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.: PACTR202008476090763 Date of Approval: 07/08/2020
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Pharmacokinetics of lEvofloxacin FORmulations in children with MDR-TB exposure (PERFORM)
Official scientific title Evaluating the pharmacokinetics and acceptability of 100 mg dispersible compared to 250 mg non-dispersible tablets of levofloxacin in children with multidrug-resistant tuberculosis exposure
Brief summary describing the background and objectives of the trial The burden of multidrug-resistant MDR-TB, i.e. Mycobacterium tuberculosis resistant to at least rifampicin (RIF) and isoniazid (INH), in children is substantial, with modelled estimates of 25,000-32,000 cases annually in children. The treatment of MDR-TB in children is complex, one of the reasons being due to limited child-friendly anti-tuberculosis drug formulations. This has necessitated crushing tablets normally intended for adults in order to treat children, which introduces many problems: inaccurate dosing, disruption of coating, improper/imprecise dose administration, potential waste of the active pharmaceutical ingredient, and poor palatability and acceptability. A new 100 mg dispersible levofloxacin formulation was developed for the treatment and prevention of MDR-TB in children. Recent pilot data showing a much higher exposure compared to non-dispersible tablets suggest that additional data on the PK, safety and tolerability of this formulation are urgently needed in order to inform practical guidance on its optimal dosing in children. We therefore aim to compare the pharmacokinetics (PK) of the novel levofloxacin 100 mg dispersible tablets to the levofloxacin crushed 250 mg non-dispersible tablets in young HIV-uninfected children routinely receiving levofloxacin for MDR-TB preventative therapy. Primary Objectives: To compare the model-estimated relative bioavailability of levofloxacin administered in a dispersible tablet formulation compared to a crushed non-dispersible tablet formulation. 2. To determine the levofloxacin weight-banded dosing algorithm that achieves similar exposure (AUC) and concentration-time profile in children with both levofloxacin formulations compared to adults target exposures.
Type of trial CCT
Acronym (If the trial has an acronym then please provide)
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Tuberculosis
Purpose of the trial Prevention
Anticipated trial start date 01/09/2020
Actual trial start date
Anticipated date of last follow up 31/08/2022
Actual Last follow-up date
Anticipated target sample size (number of participants) 24
Actual target sample size (number of participants)
Recruitment status Completed
Publication URL
Secondary Ids Issuing authority/Trial register
14443 Stellenbosch University Health Research Ethics Committee
20200321 South African Health Products Regulatory Authority
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
Crossover: all participants receive all interventions in different sequence during study Randomised Simple randomization using a randomization table created by a computer software program Allocation was determined by the holder of the sequence who is situated off site Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Levofloxacin A single dose of 100mg levofloxacin dispersible tablet to me administered on either day 1 or day 2 depending on the randomization allocation of the participant. 1 day. Participants will receive the 100mg levofloxacin dispersible tablet either on day 1 or day 2 of being on the study according to a weight based dosing schedule. 12
Experimental Group Levofloxacin A single dose of 250mg levofloxacin non-dispersible tablet to me administered on either day 1 or day 2 depending on the randomization allocation of the participant. 1 day. Participants will receive the 250mg non-dispersible levofloxacin tablet either on day 1 or day 2 of being on the study according to a weight based dosing schedule. 12
Control Group None N/A N/A 0 Uncontrolled
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. HIV-uninfected 2. Age < 6 years at enrolment 3. Started on MDR-TB preventive therapy including levofloxacin by the routine TB program for significant exposure to an MDR-TB source case 4. Receiving levofloxacin for at least 14 days prior to enrolment 5. Written informed consent including for HIV testing if HIV status is unknown 1. TB disease 2. HIV infection 3. Laboratory-documented anaemia (Hb <8 g/dl) (enrollment may be deferred until anaemia improves) 4. Body weight <3 kg (enrollment may be deferred until weight increases) and ≥ 30 kg 5. Serious chronic illness, such as clinically significant structural cardiac disease, chronic lung, renal or liver disease 6. Known hypersensitivity or intolerance to levofloxacin 7. Grade 2 or higher abnormality of any of the following at the time of screening or known within 14 days prior to enrollment, according to the DAIDS Table of Grading Severity of Adult and Pediatric Adverse Events, Version 2.1, July 2017(3): ALT, total bilirubin, or creatinine. 8. Total bilirubin 1.5 X the upper limit of normal accompanied by Grade 2 or higher elevated ALT Infant: 0 Month(s)-12 Month(s),Preschool Child: 2 Year-5 Year 14 Day(s) 6 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
Yes 27/07/2020 Stellenbosch University Health Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Stellenbosch University Faculty of Medicine and Health Science Francie van Zijl Drive Parow, Tygerberg, Cape Town Cape Town 7505 South Africa
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Model-based estimation of relative bioavailability of levofloxacin dispersible tablets and non-dispersible tablet formulations. Outcome measured after PK analysis.
Secondary Outcome 1. Plasma PK parameters of levofloxacin in children receiving MDR-TB preventive therapy by age and weight (allometry and maturation). 2. The cumulative incidence of grade 3 and 4 adverse events at least possibly related to the study levofloxacin. 3. Dosing algorithm in children derived by simulation of optimal levofloxacin doses for both the dispersible tablet and non-dispersible tablet formulations, using nonlinear mixed effects models, and an age and/or weight-banding approach. 4. 4. The acceptability of the dispersible versus the non-dispersible tablets using standard questionnaires. 5. The cumulative number and proportion of children who discontinue study drug due to an AE during the study drug-dosing period. 6. The cumulative incidence of AEs at least possibly related to levofloxacin of any grade over the total dosing period. The team will meet as needed, at least quarterly, throughout the period of study implementation to review safety data, discuss product use management, and address any potential safety concerns.
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Desmond Tutu TB Centre Stellenbosch University Faculty of Medicine and Health Science Francie van Zijl Drive Parow, 7505 Tygerberg Cape Town South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
Unitaid 40 Chemin du Pommier, 5th Floor, Grand-Saconnex Geneva 1218 Switzerland
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Stellenbosch University Tygerberg Hospital Francie van Zijl Avenue, Parow Cape Town 7505 South Africa University
COLLABORATORS
Name Street address City Postal code Country
Unitaid 40 Chemin du Pommier, 5th Floor, Grand-Saconnex Geneva Switzerland
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Louvina Elizabeth van der Laan vdlaan@sun.ac.za +27215087409 Stanberry Street ,Ysterplaat
City Postal code Country Position/Affiliation
Cape Town 7405 South Africa Principal Investigator
Role Name Email Phone Street address
Public Enquiries Tina Sachs tsachs@sun.ac.za +27219389812 Stellenbosch University ,Faculty of Medicine and Health Sciences, Francie van Zijl Drive, Parow
City Postal code Country Position/Affiliation
Cape Town South Africa Project Manager
Role Name Email Phone Street address
Scientific Enquiries Louvina Elizabeth van der Laan vdlaan@sun.ac.za +275087409 Stanberry Street ,Ysterplaat
City Postal code Country Position/Affiliation
Cape Town 7405 South Africa Principal Investigator
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes De-identified individual data reported in the primary manuscript can be shared upon request and agreement by the study team. Study Protocol No sharing time frame is available. Sharing of data can be requested and upon sponsor agreement it can be shared. There are no start and end dates to the availability thereof. Controlled access to data will be allowed upon approval of the request by the study team and agreement from the study sponsor.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
http://blogs.sun.ac.za/dttc/b enefit-kids/ Yes 16/01/2023
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result - 16/01/2023
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information