TB-CHAMP – an update

2. TB-CHAMP – an update DR-TB STAT 29th August 2019 James Seddon

3. Outline • Description of the trial • Rationale for drug choices • Impact on epidemic • What should we be doing now • Lessons learnt

4. Outline • Description of the trial • Rationale for drug choices • Impact on epidemic • What should we be doing now • Lessons learnt

6. CHAMP-TB • Aim - to assess the efficacy of preventive therapy in child contacts of MDR-TB • Three sites in South Africa • Desmond Tutu TB Centre, Stellenbosch University, Cape Town (DTTC) • Perinatal HIV Research Unit, Klerksdorp, Wits Health Consortium (PHRU) • Wits Reproductive Health and HIV Institute Shandukani Research Centre (WRHI) • Large number of diagnosed MDR-TB adults at each site • Strong linkage to TB hospitals and clinics - high capacity to identify eligible MDR-TB patients and contacts

7. Research questions Main: • Is levofloxacin given daily for 6 months effective in preventing TB and/or all-cause mortality in high-risk child household contacts of MDR-TB cases? Other questions: • Toxicity and tolerability of Levofloxacin in children? • Mortality? • Adherence? • Levofloxacin resistance for incident TB cases? • Levofloxacin cost-effectiveness and acceptability to prevent MDR-TB in child and adolescent household contacts?

8. Trial design • A phase III cluster randomised placebo-controlled superiority trial • Households randomised to: • Arm 1: Levofloxacin (15-20 mg/kg, max 750mg) given daily for six months • Arm 2: Levofloxacin placebo given once daily for six months • All children in a household allocated the same treatment

9. Endpoints Primary • TB disease (confirmed and probable) or death by 48 weeks Secondary • All-cause mortality • AEs ≥ grade 3 (possibly or likely associated with drug treatment) during 24 weeks of treatment • Percentage of levofloxacin or levofloxacin-placebo doses ingested and retained over 24 weeks of treatment • TB disease over 72 weeks • Incidence of levofloxacin-resistant TB disease

10. Inclusion and exclusion criteria

12. Sample size Initial assumptions: • 7% in placebo arm and 3.5% in levofloxacin arm develop TB disease • 2 contacts per household • 10% loss to follow up Revised assumptions: • 7% in placebo arm and 2.8% in levofloxacin arm develop TB disease • 1.3 contacts per household • 80% power and ICC 0.1 • Interim analysis when 500 children randomised and followed to 6 months

13. Children <5 years with known household exposure to an adult MDR-TB case Households (n=650) Children (n=1009) Randomise (1:1) Intervention Arm Treatment: 24 weeks daily levofloxacin Follow up: 48 weeks post treatment Control Arm Treatment: 24 weeks daily placebo Follow up: 48 weeks post treatment Primary outcome: 48 weeks post randomisation Primary outcome: 48 weeks post randomisation

15. Sub-studies • Pharmacokinetics • Health economics • Qualitative studies • Biomarkers for disease progression • Effect of fluoroquinolones on bacterial resistance • Co-infections

16. Progress • Trial opened at DTTC in Sep 2017 and at Shandukani and Matlosana in Nov 2017 • Recruitment to date 450 children (Table at 15 July 2019) • Funding provided by Global Trials Scheme (British MRC/Wellcome Trust/DfID) • Collateral funding from SA MRC • Funding ended July 2019 – recruitment paused • Discussions with Unitaid through 2019 to include TB-CHAMP as part of BENEFIT KIDS • Final outcome decision 15 Sep 2019 • If funded, trial will resume asap after then

17. Outline • Description of the trial • Rationale for drug choices • Impact on epidemic • What should we be doing now • Lessons learnt

18. Rationale for intervention regimen - considerations • Avoidance of regimens with potentially serious or common adverse events • A simple regimen with minimal pill burden • Drugs with known efficacy against MDR-TB • Trends in drug resistance patterns • Potential ARV drug interactions • Potential future extension to at-risk adult populations

19. Drugs considered for the intervention • Ethambutol • Pyrazinamide • Fluoroquinolones (levofloxacin, moxifloxacin) • Ethionamide • Cycloserine • Bedaquiline • Delamanid • PAS • Others: co-amoxiclav, clarithromycin, linezolid, clofazimine, high-dose isoniazid, standard dose isoniazid

20. Rationale for levofloxacin for preventive therapy • Single drug preventive therapy works • 60% risk reduction in progression of TB infection to TB disease with isoniazid prophylaxis • No evidence of increased resistance • Levofloxacin has comparable EBA to isoniazid • Can be used once daily • Licensed in children • Safe • Palatable

21. Drugs considered for the control • Standard dose isoniazid • High dose isoniazid • Nothing (open label) • Placebo (blinded study)

22. Outline • Description of the trial • Rationale for drug choices • Impact on epidemic • What should we be doing now • Lessons learnt

25. Outline • Description of the trial • Rationale for drug choices • Impact on epidemic • What should we be doing now • Lessons learnt

26. Balancing Act • Toxicity exists • Unclear efficacy of treatment • Child could be infected with a susceptible strain • Concerns about resistance propagation • M. tuberculosis • Other organisms • Low risk of disease progression if left alone • Not a priority High risk of disease progression if left alone in certain patient populations Severe adverse events rare Emerging evidence for efficacy High concordance within households Severe consequences of developing MDR-TB High cost of MDR-TB treatment

27. Marks et al. Clin Infect Dis 2017; 64: 1670-1677

28. Marks et al. Clin Infect Dis 2017; 64: 1670-1677

29. Fox G et al. Am J RespirCrit Care Med 2015; 192: 229–237

30. Concordance Infectious source case Intense interaction Limited social activity of contact Young age of contact No other identified source cases Low incidence setting Source case less infectious Limited interaction Extensive social activity of contact Older age of contact Other identified source cases High incidence setting High concordance Low concordance

31. Risk of progression to disease following infection Concordance between putative source case and child contact Tolerability of regimen Birth 15 years

32. What to do now? Randomised controlled trial data Increasing observational evidence Clinical treatment Time

33. Outline • Description of the trial • Rationale for drug choices • Impact on epidemic • What should we be doing now • Lessons learnt

36. Lessons Learnt • Some of assumptions incorrect regarding sample size • Very hard work finding MDR-TB cases • MDR-TB not the same as DS-TB • Large distances need to be covered • ‘Excluding’ TB disease not always straightforward • Amazing how much data and how many studies can be done within one trial

38. Questions?