Effect of Montelukast in Preventing Dengue With Warning Signs in Dengue Patients

Study Overview
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Brief Summary
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This study aims to determine the efficacy of montelukast in reducing the incidence of dengue warning signs in adult dengue patients.

Detailed Description
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Dengue has been the growing public health problem in many tropical countries. Almost 4 billion people were estimated to be at risk, with estimated 400 million infections occurring annually. In Asia, around 10% of febrile patients were virologically confirmed with dengue. The most common cause of death is from dengue shock as a result of vascular leak syndrome. This condition can occur in various clinical manifestations ranging from mild cases to life-threatening condition of dengue shock syndrome. The common sites of plasma leakage are pleural effusion and ascites. The contributing factors for endothelial dysfunction in dengue are cytokines such as soluble tumor necrosis factor receptor (sTNFR/75), interferon gamma, and vascular endothelial growth factor, NS1 antigenemia, complement activation, and activation of dendritic cells, macrophages, and mast cells. Mast cells have recently been acknowledged as an important regulator for promoting innate immune responses. Important composition of granules in mast cells are proteases, chymase and tryptase, histamine, heparin and leukotriene. The activated mast cells can undergo degranulation, releasing these cytokines. These increase capillary permeability, leading to vascular leakage. Leukotriene has an important role in promoting plasma leakage and leukocyte adhesion in postcapillary venules. In dengue patients, leukotriene levels usually elevate during febrile and defervescence stage for 35 and 38 times of the baseline values, and return to baseline in convalescence stage. Blocking leukotriene in dengue infected mice can significantly reduce plasma leakage. The management of dengue consists of only symptomatic treatment, and intravenous fluid replacement. No specific treatment has yet been demonstrated of a benefit in preventing complications. In the recent decades, mast cells have been demonstrated as a major contributor of severe forms of dengue, leading to research in reduction of vascular permeability with mast cell stabilizers or anti-histamine drugs. An animal model studies found that a tryptase inhibitor, nafamostat, or leukotriene inhibitor, montelukast, could reduce the plasma leakage. In 2018, an open-label study found that patients with montelukast had a 22% absolute risk reduction in dengue shock syndrome, compared to standard treatment. However, there has never been any randomized controlled trial evaluating the efficacy of montelukast in dengue patients. This study aims to determine the efficacy of montelukast in reducing the incidence of dengue warning signs in adult dengue patients.

Official Title
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Effect of Montelukast in Preventing Dengue With Warning Signs in Dengue Patients: a Multicenter Randomized, Double-blind, Placebo Controlled, Superiority Trial

Conditions
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Dengue, Dengue With Warning Signs, Dengue Shock Syndrome

Intervention / Treatment
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* Drug: Montelukast
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: at least 18 years old diagnosis of dengue positive NS1 antigen or polymerase chain reaction (PCR) test Exclusion Criteria: any warning sign of dengue concurrent diagnosis of other causes of fever, such as malaria or heat stroke pregnancy being unable to take medication by mouth critical illness needing intubation or admission to an intensive care unit being unable to communicate other indication of montelukast

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: a randomized, prospective, 2-arm, parallel-group, double-blind, placebo-controlled superiority trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Montelukast<br>a 10 mg tablet will be given orally immediately and every day thereafter for 10 days or until recovery, defined as the discontinuation of the follow up appointment by the attending physicians, whichever is shorter | Drug: Montelukast<br>* A 10-mg tablet will be given orally immediately and every day thereafter for 10 days or until recovery, defined as the discontinuation of the follow up appointment by the attending physicians, whichever is shorter<br>|
| Placebo Comparator: Placebo<br>a 10 mg tablet will be given orally immediately and every day thereafter for 10 days or until recovery, defined as the discontinuation of the follow up appointment by the attending physicians, whichever is shorter | Drug: Placebo<br>* A 10-mg tablet will be given orally immediately and every day thereafter for 10 days or until recovery, defined as the discontinuation of the follow up appointment by the attending physicians, whichever is shorter<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of dengue with warning signs | Rate of a composite outcome including abdominal tenderness or pain persistent vomiting clinical fluid accumulation mucosal bleeding liver enlargement >2cm increase in hematocrit concurrent with decrease in platelet count However, lethargy will be excluded as a criterion for warning sign as almost all patients reported subjective lethargy. | 14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of each component of composite outcome of dengue with warning signs | Rate of each component of composite outcome of dengue with warning signs abdominal tenderness or pain persistent vomiting clinical fluid accumulation mucosal bleeding liver enlargement >2cm increase in hematocrit concurrent with decrease in platelet count | 14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter | 
| Rate of hospitalization | Rate of admission to hospital | 14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter | 
| Length of hospital stay | Length of hospital stay | up to 90 days | 
| Rate of severe dengue | Rate of a composite outcome including shock fluid accumulation with respiratory distress severe bleeding leading to hypotension or decreased hematocrit liver transaminase >1000 impaired consciousness heart and other organ failure | 14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter | 
| Rate of dengue shock | Rate of hypotension or the pulse pressure of ≤ 20 mm Hg | 14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter | 
| 30-day mortality | death with in 30 days | 30 days |