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Trial record 3 of 8 for:    effects of progesterone on lh AND pcos AND CONTROLS

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

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ClinicalTrials.gov Identifier: NCT03440359
Recruitment Status : Completed
First Posted : February 21, 2018
Last Update Posted : February 26, 2018
Sponsor:
Collaborator:
Watson Pharmaceuticals
Information provided by (Responsible Party):
Laurel Stadtmauer, Eastern Virginia Medical School

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.

Condition or disease Intervention/treatment Phase
Polycystic Ovary Syndrome 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 Phase 2 Phase 3

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Outcomes Assessor)
Masking Description: Data analysis was completed by blinded observer who had access only to participant ID number, cycle number and treatment, and pregnancy outcome
Primary Purpose: Other
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
Actual Study Start Date : July 6, 2012
Actual Primary Completion Date : November 2, 2016
Actual Study Completion Date : December 30, 2017

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
# 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
Drug: Letrozole Oral Tablet
letrozole oral tablet 2.5 mg or 5 mg administered cycle day 3-7 for ovulation induction
Diagnostic Test: pelvic ultrasound
pelvic ultrasound performed at cycle day 11 or 12 and repeated as necessary until leading follicle size is >17 mm in diameter
Drug: Ovidrel 250 MCG Per 0.5 ML Prefilled Syringe
ovidrel 250 mcg given when leading follicle size is > 17 mm in diameter
Other Name: recombinant hCG 250 mcg
Other: Intrauterine insemination or timed intercourse
Intrauterine insemination or timed intercourse (depending on semen parameters) performed 36-40 hours after Ovidrel
Active Comparator: # 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.
Drug: 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.
Other Name: Crinone 8% vaginal gel
Drug: Letrozole Oral Tablet
letrozole oral tablet 2.5 mg or 5 mg administered cycle day 3-7 for ovulation induction
Diagnostic Test: pelvic ultrasound
pelvic ultrasound performed at cycle day 11 or 12 and repeated as necessary until leading follicle size is >17 mm in diameter
Drug: Ovidrel 250 MCG Per 0.5 ML Prefilled Syringe
ovidrel 250 mcg given when leading follicle size is > 17 mm in diameter
Other Name: recombinant hCG 250 mcg
Other: Intrauterine insemination or timed intercourse
Intrauterine insemination or timed intercourse (depending on semen parameters) performed 36-40 hours after Ovidrel



Primary Outcome Measures :
  1. 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 ]
    The primary endpoint of the trial is the Clinical Pregnancy Rate per cycle initiated


Secondary Outcome Measures :
  1. Live birth rates [ Time Frame: Up to 1 year or until delivery ]
    The secondary endpoint is the Live Birth Rate per cycle initiated (each cycle is 28 days)



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Ages Eligible for Study:   20 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03440359


Locations
United States, Virginia
Laurel A. Stadtmauer, MD, PhD
Norfolk, Virginia, United States, 23507
Sponsors and Collaborators
Eastern Virginia Medical School
Watson Pharmaceuticals
Investigators
Principal Investigator: Laurel A Stadtmauer, MD, PhD Eastern Virginia Medical School

Publications:

Responsible Party: Laurel Stadtmauer, Principal Investigator, Eastern Virginia Medical School
ClinicalTrials.gov Identifier: NCT03440359     History of Changes
Other Study ID Numbers: IRB 12-07-FB-0170
First Posted: February 21, 2018    Key Record Dates
Last Update Posted: February 26, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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.: Yes

Keywords provided by Laurel Stadtmauer, Eastern Virginia Medical School:
PCOS, crinone, vaginal progesterone, ovulation induction

Additional relevant MeSH terms:
Polycystic Ovary Syndrome
Progesterone
Physiological Effects of Drugs
Reproductive Control Agents
Syndrome
Disease
Pathologic Processes
Ovarian Cysts
Cysts
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Gonadal Disorders
Endocrine System Diseases
Letrozole
Chorionic Gonadotropin
Progestins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists