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Intravenous Estrogen in Kidney Transplant Study (PERT)

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ClinicalTrials.gov Identifier: NCT03663543
Recruitment Status : Recruiting
First Posted : September 10, 2018
Last Update Posted : June 4, 2020
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
University of Pennsylvania

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.

Condition or disease Intervention/treatment Phase
Ischemia Reperfusion Injury Drug: Conjugated Estrogen Drug: Normal saline Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
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
Official Title: The Use of Peri-Operative Intravenous Estrogen for the Mitigation of Ischemia Reperfusion Injury in the Setting of Renal Transplantation
Actual Study Start Date : August 26, 2016
Estimated Primary Completion Date : January 31, 2022
Estimated Study Completion Date : January 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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).
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

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.
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




Primary Outcome Measures :
  1. Glomerular filtration rate (GFR) [ Time Frame: Post-operative day three ]
    GFR (glomerular filtration rate) as calculated from a DTPA (Diethylenetriamine Pentaacetic Acid, a medication) renal scan.


Secondary Outcome Measures :
  1. Delayed graft function (DGF) [ Time Frame: Immediately post-operative ]
    Measurement of urine creatinine clearance and serum creatinine.


Other Outcome Measures:
  1. Graft Failure [ Time Frame: Post-operative day three and day ninety ]
    Measurement of serum creatinine.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Participants must be female
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03663543


Contacts
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Contact: Mary C Shaw, RN 215-614-0528 mary.shaw@uphs.upenn.edu

Locations
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United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Mary C Shaw, RN    215-614-0528    mary.shaw@uphs.upenn.edu   
Principal Investigator: Matthew L Levine, MD         
Sponsors and Collaborators
University of Pennsylvania
Pfizer
Investigators
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Principal Investigator: Matthew Levine, MD, PhD University of Pennsylvania Health System
Publications of Results:

Other Publications:

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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03663543    
Other Study ID Numbers: 82378
First Posted: September 10, 2018    Key Record Dates
Last Update Posted: June 4, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Reperfusion Injury
Ischemia
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Postoperative Complications
Estrogens
Estrogens, Conjugated (USP)
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs