Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202008554705202 Date of Approval: 11/08/2020
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Pharmacokinetics of twice or once daily DTG (50mg) in children with HIV and TB
Official scientific title An open-label, sequential non-randomised pharmacokinetics study of dolutegravir (DTG) plasma exposure when given as twice or once daily DTG in the presence of rifampicin in children with Human Immune Deficiency Virus (HIV) and tuberculosis (TB) between 20-35kgs in South Africa. (Stage 1 using twice daily in accordance with the standard of care dosing).
Brief summary describing the background and objectives of the trial Co-treatment of HIV and TB in children is virtually unavoidable in high endemic areas of Africa, yet options for this vulnerable population remain extremely limited. A DTG based regimen in children (>20kg), adolescents and adults, is now standard-of-care first-line therapy for HIV, so it is critically important to know how to dose children who also have TB. While double dose DTG is the only option currently available for children who require co-treatment of HIV and TB, recent PK modelling supports the continuation of daily DTG. This approach needs further clinical evaluation. Primary Objective • To determine 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. Secondary Objectives • To assess the safety and tolerability of twice-daily DTG in HIV-infected children with concomitant RIF-based anti-TB treatment. • Compare the model-based estimates of the DTG PK measures of exposure (Ctrough, Cmax and AUC0-24h) during anti-TB treatment during treatment with standard DTG doses one month after completing TB therapy. • To explore the effects of age, weight, sex, initial severity of tuberculosis and anthropometric measurements on DTG pharmacokinetics, i.e. exposure, Ctrough, Cmax and AUC0-24h concentrations with/without concomitant anti-TB treatment. • To assess adherence to therapy (questionnaire, drug accountability, and drug levels in hair) • To describe viral load evolution before, during and after co-treatment and monitor resistance in children failing therapy • To explore the effect of pharmacogenetic variants on the levels of anti-TB drugs and ARVs during co-treatment.
Type of trial CCT
Acronym (If the trial has an acronym then please provide) CAPRISAHIVPed001
Disease(s) or condition(s) being studied Infections and Infestations,Paediatrics
Sub-Disease(s) or condition(s) being studied HIV/AIDS,Tuberculosis
Purpose of the trial Treatment: Drugs
Anticipated trial start date 01/09/2020
Actual trial start date
Anticipated date of last follow up 31/08/2021
Actual Last follow-up date
Anticipated target sample size (number of participants) 20
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Non-randomised Sealed opaque envelopes Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Twice daily DTG with Rifapicin 50mg twice daily 26 weeks Twice daily DTG with Rifapicin 20
Control Group Not applicable Not applicable Not applicable Not applicable 0 Uncontrolled
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
• 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. • 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 Adolescent: 13 Year-18 Year,Child: 6 Year-12 Year,Preschool Child: 2 Year-5 Year 0 Day(s) 18 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 14/04/2020 University of KwaZulu Natal Biomedical Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Research Office, Westville Campus Govan Mbeki Building Durban 4001 South Africa
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Primary Endpoint • 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. Population plasma PK parameters of DTG in the presence or absence of RIF-based TB treatment, including absorption rate constant (ka), the volume of distribution (Vd), and oral clearance (Cl/F) and between-subject variability terms; post-hoc Bayesian predictions of secondary PK parameters of DTG including AUC and Cmin with HRZE dosing Secondary Endpoints • Pharmacokinetics 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 including ka, Vd, and CL. The effect of concomitant TB treatment, as well as other covariates on these parameters, will be evaluated in the model. The model can also be used to derive individual estimates of traditional (secondary) DTG PK measures such as Area Under the Curve (AUC), Cmax, Ctrough, tmax, half-life (t1/2). • Safety 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 (see Appendix B). • Efficacy 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 (Table 2) The clinical outcome of the anti-TB treatment will be assessed retrospectively by a central panel who will review all cases for diagnostic accuracy and response to therapy. • 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 Intensive PK sampling will be done at Week 8 and 26
Secondary Outcome • Pharmacokinetics 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 including ka, Vd, and CL. The effect of concomitant TB treatment, as well as other covariates on these parameters, will be evaluated in the model. The model can also be used to derive individual estimates of traditional (secondary) DTG PK measures such as Area Under the Curve (AUC), Cmax, Ctrough, tmax, half-life (t1/2). • Safety 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 (see Appendix B). • Efficacy 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 (Table 2) The clinical outcome of the anti-TB treatment will be assessed retrospectively by a central panel who will review all cases for diagnostic accuracy and response to therapy. • 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. Week 26
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
King Edward VIII Hospital Sydney Rd, Umbilo Durban 4013 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
National Institutes of Health 9000 Rockville Pike Bethesda MD 20892 United States of America
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Secondary Sponsor South African Medical Research Council Francie van Zijl Drive, Parowvallei Cape Town 7500 South Africa Other Collaborative Groups
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Public Enquiries Leora Sewnarain sewnarainl@ukzn.ac.za 27312604172 Department of Paediatrics and Child Health, 4th Floor, Main Building, Nelson R Mandela School of Medicine, 719 Umbilo Road
City Postal code Country Position/Affiliation
Durban 4001 South Africa Clinical Research Coordinator
Role Name Email Phone Street address
Principal Investigator Moherndran Archary archary@ukzn.ac.za +27312604318 Department of Paediatrics and Child Health, 4th Floor, Main Building, Nelson R Mandela School of Medicine, 719 Umbilo Road
City Postal code Country Position/Affiliation
Durban 4001 South Africa Senior Specialist Paediatric Infectious Diseases Unit King Edward VIII Hospital
Role Name Email Phone Street address
Scientific Enquiries Anushka Naidoo anushka.naidoo@caprisa.org +27316550550 Doris Duke Medical Research Institute, 2nd Floor, Nelson R Mandela School of Medicine, University of KwaZulu Natal, 719 Umbilo Road
City Postal code Country Position/Affiliation
Durban 4001 South Africa Senior Research Pharmacist
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Individual participant data that underlie the results of this trial after deidentification Study Protocol starting 6 months after study close Controlled access The datasets used and analysed during the current study are available from the Principal Investigator on reasonable request
URL Results Available Results Summary Result Posting Date First Journal Publication Date
Not available at this stage No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information