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SIRT-1 Antagonism for Endometrial Receptivity (SAFER)

Primary Purpose

Endometriosis, Uterine Diseases, Endometrial Diseases

Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
EX-527 (Selisistat)
Placebo
Sponsored by
Wake Forest University Health Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Endometriosis focused on measuring endometriosis, SIRT1, Progesterone resistance

Eligibility Criteria

18 Years - 40 Years (Adult)FemaleDoes not accept 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

Sites / Locations

  • Wake Forest School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

EX-527

Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
Miscarriage rate
The number of sustained pregnancies lost divided by the number of pregnancies in each group

Full Information

First Posted
November 27, 2019
Last Updated
November 8, 2021
Sponsor
Wake Forest University Health Sciences
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1. Study Identification

Unique Protocol Identification Number
NCT04184323
Brief Title
SIRT-1 Antagonism for Endometrial Receptivity
Acronym
SAFER
Official Title
SIRT1-1 Antagonist Therapy Before Embryo Transfer to Improve Endometrial Receptivity and Life Pregnancy Rates
Study Type
Interventional

2. Study Status

Record Verification Date
November 2020
Overall Recruitment Status
Withdrawn
Why Stopped
Lack of funding
Study Start Date
January 2022 (Anticipated)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Wake Forest University Health Sciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Endometriosis, Uterine Diseases, Endometrial Diseases, Infertility Unexplained, Infertility; Female, Nonimplantation
Keywords
endometriosis, SIRT1, Progesterone resistance

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Double blind, placebo controlled comparison of SirT1 inhibitor treatment for implantation failure associated with endometriosis
Masking
ParticipantCare ProviderInvestigator
Masking Description
Drug and placebo will be prepared in color coded capsules. Randomization will be performed using computer-generated lists assigned sequentially upon recruitment.
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
EX-527
Arm Type
Active Comparator
Arm Description
The drug will be administered daily for 5 days beginning with the start of progesterone therapy and ended 24 hours before embryo transfer
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
The placebo will be administered daily for 5 days beginning with the start of progesterone therapy and ended 24 hours before embryo transfer
Intervention Type
Drug
Intervention Name(s)
EX-527 (Selisistat)
Other Intervention Name(s)
SEN0014196
Intervention Description
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
Intervention Name(s)
Placebo
Intervention Description
We will use the same vehicle for producing the active drug such as maltose without any hormones or active components
Primary Outcome Measure Information:
Title
Live birth rate
Description
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
Time Frame
9 months to 2 years
Secondary Outcome Measure Information:
Title
Pregnancy rate
Description
The number of subjects with a demonstrated pregnancy based on elevated and sustained hCG levels divided by the number of embryo transfers per group
Time Frame
9 months to 2 years
Title
Miscarriage rate
Description
The number of sustained pregnancies lost divided by the number of pregnancies in each group
Time Frame
9 months to 2 years

10. Eligibility

Sex
Female
Gender Based
Yes
Gender Eligibility Description
Pregnancy is a required end point
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bruce A Lessey, MD, PhD
Organizational Affiliation
Wake Forest University Health Sciences
Official's Role
Principal Investigator
Facility Information:
Facility Name
Wake Forest School of Medicine
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The demographic data, group assignment, and outcome data for each subject will be shared with other researchers including embryo grade, stage, pregnancy results (pregnant, not pregnant, miscarriage, ongoing pregnancy, Live birth)
IPD Sharing Time Frame
After completion of the study that includes live birth data
Citations:
PubMed Identifier
25223836
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.
Results Reference
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PubMed Identifier
28754906
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.
Results Reference
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PubMed Identifier
30610661
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.
Results Reference
background
PubMed Identifier
29126613
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.
Results Reference
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SIRT-1 Antagonism for Endometrial Receptivity

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