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

Dengue Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04673422
• Other study ID #: AMEDDengue2020
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: January 15, 2021
• Est. completion date: June 17, 2023

Study information

• Verified date: July 2023
• Source: Phramongkutklao College of Medicine and Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 358
• Est. completion date: June 17, 2023
• Est. primary completion date: June 17, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Dengue
• Dengue Shock Syndrome
• Dengue With Warning Signs
• Severe Dengue
• Shock

Intervention

Drug:
• Montelukast
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
• Placebo
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

Locations

Country	Name	City	State
Thailand	Phramongkutklao Hospital	Bangkok
Thailand	Hatyai Hospital	Hat Yai	Songkhla
Thailand	Ananda Mahidol Hospital	Lopburi
Thailand	Fort Suranari Hospital	Nakhon Ratchasima

Sponsors (1)

Lead Sponsor	Collaborator
Phramongkutklao College of Medicine and Hospital

Country where clinical trial is conducted

Thailand, 

References & Publications (20)

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Dahlen SE, Bjork J, Hedqvist P, Arfors KE, Hammarstrom S, Lindgren JA, Samuelsson B. Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3887-91. doi: 10.1073/pnas.78.6.3887. — View Citation

Green S, Vaughn DW, Kalayanarooj S, Nimmannitya S, Suntayakorn S, Nisalak A, Lew R, Innis BL, Kurane I, Rothman AL, Ennis FA. Early immune activation in acute dengue illness is related to development of plasma leakage and disease severity. J Infect Dis. 1999 Apr;179(4):755-62. doi: 10.1086/314680. — View Citation

Guzman MG, Gubler DJ, Izquierdo A, Martinez E, Halstead SB. Dengue infection. Nat Rev Dis Primers. 2016 Aug 18;2:16055. doi: 10.1038/nrdp.2016.55. — View Citation

L'Azou M, Moureau A, Sarti E, Nealon J, Zambrano B, Wartel TA, Villar L, Capeding MR, Ochiai RL; CYD14 Primary Study Group; CYD15 Primary Study Group. Symptomatic Dengue in Children in 10 Asian and Latin American Countries. N Engl J Med. 2016 Mar 24;374(12):1155-66. doi: 10.1056/NEJMoa1503877. — View Citation

Leo YS, Gan VC, Ng EL, Hao Y, Ng LC, Pok KY, Dimatatac F, Go CJ, Lye DC. Utility of warning signs in guiding admission and predicting severe disease in adult dengue. BMC Infect Dis. 2013 Oct 24;13:498. doi: 10.1186/1471-2334-13-498. — View Citation

Loke WM, Chow AY, Lam Mok Sing K, Lee CY, Halliwell B, Lim EC, Quek AM, Ooi EE, Seet RC. Augmentation of 5-lipoxygenase activity and expression during dengue serotype-2 infection. Virol J. 2013 Oct 30;10:322. doi: 10.1186/1743-422X-10-322. — View Citation

Londono-Renteria B, Marinez-Angarita JC, Troupin A, Colpitts TM. Role of Mast Cells in Dengue Virus Pathogenesis. DNA Cell Biol. 2017 Jun;36(6):423-427. doi: 10.1089/dna.2017.3765. Epub 2017 May 9. — View Citation

Marone G, Varricchi G, Loffredo S, Granata F. Mast cells and basophils in inflammatory and tumor angiogenesis and lymphangiogenesis. Eur J Pharmacol. 2016 May 5;778:146-51. doi: 10.1016/j.ejphar.2015.03.088. Epub 2015 May 2. — View Citation

Nascimento EJ, Silva AM, Cordeiro MT, Brito CA, Gil LH, Braga-Neto U, Marques ET. Alternative complement pathway deregulation is correlated with dengue severity. PLoS One. 2009 Aug 26;4(8):e6782. doi: 10.1371/journal.pone.0006782. — View Citation

Rathore AP, Mantri CK, Aman SA, Syenina A, Ooi J, Jagaraj CJ, Goh CC, Tissera H, Wilder-Smith A, Ng LG, Gubler DJ, St John AL. Dengue virus-elicited tryptase induces endothelial permeability and shock. J Clin Invest. 2019 Jul 2;129(10):4180-4193. doi: 10.1172/JCI128426. — View Citation

Schmutzler W, Bolsmann K, Zwadlo-Klarwasser G. Comparison of histamine release from human blood monocytes, lymphocytes, adenoidal and skin mast cells. Int Arch Allergy Immunol. 1995 May-Jun;107(1-3):194-6. doi: 10.1159/000236974. — View Citation

Sherif NA, Zayan AH, Elkady AH, Ghozy S, Ahmed AR, Omran ES, Taha EA, Eldesoky EA, Ebied A, Tieu T, Maraie N, Kamel MG, Ngo HT, Mattar OM, Hirayama K, Huy NT. Mast cell mediators in relation to dengue severity: A systematic review and meta-analysis. Rev Med Virol. 2020 Jan;30(1):e2084. doi: 10.1002/rmv.2084. Epub 2019 Nov 10. — View Citation

Srikiatkhachorn A, Green S. Markers of dengue disease severity. Curr Top Microbiol Immunol. 2010;338:67-82. doi: 10.1007/978-3-642-02215-9_6. — View Citation

Srikiatkhachorn A, Krautrachue A, Ratanaprakarn W, Wongtapradit L, Nithipanya N, Kalayanarooj S, Nisalak A, Thomas SJ, Gibbons RV, Mammen MP Jr, Libraty DH, Ennis FA, Rothman AL, Green S. Natural history of plasma leakage in dengue hemorrhagic fever: a serial ultrasonographic study. Pediatr Infect Dis J. 2007 Apr;26(4):283-90; discussion 291-2. doi: 10.1097/01.inf.0000258612.26743.10. — View Citation

St John AL, Rathore AP, Raghavan B, Ng ML, Abraham SN. Contributions of mast cells and vasoactive products, leukotrienes and chymase, to dengue virus-induced vascular leakage. Elife. 2013 Apr 30;2:e00481. doi: 10.7554/eLife.00481. — View Citation

St John AL, Rathore AP, Yap H, Ng ML, Metcalfe DD, Vasudevan SG, Abraham SN. Immune surveillance by mast cells during dengue infection promotes natural killer (NK) and NKT-cell recruitment and viral clearance. Proc Natl Acad Sci U S A. 2011 May 31;108(22):9190-5. doi: 10.1073/pnas.1105079108. Epub 2011 May 16. — View Citation

Syenina A, Jagaraj CJ, Aman SA, Sridharan A, St John AL. Dengue vascular leakage is augmented by mast cell degranulation mediated by immunoglobulin Fcgamma receptors. Elife. 2015 Mar 18;4:e05291. doi: 10.7554/eLife.05291. — View Citation

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* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Length of hospital stay	Length of hospital stay	up to 90 days
Secondary	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
Secondary	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
Secondary	30-day mortality	death with in 30 days	30 days

External Links

•   Ahmad A, Waseem T, Butt N, Randhawa F, Malik U, Shakoori T. Montelukast Reduces the Risk of Dengue Shock Syndrome in Dengue Patients. Tropical biomedicine. 2019;35:1115-22.