SIRT-1 Antagonism for Endometrial Receptivity

NCT04184323 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: BL5280
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

endometriosis; SIRT1; Progesterone resistance

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Pregnancy rate

  9 months to 2 years

• Miscarriage rate

  9 months to 2 years

Study Arms (2)

EX-527

ACTIVE COMPARATOR

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)

Placebo

PLACEBO COMPARATOR

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

Interventions

EX-527 (Selisistat) 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

Also known as: SEN0014196

EX-527

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 18 Years - 40 Years
• Gender Eligibility Details: Pregnancy is a required end point
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• systemic illness affecting kidneys or liver; chronic headache or severe migraine
• Endometritis, hydrosalpinges, and known adenomyosis
• Uterine septum, uterine fibroids, endometrial polyps

Sponsors & Collaborators

• Wake Forest University Health Sciences: lead

Study Sites (1)

Wake Forest School of Medicine

Winston-Salem, North Carolina, 27157, United States

Location

Related Publications (4)

• 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.

  PMID: 25223836 BACKGROUND

• 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.

  PMID: 28754906 BACKGROUND

• 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.

  PMID: 30610661 BACKGROUND

• 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.

  PMID: 29126613 BACKGROUND

MeSH Terms

Conditions

Endometriosis; Uterine Diseases; Infertility; Progesterone Resistance

Interventions

6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide

Condition Hierarchy (Ancestors)

Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Study Officials

• Bruce A Lessey, MD, PhD

  Wake Forest University Health Sciences

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Drug and placebo will be prepared in color coded capsules. Randomization will be performed using computer-generated lists assigned sequentially upon recruitment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

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

Study Record Dates

• First Submitted: November 27, 2019
• First Posted: December 3, 2019
• Study Start: January 1, 2022
• Primary Completion: December 1, 2023
• Study Completion: December 1, 2023
• Last Updated: November 17, 2021

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: After completion of the study that includes live birth data

Locations

US (1)