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DenguePhase 2/3NCT04673422

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

A Phase 2/3 study testing Montelukast in people with Dengue and Dengue With Warning Signs, run by Phramongkutklao College of Medicine and Hospital at 4 sites in Thailand.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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

Who is it for?
Ages 18 years and older
What is being tested?
Montelukast
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
358 participants
Where
4 sitesThailand
Study dates
15 Jan 2021to 17 Jun 2023
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • at least 18 years old
  • diagnosis of dengue
  • positive NS1 antigen or polymerase chain reaction (PCR) test

Who cannot join

  • 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

Trial locations and contacts

4 sites in 1 country.

Thailand4 sites
  • Phramongkutklao Hospital

    Bangkok, 10400

  • Hatyai Hospital

    Hat Yai, Changwat Songkhla

  • Ananda Mahidol Hospital

    Lopburi, 15000

  • Fort Suranari Hospital

    Nakhon Ratchasima, 30000

Other trials in Thailand

About this study

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

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

Read the 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.

Being tested
Montelukast, Placebo
Medical subject headings
Dengue, Severe Dengue

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MontelukastDrug

    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

  • PlaceboDrug

    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

Study groups in NCT04673422
Study groupRoleWhat they receive
MontelukastExperimentala 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
Receives: Drug: Montelukast
PlaceboPlacebo comparatora 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
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter.

Secondary outcomes (6)
  1. 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

    Measured: 14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter

  2. Rate of hospitalization

    Rate of admission to hospital

    Measured: 14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter

  3. Length of hospital stay

    Length of hospital stay

    Measured: up to 90 days

  4. 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

    Measured: 14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter

  5. Rate of dengue shock

    Rate of hypotension or the pulse pressure of ≤ 20 mm Hg

    Measured: 14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter

  6. 30-day mortality

    death with in 30 days

    Measured: 30 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Dec 2020
  2. Study start15 Jan 2021
  3. Primary completion17 Jun 2023
  4. Study completion17 Jun 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
a randomized, prospective, 2-arm, parallel-group, double-blind, placebo-controlled superiority trial
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
358 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04673422
Sponsor's protocol ID
AMEDDengue2020
Status last verified
Jul 2023
First submitted
9 Dec 2020
Last updated
18 Jul 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: 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).

Publications

  • 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.

    PubMed 27534439
  • 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.

    PubMed 27007959
  • 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.

    PubMed 30696575
  • 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.

    PubMed 17414388
  • 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.

    PubMed 9498463
  • 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.

    PubMed 19802579
  • 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.

    PubMed 10068569
  • 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.

    PubMed 16544248
  • 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.

    PubMed 19707565
  • 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.

    PubMed 28486041
  • 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.

    PubMed 21576486
  • 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.

    PubMed 7542070
  • 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.

    PubMed 25941082
  • 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.

    PubMed 23638300
  • 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.

    PubMed 25783751

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Montelukast in people with Dengue and Dengue With Warning Signs, run by Phramongkutklao College of Medicine and Hospital at 4 sites in Thailand.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in Thailand. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Rate of dengue with warning signs (time frame: 14 days or until the discontinuation of the follow up appointment by the attending physicians, whichever is shorter.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04673422, which also lists 21 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jul 2023.

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