrasonography; No Multiple Gestation: either no intrauterine pregnancy, or an intrauterine pregnancy with a single fetal heart rate determined by ultrasonography	9-10 months after treatment
Live Birth	Live Birth: delivery of a live infant; No Live Birth: no delivery of a live infant	9-10 months after treatment
Pregnancy Loss	Pregnancy Loss: any pregnancy loss including biochemical pregnancy, ectopic pregnancy, and miscarriage; No Pregnancy Loss: no pregnancy loss including biochemical pregnancy, ectopic pregnancy, or miscarriage.	9-10 months after treatment

Collaborators and Investigators

• Sponsor: Rachel Mejia
• Investigators: Principal Investigator: Rachel Mejia, DO, University of Iowa Hosptials & Clinics; Principal Investigator: Brad Van Voorhis, MD, University of Iowa Hospitals & Clinics

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: August 1, 2016
• Primary Completion (Actual): May 1, 2018
• Study Completion (Actual): February 1, 2019

Study Registration Dates

• First Submitted: June 9, 2016
• First Submitted That Met QC Criteria: June 13, 2016
• First Posted (Estimate): June 16, 2016

Study Record Updates

• Last Update Posted (Actual): September 27, 2019
• Last Update Submitted That Met QC Criteria: September 25, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Polycystic Ovary Syndrome; Syndrome; Infertility; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Letrozole; Clomiphene; Enclomiphene; Zuclomiphene
• Other Study ID Numbers: 201606806

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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