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TuberculosisPhase 4DATiCNCT01637558

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

A Phase 4 study testing 8 hourly LPV/r during TB treatment, Nevirapine and Lopinavir/Ritonavir in people with Tuberculosis and HIV, run by University of Cape Town at 4 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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… Read more about this study

Who is it for?
Ages 1 month to 12 years
Conditions the study is for
Tuberculosis, HIV
What is being tested?
8 hourly LPV/r during TB treatment, Nevirapine and Lopinavir/Ritonavir
Could I receive a placebo?
No, everyone receives an active treatment
How many people
200 participants
Where
4 sitesin 2 countries
Study dates
Nov 2012to 31 Jul 2017
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 month to 12 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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).
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  • 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.

Who cannot join

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

Trial locations and contacts

4 sites in 2 countries.

4 sites in 2 countries

South Africa3 sites

  • Red Cross Childrens Hospital

    Cape Town, Western Cape, 7700

  • KIDCRU, Tygerberg Hospital, Department of Paediatrics and Child Health, Stellenbosch University, South Africa.

    Cape Town, Western Cape, 7725

  • Desmond Tutu Centre

    Cape Town, Western Cape

Other trials in South Africa

Malawi1 site

  • Queen Elizabeth Central Hospital

    Blantyre

Other trials in Malawi

About this study

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.
Read the 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.

Conditions
Tuberculosis, HIV
Being tested
8 hourly LPV/r during TB treatment, Nevirapine, Lopinavir/Ritonavir
Medical subject headings
Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 8 hourly LPV/r during TB treatmentDrug

    8 hourly LPV/r during TB treatment

  • NevirapineDrug

  • Lopinavir/RitonavirDrug

Study groups in NCT01637558
Study groupRoleWhat they receive
Main TB cohortNo interventionChildren with tuberculosis 0-12 years of age
Lopinavir/Ritonavir - CasesExperimentalchildren 3-20 kg with tuberculosis and indication for LPV/r-based ART
Receives: Drug: 8 hourly LPV/r during TB treatment
Lopinavir/Ritonavir - ControlsExperimentalChildren 3-20 kg on LPV/r-based ART; no TB
Receives: Drug: Lopinavir/Ritonavir
Nevirapine armExperimentalchildren with TB and indication for nevi rapine-based ART
Receives: Drug: Nevirapine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Jul 2012 (estimated)
  2. Study startNov 2012
  3. Primary completion31 Jul 2017
  4. Study completion31 Jul 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
200 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01637558
Sponsor's protocol ID
DATiC
Acronym
DATiC
Status last verified
Oct 2017
First submitted
2 Jul 2012
Last updated
27 Oct 2017
Results posted
No
Data monitoring committee
Yes
Individual data sharing
Undecided

Publications

  • Galileya LT, Wasmann RE, Chabala C, Rabie H, Lee J, Njahira Mukui I, Hesseling A, Zar H, Aarnoutse R, Turkova A, Gibb D, Cotton MF, McIlleron H, Denti P. Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis. PLoS Med. 2023 Nov 21;20(11):e1004303. doi: 10.1371/journal.pmed.1004303. eCollection 2023 Nov.

    PubMed 37988391

  • 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.

    PubMed 31081020

  • 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.

    PubMed 26810651

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing 8 hourly LPV/r during TB treatment, Nevirapine and Lopinavir/Ritonavir in people with Tuberculosis and HIV, run by University of Cape Town at 4 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Oct 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in South Africa, Malawi. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Area under the concentration time curve (AUC) for rifampicin, isoniazid, pyrazinamide, ethambutol, lopinavir and nevirapine (time frame: 5 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01637558, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Oct 2017.

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