SIRT-1 Antagonism for Endometrial Receptivity

Endometriosis Clinical Trial

— SAFER  

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT04184323
• Other study ID #: BL5280
• Status: Withdrawn
• Phase: Phase 2
• Start date: January 2022
• Est. completion date: December 2023

Study information

• Verified date: November 2020
• Source: Wake Forest University Health Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: December 2023
• Est. primary completion date: December 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 40 Years

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

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

Locations

Country	Name	City	State
United States	Wake Forest School of Medicine	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Wake Forest University Health Sciences

Country where clinical trial is conducted

United States, 

References & Publications (4)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Miscarriage rate	The number of sustained pregnancies lost divided by the number of pregnancies in each group	9 months to 2 years