Ketotifen as a Treatment for Vascular Leakage During Dengue Fever

NCT02673840 | Unknown Phase 4 DMC

• 1 other identifier: EID-DF-02
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 2

Brief Summary

Rationale and Aims: Infection by dengue virus (DENV) causes major morbidity and mortality throughout the world. In 2012, an estimated 3.6 billion people live in areas at risk for DENV infection, including Singapore. The key pathology of DENV infection is vascular leakage, which can occur in mild cases and can become life-threatening in severe cases when patients may develop dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Mast cells (MCs) are strongly activated by DENV with preliminary studies showing that activation levels are correlated to disease severity in human patients. Thus, the investigators propose to use the MC stabilizing drug, ketotifen, to limit the immune pathology that is characteristic of dengue infection and treat dengue-induced vascular leakage. Methods: The ability of Ketotifen to reduce vascular leakage in DENV patients will be determined by assessing the pooling of fluid in the pleural cavity (measured by MRI and CXR) after 5 days of drug administration, evaluated as a percent change compared to baseline fluid levels. Additional measures of vascular leakage and immune pathology will be compared as secondary objectives. The trial will be conducted as a randomized, double-blind study comparing the responses of dengue patients given either ketotifen or placebo (n=55 per arm). Importance of proposed research: Currently, no targeted treatments exist to limit vascular leakage during DENV infection. If Ketotifen is identified as effective for preventing pleural effusion and/or plasma leakage in DENV patients, this would constitute an advance for the clinical management of DENV fever. This finding would also support a large-scale trial to determine whether Ketotifen can be used to prevent severe vascular leakage as occurs during DHF/DSS. Benefits/Risks: Ketotifen has a record of safety and tolerability in humans, regulatory approval, and widespread use. Side effects are generally mild. The potential exists that, if effective, many of the painful and life-threatening symptoms of DENV infection that result from plasma leakage would be improved.

Conditions

Dengue Fever; Pleural Effusion

Keywords

dengue fever; dengue hemorrhagic fever; ketotifen; vascular leakage; pleural effusion; plasma leakage

Outcome Measures

Primary Outcomes (1)

• reduced fluid accumulation in the pleural cavity

  fluid accumulation in the pleural cavity will be measured by MRI

  day 5-7

Secondary Outcomes (4)

• reduced serum biomarker chymase

  day 5-7

• reduced hemoconcentration

  day 5-7

• Number of patients with symptoms associated with DF

  day 5-7

• time to viral clearance

  day 5-7

Other Outcomes (2)

• Number of patients with abnormal immunoprofiles

  day 5-7

• patients with Fluid accumulation in the liver, spleen or kidney

  day 5-7

Study Arms (2)

Ketotifen

EXPERIMENTAL

Drug: Ketotifen

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Ketotifen DRUG

2 mg of Ketotifen, twice a day for a total of ten (10) doses

Also known as: Zaditor, C19H19NOS, Drugbank Identifier: DB00920

Ketotifen

Placebo DRUG

Identical tablets containing 0 mg of Ketotifen, twice a day for a total of ten (10) doses

Also known as: Sugar Pill

Placebo

Eligibility Criteria

• Age: 21 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female, age 21-60 years
• Fever of ≥ 37.5°C (directly measured or patient reported) of ≤ 72 hr duration.
• Positive Nonstructural protein 1 (NS1) strip assay or dengue polymerase chain reaction (PCR)
• Able and willing to give written or oral informed consent
• Willing to be an outpatient from Study Day 1 to 5, to undergo an MRI and chest X-ray day 1 at the hospital, to return to the hospital on day 5 for an MRI and chest X-ray, and return on Study Days 7 and 21.
• Willing to keep a diary of pain medication usage and side effects

You may not qualify if:

• Clinical signs and symptoms for severe dengue, such as: a. Persistent vomiting b. Altered mental state c. Liver enlargement \> 2 cm
• A person with any of the following laboratory values: a. aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 1000 U/L
• Current usage of any anticoagulant drugs including, but not limited to, aspirin, warfarin, or clopidogrel.
• Current usage of any drugs that are known to block the functions of ketotifen, such as propranolol.
• Current usage of oral anti-diabetic agents.
• Any other clinically significant acute illness within 7 days prior to first study drug administration.
• Patients with renal impairment.
• Exposure to any new investigational agent within 30 days prior to the study drug administration.
• Clinically significant abnormal physical examination unrelated to dengue infection.
• Females of childbearing potential who are pregnant, breast feeding, or unwilling to avoid pregnancy by the use of appropriate contraception, including oral and subcutaneous implantable hormonal contraceptives, condoms, diaphragm, or intrauterine device (IUD), during the period that the experimental drug is administered. Prospective female participants of childbearing potential must have a negative pregnancy test (point of care).
• Current significant medical condition or illness including cardiac arrhythmias, cardiomyopathy or other cardiac disease, immunocompromised state including known HIV infection, or any other illness that the Investigator considers should exclude the patient, especially those that require continuation of other medications likely to have an interaction with the study drug. Patients with a history of allergy will not be excluded unless the allergy may be directed to the Study Drug or other tablet ingredient.
• Any condition that would render the informed consent invalid, or limit the ability of the patient to comply with the study requirements.
• Any condition that, in the opinion of the investigator, would complicate or compromise the study or well being of the patient.

Sponsors & Collaborators

• National University Hospital, Singapore: lead
• Duke-NUS Graduate Medical School: collaborator
• Singapore General Hospital: collaborator

Study Sites (2)

National University Hospital (Investigational Medicine Unit)

Singapore, 117599, Singapore

RECRUITING

Singapore General Hospital

Singapore, 169698, Singapore

RECRUITING

Related Publications (18)

• 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.

  PMID: 23638300 BACKGROUND

• 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.

  PMID: 25783751 BACKGROUND

• Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control: New Edition. Geneva: World Health Organization; 2009. Available from http://www.ncbi.nlm.nih.gov/books/NBK143157/

  PMID: 23762963 BACKGROUND

• Halstead SB. Dengue. Lancet. 2007 Nov 10;370(9599):1644-52. doi: 10.1016/S0140-6736(07)61687-0.

  PMID: 17993365 BACKGROUND

• Craps LP. Immunologic and therapeutic aspects of ketotifen. J Allergy Clin Immunol. 1985 Aug;76(2 Pt 2):389-93. doi: 10.1016/0091-6749(85)90659-1.

  PMID: 4019961 BACKGROUND

• Disodium cromoglycate. Lancet. 1972 Dec 16;2(7790):1299. No abstract available.

  PMID: 4117822 BACKGROUND

• Abraham SN, St John AL. Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol. 2010 Jun;10(6):440-52. doi: 10.1038/nri2782.

  PMID: 20498670 BACKGROUND

• Atrasheuskaya A, Petzelbauer P, Fredeking TM, Ignatyev G. Anti-TNF antibody treatment reduces mortality in experimental dengue virus infection. FEMS Immunol Med Microbiol. 2003 Jan 21;35(1):33-42. doi: 10.1111/j.1574-695X.2003.tb00646.x.

  PMID: 12589955 BACKGROUND

• Gowen BB, Julander JG, London NR, Wong MH, Larson D, Morrey JD, Li DY, Bray M. Assessing changes in vascular permeability in a hamster model of viral hemorrhagic fever. Virol J. 2010 Sep 16;7:240. doi: 10.1186/1743-422X-7-240.

  PMID: 20846417 BACKGROUND

• Humbert H, Cabiac MD, Bosshardt H. In vitro-in vivo correlation of a modified-release oral form of ketotifen: in vitro dissolution rate specification. J Pharm Sci. 1994 Feb;83(2):131-6. doi: 10.1002/jps.2600830205.

  PMID: 8169778 BACKGROUND

• Kunder CA, St John AL, Abraham SN. Mast cell modulation of the vascular and lymphatic endothelium. Blood. 2011 Nov 17;118(20):5383-93. doi: 10.1182/blood-2011-07-358432. Epub 2011 Sep 8.

  PMID: 21908429 BACKGROUND

• McClean SP, Arreaza EE, Lett-Brown MA, Grant JA. Refractory cholinergic urticaria successfully treated with ketotifen. J Allergy Clin Immunol. 1989 Apr;83(4):738-41. doi: 10.1016/0091-6749(89)90008-0.

  PMID: 2651507 BACKGROUND

• Oliveira GA, Machado RC, Horvat JV, Gomes LE, Guerra LR, Vandesteen L, Oliveira FT, Lousada NS, Moreira-Silva S, de Fatima Ceolin M. Transient reticular gallbladder wall thickening in severe dengue fever: a reliable sign of plasma leakage. Pediatr Radiol. 2010 May;40(5):720-4. doi: 10.1007/s00247-009-1489-x. Epub 2009 Dec 15.

  PMID: 20012951 BACKGROUND

• Sendo T, Sumimura T, Itoh Y, Goromaru T, Aki K, Yano T, Oike M, Ito Y, Mori S, Nishibori M, Oishi R. Involvement of proteinase-activated receptor-2 in mast cell tryptase-induced barrier dysfunction in bovine aortic endothelial cells. Cell Signal. 2003 Aug;15(8):773-81. doi: 10.1016/s0898-6568(03)00014-7.

  PMID: 12781870 BACKGROUND

• 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.

  PMID: 21576486 BACKGROUND

• Theoharides TC, Sieghart W, Greengard P, Douglas WW. Antiallergic drug cromolyn may inhibit histamine secretion by regulating phosphorylation of a mast cell protein. Science. 1980 Jan 4;207(4426):80-2. doi: 10.1126/science.6153130.

  PMID: 6153130 BACKGROUND

• Venkata Sai PM, Dev B, Krishnan R. Role of ultrasound in dengue fever. Br J Radiol. 2005 May;78(929):416-8. doi: 10.1259/bjr/54704044.

  PMID: 15845934 BACKGROUND

• Wilder-Smith A, Renhorn KE, Tissera H, Abu Bakar S, Alphey L, Kittayapong P, Lindsay S, Logan J, Hatz C, Reiter P, Rocklov J, Byass P, Louis VR, Tozan Y, Massad E, Tenorio A, Lagneau C, L'Ambert G, Brooks D, Wegerdt J, Gubler D. DengueTools: innovative tools and strategies for the surveillance and control of dengue. Glob Health Action. 2012;5. doi: 10.3402/gha.v5i0.17273. Epub 2012 Mar 22.

  PMID: 22451836 BACKGROUND

MeSH Terms

Conditions

Dengue; Pleural Effusion; Severe Dengue

Interventions

Ketotifen; ketotifen fumarate ophthalmic solution; Sugars

Condition Hierarchy (Ancestors)

Mosquito-Borne Diseases; Vector Borne Diseases; Infections; Arbovirus Infections; Virus Diseases; Flavivirus Infections; Flaviviridae Infections; RNA Virus Infections; Hemorrhagic Fevers, Viral; Pleural Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Carbohydrates

Study Officials

• Ashley L St John

  Duke-NUS Graduate Medical School

  STUDY DIRECTOR

• Paul A Tambyah

  National University Hospital; National University of Singapore

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Wei Cong Lam

CONTACT

+65 6601 2541; wei_cong_lam@nuhs.edu.sg

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 30, 2015
• First Posted: February 4, 2016
• Study Start: March 1, 2015
• Primary Completion: July 1, 2016
• Study Completion: July 1, 2017
• Last Updated: February 4, 2016

Record last verified: 2016-02

Locations

SG (2)