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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: www.pactr.org

Trial no.: PACTR201302000426554 Date registered: 2012/10/04
TRIAL DESCRIPTION
Public title Pharmacokinetics of lopinavir/ritonavir superboosting in infants and young children co-infected with HIV and TB
Official scientific title An open label, sequential non-randomised pharmacokinetics study comparing lopinavir plasma exposure when given as lopinavir superboosted with ritonavir (1:1 ratio) in the presence of rifampicin or lopinavir boosted with ritonavir (4:1 ratio) in the absence of rifampicin in HIV and TB co-infected children in South Africa
Brief summary describing the background
and objectives of the trial
Currently available data describing the pharmacokinetics, safety and efficacy of superboosted LPV/r is limited to 15 children mostly between 1 and 2 years of age. Subsequently doses of rifampicin and other anti-TB drugs have been increased. More data is needed to support superboosting in children of various ages and clinical conditions using the new rifampicin doses. The proposed study will evaluate the pharmacokinetics of LPV/r 1:1 with rifampicin in young children weighing 3-15kg based on South African treatment guidelines. It will serve as a benchmark for future evaluation of the solid, dispersible, child friendly formulation of RTV to be used as a booster, which DNDi is currently developing.
Type of trial Others
Acronym (If the trial has an acronym then please provide)
Disease(s) or condition(s) being studied HIV/AIDS , Tuberculosis ,
Purpose of the trial Treatment
Anticipated trial start date 2012-12-01
Actual trial start date
Anticipated date of last follow up 2014-07-01
Actual date of last follow up
Anticipated target sample size (number of participants) 90   
Actual target sample size (number of participants)   
Recruitment status Open to recruitment: actively recruiting participants
Secondary Ids Issuing authority/Trial register Links to Secondary ID

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
Single group: all participants receive same intervention throughout study Non-randomised Open-label (masking not used)

INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental group Superboosting LPV/r 1:1 LPV/r (1:1) twice daily based on child's weight Entire TB therapy LPV/r solution with additional RTV solution to make LPV/r 1:1 during rifampicin containing TB therapy 90

ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Min age Max age Gender
Documentation of a confirmed diagnosis of HIV-1 infection following SA clinical guidelines Weight >3kg and </=15 kg at enrolment > 42 weeks gestational age On LPV/r-based therapy or about to start a LPV/r-based antiretroviral combination therapy with 2 NRTIs [ABC+3TC or AZT+3TC or d4T+3TC] Clinical diagnosis of TB requiring rifampicin-based therapy Parent or legal guardian able and willing to provide written informed consent and able to attend study visits. For neonates, less than 42 weeks gestation and 14 days old Concomitant/chronic treatment with potent enzyme-inducing/inhibiting drugs other than those in the study treatments . See Appendix E (minor inducers/inhibitors and drugs used as part of management of the condition are allowed eg. Steroids) Anticipation at the start that anti-TB treatment duration will be longer than 9 months Any other condition/finding that, in the investigator¿s opinion, would compromise the child¿s participation in this study eg. alanine transferase (ALT) more than 10 times upper limit of normal (ULN), or chronic renal, hepatic or gastrointestinal disease such as malabsorption. Children with known malignancies and contraindications to taking LPV/r Treatment with experimental drugs for any indication within 30 days prior to study entry; participation in another study may be approved by the study team. 2 Weeks 5 Years 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
Yes 2012/09/07 Human Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
University of the Witwatersrand, Postnet Suite 189, Private Bag X2600, Houghton Johannesburg 2041 South Africa
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval
Name of the ethics committee
Yes 2012/08/22 Health Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
University of Stellenbosch,PO Box 19063, Tygerberg Cape Town 7505 South Africa
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval
Name of the ethics committee
Yes 2013/01/31 Human Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Groote Schuur Hospital, Old Main Building, Observatory Cape Town 7925 South Africa
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval
Name of the ethics committee
Yes 2013/06/03 Pharma-Ethics (PTY) Ltd
Ethics Committee Address
Street address City Postal code Country
123 Amcor Road Lyttelton Manor 0157 South Africa
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval
Name of the ethics committee
Yes 2013/06/03 Pharma-Ethics (PTY) Ltd
Ethics Committee Address
Street address City Postal code Country
123 Amcor Road Lyttelton Manor 0157 South Africa

OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome To demonstrate that the proportion of subjects achieving LPV C0/morning trough above 1mg/L during superboosting of LPV with RTV (in a 1:1 ratio) while on RIF-based anti-TB treatment, is not inferior the proportion of subjects achieving LPV C0/morning trough above 1 mg/L during ART with LPV/r (in a 4:1 ratio) in the absence of anti-TB treatment Proportions of children treated with lopinavir morning C0/morning trough <1mg/L at each of the intensive PK evaluations.
Secondary Outcome To assess the safety and tolerability of LPV/r liquid formulation in HIV-infected infants and children with RTV superboosting (1:1 ratio LPV/r) with concomitant RIF-based anti-TB treatment. Liver function monitoring through clinical and biochemical monitoring. Cardiac effect monitored by electrocardiogram at the beginning of anti-TB and HIV concomitant therapy.
Secondary Outcome Compare the model-based estimates of the LPV PK measures of exposure (C0/morning trough, C12/evening trough, Cmax, AUC) during anti-TB treatment and superboosting vs. during treatment with standard LPV/r doses 1 month after completing TB therapy. Compare the exposures of LPV/r 1:1 during rifampicin containing TB therapy and LPV/r 4:1 after TB therapy. HIV infected children 3-15kg
Secondary Outcome To explore the effects of age, weight, sex, initial severity of tuberculosis and anthropometric measurements on LPV & RTV pharmacokinetics, i.e. exposure, C12/evening trough, Cmax and C0/morning trough concentrations with/without concomitant anti-TB treatment. Age, weight, sex, severity of TB, malnutrition indices
Secondary Outcome To determine the pharmacokinetics of anti-TB drugs concomitantly administered with superboosted PI. Exposures of rifampicin, isoniazid, pyrazinamde and ethambutol in children 3-15 kg
Secondary Outcome To assess adherence to therapy questionnaire, drug accountability, and drug levels in hair
Secondary Outcome To describe viral load evolution before, during and after superboosting and monitor resistance in children failing therapy Viral load, resistance testing
Secondary Outcome To compare abacavir (ABC) blood levels during and after co-treatment with rifampicin based anti-TB therapy ABC exposures during rifampicin containing TB therapy and after
Secondary Outcome To determine the pharmacokinetics of anti-TB drugs concomitantly administered with superboosted PI. Exposures of rifampicin, isoniazid, pyrazinamde and ethambutol in children 3-15 kg

RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Shandukani Research WRHI 2nd Floor, Hillbrow Health Precinct, Hillbrow Johannesburg 2001 South Africa
Empilweni Services and Research Unit Department of Paediatrics and Child Health, Rahima Moosa Mother and Child Hospital,Cnr Oudtshoorn & Fuel Street, Coronationville Johannesburg 2093 South Africa
Enhancing Care Foundation King Edward VIII Hospital, Cnr Sydney and Francois Roads Durban 4013 South Africa
Perinatal HIV Research Unit Chris Hani Baragwanath Hospital, P.O. Box 114, Diepkloof, Soweto Johannesburg 1864 South Africa
The Children's Infectious Diseases Clinical Research Unit Ward J8, Tygerberg Hospital, Francie van Zijl Avenue, Parow Valley Cape Town South Africa

FUNDING SOURCES
Name of source Street address City Postal code Country
Médecins Sans Frontières - Norway Postbox 8813, Youngstorget Oslo NO-0028 Norway
UBS Foundation Switzerland

SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Drugs for Neglected Diseases Initiative 15 Chemin Louis Dunant Geneva 1202 Switzerland Foundation

COLLABORATORS
Name Street address City Postal code Country
Division of Clinical Pharmacology, University of Cape Town K45 Old Main Building, Groote Schuur Hospital, Observatory Cape Town 7925 South Africa

CONTACT PEOPLE
Role Name Email Phone Fax
Principal Investigator Prof Mark Cotton mcot@sun.ac.za +27 21 938 4219
Street address City Postal code Country Position / Affiliation
The Children's Infectious Diseases Clinical Research Unit,Tygerberg Hospital, Francie van Zijl Avenue, Parow Valley Cape Town South Africa Professor and paediatrician
Role Name Email Phone Fax
Public Enquiries Dr Marc Lallemant mlallemant@dndi.org +41 79 293 1205 +41 22 906 9231
Street address City Postal code Country Position / Affiliation
Drugs for Neglected Diseases initiative, 15 Chemin Louis Dunant Geneva 1202 Switzerland Head of Paediatric HIV Program
Role Name Email Phone Fax
Scientific Enquiries Dr Marc Lallemant mlallemant@dndi.org +41 79 293 1205 +41 22 906 9231
Street address City Postal code Country Position / Affiliation
Drugs for Neglected Diseases Initiative, 15 Chemin Louis Dunant Geneva 1202 Switzerland Head of Paediatric HIV Program