Evaluating the current dosing guidelines in children taking the half-strength paediatric tablets will provide reassurance that the recommended lopinavir/ritonavir dose provides adequate drug exposure and maintains efficacy.This trial will evaluate…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
In order to compare the proportion of children ever recording plasma RNA *50
copies/ml
(confirmed within 4 weeks) on QD compared to BID therapy over 48 weeks, HIV-1
viral load will
be measured at screening, week 0 and at all follow-up protocol visits. If at
any time the HIV-1
viral load is >50 copies/ml, the family should be contacted so the HIV-1 viral
load can be remeasured
as soon as possible and within 4 weeks after the raised value. Samples will be
taken and
stored for confirmatory HIV-1 viral load testing in a centralised laboratory at
the end of the trial.
In order to evaluate the pharmacokinetics of twice-daily lopinavir/ritonavir
half strength
formulation tablets based on body weight a minimum of the first 16 children in
each weight band
(P15 to Q25kg, >25 to Q35kg, >35kg) will have an intensive PK day while on BID
half strength
formulation (day 0). Plasma concentrations of lopinavir and ritonavir will be
determined by a
validated high performance liquid chromatography assay with UV detection in a
central laboratory
(Radboud University Nijmegen).
To compare the pharmacokinetics of twice-daily lopinavir/ritonavir tablets with
once-daily dosing in
the same children, children who have undergone an intensive PK day and have
been subsequently
randomised to QD dosing will have a second intensive PK day four weeks after
starting QD dosing
of lopinavir/ritonavir tablets.
Secondary outcome
The stage of children*s HIV disease by CDC classification (Appendix 8) will be
recorded at entry to
the trial and at each protocol visit, disease progression will be recorded on
the follow-up CRF as
well as any adverse events. Efficacy of twice- and once-daily dosing of
lopinavir/ritonavir tablets
will also be compared through analysis of HIV-1 viral load and T cell subsets
measured locally at
each protocol visit, and the presence of HIV mutations conferring resistance to
drugs taken at
randomisation or during the trial.
Background summary
Several issues complicate treatment of HIV-1 infection in children and
adolescents. One challenge is to give the correct antiretroviral dose to
provide adequate drug exposure as a child grows to minimise toxicity and
maintain efficacy. Dosing guidelines typically use weight or body surface area
to adjust doses for children. As drug pharmacokinetics in children differ
greatly from that in adults due to age-related variations in renal, hepatic and
gastric function, which result in altered drug
absorption and metabolism, it is important to conduct studies in children to
inform dosing guidelines rather than extrapolate from adult data.
The protease inhibitor (PI) lopinavir/ritonavir (Kaletra) is recommended by
European and American guidelines for treatment of children with HIV-1 infection
and has been approved for use in children by the European Medicines Agency
(EMEA) (age 2 years and older) and the United States Food and Drug
Administration (FDA) (age 14 days and older). Lopinavir/ritonavir is available
as oral solution or tablets in dosage strengths of 200/50 mg and 100/25 mg. The
200/50 mg tablet replaced the original soft-gel capsule in 2006, and the
half-strength lopinavir/ritonavir tablet (100/25 mg) was approved by the EMEA
and FDA in 2008, designed to provide flexible dosing for
paediatric patients. Lopinavir/ritonavir tablets are approved for paediatric
use, to be taken twicedaily. The number of tablets to be taken as the child
grows is based on body weight bands under FDA approval whereas it is based on
body surface area (BSA) by the EMEA. This leads to some differences in the
number of tablets recommended for a child (see section 2.2.1), e.g. a child who
weighs 40kg, which is approximately equivalent to a BSA of 1.3m2, would be
recommended to take
three 100/25mg tablets twice-daily under the EMEA approval compared to four
100/25mg tablets twice-daily under FDA approval.
No studies have been conducted to evaluate these dosing guidelines in children
taking the half strength paediatric tablets.
Another challenge for the treatment of HIV-1 infection in children and
adolescents is to improve medication adherence in particular for children who
rely on caregivers for medication administration, and for adolescents
undergoing the transition to adulthood. Adherence is related to several
factors, including palatability and number of pills or volume of medication,
complexity of medication schedules and interference with the child or
caregiver*s daily activities. Decreasing the frequency of dosing is likely to
increase convenience and enhance adherence to antiretroviral
therapy in HIV-1 infected children and adolescents.
Study objective
Evaluating the current dosing guidelines in children taking the half-strength
paediatric tablets will provide reassurance that the recommended
lopinavir/ritonavir dose provides adequate drug exposure and maintains efficacy.
This trial will evaluate whether once-daily dosing of lopinavir/ritonavir is
comparable to twice-daily dosing in terms of virological suppression over 48
weeks and to compare the pharmacokinetics of twice-daily lopinavir/ritonavir
tablets with oncedaily dosing in the same children.
( 2.7 protocol)
Study design
KONCERT is a prospective, open label, multicentre, randomised (1:1) phase
II/III trial. Children
will be randomised 1:1 into two groups:
1. Twice-daily lopinavir/ritonavir (BID arm)
2. Once-daily lopinavir/ritonavir (QD arm)
Randomisation will be stratified by body weight band (P15 to Q25kg, >25 to
Q35kg, >35kg).
It is planned to recruit 160 young people over 18 months. All participants must
be followed until
the last participant has completed 48 weeks of follow-up.
Intervention
3 additional visits are required for the trial above the normal 3-monthly
clinic visit schedule
(screening, week 4 and week 8). This may involve children taking extra time out
of school
and parents having to take time off work
* Children in the PK group will undergo one (or two if assigned to once-daily
lopinavir/ritonavir) 12-hour blood sampling visits at weeks 0 and 4. This may
involve an
overnight stay prior to blood sampling. This may present problems in terms of
taking time
out of work, childcare issues for siblings and wellbeing of the children in the
trial
Study burden and risks
There is a small risk that the viral load will become detectable for those
children
randomised on trial. If a raised viral load is confirmed on repeat testing (to
be done within
4 weeks) for a participant randomised to once-daily lopinavir/ritonavir
consideration should
be given to switching QD-dosed subjects to BID therapy, and BID-dosed subjects
to
alternative treatment options as appropriate.
Clinica Pediatrica, via Gustinianni 3
31528 Universita di Padova
IT
Clinica Pediatrica, via Gustinianni 3
31528 Universita di Padova
IT
Listed location countries
Age
Inclusion criteria
inclusiecriteria:
* Aged <18 years (up to 18th birthday) with confirmed HIV1
infection
* Weight *15 kg
* Able to swallow tablets
* Stable (i.e. CD4 not declining) on a combination antiretroviral regimen that has included lopinavir/ritonavir for at least 24 weeks
* Taking lopinavir/ritonavir dosed twicedaily and be willing at the screening visit to change to tablet formulation (if not currently taking tablets) and to change the lopinavir/ritonavir dose to follow the recommended FDA dosing plan based on body weight bands as necessary; if participating in the PK study*, be willing at the screening visit to change to lopinavir/ritonavir half strength formulation tablets (100/25mg) only, dosed twicedaily and change the lopinavir/ritonavir dose to follow the recommended FDA dosing plan based on body weight bands as necessary
* Viral suppression (HIV1 RNA <50 copies/ml) for at least the prior 24 weeks (minimum of 2 measurements).
* Children and caregivers willing to participate in the PK study if they are among a minimum of the first 16 children enrolled in each body weight band in the trial, including a second PK assessment if randomised to switch to oncedaily lopinavir/ritonavir.
* Parents/carers and children, where applicable, give informed written consent;* a minimum of the first 16 children per weight band will be entered into the PK study and must be willing to change to taking halfstrength formulation lopinavir/ritonavir tablets (100/25mg) only, dosed according to the FDA recommended dosing plan based on their body weight, at the screening visit. Once it has been confirmed that the PK study has full evaluable PK data evaluable PK data has been obtained on 16 children in each weight band on twicedaily dosing and 8 in each weight band on oncedaily dosing, it will no longer be necessary for children entering the trial to be willing to take half strength formulation lopinavir/ritonavir tablets only
Exclusion criteria
Exclusion criteria
* children on an antiretroviral regimen that includes a NNRTI, fosamprenavir or nelfinavir
* children who have previously failed virologically on a PI containing regimen (where
virological failure is defined as two successive HIV-1 RNA results>1000 copies/ml
(confirmed) more than 24 weeks after starting HAART, i.e changes for toxicity are not
counted as failure)* acute illness
* abnormal renal or liver function (grade 3 or above)
* receiving concomitant therapy except for prophylaxis; Some treatments may be allowed,
but must first be discussed with a trial medical expert
* pregnancy or risk of pregnancy in females of child bearing potential
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-013648-35-NL |
| CCMO | NL32178.018.10 |