Uterus Transplant for Infertility

(OPRTUNTI Trial)

Overseen By Richard Redett, MD

Age: 18 - 65

Sex: Female

Trial Phase: Phase 2 & 3

Sponsor: Johns Hopkins University

Must be taking: Immunosuppressants

Disqualifiers: Diabetes, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores uterus transplants to assist women unable to have children due to the absence of a uterus. The goal is for participants to experience pregnancy and give birth to one or two healthy babies. Women with fertilized, frozen embryos stored at Johns Hopkins who are willing to find a uterus donor may be suitable candidates. The transplant is temporary, lasting about five years, and requires medication to prevent organ rejection. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in reproductive medicine.

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 prior data suggests that uterus transplantation is safe for treating uterine factor infertility?

Research has shown that uterus transplantation is generally safe, though it remains a new procedure. In one study, 70% of the 20 participants had a successful transplant and at least one live birth. However, taking drugs to prevent transplant rejection carries some risks.

Tacrolimus, one of these drugs, is considered safe during pregnancy and does not increase the risk of birth defects. Azathioprine, another drug, is also regarded as safe during pregnancy, with no reported negative effects on fertility in the available data.

While these results are encouraging, remember that uterus transplantation is still evolving, and potential risks exist. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for uterine factor infertility focus on assisted reproductive technologies, like IVF, which do not address the absence or dysfunction of a uterus. Unlike these standard options, the uterus transplant procedure offers a groundbreaking solution by providing a functional uterus to women who lack one, enabling them to carry a pregnancy to term. This treatment is unique because it involves surgically transplanting a healthy uterus into the recipient, combined with the short-term use of immunosuppressive drugs like Azathioprine and Tacrolimus to prevent organ rejection. Researchers are excited about this approach because it offers the potential for women with uterine factor infertility to experience pregnancy and childbirth themselves, opening up possibilities that were previously unavailable.

What evidence suggests that uterine allotransplantation is effective for treating uterine factor infertility?

Research shows that uterus transplantation can help women who cannot have children due to the absence of a uterus. In studies, about 70% to 74% of women who received a uterus transplant experienced a successful transplant, meaning the new uterus functioned properly. Among these women, up to 83% had a live birth. The chance of becoming pregnant with each embryo transfer was about 36.3%, and the chance of having a live birth with each embryo transfer was 22%. Although this procedure remains new, these results offer promise for women unable to carry a child because they lack a uterus. ^{4 6 7 8 9}

Who Is on the Research Team?

Richard J Redett, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Azathioprine
• Tacrolimus
• Uterine Allotransplantation

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.

How Is the Trial Designed?

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 European Union, United States, Canada for the following indications:

Approved in European Union as Imuran for:

• Prevention of rejection in organ transplantation
• Treatment of autoimmune diseases such as rheumatoid arthritis

Approved in United States as Imuran for:

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

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/2822479

Uterus Transplant in Women With Absolute Uterine-Factor ... Findings In this series of 20 participants, uterus allograft was successful in 70% of recipients and was associated with at least 1 live birth ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12109914/

Uterine Transplantation: Advances, Challenges, and ... The UTx success rate was 74.0%; clinical pregnancy rate (CPR) and live birth rates (LBR) per embryo transfer (ET) were 36.3% and 22.0%, ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02573415

Study Details | NCT02573415 | Uterine Transplantation for ... Framing the diagnosis and treatment of absolute uterine factor infertility: Insights from in-depth interviews with uterus transplant trial participants.

4. mdpi.com mdpi.com/2813-4966/2/1/7

Uterine Transplantation for Absolute Uterine Factor Infertility Conclusions: Although uterine transplantation remains an emerging treatment, its development suggests that the benefits may outweigh the risks, offering new ...

5. consultqd.clevelandclinic.org consultqd.clevelandclinic.org/the-first-five-years-of-uterus-transplantation-in-the-united-states

The First Five Years of Uterus Transplantation in the United ... Study results and the impact of collaboration · A one-year graft survival of 74% · A live-birth rate of 83% among recipients with a viable graft ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S156899722030080X#!

In utero exposure to Azathioprine in autoimmune disease. ... Azathioprine (AZA), an oral immunosuppressant, is safe during pregnancy. Some reports suggested different impairments in the offspring of mothers with ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4618138/

Immunosuppressive drugs and fertility - PMC - PubMed Central There is little published data in women, but azathioprine does not seem to have detrimental effects on fertility. The AMH concentrations of ...

8. ojrd.biomedcentral.com ojrd.biomedcentral.com/articles/10.1186/s13023-015-0332-8

Immunosuppressive drugs and fertility There is little published data in women, but azathioprine does not seem to have detrimental effects on fertility. The AMH concentrations of ...

9. jamanetwork.com jamanetwork.com/journals/jamasurgery/fullarticle/2793976

The First 5 Years of Uterus Transplant in the US This cohort study reviews transplant and birth outcomes of uterus transplant recipients in the US since the first case in 2016.