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Trial registered on ANZCTR


Registration number
ACTRN12619000808145p
Ethics application status
Submitted, not yet approved
Date submitted
22/05/2019
Date registered
3/06/2019
Date last updated
3/06/2019
Date data sharing statement initially provided
3/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Is a uterine transplant a safe and effective option for women who do not have a uterus (for various reasons) to achieve pregnancy and gain parenthood.
Scientific title
Uterus Transplantation and Pregnancy Induction in Women affected by Absolute Uterine Factor Infertility
Secondary ID [1] 298261 0
None
Universal Trial Number (UTN)
U1111-1233-6374
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Women with absolute uterine factor infertility (AUFI) 312869 0
Condition category
Condition code
Reproductive Health and Childbirth 311366 311366 0 0
Fertility including in vitro fertilisation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a prospective cohort study whose primary objective is to assess the outcomes of UT as a treatment for AUFI. There are seven distinct clinical stages as detailed below.
1. Screening/pre-transplant assessment - The donor and recipient will undergo a series of assessments/tests to determine suitability into the study. Assessments include: past medical history, CT/MRI scans, appointments with gynaecology/vascular surgery, psychiatry and fertility counsellor, neonatology, and maternal fetal medicine. After the multi disciplinary team decides the donor/recipient are suitable for the study consent is them taken from the patients.
2. Creation of embryos via IVF - The prospective recipient will begin the in vitro fertilisation process. This involves: * superovulation - medications to stimulate the growth of the follicles
* Egg retrieval - One or more eggs to be taken from the ovaries by follicle aspiration under ultrasound guidance
* Fertilisation/Insemination - In the laboratory the eggs that have matured will be fertilised by standard IVF or inserting a single sperm into each egg
* Embryo transfer - After day 5 of developing the embryo will be assessed by the embryologist and suitable embryos are frozen until it is time to transfer into the recipient under ultra sound guidance.
3. Transplant - Donor will undergo an abdominal hysterectomy, the recipient will receive a midline incision between the pubis and umbilicus. The uterus will be placed in its normal position in the pelvis.
4. Recovery with immunosuppression- The recipient will be placed on up to 3 immunosuppressive drugs to avoid graft rejection. Doses and length of therapy vary and the decision will be made by transplant team.
5. Embryo transfer - On the day of transfer the embryo will be thawed and transferred into the uterus by means of a sterile catheter system under ultrasound. 9-12 days later a blood test will be done to detect pregnancy.
6. Pregnancy care and delivery - The recipient will undergo many tests to ensure graft survival including: gynaecological assessments, lab tests (bloods every 2-4 weeks), ultrasounds every 2-4 weeks, biopsy of the cervix at each trimester. High risks obstetrics will be involved with visits every 2-4 weeks or as needed.
7. Post delivery, potential second pregnancy, and explant with follow-up. - The infant will be cared for by neonatal team and visits to the infant will be: 2-5 days, 6 weeks, then monthly. 6 months after the first birth, a second pregnancy can be discussed with the option of on explant if the recipient does not wish to have a second child. Counselling will be provided heavily at this stage.

For the initial study, we intend on recruiting 10 females of reproductive age with AUFI. These patients will have intact ovarian function or are willing to use a donor oocyte(s). They will then go on to receive a UT from a living donor.
A corresponding number of live female donors who are prepared to undergo an abdominal hysterectomy in order to assist women with AUFI achieve a live birth will be recruited.

Donor: total abdominal hysterectomy and upper vaginectomy with preservation of the major feeding arteries and veins to the uterus of the donor. The ovaries are not removed. This surgery will take between 4-6 hours. The donor will then be transferred to recovery then to a standard hospital room.

Recipient: implantation of the donor uterus in the pelvis of the recipient. Vascular anastomosis between the 2 major uterine arteries and uterine veins or ovarian veins is performed to the external iliac vessels using transplant microvascular techniques. Finally, the vaginal rim of the transplanted uterus is anastomosed to the recipient’s vaginal vault. This surgery will take between 4-8 hours. The recipient will be transferred to ICU for 24-48 hours then to a standard room.

To monitor adherence to the intervention we have data collection forms for both the donor and recipient where routine pre op, intra op, and post op observations are recorded as either "between the flags" (within normal parameters) or not "between the flags"(abnormal and documented as an adverse event). This ensures auditing is done on every patient as part of standard of care.


Pre-transplantation, the recipient will require IVF in order to cryostore embryos. Post-transplantation, the recipient will then require immunosuppression, embryo transfer, Caesarean section (for 1-2 pregnancies), and then removal of the donor uterus (explant).
Multi-Disciplinary Team

Transplant Research Nurse Coordinator provides education and support during all phases of the study as described above. They also serve as the primary contact should the donor or recipient have concerns.

Reproductive Endocrinology and Infertility (REI) Specialists will serve as lead clinicians for this study. Prospective recipients and their partners will be thoroughly counselled about all of their options to gain parenthood. The REI specialist will manage the in-vitro fertilization process. Prospective donors and recipients will be counselled about the research nature of the trial.

Transplant Surgeon and Vascular Surgeon will discuss and manage the surgical aspects of UT for the prospective donor and recipients. This will include consenting for the surgical procedures after discussing the risks of surgery and potential complications. The transplant surgeon will act as a donor ‘advocate’. This process has worked well in overseas centres – Gothenburg, Sweden.

Radiologist will be involved in the pre-operative assessment of the potential donor and recipient in order to determine suitability.

Transplant Physician will meet with the prospective recipient to discuss the type of immunosuppression needed after the transplant, the side effects and potential complications. They are also responsible for the administration and monitoring of the immunosuppression.

Psychiatrist and Fertility Counsellor are responsible for the psychosocial assessment and management of the prospective donor and recipient.

Maternal-Fetal Medicine Specialists will be responsible for the pre-transplant obstetric counselling and subsequent management of any ongoing pregnancy. They are also responsible for all sonographic imaging.

Neonatologist will be responsible for the pre-transplant counselling of the prospective recipient (and her partner) regarding potential issues affecting the neonate. They will also be the primary carers of the neonate.

Pathologist will be responsible for the pre- and post-transplant assessment of histopathology. This will include looking for histological features suggestive of allograft rejection. Recruitment

Women will be self-referred or referred by a medical practitioner. The study investigators will be liaising with various support groups e.g. ‘Sisters for Love’ – MRKH support group in Australia. At this stage, we anticipate that all donors will be known to the recipient.
Donation must be altruistic in nature.


Intervention code [1] 314506 0
Treatment: Surgery
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 320095 0
Primary outcomes:
- Successful transplantation of a human uterus with achievement of menstrual cycles
International standards suggest menstrual cycles normally return between 6-12 weeks post transplant. We will be constantly reviewing our patients (post-transplant) every 2 weeks for the first month, than every 4 weeks until pregnancy. Each review will include a physical and gynaecological exam and will be recorded in the patients medical record.
Timepoint [1] 320095 0
After transplant is successfully performed the recipient will go on immunosuppressive agents to prevent graft rejection. Primary outcome time point will be up to 12 weeks post surgery.
Secondary outcome [1] 370527 0
Secondary outcomes:
- Successful establishment of pregnancy (up to 2) via in vitro fertilization;
This outcome will be assessed by medical records and the patient having a blood test to detect the pregnancy hormone (HCG) after embryo transfer.


Timepoint [1] 370527 0
The time point which this outcome will be assessed is 12 days after the embryo transfer.
Secondary outcome [2] 370796 0
Successful live birth
This outcome will be assessed by medical records.
Timepoint [2] 370796 0
Delivery will be by caesarean at 37 weeks.
Secondary outcome [3] 370797 0
Documentation of adverse events including IVF, donor/recipient surgery, recipient immunosuppression, and pregnancy. This will be assessed through medical records.
Timepoint [3] 370797 0
Patients are assessed constantly every 2-4 weeks until delivery of baby, then the infant is reviewed at birth, 2-5days post, weekly while in hospital, then monthly. At each review any adverse events are documented in medical records.
Secondary outcome [4] 370798 0
Documentation of psychosocial impact on donor/recipient
This outcome is assessed by validated questionaries (Stanford Integrated Psychosocial Assessment for Transplant (SIPAT)).
Timepoint [4] 370798 0
Donor and recipient will complete the questionnaire pre-operatively, and post explant (removal of uterus after 1 or 2 births) at 6 and 12 months post operatively.
Secondary outcome [5] 370972 0
Quality of life (SF-36)
This is assessed through a validated questionnaire.
Timepoint [5] 370972 0
This will be assessed pre-operatively, 3 months post operatively (uterus transplant for both donor and recipient), then 3 months post explant (removal of the transplanted uterus in both donor and recipient).

Eligibility
Key inclusion criteria
Donor inclusion / exclusion criteria

1. Inclusion criteria
a. The prospective donor must be between 25 – 65 years of age. If the prospective donor is less than 40 years old she must be certain that she does not wish to carry more children;
b. The prospective donor must have a normal uterus on ultrasound and CT;
c. The prospective donor must meet psychosocial criteria;
d. The prospective donor must have had at least one prior live birth (gestation > 34-weeks).

1. Inclusion Criteria Recipient
a. Prospective recipient must be diagnosed with AUFI and have at least one functioning ovary;
b. Prospective recipient must be of childbearing age 18 – 45;
c. Prospective recipient must have received counselling regarding alternatives to UT such as adoption or surrogate pregnancy;
d. Prospective recipient must be willing to undergo in-vitro fertilization;
e. Prospective recipient must have been evaluated by a fertility specialist and determined to have good ovarian reproductive potential or are prepared to use donor oocytes;
f. Prospective recipient must meet psychosocial criteria;
g. Prospective recipient must be willing to complete questionnaires about their infant’s growth and development and return them to the study team.

Minimum age
25 Years
Maximum age
45 Years
Gender
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
2. Exclusion Criteria for donors
a. Prospective donor over the age of 65;
b. Body mass index >35;
c. There should be no history of significant uterine or cervical surgery;
d. History of cigarette smoking in the past 3-months;
e. Prospective donor with active human 142 papillomavirus (HPV) or active cervical dysplasia;
f. Prospective Donor with untreated Gonorrhoea, Chlamydia or Syphilis;
g. In prospective donors who are positive for HSV-2 the prospective recipient will require additional counselling; the prospective donor should receive preventative therapy in order to prevent a flare in the peri-operative phase; the prospective recipient may also require preventative therapy;
h. Prospective donor with an active infection;
i. Prospective donor who is seropositive for HIV;
j. In prospective donors who are seropositive for HBV or HCV the prospective recipient will require additional counselling;
k. Prospective donor who has had cancer in last five years;
l. Prospective donor with any pre-existing clinical or medical conditions that would pose the donor at an increased risk, as per the investigator’s discretion;
m. Prospective donor unwilling or unable to comply with study requirements.

2. Exclusion Criteria for recipients
a. Prospective recipient who has active human 142 papillomavirus (HPV);
b. Prospective recipient with untreated Gonorrhoea, Chlamydia or Syphilis;
c. In prospective recipients who are positive for HSV-2 the prospective recipient will require additional counselling; the prospective recipient may also require preventative therapy;
d. Prospective recipient with Diabetes Mellitus Type I or II;
e. Prospective recipient with a known hypersensitivity to immunosuppressive medications;
f. Prospective recipient with existing hypertension, per investigator’s discretion;
g. Prospective recipient who has a history of solid organ or bone marrow transplant, per investigator’s discretion;
h. Prospective recipient who has a history of cancer in last five years, per investigator’s discretion;
i. Prospective recipient with a body mass index >35;
j. Prospective recipient with an active infection;
k. Prospective recipient who is seropositive for HIV;
l. In a prospective recipient who is seropositive for HBV or HCV the prospective recipient will require additional counselling and possible treatment;
m. Prospective recipient with technical obstacles as per anatomical malformations, which pose a high surgical risk in the judgment of the investigator;
n. Prospective recipient unwilling or unable to comply with study requirements;
o. Prospective recipient unable to undergo in-vitro fertilization;
p. Prospective recipient who has smoked within the last 3 months, per investigator’s discretion;
q. Prospective recipient who has alcohol or drug abuse within 12 months of screening;
r. Prospective recipient with any pre-existing clinical or medical conditions that would pose the subject at an increased risk, as per the investigator’s discretion.


Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
This is a new procedure in Australia, however Recently Uterus Transplantation (UT) has become an alternative option for women of reproductive age with AUFI to bear children. As of January 2019, UT has been successfully performed, with 13 reported live births worldwide – 8 in Sweden, 2 in the United States, and 1 in Brazil, China, and India . Of the 13 live births, all have been from a living donor UT, except the 1 in Brazil which used the uterus from a deceased donor.
Phase
Phase 0
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Power calculations are not relevant for this type of study. We aim to recruit 4-6 cases per year and results/statistics with be based on each individual case.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 13767 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 26517 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 302805 0
Hospital
Name [1] 302805 0
Royal Prince Alfred Hospital
Address [1] 302805 0
Building 89, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050
Country [1] 302805 0
Australia
Primary sponsor type
Government body
Name
Sydney Local Health district
Address
Building 89, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050
Country
Australia
Secondary sponsor category [1] 302752 0
None
Name [1] 302752 0
none
Address [1] 302752 0
n/a
Country [1] 302752 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 303390 0
Sydney Local health distrcit
Ethics committee address [1] 303390 0
Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 303390 0
Australia
Date submitted for ethics approval [1] 303390 0
22/05/2019
Approval date [1] 303390 0
Ethics approval number [1] 303390 0

Summary
Brief summary
Absolute uterus factor infertility (AUFI) affects 1-5% of reproductive-aged infertile women AUFI may result from:
- Major congenital anomaly e.g. MRKH syndrome where the woman is born without a uterus;
- Hysterectomy for benign or malignant reasons;
- Acquired condition rendering the uterus non-functional e.g. Asherman syndrome (intra-uterine adhesions).

Traditionally, women with AUFI could only obtain parenthood through gestational surrogacy or adoption. However, these options may not be acceptable for some women and their partners due to legal, religious, financial or ethical concerns. Furthermore, achieving a pregnancy and delivering a baby is a basic human right.

Recently, Uterus Transplantation (UT) has become an alternative option for women of reproductive age with AUFI to bear children. As of January 2019, UT has been successfully performed, with 13 reported live births worldwide – 8 in Sweden, 2 in the United States, and 1 in Brazil, China, and India . Of the 13 live births, all have been from a living donor UT, except the 1 in Brazil which used the uterus from a deceased donor
Once the results of the initial trial demonstrate efficacy, safety and operational viability, we intend on providing a nation-wide tertiary referral service offering UT as a viable option for women with AUFI through RPAH. In order to achieve this, we need to create a multi-disciplinary team with adequate infrastructure for the selection, assessment, and management of appropriate patients as donors and recipients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 93510 0
Dr Anthony Marren
Address 93510 0
Building 89, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050
Country 93510 0
Australia
Phone 93510 0
+61 2 1300 330 990
Fax 93510 0
Email 93510 0
anthony@marrencampbellmackie.com.au
Contact person for public queries
Name 93511 0
Miss Dana Georgevsky
Address 93511 0
Level 9, Building 89, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050
Country 93511 0
Australia
Phone 93511 0
+61 2 9515 3193
Fax 93511 0
Email 93511 0
dana.georgevsky@health.nsw.gov.au
Contact person for scientific queries
Name 93512 0
Miss Dana Georgevsky
Address 93512 0
Level 9, Building 89, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050
Country 93512 0
Australia
Phone 93512 0
+61 2 9515 3193
Fax 93512 0
Email 93512 0
dana.georgevsky@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified individual participant data underlying published results only
When will data be available (start and end dates)?
Beginning 3 months and ending 5 years following main results publication.
Available to whom?
Only researchers who provide a methodologically sound proposal on a case-by-case basis at the discretion of Primary Sponsor and Chief investigators
Available for what types of analyses?
Only to achieve the aims in the approved proposal.
How or where can data be obtained?
Access will be subject to approvals by Principal Investigator and approved proposals will require a signed data access agreement.
What supporting documents are/will be available?
No other documents available
Summary results
No Results