Effect of Montelukast Versus Co Enzyme in Sepsis

Study Overview
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Brief Summary
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Sepsis is a leading cause of morbidity and mortality in intensive care units. Sepsis is a life-threatening organ dysfunction linked to a dysregulated host response to infection. It leads to overwhelming of systemic inflammation causing release of proinflammatory cytokines, which trigger overproduction of reactive oxygen species. Several animal studies with sepsis proved the effectiveness of montelukast and coenzyme Q10 as anti-inflammatory and antioxidants in preventing end organ damage, deterioration, and reducing mortality. Therefore, a clinical trial will be carried out to compare the efficacy and safety of montelukast versus co enzyme Q10 on the clinical outcome in patients with sepsis.

Detailed Description
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Sepsis is now defined as a life-threatening organ dysfunction linked to a dysregulated host response to infection. This organ dysfunction can be identified using the Sequential Organ Failure Assessment (SOFA). Sepsis is a leading cause of morbidity and mortality in the intensive care unit (ICU). It has been reported that the short-term mortality rate ranges from 30 to 50%, depending on illness severity. The global epidemiological burden of sepsis is, however, difficult to ascertain. It is estimated more than 30 million people are affected by sepsis every year worldwide, resulting in potentially 6 million deaths annually. The mortality rate estimated to be 30% in sepsis and 80% in septic shock in the USA, and 12.8% in sepsis and 45.7% in septic shock in Europe. Reduced rates of reporting may influence estimations in developing countries. Sepsis is characterized by overwhelming systemic inflammation causing a release of proinflammatory cytokines. The presence of infection leads to initial activation of the innate immune response. The resulting pro-inflammatory host response is both complex and redundant, involving many soluble inflammatory mediators, including cytokines [e.g., tumor necrosis factor (TNF) α and interleukin (IL) 6] and reactive oxygen/nitrogen species (e.g., nitric oxide (NO) and peroxynitrite), as well as multiple cell types, including neutrophils, macrophages, platelets, and endothelial cells. The up regulation of pro- and anti-inflammatory pathways leads to a system-wide release of cytokines, mediators, and pathogen-related molecules, resulting in activation of coagulation, and complement cascades, the resulting inflammation leads to progressive tissue damage, finally causing multi-organ dysfunction. Sepsis-induced mitochondrial damage or dysfunction can result in cellular metabolic disorders, insufficient energy production, and oxidative stress, which give rise to the apoptosis of organ cells and immune cells, thus ultimately generate immune disorders, multiple organ failure, and even death. As during sepsis limited amount of oxygen supply, the free radical production increases dramatically while the machinery of the antioxidant system becomes damaged. Activated leukocytes release inflammatory cytokines, which trigger overproduction of reactive nitrogen species (RNS) and nitrogen oxide. Nitrogen oxide can bind to reactive oxygen species (ROS) peroxides to form RNS, which unfortunately brings about further damage to mitochondria, including mitochondrial, and mitochondrial DNA damage. Hence, different treatment strategies have focused in minimizing this inflammatory syndrome without reaching a consensus. Numerous anti-inflammatory and antioxidants therapies have been proposed and studied, including corticosteroids, anti-cytokine approaches, selenium, vitamin C, as well as other various basic research-driven therapies. Montelukast is a cysteinyl leukotriene receptor antagonist with anti-inflammatory and antioxidant properties. Cysteinyl leukotrienes (CysLTs) are formed by inflammatory cells, such as mast cells, eosinophils, and basophils. CysLTs are potent pro-inflammatory mediators that increase microvascular permeability and are effective chemotactic agents. CysLT receptors are present in the airways, liver, and other organs. CysLT1 antagonists, such as Montelukast, have been reported to ameliorate experimental colitis, burn- and sepsis-induced multi-organ damage. Montelukast acts by inhibiting neutrophil infiltration, balancing oxidant-antioxidant status, and controlling inflammatory mediator generation. Montelukast possesses anti-inflammatory effect through the inhibition of TNF-alpha stimulated by IL-8 expression through changes in nuclear factor-Kb, and the antioxidant effect is due to decreasing the ROS, and reactive nitrogen species (e.g. NO) production, and hence it could help ameliorate inflammation associated with sepsis. Several studies reported montelukast as a safe and tolerable medication. It was reported in 1996 that the administration of 10 mg orally, montelukast to healthy adult patients, was well tolerated. Four years later, Storms and colleagues published safety data from 11 multicenters, randomized, controlled montelukast phase, which included numerous adult and pediatric patients. They reported that the administration of montelukast over 5 months as 200 mg/day, which is 20 times higher than the recommended clinical dose, was also tolerable and similar to placebo. Many experimental model studies showed how montelukast is effective against sepsis. Şener and his colleagues postulated that montelukast possesses an anti-inflammatory effect on sepsis-induced hepatic and intestinal damage and protects against oxidative injury by a neutrophil-dependent mechanism. Another study concluded that montelukast treatment after Cecal Ligation and Puncture-Induced Sepsis potentially reduced mortality in experimental sepsis that was attributed to the reduction of organs' oxidative stress and the decrease in plasma cytokine levels. It was found also that montelukast might have cardioprotective effects against the inflammatory process during endotoxemia. This effect was attributed to its antioxidant and/or anti-inflammatory properties. Coenzyme Q10 (Co enzyme Q10) is a fat-soluble molecule, naturally found in the diet and synthesized endogenously by all cells of our body in the mitochondrial inner membrane, that exists both in oxidized form (ubiquinone) and reduced form (ubiquinol). Co enzyme Q10 plays an essential role in the electron transport chain of mitochondria as the carrier of electrons from complex I and II to complex III. Disruption of this mechanism can compromise oxidative phosphorylation, thereby leading to decreased levels of cellular energy (adenosine triphosphate (ATP)) production. Previous studies have reported that Co enzyme Q10 (Co enzyme Q10) can prevent the start and diffusion of lipid peroxidation, scavenge free radicals, and decrease pro-inflammatory cytokine production. The deficiency of Co enzyme Q10 induced by mitochondrial failure in sepsis may play a role in hypoxia, oxidative organ damage, hypo-perfusion, and ultimately leading to death. There is considerable evidence from randomized controlled clinical studies that Co enzyme Q10 can ameliorate such inflammation, via effects on circulatory pro-inflammatory markers such as C-reactive protein (CRP), interleukins 1 and 8 (IL-1, IL-8), and tumor necrosis factor-alpha (TNF). CoenzymeQ10 showed its activity against sepsis in many previous studies. Coenzyme Q10 administered during the hypodynamic phase of sepsis decreased splenic, renal and cardiac damage and organ damage. It also assisted in the reduction of septic liver injury as indicated by the upregulation of beclin 1 as well as the suppression of AST, ALT, ALP, p62, IL-6, TNF-α, NLRP 3, and IL-1β as reported in another animal study. Moreover, it has been reported that critically ill patients had lower levels of CoenzymeQ10 levels on ICU admission compared to healthy controls and exhibited a further decrease in sepsis and septic shock. Donnino and colleagues provided original data suggesting a CoenzymeQ10 deficiency in patients with septic shock, and this is a new step toward a study testing CoenzymeQ10 as a potential therapeutic agent for patients with septic shock

Official Title
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The Effect of Montelukast Versus Co Enzyme Q10 on the Clinical Outcome of Patients With Sepsis

Conditions
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Sepsis

Intervention / Treatment
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* Drug: Montelukast Sodium 10 mg
* Drug: Co-Enzyme Q10
* Drug: Standard Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years old. Males and females Confirmed diagnosis of sepsis according to the third sepsis definition which include documented or suspected infection, plus an acute change in total SOFA score ≥ 2 points Exclusion Criteria: Pregnancy A severe moribund state An anticipated ICU stay of less than 24 hours. Patients with a history of hypersensitivity to montelukast or co enzyme Q10. Patients with systemic eosinophilia in the blood or vasculitis. Patients with neuropsychiatric diseases as hallucinations, depression or suicidal thoughts that put the patient at risk when participating in the study. Unable to receive enteral medications.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective randomized controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Montelukast group<br>30 patients will receive montelukast sodium 10 mg/day film coated tablets (Singulair®; Merck & Co Inc) or (Clear air®; Amoun Pharmaceutical Company S.A.E., Egypt) in addition to the standard sepsis treatment starting from the onset of the diagnosis of sepsis till discharge from ICU, or death. | Drug: Montelukast Sodium 10 mg<br>* Film coated tablets containing 10 mg montelukast<br>* Other names: (Singulair®; Merck & Co Inc) or (Clear air®; Amoun Pharmaceutical Company S.A.E., Egypt);Drug: Standard Treatment<br>* Standard sepsis treatment includes fluid resuscitation, early administration of intravenous broad spectrum antibiotic (ceftriaxone 2gm/24 hour or meropenem 1g/8 hours, linezolid 600/12hours) till obtaining the microbiological culture to narrow the coverage, paracetamol intravenous antipyretic (paracetamol 1gm/8 hours) till no fever and temperature less than 380c, and prophylactic anticoagulant low molecular weight heparin (enoxaparin 40/24 hours), prophylactic stress ulcer (pantoprazole 40mg/24hours)<br>* Other names: Standard sepsis treatment;|
| Experimental: Co Enzyme Q10 group<br>30 patients will receive co enzyme Q10 capsule 210 mg / day (MEPACO Pharmaceutical Company (Egypt) in addition to the standard sepsis treatment starting from the onset of the diagnosis of sepsis till discharge from ICU, or death. | Drug: Co-Enzyme Q10<br>* Capsules contain 210 mg Co-Enzyme Q10<br>* Other names: Co enzyme Q10(MEPACO Pharmaceutical Company (Egypt);Drug: Standard Treatment<br>* Standard sepsis treatment includes fluid resuscitation, early administration of intravenous broad spectrum antibiotic (ceftriaxone 2gm/24 hour or meropenem 1g/8 hours, linezolid 600/12hours) till obtaining the microbiological culture to narrow the coverage, paracetamol intravenous antipyretic (paracetamol 1gm/8 hours) till no fever and temperature less than 380c, and prophylactic anticoagulant low molecular weight heparin (enoxaparin 40/24 hours), prophylactic stress ulcer (pantoprazole 40mg/24hours)<br>* Other names: Standard sepsis treatment;|
| Active Comparator: Control group<br>30 patients will receive the standard treatment of sepsis from the onset of the diagnosis of sepsis till discharge from ICU, or death. | Drug: Standard Treatment<br>* Standard sepsis treatment includes fluid resuscitation, early administration of intravenous broad spectrum antibiotic (ceftriaxone 2gm/24 hour or meropenem 1g/8 hours, linezolid 600/12hours) till obtaining the microbiological culture to narrow the coverage, paracetamol intravenous antipyretic (paracetamol 1gm/8 hours) till no fever and temperature less than 380c, and prophylactic anticoagulant low molecular weight heparin (enoxaparin 40/24 hours), prophylactic stress ulcer (pantoprazole 40mg/24hours)<br>* Other names: Standard sepsis treatment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Twenty-eight-day mortality | All patients will be followed up in the ICU and by phone calls after discharge. The 28-day mortality rate will be evaluated and recorded. | Starting from the randomization date up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sequential organ failure assessment score | It measures sepsis related end organ damage. It includes serum creatinine level as the renal component, total bilirubin level as the hepatic component, Glasgow coma score as the central nervous system component, mean arterial pressure, PaO2, and platelet count. The minimum value is zero, and the maximum value is 24, the higher the score, the worse the outcome, as the maximum value means the expected mortality is more than 90%, and the minimum value means the expected mortality is less than 10% | Starting from the randomization date,on day 3, on day7, and then every 3 days till patient ICU discharge or death from any cause, which comes first, assessed up to 30 days. | 
| C- reactive protein | Marker C- reactive protein will evaluate the state of inflammation in septic patients. | Starting from the randomization date,on day 3, and on day7 | 
| Heart rate | Heart rate will be monitored and recorded for septic patients | Starting from the randomization date till patient ICU discharge or death from any cause, which comes first, assessed up to 30 days. | 
| ICU length of stay | Length of patient stay in the ICU. | Starting from the randomization date till patient ICU discharge or death from any cause, which comes first, assessed up to 30 days. | 
| Length of hospital stay | Length of patient stay in the hospital. | Starting from the randomization date till patient ICU discharge or death from any cause, which comes first, assessed up to 30 days. | 
| The need for mechanical ventilation The number of patients who will need mechanical ventilation in addition to the duration of ventilation will be recorded | The number of patients who will need mechanical ventilation in addition to the duration of ventilation will be recorded | Starting from the randomization date till patient ICU discharge or death from any cause, which comes first, assessed up to 30 days. | 
| The need for vasopressors | The number of patients who will receive vasopressors in addition to the dose and duration of vasopressor use will be recorded. | Starting from the randomization date till patient ICU discharge or death from any cause, which comes first, assessed up to 30 days. | 
| The incidence of treatment side effects and the number of their occurrence | Record the incidence of treatment side effects and the number of their occurrence including dermatological reactions, nausea, vomiting or diarrhea, cough or acute bronchitis, headache, gastrointestinal disorders, fatigue, gastrointestinal upset, and heartburn. | Starting from the randomization date till patient ICU discharge or death from any cause, which comes first, assessed up to 30 days. | 
| Serum tumor necrosis factor α level | An inflammatory marker | Starting from the randomization date, and on day 7 | 
| Serum MDA level | An oxidative stress marker | Starting from the randomization date, and on day 7 | 
| Temperature | Temperature will be recorded for septic patients | Starting from the randomization date till patient ICU discharge or death from any cause, which comes first, assessed up to 30 days. | 
| Blood pressure | Both systolic and diastolic blood pressures will be monitored and recorded for septic patients | Starting from the randomization date till patient ICU discharge or death from any cause, which comes first, assessed up to 30 days. |