Clinical trial NCT00802347: I5NP for Prophylaxis of Delayed Graft Function in Kidney Transplantation
Official title: Controlled, Randomized, Prospective, Double-Blind, Multicenter, Phase I/II, Dose-Escalation Study of the Safety, PK, and Clinical Activity of I5NP for Prophylaxis of Delayed Graft Function in Patients Undergoing Deceased Donor Kidney Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Delayed Graft Function
Other Complication of Kidney Transplant
Keywords: Delayed Graft Function
Kidney Transplant
Renal Transplant
small interfering ribonucleic acid (siRNA)
Lead sponsor: Quark Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2008-12-04
Enrollment: 374
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to determine whether a single administration of QPI-1002 (also known as I5NP) can prevent DGF in patients undergoing deceased donor kidney transplantation. In this Phase I /II study, patients who are undergoing renal transplantation with organs from DCD donors, ECD donors or SCD donors with ≥ 24 hours of cold ischemia time who meet study entry criteria will be studied to evaluate the safety and pharmacokinetic profile of I5NP (Part A) and clinical activity of I5NP administration (Part B). Data from this study will be used to identify doses of I5NP to be used in follow-on efficacy studies.

Part A will be a randomized, dose escalation study to determine the highest or maximum tolerated dose (MTD). Part A will enroll 40 patients at approximately 20 sites; patients will be randomized to receive either I5NP or placebo in a ratio of 8:2 in each cohort (cohorts 1-4).

Part B will utilize the dose identified in Part A to further evaluate, in a double-blind manner, the safety, and clinical activity of I5NP. In Part B, up to 326 patients will participate at approximately 60 sites; up to 163 patients will be randomized to receive I5NP and up to 163 patients randomized to receive placebo.

Detailed description: Although the etiology of DGF is not fully understood and may be multifactorial, the pathophysiology appears to be primarily related to ischemia-reperfusion (IR) injury resulting from organ preservation between the times of harvesting from the donor and reperfusion following vascular reanastomosis in the recipient.

I5NP is a small interfering RNA (siRNA) that is being developed for the prophylaxis of delayed graft function (DGF) in patients receiving renal transplants.

Eligibility criteria: Inclusion Criteria:

1. Patient is at least 18 years of age.
2. Patient has given informed consent.
3. Patient is willing to practice birth control. Female patients must be: (1) post-menopausal (2) surgically sterile, or (3) using an effective means of contraception (per the site-specific guidelines or using 2 methods of birth control concurrently, whichever is more stringent) which will be continued until the Study Day 90 visit with a negative pregnancy test within 48 hours prior to administration of study drug. Male patients with female partners of child bearing potential must agree to use an effective means of contraception (per the site-specific guidelines or using 2 methods of birth control concurrently, whichever is more stringent) which will be continued until the Study Day 90 visit. Note: For the purpose of this study, post menopausal is defined as the absence of menses consistent with ESRD. A woman is considered to be surgically sterilized if she has had a bilateral tubal ligation for at least 6 months prior to administration of study drug, bilateral oophorectomy, or complete hysterectomy.
4. Women of childbearing potential test negative for pregnancy (either urine or serum) within 48 hours prior to transplant.
5. Patient is up-to-date on cancer screening according to site-specific guidelines and the past medical history is negative for biopsy-confirmed malignancy within 5 years of randomization, with the exception of adequately treated basal cell or squamous cell carcinoma in situ.
6. Patient is scheduled to receive kidney transplant from a deceased donor meeting the following criteria:

   Part A:
   * receipt of an extended criteria donor (ECD) kidney, or
   * receipt of a kidney donated after cardiac death (DCD), or
   * receipt of a standard criteria donor (SCD) with cold ischemia time (CIT) ≥ 24 hours.

   Part B:
   * receipt of an ECD kidney that has been preserved by cold storage (ECD/CS) for the entire period of cold ischemia time (CIT), regardless of duration
   * receipt of an ECD kidney that has been preserved by machine perfusion (ECD/MP) for any interval of time during the period of cold ischemia, where total CIT has been at least 26 hours
   * receipt of an SCD kidney that has been preserved by cold storage (SCD/CS) where total CIT has been at least 26 hours
   * receipt of an SCD kidney that has been preserved by machine perfusion (SCD/MP) for any interval of time during the period of cold ischemia, where total CIT has been at least 26 hours.
7. Patient is dialysis dependent at the time of transplant as documented by: a) the requirement for at least 2 dialysis sessions/week during the 56 days prior to transplant, or b) the planned removal of any remaining native kidney at the time of transplant, or c) the opinion of the investigator that the patient has no remaining native renal function (Part A only), or d) the investigator has provided documentation to the Medical Monitor that the patient has no remaining native renal function (e.g., documentation that the patient is anuric, with urine output \<50 mL/day) (Part B only).

Exclusion Criteria:

1. Patient has participated in an investigational drug study in the last 30 days.
2. Patient has known allergy or has participated in prior study with siRNA.
3. Patient is HCV-positive
4. Patient is HIV-positive
5. Patient is scheduled to undergo multiorgan transplantation.
6. Patient has a planned transplant of kidneys that are implanted en bloc (dual kidney transplant).
7. Patient has planned transplant of kidneys from donors \< 6 years of age.
8. Patient has planned transplant of dual kidneys (from the same donor) transplanted not en bloc (as in the case of dual ECD donor kidneys).
9. Patient is scheduled for transplantation of a kidney from a donor who is known to have received an investigational therapy (under another IND) for ischemic/reperfusion injury immediately prior to organ recovery.
10. Patient is scheduled to receive a living donor kidney.
11. Patient is scheduled to receive an ABO-incompatible donor kidney.
12. Patient is scheduled to receive an organ from a donor that meets both DCD and ECD criteria.
13. Patient is scheduled to receive an organ from a donor that meets DCD criteria (exclusion applicable to Part B only).
14. Patient has history or presence of a medical condition or disease that in the investigator's assessment would place the patient at an unacceptable risk for study participation.

Primary outcomes:
measure: Part A: The outcome measure is safety. Additionally, plasma blood levels will be measured to characterize the PK of I5NP in this patient population. Part B: The outcome measure will be safety and the incidence of delayed graft function.
timeFrame: Part A: DSMB review at conclusion of each cohort / Part B: Interim analyses will be performed after the 66th, 130th, and 196th patient enrolled
Secondary outcomes:
measure: Part B: Treatment differences in the rate of improvement in renal function over time and treatment differences in the need for renal replacement therapy.
timeFrame: Part B: Interim analyses will be performed after the 66th, 130th, and 196th patient enrolled
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Birmingham
state: Alabama
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: Transplant Research Institute (TRI; formerly NIT)
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Health Science Center
state: Colorado
city: Washington
country: United States
facility: Washington Hospital Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: Lifelink Healthcare Institute
state: Florida
city: Atlanta
country: United States
facility: Piedmont Hospital
state: Georgia
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Rush University
state: Illinois
city: Chicago
country: United States
facility: University of Illinois Chicago
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Livingston
country: United States
facility: Saint Barnabas Medical Center
state: New Jersey
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Cornell University
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Medical Center
state: North Carolina
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Baylor All Saints Medical Center
state: Texas
city: Houston
country: United States
facility: The Methodist Hospital
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University (MCV)
state: Virginia
city: Vancouver
country: Canada
facility: St. Paul's Hospital, Univeristy of BC
state: British Columbia
city: Vancouver
country: Canada
facility: UBC - Division of Nephrology
state: British Columbia
city: Halifax
country: Canada
facility: QE II Capital District Health Authority, Halifax
state: Nova Scotia
city: Montreal
country: Canada
facility: MUHC Royal Victoria Hospital
state: Quebec
city: Nice
country: France
facility: Hôpital Pasteur
city: Paris
country: France
facility: Hôpital Necker
city: Toulouse
country: France
facility: CHU Rangueil
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Berlin
country: Germany
facility: Charité, Campus Virchow-Klinikum
city: Cologne
country: Germany
facility: Kliniken der Stadt Köln gGmbH
city: Hamburg
country: Germany
facility: Universitätklinikum Hamburg-Eppendorf
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Barcelona
country: Spain
facility: Hospital de bellvitge
city: Barcelona
country: Spain
facility: Hospital del mar
city: Barcelona
country: Spain
facility: Hospital Vall Hebron
Study officials:
affiliation: Quark Pharmaceuticals
name: Shai Erlich, Ph.D.
role: STUDY_DIRECTOR
References: