Pentaerithrityl Tetranitrate in Chronic Stable Angina
Pentaerithrityl Tetranitrate in Chronic Stable Angina
The trial (CLEOPATRA study) was designed as a phase III, randomized, double-blind, placebo-controlled, multicentre trial. A total of 127 centres were initiated in Belarus, Bulgaria, Georgia, Germany, Hungary, Iceland, India, Poland, Romania, Russia, and Serbia (only 95 centres recruited at least one patient). The study was approved by all relevant competent authorities and received a favourable opinion from all responsible independent ethics committees. All patients gave voluntary written informed consent.
Patients were included in the study if all the following criteria were satisfied: (i) voluntary informed consent in writing; (ii) age >18 years; (iii) history of stable effort angina for >3 months prior to study entry; (iv) clinical stability; (v) CAD documented by at least one of the following: history of myocardial infarction (Q-wave and/or cardiac enzyme elevation) at least 3 months before inclusion, coronary angioplasty at least 6 months before inclusion, bypass graft at least 3 months before inclusion, coronary angiography showing a significant stenosis (at least 50% relative diameter reduction in the proximal two-thirds of at least one of the major coronary arteries), exercise-induced reversible ischaemia in patients without left bundle branch block, a positive stress echocardiography showing regional wall motion abnormalities or no improvement in left ventricular ejection fraction under exercise; (vi) no ST-segment abnormality in a 12-lead electrocardiogram (ECG) at rest, and no bundle branch block or conditions precluding ST-segment interpretation at rest or during exercise, and sinus rhythm; (vii) at least four angina pectoris attacks in the 4-week period preceding randomization; (viii) compliance to treatment (calculated compliance ≥85%, with less than one full daily placebo dose missed during the placebo run-in period); (ix) a positive and repeatable exercise treadmill test (see definition below).
Exclusion criteria comprised: recent acute infarction or bypass surgery, unstable angina, significant valvular disease, hypersensitivity to nitrates, anticipated revascularization procedures, incapacity to perform an exercise test, significant left main stem stenosis, congestive heart failure NYHA III–IV, symptomatic hypotension, uncontrolled hypertension, atrial fibrillation, flutter, pacemaker or implantable defibrillator, ECG abnormalities confounding the interpretation of ST-changes, hepatic and electrolyte disorders, anaemia, thyroid disorders, treatment with amiodarone, use of digitalis, inability to suspend therapy with long-acting nitrates or calcium antagonist prior to inclusion, treatment with phosphodiesterase-5 inhibitors, hepatitis B, C, or HIV infection, psychiatric disorders, use of an investigational drug within 30 days of inclusion in the study, malignant disease, pregnancy or breast feeding, participation in another clinical trial, and poor compliance.
The study design is depicted in Figure 1. Before randomization, patients were requested to return to the study centres on two occasions. During the 'inclusion visit', the criteria listed above were evaluated and therapy with long-acting nitrates and calcium-channel antagonists was suspended for at least four half-lives. During the 'selection visit', the first exercise treadmill test was performed. All patients were then administered placebo tablets to be taken b.i.d. (single-blind placebo run-in period) for 1 week, after which ('randomization visit', V0) a second ETT was performed. At this point, patients were randomized to receive PETN 80 mg or placebo b.i.d. (8 a.m. and 1 p.m.). Background anti-anginal therapy with beta-blockers, ivabradine, ACE-inhibitors and/or angiotensin receptor blockers, statins, and diuretics was protracted as indicated. Patients, investigators, central readers of the ETT data, and the sponsor were blinded to the treatment received by the patients. After 6 weeks and 12 weeks of therapy, a third (6-week ETT, 'control visit', V1) and fourth ETT (12-week ETT, 'end of trial visit', V2) were performed. At each visit, data on the frequency of angina attacks and consumption of short-acting nitrates were collected from patient diaries and standard questionnaires. Patients also underwent a physical examination as well as sampling of blood chemistry and haematology prior to randomization (selection visit) and at the end of the trial (V2). 12-lead ECGs at rest were performed on each visit. Concomitant treatment with long-acting nitrates and calcium antagonists or substances that would interfere with the interpretation of the ECG such as antiarrhythmic agents and digitalis was considered to be an exclusion criterion.
(Enlarge Image)
Figure 1.
Study protocol. All patients underwent four exercise treadmill tests: the first at the moment of enrolment into the study, the second 1 week later after a 7-day patient-blinded run-in period during which they received placebo treatment. The third and fourth treadmill tests were performed at 6 and 12 weeks into treatment.
In order to reduce the variability in test performance, two ETTs were performed before randomization using a modified Bruce treadmill ergometer protocol. A positive ETT was defined as occurrence of limiting angina with ST-segment depression of at least 1 mm (horizontal or down sloping and persisting for at least 0.08 s after J-point, on at least three consecutive complexes) between 2.5 and 12 min of initiation of an ETT (between 2.5 and 9 in the first version of the protocol, later extended to 12 min to accelerate recruitment). The ECG changes had to be present in both ETTs performed before randomization with a difference of <20% in total exercise duration (TED) between visits. If one of the two ETTs was interrupted for any reason other than limiting angina, the patient was not included.
All ETTs were performed at the end of the first daily dosing interval, i.e. 5 h after the intake of the morning dose. Symptom-limited ETTs (modified Bruce protocol) were performed using calibrated treadmill ergometers. All ECG data were analysed centrally by a physician blinded to the patients' treatment and not involved in other study procedures. The following intervals were documented in seconds: time to onset of angina (TAP); time to limiting angina (exercise duration beyond which the patient would not be able to continue with the exercise due to anginal pain, TLA); time to 1 mm ST-segment depression (TST), as defined by a horizontal or down-sloping ST-segment for >0.08 s after the J-point; TED (indications for terminating exercise testing were based on the clinical criteria by Gibbons et al.). Smoking and short-acting nitrates were prohibited for at least 2 h before the exercise test.
The trial endpoints used in the current trial are in accordance with the EMA guideline CPMP/EWP/234/95 (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003316.pdf). Primary efficacy endpoint was the change in TED (in seconds) after 12 weeks of treatment with PETN 80 mg b.i.d. compared with placebo b.i.d. assessed in the trough between the morning and the mid-day dose (i.e. at 5 h after intake of morning dose of trial medication). Secondary efficacy endpoints included changes in TED (seconds) after 6 weeks of treatment as well as the following (at 6 and 12 weeks): TAP, TLA, TST, exercise capacity (METs), angina attack frequency (according to patient diary), concomitant use of short-acting nitrates (according to patient diary), health-related quality of life scores using the Seattle Standard Questionnaire and the EQ-5D; the patient's perceived exertion level was recorded using the Borg scale.
All the data were collected using an electronic case report form and analysed by an independent statistician based on a pre-defined statistical analysis plan. The analysis of efficacy was performed for the intention-to-treat (ITT) population with regard to primary and secondary efficacy endpoints. All patients who received at least one dose of study medication and had at least one post-baseline efficacy measurement were included in the ITT population. Non-completers were included in the ITT population, using the last-observation-carried-forward approach. In addition, all analyses were performed on the per-protocol population as secondary efficacy analyses. Safety data were presented for the safety population, which includes all patients who received at least one dose of study medication.
The primary efficacy endpoint 'change in TED after 12 weeks' and the secondary efficacy endpoints were analysed using an analysis of covariance (ANCOVA), including country, treatment, use of anti-anginal background therapy as fixed class effects and baseline TED (ETT before randomization) as a covariate.
Subgroup analyses were carried out on the ITT population restricted to the change in TED, TAP, and TST from randomization to week 12. Subgroup analyses included country and anti-anginal background therapy, gender, age (< or >65 years), TED at baseline (divided in quartiles), co-morbidities (diabetes mellitus, hypertension, hyperlipidaemia as well as smoking habits), protocol version (version 1 allowing inclusion of patients with a baseline TED ≤9 min only, version 2 extending this limit to 12 min). Since long-term therapy with organic nitrates is generally applied in symptomatic patients, the same analysis was performed in a subset of patients meeting the following criteria: TED at inclusion between 2.5 and 9 min; occurrence of more than one angina attack during the run-in week; consumption of more than one dose of short-acting nitrates during the run-in week.
With a one-sided significance level of 0.025 and anticipated 90% power, power calculations showed that 350 patients in each treatment group (700 overall) were needed to detect an anticipated therapeutic effect of 41.5 s for PETN vs. placebo (SD assumed: 169 s). Statistical analyses were performed using SAS® version 9.2.
Methods
The trial (CLEOPATRA study) was designed as a phase III, randomized, double-blind, placebo-controlled, multicentre trial. A total of 127 centres were initiated in Belarus, Bulgaria, Georgia, Germany, Hungary, Iceland, India, Poland, Romania, Russia, and Serbia (only 95 centres recruited at least one patient). The study was approved by all relevant competent authorities and received a favourable opinion from all responsible independent ethics committees. All patients gave voluntary written informed consent.
Patient Selection
Patients were included in the study if all the following criteria were satisfied: (i) voluntary informed consent in writing; (ii) age >18 years; (iii) history of stable effort angina for >3 months prior to study entry; (iv) clinical stability; (v) CAD documented by at least one of the following: history of myocardial infarction (Q-wave and/or cardiac enzyme elevation) at least 3 months before inclusion, coronary angioplasty at least 6 months before inclusion, bypass graft at least 3 months before inclusion, coronary angiography showing a significant stenosis (at least 50% relative diameter reduction in the proximal two-thirds of at least one of the major coronary arteries), exercise-induced reversible ischaemia in patients without left bundle branch block, a positive stress echocardiography showing regional wall motion abnormalities or no improvement in left ventricular ejection fraction under exercise; (vi) no ST-segment abnormality in a 12-lead electrocardiogram (ECG) at rest, and no bundle branch block or conditions precluding ST-segment interpretation at rest or during exercise, and sinus rhythm; (vii) at least four angina pectoris attacks in the 4-week period preceding randomization; (viii) compliance to treatment (calculated compliance ≥85%, with less than one full daily placebo dose missed during the placebo run-in period); (ix) a positive and repeatable exercise treadmill test (see definition below).
Exclusion Criteria
Exclusion criteria comprised: recent acute infarction or bypass surgery, unstable angina, significant valvular disease, hypersensitivity to nitrates, anticipated revascularization procedures, incapacity to perform an exercise test, significant left main stem stenosis, congestive heart failure NYHA III–IV, symptomatic hypotension, uncontrolled hypertension, atrial fibrillation, flutter, pacemaker or implantable defibrillator, ECG abnormalities confounding the interpretation of ST-changes, hepatic and electrolyte disorders, anaemia, thyroid disorders, treatment with amiodarone, use of digitalis, inability to suspend therapy with long-acting nitrates or calcium antagonist prior to inclusion, treatment with phosphodiesterase-5 inhibitors, hepatitis B, C, or HIV infection, psychiatric disorders, use of an investigational drug within 30 days of inclusion in the study, malignant disease, pregnancy or breast feeding, participation in another clinical trial, and poor compliance.
Study Protocol
The study design is depicted in Figure 1. Before randomization, patients were requested to return to the study centres on two occasions. During the 'inclusion visit', the criteria listed above were evaluated and therapy with long-acting nitrates and calcium-channel antagonists was suspended for at least four half-lives. During the 'selection visit', the first exercise treadmill test was performed. All patients were then administered placebo tablets to be taken b.i.d. (single-blind placebo run-in period) for 1 week, after which ('randomization visit', V0) a second ETT was performed. At this point, patients were randomized to receive PETN 80 mg or placebo b.i.d. (8 a.m. and 1 p.m.). Background anti-anginal therapy with beta-blockers, ivabradine, ACE-inhibitors and/or angiotensin receptor blockers, statins, and diuretics was protracted as indicated. Patients, investigators, central readers of the ETT data, and the sponsor were blinded to the treatment received by the patients. After 6 weeks and 12 weeks of therapy, a third (6-week ETT, 'control visit', V1) and fourth ETT (12-week ETT, 'end of trial visit', V2) were performed. At each visit, data on the frequency of angina attacks and consumption of short-acting nitrates were collected from patient diaries and standard questionnaires. Patients also underwent a physical examination as well as sampling of blood chemistry and haematology prior to randomization (selection visit) and at the end of the trial (V2). 12-lead ECGs at rest were performed on each visit. Concomitant treatment with long-acting nitrates and calcium antagonists or substances that would interfere with the interpretation of the ECG such as antiarrhythmic agents and digitalis was considered to be an exclusion criterion.
(Enlarge Image)
Figure 1.
Study protocol. All patients underwent four exercise treadmill tests: the first at the moment of enrolment into the study, the second 1 week later after a 7-day patient-blinded run-in period during which they received placebo treatment. The third and fourth treadmill tests were performed at 6 and 12 weeks into treatment.
Exercise Treadmill Tests
In order to reduce the variability in test performance, two ETTs were performed before randomization using a modified Bruce treadmill ergometer protocol. A positive ETT was defined as occurrence of limiting angina with ST-segment depression of at least 1 mm (horizontal or down sloping and persisting for at least 0.08 s after J-point, on at least three consecutive complexes) between 2.5 and 12 min of initiation of an ETT (between 2.5 and 9 in the first version of the protocol, later extended to 12 min to accelerate recruitment). The ECG changes had to be present in both ETTs performed before randomization with a difference of <20% in total exercise duration (TED) between visits. If one of the two ETTs was interrupted for any reason other than limiting angina, the patient was not included.
Exercise Testing
All ETTs were performed at the end of the first daily dosing interval, i.e. 5 h after the intake of the morning dose. Symptom-limited ETTs (modified Bruce protocol) were performed using calibrated treadmill ergometers. All ECG data were analysed centrally by a physician blinded to the patients' treatment and not involved in other study procedures. The following intervals were documented in seconds: time to onset of angina (TAP); time to limiting angina (exercise duration beyond which the patient would not be able to continue with the exercise due to anginal pain, TLA); time to 1 mm ST-segment depression (TST), as defined by a horizontal or down-sloping ST-segment for >0.08 s after the J-point; TED (indications for terminating exercise testing were based on the clinical criteria by Gibbons et al.). Smoking and short-acting nitrates were prohibited for at least 2 h before the exercise test.
Endpoints
The trial endpoints used in the current trial are in accordance with the EMA guideline CPMP/EWP/234/95 (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003316.pdf). Primary efficacy endpoint was the change in TED (in seconds) after 12 weeks of treatment with PETN 80 mg b.i.d. compared with placebo b.i.d. assessed in the trough between the morning and the mid-day dose (i.e. at 5 h after intake of morning dose of trial medication). Secondary efficacy endpoints included changes in TED (seconds) after 6 weeks of treatment as well as the following (at 6 and 12 weeks): TAP, TLA, TST, exercise capacity (METs), angina attack frequency (according to patient diary), concomitant use of short-acting nitrates (according to patient diary), health-related quality of life scores using the Seattle Standard Questionnaire and the EQ-5D; the patient's perceived exertion level was recorded using the Borg scale.
Statistical Analysis
All the data were collected using an electronic case report form and analysed by an independent statistician based on a pre-defined statistical analysis plan. The analysis of efficacy was performed for the intention-to-treat (ITT) population with regard to primary and secondary efficacy endpoints. All patients who received at least one dose of study medication and had at least one post-baseline efficacy measurement were included in the ITT population. Non-completers were included in the ITT population, using the last-observation-carried-forward approach. In addition, all analyses were performed on the per-protocol population as secondary efficacy analyses. Safety data were presented for the safety population, which includes all patients who received at least one dose of study medication.
The primary efficacy endpoint 'change in TED after 12 weeks' and the secondary efficacy endpoints were analysed using an analysis of covariance (ANCOVA), including country, treatment, use of anti-anginal background therapy as fixed class effects and baseline TED (ETT before randomization) as a covariate.
Subgroup analyses were carried out on the ITT population restricted to the change in TED, TAP, and TST from randomization to week 12. Subgroup analyses included country and anti-anginal background therapy, gender, age (< or >65 years), TED at baseline (divided in quartiles), co-morbidities (diabetes mellitus, hypertension, hyperlipidaemia as well as smoking habits), protocol version (version 1 allowing inclusion of patients with a baseline TED ≤9 min only, version 2 extending this limit to 12 min). Since long-term therapy with organic nitrates is generally applied in symptomatic patients, the same analysis was performed in a subset of patients meeting the following criteria: TED at inclusion between 2.5 and 9 min; occurrence of more than one angina attack during the run-in week; consumption of more than one dose of short-acting nitrates during the run-in week.
With a one-sided significance level of 0.025 and anticipated 90% power, power calculations showed that 350 patients in each treatment group (700 overall) were needed to detect an anticipated therapeutic effect of 41.5 s for PETN vs. placebo (SD assumed: 169 s). Statistical analyses were performed using SAS® version 9.2.
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