Effect of Montelukast in Preventing Dengue With Warning Signs in Dengue Patients
Primary Purpose
Dengue, Dengue With Warning Signs, Dengue Shock Syndrome
Status
Completed
Phase
Phase 2
Locations
Thailand
Study Type
Interventional
Intervention
Montelukast
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Dengue
Eligibility Criteria
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
Sites / Locations
- Hatyai Hospital
- Phramongkutklao Hospital
- Ananda Mahidol Hospital
- Fort Suranari Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Montelukast
Placebo
Arm Description
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
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
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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
Rate of hospitalization
Rate of admission to hospital
Length of hospital stay
Length of hospital stay
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
Rate of dengue shock
Rate of hypotension or the pulse pressure of ≤ 20 mm Hg
30-day mortality
death with in 30 days
Full Information
NCT ID
NCT04673422
First Posted
December 9, 2020
Last Updated
July 17, 2023
Sponsor
Phramongkutklao College of Medicine and Hospital
1. Study Identification
Unique Protocol Identification Number
NCT04673422
Brief Title
Effect of Montelukast in Preventing Dengue With Warning Signs in Dengue Patients
Official Title
Effect of Montelukast in Preventing Dengue With Warning Signs in Dengue Patients: a Multicenter Randomized, Double-blind, Placebo Controlled, Superiority Trial
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Completed
Study Start Date
January 15, 2021 (Actual)
Primary Completion Date
June 17, 2023 (Actual)
Study Completion Date
June 17, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Phramongkutklao College of Medicine and Hospital
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This study aims to determine the efficacy of montelukast in reducing the incidence of dengue warning signs in adult dengue patients.
Detailed 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Dengue, Dengue With Warning Signs, Dengue Shock Syndrome
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Model Description
a randomized, prospective, 2-arm, parallel-group, double-blind, placebo-controlled superiority trial
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
358 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Montelukast
Arm Type
Experimental
Arm Description
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
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Montelukast
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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
Primary Outcome Measure Information:
Title
Rate of dengue with warning signs
Description
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.
Time Frame
14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter.
Secondary Outcome Measure Information:
Title
Rate of each component of composite outcome of dengue with warning signs
Description
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
Time Frame
14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter
Title
Rate of hospitalization
Description
Rate of admission to hospital
Time Frame
14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter
Title
Length of hospital stay
Description
Length of hospital stay
Time Frame
up to 90 days
Title
Rate of severe dengue
Description
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
Time Frame
14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter
Title
Rate of dengue shock
Description
Rate of hypotension or the pulse pressure of ≤ 20 mm Hg
Time Frame
14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter
Title
30-day mortality
Description
death with in 30 days
Time Frame
30 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Worapong Nasomsong, MD
Organizational Affiliation
Phramongkutklao College of Medicine and Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Worayon Chuerboonchai, MD
Organizational Affiliation
Ananda Mahidol Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hatyai Hospital
City
Hat Yai
State/Province
Songkhla
Country
Thailand
Facility Name
Phramongkutklao Hospital
City
Bangkok
ZIP/Postal Code
10400
Country
Thailand
Facility Name
Ananda Mahidol Hospital
City
Lopburi
ZIP/Postal Code
15000
Country
Thailand
Facility Name
Fort Suranari Hospital
City
Nakhon Ratchasima
ZIP/Postal Code
30000
Country
Thailand
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Data requests can be made anytime from 6 months after the publication of this trial. De-identified participant data can be requested by researchers for use in independent scientific research and will be provided following review and approval of the research proposal (including statistical analysis plan).
IPD Sharing Time Frame
starting 6 months after publication
IPD Sharing Access Criteria
De-identified participant data can be requested by researchers for use in independent scientific research and will be provided following review and approval of the research proposal (including statistical analysis plan). Requests should be sent to the corresponding author after publication.
Citations:
PubMed Identifier
27534439
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.
Results Reference
background
PubMed Identifier
27007959
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.
Results Reference
background
PubMed Identifier
30696575
Citation
Wilder-Smith A, Ooi EE, Horstick O, Wills B. Dengue. Lancet. 2019 Jan 26;393(10169):350-363. doi: 10.1016/S0140-6736(18)32560-1.
Results Reference
background
PubMed Identifier
17414388
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.
Results Reference
background
PubMed Identifier
9498463
Citation
Bethell DB, Flobbe K, Cao XT, Day NP, Pham TP, Buurman WA, Cardosa MJ, White NJ, Kwiatkowski D. Pathophysiologic and prognostic role of cytokines in dengue hemorrhagic fever. J Infect Dis. 1998 Mar;177(3):778-82. doi: 10.1086/517807.
Results Reference
background
PubMed Identifier
19802579
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.
Results Reference
background
PubMed Identifier
10068569
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.
Results Reference
background
PubMed Identifier
16544248
Citation
Avirutnan P, Punyadee N, Noisakran S, Komoltri C, Thiemmeca S, Auethavornanan K, Jairungsri A, Kanlaya R, Tangthawornchaikul N, Puttikhunt C, Pattanakitsakul SN, Yenchitsomanus PT, Mongkolsapaya J, Kasinrerk W, Sittisombut N, Husmann M, Blettner M, Vasanawathana S, Bhakdi S, Malasit P. Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement. J Infect Dis. 2006 Apr 15;193(8):1078-88. doi: 10.1086/500949. Epub 2006 Mar 9.
Results Reference
background
PubMed Identifier
19707565
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.
Results Reference
background
PubMed Identifier
28486041
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.
Results Reference
background
PubMed Identifier
21576486
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.
Results Reference
background
PubMed Identifier
7542070
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.
Results Reference
background
PubMed Identifier
25941082
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.
Results Reference
background
PubMed Identifier
23638300
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.
Results Reference
background
PubMed Identifier
25783751
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.
Results Reference
background
PubMed Identifier
6267608
Citation
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.
Results Reference
background
PubMed Identifier
24168271
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.
Results Reference
background
PubMed Identifier
31709696
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.
Results Reference
background
PubMed Identifier
31265436
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.
Results Reference
background
PubMed Identifier
24152678
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.
Results Reference
background
Links:
URL
https://msptm.org/files/Vol35No4/1115-1122-Tania-Shakoori.pdf
Description
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.
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Effect of Montelukast in Preventing Dengue With Warning Signs in Dengue Patients
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