Clinical trial NCT04184323: SIRT-1 Antagonism for Endometrial Receptivity
Official title: SIRT1-1 Antagonist Therapy Before Embryo Transfer to Improve Endometrial Receptivity and Life Pregnancy Rates
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Endometriosis
Uterine Diseases
Endometrial Diseases
Infertility Unexplained
Infertility; Female, Nonimplantation
Keywords: endometriosis
SIRT1
Progesterone resistance
Lead sponsor: Wake Forest University Health Sciences
Sponsor class: OTHER
First posted: 2019-12-03
Enrollment: 0
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double blind, placebo controlled comparison of SirT1 inhibitor treatment for implantation failure associated with endometriosis
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Live birth rate
timeFrame: 9 months to 2 years
Secondary outcomes:
measure: Pregnancy rate
timeFrame: 9 months to 2 years
measure: Miscarriage rate
timeFrame: 9 months to 2 years
Other outcomes:
Locations:
city: Winston-Salem
country: United States
facility: Wake Forest School of Medicine
state: North Carolina
Study officials:
affiliation: Wake Forest University Health Sciences
name: Bruce A Lessey, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
citation: 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.