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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2013 by University of Cape Town
Sponsor:
Collaborators:
Liverpool School of Tropical Medicine
Uppsala University
University of North Carolina
Information provided by (Responsible Party):
Helen Margaret McIlleron, University of Cape Town
ClinicalTrials.gov Identifier:
NCT01637558
First received: July 2, 2012
Last updated: May 7, 2013
Last verified: May 2013
  Purpose

The aims of this project are to:

  1. 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.
  2. 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.
  3. To evaluate the pharmacokinetics of nevirapine in children in Malawi receiving rifampicin-based antituberculosis treatment.

Condition Intervention Phase
Tuberculosis
HIV
Drug: 8 hourly LPV/r during TB treatment
Drug: Nevirapine
Drug: Lopinavir/Ritonavir
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Optimal Dosing of 1st Line Antituberculosis and Antiretroviral Drugs in Children (a Pharmacokinetic Study)

Resource links provided by NLM:


Further study details as provided by University of Cape Town:

Primary Outcome Measures:
  • Area under the concentration time curve (AUC) for rifampicin, isoniazid, pyrazinamide, ethambutol, lopinavir and nevirapine [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 240
Study Start Date: November 2012
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Main TB cohort
Children with tuberculosis 0-12 years of age
Experimental: Lopinavir/Ritonavir - Cases
children 3-20 kg with tuberculosis and indication for LPV/r-based ART
Drug: 8 hourly LPV/r during TB treatment
8 hourly LPV/r during TB treatment
Experimental: Lopinavir/Ritonavir - Controls
Children 3-20 kg on LPV/r-based ART; no TB
Drug: Lopinavir/Ritonavir
Experimental: Nevirapine arm
children with TB and indication for nevi rapine-based ART
Drug: Nevirapine

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.

  Eligibility

Ages Eligible for Study:   1 Month to 12 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

  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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01637558

Contacts
Contact: Heln McIlleron, PhD 27214066292 helen.mcilleron@uct.ac.za

Locations
Malawi
Queen Elizabeth Central Hospital Recruiting
Blantyre, Malawi
Contact: Carmen Gonzalez, MD, MSc    0026 5991416730    Gonzalez@liverpool.ac.uk   
Principal Investigator: Gerraint Davies, PhD         
South Africa
Red Cross Childrens Hospital Recruiting
Cape Town, Western Cape, South Africa, 7700
Contact: Heather ZAR, PhD    27216585350    heather.zar@uct.ac.za   
Contact: Margaretha Prins    27216863163    margaretha.prins@uct.ac.za   
Principal Investigator: Heather ZAR, PhD         
Sponsors and Collaborators
University of Cape Town
Liverpool School of Tropical Medicine
Uppsala University
University of North Carolina
Investigators
Principal Investigator: Helen M McIlleron, PhD University of Cape Town
Principal Investigator: Heather Zar, PhD University of Cape Town
  More Information

No publications provided

Responsible Party: Helen Margaret McIlleron, Assistant Prof, University of Cape Town
ClinicalTrials.gov Identifier: NCT01637558     History of Changes
Other Study ID Numbers: DATiC
Study First Received: July 2, 2012
Last Updated: May 7, 2013
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Tuberculosis
Actinomycetales Infections
Bacterial Infections
Gram-Positive Bacterial Infections
Mycobacterium Infections
Antitubercular Agents
Lopinavir
Nevirapine
Ritonavir
Anti-Bacterial Agents
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
HIV Protease Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Protease Inhibitors
Reverse Transcriptase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 30, 2014