Ketotifen as a Treatment for Vascular Leakage During Dengue Fever

• Status: Unknown status
• Trial end date: 2017-07-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National University Hospital, Singapore
• Collaborators: Duke-NUS Graduate Medical School; Singapore General Hospital
• Treatments: Ketotifen

Criteria

Inclusion Criteria:

1. Male or female, age 21-60 years

2. Fever of ≥ 37.5°C (directly measured or patient reported) of ≤ 72 hr duration.

3. Positive Nonstructural protein 1 (NS1) strip assay or dengue polymerase chain reaction (PCR)

4. Able and willing to give written or oral informed consent

5. 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.

6. Willing to keep a diary of pain medication usage and side effects

Exclusion Criteria:

1. Clinical signs and symptoms for severe dengue, such as: a. Persistent vomiting b. Altered mental state c. Liver enlargement > 2 cm

2. A person with any of the following laboratory values: a. aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 1000 U/L

3. Current usage of any anticoagulant drugs including, but not limited to, aspirin, warfarin, or clopidogrel.

4. Current usage of any drugs that are known to block the functions of ketotifen, such as propranolol.

5. Current usage of oral anti-diabetic agents.

6. Any other clinically significant acute illness within 7 days prior to first study drug administration.

7. Patients with renal impairment.

8. Exposure to any new investigational agent within 30 days prior to the study drug administration.

9. Clinically significant abnormal physical examination unrelated to dengue infection.

10. 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).

11. 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.

12. Any condition that would render the informed consent invalid, or limit the ability of the patient to comply with the study requirements.

13. Any condition that, in the opinion of the investigator, would complicate or compromise the study or well being of the patient.