search
Back to results

Optimal Dosing of 1st Line Antituberculosis and Antiretroviral Drugs in Children (a Pharmacokinetic Study) (DATiC)

Primary Purpose

Tuberculosis, HIV

Status
Completed
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
8 hourly LPV/r during TB treatment
Nevirapine
Lopinavir/Ritonavir
Sponsored by
University of Cape Town
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberculosis

Eligibility Criteria

1 Month - 12 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

ALL STUDY PARTICIPANTS

  • Aged < 12 years.
  • Weighing > 1.5 kg and < 30 kg.
  • Written informed permission of parent or legal guardian for their child to participate.
  • Absence of clear indication of unwillingness or refusal to participate, and in children > 7 years of age, assent to participate.
  • No contraindications to PK sampling (children with obviously very poor venous access will not be included).
  • Able to comply with study visits and procedures including regular adherence to routine medication, and adherence to the study medication.
  • Enrollment will be deferred in children with acute severe illness which would likely jeopardize participation (such as illness causing severe respiratory impairment, acute severe diarrhea, acute central nervous system impairment, severe life threatening systemic illness, or other severe conditions requiring hospitalization which would jeopardize participation). Children may be enrolled after recovery from acute illness.

ADDITIONAL CRITERIA FOR THE MAIN TB COHORT AND SUBSTUDIES

  1. Main TB cohort

    INCLUSION A recent diagnosis of TB and receiving intensive phase antiTB treatment with 1st-line drugs (rifampicin, isoniazid, pyrazinamide with or without ethambutol, in standard doses).

  2. LPV SUBSTUDY

    CASES & CONTROLS

    • Children in whom ART with a LPV/r-containing regimen is indicated, OR, Children established on a LPV/r-containing regimen.
    • ALT < 5-times the upper limit of the normal range.
    • Children weighing 3.0 - 19.9 kg.
    • Neonates must have a postmenstrual age of at least 42 weeks and a postnatal age of at least 14 days.

    CASES

    - HIV infected children enrolled to the main cohort with at least 2 weeks remaining before the end of intensive phase antiTB treatment such that PK sampling can be scheduled after 2 weeks of combined ART and antiTB treatment, but before the continuation phase of antiTB treatment is started.

    CONTROLS

    - HIV infected children without TB.

    Weighted enrollment of controls will be performed such that the number of controls in each of the age groups < 6 months, 6 months to 2 years, and > 2 years, will be approximately equal to the numbers of cases in those age groups. As most of the children with TB will be started on ART after their TB diagnosis, recruitment of controls will be focused on children who have recently started ART (on treatment < 3 months).

  3. NVP SUBSTUDY

    • HIV infected children receiving intensive phase antiTB treatment and enrolled to the main study cohort
    • Started on ART including NVP (in WHO's recommended weight band-based doses) and 2 nucleoside reverse transcriptase inhibitors.

Exclusion Criteria:

  • Indication for increased or reduced doses of 1st-line antiTB drugs (e.g. marked hepatic or renal impairment, TB meningitis).

Sites / Locations

  • Queen Elizabeth Central Hospital
  • Red Cross Childrens Hospital
  • KIDCRU, Tygerberg Hospital, Department of Paediatrics and Child Health, Stellenbosch University, South Africa.
  • Desmond Tutu Centre

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

No Intervention

Experimental

Experimental

Experimental

Arm Label

Main TB cohort

Lopinavir/Ritonavir - Cases

Lopinavir/Ritonavir - Controls

Nevirapine arm

Arm Description

Children with tuberculosis 0-12 years of age

children 3-20 kg with tuberculosis and indication for LPV/r-based ART

Children 3-20 kg on LPV/r-based ART; no TB

children with TB and indication for nevi rapine-based ART

Outcomes

Primary Outcome Measures

Area under the concentration time curve (AUC) for rifampicin, isoniazid, pyrazinamide, ethambutol, lopinavir and nevirapine
Population PK model-derived AUC's (in mg.h/L)for each of the first line anti-TB drugs, and for the substudies, lopinavir and nevirapine respectively.

Secondary Outcome Measures

Full Information

First Posted
July 2, 2012
Last Updated
October 26, 2017
Sponsor
University of Cape Town
Collaborators
Liverpool School of Tropical Medicine, Uppsala University, University of North Carolina
search

1. Study Identification

Unique Protocol Identification Number
NCT01637558
Brief Title
Optimal Dosing of 1st Line Antituberculosis and Antiretroviral Drugs in Children (a Pharmacokinetic Study)
Acronym
DATiC
Official Title
Optimal Dosing of 1st Line Antituberculosis and Antiretroviral Drugs in Children (a Pharmacokinetic Study)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2017
Overall Recruitment Status
Completed
Study Start Date
November 2012 (Actual)
Primary Completion Date
July 31, 2017 (Actual)
Study Completion Date
July 31, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Cape Town
Collaborators
Liverpool School of Tropical Medicine, Uppsala University, University of North Carolina

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The aims of this project are to: To evaluate the pharmacokinetics of first line antituberculosis drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) when applying the 2010 WHO/IUATLD dosing guidelines across pediatric populations (0-12 years of age, HIV infected and uninfected, and with varied nutritional status) in Cape Town, South Africa and Blantyre, Malawi. To evaluate an 8-hourly weight band-based dosing strategy for lopinavir/ritonavir using the commercially available lopinavir/ritonavir (4:1 ratio) in children in South Africa receiving rifampicin-based antituberculosis treatment. To evaluate the pharmacokinetics of nevirapine in children in Malawi receiving rifampicin-based antituberculosis treatment.
Detailed Description
HIV and tuberculosis are a major public health problem in children. Challenges to treat children with tuberculosis include a lack of knowledge about optimal dosing of first line antituberculosis drugs across ages, nutritional status and HIV infection status, the absence of an appropriate regimen to co-administer rifampin and lopinavir/ritonavir, the key first line drugs for tuberculosis and HIV, and uncertainty about NVP exposure in young children during rifampin-based tuberculosis therapy. In total, 240 children < 12 years of age with tuberculosis will be enrolled at Red Cross Children's Hospital in Cape Town and Queen Elizabeth Central Hospital, Blantyre. In the second month of antituberculosis treatment, one dose of the drugs in their first-line regimens will be administered according to 2010 WHO/IUATLD guidelines (study drugs) and blood will be sampled for pharmacokinetic analysis over the following 8-10 hours. Children on antiretroviral treatment (started prior to or during TB treatment) will receive 2 weeks of antiretrovirals (lopinavir/ritonavir or nevirapine) according in the study doses (adjusted 8 hourly doses of lopinavir/ritonavir, or nevirapine doses according to WHO's recommended weight band-based doses) in combination with antituberculosis treatment, prior to pharmacokinetic assessments of both antiretroviral and antituberculosis drugs. Children receiving nevirapine will also undergo pharmacokinetic evaluation 1 month after completion of antituberculosis treatment to evaluate nevirapine concentrations in the absence of antituberculosis drugs. In addition to the 240 children with tuberculosis, 25 HIV infected South African children without tuberculosis will be recruited to evaluate lopinavir concentrations in the absence of antituberculosis drugs. A population approach will be used to estimate the optimal doses of rifampicin, isoniazid, pyrazinamide and ethambutol in children according to covariates (e.g. age, weight, HIV status, nutritional status) found to have an important influence on the drug concentrations. Similarly population models will be used to describe lopinavir/ritonavir and nevirapine pharmacokinetics in children receiving rifampicin-based antituberculosis treatment, evaluate the dosing approaches and to simulate alternative optimal dosing approaches as indicated.

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
200 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Main TB cohort
Arm Type
No Intervention
Arm Description
Children with tuberculosis 0-12 years of age
Arm Title
Lopinavir/Ritonavir - Cases
Arm Type
Experimental
Arm Description
children 3-20 kg with tuberculosis and indication for LPV/r-based ART
Arm Title
Lopinavir/Ritonavir - Controls
Arm Type
Experimental
Arm Description
Children 3-20 kg on LPV/r-based ART; no TB
Arm Title
Nevirapine arm
Arm Type
Experimental
Arm Description
children with TB and indication for nevi rapine-based ART
Intervention Type
Drug
Intervention Name(s)
8 hourly LPV/r during TB treatment
Intervention Description
8 hourly LPV/r during TB treatment
Intervention Type
Drug
Intervention Name(s)
Nevirapine
Intervention Type
Drug
Intervention Name(s)
Lopinavir/Ritonavir
Primary Outcome Measure Information:
Title
Area under the concentration time curve (AUC) for rifampicin, isoniazid, pyrazinamide, ethambutol, lopinavir and nevirapine
Description
Population PK model-derived AUC's (in mg.h/L)for each of the first line anti-TB drugs, and for the substudies, lopinavir and nevirapine respectively.
Time Frame
5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Month
Maximum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: ALL STUDY PARTICIPANTS Aged < 12 years. Weighing > 1.5 kg and < 30 kg. Written informed permission of parent or legal guardian for their child to participate. Absence of clear indication of unwillingness or refusal to participate, and in children > 7 years of age, assent to participate. No contraindications to PK sampling (children with obviously very poor venous access will not be included). Able to comply with study visits and procedures including regular adherence to routine medication, and adherence to the study medication. Enrollment will be deferred in children with acute severe illness which would likely jeopardize participation (such as illness causing severe respiratory impairment, acute severe diarrhea, acute central nervous system impairment, severe life threatening systemic illness, or other severe conditions requiring hospitalization which would jeopardize participation). Children may be enrolled after recovery from acute illness. ADDITIONAL CRITERIA FOR THE MAIN TB COHORT AND SUBSTUDIES Main TB cohort INCLUSION A recent diagnosis of TB and receiving intensive phase antiTB treatment with 1st-line drugs (rifampicin, isoniazid, pyrazinamide with or without ethambutol, in standard doses). LPV SUBSTUDY CASES & CONTROLS Children in whom ART with a LPV/r-containing regimen is indicated, OR, Children established on a LPV/r-containing regimen. ALT < 5-times the upper limit of the normal range. Children weighing 3.0 - 19.9 kg. Neonates must have a postmenstrual age of at least 42 weeks and a postnatal age of at least 14 days. CASES - HIV infected children enrolled to the main cohort with at least 2 weeks remaining before the end of intensive phase antiTB treatment such that PK sampling can be scheduled after 2 weeks of combined ART and antiTB treatment, but before the continuation phase of antiTB treatment is started. CONTROLS - HIV infected children without TB. Weighted enrollment of controls will be performed such that the number of controls in each of the age groups < 6 months, 6 months to 2 years, and > 2 years, will be approximately equal to the numbers of cases in those age groups. As most of the children with TB will be started on ART after their TB diagnosis, recruitment of controls will be focused on children who have recently started ART (on treatment < 3 months). NVP SUBSTUDY HIV infected children receiving intensive phase antiTB treatment and enrolled to the main study cohort Started on ART including NVP (in WHO's recommended weight band-based doses) and 2 nucleoside reverse transcriptase inhibitors. Exclusion Criteria: Indication for increased or reduced doses of 1st-line antiTB drugs (e.g. marked hepatic or renal impairment, TB meningitis).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Helen M McIlleron, PhD
Organizational Affiliation
University of Cape Town
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Heather Zar, PhD
Organizational Affiliation
University of Cape Town
Official's Role
Principal Investigator
Facility Information:
Facility Name
Queen Elizabeth Central Hospital
City
Blantyre
Country
Malawi
Facility Name
Red Cross Childrens Hospital
City
Cape Town
State/Province
Western Cape
ZIP/Postal Code
7700
Country
South Africa
Facility Name
KIDCRU, Tygerberg Hospital, Department of Paediatrics and Child Health, Stellenbosch University, South Africa.
City
Cape Town
State/Province
Western Cape
ZIP/Postal Code
7725
Country
South Africa
Facility Name
Desmond Tutu Centre
City
Cape Town
State/Province
Western Cape
Country
South Africa

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
31081020
Citation
Rabie H, Rawizza H, Zuidewind P, Winckler J, Zar H, Van Rie A, Wiesner L, McIlleron H. Pharmacokinetics of adjusted-dose 8-hourly lopinavir/ritonavir in HIV-infected children co-treated with rifampicin. J Antimicrob Chemother. 2019 Aug 1;74(8):2347-2351. doi: 10.1093/jac/dkz171.
Results Reference
derived
PubMed Identifier
26810651
Citation
Bekker A, Schaaf HS, Draper HR, van der Laan L, Murray S, Wiesner L, Donald PR, McIlleron HM, Hesseling AC. Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines. Antimicrob Agents Chemother. 2016 Mar 25;60(4):2171-9. doi: 10.1128/AAC.02600-15. Print 2016 Apr.
Results Reference
derived

Learn more about this trial

Optimal Dosing of 1st Line Antituberculosis and Antiretroviral Drugs in Children (a Pharmacokinetic Study)

We'll reach out to this number within 24 hrs