Effect of Molsidomine on the Endothelial (Internal Layer of Blood Vessels) Dysfunction in Patients With Angina Pectoris

Double-blind Parallel Placebo-controlled Study to Evaluate the Effect of Molsidomine on the Endothelial Dysfunction in Patients With Stable Angina Pectoris Undergoing a Percutaneous Coronary Intervention

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.

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.

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).