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Uterine Transplantation for the Treatment of Uterine Factor Infertility

This study is currently recruiting participants. (see Contacts and Locations) ClinicalTrials.gov Identifier:

Verified October 2015 by The Cleveland Clinic NCT02573415 First received: October 8, 2015 Sponsor: Last updated: October 28, 2015 The Cleveland Clinic Last verified: October 2015 Information provided by (Responsible Party): History of Changes The Cleveland Clinic

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Purpose

This feasibility study aims to enroll ten subjects who will undergo deceased donor uterine transplantation at Cleveland Clinic. We estimate that fifty to one hundred patients with uterine factor infertility will need to be screened to identify 10 appropriate subjects. There are seven phases involved in this study: Primary and Secondary Screening, Medical Evaluation, IVF, Transplantation, Embryo Transfer, Pregnancy/Delivery and Follow up

Condition Intervention Phase

Primary Uterine Infertility Procedure: Uterus Transplant Phase 1

Study Type: Interventional Study Design: Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment

Official Title: Uterine Transplantation for the Treatment of Uterine Factor Infertility

Resource links provided by NLM:

MedlinePlus related topics: Infertility

U.S. FDA Resources

Further study details as provided by The Cleveland Clinic:

Primary Outcome Measures: Number of successful live births after uterus transplant and IVF [ Time Frame: 2 years after transplantation ] [ Designated as safety issue: Yes ] Full term birth by cesarian section after IVF followed by uterus transplant

Secondary Outcome Measures: rate of pregnancy complications after IVF and uterus transplant [ Time Frame: 9 months after successful implantation of embryo ] [ Designated as safety issue: Yes ] The following complications will be monitored: a. Hypertension b. pre­eclampsia c. intrauterine growth restriction d. premature rupture of membranes e. preterm delivery f. intrauterine fetal demise

rate of neonatal complications [ Time Frame: birth by cesarian section to discharge from hospital ] [ Designated as safety issue: Yes ] The following neonatal complications will be monitored: a. birth defects b. perinatal infections c. low birth weight d. neonatal death e. neonatal intensive care unit admissions

Estimated Enrollment: 10 Study Start Date: October 2015 Estimated Study Completion Date: October 2021 Estimated Primary Completion Date: October 2020 (Final data collection date for primary outcome measure)

Arms Assigned Interventions

Experimental: Uterus Transplantation Procedure: Uterus Transplant Women will undergo deceased donor uterine transplantation after IVF. transplant of a deceased donor uterus.

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Eligibility

Ages Eligible for Study: 18 Years to 45 Years Genders Eligible for Study: Female Accepts Healthy Volunteers: No

Criteria Inclusion Criteria: 1. Must meet criteria for uterine factor infertility a. Prior hysterectomy b. Congenital absence or malformation of the uterus preventing pregnancy c, Infertility due to uterine damage from prior injury or infection 2. Must be between the ages of 21­45 and the embryos must have been produced between the age of 21­39. (age at the time the embryos are produced, not current age) 3. Must be willing to undergo a psychiatric and social work pre­transplant evaluation 4. Must be willing to undergo general anesthesia, in vitro fertilization, major gynecologic surgery, pregnancy with potential high risk complications, cesarean delivery and eventual hysterectomy to remove the graft 5. Must be willing and able to receive potent immunosuppressive medications and must be able to follow standard infection prophylaxis protocols 6. Must be willing to receive standard vaccinations such as influenza, pneumococcus, human papillomavirus (HPV) and hepatitis B 7. Must be willing and able to sign informed consent and follow all outlined procedures and recommendations in the protocol Exclusion Criteria: 1. History of hypertension, diabetes, or significant heart, liver, kidney or central nervous system disease 2. Any medical diagnosis placing the subject at high risk of surgical complications based on the transplant team's review of medical history. 3. Current smoker (smoking cessation must have occurred 3 months prior to enrollment) 4. History of prior malignancy except for cervical cancer in stage 1a or 1b after 3 years. 5. Human immunodeficiency virus, mycobacteria, hepatitis B (Hepatitis risk is for those with hepatitis B (HB) surface and/or core antigen and/or hepatitis B virus (HBV) DNA positive. Thos that are HB core antibody positive are at minimal risk and everyone else is not at risk), or hepatitis C. 6. Presence of active documented systemic infection or recent systemic infection within the past three months 7. Chemical and/or alcohol dependency or abuse 8. Presence of low lying pelvic kidney(s). Pelvic and horse shoe kidneys are common in the Rokitansky syndrome, and occur with a frequency as high as 30­40%. These abnormalities are usually known to subjects as part of their Mullerian agenesis diagnosis. If the patient is unsure about the status of their kidneys, the performance of a renal ultrasound is considered standard of care. These patients need to be informed of any kidney abnormalities, as they are frequently associated with kidney stones or obstructive kidney disease. 9. BMI greater than 30 kg/m2

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02573415

Contacts Contact: Chris Roddy 954­659­5770 [email protected] Contact: Deborah Sears 954­659­5133 [email protected]

Locations

United States, Florida Cleveland Clinic Florida Recruiting Weston, Florida, United States, 33331 Contact: Andreas Tzakis, MD 954­659­5133 [email protected] Contact: Sears, Deborah Sears, RN 954­659­5133 [email protected]

Sponsors and Collaborators The Cleveland Clinic

Investigators Principal Investigator: Andreas Tzakis, MD Cleveland Clinic Florida

More Information

Publications:

Brännström M, Wranning CA, Altchek A. Experimental uterus transplantation. Hum Reprod Update. 2010 May­Jun;16(3):329­45. doi: 10.1093/humupd/dmp049. Epub 2009 Nov 7. Review.

Brännström M, Diaz­Garcia C, Hanafy A, Olausson M, Tzakis A. Uterus transplantation: animal research and human possibilities. Fertil Steril. 2012 Jun;97(6):1269­76. doi: 10.1016/j.fertnstert.2012.04.001. Epub 2012 Apr 28. Review.

Brännström M, Johannesson L, Dahm­Kähler P, Enskog A, Mölne J, Kvarnström N, Diaz­Garcia C, Hanafy A, Lundmark C, Marcickiewicz J, Gäbel M, Groth K, Akouri R, Eklind S, Holgersson J, Tzakis A, Olausson M. First clinical uterus transplantation trial: a six­month report. Fertil Steril. 2014 May;101(5):1228­36. doi: 10.1016/j.fertnstert.2014.02.024. Epub 2014 Feb 27.

Fageeh W, Raffa H, Jabbad H, Marzouki A. Transplantation of the human uterus. Int J Gynaecol Obstet. 2002 Mar;76(3):245­51.

Ozkan O, Akar ME, Ozkan O, Erdogan O, Hadimioglu N, Yilmaz M, Gunseren F, Cincik M, Pestereli E, Kocak H, Mutlu D, Dinckan A, Gecici O, Bektas G, Suleymanlar G. Preliminary results of the first human uterus transplantation from a multiorgan donor. Fertil Steril. 2013 Feb;99(2):470­6. doi: 10.1016/j.fertnstert.2012.09.035. Epub 2012 Oct 18.

Erman Akar M, Ozkan O, Aydinuraz B, Dirican K, Cincik M, Mendilcioglu I, Simsek M, Gunseren F, Kocak H, Ciftcioglu A, Gecici O, Ozkan O. Clinical pregnancy after uterus transplantation. Fertil Steril. 2013 Nov;100(5):1358­63. doi: 10.1016/j.fertnstert.2013.06.027. Epub 2013 Jul 3.

Johannesson L, Enskog A, Mölne J, Diaz­Garcia C, Hanafy A, Dahm­Kähler P, Tekin A, Tryphonopoulos P, Morales P, Rivas K, Ruiz P, Tzakis A, Olausson M, Brännström M. Preclinical report on allogeneic uterus transplantation in non­human primates. Hum Reprod. 2013 Jan;28(1):189­ 98. doi: 10.1093/humrep/des381. Epub 2012 Oct 28.

El­Akouri RR, Mölne J, Groth K, Kurlberg G, Brännström M. Rejection patterns in allogeneic uterus transplantation in the mouse. Hum Reprod. 2006 Feb;21(2):436­42. Epub 2005 Oct 27.

Groth K, Akouri R, Wranning CA, Mölne J, Brännström M. Rejection of allogenic uterus transplant in the mouse: time­dependent and site­specific infiltration of leukocyte subtypes. Hum Reprod. 2009 Nov;24(11):2746­54. doi: 10.1093/humrep/dep248. Epub 2009 Jul 17.

Wranning CA, Akhi SN, Diaz­Garcia C, Brännström M. Pregnancy after syngeneic uterus transplantation and spontaneous mating in the rat. Hum Reprod. 2011 Mar;26(3):553­8. doi: 10.1093/humrep/deq358. Epub 2010 Dec 15. Racho El­Akouri R, Kurlberg G, Brännström M. Successful uterine transplantation in the mouse: pregnancy and post­natal development of offspring. Hum Reprod. 2003 Oct;18(10):2018­23.

Díaz­García C, Akhi SN, Wallin A, Pellicer A, Brännström M. First report on fertility after allogeneic uterus transplantation. Acta Obstet Gynecol Scand. 2010 Nov;89(11):1491­4. doi: 10.3109/00016349.2010.520688. Epub 2010 Sep 30.

Avison DL, DeFaria W, Tryphonopoulos P, Tekin A, Attia GR, Takahashi H, Jin Y, Palaios E, Pararas N, Carreno MR, Santiago S, Bazer F, Ruiz P, Tzakis A. Heterotopic uterus transplantation in a swine model. Transplantation. 2009 Aug 27;88(4):465­9. doi: 10.1097/TP.0b013e3181b07666.

Wranning CA, Marcickiewicz J, Enskog A, Dahm­Kähler P, Hanafy A, Brännström M. Fertility after autologous ovine uterine­tubal­ovarian transplantation by vascular anastomosis to the external iliac vessels. Hum Reprod. 2010 Aug;25(8):1973­9. doi: 10.1093/humrep/deq130. Epub 2010 Jun 2.

Ramirez ER, Ramirez Nessetti DK, Nessetti MB, Khatamee M, Wolfson MR, Shaffer TH, Ramirez VZ, Ramirez HA. Pregnancy and outcome of uterine allotransplantation and assisted reproduction in sheep. J Minim Invasive Gynecol. 2011 Mar­Apr;18(2):238­45. doi: 10.1016/j.jmig.2010.11.006.

Enskog A, Johannesson L, Chai DC, Dahm­Kähler P, Marcickiewicz J, Nyachieo A, Mwenda JM, Brännström M. Uterus transplantation in the baboon: methodology and long­term function after auto­transplantation. Hum Reprod. 2010 Aug;25(8):1980­7. doi: 10.1093/humrep/deq109. Epub 2010 Jun 2.

Del Priore G, Schlatt S, Malanowska­Stega J. Uterus transplant techniques in primates: 10 years' experience. Exp Clin Transplant. 2008 Mar;6(1):87­94.

Kisu I, Mihara M, Banno K, Hara H, Yamamoto T, Araki J, Iida T, Hayashi Y, Moriguchi H, Aoki D. A new surgical technique of uterine auto­ transplantation in cynomolgus monkey: preliminary report about two cases. Arch Gynecol Obstet. 2012 Jan;285(1):129­37. doi: 10.1007/s00404­011­1901­2. Epub 2011 Apr 8.

Mihara M, Kisu I, Hara H, Iida T, Araki J, Shim T, Narushima M, Yamamoto T, Moriguchi H, Kato Y, Tonsho M, Banno K, Aoki D, Suganuma N, Kagawa N, Takehara Y, Kato O, Koshima I. Uterine autotransplantation in cynomolgus macaques: the first case of pregnancy and delivery. Hum Reprod. 2012 Aug;27(8):2332­40. doi: 10.1093/humrep/des169. Epub 2012 May 30.

Johannesson L, Enskog A, Dahm­Kähler P, Hanafy A, Chai DC, Mwenda JM, Díaz­García C, Olausson M, Brännström M. Uterus transplantation in a non­human primate: long­term follow­up after autologous transplantation. Hum Reprod. 2012 Jun;27(6):1640­8. doi: 10.1093/humrep/des093. Epub 2012 Mar 27.

Gauthier T, Bertin F, Fourcade L, Maubon A, Saint Marcoux F, Piver P, Marquet P, Pommepuy I, Plainard X, Couquet C, Cornuejols MJ, Essig M, Aubard Y. Uterine allotransplantation in ewes using an aortocava patch. Hum Reprod. 2011 Nov;26(11):3028­36. doi: 10.1093/humrep/der288. Epub 2011 Sep 6.

Wranning CA, El­Akouri RR, Groth K, Mölne J, Parra AK, Brännström M. Rejection of the transplanted uterus is suppressed by cyclosporine A in a semi­allogeneic mouse model. Hum Reprod. 2007 Feb;22(2):372­9. Epub 2006 Oct 24.

Todo S, Demetris A, Ueda Y, Imventarza O, Cadoff E, Zeevi A, Starzl TE. Renal transplantation in baboons under FK 506. Surgery. 1989 Aug;106(2):444­50; discussion 450­1.

Han D, Berman DM, Willman M, Buchwald P, Rothen D, Kenyon NM, Kenyon NS. Choice of immunosuppression influences cytomegalovirus DNAemia in cynomolgus monkey (Macaca fascicularis) islet allograft recipients. Cell Transplant. 2010;19(12):1547­61. doi: 10.3727/096368910X513973. Epub 2010 Jun 29.

Tryphonopoulos P, Tzakis AG, Tekin A, Johannesson L, Rivas K, Morales PR, Wagner J, Mölne J, Enskog A, Diaz­Garcia C, Dahm­Kähler P, Berho M, Zimberg S, Falcone T, Ruiz P, Olausson M, Brännström M. Allogeneic uterus transplantation in baboons: surgical technique and challenges to long­term graft survival. Transplantation. 2014 Sep 15;98(5):e51­6. doi: 10.1097/TP.0000000000000322.

McKay DB, Josephson MA. Pregnancy in recipients of solid organs­­effects on mother and child. N Engl J Med. 2006 Mar 23;354(12):1281­93. Review.

Responsible Party: The Cleveland Clinic ClinicalTrials.gov Identifier: NCT02573415 History of Changes Other Study ID Numbers: FLA 14­085 Study First Received: October 8, 2015 Last Updated: October 28, 2015 Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms: Infertility Genital Diseases, Female Genital Diseases, Male