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Penn Uterine Transplantation for Uterine Factor Infertility Trial (UNTIL)

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ClinicalTrials.gov Identifier: NCT03307356
Recruitment Status : Recruiting
First Posted : October 11, 2017
Last Update Posted : August 29, 2018
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania

October 5, 2017
October 11, 2017
August 29, 2018
November 6, 2017
July 1, 2020   (Final data collection date for primary outcome measure)
Successful engraftment of deceased donor uterus [ Time Frame: Assessed 12 months after transplant ]
Uterus remains in recipient with no complications (i.e. infection or rejection) or any complications that did arise could be successfully treated.
Same as current
Complete list of historical versions of study NCT03307356 on ClinicalTrials.gov Archive Site
Postoperative complications [ Time Frame: Assessed 12 months after transplant ]
Including but not limited to evidence of damage to surrounding organs/vessels, need for reoperation, thromboembolic event, infection, rejection episodes (clinical and histologic), impaired renal function
Same as current
Not Provided
Not Provided
 
Penn Uterine Transplantation for Uterine Factor Infertility Trial
Penn Uterine Transplantation for Uterine Factor Infertility Trial: Phase I

Options for childbearing are limited for the thousands of women in the United States who suffer from absolute uterine factor infertility. Uterine transplantation is an emerging treatment that provides hope for these individuals.

In the Penn UNTIL trial, the investigators propose to successfully achieve live birth after uterus transplantation from deceased donors. The investigators plan to transplant five women who will ultimately undergo embryo transfer, pregnancy, delivery, and then transplant removal.

The Penn UNTIL trial is divided into two distinct phases. In Phase I, study subjects are screened, enrolled, evaluated, generate embryos, and ultimately undergo uterine transplantation. This phase of the trial is a feasibility study whose primary outcome is successful transplant of a uterus from a deceased donor into a living recipient. In Phase II, women with successful deceased donor uterine transplants will have embryos implanted to ultimately attain the objective of live birth. This trial promises to expand the benefits of transplantation to a novel group of individuals who have a devastating diagnosis.

For more information please visit: https://clinicalresearch.itmat.upenn.edu/clinicaltrial/4821/congenital-abnormalitiesfemale-infertility-penn-ut/

BACKGROUND The inability to conceive children can be one of the most devastating and traumatic situations to arise in the life of an individual or couple. While assisted reproductive technologies have been developed that help overcome many causes of infertility, uterine factor infertility has remained an intractable condition. Absolute uterine factor infertility (AUFI) occurs when the uterus is either not present (congenitally absent or surgically removed) or is present but is not capable of sustaining a pregnancy. AUFI can result from either congenital absence of a uterus (Mayer-Rokitansky-Kuster-Hauser [MRKH] syndrome) or other Müllerian anomalies. MRKH occurs in 1:4000 of females. It is difficult to determine the exact number of women that suffer from AUFI, however estimates are as high as 7 million women between the ages of 15-34 may suffer from this condition in the United States.

Existing options for individuals with AUFI to achieve parenthood are adoption and gestational surrogacy. Gestational surrogacy is the only alternative that allows an individual or couple to have a child genetically related to the intended parent(s). These options are considered acceptable to many women with AUFI; however, there are a number of significant limitations to these alternatives. Gestational surrogacy is fraught with ethical, legal, and social controversy because it shifts the burden of gestation from one woman to another, usually for payment. Additionally, adoption and/or surrogacy may not be permissible to a couple due to social, ethical, moral or religious considerations. If these alternatives are acceptable to a couple, they may not be affordable. Finally, these alternatives may not be accessible as barriers to domestic and international adoption have increased and compensated surrogacy is not legally protected in most states (and is illegal in some states). The limitations of these alternatives may account for the extraordinary interest in UTx by women with AUFI, as 92% of women with AUFI would undergo UTx as first line management for their AUFI, above adoption and surrogacy.

Understanding the limitations of these alternatives, uterine transplantation (UTx) began to be explored as a concept in animal studies in the 1970s. In 2012, a Swedish team led by Dr. Mats Brannstrom started the first human uterine transplantation trial. The first live birth after successful UTx occurred in Sweden in 2014. Since 2014, in total eight children have been born to women who underwent uterine transplantation in Sweden.

Unlike all other transplants, uterine transplantation is "ephemeral". This means that a uterine transplant is only maintained during the individual's child-bearing period which, in the case of uterine transplantation, will be the time necessary to produce one or two children (<10 years). Although pregnancy after transplant is considered high risk, more than 15,000 babies have been born to female recipients of solid organ transplants that were immunosuppressed with no reported increased risk of fetal malformations.

Several centers in the world are either embarking on or are considering the development of uterine transplantation protocols. Although multiple centers have had successful organ engraftment occur following uterine transplants from both living and deceased donors, as of September 2017, no live births have occurred outside of Sweden.

STUDY DESIGN Recognizing that the University of Pennsylvania has been a leader in all of the domains required to build a successful uterus transplant program, planning for the Penn UNTIL trial began in October 2016. The UNTIL trial is is a nonrandomized, interventional human study whose goal is to achieve live birth after deceased donor uterus transplantation (DDUTx). There are two phases to the trial. In Phase 1, the investigators plan to evaluate approximately 40 women with AUFI. From this cohort, the investigators will select five candidates who fulfill the inclusion criteria and are deemed the most suitable candidates for uterine transplant. Prior to being listed for transplant, the women will need to create embryos through ovarian stimulation, oocyte retrieval and in vitro fertilization that will be cryopreserved. After undergoing deceased donor uterus transplantation, participants will be monitored for rejection, infection and other complications for twelve months.

If the graft is clinically stable and any complications that arise are successfully treated 12 months after transplantation, the women will enter Phase 2 of the trial. In Phase 2, the embryos created prior to transplantation will be directly placed into the uterus in order for the women to achieve pregnancy. If pregnancy is achieved the participant will be monitored by a Maternal Fetal Medicine specialist (high-risk obstetrician) with goal to deliver at 37-39 weeks unless otherwise indicated. All deliveries will occur via cesarean delivery. If the participant and partner wish to attempt an additional pregnancy and the medical team feel it is safe to proceed, attempts at a second pregnancy will be undertaken. Again, if pregnancy is achieved following embryo transfer the participant will be monitored for the duration of her pregnancy by a Maternal Fetal Medicine specialist with goal to deliver at 37-39 weeks through repeat cesarean delivery unless otherwise indicated. Two months after the second cesarean delivery when the uterus has returned to its normal size, a hysterectomy will be performed and immunosuppression withdrawn.

For more information please visit: https://clinicalresearch.itmat.upenn.edu/clinicaltrial/4821/congenital-abnormalitiesfemale-infertility-penn-ut/

Interventional
Not Applicable
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Mayer Rokitansky Kuster Hauser Syndrome
  • Uterine Agenesis
  • Infertility, Female, of Uterine Origin
  • Uterine Factor Infertility
Other: Uterine Transplant
Transplant of a uterus from a deceased donor
Other Name: Deceased Donor Uterine Transplant
Experimental: Uterine Transplantation
Women will undergo extensive medical and psychological screening. Five women that meet all inclusion and exclusion criteria will undergo ovarian stimulation, oocyte retrieval and will create embryos that will be stored for future use. Women will then undergo uterine transplantation from a deceased donor. Following transplant women will be closely monitored for complications (including infection and rejection). If no complications arise, or complications that do arise can be treated, attempts at pregnancy will begin approximately 12 months after transplant. Pregnancy in the setting of uterine transplant requires directly placing embryos directly into the uterus.
Intervention: Other: Uterine Transplant

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
5
Same as current
July 1, 2029
July 1, 2020   (Final data collection date for primary outcome measure)

Participant Inclusion Criteria:

  1. XX-bearing individual diagnosed with Absolute Uterine Factor Infertility (AUFI) as a result of: A) prior hysterectomy or B) congenital absence or malformation of the uterus preventing pregnancy
  2. Age 21-40
  3. Received counseling regarding alternatives to uterine transplant such as adoption or surrogacy
  4. Intact ovaries and normal ovarian reserve (defined as anti-Müllerian hormone level ≥2 ng/mL and/or follicle-stimulating hormone level ≥10 IU/L)
  5. Vaginal length >6 cm (average vaginal length established with dilators)
  6. Body mass index <30 kg/m2
  7. Fluent in the English Language
  8. If cervix present/previously present, human papillomavirus (HPV)) negative or received vaccination for HPV
  9. Willing to comply with screening, protocol and all required procedures
  10. In stable committed relationship for ≥3 years
  11. Has undergone controlled ovarian hyperstimulation, egg retrieval, in vitro fertilization, preimplantation genetic screening and embryo freezing and has frozen embryos of sufficient embryo quality/quantity (minimum 4 blastocysts ≥3BB grade or ≥2 chromosomally normal embryos)

Participant Exclusion Criteria:

  1. Previous multiple major abdominal/pelvic surgery
  2. Severe endometriosis
  3. History of hypertension, diabetes mellitus, thrombophilia or other clotting or bleeding disorders, significant heart, liver, kidney or central nervous system disease
  4. History of prior malignancy except for cervical cancer in stage 1a or 1b (must be in remission for 3 years)
  5. History of significant psychiatric illness
  6. Allergy, hypersensitivity, or intolerance of expected immunosuppressive agents (i.e. Thymoglobulin®, tacrolimus, etc.)
  7. Allergy, hypersensitivity, or intolerance of heparin or aspirin
  8. Presence of active documented systemic infection or recent systemic infection within the past 3 months
  9. Seropositivity for HIV, HBV, HCV, HTLV-1
  10. Current smoker (smoking cessation must have occurred 3 months prior to enrollment)
  11. Chemical and/or alcohol dependency or abuse
  12. Psychosocial problems (including alcoholism, drug abuse, documented behavioral disorders)
  13. Renal abnormalities, specifically single kidney or pelvic kidneys
  14. Contraindications to pregnancy
  15. Unwilling to receive a transfusion of blood or blood products
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Gender Eligibility Description: Female sex; specifically XX-bearing individual
21 Years to 40 Years   (Adult)
No
Contact: Kathleen E O'Neill, MD, MTR (215) 662-6100 UterineTransplant@uphs.upenn.edu
Contact: Bridget Nolan (215) 662-3324 Bridget.Nolan@uphs.upenn.edu
United States
 
 
NCT03307356
827853
Yes
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: Undecided
Plan Description: Select trial data may be shared with the International Society of Uterine Transplantation (ISUTx) Registry. No protected health information will be shared.
University of Pennsylvania
University of Pennsylvania
Not Provided
Principal Investigator: Kathleen E O'Neill, MD, MTR University of Pennsylvania
University of Pennsylvania
August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP