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.: PACTR201505001141379 Date of Approval: 14/05/2015
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Shorter treatment for minimal TB in children
Official scientific title A randomised trial of therapy shortening for minimal tuberculosis with new WHO-recommended doses/fixed-dose-combination drugs in African and Indian HIV+ and HIV- children
Brief summary describing the background and objectives of the trial Of the estimated 9 million tuberculosis (TB) cases globally per annum, more than half a million are in children, this burden being highest in Africa and South East Asia and resulting in 100,000 deaths. In Africa, where the TB and HIV epidemics are closely linked, children contribute up to 30% of incident TB cases. Furthermore, in countries with high HIV prevalence, the peak age-prevalence of infectious TB has decreased, and as these adults are often parents of children, the risk of TB to young children is increased. Regimens for prevention and treatment of TB in children have lagged considerably behind adults, as discussed in the 2012 WHO TB report which included estimates for children for the first time. The appropriate treatment period for minimal TB in children, has never been subjected to a randomised trial. The original studies of 6-month first-line drug regimens in adults reported excellent outcomes with minimal toxicity. However paediatric guidelines have been extrapolated from adult trials. Treatment outcomes appear considerably better in children than adults. The principal objective is to determine whether the standard 6 month regimen (8 weeks HRZ(E) followed by 16 weeks HR) can be reduced with similar efficacy, to 4 months (8 weeks HRZ(E) followed by 8 weeks HR), in HIV-infected and uninfected African and Indian children with minimal TB, using recently revised dosing guidelines for anti-TB drugs in children. Other objectives: a)To determine whether the higher WHO-recommended doses of daily first-line anti-TB drugs, prescribed according to weight bands, result in appropriate drug exposures when compared with historical paediatric and adult pharmacokinetic (PK) data (PK substudy 1), and compared to dosing of single products (PK substudy 3) b) To determine in HIV-infected children, whether currently recommended adjusted strategies and doses of antiretroviral drugs (ARVs) can appropriately overcome the effect of R at the new higher doses (PK substudy 2)
Type of trial RCT
Acronym (If the trial has an acronym then please provide) SHINE
Disease(s) or condition(s) being studied Infections and Infestations,Paediatrics
Sub-Disease(s) or condition(s) being studied Tuberculosis
Purpose of the trial Treatment: Other
Anticipated trial start date 31/07/2015
Actual trial start date 30/06/2016
Anticipated date of last follow up 31/10/2017
Actual Last follow-up date
Anticipated target sample size (number of participants) 1200
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
ISRCTN63579542 ISRCTN Registry
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 Randomised Simple randomisation using a web-based system Allocation was determined by someone situated elsewhere Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group 4-month regimen Daily dose dependent on revised WHO dosage recommendations and weight band of the patient. Sixteen (16) weeks. Intensive 8 weeks Isoniazid (H), Rifampicin (R), Pyrazinamide (Z) with or without Ethambutol (E) according to local practice followed by continuation of 8 weeks HR. 600
Control Group 6 month regimen Daily dose dependent on revised WHO dosage recommendations and weight band of the patient. 24 weeks Standard daily first-line anti-TB treatment for 24 weeks dosed according to revised WHO dosage recommendations: intensive 8 weeks HRZ(E), followed by continuation of 16 weeks HR. 600
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. Age 0-16 years 2. Weight ¿ 3kg. 3. Clinician has decided to treat with standard first-line regimen (intensive phase of 4 drugs or 3 drugs as per local practice) 4. Symptomatic but non-severe TB including: a)extrathoracic lymph node TB; intra-thoracic uncomplicated (hilar) lymph node TB b) minimal or no parenchymal abnormality on CXR c) smear gastric aspirate/other respiratory sample (minimal 2 samples) negative Note: GeneXpert may be positive or negative; culture of respiratory sample may be positive or negative; lymph node aspirate may be smear/culture/GeneXpert positive or negative) 5. Not previously treated for TB or successfully treated for TB >2 years since last completed treatment 6. Known HIV status; HIV-infected or HIV -uninfected 7. Willing and likely to adhere to 72 weeks follow up 8. Informed written consent from the parent/legal caregiver(s) and assent in children, as per local Ethics Committee guidance 9. Home address accessible for visiting and intending to remain within the recruitment area for follow-up 1. Smear-positive respiratory sample TB (note: smear-positive peripheral lymph node sample is allowed) 2. Premature (<37 weeks) and aged under 3 months 3. Miliary TB, spinal TB, TB meningitis, osteoarticular TB,abdominal TB, congenital TB 4. Pre-extisting non-tuberculous disease likely to prejudice the response to, or assessment of, treatment e.g. liver or kidney disease, peripheral neuropathy, cavitation 5. Any known contraindication to taking anti-TB drugs 6. Known contract with MDR, pre-XDR or XDR adult source case 7. Proven drug resistance in the child (R resistance with or without H resistance), H mono-resistance allowed 8. Severely sick 9. Pregnancy 0 Year(s) 16 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 22/05/2014 UCL Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Gower Street London WC1E 6BT United Kingdom
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome TB disease-free survival 72 weeks post-randomisatio will be determined by the ERC and categorised as: favourable, unfavourable (including death, reinfection or relapse) or not assessable (e.g. lost to follow-up) 72 weeks
Secondary Outcome 1. Mortality Anytime
Secondary Outcome 2. Adverse drug reactions within 30 days of completing treatment 30 days after treatment completion
Secondary Outcome 3. Relapse/re-infection-free survival including only cases adjudicated to be TB by the independent ERC Anytime
Secondary Outcome 4. Suppressed HIV viral load at 24 and 48 weeks in HIV-infected children 24 and 48 weeks
Secondary Outcome 5. adherence and Acceptability End of treatment phase
Secondary Outcome 6. Bacterial infections Anytime
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
National Institute for Research in Tuberculosis No.1, Mayor Sathiyamoorthy Road Chetpet, Chennai 600 031 India
BJ Medical Colege Jai Prakash Narayan Road Pune 411001 India
University Teaching Hospital Ridgeway Lusaka P.O BOX 50110 Zambia
MU-JHU Care Ltd Upper Mulago Hill Road Kampala P. O. Box 23491 Uganda
Desmond Tutu TB centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University Francie van Zijl Avenue Tygerberg 7505 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
Joint Global Health Trials Scheme of MRC UK/DfID/Wellcome Trust North Star Avenue Swindon SN2 1ET United Kingdom
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor University College London Gower Street London WC1E 6BT United Kingdom University
COLLABORATORS
Name Street address City Postal code Country
University of Cape Town Old Main Building, Groote Schuur Hospital Cape Town South Africa
Radbourd University Medical Center eert Grooteplein Noord 9 Nijmegen 6525 EZ Netherlands
University of York Heslington York YO10 5DD United Kingdom
MRC/UVRI Uganda Research Unit on AIDS Entebbe Uganda
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Diana Gibb diana.gibb@ucl.ac.uk +44 (0) 20 7670 4709 Aviation House, 125 Kingsway
City Postal code Country Position/Affiliation
London WC2B 6NH United Kingdom Chief Investigator
Role Name Email Phone Street address
Public Enquiries Jacqueline Teera j.teera@ucl.ac.uk +44 (0) 20 7670 4738 Aviation House, 125 Kingsway
City Postal code Country Position/Affiliation
London WC2B 6NH United Kingdom Trial Manager
Role Name Email Phone Street address
Scientific Enquiries Anna Turkova a.turkova@ucl.ac.uk +44 (0) 20 7670 4658 Aviation House, 125 Kingsway
City Postal code Country Position/Affiliation
London WC2B 6NH United Kingdom Trial Physician
REPORTING
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