SAFER: SIRT-1 Antagonism for Endometrial Receptivity

Sponsor

Wake Forest University Health Sciences (Other)

Overall Status

Withdrawn

CT.gov ID

NCT04184323

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Endometriosis Uterine Diseases Endometrial Diseases Infertility Unexplained Infertility; Female, Nonimplantation	Drug: EX-527 (Selisistat) Drug: Placebo	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Double blind, placebo controlled comparison of SirT1 inhibitor treatment for implantation failure associated with endometriosisDouble blind, placebo controlled comparison of SirT1 inhibitor treatment for implantation failure associated with endometriosis

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

Drug and placebo will be prepared in color coded capsules. Randomization will be performed using computer-generated lists assigned sequentially upon recruitment.

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jan 1, 2022

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: EX-527 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) 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 Other Names: SEN0014196
Placebo Comparator: Placebo 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 We will use the same vehicle for producing the active drug such as maltose without any hormones or active components

Arm

Intervention/Treatment

Active Comparator: EX-527

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)

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

Other Names:

SEN0014196

Placebo Comparator: Placebo

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

We will use the same vehicle for producing the active drug such as maltose without any hormones or active components

Outcome Measures

Primary Outcome Measures

Live birth rate [9 months to 2 years]
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

Secondary Outcome Measures

Pregnancy rate [9 months to 2 years]
The number of subjects with a demonstrated pregnancy based on elevated and sustained hCG levels divided by the number of embryo transfers per group
Miscarriage rate [9 months to 2 years]
The number of sustained pregnancies lost divided by the number of pregnancies in each group

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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