I5NP for Prophylaxis of Delayed Graft Function in Kidney Transplantation

Delayed Graft Function Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00802347
• Other study ID #: QRK.006
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: December 2, 2008
• Last updated: September 8, 2014
• Start date: December 2008
• Est. completion date: May 2014

Study information

• Verified date: September 2014
• Source: Quark Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health CanadaGermany: Federal Institute for Drugs and Medical DevicesFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Spain: Agencia Española de Medicamentos y Productos Sanitarios
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 374
• Est. completion date: May 2014
• Est. primary completion date: November 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Delayed Graft Function
• Other Complication of Kidney Transplant

Intervention

Drug:
• I5NP
Single IV injection of I5NP Part A: dose-escalation study; cohort 1 = 0.5 mg/kg; cohort 2 = 1.5 mg/kg; cohort 3 = 5.0 mg/kg; cohort 4 = 10.0 mg/kg Part B: 10.0 mg/kg
• Saline
Single IV injection of saline Part A: dose-escalation study; cohort 1 = 0.5 mg/kg; cohort 2 = 1.5 mg/kg; cohort 3 = 5.0 mg/kg; cohort 4 = 10.0 mg/kg Part B: 10.0 mg/kg

Locations

Country	Name	City	State
Canada	QE II Capital District Health Authority, Halifax	Halifax	Nova Scotia
Canada	MUHC Royal Victoria Hospital	Montreal	Quebec
Canada	St. Paul's Hospital, Univeristy of BC	Vancouver	British Columbia
Canada	UBC - Division of Nephrology	Vancouver	British Columbia
France	Hôpital Pasteur	Nice
France	Hôpital Necker	Paris
France	CHU Rangueil	Toulouse
Germany	Charité - Universitätsmedizin Berlin	Berlin
Germany	Charité, Campus Virchow-Klinikum	Berlin
Germany	Kliniken der Stadt Köln gGmbH	Cologne
Germany	Universitätklinikum Hamburg-Eppendorf	Hamburg
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätsmedizin Mannheim	Mannheim
Germany	Universitätsklinikum Tübingen	Tübingen
Spain	Hospital de bellvitge	Barcelona
Spain	Hospital del mar	Barcelona
Spain	Hospital Vall Hebron	Barcelona
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	Piedmont Hospital	Atlanta	Georgia
United States	University of Colorado Health Science Center	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Maryland	Baltimore	Maryland
United States	University of Alabama Birmingham	Birmingham	Alabama
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Rush University	Chicago	Illinois
United States	University of Illinois Chicago	Chicago	Illinois
United States	Baylor University Medical Center	Dallas	Texas
United States	Duke University	Durham	North Carolina
United States	Baylor All Saints Medical Center	Fort Worth	Texas
United States	University of Florida	Gainesville	Florida
United States	The Methodist Hospital	Houston	Texas
United States	Saint Barnabas Medical Center	Livingston	New Jersey
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Transplant Research Institute (TRI; formerly NIT)	Los Angeles	California
United States	UCLA Medical Center	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	University of Miami	Miami	Florida
United States	Columbia University	New York	New York
United States	Cornell University	New York	New York
United States	Virginia Commonwealth University (MCV)	Richmond	Virginia
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	UC Davis Medical Center	Sacramento	California
United States	California Pacific Medical Center	San Francisco	California
United States	UCSF Medical Center	San Francisco	California
United States	Lifelink Healthcare Institute	Tampa	Florida
United States	Washington Hospital Center	Washington	District of Columbia
United States	Wake Forest University Medical Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Quark Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.		Part A: DSMB review at conclusion of each cohort / Part B: Interim analyses will be performed after the 66th, 130th, and 196th patient enrolled	No
Secondary	Part B: Treatment differences in the rate of improvement in renal function over time and treatment differences in the need for renal replacement therapy.		Part B: Interim analyses will be performed after the 66th, 130th, and 196th patient enrolled	No