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Polycystic Ovary SyndromePhase 2/3NCT03440359

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

A Phase 2/3 study testing Progesterone Vaginal Gel 8%, Letrozole Oral Tablet and pelvic ultrasound in people with Polycystic Ovary Syndrome, run by Eastern Virginia Medical School at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 20 to 40 years, women only
Conditions the study is for
Polycystic Ovary Syndrome
What is being tested?
Progesterone Vaginal Gel 8%, Letrozole Oral Tablet and pelvic ultrasound
Could I receive a placebo?
No, everyone receives an active treatment
How many people
52 participants
Where
1 siteUnited States
Study dates
6 Jul 2012to 30 Dec 2017
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 20 to 40 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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.

Who cannot join

  • 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
Show all 10Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Laurel A. Stadtmauer, MD, PhD

    Norfolk, Virginia, 23507

Other trials in United States

About this study

Official title: "Supplementation of the Luteal Phase With Vaginal Progesterone (Crinone 8%) in Women With Polycystic Ovary Syndrome Undergoing Ovulation Induction With Letrozole: A Prospective and Randomized Controlled Trial

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.

Read the 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.

Being tested
Progesterone Vaginal Gel 8%, Letrozole Oral Tablet, pelvic ultrasound, Ovidrel 250 MCG Per 0.5 ML Prefilled Syringe, Intrauterine insemination or timed intercourse
Keywords
PCOS, crinone, vaginal progesterone, ovulation induction
Medical subject headings
Polycystic Ovary Syndrome

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Progesterone Vaginal Gel 8%Drug

    Also called Crinone 8% vaginal gel

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

  • Letrozole Oral TabletDrug

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

  • pelvic ultrasoundDiagnostic 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 SyringeDrug

    Also called recombinant hCG 250 mcg

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

  • Intrauterine insemination or timed intercourseOther

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

Study groups in NCT03440359
Study groupRoleWhat they receive
# 1- no progesterone therapyOtherLetrrozole 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
Receives: 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 comparatorLetrrozole 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.
Receives: 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

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Clinical pregnancy rates

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

    Measured: 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)

  1. Live birth rates

    The secondary endpoint is the Live Birth Rate per cycle initiated (each cycle is 28 days)

    Measured: Up to 1 year or until delivery

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Feb 2018
  2. Study start6 Jul 2012
  3. Primary completion2 Nov 2016
  4. Study completion30 Dec 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Other
Allocation
Randomised
Intervention model
Parallel groups
Model description
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.
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
52 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03440359
Sponsor's protocol ID
IRB 12-07-FB-0170
Status last verified
Feb 2018
First submitted
7 Feb 2018
Last updated
26 Feb 2018
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 14560891

  • 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.

    PubMed 13899931

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

    PubMed 12952386

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

    PubMed 12958117

  • 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.

    PubMed 9637695

  • 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.

    PubMed 14711538

  • 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.

    PubMed 19127427

  • 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.

    PubMed 17604615

  • 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.

    PubMed 19584394

  • 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.

    PubMed 8062942

  • 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.

    PubMed 15652895

  • 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.

    PubMed 19515366

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Progesterone Vaginal Gel 8%, Letrozole Oral Tablet and pelvic ultrasound in people with Polycystic Ovary Syndrome, run by Eastern Virginia Medical School at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Feb 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Clinical pregnancy rates (time frame: 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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03440359, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Feb 2018.

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