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

Quark Pharmaceuticals

Status and phase

Completed

Phase 1

Conditions

Injury of Kidney

Acute Renal Failure

Treatments

Drug: I5NP (a small interfering RNA)

Drug: placebo

Study type

Interventional

Funder types

Industry

Identifiers

NCT00554359

QRK.002

Details and patient eligibility

About

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.

Full 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.

Enrollment

16 patients

Sex

All

Ages

21 to 85 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria (before surgery):

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.

Inclusion Criteria (during surgery):

Patient must have been on cardiopulmonary bypass machine (CBM)

Inclusion Criteria (after surgery):

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

Exclusion Criteria (before surgery):

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

Exclusion Criteria (during surgery):

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

Exclusion Criteria (2-3 days post-removal of CBM):

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