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

Hiv Clinical Trial

— ORCHID  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04746547
• Other study ID #: CAPRISA258 (CAP258)
• Status: Recruiting
• Phase: Phase 4
• Start date: August 19, 2021
• Est. completion date: July 31, 2025

Study information

• Verified date: January 2024
• Source: University of KwaZulu
• Contact: Moherndran Archary, MBChB, PhD
• Phone: +27312604318
• Email: archary[@]ukzn.ac.za
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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. Note: An amendment has been added to include children from 3kgs and a dose of 10mg dispersible DTG

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: July 31, 2025
• Est. primary completion date: July 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 23 Months to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Hiv
• Tuberculosis

Intervention

Drug:
• Dolutegravir 50 MG
Twice daily dolutegravir with rifampicin containing TB treatment
• Dolutegravir 10 MG
Twice daily dolutegravir with rifampicin containing TB treatment

Locations

Country	Name	City	State
South Africa	King Edward VIII Hospital	Durban	KwaZulu-Natal

Sponsors (2)

Lead Sponsor	Collaborator
University of KwaZulu	Centre for the AIDS Programme of Research in South Africa

Country where clinical trial is conducted

South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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