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

NCT03440359 | Completed Phase 2 FDA Drug

• 1 other identifier: IRB 12-07-FB-0170
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

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.

Conditions

Polycystic Ovary Syndrome

Keywords

PCOS, crinone, vaginal progesterone, ovulation induction

Outcome Measures

Primary Outcomes (1)

• Clinical pregnancy rates

  The primary endpoint of the trial is the Clinical Pregnancy Rate per cycle initiated

  Per initiated cycle of treatment. At the end of Cycle 1, 2, and 3 (each cycle is 28 days) and if pregnant up to 8 weeks after completion of cycle

Secondary Outcomes (1)

• Live birth rates

  Up to 1 year or until delivery

Study Arms (2)

# 1- no progesterone therapy

OTHER

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

Drug: Letrozole Oral Tablet; Diagnostic Test: pelvic ultrasound; Drug: Ovidrel 250 MCG Per 0.5 ML Prefilled Syringe; Other: Intrauterine insemination or timed intercourse

# 2 - Progesterone Vaginal Gel 8%

ACTIVE COMPARATOR

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.

Drug: Progesterone Vaginal Gel 8%; Drug: Letrozole Oral Tablet; Diagnostic Test: pelvic ultrasound; Drug: Ovidrel 250 MCG Per 0.5 ML Prefilled Syringe; Other: Intrauterine insemination or timed intercourse

Interventions

Progesterone Vaginal Gel 8% DRUG

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

Also known as: Crinone 8% vaginal gel

# 2 - Progesterone Vaginal Gel 8%

Letrozole Oral Tablet DRUG

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

# 1- no progesterone therapy; # 2 - Progesterone Vaginal Gel 8%

pelvic ultrasound DIAGNOSTIC_TEST

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

# 1- no progesterone therapy; # 2 - Progesterone Vaginal Gel 8%

Ovidrel 250 MCG Per 0.5 ML Prefilled Syringe DRUG

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

Also known as: recombinant hCG 250 mcg

# 1- no progesterone therapy; # 2 - Progesterone Vaginal Gel 8%

Intrauterine insemination or timed intercourse OTHER

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

# 1- no progesterone therapy; # 2 - Progesterone Vaginal Gel 8%

Eligibility Criteria

• Age: 20 Years - 40 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Eastern Virginia Medical School: lead
• Watson Pharmaceuticals: collaborator

Study Sites (1)

Laurel A. Stadtmauer, MD, PhD

Norfolk, Virginia, 23507, United States

Location

Related Publications (12)

• Franks S. Assessment and management of anovulatory infertility in polycystic ovary syndrome. Endocrinol Metab Clin North Am. 2003 Sep;32(3):639-51. doi: 10.1016/s0889-8529(03)00044-6.

  PMID: 14560891 BACKGROUND

• GOLDZIEHER JW, GREEN JA. The polycystic ovary. I. Clinical and histologic features. J Clin Endocrinol Metab. 1962 Mar;22:325-38. doi: 10.1210/jcem-22-3-325. No abstract available.

  PMID: 13899931 BACKGROUND

• Richardson MR. Current perspectives in polycystic ovary syndrome. Am Fam Physician. 2003 Aug 15;68(4):697-704.

  PMID: 12952386 BACKGROUND

• Hamilton-Fairley D, Taylor A. Anovulation. BMJ. 2003 Sep 6;327(7414):546-9. doi: 10.1136/bmj.327.7414.546. No abstract available.

  PMID: 12958117 BACKGROUND

• Vendola KA, Zhou J, Adesanya OO, Weil SJ, Bondy CA. Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest. 1998 Jun 15;101(12):2622-9. doi: 10.1172/JCI2081.

  PMID: 9637695 BACKGROUND

• Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004 Jan;81(1):19-25. doi: 10.1016/j.fertnstert.2003.10.004.

  PMID: 14711538 BACKGROUND

• Ganesh A, Goswami SK, Chattopadhyay R, Chaudhury K, Chakravarty B. Comparison of letrozole with continuous gonadotropins and clomiphene-gonadotropin combination for ovulation induction in 1387 PCOS women after clomiphene citrate failure: a randomized prospective clinical trial. J Assist Reprod Genet. 2009 Jan;26(1):19-24. doi: 10.1007/s10815-008-9284-4. Epub 2009 Jan 7.

  PMID: 19127427 BACKGROUND

• Casper RF. Aromatase inhibitors in ovarian stimulation. J Steroid Biochem Mol Biol. 2007 Aug-Sep;106(1-5):71-5. doi: 10.1016/j.jsbmb.2007.05.025. Epub 2007 May 24.

  PMID: 17604615 BACKGROUND

• Eckmann KR, Kockler DR. Aromatase inhibitors for ovulation and pregnancy in polycystic ovary syndrome. Ann Pharmacother. 2009 Jul;43(7):1338-46. doi: 10.1345/aph.1M096. Epub 2009 Jul 7.

  PMID: 19584394 BACKGROUND

• Miles RA, Paulson RJ, Lobo RA, Press MF, Dahmoush L, Sauer MV. Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study. Fertil Steril. 1994 Sep;62(3):485-90. doi: 10.1016/s0015-0282(16)56935-0.

  PMID: 8062942 BACKGROUND

• Cortinez A, De Carvalho I, Vantman D, Gabler F, Iniguez G, Vega M. Hormonal profile and endometrial morphology in letrozole-controlled ovarian hyperstimulation in ovulatory infertile patients. Fertil Steril. 2005 Jan;83(1):110-5. doi: 10.1016/j.fertnstert.2004.05.099.

  PMID: 15652895 BACKGROUND

• Montville CP, Khabbaz M, Aubuchon M, Williams DB, Thomas MA. Luteal support with intravaginal progesterone increases clinical pregnancy rates in women with polycystic ovary syndrome using letrozole for ovulation induction. Fertil Steril. 2010 Jul;94(2):678-83. doi: 10.1016/j.fertnstert.2009.03.088. Epub 2009 Jun 9.

  PMID: 19515366 BACKGROUND

MeSH Terms

Conditions

Polycystic Ovary Syndrome

Interventions

Crinone; Vaginal Creams, Foams, and Jellies; Letrozole; Ovidrel

Condition Hierarchy (Ancestors)

Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations; Feminine Hygiene Products; Equipment and Supplies; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Laurel A Stadtmauer, MD, PhD

  Eastern Virginia Medical School

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Data analysis was completed by blinded observer who had access only to participant ID number, cycle number and treatment, and pregnancy outcome
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Participants who met criteria were randomized to either Crinone vaginal therapy versus no therapy in the luteal phase of an ovulation induction cycle. Participants who did not achieve a pregnancy were able to participate in up to 3 cycles, and were re-randomized with each cycle.

Study Record Dates

• First Submitted: February 7, 2018
• First Posted: February 22, 2018
• Study Start: July 6, 2012
• Primary Completion: November 2, 2016
• Study Completion: December 30, 2017
• Last Updated: February 26, 2018

Record last verified: 2018-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)