Vaginal Progesterone Supplementation in Women With PCOS Undergoing Ovulation Induction With Letrozole

NCT ID: NCT03440359

Last Updated: 2018-02-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-06
• Study Completion Date: 2017-12-30

Brief Summary

Aromatase inhibitors such as letrozole are hypothesized to maintain normal hypothalamic/ pituitary feedback mechanisms and in the case of OI (ovulation induction) in women with PCOS, may act to increase follicular sensitivity to FSH by increasing intrafollicular androgen levels. Letrozole also may act to increase midluteal P levels presumably by induction of follicles and corpora lutea. The investigators are asking the question whether P supplementation with Crinone (8%) may have an additive beneficial effect on endometrial development in those women taking letrozole. Progesterone levels in the endometrium (tissue levels) have been documented to be significantly higher than serum levels after vaginal administration which may lead to higher pregnancy rates. In addition P has been shown to decrease LH pulse frequency which is elevated in PCOS and has been shown to down regulate endometrial androgen receptors. There have been retrospective studies showing progesterone supplementation seems to benefit both CC and letrozole treatment groups. In fact, this study showed the only pregnancies in the letrozole group were those in women who took P supplementation. However the number of cycles studied was small. There is a place for a randomized controlled trial (RCT) to determine if luteal phase P supplementation with Crinone should be used in all women using letrozole for Ovulation Induction (OI) in combination with Intrauterine Insemination (IUI) or Timed Intercourse (TI). This is currently not done in all clinical practices.

Detailed Description

Approval of the study was obtained from the local IRB. Prospective volunteers had had an infertility workup including blood hormone levels (FSH, LH, E2, Progesterone, Prolactin, and Thyroid), partner's semen analysis, HSG, laparoscopy or hydrosonogram, plus a baseline evaluation including ultrasound of ovaries and uterus performed as standard of care. If the results of these tests and the remaining Inclusion/Exclusion criteria were met, the study consent was reviewed with participants and signatures were obtained. Participants contacted the clinic at the start of their menses (spontaneous or progesterone-induced) to start the treatment cycle. Eligibility criteria was reviewed, and Letrozole 2.5-7.5 mg day 3-7 was initiated based on BMI and prior response. An ultrasound was performed on cycle day 11 or 12 and repeated if needed to determine response until at least 1 follicle with mean diameter > 17mm in size was observed. When the appropriate follicle size was reached, participants were randomized into one of the two treatment groups as determined by a randomization table, and Ovidrel (250mcg) was administered. If there was no response identified by follicle growth on day 21, the participant was considered a letrozole failure, the cycle was stopped, and the participant was dropped from the study and was not included in subsequent cycles.

IUI/TI was performed at 24-48 hours after the Ovidrel (hCG) injection. If the participant was randomized to progesterone (Crinone), the luteal phase was supplemented once daily with vaginal progesterone (Crinone 8%) starting the second day after the IUI or TI and continued for 14 days. A urine or serum pregnancy test was performed as standard of care 16 days after the IUI/TI. If the test was positive, a confirmatory blood level (βhCG) was performed as standard of care X2 (1 week apart) and an ultrasound on post-hCG day 35-42 was done. Any pregnancies occurring in either treatment group were followed for delivery outcomes. Information regarding the delivery (induced, vaginal, cesarean section), date of birth, infant measurements (weight and length) and other important information regarding the infant's condition was obtained. Participants were allowed to undergo up to 3 cycles of letrozole as the pregnancy rates for the first 3 cycles have been shown to be similar. The participants were re-randomized each cycle. If the participant was pregnant, Crinone (8%) was continued until 10 weeks gestation in both groups.

Each participant was able to proceed with up to 3 cycles (consecutively, if desired) of OI over the next 6 months and was re-randomized each cycle.

Conditions

Polycystic Ovary Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: SINGLE

Study Groups

# 1- no progesterone therapy

Letrrozole 2.5 to 5 mg oral tablet cycle day 3-7.Pelvic ultrasound at cycle day 11 or 12 and repeat if needed until leading follicle is \>17 mm. Ovidrel 250 mcg injected sq. Timed intercourse or intrauterine insemination. No supplemental progesterone therapy in luteal phase

Group Type: OTHER

Letrozole Oral Tablet

Intervention Type: DRUG

letrozole oral tablet 2.5 mg or 5 mg administered cycle day 3-7 for ovulation induction

pelvic ultrasound

Intervention Type: DIAGNOSTIC_TEST

pelvic ultrasound performed at cycle day 11 or 12 and repeated as necessary until leading follicle size is \>17 mm in diameter

Ovidrel 250 MCG Per 0.5 ML Prefilled Syringe

Intervention Type: DRUG

ovidrel 250 mcg given when leading follicle size is \> 17 mm in diameter

Intrauterine insemination or timed intercourse

Intervention Type: OTHER

Intrauterine insemination or timed intercourse (depending on semen parameters) performed 36-40 hours after Ovidrel

# 2 - Progesterone Vaginal Gel 8%

Letrrozole 2.5 to 5 mg oral tablet cycle day 3-7. Pelvic ultrasound at cycle day 11 or 12 and repeat if needed until leading follicle is \>17 mm. Ovidrel 250 mcg injected sq. Timed intercourse or intrauterine insemination.Crinone 8% (progesterone) vaginal therapy was provided in luteal phase for 14 days .Administration was started the second day after intrauterine insemination or timed intercourse.

Group Type: ACTIVE_COMPARATOR

Progesterone Vaginal Gel 8%

Intervention Type: DRUG

progesterone supplementation for luteal phase support administered with vaginal applicators and used instead of progesterone intramuscular injections or progesterone vaginal suppositories.

Letrozole Oral Tablet

Intervention Type: DRUG

letrozole oral tablet 2.5 mg or 5 mg administered cycle day 3-7 for ovulation induction

pelvic ultrasound

Intervention Type: DIAGNOSTIC_TEST

pelvic ultrasound performed at cycle day 11 or 12 and repeated as necessary until leading follicle size is \>17 mm in diameter

Ovidrel 250 MCG Per 0.5 ML Prefilled Syringe

Intervention Type: DRUG

ovidrel 250 mcg given when leading follicle size is \> 17 mm in diameter

Intrauterine insemination or timed intercourse

Intervention Type: OTHER

Intrauterine insemination or timed intercourse (depending on semen parameters) performed 36-40 hours after Ovidrel

Interventions

Progesterone Vaginal Gel 8%

progesterone supplementation for luteal phase support administered with vaginal applicators and used instead of progesterone intramuscular injections or progesterone vaginal suppositories.

Intervention Type: DRUG

Letrozole Oral Tablet

letrozole oral tablet 2.5 mg or 5 mg administered cycle day 3-7 for ovulation induction

Intervention Type: DRUG

pelvic ultrasound

pelvic ultrasound performed at cycle day 11 or 12 and repeated as necessary until leading follicle size is \>17 mm in diameter

Intervention Type: DIAGNOSTIC_TEST

Ovidrel 250 MCG Per 0.5 ML Prefilled Syringe

ovidrel 250 mcg given when leading follicle size is \> 17 mm in diameter

Intervention Type: DRUG

Intrauterine insemination or timed intercourse

Intrauterine insemination or timed intercourse (depending on semen parameters) performed 36-40 hours after Ovidrel

Intervention Type: OTHER

Other Intervention Names

Crinone 8% vaginal gel; recombinant hCG 250 mcg

Eligibility Criteria

Inclusion Criteria

• Women who have anovulatory or oligoovulatory infertility who are undergoing ovulation induction for infertility with TI or IUI , with or without regular cycles defined as cycle length > 35 days, < 26 days or amenorrhea (no cycles in the past six months), and who meet 2 out of 3 of the Rotterdam Criteria (1. Chronic anovulation or irregular cycles, 2. Clinical or biochemical hyperandrogenism, 3. Polycystic appearing ovaries on ultrasound.)
• Day 3 FSH(Follicle stimulating hormone)< 10 (obtained within 2 years prior to screening
• Documented infertility for at least 1 year or documented anovulation
• Willing to participate in up to 3 cycles of OI with letrozole and IUI or TI
• Partner's or donor's SA> 5 million motile sperm within 2 years of screening
• Patients may have received clomiphene citrate or letrozole treatment in the past.

Exclusion Criteria

• Untreated thyroid or prolactin abnormalities
• Pregnancy in the last 3 months
• BMI< 18 or >40kg/m2
• Abnormal uterine bleeding of undetermined origin
• Contraindications to pregnancy
• Progesterone sensitivity
• Uterine anomalies seen on ultrasound (performed within 6 months prior to screening) that can affect pregnancy chances such as submucosal uterine fibroids or polyps
• Three or more previous consecutive pregnancy losses
• Blocked fallopian tubes X2 (documented by HSG, laparoscopy, or hydrosonogram completed within past 3 years)
• More than 3 failed monitored letrozole cycles prior to enrolling

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Watson Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Eastern Virginia Medical School

OTHER

Sponsor Role: lead

Responsible Party

Laurel Stadtmauer

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Laurel A Stadtmauer, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Eastern Virginia Medical School

Locations

Laurel A. Stadtmauer, MD, PhD

Norfolk, Virginia, United States

Countries

United States

References

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Other Identifiers

IRB 12-07-FB-0170

Identifier Type: -

Identifier Source: org_study_id