The primary objective of this study is to:• Evaluate the efficacy of ranolazine as compared with placebowhen used as part of standard medical therapy in chronicangina subjects with incomplete revascularization post percutaneous coronary intervention…
ID
Source
Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is the time from randomization to the first
occurrence of ischemia-driven revascularization or ischemia-driven
hospitalization without revascularization.
Secondary outcome
Secondary endpoints are:
• Time from randomization to sudden cardiac death
• Time from randomization to CV death
• Time from randomization to MI
Additional secondary endpoints will include:
• Evaluation of QoL and health related costs, as detailed in the Integrated QoL
Study and Health Economics Sub-Study
• Exploratory endpoints will include:
• Change in HbA1c in the subgroup of subjects with T2DM on ranolazine versus
placebo at Month 6 and 12 compared to baseline
• New onset T2DM in the ranolazine group versus the placebo group
• Worsening glucose control, defined as an increase of >= 1% in HbA1c, at Month
12 compared to baseline (in subjects with T2DM)
Safety endpoints will include:
• All-cause mortality
• Stroke
• TIA
• CV death, MI or stroke
• Heart failure hospitalization
• Overall adverse events and vital signs
Background summary
See Protocol V4.1 - Page 21 - Section 1.1 Background
Study objective
The primary objective of this study is to:
• Evaluate the efficacy of ranolazine as compared with placebowhen used as part
of standard medical therapy in chronic
angina subjects with incomplete revascularization post percutaneous coronary
intervention (PCI) on the incidence of
major adverse cardiovascular events (MACE), defined as the composite of
cardiovascular (CV) death, myocardial infarction
(MI), or hospitalization for ischemia or angina
The secondary objectives of this study are to:
• Evaluate the efficacy of ranolazine as compared with placebo when used as
part of standard medical therapy in chronic
angina subjects with incomplete revascularization post-PCI on the incidence of
the individual components of the primary endpoint
• Evaluate the efficacy of ranolazine as compared with placebo when used as
part of standard medical therapy in chronic
angina subjects with incomplete revascularization post-PCI on the incidence of
repeat revascularization for ischemia or angina
• Evaluate the efficacy of ranolazine as compared with placebo when used as
part of standard medical therapy in chronic
angina subjects with incomplete revascularization post-PCI on the incidence of
sudden cardiac death
• Assess quality of life (QoL) in the ranolazine group as compared to the
placebo group at Month 1, 6 and 12
• Assess the pharmacoeconomic benefit of ranolazine post-PCI
• Evaluate the tolerability and safety of ranolazine post-PCI
The exploratory objective of this study is to:
• Evaluate the anti-hyperglycemic effect of ranolazine in a subgroup of
subjects with type 2 diabetes mellitus (T2DM)
Study design
Upon providing written consent, subjects will be seen in the catheterization
laboratory, hospital, or outpatient clinic, and assessed for study
participation during Screening. Subjects who undergo PCI for ACS or a non-ACS
indication, and who meet all eligibility criteria, will be eligible for
Randomization once stable post-PCI.
Prior to Randomization, a CK-MB and/or troponin I/T laboratory sample will be
collected post-PCI to obtain a new baseline. For subjects randomized
in-hospital prior to the day of planned discharge, the laboratory sample must
be collected at least 3 hours post-PCI and the results must be reviewed prior
to Randomization to verify stability and confirm subject eligibility. For
subjects randomized in clinic or on the day of planned hospital discharge, the
laboratory sample can be collected anytime post-PCI and Randomization may occur
prior to the receipt of the results and irrespective of the result measured.
Once stable, subjects will be randomized after completing the PCI, but no later
than 14 days post-PCI. In the case of a planned or possible staged procedure,
subjects will be randomized once they are stable after the last PCI, but no
later than 14 days after the last PCI. Subjects may be randomized starting on
the day of PCI and anytime during the following 14 days. PCI is defined as an
attempt to cross the lesion with a wire with the intention of performing
revascularization.
Following PCI, subjects will be treated with standard medical therapies per the
discretion of the Investigator unless contraindicated (eg, aspirin, any second
anti-platelet agent, a lipid-lowering agent, beta-blocker, calcium channel
blockers, nitrates, other antianginals, angiotensin converting enzyme [ACE]
inhibitors, and/or angiotensin receptor blockers [ARBs]). Recommended standard
medical therapies are detailed in Appendix 7. Investigators are encouraged to
follow practice guidelines for the treatment of CAD patients undergoing PCI.
Eligible subjects will be randomized 1:1 to receive either ranolazine or
matching placebo. Randomization will be stratified by reason for undergoing PCI
(ACS versus non-ACS indication) and history of DM (history of type 1 or type 2
DM versus no history of DM).
Subjects will take either ranolazine or matching placebo in addition to their
standard medical therapies for a minimum of 1 year. Dosing of ranolazine or
matching placebo will be 1 tablet twice daily for 7 days, followed by 2 tablets
twice daily for the duration of the study (unless otherwise contraindicated).
Down-titration or interruption of study drug is permitted at any time during
the study in the event of intolerance to the study drug. Subsequent
up-titration to 2 tablets twice daily is also permitted at any time during the
study per Investigator discretion.
In cases where the Investigator has concerns that renal function may
deteriorate below 30mL/min/1.73m2, continuation and up titration of study drug
are left to the discretion of the Investigator, and consultation with the
Medical Monitor is recommended.
Subjects taking moderate CYPP3A4 inhibitors, such as diltiazem, verapamil,
ciprofloxacin or erythromycin, will take a dose of 1 tablet (ranolazine or
matching placebo) twice daily for the duration of the concomitant therapy.
During the Treatment and Follow-Up Period, study visits will occur at
Randomization, Month 1, Month 6, and every 6 months thereafter until the End of
Study. Safety assessments will include an abbreviated physical examination and
vital signs. In addition, an ECG will be performed at Randomization and Month
1. Clinical laboratory samples will also be collected at Randomization, and at
Months 1, 6 and 12, and will be analyzed by a central laboratory.
Subjects will be contacted at 1 week and 2 weeks after Randomization to assess
for tolerability of study drug and encourage compliance with dosing. Subjects
will also be contacted every 3 months in between study visits.
A QoL questionnaire, as detailed in the accompanying Integrated QoL Study and
Health Economics Sub-Study (Appendix 6), will be administered at Randomization,
Month 1, Month 6, and Month 12 (and at the End of Treatment visit for subjects
who withdraw from the study any time prior to the Month 12 visit).
Upon permanent discontinuation of study drug for any reason, an End of
Treatment visit will be performed for all subjects. Telephone follow-up will be
conducted 14 (* 3) days after the last study drug dose to assess the subject*s
condition.
Subjects who permanently discontinue study drug prior to the End of Study and
have not withdrawn consent will enter the Extended Follow-Up Period and will
continue to be followed until the End of Study, or withdrawal of consent. Such
subjects will return to the site for study visits per the visit schedule
established at the time of Randomization to be assessed for safety and for
primary and secondary efficacy endpoint events, as well as heart failure
hospitalizations and possible strokes/transient ischemic attacks (TIA). The
subjects in Extended Follow-Up will also be contacted every 3 months in between
visits. At the End of Study, the subjects will return to the site for an End of
Extended Follow-Up visit.
All randomized subjects must be followed through to their final visit in
accordance with their visit schedule established at the time of Randomization,
regardless of treatment status.
Subjects who withdraw consent will continue to be followed for vital status
from public records such as government vital statistics or obituaries.
During the study, an independent Data Safety Monitoring Board (DSMB) will
monitor primary and secondary endpoint data and safety data at regular
intervals.
All potential primary endpoint events and secondary clinical endpoint events
(all repeat hospitalizations, all repeat coronary angiography with or without
revascularization, all MIs, and all deaths), as well as heart failure
hospitalizations and possible strokes/TIAs will be assessed and adjudicated by
members of an independent Clinical Events Committee (CEC) blinded to treatment
allocation. The study will continue until at least 1 year post-randomization
follow-up has been achieved for all subjects, and at least 720 adjudicated
first post-randomization primary endpoint events (ischemia-driven
revascularization or ischemia-driven hospitalization without revascularization)
have been observed.
Intervention
Ranolazine 500 mg administered orally twice daily for 7 days, followed by 1000
mg (two 500 mg tablets) administered orally twice daily (morning and evening,
approximately 12 hours apart) for the duration of the study.
Subjects taking moderate CYP3A4 inhibitors, such as diltiazem, verapamil,
ciprofloxacin, or erythromycin, will receive ranolazine 500 mg (one 500 mg
tablet) administered orally twice daily (morning and evening, approximately 12
hours apart) for the duration of the concomitant therapy.
One matching placebo tablet, administered orally twice daily for 7 days,
followed by two matching placebo tablets administered orally twice daily
(morning and evening, approximately 12 hours apart) for the duration of the
study.
Subjects taking moderate CYP3A4 inhibitors, such as diltiazem, verapamil,
ciprofloxacin, or erythromycin, will receive one placebo tablet twice daily
(morning and evening, approximately 12 hours apart) for the duration of the
concomitant therapy.
Study burden and risks
An overview of the risks can be found in the informed consent form Appendix 2.
Study procedures can be found in the appendix 2 of the protocol and in the
informed consent form in Appendix 1.
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Age
Inclusion criteria
1.Written informed consent
2.Males and females aged 18 years and older
3.History of chronic angina defined as at least 2 episodes of anginal pain or discomfort in the chest, jaw, shoulder, back, neck, or arm that is precipitated by exertion or emotional stress, and relieved by rest or sublingual nitroglycerin, which occurred on at least 2 separate days and at least 14 days prior to PCI (in the case of staged PCI procedures, at least 14 days prior to the first PCI in the series). Subjects may or may not have additional angina episodes within the 14 days prior to their first PCI in the series, as well as any time prior to Randomization.
4.PCI for any indication (ACS or non-ACS). For the purposes of stratification at randomization, ACS will be defined as hospitalization for anginal pain or discomfort within the previous 24 hours to their hospitalization with any one (or more) of the following criteria:
i.Elevated troponin or creatinine kinase-MB (CK-MB) consistent with MI, as reported by local laboratory and measured prior to index PCI
ii.Electrocardiographic changes (including transient changes) comprising new or presumably new ST segment depression >= 0.1 mV (>= 1 mm), or ST segment elevation >=0.1 mV (>=1 mm) in at least 2 contiguous leads, or new or presumably new Left Bundle Branch Block
5. Randomization within 14 days post-PCI. In the case of staged PCI procedures, randomization has to occur within 14 days of the last PCI in the series. Subjects may be randomized starting
on the day of PCI and anytime during the following 14 days. PCI is defined as an attempt to cross the lesion with a wire with the intention of performing revascularization.
6.Post-PCI (post the last PCI for staged procedures) evidence of incomplete revascularization defined as the presence of one or more visually estimated >= 50% stenoses in one or more coronary arteries with reference vessel diameter of at least 2.0 mm, whether in the target vessel or in a non-target vessel regardless of the presence or absence of coronary collaterals. In the case of a subject post-CABG, incomplete revascularization is defined as the presence of one or more visually estimated >= 50% stenoses in an unbypassed epicardial vessel with a reference diameter >= 2.0 mm, or one or more visually estimated >= 50% stenoses in a bypass graft supplying an otherwise unrevascularized myocardial territory.
7.Clinically stable post-PCI. Subjects randomized in-hospital on day of planned discharge or in clinic are considered stable. Subjects randomized in-hospital prior to day of planned discharge are considered stable if they meet all of the following criteria:
i.CK-MB < 3 times the upper limit of normal (ULN) at least 3 hours post-PCI, or if >= 3 times the ULN with evidence of decreasing CK-MB (decreased by at least 20% from the prior measure), as reported by local laboratory. If CK-MB is not available, a subject must have evidence of normal or decreasing troponin levels (decreased by at least 20% from the prior measure) at least 3 hours post-PCI, as reported by local laboratory.
ii.Systolic blood pressure >= 90 mm Hg and not receiving pressors or inotropes
iii.No current requirement for an intra-aortic balloon pump (IABP) or any left ventricular assist device
iv.No current requirement for intravenous (IV) nitroglycerin
8.Ability and willingness to comply with all study procedures during the course of the study
9.Females of childbearing potential must have a negative pregnancy test at Screening (unless surgically sterile or post-menopausal) and must agree to use highly effective contraception methods from Screening throughout the duration of study treatment and for 14 days following the last dose of study drug. See Section 8.7 for a description of acceptable methods of contraception and definition of post-menopausal status.
Exclusion criteria
1.Any future planned revascularization (including staged procedures) or possible planned revascularization (ie, planned stress test to assess the imminent need for additional revascularization). Future planned stress tests for purposes of monitoring are permitted but strongly discouraged. Subjects may be enrolled after the last PCI in the staged series or once a decision is made not to perform a follow up PCI, as long as Randomization occurs within 14 days from the last PCI. If a subject has had a stress test post-PCI and prior to Randomization and no further intervention is planned, the subject may be enrolled within 14 days from the last PCI.
2.Unrevascularized left main coronary artery stenosis >= 50%. Subjects with history of CABG to the left coronary system will be considered to have a revascularized left main if at least one graft is patent.
3.Major complication during or after the index PCI (in the case of staged PCI, the last in the series) including any of the following:
i.Major bleeding (TIMI Bleeding classification [Appendix 5] or any bleeding requiring >= 2 units of red blood cells)
ii.Coronary perforation requiring treatment
iii.Procedural complication requiring surgery (including CABG or peripheral vascular surgery)
4.Stroke within 90 days prior to Randomization, or any history of stroke with permanent major neurologic disability (eg, aphasia or significant motor dysfunction)
5.Cardiogenic shock within 90 days prior to Randomization (transient decreases in blood pressure without clinical sequelae are not considered to be cardiogenic shock)
6.New York Heart Association (NYHA) Class III or IV heart failure
7.Severe renal insufficiency as assessed by an estimated GFR < 30 mL/min/1.73m2 using the 4 variable modification of diet in renal disease (MDRD) equation (Appendix 8) per local laboratory (based on the last available measurement prior to Randomization, collected within 1 month prior to the index PCI [in the case of staged PCI, the last in the series])
8.Liver cirrhosis
9.Use of Class Ia, Ic, or Class III antiarrhythmics, except for amiodarone (as detailed in Appendix 4)
10.Current treatment with strong inhibitors of CYP3A (as detailed in Appendix 3)
11.Current treatment with CYP3A4 inducers or P-gp inducers (as detailed in Appendix 3)
12.Subjects taking > 20 mg simvastatin daily or > 40 mg lovastatin daily who cannot reduce the dose to 20 mg once daily for simvastatin or 40 mg once daily for lovastatin, or who cannot switch to another statin
13.Subjects taking greater than a total of 1000 mg daily of metformin who cannot reduce the dose to a maximum total of 1000 mg daily (additional anti-diabetic medications may be added as clinically indicated to allow subjects to decrease their metformin dose and maintain glycemic control)
14.Previous treatment with ranolazine for > 7 consecutive days within 30 days prior to Randomization, or known hypersensitivity or intolerance to ranolazine or to any of the excipients
15.Participation in another investigational drug or investigational device study within 30 days prior to Randomization (participation in registries is allowed)
16.Women who are pregnant or breast feeding
17.Non-CAD comorbid conditions (eg, advanced malignancy, severe aortic stenosis) which are likely to result in death within 2 years of Randomization
18.Any condition that in the opinion of the investigator would preclude compliance with the study protocol
Any condition that in the opinion of the investigator would preclude compliance with the study protocol
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-002507-15-NL |
| ClinicalTrials.gov | NCT01442038 |
| CCMO | NL38766.101.11 |