SIRT-1 Antagonism for Endometrial Receptivity

Study Overview
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Brief Summary
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Progesterone resistance is mediated through epigenetic modification through SirT1 activation and is thought to contribute to infertility and progression of endometriosis. Endometriosis is a leading cause of unexplained IVF failure secondary to inflammatory changes that induce SirT1. The current study is designed to investigate a small molecule inhibitor of SirT1, in the clinical setting of In Vitro Fertilization and Embryo Transfer. The SAFER trial will compare EX-527 to placebo in a randomized, double-blind trial. Primary endpoints include Live Birth Rate (LBR) and secondary outcomes include pregnancy rate (PR), miscarriage rate (MR) and implantation failure rate.

Detailed Description
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The SAFER Trial will enroll women with unexplained failure after embryo transfer with euploid embryos. Subjects must have existing euploid embryos for transfer and test positive for SirT1 testing on endometrial biopsy. To qualify, they must be 18 to 40 years of age, have a normal uterine cavity, no serious systemic diseases (diabetes, lupus, cancer, etc) and be willing to be randomized to treatment with a SirT1 inhibitor, EX-527 or placebo. The medication will be provided and administered for 5 days prior to embryo transfer, after progesterone therapy is begun. The drug will be stopped 24 hr before embryo transfer. Standard protocols will be used including administration of progesterone, checking hCG 8 days after transfer, ultrasound monitoring of pregnancy and pregnancy outcomes recording, with Live Birth Rate (LBR) being the primary outcome of interest. We expect to enroll 30 women, with 15 subjects per arm. The goal of this study is to demonstrate efficacy for a specific inhibitor of SirT1 as a primary treatment of defects in endometrial receptivity due to endometriosis.

Official Title
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SIRT1-1 Antagonist Therapy Before Embryo Transfer to Improve Endometrial Receptivity and Life Pregnancy Rates

Conditions
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Endometriosis, Uterine Diseases, Endometrial Diseases, Infertility Unexplained, Infertility; Female, Nonimplantation

Intervention / Treatment
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* Drug: EX-527 (Selisistat)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must test positive for SIRT1 on mid-luteal endometrial biopsy Prior failed embryo transfer with euploid embryos Have at least one euploid embryo for transfer Exclusion Criteria: systemic illness affecting kidneys or liver; chronic headache or severe migraine Endometritis, hydrosalpinges, and known adenomyosis Uterine septum, uterine fibroids, endometrial polyps

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double blind, placebo controlled comparison of SirT1 inhibitor treatment for implantation failure associated with endometriosis
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: EX-527<br>The drug will be administered daily for 5 days beginning with the start of progesterone therapy and ended 24 hours before embryo transfer | Drug: EX-527 (Selisistat)<br>* EX-527 is a specific inhibitor of the histone deacetylase Sirtuin-1 (SirT1). It is being given to reverse the effects of endometriosis, namely progesterone resistance, that is thought to interfere with the establishment of pregnancy in women with endometriosis<br>* Other names: SEN0014196;|
| Placebo Comparator: Placebo<br>The placebo will be administered daily for 5 days beginning with the start of progesterone therapy and ended 24 hours before embryo transfer | Drug: Placebo<br>* We will use the same vehicle for producing the active drug such as maltose without any hormones or active components<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Live birth rate | The number of successful pregnancies ending in live birth at the conclusion of the study divided by the number of embryo transfers in each group | 9 months to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pregnancy rate | The number of subjects with a demonstrated pregnancy based on elevated and sustained hCG levels divided by the number of embryo transfers per group | 9 months to 2 years | 
| Miscarriage rate | The number of sustained pregnancies lost divided by the number of pregnancies in each group | 9 months to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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endometriosis, SIRT1, Progesterone resistance