Clinical Trials Register

Summary
EudraCT Number:	2014-004649-28
Sponsor's Protocol Code Number:	CTO-201
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2015-05-26
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2014-004649-28

A.3

Full title of the trial

A 2-stage study to evaluate single doses of MZ-004 at different dose levels in patients with chronic total occlusions. STAGE 1: Open label Training Stage. STAGE 2: Double-blind, randomized, Placebo-Controlled Stage. The TOSCA-5 Study (Total Occlusion Study in Coronary Arteries-5)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Title of the trial for lay people, in easily understood, i.e. non-technical, language: Testing of MZ-004 (investigational product) at different doses in patients who have a completely blocked coronary artery and comparing the results to a placebo or inactive product.

A.3.2

Name or abbreviated title of the trial where available

CTO-201 or TOSCA-5 Study

A.4.1

Sponsor's protocol code number

CTO-201

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01471522

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Matrizyme Pharma Corporation
B.1.3.4	Country	Canada
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Matrizyme Pharma Corporation
B.4.2	Country	Canada
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Matrizyme Pharma Corporation
B.5.2	Functional name of contact point	Administrative Assistant
B.5.3	Address:
B.5.3.1	Street Address	65 B West Beaver Creek Rd.,
B.5.3.2	Town/ city	Richmond Hill, Ontario
B.5.3.3	Post code	L4B 1K4
B.5.3.4	Country	Canada
B.5.4	Telephone number	+001905 771-0333 0
B.5.5	Fax number	+001289475-5166
B.5.6	E-mail	TOSCA-5.internal@matrizyme.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Collagenase
D.3.2	Product code	MZ-004
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarterial use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not Applicable
D.3.9.1	CAS number	9001-12-1
D.3.9.2	Current sponsor code	MZ-004
D.3.9.3	Other descriptive name	COLLAGENASE
D.3.9.4	EV Substance Code	SUB13443MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Biologic derived from bacterial expression of Clostridium histolyticum

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intraarterial use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

The use of MZ-004 to facilitate percutaneous coronary intervention in symptomatic patients with a chronic total occlusion who are indicated for revascularization

E.1.1.1

Medical condition in easily understood language

Patients with a chronic total occlusion in the heart

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To obtain an estimate of the anterograde PCI success rate for patients with a confirmed target CTO in each treatment group and to explore safety and tolerability in these patients.

E.2.2

Secondary objectives of the trial

To compare among the 3 treatment groups, between patients with anterograde PCI success and anterograde PCI failure:
•Fluoroscopy time
•Total procedure time
•Soft wire crossing
-True-to-true soft wire crossing
- Soft wire penetration (2 cm beyond the proximal cap [intraluminal or extraluminal])

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Screening Inclusion Criteria
A patient will be eligible for the study if s/he meets all of the following criteria:
1.Patient has provided signed and dated informed consent in accordance with required regulations.
2.Patient is male or female and greater than or equal to 18 years of age.
3.If patient is a female of childbearing potential, patient is willing to utilize contraception from Screening through the duration of the study. Adequate contraceptive measures include oral contraceptives (stable use for 2 or more cycles prior to Screening), intra-uterine device (IUD), Depo-Provera®, Norplant® System Implants, surgical sterilization (bilateral tubal ligation, hysterectomy, partner vasectomy), condom or diaphragm or cervical cap plus either contraceptive sponge, foam or jelly. For the purpose of this Study, women of non-childbearing potential are:
a.Females, regardless of age, with functioning ovaries who have a current documented tubal ligation, or who are surgically sterile (i.e. documented total hysterectomy or bilateral oophorectomy) or
b. Females 45 years of age who are post-menopausal for greater than 1 year (i.e. last menstrual period > 1 year) at Screening.
4.Patient is willing and able to comply with the protocol requirements during the study and be willing to refrain from any other elective cardiac revascularization procedures for the duration of study participation, unless medically necessary.
5.The patient has a clinically driven, planned PCI of the target CTO, in a major epicardial coronary artery, without planned revascularization of other coronary stenosis/stenoses in major epicardial segments.
6.Target CTO must be ≥ 3 calendar months old by either:
a. Proven Chronicity: Angiographic documentation (conventional or coronary) of the target CTO 3 or more calendar months prior to Screening or
b. Assumed Chronicity: Identification of the target occlusion has occurred in the setting of chronic ischemic heart disease, with no known or suspected acute coronary syndrome (ACS) within 3 months.
7.The patient is receiving a course of optimal anti-ischemic medical therapy (at least 2 anti-anginal agents or the maximum tolerated anti-anginal therapy). Medical therapy should include adequate ventricular rate-limiting medication (i.e. Beta-blocker or calcium antagonist) where appropriate.

E.4

Principal exclusion criteria

A patient who meets any of the following criteria will not be eligible for the study:
1.Patient has documented chest radiation exposure > 4.0 Gray within 8 weeks of Day 0 (not including any Day 0 procedures). In the absence of Gray dosimetry, patients with > 60 minutes fluoroscopy time within 8 weeks of Day 0 will be excluded.
2.Patient’s target vessel is a saphenous vein graft occlusion.
3.Patient’s target lesion includes an occluded coronary stent.
4.Patient had ACS < 4 weeks from Screening, attributable to any coronary vessel.
5.Patient had ACS from 4 weeks to 3 calendar months prior to Screening, attributable to the target CTO. NOTE: If ACS is attributable to a different CTO the patient may still qualify.
6.Patient has known sensitivity to collagenase.
7.Patient has prior injected collagenase and/or any intra-coronary administration of collagenase.
8.Patient was treated in study CTO-1.
9.Patient has a known sensitivity to contrast dye.
10.Patient has estimated glomerular filtration rate (GFR) is < 30 mL/min, as provided for in the clinical chemistry results available at/for Screening.
11.Patient has any medical condition, which in the judgment of the Investigator and/or Sponsor makes the patient a poor candidate for the investigational procedure.
12.Patient is a pregnant or lactating female (check at Screening and Day 0 before randomization).
13.Patient used any investigational or experimental drug or device within 30 days of Screening.

E.5 End points

E.5.1

Primary end point(s)

The following primary endpoint will be used:
PCI Success – The proportion of patients in each treatment group (placebo and MZ-004) with improved anterograde PCI success based on the independent blinded angiographic core laboratory assessment

E.5.1.1

Timepoint(s) of evaluation of this end point

post PCI attempt and after adjudicated angiographic assessment

E.5.2

Secondary end point(s)

•Fluoroscopy Time: The time from proximal CTO engagement to either (i) operator-defined successful wire crossing, or (ii) in the absence of successful wire crossing, to procedural abandonment, calculated for each treatment group (MZ-004 vs. placebo), based on the ITT population;
•Soft-wire Crossing: The proportion of patients with PCI success using only soft tipped guide wires (tip strength ≤ 1.5 grams, and no use of Miracle Bros, Progress, Confianza, or Pilot 100, 150 or 200 guide wires), calculated for each treatment group (placebo and MZ-004); based on the ITT population;
•Total procedural time, defined as the time the lesion is first engaged with the first CTO guide wire until the time of the last coronary angiogram, calculated for each treatment group (placebo and MZ-004);

E.5.2.1

Timepoint(s) of evaluation of this end point

Post PCI attempt.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

Israel

Netherlands

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

110

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Normal medical supervision as per standard of care.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-05-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-09

P. End of Trial
P.	End of Trial Status	Ongoing

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