Pharmacokinetics of Twice or Once Daily DTG (50mg) in Children With HIV and TB

Study Overview
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Brief Summary
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Stage 1 proposed study will provide evidence to support the use of twice-daily dose 50mg DTG in children (20-35kgs) co-treated with RIF.

Detailed Description
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This is a single centre, open-label, non-randomised, prospective study evaluating the steady-state pharmacokinetics of twice-daily dose DTG administered during concurrent RIF treatment and assessing safety and tolerance in HIV-TB co-infected children weighing 20 to 35 kg. DTG will be administered as a twice-daily dose 50mg tablet formulation both before starting and after completion of the standard six-month RIF-based anti-TB treatment. The NRTI background and anti-TB drugs will be prescribed following the national weight band dosing guidelines. Those initially diagnosed with TB are likely to be sicker, and the recommendation is to start anti-TB treatment first and follow with ART two weeks later.

Official Title
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An Open-label, Sequential Non-randomised Pharmacokinetics Study of DTG Plasma Exposure When Given as Twice or Once Daily DTG in the Presence of Rifampicin in Children With HIV and TB Between 20-35kgs in SA

Conditions
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Tuberculosis, Hiv

Intervention / Treatment
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* Drug: Dolutegravir 50 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children <18 years with confirmed HIV-1 infection weighing 20-35kg ART-naive or experienced, with plans to use DTG for HIV treatment Diagnosis of TB disease with clinician initiating rifampicin-containing first-line therapy Parents/legal guardians/caregivers and children give informed written consent (or assent, where applicable) to be in the study Girls who have reached menses must have a negative pregnancy test at screening and be willing to adhere to two effective methods of contraception (barrier and a non-barrier form of contraception during the study, starting at least 14 days prior to enrolment) if sexually active. The parents/caregivers will be counselled together with the child if the child tests positive in order to reduce any social harm which may arise. Exclusion Criteria: History or presence of known allergy or contraindications to DTG Alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN), OR ALT ≥3xULN and bilirubin ≥2xULN Severe hepatic impairment or unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), known biliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones) Pregnancy or breastfeeding A concurrent illness that could influence drug PK, i.e. severe diarrhoea, vomiting, renal or liver disease Treatment with concomitant medications known to have interactions with DTG Participants that are eligible for the study but refuse to give consent and/or assent

Ages Eligible for Study
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Minimum Age: 23 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Pharmacokinetic evaluation of DTG in children receiving Rifampicin containing TB treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Twice Daily DTG<br>Twice daily Dolutegravir (50mg) with Rifampicin containing TB treatment | Drug: Dolutegravir 50 MG<br>* Twice daily dolutegravir with rifampicin containing TB treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (Ctrough) of DTG 50mg twice daily | Description of the pharmacokinetics (Ctrough, Cmax and AUC0-24h) of DTG 50mg twice daily in children (20-35kg) who are taking rifampicin-based regimen for the treatment of tuberculosis. | 48 weeks | 
| Pharmacokinetics (Cmax) of DTG 50mg twice daily | Description of the pharmacokinetics (Cmax) of DTG 50mg twice daily in children (20-35kg) who are taking rifampicin-based regimen for the treatment of tuberculosis. | 48 weeks | 
| Pharmacokinetics (AUC0-24h) of DTG 50mg twice daily | Description of the pharmacokinetics (AUC0-24h) of DTG 50mg twice daily in children (20-35kg) who are taking rifampicin-based regimen for the treatment of tuberculosis. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To develop an integrated model which will be used to estimate the primary PK parameters of DTG | Nonlinear mixed-effects models (NLMEM) will be used to describe the PK of DTG in an integrated model which will be used to estimate the primary PK parameters of DTG. The effect of concomitant TB treatment, as well as other covariates on these parameters, will be evaluated in the model. | 48 weeks | 
| Adverse events | Subjects will be monitored clinically and biologically for safety. Biological monitoring will focus on liver function. Adverse Events and Serious Adverse Events will be graded following DAIDS grading tables | 48 weeks | 
| Virological suppression | Antiretroviral efficacy is based on HIV viral suppression. The cut-off value related to virological failure is defined as a viral load superior to 400 copies per mL, confirmed within a month. Viral load will be assessed as per the SOE | 48 weeks | 
| Enzyme polymorphisms | Enzyme polymorphism analysis will be conducted at a later stage from stored samples to determine the importance of polymorphisms in genes regulating anti-TB drug and antiretroviral concentrations and effects in the study population. | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dolutegravir (DTG), Paediatrics, HIV/TB co-infection