PAEDIATRIC TB TRIAL UPDATE

Transcription

1 PAEDIATRIC TB TRIAL UPDATE ANNEKE C. HESSELING PROFESSOR IN PAEDIATRICS AND CHILD HEALTH DIRECTOR: DESMOND TUTU TB CENTRE DEPARTMENT OF PAEDIATRICS AND CHILD HEALTH STELLENBOSCH UNIVERSITY, SOUTH AFRICA TUBERCULOSIS PK 2018 WHO CHILDHOOD TB MEETNG 23 OCTOBER 2018, DEN HAAG

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3 Research Area Gaps for children Priority studies DS-TB Dose optimization (rifampicin) Treatment of Severe TB 3 PK studies first-line drugs at higher doses: OptiRif Kids PK/efficacy study in children: SURE, TBM-Kids Treatment shortening: non-severe TB SHINE DR-TB PK/dosing second-line drugs (FQ, aminoglycosides, linezolid, clofazimine, hd INH) New drugs: PK and safety (bedaquiline, delamanid, PA-824, sutezolid) Modeling existing data, testing doses predicted to achieve PK targets PK/safety studies bedaquiline, PA- 824, DLM, BDQ and combinations: MDR PK1, MDR PK2 P1108, C211, Otsuka 232/233, P2005 Co-treatment TB/HIV Injectable sparing shorter regimen Super boosting LPV/r in young children taking HRZE EFV-based regimen in children < 3 years INSTI-based ART with standard TB drugs (HRZE) IMPAACT 2020 (SMART-Kids) DnDI: Super-boosted PI with HRZE EFV+HRZE in slow CYP2B6 genotype RAL or DTG-based ART with TB drugs: Odussey LTBI 3 HP: Safety/tolerability/PK once-weekly 1 HP: Safety/tolerability/PK once-weekly TBTC Study 35 CAP 543

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5 N=1200 children New FDC; 75, 50, 150 (McCleods) Status: n=1204 patients enrolled: f/u ongoing: results early 2020 non-severe TB only

6 DEFINITION OF TARGET PK DRIVERS OF TREATMENT RESPONSE RIFAMPICIN PYRAZINAMIDE ISONIAZID Cmax AUC Cmax AUC Cmax AUC Model-based Cmax and AUC estimates in first 47 children enrolled to the DATiC study (Zvada et al. 7 th Int WS TB Pharm 2014; Chigutsa et al. AAC 2015).

7 Boeree, AJRCCM, 2015

8 Study design n = 20 per cohort 0-12 years Standard RHZE 0, 1, 2, 4, 6, 8, 24 h 0, 2, 4, 8, 24 h PK PK PK Rifampicin ~ 20 mg/kg Standard HZE HD Single high-dose rifampicin ~35mg/kg Standard RHZE Day Monitoring for adverse events See Svensson et al, Union oral

9 OptiRif Kids Dosing cohorts: n=20 per cohorts: A minimum of 60 (20 children per cohort) and a maximum of 100 evaluable child participants (i.e. 5 dosing cohorts) enrolled At least 3 dosing cohorts required, to demonstrate exposures in children similar to those achieved in adults receiving mg/kg in HIGHRIF1 No age de-escalation. Children enrolled in 3 age groups, with children in all 3 age groups included in each dosing cohort: Age group 1: Age 6 to < 12 years: completed Age group 2: Age 2 to < 6 years: completed Age group 3: Age 0 to < 2 years: open (October 2018)

10 MDR-TB in adults: low Treatment Success and High Mortality 10 MDR TB: 50% treatment success, 16% death XDR TB: 24% treatment success, 30% death WHO Global TB Report 2015

11 Global MDR-TB treatment outcomes in children Table 3. Summary of treatment outcomes for children with multidrug-resistant tuberculosis Clinically diagnosed MDR-TB n=238 Confirmed MDR-TB without confirmed XDR-TB n=701 Cured (46.6%) 23 (64%) Completed treatment 166 (69.7%) 209 (29.8%) 7 (19%) Fail or relapse 0 14 (1.9%) 1 (3%) Death 7 (2.9%) 73 (10.4%) 3 (8%) Lost-to-follow-up 19 (8%) 77 (11%) 2 (6%) * Confirmed XDR-TB n=36 *76.4% Update planned: 2019 Seddon, Clin Infect Dis 2013 Harausz et al, PLOS Med 2018

12 Individual drugs gaps: MDR TB trials Key second-line TB drugs, key knowledge gaps in children and ongoing or planned paediatric studies Drug Current Key gaps Ongoing/planned studies Levofloxacin PK data in TB across ages; low exposures Optimal dose and safety; formulation MDRPK1, MDRPK2 Moxifloxacin PK data in TB, >8y only; low exposures PK data in <8y; optimal dose and safety; formulation MDRPK1, MDRPK2 (interim analysis ongoing) Bedaquiline No PK data PK data, optimal dose, safety; HIV P1108; Jannsen-trial; IMPAACT capsule (BDQ- Delamanid PK data >6y PK data in children <6y, safety; HIV Linezolid PK data in non-tb across ages PK data in TB, optimal dose, safety; formulation Clofazimine Limited published PK data PK data, safety optimal dose; formulation Pretomanid: No data; PIP in progrres PK, safety, formulations?2019 DLM) Otsuka 232/233; IMPAACT 2005; IMPAACT capsule (BDQ-DLM) MDRPK2 (interim analysis ongoing)?? IMPAACT Capsule

13 MDR-TB: phase I/II paediatric bedaquiline trials C211: Bedaquiline PK and safety in HIV-uninfected children (n=60) P1108: PK, safety and tolerability of bedaquiline with OBR in HIV-infected and uninfected children with MDR-TB (n=54-72) Sponsor Janssen Pharmaceuticals NIH (DAIDS, IMPAACT) Design Age de-escalation Modified age de-escalation Inclusion 0-<18y, HIV-uninfected only 0-<18y; both HIV-infected and uninfected Accrual Open 2106, South Africa, Philippines, Russia, India Open 2018 South Africa, India, Haiti Other Adult, pediatric formulations Adult formulation,? pediatric formulation Progress Data from cohort 1 (12-17y) shared with WHO Data from cohort 1 (6-17y) shared with WHO

14 IMPAACT P1108: Phase I/II: PK, safety and tolerability of bedaquiline in HIV-infected and uninfected children with MDR-TB Modified age de-escalation trial: 0-17 years; n=54 Dose-finding; pharmacometric modeling, dose adjustment; adaptive design, semi-real time modeling Younger cohorts open in parallel (0-2 and 3-5 years) Adult formulation: whole/crushed Long-term safety; treatment outcome

15 P1108 Interim pharmacokinetics analysis

16 BDQ CRUSH Design Objectives Setting Patients Randomized open-label two-period crossover study Primary: To evaluate BA of whole vs crushed BDQ Secondary: To characterize 1) rate of absorption, 2) short term safety, 3) acceptability of whole vs crushed BDQ TASK (Cape Town, SA); Sponsor DAIDS/IMPAACT Healthy adult volunteers Dosing Assays Analysis Sequence 1: 4 x 100 mg BDQ whole, then 4 x 100 mg BDQ dissolved, both with food Sequence 2: 4 x 100 mg BDQ dissolved, then 4 x 100 mg BDQ whole, both with food UCT HPLC-MS/MS for BDQ and M2 NLME (primary endpoint = bioavailability parameter)

17 BDQ CRUSH: impact of dissolving on a typical BDQ PK profile Mean absorption time slightly longer for dissolved tablets: +23% (p=0.03, CI 95% %) T max : 4.3 to 5.2h C max : 5% Difference in bioavailability dissolved vs whole tablets not statistically significant (p=0.92, CI 95% %) Bioequivalence criteria fulfilled Analysis and slide courtesy of Elin Svensson

18 Delamanid: 232 and 233: Median delamanid and DM-6705 plasma PK parameters for Groups 1-3 in pediatric trial 232 Median DLM C max (ng/ml) Median DLM AUC 0-24 (ng*h/ml) Median DM-6705 C max (ng/ml) Median DM-6705 AUC 0-24 (ng*h/ml) Group 1 (12 17y) (n=7) Group 2 (6-11y) (n=6) Group 3 (3-5y) (n=12) Adults *Day 10 values from 232 for Groups 1 and 2; Day 14 values from adult trials

19 Novel TB drugs in children Delamanid Children 6-17y same indications as in adults Children <6y case-by-case basis Access? DLM CRUSH? Bedaquiline Children >12y same indications as in adults Children <6y case-by-case basis Access in younger kids? Watch this space

20 IMPAACT 2020 (SMaRT Kids) Design: Phase 2 multi-centre trial Eligibility Children 0 to <15 years of age; Probable or confirmed pulmonary or extrapulmonary MDR/RMR- TB/Rif-R, and MDR-TB with additional SLI-res or FQN-res HIV-infected and uninfected Exclusion - Probable or confirmed Stage 2 or 3 TB meningitis or osteoarticular TB Assignment to 1 of 2 arms based on FQN-susc Arm 1 FQN-Susc 26 weeks BDQ-DLM-Levo, 8 weeks Lzd Arm 2 FQN-Res 26 weeks BDQ-DLM-CFZ, 8 weeks Lzd Objectives 1 o - Safety; 2 o - outcomes, PK, others N=148

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22 New WHO recommended regimens: DS-TB WHO LTBI Guidelines,

23 Evidence gaps: shorter regimens: DS-TB 3HR: Rigorous implementation science needed to guide optimal and cost effective implementation of 3HRincluding health systems strengthening (FDCs to support preventive therapy already WHO prequalified) 3HP: PK and safety data on rifapentine and INH (12 doses over 12 weeks in total) : TBTC Study 35 in 0-12 years (HIV+/-) will open in Q under FDA IND, for licensure, with Sanofi: will include HIV+ (EFV, DTG) 1 HP: Paediatric PK and safety data needed (HIV-/+): IMPAACT HP vs. 3 HP?: Safety, completion: PROTEA 4 R: any need for paediatric data?

24 TB-CHAMP V-QUIN PHOENIx Intervention LVF vs. placebo daily for 6 months LVF vs. placebo daily for 6 months DLM vs. standard dose INH daily for 26 weeks Target Population <5 years regardless of IGRA or HIV status Only study powered for efficacy in children All ages TST + Children not yet treated HIV + Children <5 years TST/IGRA + >5 years Sample size 778 Households 1556 contacts < 5 y 1326 Households 2785 contacts 1726 Households 3452 contacts Sites South Africa DTTC, Shandukani, PHRU Matlosana Viet Nam NTP ACTG & IMPAACT sites Timelines Open; n=230 enrolled Open ; 70% enrolled Q Funder, PI BMRC/Wellcome Trust/DFID, SA MRC SHIP; Hesseling Australian MRC Fox, Nguyen SA NTP DAIDS, ACTH/IMPAACT Churchyard, Gupta,

25 TB-CHAMP Cluster randomised phase III superiority trial of Levofloxacin vs. placebo for the prevention of TB in child contacts of DR-TB index cases Levofloxacin mg/kg vs. placebo, 6 months: n=1556 Novel formulation: 100 mg scored dispersible

26 A deterioration in the control of TB thus immediately hurts the youngest generation Rieder, 1997

27 NICHD - The Eunice Kennedy Shriver National Institute of C... Health Information Research Funding News & Media About NICHD View all slides News Releases October NICHD Director's podcast now on line NIH establishes Down syndrome patient registry NIH study shows drug fails to prevent preterm birth in high risk group More news releases...