A Dose Escalation and Safety Study of I5NP in Patients Undergoing Major Cardiovascular Surgery

NCT ID: NCT00554359

Last Updated: 2011-02-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 16 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-08-31
• Study Completion Date: 2010-11-30

Brief Summary

This is a Phase 1, randomized, double-blind, dose escalation, safety and pharmacokinetic study. The study will be conducted in approximately 8-10 centers in the United States and Switzerland. Up to 32 patients who have undergone major cardiovascular surgery will participate. Patients will receive a single IV injection of I5NP or placebo following cardiovascular surgery. I5NP will be administered 4 hours (+/- 30 minutes) following removal of the cardiopulmonary bypass machine (CBM).

The duration of the study is approximately 44 days, inclusive of a 14 day screening period. Patients will be contacted by phone at 6 and 12 months for follow-up questions. Patient visits are screening, day of surgery, hospital in-patient Days 1, 2, 3 and Day 7 or hospital discharge. Safety follow-up will continue until 30 days post-surgery. 2 phone calls will be made at 6 and 12 months after date of surgery.

Detailed Description

The drug (I5NP) is a small interfering RNA that is being developed to protect patients from acute kidney injury after cardiac bypass surgery. This first-in-man study will test the safety of I5NP and measure how long the drug stays in the blood stream after injection. This study is not meant to test if I5NP protects kidneys from the damage that may occur in rare cases during surgery. Another purpose of this dose escalation study is to find out the right dose of the experimental drug to be given to study subjects in future studies. Even though there were no harmful effects seen in the animals tested, we do not know what side effects the experimental drug might cause in humans.

Conditions

Injury of Kidney; Acute Renal Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

I5NP drug

Group Type: EXPERIMENTAL

I5NP (a small interfering RNA)

Intervention Type: DRUG

Single IV injection of experimental drug

Placebo

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

Single IV injection of saline

Interventions

I5NP (a small interfering RNA)

Single IV injection of experimental drug

Intervention Type: DRUG

placebo

Single IV injection of saline

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Patient age between 21 years and 85 years old
• Patient is capable of giving consent
• Patient is willing and able to comply with the visit schedule and study procedures including post-hospitalization discharge follow-up
• Patient is undergoing non-emergent coronary artery bypass graft (CABG) and/or valve replacement surgery
• Patient has a cumulative score of 0 to 8 on the Cleveland Clinic Foundation (CCF) Acute Kidney Injury (AKI) risk factor scale
• The patient reports that they are up to date and have had normal findings on their age- and sex-appropriate cancer screening, per American Cancer Society guidelines, for breast cancer, cervical cancer, rectal cancer, and prostate cancer. If a patient is not up to date, the relevant screening test must be performed and a normal result documented prior to dosing.

• Patient must have been on cardiopulmonary bypass machine (CBM)

• Patient must be in the ICU for dosing to facilitate study procedures including PK blood draws and PK urine sampling

Exclusion Criteria

• Patient has undergone any organ transplant
• Patient who has had cancer or may be predisposed to develop cancers such as those with family history of cancers in multiple relatives {i.e., Familial Polyposis Coli, those with family history of Von Hippel Landau disease (associated with renal cell cancers and renal cysts) and those with family history of Li-Fraumeni syndrome (associated with inherited mutations of the p53 tumor-suppressor gene)}
• Patient has a history of any abnormality on chest X-ray that could represent a malignancy
• Patient has a clinically significantly elevated pancreatic and/or hepatic enzyme level, defined as any grade 2, 3 or 4 value according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 3.0
• Patient has an underlying medical condition which increases the risk of perioperative complications, such as poorly controlled diabetes mellitus or hypertension or significant chronic obstructive pulmonary disease (COPD)
• Women of childbearing potential are to be excluded from this study. Every female subject is considered of childbearing potential unless she has had sterilization surgery, or is post-menopausal.

• Women 21-59, post-menopausal is defined as no menses for at least 12 months and an elevated follicle stimulating hormone (FSH) level.
• Women 60-85, post-menopausal is defined as no menses in at least 12 months.
• Patient has participated in a study of an experimental therapy in the last 30 days
• Patient is currently receiving immunosuppressive therapy [this criterion does NOT apply to topical steroids and inhalation steroids for chronic obstructive pulmonary disease (COPD) and/or asthma]
• Patient requires pre-operative dialysis or is currently on dialysis
• Patient is undergoing aortic aneurism repair
• Pre-operative extracorporeal membrane oxygenation
• Pre-operative tracheotomy, or mechanical ventilation
• Patient has Intra-Arterial Balloon Pump (IABP) or other Left Ventricular Assist Device (LVAD)
• Evidence that patient is experiencing possible AKI prior to surgery, defined as a > 1.5 times increase in serum creatinine from screening to any time prior to surgery
• Baseline serum creatinine > 3.0 mg/dL and/or an estimated GFR of < 30 mL/min/1.73 m2, as calculated by the Modification of Diet in Renal Disease [MDRD] Study equation: eGFR (mL/min/1.73 m2) = [186 x (SCr)] - [1.154 x (Age)] - [0.203 x (0.742 if female or 1.210 if African-American female)] where SCr: serum creatinine in mg/dL and age is in years
• Patient has comfort measures only or do not resuscitate (DNR) status
• Patient is participating in a concurrent interventional study
• Patient has received intravenous contrast material < 48 hours prior to surgery
• In the opinion of the investigator a pre-operative concomitant disease or clinical finding such as an abnormality in clinical lab results, chest X-ray, EKG, or physical examination finding that significantly raises the risk of perioperative complications precludes dosing of the patient

• Patient on CBM for > 3 hours
• Patient experienced major blood loss (>15 units)
• Use of balloon pump or other LVAD during surgery;
• In the opinion of the investigator, an intra-operative complication precludes dosing of the patient

• Cardiac Index < 2.1 L/min/m2 (applies only to patients with a Swan-Ganz or other PA catheter)
• Patient has a body temperature ≥ 40 °C
• Use of IABP post-surgery
• Fluid imbalance in excess of 15 liters
• PaO2:FiO2 < 250
• Patient receiving ≥ 3 concurrent vasopressors to maintain hemodynamic stability
• In the opinion of the investigator a post-operative complication precludes dosing of the patient

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Quark Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Quark Pharmaceuticals, Inc.

Principal Investigators

Martin S. Polinsky, M.D.

Role: STUDY_DIRECTOR

Quark Pharmaceuticals

Locations

George Washington University

Washington D.C., District of Columbia, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Cleveland Clinic Foundation

Cleveland, Ohio, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Texas Heart Institute at St. Luke's Episcopal Hospital

Houston, Texas, United States

University of Virginia School of Medicine

Charlottesville, Virginia, United States

Shaare Zedek Medical Center

Jerusalem, , Israel

Rabin Medical Center

Petah Tikva, , Israel

Tel Aviv Sourasky Medical Center

Tel Aviv, , Israel

University Hospital of Geneva

Geneva, , Switzerland

Lausanne University Hospital (CHUV)

Lausanne, , Switzerland

Countries

United States; Israel; Switzerland

Other Identifiers

QRK.002

Identifier Type: -

Identifier Source: org_study_id