Uterus Transplant for Infertility

(OPRTUNTI Trial)

Overseen By Richard Redett, MD

Age: 18 - 65

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: Johns Hopkins University

Must be taking: Immunosuppressants

Disqualifiers: Diabetes, HIV, Hepatitis, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This research study will use uterus transplantation to treat uterine factor infertility, also known as the inability to bear children due to not having a uterus. The purpose of this study is to enable women seeking genetically-related children and the childbearing experience to experience pregnancy and birth a child. In this study, living donors will undergo surgery to give the donor's uterus to another woman. The woman who receives the transplant will take immunosuppression to keep the uterus and herself healthy. Because taking immunosuppressive medicine has side effects, uterus transplantation is intended to be temporary, lasting about 5 years. The goals of the study are successful pregnancy and the birth of one, and possibly two, healthy babies per transplant patient. The uterus is to be removed and immunosuppression stopped following the birth of a child. Offspring are delivered by Caesarian section, at which time the transplant may also be removed. Transplant candidates must have fertilized, frozen (cryopreserved) embryos at a Johns Hopkins facility before undergoing transplantation. Transplant candidates will be asked to identify candidates' potential uterus donor. Altruistic donors, or women who want to donate without knowing a potential recipient, may also participate. All potential donors will be screened to see if the donors are a good match for a recipient and are healthy enough to have the donation surgery. Study Duration: * Uterus Donors: Screening through about 12 months following the transplant operation. * Uterus Recipients: Recipients may have the uterus for about 5 years. After the transplant is removed, the study team will ask for yearly follow-ups for another 5 years. * Children born from transplanted uteruses: The study team asks to follow offspring yearly through age 21 years.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, since you will be taking immunosuppressive drugs after the transplant, it's important to discuss your current medications with the study team to ensure there are no interactions.

What data supports the effectiveness of the drug tacrolimus in uterus transplantation for infertility?

Tacrolimus, used in other organ transplants like kidney and lung, has shown effectiveness in preventing organ rejection, which is crucial for the success of transplants. Studies indicate that both immediate-release and extended-release forms of tacrolimus are effective in maintaining graft survival and improving patient adherence to medication. ^{1 2 3 4 5}

Is uterus transplant safe for humans?

Tacrolimus, a drug used in uterus transplants, has been used safely in kidney, liver, heart, and lung transplants, but it can have toxic side effects and requires careful monitoring. Extended-release versions like Advagraf have similar safety profiles to the regular version, though they may increase adherence to medication. ^{1 2 5 6 7}

How is the uterus transplant treatment for infertility unique?

Uterus transplantation is a novel treatment for infertility that involves transplanting a healthy uterus into a person who cannot conceive due to uterine factor infertility. This approach is unique because it combines surgical transplantation with immunosuppressive drugs like tacrolimus and azathioprine to prevent organ rejection, offering a potential solution for those who cannot benefit from traditional fertility treatments. ^{1 2 8 9 10}

Research Team

Richard J Redett, MD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

This trial is for women with uterine factor infertility who want to become pregnant and have a child. Candidates must be non-smokers, aged 18-38, with cryopreserved embryos at Johns Hopkins. Donors should have had successful pregnancies before, be aged 25-65, and meet health criteria including BMI ≤35 and no recent malignancies.

Inclusion Criteria

Recipient Inclusion Criteria: Negative crossmatch with donor

Donor and Recipient Inclusion Criteria: USA citizen or equivalent

Donor and Recipient Inclusion Criteria: No co-existing psycho-social problems (i.e., alcoholism, drug abuse)

Exclusion Criteria

Recipient Only Exclusion Criteria: Conditions that, in the opinion of the study team, may expose the recipient to unacceptable risks under immunosuppressive treatment

I have never had a C-section, abdominal radiation, or other conditions that doctors say would prevent me from donating.

Donor and Recipient Exclusion Criteria: Positive for any of the following conditions: Insulin-dependent diabetes mellitus, Untreated sepsis, HIV (active or seropositive), Active tuberculosis, Active Hepatitis B infection, Active Hepatitis C infection, Viral encephalitis, Toxoplasmosis, Current/recent (within 3 months of donation/screening consent) IV drug abuse, Significant cardiac disease, Significant vascular disease, Sensitized recipients with high levels (50%) of panel-reactive Human Leukocyte Antigens (HLA) antibodies, Conditions that may impact the success of the surgical procedure or increase the risk of postoperative complications including inherited coagulopathies like Hemophilia, Von-Willebrand's disease, Protein C and S deficiency, Thrombocythemias, Thalassemias, Sickle Cell disease, etc., Mixed connective tissue diseases and collagen diseases that can result in poor wound healing after surgery, Severe neurologic deficits, Patients considered unsuitable per the consulted Psychiatric/Psychologic appraisal, A history of medical non-compliance

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Telephone and in-person visits

In Vitro Fertilization (IVF) & Embryo Cryopreservation

Participants undergo IVF and embryo cryopreservation if embryos are not already banked

Varies

Transplantation

Uterus transplantation surgery is performed

1 day for surgery, followed by recovery

Hospital stay for surgery and recovery

Embryo Transfer

Embryo transfer may be attempted as early as 2 months post-transplant

Varies

Pregnancy to Childbirth

Participants are monitored throughout pregnancy until childbirth

Up to 5 years or until birth of two children

Regular obstetric visits

Uterus Explantation

Uterus is removed after childbirth or after 5 years

1 day for surgery, followed by recovery

Hospital stay for surgery and recovery

Longitudinal Follow-Up

Participants are monitored for 5 years post-explantation

5 years

Yearly follow-up visits

Treatment Details

Interventions

• Azathioprine (Immunosuppressant)
• Tacrolimus (Immunosuppressant)
• Uterine Allotransplantation (Procedure)

Trial Overview The study tests uterus transplantation from living donors to recipients using immunosuppressive drugs (Imuran and Tacrolimus) to prevent organ rejection. The goal is for the recipient to achieve pregnancy and give birth via Caesarean section. Afterward, the transplanted uterus will be removed.

Participant Groups

Group I: Uterus Transplant Recipient Experimental Treatment 3 Interventions

Uterus recipients, who are otherwise healthy, adult, genotypic females affected by uterine factor infertility, will undergo the surgically innovative uterus transplantation procedure combined with short-term use of conventional calcineurin inhibitor-based immunosuppression in to support a fetus to a viable delivery via Caesarian section.

Azathioprine is already approved in Canada for the following indications:

Approved in Canada as Imuran for:

• Prevention of rejection in organ transplantation
• Treatment of rheumatoid arthritis

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

Findings from Research

A case study of a 32-year-old woman who had a lung transplant and became pregnant while on tacrolimus showed that she maintained stable lung function throughout her pregnancy, indicating that tacrolimus can be safely used during pregnancy in lung transplant recipients.

The successful delivery of a healthy infant and minimal acute cellular rejection postpartum suggests that tacrolimus may support both maternal health and fetal development in this unique patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful pregnancy outcome in a lung transplant recipient with tacrolimus immunosuppression. A case report. Kruszka, SJ., Gherman, RB.[2013]

Extended release tacrolimus (Advagraf©, Astagraf XL©) offers a once-daily dosing option for kidney transplant recipients, potentially improving medication adherence while maintaining a similar safety and efficacy profile to the traditional twice-daily tacrolimus (Prograf©).

While extended release tacrolimus shows comparable pharmacokinetics to the standard formulation, it is not recommended for liver transplant patients due to an increased risk of mortality in female recipients, and there is limited data on its use in heart and lung transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overview of extended release tacrolimus in solid organ transplantation. Patel, N., Cook, A., Greenhalgh, E., et al.[2022]

A retrospective analysis of 120 renal transplant patients showed that switching from the brand-name tacrolimus (Prograf) to the generic formulation (Adoport) did not result in significant differences in key clinical outcomes, including tacrolimus levels, acute rejection rates, and renal function at 6 months post-transplant.

The study also confirmed the safety and efficacy of the generic tacrolimus through protocol biopsies, showing no differences in histological outcomes or the development of de novo donor-specific antibodies between the two formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

De novo use of a generic formulation of tacrolimus versus reference tacrolimus in kidney transplantation: evaluation of the clinical results, histology in protocol biopsies, and immunological monitoring. Melilli, E., Crespo, E., Sandoval, D., et al.[2021]

FK-506 ointment (Protopic) therapy demonstrated a comparable ability to prolong skin graft survival (16.7 days) compared to intravenous FK-506 (Prograf) injection (15.8 days) in a rat model, suggesting its efficacy in preventing allograft rejection.

The ointment resulted in significantly lower blood levels of tacrolimus (<0.2 ng/mL) compared to the injection (0.45 ng/mL), indicating a potentially safer option with reduced systemic exposure while maintaining similar immunosuppressive effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of FK506 ointment (Protopic) on rat skin allograft model. Kim, YE., Eun, SC.[2014]

The extended-release formulation of tacrolimus (Advagraf®/Astagraf XL®) shows similar efficacy to the immediate-release version (Prograf®) in kidney transplant recipients, with no significant differences in patient/graft survival, acute rejection rates, or renal function across studies involving over 2,500 patients.

Advagraf® significantly improves medication adherence compared to Prograf®, which is crucial for long-term transplant success, and it has also been associated with favorable outcomes when combined with mTOR inhibitors, potentially reducing the risk of late-onset cytomegalovirus infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advagraf® with or without an induction therapy for de novo kidney-transplant recipients. Noble, J., Jouve, T., Rostaing, L., et al.[2021]

In a study comparing 26 patients on once-daily Advagraf and 26 on twice-daily Prograf after kidney transplantation, both formulations showed similar short-term efficacy and safety profiles.

However, patients taking Advagraf required significantly higher doses of tacrolimus (up to 50% more) to achieve comparable drug levels in the blood during the first 6 months post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to get therapeutic levels. Crespo, M., Mir, M., Marin, M., et al.[2015]

The Waters MassTrak Immunosuppressants assay for measuring tacrolimus levels in whole blood shows good precision and linearity, but it has an average negative bias of 18.5% compared to the Abbott Architect assay, indicating potential discrepancies in results between the two methods.

Both assays are crucial for therapeutic drug monitoring of tacrolimus, which is essential for maintaining organ transplant health, but caution is needed when interpreting results due to their lack of agreement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the Waters MassTrak LC-MS/MS Assay for Tacrolimus and a Comparison to the Abbott Architect Immunoassay. Saitman, A., Metushi, IG., Mason, DS., et al.[2017]

Tacrolimus effectively suppresses the rejection of transplanted uteri in female rats, as evidenced by normal uterine morphology and low T-lymphocyte counts in the treated group compared to untreated controls.

The treatment with tacrolimus also normalizes the expression of inflammatory markers IL-1α and IP-10, indicating its role in reducing inflammation associated with organ rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Uterine rejection after allogeneic uterus transplantation in the rat is effectively suppressed by tacrolimus. Akhi, SN., Diaz-Garcia, C., El-Akouri, RR., et al.[2015]

Uterine transplantation in sows is a feasible experimental technique, involving careful surgical procedures and minimal doses of cyclosporine for immunosuppression.

Despite initial success in five out of six surgeries with good blood flow, histological analysis revealed that five animals experienced rejection by the seventh postoperative day, highlighting the importance of monitoring immunosuppressant doses to prevent rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Description and evaluation of experimental models for uterine transplantation in pigs. Oliveira, E., Tavares, KADS., Gomes, MTV., et al.[2021]

In a mouse model of uterine transplantation, the immunosuppressant cyclosporine A (CyA) was found to delay the rejection of transplanted uteri, indicating its potential role in improving outcomes for uterine transplants.

While CyA treatment reduced necrosis and inflammation in the transplanted uteri, it did not fully suppress T cell infiltration, and interestingly, it increased the number of CD8+ T cells, suggesting a complex interaction with immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rejection of the transplanted uterus is suppressed by cyclosporine A in a semi-allogeneic mouse model. Wranning, CA., El-Akouri, RR., Groth, K., et al.[2013]

References

1. United States pubmed.ncbi.nlm.nih.gov

Successful pregnancy outcome in a lung transplant recipient with tacrolimus immunosuppression. A case report. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Overview of extended release tacrolimus in solid organ transplantation. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

De novo use of a generic formulation of tacrolimus versus reference tacrolimus in kidney transplantation: evaluation of the clinical results, histology in protocol biopsies, and immunological monitoring. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Effect of FK506 ointment (Protopic) on rat skin allograft model. [2014]

5. England pubmed.ncbi.nlm.nih.gov

Advagraf® with or without an induction therapy for de novo kidney-transplant recipients. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to get therapeutic levels. [2015]

7. United States pubmed.ncbi.nlm.nih.gov

Evaluation of the Waters MassTrak LC-MS/MS Assay for Tacrolimus and a Comparison to the Abbott Architect Immunoassay. [2017]

8. United States pubmed.ncbi.nlm.nih.gov

Uterine rejection after allogeneic uterus transplantation in the rat is effectively suppressed by tacrolimus. [2015]

9. Brazil pubmed.ncbi.nlm.nih.gov

Description and evaluation of experimental models for uterine transplantation in pigs. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Rejection of the transplanted uterus is suppressed by cyclosporine A in a semi-allogeneic mouse model. [2013]