TB-CHAMP A PHASE 3 CLUSTER RANDOMIZED TRIAL FOR PREVENTION OF TB IN CHILD HOUSEHOLD CONTACTS

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1 TB-CHAMP A PHASE 3 CLUSTER RANDOMIZED TRIAL FOR PREVENTION OF TB IN CHILD HOUSEHOLD CONTACTS ANNEKE C. HESSELING RESIST TB WEBINAR 20 APRIL 2017 DESMOND TUTU TB CENTRE PROFESSOR IN PAEDIATRICS AND CHILD HEALTH STELLENBOSCH UNIVERSITY

2 Key transitions in tuberculosis Susceptible Exposed Infected Diseased Infectious Sick Accessed care Recognized Diagnosed Treated Completed Cured Mortality Don Enarson, The Union

3 Age related TB disease risk Marais et al. Int J Tuberc Lung Dis. 2004

4 Multi-Drug Resistant TB (MDR TB) 30-50,000 paediatric cases; 400,000 infections 1 million children exposed to MDR-TB annually Data and formulations for treatment of MDR and XDR TB in children are lacking WHO Global TB Report 2015 Jenkins HE et al. Lancet 2014; Dodd PJ et al. Lancet Global Health 2014 WHO Global TB report, 2013

5 Treatment outcome in children with MDR-TB (N=149) Outcome N = 149 (%) Cure 36 (24.2) Probable cure * 101 (67.8) Transferred out 1 (0.7) Lost to follow up 8 (5.4) Died 3 (2.0) Includes 8 patients who stopped their therapy before indicated but were clinically well at follow up Seddon, Thorax, 2013

6 Adverse events in children with MDR-TB (N = 137) Grade of AE Gr 0 Gr 1 Gr 2 Gr 3-4 Any AE (%) Joint, muscle or bone pain (1.5) 15 (10.9) Skin rashes (0.7) 33 (24.1) Itchy skin (0.7) 27 (19.7) Headache (12.4) Sleep/mood problem (0.7) 13 (9.5) Lethargy (0.7) 19 (13.9) Visual problem (3.6) Vomiting (0.7) 24 (17.5) Diarrhoea (0.7) 12 (8.8) Jaundice (0.7) 4 (2.9) Appetite/nausea (0.7) 18 (13.1) Hearing loss (n=142) 25 (17.6) Thyroxine supplementation (n=142; TSH & ft4) 32 (22.5) Seddon, Clin Infect Dis 2013

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8 ntervention TB-CHAMP LVF (novel paediatric dispersible formulation) vs. placebo daily for 6 months V-QUIN LVF vs. placebo daily for 6 months PHOENIx A5300/I2003 DLM vs standard dose INH daily for 26 weeks esign Cluster randomized; superiority Community-based arget Population 0-5 y regardless of TST or HIV status Cluster randomized; superiority Community-based All ages Paediatric enrolment currently on hold TST + Cluster randomized; superiority Community-based HIV + Children 0-5 yrs TST/IGRA + > 5 y ssumptions LVF decreases TB incidence from 7 to 3.5% 80% power LVF decreases TB incidence by 70% from 3% untreated 80% power DLM decreases TB incidence by 50% from 5% to 2.5% 90% power ample size 778 Households 1556 contacts 1326 Households 2785 contacts 1726 Households 3452 contacts ites South Africa: DTTC, Matlsosana, THINK, Viet Nam NTP ACTG & IMPAACT sites N=20-15 Shandukani imelines to open Q (PK lead-in) Open (Q1 2016) Q4 2017

9 TB-CHAMP Cluster randomised phase III superiority trial of LFX vs. placebo in child contacts of MDR-TB Levofloxacin* mg/kg vs. placebo, 6 months In partnership with MRC CTU at UCL (trial management) 4 SA sites: DTTC, Shandukani, Matlosana, THINK

10 Regimen selection: why fluoroquinolones? Highly bactericidal, key components of existing MDR-TB regimens Components of novel regimens - DS and DR-TB Levo NEXT-TB, TB CHAMP, V-Quin, PHOENIX Moxi STREAM, STAND PK/safety of repurposed drugs Shorter, efficacious treatment regimens Understand OBR before introducing novel medications >80% MDR isolates likely to be susceptible Phoenix A5300/I2003: DML vs standard dose INH

11 Trial rationale Observational studies suggest that MDR preventive therapy may be effective; trials required to prove efficacy Current guidance: conflicting; absence of trial evidence: WHO: no treatment regimen recommended; f/u for 2 years ( watch and wait ) Limited evidence base for DLM in children Using licenced secondline line TB drugs with extensive paediatric experience and PK and safety data a viable option to prevent MDR-TB

12 Regimen selection Prevalence of resistance to FQN in adults and children with MDR-TB in SA: ~ 15%. Benefit of high dose LFX even in resistant strains Although moxifloxacin has good efficacy against metabolically active mycobacteria, LFX has best activity against mycobacteria in latent phases. LFX: licensed, widely used in children, has low toxicity at current doses (15-20 mg/kg) Paediatric formulation developed for the trial Future substudy planned: delamanid Evidence needed regarding efficacy and safety of LFX Cremades J Antimicrob Chemother 2011 Fox G, AJRCCM 2016

13 Preliminary data: Risk of infection, disease and MDR-TB preventive therapy in children 228 MDR-TB-exposed children <5 years of age were enrolled during May April % were TST positive and 6.6% had prevalent TB at enrolment. Children without TB received a regimen of INH (15-20mg/kg), ofloxacin (15-20mg/kg) and ethambutol (20-25mg/kg) daily for 6 months. Ofloxacin was available at the time; LFX now used in children < 8 years. Children were monitored for clinical outcomes and adverse events, resulting in >200 patient years of followup. No children on MDR-TB regimen and were adherent developed TB Seddon. Clin Infect Dis. 2013

14 Summary: safety and dosing No QTc prolongation (QTc>450ms) occurred and no other safety issues (arthropathy, electrolyte abnormalities) were observed. Simulation the optimal LFX dose in children through population PK modelling - R. Savic (UCSF) Based on an assumed MIC of 0.5 mcg/ml from adult literature, a dose of 20 mg/kg is proposed (15 mg/kg in children < 2 years of age due to immature renal function based on modelling data), which will result in a C max of > 10 mcg/ml

15 Trial type A 4-year community-based, multicentre, cluster randomised phase III superiority trial of LFX vs. placebo for the prevention of MDR-TB in HIV-infected and uninfected child contacts 0-5 years of age of confirmed adult pulmonary MDR-TB source cases

16 Primary objective Is levofloxacin (LFX) [intervention arm], given daily for 6 months, effective to prevent MDR-TB in child household contacts (HHC) of MDR-TB cases?

17 Secondary objectives 1. Does LFX have acceptable toxicity and tolerability in children? 2. Is there a difference in mortality between study arms? 3. Is adherence similar between study arms? 4. Are there differences in LFX resistance between study arms for children developing incident TB? 5. Is LFX cost-effective and acceptable to prevent MDR-TB in child and adolescent HHC? 6. Nested economic and qualitative feasibility sub-studies will evaluate the cost, impact and acceptability of the preventive strategies 7. Nested PK lead in study (single site) 8. Biomarker, microbiome studies planned (correlates of risk, effect of LFX on gut biome, non-specific effects)

18 Exclusion criteria 1. Prevalent TB at enrolment 2. On FQN or INH for 14 days 3. Known concurrent exposure to an INH-susceptible source case 4. CNS disease (myasthenia gravis) Children with FQN resistant, pre-xdr or XDR-TB exposure (typically detected retrospectively) will not be excluded (considered in sample size; subgroup analyses) Children with DS-TB exposure will receive INH Children with RMR-exposure will receive INH Plan for DLM sub study in future (pre-xdr and XDR-TB) (Otsuka) EDCPT grant submitted

19 Trial procedures Adults routinely diagnosed with MDR-TB and receiving treatment through the NTP will be identified and assessed as eligible source cases if: a) 18 years old b) diagnosed in the preceding 6 months with MDR-TB c) pulmonary TB (sputum smear and/or or culture+ and at least MTB/RIF positive with Rif resistance INH resistance testing pending/confirmed). Source cases will have additional DST of available (routine NHLS) and research sputum samples to allow for appropriate management, subgroup analyses

20 Randomization 1. Randomisation will performed at the household level (each household forming a cluster with all members allocated to same study treatment), in a 1:1 ratio to Arms 1 or 2 2. Randomised block design, with institutional balancing 3. Not all eligible household members need to participate in order for child members to participate

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22 Children < 5 years with known household MDR-TB adult contact TST+ and TST- HIV-infected and uninfected N=778 households/1556 children Randomise (1:1) INTERVENTION ARM Treatment Phase: 24 weeks daily dosing of levofloxacin Follow-up phase: 72 weeks post-treatment Primary outcome at 48 weeks post randomisation CONTROL ARM Treatment Phase: 24 weeks daily dosing of placebo Follow-up phase: 72 weeks post-treatment Primary outcome at 48 weeks post randomisation

23 Primary outcome Incident TB disease by 48 weeks postrandomisation. Primary end point analysis will consider bacteriologically confirmed and clinical cases using international consensus case definition (contact tracing studies) Incident TB: adjudicated by an independent ERC blinded to treatment allocation, based on available clinical, microbiological and molecular data using standard case definitions; dual central blinded CXR review

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25 Lab considerations Safety labs and TB micro during trial: BARC Routine ( historical ) NHLS lab results for adult index case (e.g. Xpert Rif +, with or without LPA, phenotypic DST): INH resistance pending accepted but needs to be confirmed ASAP Research sputum sample taken by team at time of screening; cultured and stored for future use; additional DST as needed in real time or later Central research analysis; WGS, MIC, microtitre (retrospective- future use

26 Oflox: 200 mg Levo: 250 mg Moxi: 400 mg

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28 Weight banding for LVX dosing! Levofloxacin, 100,mg,tabs, Levofloxacin, 250,mg,tabs,! 15920,mg/kg, Once,daily, 15920,mg/kg, Once,daily, Weight, Max,750,mg, Max,750,mg, 5.0,,7.49,kg, 1!tab! &&! 7.5,,9.99,kg, 1.5!tabs! &&! 10.0,,12.49,kg, 2.0!tabs! &&! 12.5,,14.99,kg, 2.5!tabs! &&! 15.0,,17.49,kg, 3!tabs! &&! 17.5,,19.99,kg, 3.5!tabs! &&! 20.0,,24.99,kg, &&! 1.5!tabs! 25.0,,29.99,kg, &&! 2!tabs! 30.0,,39.99,kg, &&! 2.5!tabs!

29 PK lead-in study Single site (DTTC) N=24 children 0-5 years exposed to MDR-TB HIV-uninfected LFX 100 mg scored dispersible formulation Bio-availability compared to 250 mg LFX compared with historical data (N=106 children, LFX) Acceptability and palatbility: excellent (n=15 participants) Opened Q1 2017; n=18 enrolled Assays: UCT; PK modelling (Paolo Denti, UCT)

30 Accrual over 24 months Average 14 children per month per site Staggered start-up: DTTC, Matlosana, Shandukani, followed by THINK Start-up of randomization: June 2017 *Interim analysis planned: efficacy: n= 778

31 Sponsor Funders Sites Trial management PK Diagnostics, biomarkers: NHLS, SUN IRG Local health departments