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Pharmacokinetics and Pharmacodynamics of Ivermectin in Pediatric Dengue Patients (PKIDEN)

Primary Purpose

Dengue Hemorrhagic Fever

Status

Completed

Phase

Phase 2

Locations

Thailand

Study Type

Interventional

Intervention

Ivermectin

About this trial

This is an interventional treatment trial for Dengue Hemorrhagic Fever

Eligibility Criteria

1 Year - 15 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Faculty of Tropical Medicine Siriraj Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Group 1 (6 dengue patients)

Group 2 (6 dengue patients)

Group 3 (6 dengue patients)

Group 4 (6 dengue patients)

Arm Description

Volunteers weighed > 30 kg receiving 400 µg of ivermectin per 1 kg of body weight

Volunteers weighed 15 to 30 kg receiving 400 µg of ivermectin per 1 kg of body weight

Volunteers weighed > 30 kg receiving 600 µg of ivermectin per 1 kg of body weight

Volunteers weighed 15 to 30 kg receiving 600 µg of ivermectin per 1 kg of body weight

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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.

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.

Viremia clearance

Time between the first drug administration and the point of specimen collection at which viral load becomes undetectable

NS1 antigenemia clearance

Time between the first drug administration and the point of specimen collection at which NS1 antigen becomes undetectable

Occurrences of adverse events

The number of volunteers with any adverse events by the total number of volunteers in the treatment group

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.

Full Information

NCT ID

NCT03432442

First Posted

December 21, 2017

Last Updated

February 23, 2021

Sponsor

Mahidol University

1. Study Identification

Unique Protocol Identification Number

NCT03432442

Brief Title

Pharmacokinetics and Pharmacodynamics of Ivermectin in Pediatric Dengue Patients

Acronym

PKIDEN

Official Title

Pharmacokinetics and Pharmacodynamics of Ivermectin in Pediatric Dengue Patients

Study Type

Interventional

2. Study Status

Record Verification Date

February 2021

Overall Recruitment Status

Completed

Study Start Date

September 4, 2018 (Actual)

Primary Completion Date

September 22, 2020 (Actual)

Study Completion Date

September 22, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Mahidol University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Dengue Hemorrhagic Fever

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

24 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group 1 (6 dengue patients)

Arm Type

Experimental

Arm Description

Volunteers weighed > 30 kg receiving 400 µg of ivermectin per 1 kg of body weight

Arm Title

Group 2 (6 dengue patients)

Arm Type

Experimental

Arm Description

Volunteers weighed 15 to 30 kg receiving 400 µg of ivermectin per 1 kg of body weight

Arm Title

Group 3 (6 dengue patients)

Arm Type

Experimental

Arm Description

Volunteers weighed > 30 kg receiving 600 µg of ivermectin per 1 kg of body weight

Arm Title

Group 4 (6 dengue patients)

Arm Type

Experimental

Arm Description

Volunteers weighed 15 to 30 kg receiving 600 µg of ivermectin per 1 kg of body weight

Intervention Type

Drug

Intervention Name(s)

Ivermectin

Intervention Description

Ivermectin once every 24 hours for three administrations

Primary Outcome Measure Information:

Title

Pharmacokinetics of ivermectin in pediatric dengue patients

Description

Blood samples will be collected, and ivermectin plasma concentrations will be measured with High Performance Liquid Chromatography-Tandem Mass Spectrometry (HPLC-MS/MS).

Time Frame

7 days

Secondary Outcome Measure Information:

Title

Pharmacodynamic effects of ivermectin on viral load in plasma of pediatric dengue patients

Description

Blood samples will be collected, and viral load in plasma will be measured with quantitative RT-PCR.

Time Frame

7 days

Title

Pharmacodynamic effects of ivermectin on NS1 antigen in plasma of pediatric dengue patients

Description

Blood samples will be collected, and NS1 antigen in plasma will be measured with NS1-ELISA assay.

Time Frame

7 days

Title

Viremia clearance

Description

Time between the first drug administration and the point of specimen collection at which viral load becomes undetectable

Time Frame

7 days

Title

NS1 antigenemia clearance

Description

Time between the first drug administration and the point of specimen collection at which NS1 antigen becomes undetectable

Time Frame

7 days

Title

Occurrences of adverse events

Description

The number of volunteers with any adverse events by the total number of volunteers in the treatment group

Time Frame

7 days

Title

Occurrences of abnormal laboratory result

Description

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.

Time Frame

7 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Year

Maximum Age & Unit of Time

15 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Panisadee Avirutnan, Assoc. Prof.

Organizational Affiliation

Faculty of Medicine Siriraj Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Faculty of Tropical Medicine Siriraj Hospital

City

Bangkok Noi

State/Province

Bangkok

ZIP/Postal Code

10700

Country

Thailand

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Pharmacokinetics and Pharmacodynamics of Ivermectin in Pediatric Dengue Patients

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