Ketotifen as a Treatment for Vascular Leakage During Dengue Fever

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

Interventions

DRUG

Ketotifen

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

DRUG

Placebo

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

Sponsors & Collaborators

• Duke-NUS Graduate Medical School

  collaborator OTHER

• Singapore General Hospital

  collaborator OTHER

• National University Hospital, Singapore

  lead OTHER

Principal Investigators

• Ashley L St John · Duke-NUS Graduate Medical School

• Paul A Tambyah · National University Hospital; National University of Singapore

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

21 Years

Max Age

60 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2015-03-31

Primary Completion

2016-07-31

Completion

2017-07-31

Countries

• Singapore

Study Locations