| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| arteries clogged up by fatty substances known as plaques |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the effect of MDCO-216 treatment on the change in percent atheroma volume (PAV) of a target coronary artery as measured by intravascular ultrasound (IVUS) imaging following five weekly infusions of MDCO-216 in subjects with a recent acute coronary syndrome. |
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| E.2.2 | Secondary objectives of the trial |
•To evaluate the effect of MDCO-216 on the following additional atheroma parameters measured by IVUS:
o change in total atheroma volume (TAV);
o change in TAV in the 10 mm subsegment containing the most amount of disease at baseline;
o proportion of subjects who demonstrate regression of coronary atherosclerosis, defined as a change PAV of less than zero (ie, an reduction in PAV) and an additional analysis of those with more than two standard deviations of the test/re-test variability.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PK Substudy
The first twenty four subjects who are enrolled and randomized in the study (approximately 12 in each dose group), at selected sites with the capabilities to meet the detailed PK requirements, including in patient stay for 24 hours for multiple blood samples and observation,will undergo extensive blood sampling for potential PK analysis and in-patient stay for 24 hours for safety monitoring after the first two and the final infusions. They will also undergo an in-patient stay of 24 hours after the fifth infusion for PK sampling. The purpose of this PK sub-study is to evaluate PK parameters after single (Infusion 1) and multiple (Infusion 5) administrations of MDCO-216. Analysis will only be performed on subjects receiving MDCO-216.
Blood samples for analysis of MDCO-216 concentration will be collected at the following time points: before infusion (0 min), 30 minutes after commencement of infusion, 2 h (at end of infusion), 4 h, 6 h, 12 h, 24 h and 168 h after commencement of infusion. Pharmacokinetic assessments of MDCO-216 will include Cmax, t1/2, Vd, Cl, AUC0-24, and AUCinf.
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| E.3 | Principal inclusion criteria |
1) Male or female subjects ≥ 18 years of age.
2) Have experienced a recent ACS event within 14 days of screening that requires a clinically indicated coronary angiogram.
3) A qualifying ACS event will be defined as follows:
A diagnosis of a qualifying MI event will be defined by abnormal levels of cardiac biomarkers (troponin I or T or CK-MB mass) with at least one determination greater than the 99th percentile or upper limits of normal for the laboratory and at least one of the following:
•Chest discomfort or symptoms of myocardial ischemia (≥ 10 minutes) at rest within 24 hours prior to hospitalization for MI.
•New ECG findings (or presumed new if no prior ECG available) indicative of acute myocardial ischemia in absence of left ventricular hypertrophy (LVH) and left bundle branch block (LBBB) as listed:
oNew or presumed new ST depression greater than 0.5 mm in 2 contiguous leads or T wave inversion greater than 1mm in leads with predominant R wave or R/S greater than 1 in 2 contiguous leads.
oNew or presumed new ST elevation at the J point in ≥ 2 contiguous leads with the cut-off points: ≥ 0.2 mV in men or ≥ 0.15mV in women in leads V2-V3 and/or ≥0.1 mV in other leads or new or presumed new LBBB.
oNew tall R wave > 40 ms in V1, V2 and R/S ≥ 1 in V1 with concordant positive T-wave in the absence of a conduction defect.
oNew Q waves ≥ 30 ms wide and > 1mm deep in any 2 leads of a contiguous lead grouping or Q wave >20ms or QS complex in leads V2 and V3 (These criteria also apply to silent MI detected during a routine follow-up visit).
oLoss of viable myocardium based on imaging evidence of new or presumed new wall motion or perfusion deficit (eg, echocardiography, left ventriculography during cardiac catheterization radionuclide angiography, single-photon emission tomography, MRI).
4) Baseline coronary angiogram must meet all of the following criteria for IVUS interrogation of TARGET ARTERY:
•Must be accessible to the IVUS catheter.
•Must have a stenotic area of ≥ 20% and < 50% in lumen diameter by angiographic visual estimation within the length of the native coronary artery (“target segment”) for imaging by IVUS.
•The target artery has not undergone prior percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG).
•The target artery is not currently a candidate for intervention or a likely candidate for intervention over the treatment phase of the study and until the second IVUS interrogation at Day 36.
•The target artery may not be a bypass graft.
•The target artery may not be the culprit vessel for a previous MI.
•TARGET ARTERY MAY HAVE:
o A lesion of up to 60% stenosis, distal to the target segment, provided that this area is not a target for PCI or CABG.
o A single branch of the “target vessel” may have a narrowing ≤ 70% by visual estimation, provided that the branch in question is not a target for PCI or CABG.
5) Willing and able to give informed consent before initiation of any study-related procedures and willing to comply with all required study procedures. |
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| E.4 | Principal exclusion criteria |
1) Baseline IVUS not completed due to non-qualifying coronary angiogram as demonstrated by:
a) Greater than 50% reduction in lumen of the left main coronary artery by visual estimation.
b) Extensive CAD with no target vessel for IVUS interrogation.
2) Baseline IVUS interrogation determined to be unacceptable by the Atherosclerosis Imaging Core Laboratory (AICL).
3) Previous STEMI within the last 90 days (not including qualifying ACS event)
4) Clinically significant heart disease which, in the opinion of the Investigator, is likely to require CABG, PCI cardiac transplantation, surgical or percutaneous valve repair and/or replacement following index IVUS imaging (does not apply to PCI that occurs as a result of initial screening angiogram and completed prior to index IVUS imaging).
5) New York Heart Failure Association (NYHA) class III or IV heart failure or last known left ventricular ejection fraction < 30%.
6) Coronary artery bypass surgery < 6 weeks prior to the qualifying IVUS.
7) Cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication.
8) Uncontrolled severe hypertension: systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg prior to randomization despite anti-hypertensive therapy.
9) Poorly controlled diabetes mellitus and an HbA1c > 10.0% prior to randomization.
10) Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver OR alanine aminotransferase (ALT), aspartate aminotransferase (AST), elevation > 2x ULN OR total bilirubin elevation > 1.5x ULN at screening confirmed by a repeat measurement at least one week apart.
11) Fasting triglyceride value > 400 mg/dL.
12) Impaired kidney function defined as calculated glomerular filtration rate < 60 mL/min by eGFR. In addition, subjects with a 0.3 mg/dL or 25% increase in serum creatinine in the initial 3-5 days following angiography will be excluded from the study.
13) Serious comorbid disease in which the life expectancy of the subject is shorter than the duration of the trial (eg, acute systemic infection, cancer, or other serious illnesses). This includes all cancers with the exception of treated basal-cell carcinoma occurring > 3 years before screening.
14) Body weight > 120 kg.
15) Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least two methods of contraception (oral contraceptives, barrier methods, approved contraceptive implant, long- term injectable contraception, intrauterine device or tubal litigation). Women who are > 2 years postmenopausal defined as ≥ 1 year since last menstrual period AND if less than 55 years old with a negative pregnancy test within 24 hours of randomization or surgically sterile are exempt from this exclusion.
16) Males who are unwilling to use an acceptable method of birth control during the entire study period (ie, condom with spermicide).
17) Previous participation in this study or any preceding study with ETC-216, MDCO-216, or similar investigational medicines containing ApoA-I proteins.
18) Known allergy to the phospholipid or any other component of the investigational product (dimeric rApoA-IM, POPC, or mannitol and sucrose in phosphate buffer)
19) Treatment with other investigational medicinal products or devices within 30 days orfive half˗lives, whichever is longer.
20) Known history of alcohol and/or drug abuse.
21) Use of other investigational medicinal products or devices during the course of the study, excluding Post-Marketing Registries.
22) Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to:
a) Inappropriate for this study, including subjects who are unable to communicate or to cooperate with the investigator.
b) Unable to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study (including subjects whose cooperation is doubtful due to drug abuse or alcohol dependency).
c) Unlikely to comply with the protocol requirements, instructions and study-related restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study).
d) Have any medical or surgical condition, which in the opinion of the investigator would put the subject at increased risk from participating in the study.
e) Involved or a relative of someone directly involved in the conduct of the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is defined as change from baseline to study end (Day 36 post-randomization) in coronary PAVas determined by IVUS. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints of this trial are:
•Change in TAV from baseline to Day 36 post-randomization, as determined by IVUS
•The proportion of subjects in each group with regression of coronary atherosclerosis, defined as a reduction in PAV from baseline to Day 36 of more than 2 standard deviations of the test-retest variability.
•Proportion of subjects in each group with regression of coronary atherosclerosis, defined as a change in PAV from baseline to Day 36 of less than zero.
•Change in TAV for the 10-mm subsegment with the greatest disease burden at baseline |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| 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 | No |
| 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 |
| Czech Republic |
| Hungary |
| Netherlands |
| Poland |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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