Colchicine in Pulmonary Artery Hypertension Patients

Introduction

Pulmonary hypertension (PH) is a pathophysiological disorder that may involve multiple clinical conditions and may be associated with a variety of cardiovascular and respiratory diseases.1PH is a major global health problem, affecting all age groups. Current estimates suggest that the prevalence of pulmonary hypertension is -1% of the world's population.2. Because pulmonary hypertension has both cardiac and pulmonary causes, the prevalence is higher in individuals over 65 years of age. Globally, left heart disease (LHD) is the leading cause of pulmonary hypertension.2. Lung diseases, particularly chronic obstructive pulmonary disease (COPD), are the second most common cause.2. Regardless of the underlying condition, PH is associated with worsening symptoms and increased mortality. In developing countries, congenital heart disease, certain infectious diseases (such as schistosomiasis and HIV), and high altitude are important, though understudied, causes of PH.2.

Pulmonary hypertension is defined as a mean pulmonary arterial pressure (mPAP) >20 mmHg at rest.3-5. It is essential to include pulmonary vascular resistance (PVR) and pulmonary arterial wedge pressure (PAWP) in the definition of pre-capillary PH, to discriminate elevated PAP due to pulmonary vascular disease (PVD) from that due to left heart disease (LHD), elevated pulmonary blood flow, or increased intrathoracic pressure.6-9.PH is classified into five groups: pulmonary arterial hypertension, PH associated with left ventricular disease, PH associated with lung disease and/or hypoxia, PH associated with pulmonary artery occlusion, and PH of unclear and/or multifactorial mechanisms, maintaining the basic classification structure derived from the 2015 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension and the proceedings of the 6th World Congress on Pulmonary Hypertension. The overall aim of the clinical classification of PH is to categorize concurrent clinical cases based on similar pathophysiological mechanisms, clinical symptoms, hemodynamic characteristics, and treatment approaches.1.

The symptoms of PH are primarily related to right ventricular dysfunction and are usually associated with exercise in the early stages of the disease10,11. The cardinal symptom is dyspnea on progressively minor exertion. Other common symptoms are related to the stage and severity of the disease. They are classified as follows: Early stage, which includes exercise-induced dyspnea, rapid fatigue and exhaustion, shortness of breath when bending forward (bendopnea), palpitations, hemoptysis, abdominal distension and nausea during exercise, weight gain due to fluid retention, and syncope (during or shortly after physical exertion); and late stage, which includes rare symptoms resulting from pulmonary aneurysms such as exercise-induced chest pain (dynamic compression of the left main coronary artery), hoarseness (dysphonia) (compression of the left recurrent laryngeal nerve (cardiovocal syndrome or Ortner syndrome)), shortness of breath, wheezing, coughing, lower respiratory tract infection, and atelectasis. Importantly, a physical examination may also be key to determining the underlying cause of PH12-14.

Patients with pulmonary arterial hypertension (PAH) are hemodynamically characterized by precapillary PH in the absence of other causes of pre-capillary PH, such as chronic thrombo-embolic pulmonary hypertension (CTEPH) and PH associated with lung diseases. Recent registry data from economically developed countries indicate a PAH incidence and prevalence of -6 and 48-55 cases/million adults, respectively.15It is thought to affect mostly younger individuals, predominantly females.16,17. This is currently true for heritable pulmonary arterial hypertension (HPAH), which affects twice as many females as males. However, recent data from the USA and Europe indicate that HPAH is now being diagnosed more frequently in older patients (i.e., those aged 65 years and older, who often have concomitant cardiovascular disease, resulting in a more even sex distribution).In most HPAH registries, idiopathic pulmonary arterial hypertension (IPAH) was the most common subtype (50-60% of all cases), PAH associated with connective tissue disease (CTD), CHD, and portal hypertension (porto-pulmonary hypertension [PoPH])16.

PAH causes significant structural and functional impairment, resulting from obstructive remodeling of the pulmonary blood vessels and the consequent increase in pressure on the right ventricle18,19 . The disease course is primarily characterized by a progressive decline in right ventricular function, which can lead to death from right ventricular heart disease.20,21 . Current treatments mainly focus on pulmonary vessels, yet the prognosis remains poor. Median survival after diagnosis is 5-7 years, with a 1-year mortality rate of 15-20% [5-7]. Decreased right ventricular function appears to be the most important predictor of mortality and morbidity.22-24. To prolong patient survival, therapeutic strategies that specifically target, maintain, or improve right ventricular function are needed.

Colchicine, a well-known drug used to treat gout, coronary artery disease, and pericarditis, has recently gained significant attention for its potential benefits in preventing cardiovascular and pulmonary diseases. However, its effects on preserving or improving right ventricular function in pulmonary hypertension have only been explored in a limited number of experimental studies.25-27.

In an animal study presented by K. Ordog et al., colchicine showed promising effects in preventing the development of right ventricular dysfunction by protecting against inflammation in both the pulmonary blood vessels and the right ventricle. The main finding of this study was that "echocardiographic and histopathological findings showed that colchicine treatment reduced vascular and cardiac remodeling," with "favorable changes in signaling pathways and cytokine production" that maintain "cardiovascular physiology in pulmonary hypertension." Colchicine significantly reduced pulmonary artery remodeling by decreasing, α-smooth muscle actin(α-SMA) and collagen deposition and had a beneficial protective effect on the right ventricle by reducing interstitial collagen buildup and decreasing the mean diameter of cardiomyocytes, accompanied by a decrease in the ventricular weight-to-body weight (VW/BW) and ventricular weight-to-tibia length (VW/TL)ratios, and an improvement in pulmonary artery acceleration time (PAT) and tricuspid annular plane systolic excursion (TAPSE). Colchicine reduced α-smooth muscle actin(TGFβ/SMAD), p38 mitogen-activated protein kinase (p38-MAPK), and c-Jun N-terminal Kinase (JNK) levels while increasing Mitogen-Activated Protein Kinase Phosphatase-1 (MKP-1) levels, along with increased extracellular signal-regulated kinases 1 and 2 (ERK1/2), protein kinase B (PKB) isoform 1 (Akt-1), and glycogen synthase kinase 3 beta (GSK3β) levels, indicating a shift toward a more regulated and less inflammatory state. Colchicine restored metabolic homeostasis by enhancing pyruvate dehydrogenase (PDH), decreasing lactate dehydrogenase, and reversing mitochondrial dysfunction with the restoration of citrate synthase and NADH: cytochrome C oxidoreductase (compounds I and III). Colchicine also reduced chemokine (C-X-C motif) ligand 7 (CXCL7), soluble intercellular adhesion molecule-1 (sICAM-1), L-selectin, vascular endothelial growth factor - A(VEGF-A), and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels, suggesting a reduction in chronic inflammation that contributes to cardiovascular remodeling and endothelial dysfunction, thereby stabilizing the right ventricle and preventing further damage28.

Despite promising results supporting colchicine's ability to protect cardiac function, it has not yet been established as a potential routine treatment for right ventricular dysfunction in pulmonary hypertension. Given the progressive nature of right heart dysfunction in pulmonary hypertension, further research into the therapeutic potential of colchicine in this context is essential, as its current use remains limited. In this current study, we aimed to elucidate the effects of short-term, low-dose colchicine treatment on right ventricular remodeling induced by PH. It is also important to consider the potential side effects of colchicine. In clinical trials of colchicine, diarrhea was the most common side effect, while other gastrointestinal side effects (nausea, abdominal pain) and muscle pain were reported less frequently. 29-33

Aim of the work The objective of this study is to evaluate the effects of oral Colchicine (Colchicine®, Tablets with a concentration of 500 micrograms, manufactured by Adwick-Al Nasr Pharmaceutical Chemicals Company, Abu Zaabal, Egypt) treatment versus control in clinically stable patients with pulmonary arterial hypertension on background vasodilator combination therapy on pulmonary vascular hemodynamics and right ventricular (RV) function.

Primary Outcome To determine whether low-dose colchicine (0.5 mg/day; Adapted from numerous well-documented cardiovascular studies25,26,34) improves exercise capacity and cardiopulmonary hemodynamics in patients with PAH over three months, specifically, World Health Organization functional class (WHO-FC)

Secondary Outcomes

1. To assess the effects on functional capacity (6-Minute Walk Distance (6 MWD)).
2. N-terminal pro-brain natriuretic peptide (NT-proBNP)
3. To assess changes in risk classification during follow-up, a four-tier model (low, intermediate-low, intermediate-high, and high risk) will be used based on the WHO-FC, 6MWT, and NT-proBNP criteria.
4. To assess whether colchicine reduces early clinical exacerbations.
5. To assess the safety and tolerability of colchicine in the treatment of pulmonary hypertension.

Patients and Methods Study design It is a prospective, randomized, open-label, two-arm, parallel study in adult patients with PAH. Upon recruitment, patients will be randomly assigned by permuted block randomization to one of the two study groups.

Duration 12 weeks.

Study setting Patients will be recruited from the National Heart Institute.

Patients Adult patients admitted to the National Heart Institute who have been diagnosed with PAH will be assessed according to eligibility criteria. Patients who meet the following inclusion and exclusion criteria will be enrolled in the study and will be asked to sign an informed consent form.

Eligible patients will be selected according to the following inclusion and exclusion criteria:

Inclusion Criteria 1. A diagnosis of PAH group 1 in any of the following subtypes:

1. Idiopathic
2. Heritable
3. Associated with drugs and toxins
4. Associated with • Connective tissue disease • Portal hypertension

• Congenital heart disease 2. Symptomatic PAH in WHO functional class II-III. 3. Clinically stable. Clinical stability is defined as the absence of symptom exacerbation, as determined by the treating physician, and no need for unplanned hospitalization due to worsening pulmonary hypertension within three months before the study.) 4. Fertile women (under 50 years of age) must use reliable contraception (such as intrauterine devices or hormonal contraceptives) throughout the study and must maintain a negative pregnancy test.

1. Age ≥ 18 years. 6. Ability to perform cardio-pulmonary exercise test. Exclusion Criteria:
2. Diagnosis of PH group 2, 3,4, or 5.
3. Known allergy to colchicine.
4. Unstable PAH requiring treatment escalation or hospitalization.
5. Listed for lung transplantation at the time of screening
6. Planned initiation of IV prostacyclin therapy or current dose escalation planned.
7. Treatment with colchicine before recruitment.
8. Impaired renal function with an eGFR < 30 mL/min/m2 within four weeks of screening.
9. Severe liver dysfunction (Child-Pugh class C).
10. Patients with blood dyscrasias.
11. Concomitant strong CYP3A4 inhibitors.
12. Concomitant P-glycoprotein inhibitors.
13. Pregnancy or breastfeeding. Ethical approval The study is designed and will be conducted in accordance with the principles outlined in the Declaration of Helsinki. The study protocol will be submitted to the Ethics Committee of the Faculty of Pharmacy, Ain Shams University (ACUC-FP-ASU) for approval before the study commences. The study will also be registered on clinicaltrials.gov. Patients will be informed of the study protocol and will receive written informed consent from their treating physician. Patients will be required to sign a written informed consent form to participate in the study. Study Groups: Eligible patients receiving pulmonary vasodilator therapy with Phosphodiesterase 5 inhibitors (PDE5), Endothelin receptor antagonists (ERA), and Prostacyclin analogues (PA), either alone or in combination, without any consideration by the treating medical team for escalation of treatment, will be randomly assigned by permuted block randomization to one of the two study groups in a 1:1 ratio. Colchicine group: Thirty patients shall receive standard of care treatment in addition to 0.5 mg colchicine tablets per oral once daily for 12 weeks (Colchicine®, Tablets with a concentration of 500 micrograms, manufactured by Adwick-Al Nasr Pharmaceutical Chemicals Company, Abu Zaabal, Egypt).25,26,34. Control group: Thirty patients shall receive standard of care treatment for 12 weeks. Standard of care treatment received by both groups would include pulmonary vasodilator therapy with Phosphodiesterase 5 inhibitors (PDE5), Endothelin receptor antagonists (ERA), and Prostacyclin analogues (PA), either alone or in combination, without any consideration by the treating medical team for escalation of treatment. Methodology After obtaining informed consent, all study participants will undergo a comprehensive medical history review and a thorough clinical examination. Sample Collection and Analysis Data Collection and Timeline:
14. At baseline I. Patient demographics: age, gender, social history II. Medical history: comorbidities, PH duration III. Medication history: current OTC and prescribed medications IV. WHO-FC (One of the strongest predictors of survival at diagnosis and follow-up and worsening WHO-FC is one of the most alarming indicators of disease progression, which should trigger further investigation to identify the cause(s) of clinical deterioration)1.
15. 6-MWD(The most widely used measure of exercise capacity in PH patients. Change in 6MWD is one of the most used parameters in PAH clinical trials as a primary endpoint, key secondary endpoint, or component of clinical worsening)1. VI. Laboratory tests
16. Complete blood count (CBC) 2. Liver function tests (Alanine transaminase (ALT), Aspartate transaminase (AST)) 3. Serum creatinine 4. NT-proBNP using the ELISA technique
17. Follow-up: Patients will be followed by using phone calls every week and during monthly visits to monitor the safety of colchicine via reporting common side effects and for adherence monitoring every other week via the pill count method. Patients who prove to be less than 80% compliant with their treatment regimens would be excluded. Possible side effects of colchicine include:
18. Gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and diarrhea.
19. If any signs or symptoms of blood cell disorders appear, such as fever, mouth sores, sore throat, or persistent bleeding, colchicine treatment should be stopped immediately, and a complete blood count should be performed.
20. End of study assessment (After 12 weeks) I. WHO-FC1. II. 6-MWD1. III. Laboratory tests
21. Complete blood count (CBC) 2. Liver function tests (ALT, AST) 3. Serum creatinine 4. NT-proBNP Primary Efficacy Parameter 1. Change in WHO-FC Secondary Efficacy Parameters I. Functional Capacity 1. Change in 6-MWD II. Inflammatory profile
22. The change in systemic inflammatory activity and cardiac stress, assessed by NT-proBNP, captures colchicine's anti-inflammatory and vascular anti-remodeling (antimodulatory) effects. Adverse effects caused by colchicine This information will be documented during the patient's weekly telephone calls and also through interviews with patients. Patient adherence to study medications will be assessed at every other weekly visit using the pill counting method. Exploratory Efficacy Parameters This study will explore the mechanism of action of colchicine in reducing systemic inflammation and cardiac stress, as reflected by anticipated changes in biomarkers such as NT-proBNP. . Furthermore, the study will investigate how improvements in exercise capacity and cardiopulmonary hemodynamics are reflected in predicted changes in functional capacity, as assessed by the 6-MWD and the WHO-FC. Safety and Tolerability Assessing the patient's tolerance to colchicine for PAH, including the ability to complete the three-month protocol. A one-month follow-up will be conducted by telephone after the treatment course ends. Possible side effects of colchicine include:
23. Gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and diarrhea.
24. If any signs or symptoms of blood cell disorders appear, such as fever, mouth sores, sore throat, or persistent bleeding, colchicine treatment should be stopped immediately, and a complete blood count should be performed. Sample size calculation: Due to a lack of studies of colchicine or related drugs of similar mechanism of action on WHO-FC, we assumed a large effect size (Cohen's h = 0.8). In a previous study, 35% of PAH patients treated with standard of care showed improvement in WHO-FC.35 To detect a large effect size with 80% power while setting the alpha level at 0.05, 25 patients per group would be required. To account for dropout, a total of 60 patients (30 per group) would be recruited. Statistical analysis Statistical analysis will be done using SPSS statistical software package, and a two-sided probability value of equal to or less than 0.05 will be considered statistically significant. Numerical data will be represented as mean ± SD or median (interquartile range) as appropriate, while categorical data will be represented as frequency and percentages. The statistical significance of categorical data between the groups will be assessed using Chi-square or Fisher's exact tests, as appropriate. Quantitative variables will be tested for normality using the Kolmogorov-Smirnov test and the Shapiro-Wilk test. Comparisons between the two groups will be done using Student's t-test or Mann-Whitney U test, as appropriate. Paired -t- test and Wilcoxon-Signed Rank test will be used to compare two consecutive measures of numerical variables as appropriate.