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

• Status: Completed
• Trial end date: 2010-11-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Quark Pharmaceuticals

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