Intravenous Estrogen in Kidney Transplant Study

NCT03663543

Last updated date
Study Location
University of Pennsylvania
Philadelphia, Pennsylvania, 19104, United States
Contact
215-614-0528

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Ischemia Reperfusion Injury
Sex
Female
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
21 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

1. Female gender

2. Age > 21 years at time of transplant

3. Pre-existing dialysis dependence of at least 1-months duration at the time of transplant

4. Receiving a deceased donor renal transplant

5. Receiving their first (primary) kidney transplant

6. Subjects must receive between 500-5000U intravenous systemic heparin during their kidney transplant

7. Subjects must receive between 2500-7500U subcutaneous heparin prophylaxis three times daily during hospital stay

8. Written informed consent obtained from subject and ability for subject to comply with the requirements of the study

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


1. Receiving a non-primary (second, third, fourth, etc.) kidney transplant


2. Receiving a combined heart-kidney transplant, liver-kidney transplant, or other
multi-visceral organ transplant


3. Receiving a live donor kidney transplant


4. Personal history of deep vein thrombosis (DVT) or pulmonary embolism (PE)


5. Personal history of hypercoagulable condition including but not limited to Lupus
Anticoagulant, Leiden Factor V Mutation, Prothrombin Gene Mutation, Protein C or S
deficiency, or any other hypercoagulable condition considered by the attending
transplant surgeon on clinical service or Data and Safety Monitoring Board (DSMB) to
warrant exclusion from the study


6. Personal history of an estrogen sensitive cancer (breast, endometrial, ovarian)


7. Personal history of arterial thromboembolic disease such as stroke or myocardial
infarction in the 6 months prior to transplantation


8. Patient already on estrogen (including oral contraceptive pills) or anti-estrogen
therapy for other indications


9. Patient who is expected to not tolerate a dose of 500-5000U intravenous heparin at the
time of transplant as determined by the transplant surgeon


10. Patient who has a contraindication or allergy to or is expected to not tolerate a dose
of 2500-7500U subcutaneous heparin prophylaxis three times daily during hospital stay
as determined by the transplant surgeon


11. Pregnant and breast feeding patients will be excluded from the study due to the small
risk of radiation associated with the DTPA renal scan


12. Patient body mass index (BMI) > 40Kidney donor profile index (KDPI) < 40


13. Known anaphylactic reaction and angioedema to Premarin Intravenous therapy


14. Presence of a condition or abnormality that in the opinion of the investigator or
attending transplant surgeon primarily responsible for the patient's care would
compromise the safety of the patient or the quality of the data

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Ischemia Reperfusion InjuryIntravenous Estrogen in Kidney Transplant Study
NCT03663543
  1. Philadelphia, Pennsylvania
Female
21 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE Intravenous Estrogen in Kidney Transplant Study
Official Title  ICMJE The Use of Peri-Operative Intravenous Estrogen for the Mitigation of Ischemia Reperfusion Injury in the Setting of Renal Transplantation
Brief Summary Ischemia perfusion injury (IRI) is a major cause of organ injury during kidney transplantation. Currently there are no treatments for IRI other than dialysis. Preliminary studies in female mice have found protection from IRI when given short term estrogen supplements. This study will look at the effect of intravenous estrogen given peri-operatively to reduce the effect of IRI in female kidney transplant recipients.
Detailed Description

Ischemia-reperfusion injury (IRI) is a major etiology of organ injury and dysfunction that occurs during transplantation. In renal transplantation, the clinical manifestation of IRI is delayed graft function (DGF), typically defined as a recipient requiring dialysis within the first week after transplant. At present, there are no directed treatments for IRI associated with kidney transplantation and resultant DGF, other than supportive care with dialysis. This represents an unmet clinical need. While dialysis enables the support of patients until DGF resolves, DGF is associated with increased medical costs, increased length of hospital stay, increased rates of readmission to the hospital after transplantation, increased rates of rejection, and decreased graft survival. Therapies to reduce IRI might alleviate clinical complications associated with DGF, reduce costs associated with transplantation, and ease organ shortages by facilitating use of more marginal organs.

Despite acceptance of gender disparities in IRI tolerance in animal systems, attempts to utilize hormonal manipulation in humans to achieve improved IRI tolerance have not been undertaken. In an effort to design such a translation, the investigators investigated if similar gender disparities exist in humans who have undergone kidney transplantation. After review of the United Network for Organ Sharing database, the investigators established that male recipient gender was highly associated with DGF. Then, the investigators demonstrated that manipulation of the pre-ischemic environment with short-term estrogen supplementation in female mice provides protection from renal IRI. As a logical next stop, the investigators propose hormonal manipulation with perioperative administration of intravenous conjugated estrogens as a novel therapeutic strategy to reduce the effect of IRI in female humans undergoing kidney transplantation. The investigators have designed an investigational new drug (IND) late phase I/early phase II prospective, single center, double blind, randomized, placebo-controlled trial to test the safety, feasibility, and efficacy of this therapy. If the administration of peri-operative intravenous administration has a positive impact on the rate of recovery of GFR after renal transplant and the inherent IRI, then this therapy would represent the first treatment for IRI and ultimately might reduce the incidence of DGF. Because DGF after kidney transplantation is associated with inferior transplant outcomes and increased costs,2 a therapy that mitigates the effect of IRI and consequently reduces the incidence of DGF not only might alleviate these complications but could also ease organ shortages by facilitating the use of more marginal organs. Moreover, if estrogen therapy does mitigate IRI in the setting of renal transplantation, it could be applied to other causes of renal IRI including supra-celiac clamping in trauma or vascular surgery or the use of cardiopulmonary bypass in cardiac surgery. Female adult subjects with a diagnosis of end stage renal disease who are dialysis dependent at the time of deceased donor renal transplantation and meet the inclusion and exclusion criteria will be eligible for participation in this study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Parallel: Participants are assigned to one of two or more groups in parallel for the duration of the study
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Ischemia Reperfusion Injury
Intervention  ICMJE
  • Drug: Conjugated Estrogen
    Dosing of conjugated estrogen will be given pre kidney transplant procedure and twice after reperfusion of the transplanted kidney.
    Other Name: Premarin
  • Drug: Normal saline
    Dosing of normal saline will be given pre kidney transplant procedure and twice after reperfusion of the transplanted kidney.
    Other Name: 0.9% sodium chloride
Study Arms  ICMJE
  • Active Comparator: Active Arm
    Participants randomized to the active arm will receive a single infusion of conjugated estrogens at the time of admission if within 8 hours of the expected surgery time or at approximately 8 hours to the expected surgery time if admission is earlier than that. Participants will then receive two daily infusions of conjugated estrogens after transplant given at 8 hours after reperfusion of the transplanted kidney and 24 hours after the first post transplant dose (32 hours after reperfusion of the transplanted kidney).
    Intervention: Drug: Conjugated Estrogen
  • Placebo Comparator: Placebo Arm
    Participants randomized to the placebo arm will receive normal saline (0.9% sodium chloride) at the same rate as the active arm.
    Intervention: Drug: Normal saline
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 5, 2018)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 31, 2022
Estimated Primary Completion Date January 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Female gender
  2. Age > 21 years at time of transplant
  3. Pre-existing dialysis dependence of at least 1-months duration at the time of transplant
  4. Receiving a deceased donor renal transplant
  5. Receiving their first (primary) kidney transplant
  6. Subjects must receive between 500-5000U intravenous systemic heparin during their kidney transplant
  7. Subjects must receive between 2500-7500U subcutaneous heparin prophylaxis three times daily during hospital stay
  8. Written informed consent obtained from subject and ability for subject to comply with the requirements of the study

Exclusion Criteria:

  1. Receiving a non-primary (second, third, fourth, etc.) kidney transplant
  2. Receiving a combined heart-kidney transplant, liver-kidney transplant, or other multi-visceral organ transplant
  3. Receiving a live donor kidney transplant
  4. Personal history of deep vein thrombosis (DVT) or pulmonary embolism (PE)
  5. Personal history of hypercoagulable condition including but not limited to Lupus Anticoagulant, Leiden Factor V Mutation, Prothrombin Gene Mutation, Protein C or S deficiency, or any other hypercoagulable condition considered by the attending transplant surgeon on clinical service or Data and Safety Monitoring Board (DSMB) to warrant exclusion from the study
  6. Personal history of an estrogen sensitive cancer (breast, endometrial, ovarian)
  7. Personal history of arterial thromboembolic disease such as stroke or myocardial infarction in the 6 months prior to transplantation
  8. Patient already on estrogen (including oral contraceptive pills) or anti-estrogen therapy for other indications
  9. Patient who is expected to not tolerate a dose of 500-5000U intravenous heparin at the time of transplant as determined by the transplant surgeon
  10. Patient who has a contraindication or allergy to or is expected to not tolerate a dose of 2500-7500U subcutaneous heparin prophylaxis three times daily during hospital stay as determined by the transplant surgeon
  11. Pregnant and breast feeding patients will be excluded from the study due to the small risk of radiation associated with the DTPA renal scan
  12. Patient body mass index (BMI) > 40Kidney donor profile index (KDPI) < 40
  13. Known anaphylactic reaction and angioedema to Premarin Intravenous therapy
  14. Presence of a condition or abnormality that in the opinion of the investigator or attending transplant surgeon primarily responsible for the patient's care would compromise the safety of the patient or the quality of the data
Sex/Gender  ICMJE
Sexes Eligible for Study:Female
Gender Based Eligibility:Yes
Gender Eligibility Description:Participants must be female
Ages  ICMJE 21 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Mary C Shaw, RN215-614-0528[email protected]
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03663543
Other Study ID Numbers  ICMJE 82378
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD:No
Responsible Party University of Pennsylvania
Study Sponsor  ICMJE University of Pennsylvania
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Principal Investigator:Matthew Levine, MD, PhDUniversity of Pennsylvania Health System
PRS Account University of Pennsylvania
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP