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SIRT-1 Antagonism for Endometrial Receptivity

NCT ID: NCT04184323

Last Updated: 2021-11-17

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

WITHDRAWN

Clinical Phase

PHASE2

Study Classification

INTERVENTIONAL

Study Start Date

2022-01-31

Study Completion Date

2023-12-31

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.

Conditions

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

Keywords

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endometriosis SIRT1 Progesterone resistance

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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

TREATMENT

Blinding Strategy

TRIPLE

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

Study Groups

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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

Group Type ACTIVE_COMPARATOR

EX-527 (Selisistat)

Intervention Type DRUG

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

Placebo

The placebo will be administered daily for 5 days beginning with the start of progesterone therapy and ended 24 hours before embryo transfer

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

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

Interventions

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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

Intervention Type DRUG

Placebo

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

Intervention Type DRUG

Other Intervention Names

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SEN0014196

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
Minimum Eligible Age

18 Years

Maximum Eligible Age

40 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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Wake Forest University Health Sciences

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Bruce A Lessey, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Wake Forest University Health Sciences

Locations

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Wake Forest School of Medicine

Winston-Salem, North Carolina, United States

Site Status

Countries

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United States

References

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Westerberg G, Chiesa JA, Andersen CA, Diamanti D, Magnoni L, Pollio G, Darpo B, Zhou M. Safety, pharmacokinetics, pharmacogenomics and QT concentration-effect modelling of the SirT1 inhibitor selisistat in healthy volunteers. Br J Clin Pharmacol. 2015 Mar;79(3):477-91. doi: 10.1111/bcp.12513.

Reference Type BACKGROUND
PMID: 25223836 (View on PubMed)

Yoo JY, Kim TH, Fazleabas AT, Palomino WA, Ahn SH, Tayade C, Schammel DP, Young SL, Jeong JW, Lessey BA. KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance. Sci Rep. 2017 Jul 28;7(1):6765. doi: 10.1038/s41598-017-04577-w.

Reference Type BACKGROUND
PMID: 28754906 (View on PubMed)

Likes CE, Cooper LJ, Efird J, Forstein DA, Miller PB, Savaris R, Lessey BA. Medical or surgical treatment before embryo transfer improves outcomes in women with abnormal endometrial BCL6 expression. J Assist Reprod Genet. 2019 Mar;36(3):483-490. doi: 10.1007/s10815-018-1388-x. Epub 2019 Jan 4.

Reference Type BACKGROUND
PMID: 30610661 (View on PubMed)

Almquist LD, Likes CE, Stone B, Brown KR, Savaris R, Forstein DA, Miller PB, Lessey BA. Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study. Fertil Steril. 2017 Dec;108(6):1063-1069. doi: 10.1016/j.fertnstert.2017.09.017. Epub 2017 Nov 7.

Reference Type BACKGROUND
PMID: 29126613 (View on PubMed)

Other Identifiers

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BL5280

Identifier Type: -

Identifier Source: org_study_id