Study design
The INCODER study is a multicenter, randomized, double-blind, parallel controlled, superiority clinical trial. Patients will be randomly divided into two group: intensive treatment group (CDDP 20 pills three times per day) or control group (CDDP 10 pills three times per day). Figure 1 shows the design and procedures through the trial.
Study hypothesis
The administration of CDDP 20 pills three times per day is superior to 10 pills three times per day with respect to efficacy and safety in patients with refractory angina with ICR.
Study population, eligibility criteria and recruitment
Patients aged 18 to 85 years with a diagnosis of stable refractory angina with ICR are eligible for participation. Patients were eligible for inclusion in the study if they had a history of CAD with refractory angina (Canadian Cardiovascular Society [CCS] class II to III) despite optimal medical therapy for at least one month. Optimal medical therapy is defined as guideline-recommended treatment including secondary prevention and at least two antianginal drugs: one is nitrates, another is beta-blocker or calcium channel blocker, except for medication contraindications. 20 ICR is defined as the presence of ≥ 1 lesion with visually estimated ≥ 50% diameter stenosis in any coronary artery (including branch vessels) of ≥ 2.0 mm in diameter, whether in the target vessel or in a nontarget vessel. In the case of a participant post-CABG, ICR is defined as the presence of ≥ 1 lesion with visually estimated ≥ 50% diameter stenosis in a nonbypassed epicardial vessel ≥ 2.0 mm in diameter, or ≥ 1 visually estimated ≥ 50% diameter stenosis in a bypass graft supplying an otherwise nonrevascularized myocardial territory. 21 The ejection fraction should be at least 30%. Patients are willing to sign the informed consent form.
The exclusion criteria are detailed in Table 1. Patients with acute coronary syndrome within 1 months or planned coronary revascularization during the study period, or history of transient ischemia attack within 2 months are excluded. Patients with severe joint diseases, severe peripheral vascular disease, severe pulmonary hypertension, uncontrolled chronic obstructive pulmonary disease and other comorbidities that might affect the results of the cardiopulmonary exercise testing are excluded. We also exclude patients with abnormalities in electrocardiogram in the rest including preexcitation syndrome ventricular pacing rhythm, ST segment depressed more than 1 mm in the rest, left bundle branch block or any intraventricular conduction block and QRS duration more than 120 ms that might influence the interpretation of the termination of CPET. Patients with severe comorbidity, pregnant or lactation are also excluded. Study candidates will be assessed for eligibility within 2 weeks prior to enrolment.
Table 1
Inclusion criteria
1. Age 18 to 85 years.
2. Had a history of coronary artery disease with refractory angina [Canadian Cardiovascular Society (CCS) class II to III] despite optimal medical therapy for at least one month.
- Optimal medical therapy is defined as guideline-recommended treatment including secondary prevention and at least two antianginal drugs: one is nitrates, another is beta-blocker or calcium channel blocker, except for medication contraindications.
3. With incomplete revascularization (ICR).
- ICR is defined as the presence of ≥ 1 lesion with visually estimated ≥ 50% diameter stenosis in any coronary artery (including branch vessels) of ≥ 2.0 mm in diameter, whether in the target vessel or in a nontarget vessel. In the case of a participant post-CABG, ICR is defined as the presence of ≥ 1 lesion with visually estimated ≥ 50% diameter stenosis in a nonbypassed epicardial vessel ≥ 2.0 mm in diameter, or ≥ 1 visually estimated ≥ 50% diameter stenosis in a bypass graft supplying an otherwise nonrevascularized myocardial territory.
4. The ejection fraction ≥ 30%.a
5. Willing to sign the informed consent form.
Exclusion criteria
1. Acute coronary syndrome within 1 month or planned coronary revascularization during the study period;
2. Episode of transient ischemia attack, ischemic or hemorrhagic stroke within 2 months;
3. Presence of neuromuscular, orthopedic or other non-cardiac condition such as severe peripheral artery disease, severe pulmonary hypertension and uncontrolled chronic obstructive pulmonary disease or asthma that prevents the patient from exercise testing on a cycle ergometer;
4. Patients with the following resting electrocardiographic abnormalities that might influence the interpretation of the termination of CPET:
- Pre-excitation (Wolff-Parkinson-White) syndrome
- Electronically paced ventricular rhythm
- 1 mm or more of resting ST depression
- Complete left bundle-branch block or any interventricular conduction defect with a QRS duration greater than 120 ms
5. Uncontrolled symptomatic heart failure;
6. Moderate to severe symptomatic aortic stenosis;
7. Hypertrophic cardiomyopathy;
8. Acute myocarditis or pericarditis;
9. Active endocarditis;
10. Acute pulmonary embolism;
11. Suspected or known acute aortic dissection;
12. Severe hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg at screening);
13. Severe anemia (Hemoglobin < 60 g/L);
14. Active psychosis requiring anticonvulsant treatment;
15. Pregnant or lactating women.
16. Participation in other clinical studies within 30 days before the first visit.
|
CABG, coronary artery bypass grafting; CPET, cardiopulmonary exercise testing. |
a Echocardiographic results measured with 3 months before obtaining informed consent can be used for assessing eligibility. |
The study will be conducted in 10 medical centers in China. Patients will be recruited by local physicians using posters and advertisement in the hospital and nearby communities. Posters and advertisements contain brief introductions about the study and the contact information of the investigators. The study will be detailed explained to the potential participants and informed written consent will be obtained prior to enrolment.
Randomization, allocation and blinding
Randomization is generated using computer-generated random permuted blocks by a designated statistician not involved in study operations using SAS V9.4 software. Either CDDP or placebo will be packaged identically and labeled with a number according to the randomization list. The treatment kit numbers will be obtained by the investigatiors at the time of patients’ randomization and treatment kits will be strictly sequentially allocated to patients according to the randomization list. In accordance with the double-blind design, the sponsor, study patients, investigators and study site personnel will remain blinded to study treatment.
The randomization code will be kept in opaque sealed envelopes and secured by both the sponsor and the principal investigator and can only be broken in exceptional circumstances when knowledge of the investigational drug is essential for treating the patient. If the randomization code is uncovered, the investigator should document the reason for unblinding, and the administration of investigational drug will be discontinued.
Intervention
The intensive treatment group is administered with CDDP (produced by Tasly Pharmaceutical Group Co. Ltd., China) at a dose of 20 pills three times per day while the control group taking a traditional dose of 10 pills CDDP and 10 pills placebo three times per day orally after meals. All the patients will be treated for 6 weeks. CDDP or placebo pills are identical in size and smell. Every 20 pills (20 pills CDDP for intensive treatment group or 10 pills CDDP and 10 pills placebo for control group) are stored in one identical bottle. Patients take one bottle three times per day.
Concomitant medication
Study participants should be treated with standard CAD therapies as per recommended guidelines. The following drugs are prohibited during the whole study including ivabradine, ranolazine, nicorandil, trimetazidine and other antianginal Chinese traditional medicine (including ginkgo biloba dropping pill, ginkgolide dropping pill, Shexiang Baoxin Pill, Xinkeshu tablet, Naoxintong, Naoxinqing, xueshuantong, Di'ao xinxuekang capsule, Yinzhan xinmai dropping pill, Xinnaoxin, Zhenyuan capsule, Suxiao Jiuxin Pill, Tongxinluo, Guanxin Danshen Dropping Pill, yindanxintai dropping pill, etc). However, other kinds of medications are taken as needed. The concomitant medication will be recorded throughout the trial and analyzed if necessary.
Outcomes
Primary outcome
The primary outcome is the change in total exercise time evaluated by CPET from baseline to week 6 in the intention-to-treat (ITT) population.
Secondary outcomes
The secondary outcomes include change from baseline to week 6 in the following parameters including frequency of angina, nitroglycerin use, CCS angina class improvement, Seattle Angina Questionnaire (SAQ) scores, CPET indexes as well as plasma C-reactive protein (CRP), homocysteine and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Safety assessment includes adverse events during the whole study period, vital signs, physical examination, 12-lead electrocardiogram (ECG), laboratory tests and rescue medication use (Table 2).
Table 2
Efficacy and safety endpoints
Primary endpoint
The changes in total exercise time evaluated by CPET from baseline to week 6
Secondary endpoint
The changes of the following parameters from baseline to week 6
1. Frequency of angina
2. Frequency of nitroglycerine use
3. Proportion of patients experiencing an improvement of ≥ 1 CCS angina classes
4. Proportion of patients experiencing an improvement of ≥ 2 CCS angina classes
5. The SAQ scores subdivided in the following 5 dimensions
- Physical limitation;
- Anginal stability;
- Anginal frequency;
- Treatment satisfaction;
- Disease perception.
6. CPET parameters
- Peak VO2 (ml/min)
- Peak VO2 (ml/min/kg)
- VO2 at anaerobic threshold (ml/min)
- VO2 at anaerobic threshold (ml/min/kg)
- Peak METs
- Peak work rate (W)
- O2 pulse at peak exercise (mL/beat)
- PETO2 at peak exercise (mmHg)
- PETCO2 at peak exercise (mmHg)
- VE/VCO2 slope
- ΔVO2/Δwork-rate (ml/min/W)
7. Plasma CRP, homocysteine and NT-proBNP
Safety endpoints
1. Treatment-emergent adverse event
2. Vital signs
3. Physical examination
4. ECG
5. Clinal laboratory tests
|
CPET: cardiopulmonary exercise testing; CCS, Canadian Cardiovascular Society; SAQ, Seattle Angina Questionnaire; VO2, Oxygen uptake; METs, metabolic equivalent levels; PETO2, partial pressure of end-tidal oxygen; PETCO2, partial pressure of end-tidal carbon dioxide; VE/VCO2, Ventilatory equivalent of carbon dioxide; CRP, C-reactive protein; NT-proBNP, amino-terminal pro-B-type natriuretic peptide; ECG: electrocardiography. |
Study Timelines
Screening visit (Week − 2)
Schedule of enrolment and assessments are listed in Table 3. Subjects will be evaluated at the screening visit 2 weeks prior to enrolment through a complete medical history, vital signs, physical examination, 12-lead ECG, transthoracic echocardiography (TTE), eligibility laboratory tests and a review of concomitant medications. Eligibility and baseline laboratory examinations include urine pregnancy testing for women with childbearing potential, complete blood count, serum lipids, biochemical tests, coagulation test and cardiac biomarkers. Baseline parameters for efficacy evaluation including CRP, homocysteine and NT-proBNP will also be examined. TTE measured with 3 months before obtaining informed consent can be used for eligibility assessment. Severity of angina will be assessed including CCS angina class, frequency of angina attack and nitroglycerin use.
Table 3
Visit number
|
V1
|
V2
|
V3
|
V4
|
V5
|
Week
|
-2
|
0
|
2
|
4
|
6
|
Day
|
-14 ± 3
|
0
|
14 ± 3
|
28 ± 3
|
42 ± 3
|
Informed consent
|
×
|
|
|
|
|
Inclusion/ exclusion criteria
|
×
|
×
|
|
|
|
Medical history
|
×
|
×
|
|
|
|
Concomitant medication
|
×
|
×
|
×
|
×
|
×
|
Vital signs
|
×
|
×
|
×
|
×
|
×
|
Physical examination
|
×
|
×
|
×
|
×
|
×
|
urine pregnancy testing a
|
×
|
|
|
|
|
12-lead ECG
|
×
|
×
|
×
|
×
|
×
|
Transthoracic echocardiography b
|
×
|
|
|
|
|
CCS class
|
×
|
×
|
×
|
×
|
×
|
SAQ scores
|
|
×
|
×
|
×
|
×
|
Frequency of angina
|
×
|
×
|
×
|
×
|
×
|
CPET
|
|
×
|
|
|
×
|
Laboratory tests c
|
×
|
|
|
|
×
|
Dispense study medication and collect empty study medication
|
|
×
|
×
|
×
|
×
|
Dispense nitroglycerin and collect the remaining pills;
|
×
|
×
|
×
|
×
|
×
|
Compliance evaluation
|
|
×
|
×
|
×
|
×
|
Adverse events
|
×
|
×
|
×
|
×
|
×
|
ECG: electrocardiogram; CCS, Canadian Cardiovascular Society; SAQ: Seattle angina questionnaire; CPET: cardiopulmonary exercise testing. |
a Urine pregnancy testing for women with childbearing potential for eligibility. |
b Echocardiographic results measured with 3 months before obtaining informed consent can be used for assessing eligibility. |
c Laboratory tests for efficacy and safety include: |
- Complete blood count |
- Serum lipids |
- Biochemical indexes: alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK) and creatinine |
- Coagulation indexes: prothrombin time (PT), partially activated prothrombin time (APTT), international normalized ratio (INR), coagulation time (TT), fibrinogen (FBG) and D-dimer |
- Cardiac biomarkers: myoglobin (MYO), cardiac troponin T (cTnT) and creatine kinase-MB isoenzyme (CK-MB) |
- Parameters for efficacy: C-reactive protein (CRP), homocysteine and amino-terminal pro-B-type natriuretic peptide (NT-proBNP). |
Wash-out period
Patients who are taking other antianginal drugs that are contraindicated in our study at screening will be asked to start a 2-week wash-out period, in which they will discontinue the antianginal drugs and follow the optimal medical therapy. Nitroglycerin is allowed during the wash-out period and should be recorded when used.
Baseline visit (Week 0)
Research participants will complete all baseline procedures, including: clinical evaluation, angina assessment, SAQ scores and CPET. Patients who fulfill all the inclusion criteria and none of the exclusion criteria will be randomized with a 1:1 allocation ratio to receive either CDDP 20 pills three times per day or 10 pills three times per day. Nitroglycerin will also be dispensed for angina attack when needed. Patients are asked to record every angina attack and nitroglycerin consumption during the study.
Follow-up visit (Week 2 and week 4)
Patients will be followed up every two weeks to assess safety and tolerability. Vital signs, physical examination, angina assessment and SAQ scores will be recorded. Any adverse events during the intervening period since screening/ baseline visit will be recorded. Study drug dispensed at screening/ baseline visit will be collected for compliance calculation.
Final evaluation (Week 6)
Final evaluations will be conducted 6-weeks following the baseline assessment. Vital signs, physical examination, 12-lead ECG, angina assessment, SAQ scores, laboratory analyses and adverse events will be assessed. Blood analyses including CRP, homocysteine and NT-proBNP for efficacy assessments and other parameters for safety assessments consistent with baseline will be performed. CPET will be conducted for efficacy evaluation.
Data collection, management, and analysis
Sample collection and laboratory measurements
Blood sample collection is scheduled at screening/randomization and at the final visit. Blood samples are first collected into evacuated tubes, clot for 30 min at room temperature, and then centrifugated for 10 min at 3000 × g at room temperature. Beckman Coulter AU5800 chemistry analyzer are used for further measurements. Urine samples will also be collected at screening for urine pregnancy test for women with childbearing potential. All the laboratory measurements mentioned above will be performed at the Department of Laboratory Medicine of each site with consistent external quality control.
Angina Assessment
CCS angina class, SAQ scores, frequency of angina attack and nitroglycerin use will be recorded for angina assessment during the whole study period. The SAQ scores measure five important dimensions of CAD including physical limitation, anginal stability, anginal frequency, treatment satisfaction and disease perception. 22
Cardiopulmonary Exercise Testing
CPET is conducted on an electronically braked cycle ergometer (Ergoline GmbH, Germany) using a ramp protocol according to the statement from the American Heart Association. 23, 24 Expired gases are collected and analyzed breath by breath. The test includes several stages 23: 1) rest for 3 minutes: measurements of rest ECG, blood pressure, heart rate and pulse oxygen saturation. 2) unloading exercise for 3 minutes; 3) incremental exercise: The increment rate is set between 10 W·min− 1 to 20 W·min− 1 based on patients’ characteristics in order to obtain approximately 10 min duration. The resistance gradually increases every six seconds. All patients are instructed to cycle with a pedal frequency of 60 revolutions per minute (rpm), and are encouraged to keep exercising until exhaustion, or symptoms of chest tightness, chest pain and shortness of breath, or inability to maintain the pedal frequency of 60 rpm. 4) recovery: unloading exercise for 3 minutes, then rest 5 to 10 minutes. The blood pressure is measured by using Tango M2 Stress Test Monitor. The heart rate is determined from the electrocardiogram and expressed as the percentage of the predicted value (220-age). The 12-lead electrocardiogram is continuously recorded during the test. Symptoms were assessed by means of the Borg's Rating of Perceived Exertion (RPE, Borg’s 6–20 Scale). 25 Peak exercise was considered the highest VO2 achieved during active exercise or early recovery. Heart rate and respiratory exchange ratio (RER) are objective indicators for peak exercise. Peak VO2 was determined as the highest mean VO2 over 20 s. 24 Parameters measured during CPET in our study are listed in supplementary Table 1. The indications of termination of the test are detailed in supplementary Table 2. The total exercise time and reason for termination will be recorded.
Compliance evaluation
Compliance will be evaluated by counting the number of bottles returned at every follow-up visit (total doses taken divided by total prescribed doses). Of note, the denominator (total prescribed doses) will be calculated over the actual duration the subject is in the study. Subjects will be informed of the intention to monitor compliance in the informed consent form.
Adverse events and safety
Adverse events will be assessed and recorded in the case report forms during the whole study. Given the nature of the intervention, the most common adverse reactions related to CDDP including gastrointestinal symptoms, headache and facial flushing will be monitored. Although CPET is fairly safe with the serious complications rate of < 1 to 5 per 10 000 tests and death rate around 0.5 per 10 000 tests, complications do occur and should be paid attention. 24, 26 Major complications include death, myocardial infarction, angina pectoris, arrhythmia, hemodynamic instability and orthopedic injury. 21 Therefore, the test should strictly follow the guideline for exercise stress testing especially the indications to stop the test (Supplementary Table 2).
All serious adverse events (SAEs) will be assessed and reported to the ethics committee in accordance with the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice (GCP) guidelines.27
Data management and monitoring
Data will be collected by trained research staff at each site and recorded in case report forms. This will then be entered into the INCODER database, which is located in clinical research unit in department of cardiology in the First Affiliated Hospital, Sun Yat-sen University and supervised by the trial data manager. Data from the INCODER study will be transferred securely to the Research Data Deposit at http://www.researchdata.org.cn/, where it can be accessed and traced securely via a specialized administration panel by members of the research team using an encrypted password.
The INCODER study will be overseen by the trial steering committee (TSC) in accordance with the GCP guidance. The TSC, which consists of the chief investigator, study coordinator, site investigators and statisticians, will independently monitors the process the study and give advice on the continuation, termination or amendments of the trial protocol. The study is sponsored by Tasly Pharmaceutical Group Co. Ltd. and will be subject to regular monitoring visits and audits.
Patient and public involvement
Patients were not involved in the design or in the recruitment to and conduct of the study, nor in the assessment of burden of the intervention. Results will be disseminated to participants on request.
STATISTICAL CONSIDERATION
Sample size assumptions
This is a superiority study. Sample size calculation is based on the primary outcome of change in total exercise time from baseline to follow-up at 6 weeks. According to the unpublished results of Phase II clinical trial conducted in the USA16 and our preliminary study (http://www.chictr.org.cn; Registration number: ChiCTR-IIR-17013662), the change of total exercise time is 62.5 ± 19.6 s and 54.5 ± 18.8 s from baseline to week 6 in intensive treatment group and control group respectively. We therefore assumed the changes of total exercise time as 62.5 s and 54.5 s in the two groups and both standard deviations as 20%. A sample size of 100 per group will yield 80% power to obtain a significant difference between the 2 groups, using a 2-sample t test at a 1-sided 0.025 level of significance. Considering an approximately 20% dropout rate, a total of 250 subjects (125 subjects for each group) will be enrolled.
Statistical analysis
Statistical analysis will be conducted by the SAS V9.4 software, using a two-tailed 0.05 significance level.
Baseline demographic characteristics of two groups will be presented using descriptive statistics: Continuous variables will be presented with median and interquartile range or mean ± SD. Categorical variables will be expressed as frequencies and percentages. For comparisons between two groups, t test or rank sum test will be used for continuous variables, the chi-square or Fisher’s exact test will be applied for categorical variables.
The primary outcome, changes of total exercise time between the intensive treatment group and the control group, will be estimated based on the ITT population consisting of all the randomized patients. General linear model will be used for the primary outcome with covariates of center and baseline exercise time using a 1-sided 0.025 significance level. Data will be presented as mean differences and corresponding p values. Missing data will be imputed by using the last observation carried forward method.
We will further conduct ITT and per-protocol analysis to evaluate the differences in certain secondary outcomes between the two groups. Safety analyses will also be conducted based on a safety set in which all randomized subjects receiving ≥ 1 dose of study medication.
ETHICS AND DISSEMINATION
The protocol was approved by the Clinical Research and Laboratory Animal Ethics Committee of the First Affiliated Hospital, Sun Yat-sen University ([2019]65) and all participants will provide their written informed consent. All study procedures are followed with the ethical standards of the Helsinki Declaration. The study protocol was registered at www.chictr.org.cn (ChiCTR2000032384) prior to trial commencement.
Changes to the study protocol are documented in amendments. Amendments are submitted for approval to the Ethics Committee of the First Affiliated Hospital, Sun Yat-sen University. Major changes will be updated on the trial registration website of www.chictr.org.cn.
After completion, the results will be published in a peer-reviewed journal.