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

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

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

Study Overview

• Status: Recruiting
• Conditions: Tuberculosis; Hiv
• Intervention / Treatment: Drug: Dolutegravir 50 MG; Drug: Dolutegravir 10 MG

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Moherndran Archary, MBChB, PhD; Phone Number: +27312604318; Email: archary@ukzn.ac.za

Study Locations

• South Africa
  • KwaZulu-Natal
    • Durban, KwaZulu-Natal, South Africa, 4001
      • Recruiting
      • King Edward VIII Hospital
      • Contact: Shashikant Dr Ramji, MBChB; Phone Number: +27313603854; Email: Shashikant.Ramji@kznhealth.gov.za
      • Contact: Wendy Ms Madondo; Phone Number: +27313603854; Email: Wendy.Madondo@kznhealth.gov.za
      • Principal Investigator: Moherndran Archary, MBChB, PhD
      • Sub-Investigator: Naidoo Anushka, PhD
      • Sub-Investigator: Dooley Kelly, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Twice Daily DTG; Twice daily Dolutegravir (50mg) with Rifampicin containing TB treatment / Twice daily Dolutegravir (10mg) dispersible	Drug: Dolutegravir 50 MG; Twice daily dolutegravir with rifampicin containing TB treatment; Drug: Dolutegravir 10 MG; Twice daily dolutegravir with rifampicin containing TB treatment

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of KwaZulu
• Collaborators: Centre for the AIDS Programme of Research in South Africa
• Investigators: Principal Investigator: Moherndran Archary, MBChB, PhD, University of KwaZulu

Study record dates

Study Major Dates

• Study Start (Actual): August 19, 2021
• Primary Completion (Estimated): July 31, 2025
• Study Completion (Estimated): July 31, 2025

Study Registration Dates

• First Submitted: February 1, 2021
• First Submitted That Met QC Criteria: February 4, 2021
• First Posted (Actual): February 9, 2021

Study Record Updates

• Last Update Posted (Estimated): February 1, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Paediatrics; Dolutegravir (DTG); HIV/TB co-infection
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Dolutegravir
• Other Study ID Numbers: CAPRISA258 (CAP258)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No