Collagenase Total Occlusion-1 Trial
Collagenase Total Occlusion-1 Trial
A prospective, three-center, phase I safety and tolerability dose escalation study,
 evaluating 28 subjects in 4 discrete dose cohorts of acute intracoronary injected collagenase
 ranging from 300 - 1200 µg prior to routine standard-of-care percutaneous revascularization
 procedures in subjects with chronic total coronary artery occlusions (CTOs).
Enrolment is expected to occur over 24 months with total study duration of approximately 30
 months. Five (5) subjects will be enrolled into each dose cohort. The dose cohorts will be
 studied in a sequential fashion, starting with the lowest doses and escalating to the highest
 doses. It is anticipated that each subject's involvement with the study will be 3.5 months.
 In addition, eight (8) subjects will be included in the highest dose cohort to collect
 pharmacokinetic plasma samples.

 Subject enrollment and dosing within each dose cohort will be staged such that the next
 subsequent subject will not be dosed until the previous subject has been successfully
 discharged from the hospital after the angioplasty attempt. At a minimum there will be 3 days
 in between each subject dosing to ensure product safety.

 There will be no advancement to the higher dose cohort until all 5 subjects have been
 discharged from the hospital and a safety review is conducted by the Data Safety Monitoring
 Board (DSMB) on the cardiac safety measures and the treatment deemed safe to proceed to the
 next dosing level.

 A total of 28 male and / or female subjects suffering from CAD with a CTO will be enrolled
 into the study at three sites (Sunnybrook Health Sciences Centre and St. Michael's Hospital,
 Toronto, Ontario, and and Laval Hospital Research Centre, Quebec City, Quebec,Canada). All
 subjects will have had one or more previous failed angioplasty attempt(s) of the occluded
 artery. Subjects who have signed an Informed Consent Form (ICF) and meeting all inclusion
 criteria and having none of the exclusion criteria at Visit 1 (Screening) will be included in
 the study. All potentially enrollable subjects at Sunnybrook will be reviewed by either of
 two cardiologist not involved in the study to discuss the available options for the subject
 and to approve enrollment decisions. Eligible subjects that agree to participate will be
 treated in a two part procedure. On Day0 using standard angioplasty techniques to access the
 specified occluded coronary artery, Collagenase (MZ-004) will be directly injected into the
 occluded artery through a microcatheter that has been positioned immediately adjacent to or
 into the proximal cap of the occlusion. The catheters and arterial sheath will then be
 removed and the subject will be monitored overnight on the ward. The following day (Day1),
 the subject will be brought back to the catheterization laboratory and undergo an angioplasty
 using standard angioplasty techniques. Routine post-procedural management will then be
 followed. The subject will be discharged on Day2 in the absence of any cardiac complications
 (such as elevated cardiac enzymes or large pericardial effusion as judged by the Investigator
 and determined by echocardiography). Prior to the angioplasty procedure on Day1 and again on
 Day2 prior to discharge, the subject will undergo an echocardiogram to determine the presence
 and severity of a pericardial effusion. A moderate or large pericardial effusion or any sign
 of tamponade on Day1 will be a contraindication to performing the procedure, and the subject
 will be terminated from the study. A telephone follow-up will be performed 30 days post Day1
 in all subjects who have signed an ICF and been enrolled in the study. At 3 months, subjects
 will undergo an outpatient coronary Computer Tomography (CT) angiogram to ensure there are no
 delayed effects on the treated vessel (e.g. aneurysm formation), the myocardium or the
 pericardium.

 The primary objective is to evaluate the safety and tolerability of acute intracoronary doses
 of collagenase (MZ-004) in symptomatic subjects with coronary CTO.

 The secondary objective is to obtain preliminary efficacy information of guidewire crossing
 with increasing doses of intracoronary collagenase in subjects with previously failed at
 least one previous attempt in coronary CTO.
Inclusion Criteria:

 Candidates for this study must meet ALL of the following inclusion criteria:

 -  Subject is willing and able to provide an informed consent

 -  Subject is willing and able to comply with the study procedures and follow-up

 -  Subject is 35 years of age or older

 -  Women who are non-reproductive, or reproductive women who are willing and able to
 practice effective birth control methods. A urine pregnancy test should be done at the
 screening/Day0 on all reproductive women of child bearing ability

 -  Subjects with CTO (older than 6 weeks or unknown duration based on the investigator's
 assessment of appropriateness for the study) with a clinical indication for
 revascularization. In subjects with occlusions of unknown duration, there must be
 absence of any identifiable ischemic event in the 6 weeks prior to enrolment in the
 study

 -  At least 1 previously failed attempt to cross the CTO

 -  Absence of pericardial effusion on 2D Echocardiogram

 Exclusion Criteria:

 Candidates for this study who meet any of the following criteria at the time of the
 screening visit are NOT eligible to be enrolled in this study:

 -  Culprit vessel is a saphenous vein graft occlusion

 -  True ostial LAD, LCX or RCA occlusions (since collagenase delivery will be unreliable)

 -  Presence of moderate or large pericardial effusion on echocardiogram within 2 weeks of
 the procedure

 -  Major side branch (1.5 mm diameter) within 3 mm proximal to the occlusion. (This is to
 prevent the infusate being diverted through a side branch and to prevent ischemia
 during the prolonged period of time during the infusion)

 -  Renal dysfunction (creatinine greater than 2 x ULN)

 -  Severe calcification (collagenase can not degrade calcium) based on consensus of 2
 interventional cardiologists after review of coronary angiogram.

 -  Subject has any medical condition, which in the judgment of the Investigator and/or
 designee makes the subject a poor candidate for the investigational procedure

 -  Subject is a pregnant or lactating female (women of childbearing potential must have a
 negative serum beta-HCG within 24 hours prior to the inclusion)

 -  Subject is or has been partaking in another investigational product clinical study
 within 30 days of Screening/Day0

 -  Subjects with bleeding abnormalities (e.g. Factor VIII deficiency) and /or subjects
 that have experienced any medically documented active site of bleeding within 30 days
 of the screening visit, such as, but not limited to, the gastrointestinal or
 genitourinary tract or intercerebral hemorrhage.

 -  Subjects with recent acute coronary syndrome (ACS) (< 4 weeks). For those patients who
 had ACS ≥ 4weeks ago, only the non-culprit vessel from the recent ACS can be
 considered eligible for this study if all other inclusion and exclusion criteria have
 been met.