Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000917730
Ethics application status
Approved
Date submitted
28/04/2022
Date registered
27/06/2022
Date last updated
27/03/2023
Date data sharing statement initially provided
27/06/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Live and deceased donor uterus transplantation as a treatment option for women with absolute uterine factor infertility
Scientific title
Uterus transplantation as a treatment option for women with absolute uterine factor infertility
Secondary ID [1] 307023 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Absolute uterine factor infertility
 326152 0
Condition category
Condition code
Reproductive Health and Childbirth 323469 323469 0 0
Fertility including in vitro fertilisation
Reproductive Health and Childbirth 323470 323470 0 0
Other reproductive health and childbirth disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Phase 1: Live donor and recipient transplantation
Study setting
This is a multi-site clinical research study which will be conducted across 5 tertiary hospitals within NSW Australia. The recruitment and pre-clinical screening (including imaging) of patients will be across the Royal Hospital for Women and Prince of Wales Hospital campus. Obstetric care will take place across all 4 participating sites depending on geographic proximity for antenatal and postpartum care. The uterus transplantation surgeries will take place within the theatres at the Westmead Adult Hospital. A total of 12 subjects will receive a uterine transplant as phase 1 of this clinical research study. Six subjects will receive a uterus from a living donor, and six from a deceased donor. Living donors will be screened in relation to the study inclusion criteria.

Intervention's
1. In-Vitro Fertilisation treatment
In-vitro fertilisation will be done 6 to 18 months before uterus transplantation. The patient will not be menstruating due to uterine absence. The recipient and her partner will attend the fertility clinic and undergo an orientation by a fertility nurse, outlining the process of IVF, and teaching the couple how to inject the medications. The IVF protocol will follow a standard antagonist cycle (initially injecting recombinant FSH daily [dose 75-300U] and then the GnRH antagonist [0.25mg] is added as a second daily injection. This will use the standard IVF protocol consent. During the 10-14 days of ovarian stimulation, there will be 4-5 blood tests and ultrasounds to monitor the stimulation of the ovary. Oocyte pick-up will be conducted trans-abdominally by abdominal ultrasound guidance (due to lack of a full vaginal canal in many women with uterine absence) or trans-vaginally if the length of vagina allows access to the ovaries effectively. The eggs will then be fertilised by either invitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI), depending on the semenanalysis (number and motility of sperm). The embryos are then placed through sequential media to mature the embryos to a Day 5 stage (blastocyst) and these blastocysts are subsequently frozen using a vitrification technique.

2. Uterus transplant
Uterus transplantation surgery entails isolation of the uterus with bilateral, long venous, and arterial vascular pedicles. The donor surgery is complex and involves extensive vascular dissection that includes the distal parts of the internal iliac veins and arteries. After surgical isolation, the uterus will be flushed bilaterally through the arterial ends with preservation solution. The vascular ends of the graft will be trimmed and the left-sided vein that will have been divided will be anastomosed end-to-end by a continuous suture (8-0 polypropylene).

One hour before final graft retrieval from the donor, surgery to prepare the recipient for transplantation will be initiated in an operating theatre. Through a midline incision, the external iliac vessels will be dissected and prepared for anastomosis. The vaginal vault will then be separated from the bladder and rectum. Sutures will be used for uterine fixation, and will be placed bilaterally through the round ligaments, uterosacral ligaments, and the paravaginal connective tissues.

The uterus will be brought into the pelvis and end-to-side vascular anastomoses will be conducted to connect the uterine veins to the external iliac veins (with 8-0 polypropylene sutures) and the anterior divisions of the internal iliac arteries to the external iliac arteries (with 7-0 polypropylene sutures) on both sides.

The surgeon will then open the blood flow to the uterus to ascertain that good pulses exist distal to the arterial anastomosis sites and that the uterine tissue will change from pale to reddish, with blanching, evidence of pin prick bleeding and tissue turgor, which is considered a sign of peripheral tissue perfusion. The uterus will then be fixed to the ligaments and sutured the extensive bladder peritoneum on the uterine graft on top of the recipient’s bladder to provide extra structural support. A thin wire cable will be inserted into the uterus and bought out through the midline incision to check the blood flow in the uterus. This probe will be removed after a 3-day observation period. We anticipate that the surgeries of the donor and recipient will proceed uneventfully.

It has been reported by Brännström et al that the ischaemic time of the uterine graft will be under 3 hours. It is anticipated that both the donor and recipient will be discharged from hospital after 6 days of postoperative care.

3. Immunosuppression and follow-up
Immunosuppression will be tailored to each individual circumstance as described by Brännström et al. Induction immunosuppression will start with prednisolone 20mg (2 tablets), starting 3 days before the transplantation, with a slow reduction of 2.5 mg every week until the dose reaches 10mg (1 tablet) per day, which will continue while uterus is insitu. On the day of surgery Intravenous thymoglobulin or Antithymocyte globulin (2.5 mg/kg bodyweight - 5 mg/kg body weight) will be given (received twice on the day of surgery only). The use of induction therapy intravenous drugs will be dependent on the immunological risk of the recipient.

Maintenance immunosuppression: once daily oral tacrolimus (9-15ng/mL for first month) will be started on the day of surgery and continue post transplant, this dose will be reduced to 5–10 ng/mL at 2mths after UTx) aiming at trough levels of 9–10 ng/mL during the first month, and then slow titration down to a level of 6-7 ng/ml, depending on immunological risk as well as the risk of rejection.

Mycophenolate mofetil of 1 mg twice / day to be administered orally during the first 10 months post-surgery. Azathioprine 2 mg/kg per day (will then be used instead of mycophenolate mofetil after 10 months, to avoid the potentially teratogenic effects of mycophenolate mofetil in the run-up to embryo transfer.

The recipient will be followed up by frequent clinical visits and laboratory examinations with the gynaecological surgical and transplant physician teams, initially a 1 hour appointment, twice weekly will be required during the first postoperative month and then every 2 weeks in months 2–6 with length of visit depending on findings. Subsequently, patients will be reviewed monthly. Ultrasound scans with transvaginal and abdominal probes will be conducted with the radiologist and gynaecologist to assess uterine size, and endometrial thickness and echogenicity. Uterine artery flow velocity waveforms on both sides will be assessed by Doppler ultrasound, with an abdominal probe placed just above the inguinal ligament. Biopsies of the uterine cervix will be obtained at predetermined timepoints by the gynaecologist (at 1, 2, and 4 weeks, and monthly thereafter) and in the event of pathological signs (abnormal vaginal discharge, fever, discoloured cervix, or abdominal pain) that could indicate local infection or graft rejection. The team psychologist will also be conducting fortnightly phone calls with the recipients to monitor adherence and psychological aspects. At each visit with any team member, clear documentation of the visit and findings will be kept.

The histological examination of biopsies will use a uterine rejection grading system that was initially developed for the non-human primate uterus. Any presence of cervical intraepithelial neoplasia will be followed-up by tests for human papillomavirus. Clinical follow-up will also include monitoring of blood pressure and bodyweight, and laboratory monitoring.

4. Embryo transfer
A single embryo transfer will be conducted around 6-12 months after uterus transplantation during the natural menstrual cycle in alignment with local protocols for frozen embryo transfer, with a soft embryo transfer catheter under abdominal ultrasound guidance. If the initial embryo transfer is not successful, subsequent transfers will be scheduled at monthly intervals (or when the recipient feels ready psychologically) using the remaining embryos. If all embryos are used without success, a further IVF cycle could be considered.

During pregnancy, the patient will be monitored according to routine programme for pregnant transplant patients, including frequent visits (every 2–3 weeks) to specialists in high-risk obstetrics and transplantation.

5. Uterus/Graft removal
After 2 pregnancies or 5 years of the uterus being insitu in the recipient the uterus is removed to minimise the possible harm of long term immunosuppression. This is a surgery including a big cut on the abdomen, removal of this organ and closure of the skin. The recovery is a 5 day stay in hospital, and up to 6 weeks post operative recovery time at home
Intervention code [1] 323471 0
Treatment: Surgery
Comparator / control treatment
There will be no control group as part of this study. Women who receive a uterus from a deceased donor will not be compared with women who are gifted a uterus from a matched live donor. Women will be given the opportunity to embark on either live or deceased donor pathway
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331210 0
Assess live birth outcomes following uterus transplants. All phases from the IVF, uterus transplant, pregnancy, birth and uterus removal will be conducted by the research team. Clear documentation and medical records will be audited and stored securely for analysis by the research team. Every transplant recipient will be followed closely and all pregnancies (whether it results in live birth or not) will be recorded allowing for the assessment of live birth rates versus transplant numbers.
Timepoint [1] 331210 0
Up to 5 years after transplantation. All medical records will be analysed in full to quantify final outcome once at 5years. Interim intervals and reports will be produced 6mthly.
Secondary outcome [1] 409200 0
The achievement of surviving uterus grafts at 3, 6 12 months, 2 years, and 5 years.

The recipient will be followed up by frequent clinical visits and testing, initially twice weekly during the first month following surgery and then every 2 weeks up until 6 months. Subsequently, patients will be reviewed monthly. A clinical examination will involve a gynaecological examination with visual inspection of the transplanted uterine cervix using a speculum and taking swabs or biopsies to look for infection or rejection. Ultrasound scans with either a transvaginal or abdominal ultrasound will be done to assess the vitality of the uterus. Additionally, if there are concerns which may include: abnormal vaginal discharge, fever, discoloured cervix, or abdominal pain, this could indicate that the uterus has an infection or rejection. Clinical follow-up at each of these time points indicated above will also include monitoring of blood pressure and bodyweight, and blood tests checking the recipient’s general health.

All this data will be added to the recipients medical records for tracking of graft rejection episodes and linked with outcome 1 results ie pregnancy and birth statistics
Timepoint [1] 409200 0
For up to 5 years post transplant (or until uterus is removed)

The recipient will be followed up by frequent clinical visits and testing, initially twice weekly during the first month following surgery and then every 2 weeks up until 6 months. Subsequently, patients will be reviewed monthly for the duration the uterus is in-situ.
Secondary outcome [2] 409201 0
Examination of post-operative donor complications after uterus transplant (UTx).

The donor will undergo follow up at 1-2 wks (still in hospital), 1 month, 6 mths and 12mths with the gynaecological team to assess for any complications. The duration of the living donor surgery is long with published data varying from 5hours to 13hours in length. Along with surgical risks such as infection and bleeding, potential short-term risks specific to uterus transplant for the donor include uretero-vaginal fistulae, ureteric injury, pyelonephritis, acute anaemia, faecal impaction, and vaginal cuff dehiscence. These will be monitored for during the surgery and within the first 2 weeks post-operatively. Other intermediate term risks include shortened vaginal canal, stenosis and vaginal dryness that can impact on sexual functioning. This will be monitored and assessed but the gynaecologist at 6 and 12mths.
There is also a psychological risk to the donors particular if the graft fails in the recipient. Donors will undergo psychological testing prior to inclusion and post the procedure ongoing for 3 years (3-6mthly or more if required). The lead psychologist will be responsible for collecting psychosocial data using questionnaires ( ie SF-36 Short Form Survey Instrument & The Hospital Anxiety and Depression Scale (HADS)), as well as face-to-face interviews with the donor.

Timepoint [2] 409201 0
3 years total post procedure

The donor will undergo follow up at 1-2 wks post procedure while in hospital (average stay is 5 days), 1 month, 6 mths and 12mths with the gynaecological team to assess for any complications. If there is any ongoing need individual appointments will be made with the gynaecologist.

Donors will undergo psychological testing prior to inclusion and post the procedure ongoing for 3 years (3-6mthly or more if required).
Secondary outcome [3] 409202 0
Examination of rate of pregnancy and obstetric complications after uterus transplant (UTx). The recipient will be managed as a high risk pregnancy where she will be followed up by frequent clinical visits and testing. She will see the obstetric team fortnightly (including blood tests and ongoing cervical examination for rejection episodes). throughout trimester 1 and 2 and weekly from 28wks. She will have all routine antenatal care conducted by the research team to ensure the medical records remain complete to assess pregnancy outcomes.

Most appointments will be conducted in person, however results and follow up may be conducted over the phone if appropriate.

The following complications will be monitored:
- Hypertension and pre-eclampsia
- intrauterine growth restriction
- premature rupture of membranes
- preterm delivery
- intrauterine foetal demise
Timepoint [3] 409202 0
Pregnancy and obstetric outcomes will be monitored fortnightly throughout trimester 1 and 2 and weekly from 28wks till birth. Post birth the recipient will see the obstetric team at week 1, 3 and 6 weeks to monitor for any acute rejection episodes resulting from pregnancy or other adverse outcomes. This will be repeated in subsequent pregnancy (maximum of 2 or 5 years).
Secondary outcome [4] 409203 0
Impact of uterus donation and transplant on psychological outcomes and quality of life for recipient (and partner) and donor (and partner)

As per the inclusion criteria it will a necessity for all stakeholders (recipients, recipient partners, donors, donors partners), to undergo psychological testing. The lead psychologist in conjunction with the patient’s gynaecologist and the Research Manger will assess potential uterus transplant (UTx) candidates, and their partners, to determine pre-screening eligibility for the UTx study. The lead psychologist will be responsible for collecting psychosocial data using the questionnaires as well as face-to-face interviews with the recipient and her partner; recipients separately; donor separately; donor and her partner; and all parties together. All outcomes will be assessed as a whole/composite.

Tests that will/may be used:
- SF-36 Short Form Survey Instrument
- Structured Clinical Interview for DSMV – Clinical Trial (SCID-V-CT
- Depression Anxiety Stress Scales (DASS)
- FertiQol (55)
- Paternal Antenatal Attachment Scale

The semi-structured interviews will be conducted 4-6 months pre-transplant and again during the month prior to transplant. Following the transplant in-depth interviews will be conducted with the recipient and the recipient’s partner 6-12mthly and repeated for up to nine years. Donors will undergo psychological testing prior to inclusion and post the procedure ongoing for 3 years (3-6mthly or more if required).

Timepoint [4] 409203 0
For up to 10 years; starting 3-6mths prior to inclusion (for all), recipients and partners for up to 9 years, 6-12montly and donors and partners up to 3 years 6-12mthly. If a psychological issue is identified this may be increased in frequency.
Secondary outcome [5] 409204 0
Availability of deceased donor uteri. In conjunction with the organ tissue donation service (OTDS) registry. 'ALL' registered donors will be compared with those that are 'eligible' as uterine donors' against the inclusion criteria and then compared with how many are used for uterus transplant to ascertain if enough donor uteri would be available for ongoing recipient requirements.
Timepoint [5] 409204 0
A 3 year time frame will be used to follow the OTDS donor registry, it will be assessed annually for comparison.

Eligibility
Key inclusion criteria
For recipient:
1. Diagnosed with AUFI and intact ovaries.
2. Childbearing age 18-42 years (must have embryos cryopreserved at <38 years of age).
3. A vaginal canal, measuring a minimum length of 7 cm, she can have vaginal dilator therapy during screening.
4. Non-smoker or abstinent for 6 months minimum
5. Body mass index less than or equal to 30
6. Willing to undergo in-vitro fertilization and medically cleared for in-vitro fertilization.
7. Women who wish to have a live donor transplant will be required to have a potential live donor.
8. Negative for the following sexually transmissible infections: Gonorrhoea, Chlamydia and Syphilis.
9. No active candida infection of the vagina.
10. History of Herpes (HSV-2) with no current symptoms. Subject may require preventative maintenance per study doctor discretion (anti-viral treatment).
11. Have 2 kidneys and a normal creatinine/eGFR level for their age

For living uterus (womb) donors
1. Blood type matching to the recipient permitting the donation
2. If aged < 55 years (or up to 60 years) the donor must be on hormone replacement therapy since menopause
3. You must not have had any previous cancers/malignancies
4. You must not be in poor health (i.e. you must not have diabetes, autoimmune diseases, cardiovascular disease, etc.)
5. You must have had no disease with an increased risk of thromboembolism (blood clots
6. Psychologically stable and must be prepared to undergo psychological testing
7. If the donor has a partner, he / she must be willing to participate in psychological testing
8. Non-smoker or abstinent for at least 5 years

For deceased uterus (womb) donors
1. Female
2. Aged < 55 years (or up to 60 years if on HRT if known)
3. Suitable as brain-dead multi-organ donor, and registered as multi-organ donor as per NSW Organ and Tissue Donation Service (OTDS)
4. Acceptance for donation of uterus from family or previously by donor
5. At least one normal pregnancy and childbirth
6. No systemic disease
7. No previous major surgery in the abdomen or on uterus
8. No previous hysterectomy
9. Non-smoker if known
10. BMI <35
11. No previous malignancy of the uterus or other organ or tissue
Minimum age
19 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
For recipient:
1. Subject with Diabetes Mellitus Type I and II
2. Subject has known hypersensitivity to drugs including: Tacrolimus, Thymoglobulin or CellCept.
3. Subject with existing hypertension, as per investigator’s discretion.
4. Subject who has a history of a bone marrow transplant.
5. Subject who has history of cancer in last five years.
6. Subject who has alcohol or drug abuse within 12 months of screening.
7. Subject with any pre-existing medical or psychological condition that would pose the subject at an increased risk, as per the investigator’s discretion.
8. Renal failure (abnormal creatinine / GFR)
9. Disease with an increased risk or personal history of thromboembolism

For living uterus (womb) donors
1. History of cancers in the past 5 years
2. Subject who has a history of a bone marrow transplant.
3. Systemic diseases (diabetes, autoimmune diseases, cardiovascular disease, etc.)
4. Disease with an increased risk or personal history of thromboembolism
5. Previous surgery for uterus or cervix cell changes
6. Positive HPV (16 or 18) or any cellular dysplasia of the cervix in the past 2 years
7. No previous major abdominal or uterine surgery
8. BMI >30
9. Cigarette smoker
10. Inability to consent to the risks of major morbidity and mortality

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
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
The aim for total sample size for the project is 12 recipients and their partners and 6 living and 6 deceased donors.. It is difficult to ascertain power calculations as this study is one of the first of its kind and minimal comparative literature exists.

Analysis: Chi-square test, independent t-test and ANOVA test will be used to examine recipient and live donor characteristics (e.g. maternal age, BMI, smoking and socioeconomic status). Maternal morbidities will be explored to examine whether women have higher odds of adverse outcomes using a live donor as compared with a deceased donor and to determine the risk factors associated with adverse outcomes.

A binary logistic generalised estimating equation (GEE) model will be used to estimate the likelihood of dichotomous outcome measurements (e.g. complications during transplant as well as in pregnancy etc.) for UTx recipients. Variables (p<0.20) associated with outcomes on univariate analysis and other factors identified in the literature as predictive of selected outcomes will be entered into multivariate models. Potential confounders include maternal age, BMI, socioeconomic status, area of residence and other factors identified in the literature. Final models will be determined by taking into account the likely causal pathway, collinearity, statistical significance, and goodness of fit.

The Kaplan-Meier method with log-rank test will be used to compare the survival curves (5 year survival) for women with a AUFI who gave birth following a UTx. Cox regression will be used to examine the effects of giving birth following transplantation. Confounders to be considered in the cox regression in the analysis include maternal age at the time of transplant and birth, socioeconomic status, remoteness, and clinical characteristics associated with AUFI. The Statistical Analysis System (SAS) (SAS Institute Inc.) and IBM SPSS Statistics (IBM Corporation) will be used for analyses.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/01/2023
Actual
10/01/2023
Date of last participant enrolment
Anticipated
1/04/2025
Actual
Date of last data collection
Anticipated
1/06/2035
Actual
Sample size
Target
12
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 22289 0
Royal Hospital for Women - Randwick
Recruitment hospital [2] 22290 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 37450 0
2031 - Randwick
Recruitment postcode(s) [2] 37451 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 311597 0
Hospital
Name [1] 311597 0
Royal Hospital for Women
Country [1] 311597 0
Australia
Funding source category [2] 311598 0
Hospital
Name [2] 311598 0
Westmead Hospital
Country [2] 311598 0
Australia
Funding source category [3] 311599 0
Hospital
Name [3] 311599 0
Prince of Wales Hospital
Country [3] 311599 0
Australia
Primary sponsor type
Individual
Name
Dr Rebecca Deans
Address
Royal Hospital for Women
Barker St, Randwick NSW 2031
Country
Australia
Secondary sponsor category [1] 312712 0
Individual
Name [1] 312712 0
Dr Jana Pittman
Address [1] 312712 0
Royal Hospital for Women
Barker St, Randwick NSW 2031
Country [1] 312712 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310832 0
Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 310832 0
Ethics committee country [1] 310832 0
Australia
Date submitted for ethics approval [1] 310832 0
Approval date [1] 310832 0
23/07/2020
Ethics approval number [1] 310832 0
ETH13038

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 119022 0
A/Prof Rebecca Deans
Address 119022 0
The Royal Hospital for Women
Barker Street
Randwick NSW 2031
Country 119022 0
Australia
Phone 119022 0
+61477000005
Fax 119022 0
Email 119022 0
[email protected]
Contact person for public queries
Name 119023 0
Rebecca Deans
Address 119023 0
The Royal Hospital for Women
Barker Street
Randwick NSW 2031
Country 119023 0
Australia
Phone 119023 0
+61477000005
Fax 119023 0
Email 119023 0
[email protected]
Contact person for scientific queries
Name 119024 0
Rebecca Deans
Address 119024 0
The Royal Hospital for Women
Barker Street
Randwick NSW 2031
Country 119024 0
Australia
Phone 119024 0
+61477000005
Fax 119024 0
Email 119024 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Only de-identified individual participant data highlighting published results will be shared
When will data be available (start and end dates)?
The de-identified data will be available in the beginning at 6 months and at 5 years following publication of the main results.
Available to whom?
De-identified data will only be shared with research personnel outside of the UTx study on a case by case situation and this will only be deemed appropriate by the Chief Investigator following consultation and clearance by the Data Safety Monitoring Board.
Available for what types of analyses?
To reflect the aims of the study.
How or where can data be obtained?
Access to data outcomes will only be available with the approval of the Chief Investigator, Dr Rebecca Deans. Applications that have been approved will require a signed agreement to access de-identified data by the Chief Investigator (email: [email protected])


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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