Pharmacokinetics and Pharmacodynamics of Ivermectin in Pediatric Dengue Patients

Study Overview
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Brief Summary
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Design and Outcomes This research study is designed as open-label, sequential dose-escalating clinical trial. There will be two phases of enrollment. In the first phase, pediatric dengue patients with body weight greater than 30 kg will be recruited. The first six volunteers will be administered with 400 μg/kg every 24 hours for a total of three times. The last six volunteers will be administered with 600 μg/kg every 24 hours for a total of three times. In the second phase, pediatric dengue patients with body weight between 15 to 30 kg will be recruited. Similar to the first phase, the first six and the last six volunteers will be administered with 400 μg/kg and 600 μg/kg every 24 hours for a total of three times, respectively. A total of 24 volunteers will be recruited from Faculty of Medicine Siriraj hospitals

Detailed Description
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The research team has planned to conduct three interim analyses for safety and one final report. The interim analyses will be conducted as follows: First interim analysis: After the completion of the last volunteer of the group with body weight >30 kg receiving ivermectin 400 μg/kg every 24 hours for a total of three times (i.e. the sixth volunteer). Second interim analysis: After the completion of the last volunteer of the group with body weight >30 kg receiving ivermectin 600 μg/kg every 24 hours for a total of three times (i.e. the twelfth volunteer). Third interim analysis: After the completion of the last volunteer of the group with body weight 15 to 30 kg receiving ivermectin 400 μg/kg every 24 hours for a total of three times (i.e. the twelfth volunteer). The results of each interim analyses will be submitted to DSMB to determine whether the study is safe to be conducted in the next group of volunteers. Additionally, the results of interim analyses and the safety assessments from DSMB will be submitted to all ECs

Official Title
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Pharmacokinetics and Pharmacodynamics of Ivermectin in Pediatric Dengue Patients

Conditions
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Dengue Hemorrhagic Fever

Intervention / Treatment
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* Drug: Ivermectin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 1-15 years 0 day Weight is equal or greater than 15 kg History or presence of acute fever within the last 72 hours diagnosed as acute dengue virus infection Patients who are expected to be able to start the study drug within 72 hours of fever Written informed consent to enroll in the study is obtained from parents or legal representatives and/or patients. The test for dengue nonstructural protein 1 is positive, or PCR screening for viral genome is positive Female patients with history of menarche need to have a negative result for urine pregnancy test, except during a menstrual period. Exclusion Criteria: Has significant underlying disease(s) that can affect the study outcome or the study participation may be harmful to patients with those underlying diseases including but not limited to: Kidney disease Thalassemia congenital heart disease epilepsy cerebral palsy Other underlying diseases may result in exclusion depending on the judgement of investigator. Having developed or showed the following laboratory values, warning signs or signs of severe dengue including: AST and/or ALT levels > 500 IU/L Platelets count < 50,000 cells/mm3 Abdominal pain or tenderness Persistent vomiting Clinical fluid accumulation such as pleural effusion, ascites Mucosal bleeding Lethargy/restlessness Liver enlargement >2 cm Increase in Hct concurrent with rapid decrease in platelet count Severe plasma leakage such as dengue shock syndrome, fluid accumulation with respiratory distress Severe bleeding as evaluated by clinician Severe organ involvement including but not limited to acute liver failure, altered level of consciousness (e.g. encephalopathy, encephalitis), seizure or other CNS unusual manifestation, acute renal failure, cardiomyopathy and other unusual manifestation History of ivermectin allergy or receiving medications that increase gamma-aminobutyric acid (GABA) potentiating activity such as barbiturates, benzodiazepines, sodium oxybate, valproic acid, or receiving medications that prevent p-glycoprotein transport system such as amiodarone, carvedilol, clarithromycin, cyclosporine, erythromycin, itraconazole, ketoconazole, quinidine, ritonavir, tamoxifen, verapamil, amprenavir, clotrimazole, phenothiazines, rifampin, St. John's Wort etc. Currently receiving immunosuppressive agents such as steroid (except topical steroid), chemotherapeutic agents or have discontinued these medications for less than a month Having a history of receiving ivermectin within one month Inability to ingest medications in a form of tablets as informed by patients and their parents or legal representatives

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (6 dengue patients)<br>Volunteers weighed > 30 kg receiving 400 µg of ivermectin per 1 kg of body weight | Drug: Ivermectin<br>* Ivermectin once every 24 hours for three administrations<br>|
| Experimental: Group 2 (6 dengue patients)<br>Volunteers weighed 15 to 30 kg receiving 400 µg of ivermectin per 1 kg of body weight | Drug: Ivermectin<br>* Ivermectin once every 24 hours for three administrations<br>|
| Experimental: Group 3 (6 dengue patients)<br>Volunteers weighed > 30 kg receiving 600 µg of ivermectin per 1 kg of body weight | Drug: Ivermectin<br>* Ivermectin once every 24 hours for three administrations<br>|
| Experimental: Group 4 (6 dengue patients)<br>Volunteers weighed 15 to 30 kg receiving 600 µg of ivermectin per 1 kg of body weight | Drug: Ivermectin<br>* Ivermectin once every 24 hours for three administrations<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of ivermectin in pediatric dengue patients | Blood samples will be collected, and ivermectin plasma concentrations will be measured with High Performance Liquid Chromatography-Tandem Mass Spectrometry (HPLC-MS/MS). | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamic effects of ivermectin on viral load in plasma of pediatric dengue patients | Blood samples will be collected, and viral load in plasma will be measured with quantitative RT-PCR. | 7 days | 
| Pharmacodynamic effects of ivermectin on NS1 antigen in plasma of pediatric dengue patients | Blood samples will be collected, and NS1 antigen in plasma will be measured with NS1-ELISA assay. | 7 days | 
| Viremia clearance | Time between the first drug administration and the point of specimen collection at which viral load becomes undetectable | 7 days | 
| NS1 antigenemia clearance | Time between the first drug administration and the point of specimen collection at which NS1 antigen becomes undetectable | 7 days | 
| Occurrences of adverse events | The number of volunteers with any adverse events by the total number of volunteers in the treatment group | 7 days | 
| Occurrences of abnormal laboratory result | The number of volunteers with any change of laboratory results from normal at baseline to abnormal during the study by the total number of volunteers in the treatment group. | 7 days |