Atherosclerosis, Stable Angina Pectoris
Conditions
Keywords
angina pectoris, atherosclerosis, endothelial dysfunction
Brief summary
Molsidomine used as an add-on treatment on standard care therapy should be superior to placebo used also as an add-on treatment on standard care therapy on improving the endothelial function (endothelium score measured by reactive hyperemia - peripheral arterial tonometry \[RH-PAT\]) after 12 months of treatment in patients with stable angina patients and undergoing elective percutaneous coronary intervention. The study will be double-blind, parallel-group, randomised, multicentre, sequential, placebo-controlled study. The device used to determine RH-PAT will be EndoPAT. Duration of the treatment = one year.
Detailed description
A Data Steering Committee (DSC) will blindly assess the recruitment rate, the variability of RH-PAT within and between centres, and the safety on a regular basis. Sequential approach: * In the first phase (Phase A) of the study, 180 patients will be enrolled in order to get at least 50 completers after 12 months of treatment. A statistical evaluation of the primary endpoint will be done by an Independent Biostatistician after approximately 50 patients have completed the study in accordance with the protocol. * The results will be examined by an Independent Data Monitoring Committee (IDMC)which will assess the results and advise the sponsor as to: 1. Continue the study if the primary objective has not been achieved but the difference between the two groups is at least 10% (difference considered clinically significant). In this case, the sample size will be recalculated by the Independent Biostatistician taking into account actual difference and variability. The total number of patients to be enrolled in addition in Phase B will be calculated with precision. Depending on IDMC recommendations, the number of investigating centres will be increased or not for Phase B. If the right number of patients has already been enrolled, Phase B will not start. The study will stop when all enrolled patients have completed the one-year treatment period. 2. Terminate the study, if the difference between the two groups is less than 10%. 3. Consider the study as completed if the primary endpoint has been achieved. Treatment allocation: Balanced allocation between molsidomine and placebo (1:1) with a stratification for consumption of statins, for the type of stent (drug-eluting stent or bare-metal) and for consumption of angiotensin-converting enzyme inhibitors (ACEIs). Data collection: Electronic Case Report Form (eCRF). Duration of study: A minimum of 30 months (16 months for inclusion and 14 months for the study) for Phase A. Number of investigational centres: * Up to 10 centres for Phase A * To be determined for Phase B based on Phase A.
Interventions
DRUGCoruno
Molsidomine 16 mg tablet, per os, once a day
DRUGPlacebo
Placebo (16 mg tablet, per os; once-daily)
Sponsors
Therabel Pharma SA/NV
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Aged at least 18 years. * No treatment with molsidomine and/or long-acting nitrates (oral or patches) for more than 48 hours during the month preceding percutaneous coronary intervention (PCI) and no treatment with these same drugs within 3 days before PCI. * Patients who the investigator believes that they and/or their Legally Acceptable Representative (LAR) can and will comply with the requirements of the protocol. * Written informed consent from the patient or from the LAR. * Patients who underwent PCI for stable angina pectoris one month prior to the start of the study. * Patients presenting endothelial dysfunction at Month 0 (score of the Endo-PAT \<0.40).
Exclusion criteria
* Pre-menopausal women. * Patient with a clinically-active malignancy. * Known major renal insufficiency or known significant hepatic insufficiency. * History of psychological disorder, mental dysfunction, alcohol or drug abuse or any other factor which might interfere with the ability to cooperate in the study. * Participation in another clinical trial which has not yet reached its primary endpoint or with the same primary endpoint during the previous month. * Concurrently participating in another clinical study, at any time during the study period, in which the subject will be exposed to an investigational or a non-investigational product (vaccine, drug or device). * Hypersensitivity to molsidomine or to one of its excipients. * Peri-procedural infarction: creatine kinase-muscle/brain (CK-MB) \>3 times the upper reference limit. * Clinically significant abnormal pre-PCI CK-MB and troponin: any elevation above the upper reference limit. * Intolerance to galactose, deficiency in Lapp lactase or glucose-galactose malabsorption. * Left ventricular insufficiency (New York Heart Association \[NYHA\] class III or IV) with an ejection fraction \<35%. * Acute circulatory insufficiency (e.g. cardiogenic shock). * Hypotension: systolic blood pressure \<100 mmHg and/or diastolic blood pressure \<70 mmHg. * Atrial fibrillation * Acute myocardial infarction during the preceding month. * Unsuccessful PCI: residual stenosis of at least 50%. * Patient taking phosphodiesterase-5 inhibitors, such as sildenafil (Viagra®), vardenafil (Levitra®) and tadalafil (Cialis®) * Patient taking nebivolol (Nobiten®) * Patient taking ibuprofen + L-arginine as excipient (Spidifen®) * Patient meeting any contraindication(s) from Coruno®. Please refer to Coruno® (molsidomine 16 mg o.d.)Summary of Product Characteristics (SPC).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change Versus Baseline in the Score of the EndoPAT in the Two Groups After One Year of Treatment (Month 12). | 12 months | The results are expressed mean relative change (%) between month 12 and baseline. A positive result means improvement in the score of the EndoPAT between baseline and month 12. It could be considered as a surrogate of a decrease of the endothelial dysfunction. A negative percentage means the inverse. The are no fixed limits to the scale. The minimum observed was -275% and the maximum observed was +4200%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change Versus Baseline in the Score of the EndoPAT in the Two Groups After Six Months of Treatment (Month 6). | Month 6 | The results are expressed mean relative change (%) between month 6 and baseline. A positive result means improvement in the score of the EndoPAT between baseline and month 6. It could be considered as a surrogate of a decrease of the endothelial dysfunction. A negative percentage means the inverse. The are no fixed limits to the scale. The minimum observed was -200% and the maximum observed was +6100%. |
| Change Versus Baseline in the Augmentation Index in the Two Groups After Six and Twelve Months of Treatment (Months 6 and 12). | Month 6 and Month 12 | The results are expressed mean relative change (%) between month 6 or month 12, and baseline. A positive result means improvement in the augmentation index between baseline and month 6 or month 12. It could be considered as a surrogate of a decrease of the arterial stiffness. A negative percentage means the inverse. The are no fixed limits to the scale. At month 6,the minimum observed was -139% and the maximum observed was +1600%.At month 12, the minimum observed was -524% and the maximum observed was +1600%. |
| Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | Month 12 | — |
| Frequency of Serious Cardiovascular Events (SCEs) in the Two Groups After Twelve Months of Treatment (Month 12). | Month 12 | Sum of the events collected during 12 months. |
| Frequency of AEs and SAEs in the Two Groups After Twelve Months of Treatment (Month 12). | Month 12 | Sum of the events collected during 12 months. |
Countries
Belgium
Participant flow
Pre-assignment details
The drop-out rate post-PCI was high (\>60%) mainly because the Endoscore was frequently above the pre-defined threshold post-PCI, attesting of the absence of endothelial dysfunction. Post-randomization drop-out rate was also high, 25% of patients being lost between randomization and month 12, mainly for non-serious adverse events.
Participants by arm
| Arm | Count |
|---|---|
| Molsidomine Coruno (molsidomine 16 mg tablet; per os; once daily)
Coruno: Molsidomine 16 mg tablet, per os, once a day | 18 |
| Placebo Placebo (16 mg tablet; once a day)
Placebo: Placebo (16 mg tablet, per os; once-daily) | 28 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 2 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Molsidomine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 62.4 Years STANDARD_DEVIATION 10.2 | 64.1 Years STANDARD_DEVIATION 9.9 | 63.5 Years STANDARD_DEVIATION 9.9 |
| Region of Enrollment Belgium | 18 participants | 28 participants | 46 participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 7 Participants |
| Sex: Female, Male Male | 16 Participants | 23 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 32 | 22 / 32 |
| serious Total, serious adverse events | 7 / 32 | 11 / 32 |
Outcome results
Primary
Change Versus Baseline in the Score of the EndoPAT in the Two Groups After One Year of Treatment (Month 12).
The results are expressed mean relative change (%) between month 12 and baseline. A positive result means improvement in the score of the EndoPAT between baseline and month 12. It could be considered as a surrogate of a decrease of the endothelial dysfunction. A negative percentage means the inverse. The are no fixed limits to the scale. The minimum observed was -275% and the maximum observed was +4200%.
Time frame: 12 months
Population: Per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Molsidomine | Change Versus Baseline in the Score of the EndoPAT in the Two Groups After One Year of Treatment (Month 12). | 330.60 Relative change versus baseline (%) | Standard Deviation 1014.98 |
| Placebo | Change Versus Baseline in the Score of the EndoPAT in the Two Groups After One Year of Treatment (Month 12). | 164.08 Relative change versus baseline (%) | Standard Deviation 433.41 |
Secondary
Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12).
Time frame: Month 12
Population: Per protocol population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Molsidomine | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | Endothelial microparticles | -40 Relative change versus baseline (%) | Standard Deviation 75 |
| Molsidomine | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | Platelet microparticles | 0.5 Relative change versus baseline (%) | Standard Deviation 101 |
| Molsidomine | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | Leukocyte microparticles | -39 Relative change versus baseline (%) | Standard Deviation 83 |
| Molsidomine | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | sICAM-1 | -6 Relative change versus baseline (%) | Standard Deviation 51 |
| Molsidomine | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | IL-8 | 13 Relative change versus baseline (%) | Standard Deviation 43 |
| Molsidomine | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | hs-CRP | -50 Relative change versus baseline (%) | Standard Deviation 237 |
| Molsidomine | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | MOX-LDL | 11 Relative change versus baseline (%) | Standard Deviation 80 |
| Molsidomine | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | MPO antigen | -1 Relative change versus baseline (%) | Standard Deviation 19 |
| Molsidomine | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | MPO activity | -43 Relative change versus baseline (%) | Standard Deviation 51 |
| Molsidomine | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | MPO activity/antigen ratio | -42 Relative change versus baseline (%) | Standard Deviation 60 |
| Placebo | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | MPO antigen | -32 Relative change versus baseline (%) | Standard Deviation 128 |
| Placebo | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | Endothelial microparticles | -40 Relative change versus baseline (%) | Standard Deviation 42 |
| Placebo | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | hs-CRP | -35 Relative change versus baseline (%) | Standard Deviation 163 |
| Placebo | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | Platelet microparticles | -23 Relative change versus baseline (%) | Standard Deviation 252 |
| Placebo | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | MPO activity/antigen ratio | 7 Relative change versus baseline (%) | Standard Deviation 68 |
| Placebo | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | Leukocyte microparticles | -37 Relative change versus baseline (%) | Standard Deviation 29 |
| Placebo | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | MOX-LDL | 41 Relative change versus baseline (%) | Standard Deviation 83 |
| Placebo | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | sICAM-1 | 6 Relative change versus baseline (%) | Standard Deviation 47 |
| Placebo | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | MPO activity | 8 Relative change versus baseline (%) | Standard Deviation 149 |
| Placebo | Change Versus Baseline in Some Specific Endothelial Biomarkers After Twelve Months of Treatment (Month 12). | IL-8 | -25 Relative change versus baseline (%) | Standard Deviation 149 |
Secondary
Change Versus Baseline in the Augmentation Index in the Two Groups After Six and Twelve Months of Treatment (Months 6 and 12).
The results are expressed mean relative change (%) between month 6 or month 12, and baseline. A positive result means improvement in the augmentation index between baseline and month 6 or month 12. It could be considered as a surrogate of a decrease of the arterial stiffness. A negative percentage means the inverse. The are no fixed limits to the scale. At month 6,the minimum observed was -139% and the maximum observed was +1600%.At month 12, the minimum observed was -524% and the maximum observed was +1600%.
Time frame: Month 6 and Month 12
Population: Per protocol population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Molsidomine | Change Versus Baseline in the Augmentation Index in the Two Groups After Six and Twelve Months of Treatment (Months 6 and 12). | Month 6 | 218.07 Relative change versus baseline (%) | Standard Deviation 437.38 |
| Molsidomine | Change Versus Baseline in the Augmentation Index in the Two Groups After Six and Twelve Months of Treatment (Months 6 and 12). | Month 12 | 98.57 Relative change versus baseline (%) | Standard Deviation 470.39 |
| Placebo | Change Versus Baseline in the Augmentation Index in the Two Groups After Six and Twelve Months of Treatment (Months 6 and 12). | Month 6 | 96.35 Relative change versus baseline (%) | Standard Deviation 323.14 |
| Placebo | Change Versus Baseline in the Augmentation Index in the Two Groups After Six and Twelve Months of Treatment (Months 6 and 12). | Month 12 | 95.13 Relative change versus baseline (%) | Standard Deviation 290.41 |
Secondary
Change Versus Baseline in the Score of the EndoPAT in the Two Groups After Six Months of Treatment (Month 6).
The results are expressed mean relative change (%) between month 6 and baseline. A positive result means improvement in the score of the EndoPAT between baseline and month 6. It could be considered as a surrogate of a decrease of the endothelial dysfunction. A negative percentage means the inverse. The are no fixed limits to the scale. The minimum observed was -200% and the maximum observed was +6100%.
Time frame: Month 6
Population: Per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Molsidomine | Change Versus Baseline in the Score of the EndoPAT in the Two Groups After Six Months of Treatment (Month 6). | 361.98 Relative change versus baseline (%) | Standard Deviation 1248.52 |
| Placebo | Change Versus Baseline in the Score of the EndoPAT in the Two Groups After Six Months of Treatment (Month 6). | 326.26 Relative change versus baseline (%) | Standard Deviation 1155.9 |
Secondary
Frequency of AEs and SAEs in the Two Groups After Twelve Months of Treatment (Month 12).
Sum of the events collected during 12 months.
Time frame: Month 12
Population: Intention-to-treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Molsidomine | Frequency of AEs and SAEs in the Two Groups After Twelve Months of Treatment (Month 12). | Non-serious AE | 57 Number of events |
| Molsidomine | Frequency of AEs and SAEs in the Two Groups After Twelve Months of Treatment (Month 12). | SAE | 7 Number of events |
| Placebo | Frequency of AEs and SAEs in the Two Groups After Twelve Months of Treatment (Month 12). | Non-serious AE | 79 Number of events |
| Placebo | Frequency of AEs and SAEs in the Two Groups After Twelve Months of Treatment (Month 12). | SAE | 12 Number of events |
Secondary
Frequency of Serious Cardiovascular Events (SCEs) in the Two Groups After Twelve Months of Treatment (Month 12).
Sum of the events collected during 12 months.
Time frame: Month 12
Population: Intention-to-treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Molsidomine | Frequency of Serious Cardiovascular Events (SCEs) in the Two Groups After Twelve Months of Treatment (Month 12). | 3 Number of events |
| Placebo | Frequency of Serious Cardiovascular Events (SCEs) in the Two Groups After Twelve Months of Treatment (Month 12). | 1 Number of events |