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Second-line and novel TB drugs in children: emerging data and research update
Anthony J. Garcia-Prats, M.D., MSc.
[email protected] Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University
Childhood TB Training CourseSeptember 12, 2017
Overview
• Approach to study of TB treatment in children
• Knowledge gaps and planned studies of existing second-line and novel TB drugs in children
• Other issues
• Phase 3 trials in children
• Conclusion
• Question 1: In developing TB drugs for children, the following aspects are critical to study in children themselves (may select more than one):A. Safety (the medicine is safe in children)
B. Pharmacokinetic (the medicine achieves target exposures/concentrations)
C. Efficacy (the medicine kills TB)
D. Acceptability (the medicine is acceptable to children/parents)
• Question 2: Which of the following statements accurately describe ethical considerations for studying novel TB drugs in children (may select more than one)?A. It is unethical to study new medications in children because the risk is too high
B. New medications should be studied in children along with adults from the very beginning of drug development
C. Adolescents can be included in later phase adults studies (Phase 2b/3, after some efficacy/safety demonstrated)
D. Once reasonable efficacy and safety has been demonstrated in adults, well planned paediatric studies should begin
Approach to study of TB treatment in children (1)• Evidence for TB treatment regimens in children based
on adult studies
• Challenges of evaluating efficacy of TB treatment in children– Challenge with confirming a diagnosis
– Monitoring treatment response/microbiologic endpoints
– Wide-spectrum of disease
– High rate of spontaneous resolution of minimal disease
• Not impossible, but not always necessary
• Concept of bridging– Extrapolation of efficacy from adult studies to paediatric
populations
Approach to study of TB treatment in children (2)
Dunne J, et al. Extrapolation of Adult Data and Other Data in Pediatric Drug-Development Programs. Pediatrics. 2011;128(5):e1242-e9.
Tuberculosis disease
Approach to study of TB treatment in children (3)• Importance of PK and safety
– May not be necessary to assess efficacy in children, given equivalent drug exposures
– Must demonstrate safety at that dose
• How to determine drug dosing in children?– Same mg/kg dose as in adults results in
underexposure, worse in smaller children• Influence of age (<2 y) and weight (all ages)
– Optimal dose in pediatric context – doses that result in similar drug exposures to adults doses shown to be efficacious and safe
Approach to study of TB treatment in children (4)
• Ethical considerations– Avoid exposing children to unnecessary risk
– Concern about studying drugs in children
– Not ethical to exclude populations from research that they would ultimately benefit from
• Timing– Balance
– Currently quite delayed
• Adolescents
Gaps and research priorities (1)PlannedorongoingPhase2or3trialsofMDR-TBtreatmentorpreventivetherapy
MDR-TBTreatmenttrials MDR-TBPreventivetherapytrials
Trial Componentsofinterventionarm Trial Componentsofinterventionarm
NC005 PZA,BDQ,PTA VQUIN LFXOpti-Q LFX+standardofcare TB-CHAMP LFXSTREAMI hdMFX,PZA,EMB,KAN,INH,CFZ PHOENIx DLMSTREAMII BDQ,CFZ,EMB,PZA,LFX,INH,PTO
NIX-TB LZD,BDQ,PTA STAND PZA,MFX,PTA NEXT-TB PZA,LFX,ETO/hdINH,LZD,BDQ C208 BDQ+standardofcare Trial213 DLM+standardofcare
TB-PRACTECAL BDQ,PTA,MFX,LZD,CFZ MDR-END DLM,LVF,LZD,PZA endTB LFX,MFX,BDQ,DLM,LZD,CFZ A5356 DLM,LZD,+OBR
PZA-pyrazinamide;BDQ-bedaquiline;PTA-pretomanid;LFX-levofloxacin;EMB-ethambutol;MFX-moxifloxacin;PTO-prothionamide;CFZ-clofazimine;hdINH-highdoseisoniazid;LZD-linezolid;ETO-ethionamide;DLM-delamanid
Fluoroquinolones – LFX, MFX
Novel TB drugs – BDQ, DLM, PTA
Other – CFZ, LZD
Overview
• Approach to TB drug trials in children• Knowledge gaps and ongoing or planned studies: existing
secondline TB drugs– Levofloxacin– Moxifloxacin– Linezolid– Clofazimine– Amikacin
• Knowledge gaps and ongoing or planned studies: novel TB drugs
• Other issues• Phase 3 trials• Conclusion
Summary of gaps and research priorities (2)
Keysecond-lineTBdrugs,keyknowledgegapsinchildrenandongoingorplannedpaediatricstudies
Drug Current Keygaps Ongoing/plannedstudiesLevofloxacin PKdatainTBacrossages;low
exposures
Optimaldoseandsafety;
formulation
MDRPK1,MDRPK2
Moxifloxacin PKdatainTB,>8yonly;lowexposures
PKdatain<8y;optimaldoseandsafety;formulation
MDRPK1,MDRPK2(interimanalysisongoing)
Bedaquiline NoPKdata PKdata,optimaldose,safety;HIV
P1108;Jannsen-trial;IMPAACTcapsule(BDQ-
DLM)Delamanid PKdata>6y PKdatainchildren<6y,
safety;HIVOtsuka232/233;IMPAACT2005;IMPAACTcapsule(BDQ-DLM)
Linezolid PKdatainnon-TBacrossages PKdatainTB,optimaldose,
safety;formulation
MDRPK2(interimanalysis
ongoing)Clofazimine LimitedpublishedPKdata PKdata,safetyoptimaldose;
formulation??–IMPAACTCapsule
Second-line TB drugs (1): MDRPK1
• MDRPK-1 (NIH: PI Hesseling, Schaaf, 2011-2016)• Aim: To characterize the PK and toxicity of 2nd-line
anti-TB drugs for the treatment and prevention of drug-resistant TB in HIV-infected and -uninfected children
• 318 children routinely teated with second-line TB drugs, for intensive PK sampling and safety monitoring
• Completed enrolment 2015, longitudinal follow-up ongoing
• Analysing data on ofloxacin, levofloxacin, moxifloxacin, ethionamide, terizidone, PAS, +/- clofazimine, linezolid
Second-line TB drugs (2) - MDRPK2
MDRPK-2 (NIH: PI Garcia-Prats, Savic, 2015-2019) Aim: To characterize the PK and safety of optimized
pragmatic doses of key 2nd-line TB drugs in children with DR-TB Exposures with current doses are low
What are the appropriate doses?
Which are key second-line drugs? Levofloxacin, moxifloxacin and linezolid (clofazimine)
PK and safety of modeled pragmatic optimised doses
Enrolment began in Cape Town – 2016 Target 100 children with MDR-TB - to date 53 enrolled
Interim MFX and LZD PK data
Summary: Levofloxacin
Class Flouroquinolone
Administration Oral, good bioavailability
Metabolism/elimination
Eliminated unchanged in the urine
PD Concentration dependent – AUC
Target AUC in adults (750mg once daily)
Paediatric dose 7.5-10mg/kg/dose BD (<5y), OD(>5y)
Data source •MDRPK1 and MDRPK2 study•15mg/kg and 20mg/kg once daily (exact)
Levofloxacin results: PK (1)
• N=109, median age 2.1y (0.3-8.7), HIV+ 14.7%
• Two compartment structural model
• Significant covariate effects– Allometric scaling on clearance and Vd
– Maturation effect on clearance• At 50% at 1.59 months after birth
– Administration method on speed of absorption• Crushed NGT > crushed oral > whole
• No effect on overall bioavailability
Levofloxacin: Simulated AUCAssuming 20 mg/kg dosing
Target used by Savic et al. 2015
dose: 750 mg
500 mg
1000 mg
Simulated levofloxacin exposure – 750 mg adult target
Target:750mgdoseinadults,equivalenttoAUCof101h*mg/L
Wtband(kg) <5 5-<6 6-<9 9-<1212-<15
15-<18
18-<22
22-<27
27-<32
23-<35
Dose(mg) 150 200 300 400 500 600 700 800 900 1000
Dose(mg/kg) -- 33-40 33-50 33-44 33-42 33-40 32-39 30-36 28-33 29-44
Levofloxacin safety: Adverse effects at least possibly related to levofloxacin (n=70)
AdverseEvent
#of
patients
with
event
Grade1 Grade2 Grade3 Grade4
total#
of
events
EventRate
(perperson-
yrs)
Arthralgia 2 2 0 0 0 2 0.029
Arthritis 0 0 0 0 0 0 --
Painotherthantraumaticinjury 4 4 0 0 0 4 0.058
Headache 2 1 0 1 0 2 0.029
Neurosensoryalteration 0 0 0 0 0 0 --
Insomnia 1 0 1 0 0 1 0.015
Fatigue/malaise 0 0 0 0 0 0 --
Nausea 8 9 0 0 0 9 0.131
Vomiting 14 16 0 0 0 16 0.234
Anorexia 7 4 3 0 0 7 0.102
Cutaneousreaction 7 3 4 0 0 7 0.102
Pruritus 7 7 1 0 0 8 0.117
Acutesystemicallergicreaction 0 0 0 0 0 0 --
ALT 16 16 2 0 0 18 0.263
Bilirubin 0 0 0 0 0 0 --
#ofeventsmayexceed#ofpatientswithevent,aspatientsmayhavehadmorethanoneevent
Adverseeffectspossibly,probably,definitelyattributedtolevofloxacin
Levofloxacin: Conclusions
20mg/kg vs 15mg/kg dose Still low AUC Safety data at this dose 15-20 mg/kg once daily
More optimal doses May improve outcomes further Facilitate shorter or injectable sparing regimens Important for bridging to novel regimens Carefully consider safety
100 mg dispersible tablet formulation (Macleods)
Summary: Moxifloxacin
Class Flouroquinolone
Administration Oral, good bioavailability
Metabolism/elimination
50% metabolized in the liver50% excreted unchanged in the stool/urine
PD Concentration dependent – AUC
Target AUC in adults after recommended dose
Paediatric dose 7.5-10mg/kg once daily
Data source •MDRPK1, MDRPK2•10mg/kg (exact)
Moxifloxacin results (1): Baseline characteristics (n=52)
N (%) unless specified
MDRPK1 study 33 (64%)
Median age in years (IQR) 8.4 (3.0-12.1)
Male sex 23 (44%)
HIV-infected 7 (14%)
Weight-for-age Z-score < -2 7 (14%)
Formulation• Whole tablet• Crushed tablet• Extemporaneous suspension
25 (48%)8 (15%)
19 (37%)
Moxifloxacin results (2): Model results
• Allometric scaling on Cl and V
• HIV – increased clearance
• Low HAZ – increased clearance
Cmax, μg/mLMedian (2.5%, 97.5%)
AUC, μg*h/mL Median (2.5, 97.5%)
0-<2y 3.0 (0.6, 5.7) 18.9 (14.3, 23.2)
2-<5y 2.5 (0.6, 4.2) 18.1 (13.2, 41.5)
5-10y 2.8 (1.8, 3.8) 27.9 (14.6, 43.2)
10-15y 2.5 (0.5, 5.4) 40.4 (13.9, 63.1)
Adults 4.7 (range 3.4-6.0) 1 38.7 (21.9, 69.6) 2
1 Nijland HMJ, et al. CID 2007,45:1002. 2 Zvada S, et al. AAC 2014,58(1):503.
*Analysis and figure from Rada Savic
MFX results (3): AUC vs age
Zvada S, et al.
Gaps and research priorities (2)
Keysecond-lineTBdrugs,keyknowledgegapsinchildrenandongoingorplannedpaediatricstudies
Drug Current Keygaps Ongoing/plannedstudiesLevofloxacin PKdatainTBacrossages;low
exposures
Optimaldoseandsafety;
formulation
MDRPK1,MDRPK2
Moxifloxacin PKdatainTB,>8yonly;lowexposures
PKdatain<8y;optimaldoseandsafety;formulation
MDRPK1,MDRPK2(interimanalysisongoing)
Bedaquiline NoPKdata PKdata,optimaldose,safety;HIV
P1108;Jannsen-trial;IMPAACTcapsule(BDQ-
DLM)Delamanid PKdata>6y PKdatainchildren<6y,
safety;HIVOtsuka232/233;IMPAACT2005;IMPAACTcapsule(BDQ-DLM)
Linezolid PKdatainnon-TBacrossages PKdatainTB,optimaldose,
safety;formulation
MDRPK2(interimanalysis
ongoing)Clofazimine LimitedpublishedPKdata PKdata,safetyoptimaldose;
formulation??–IMPAACTCapsule
Summary: Linezolid
Class Oxazolidinone
Administration Oral, good bioavailability
Metabolism/elimination
Complex metabolism
Target AUC in adults after 600 mg dose*
Paediatric dose 10 mg/kg/dose, OD if >10y, BD if <10y
Data source •MDRPK1, MDRPK2•10mg/kg (exact)
Linezolid results (1): Baseline characteristics (n=17)
N (%) unless specified
MDRPK1 study 7 (41%)
Median age in years (IQR) 4.8 (2.2-10.0)
Male sex 10 (59%)
HIV-infected 1 (6%)
Weight-for-age Z-score < -2 2 (12%)
Linezolid results (2)
• Allometric scaling on Cl and V
Cmax, μg/mLMedian (2.5%,
97.5%)
AUC, μg*h/mL Median (2.5,
97.5%)
Children 10.1 (5.6, 23.1)
97.7 (60.3, 294)
Adults 14.9 (range 11.9-21.3) 1
96.8 (range 47.8,143.7) 1
1 McGee B, et al. AAC 2009,53(9):3981.
Discussion• Linezolid exposures at least adequate with
current dosing strategy
– Re-analyzing with larger numbers
– Simulated optimal dosing – wt bands
– Covariates
– Analyze safety
Clofazimine
• Recommended dose: 2-4 (or 5) mg/kg/day
• Formulations: 50 mg and 100 mg soft gel caps
• PK data in children:
– ????
• MDRPK1, MDRPK2 – stored samples
• Planned paediatric study, seeking funding
Summary: Amikacin
Class Second-line injectable (kanamycin, capreomycin); aminoglycoside
Administration IM or IV
Metabolism/elimination
Eliminated unchanged in the urine
PD • Concentration dependent - Cmax• Hearing loss – cumulative exposure (AUC)
Target Cmax – 35-45μg/mL1
Paediatric dose 15-30mg/kg once daily
Data source •MDRPK1 study•Amikacin 15mg/kg and 20mg/kg (exact)
1 Peloquin CA. Drugs. 2002;62(15):2169-83
Amikacin results: Summary PK (1)
MDRPK1Mondongo et
al. 2016
Dose 15 mg/kg 20 mg/kg 750 (500-1000)
Cmax (μg/mL) 34.9(21.2-50.5)
45.0 (19.3 – 72.2)
≈ 44(22-66)
Tmax (μg/mL) 1.0 (1.0 – 2.0)
1.0(1.0 – 2.0)
AUC(0-8) (μg/mL) 89.9(58.4 – 138)
124.2 (44 – 205.3)
≈ 550 (364 – 725)
T1/2 (μg/mL) 1.4 (0.8 – 2.4)
1.5 (0.9 – 2.5)
Amikacin median Cmax (IQR) in different age groups at doses of 15mg/kg and 20mg/kg IM daily
20
30
40
50
60
70
Am
ikaci
n C
ma
x (
g/m
L)
15 mg/kg 20 mg/kg
0-2 years 2-5 years 6-15 years
Amikacin: conclusions
Age influenced AUC, not Cmax
Empiric dose of 18-20mg/kg
20mg/kg should not be routinely exceeded
TDM
Risk of hearing loss
Future work
Model-based analysis and dosing simulations
Results of safety assessments – PK-toxicity
Overview
• Approach to TB drug trials in children• Knowledge gaps and ongoing or planned studies:
existing second-line TB drugs• Knowledge gaps and ongoing or planned studies:
novel TB drugs– Bedaquiline– Delamanid– Pretomanid
• Other issues• Phase 3 trials• Conclusion
Gaps and research priorities (2)
Keysecond-lineTBdrugs,keyknowledgegapsinchildrenandongoingorplannedpaediatricstudies
Drug Current Keygaps Ongoing/plannedstudiesLevofloxacin PKdatainTBacrossages;low
exposures
Optimaldoseandsafety;
formulation
MDRPK1,MDRPK2
Moxifloxacin PKdatainTB,>8yonly;lowexposures
PKdatain<8y;optimaldoseandsafety;formulation
MDRPK1,MDRPK2(interimanalysisongoing)
Bedaquiline NoPKdata PKdata,optimaldose,safety;HIV
P1108;Jannsen-trial;IMPAACTcapsule(BDQ-
DLM)Delamanid PKdata>6y PKdatainchildren<6y,
safety;HIVOtsuka232/233;IMPAACT2005;IMPAACTcapsule(BDQ-DLM)
Linezolid PKdatainnon-TBacrossages PKdatainTB,optimaldose,
safety;formulation
MDRPK2(interimanalysis
ongoing)Clofazimine LimitedpublishedPKdata PKdata,safetyoptimaldose;
formulation??–IMPAACTCapsule
Bedaquiline (1)
• Bedaquiline PK and safety in HIV-uninfected children
– Sponsor: Janssen Pharmaceuticals
– For registration purposes
– Paediatric formulation
– Age de-escalation, HIV-uninfected children ONLY
– Enrolment – 2016, in one site in SA
Bedaquiline (2)
• IMPAACT P1108
– PK, safety and tolerability of bedaquiline with OBR in HIV-infected and uninfected infants, children and adolescents with MDR-TB
– Sponsor: NIH DAIDS/IMPAACT network
– Age de-escalation trial
– Adult formulation – whole and crushed
– Open September 2017
Ofloxacin200 mg
Levofloxacin250 mg
Moxifloxacin400 mg
BDQ CRUSH study: Relative bioavailability of whole vsdissolved bedaquiline in 24 healthy adult volunteers
BDQ CRUSH: Preliminary results
10
100
1000
0 10 20 30 40 50
Time after last dose [h]
Be
da
qu
ilin
e c
on
ce
ntr
atio
n [n
g/m
l]
Form
Whole
Disolved
First dosing occasion
Analysis and figure by Elin Svensson
Gaps and research priorities (2)
Keysecond-lineTBdrugs,keyknowledgegapsinchildrenandongoingorplannedpaediatricstudies
Drug Current Keygaps Ongoing/plannedstudiesLevofloxacin PKdatainTBacrossages;low
exposures
Optimaldoseandsafety;
formulation
MDRPK1,MDRPK2
Moxifloxacin PKdatainTB,>8yonly;lowexposures
PKdatain<8y;optimaldoseandsafety;formulation
MDRPK1,MDRPK2(interimanalysisongoing)
Bedaquiline NoPKdata PKdata,optimaldose,safety;HIV
P1108;Jannsen-trial;IMPAACTcapsule(BDQ-
DLM)Delamanid PKdata>6y PKdatainchildren<6y,
safety;HIVOtsuka232/233;IMPAACT2005;IMPAACTcapsule(BDQ-DLM)
Linezolid PKdatainnon-TBacrossages PKdatainTB,optimaldose,
safety;formulation
MDRPK2(interimanalysis
ongoing)Clofazimine LimitedpublishedPKdata PKdata,safetyoptimaldose;
formulation??–IMPAACTCapsule
Summary: Delamanid
Class Nitroimidazole
Administration/absorption
Oral, absorption influenced by food (increased 2-4 fold), medsNon-proportional dose-exposure; saturated dissolution
Metabolism/elimination
Albumin, to DM-6705Half-life: DM 30-38h; DM-6705 150-600h-
Target AUC in adults after recommended dose
Paediatric dose ??
Data source Otsuka 232 and 233 – Phase I/II study of PK and safety of DM in children with MDR-TB
Otsuka trials 232 and 233
• Otsuka 232 Trial - Phase 1 study of delamanid in children with MDR-TB– PK and short-term safety of delamanid when given for
10 days with OBR
• Otsuka 233 Trial - Phase 2 open-label extension trial – Evaluate the PK and long-term safety of delamanid
when given for 6 months with OBR
• Enrolling in Philippines and Cape Town– Age de-escalation design– HIV-uninfected children ONLY
Table. Median delamanid and DM-6705 plasma PK parameters following 100 mg BID (Group-1) and 50 mg BID (Group-2) delamanid doses in pediatric trial 232
Group 1(12 – 17y)
(n=7)
Group 2(6-11y)(n=6)
Adults
Median DLM Cmax
(ng/mL)557 573 357
Median DLM AUC0-24
(ng*h/mL)9730 12000 6811
Median DM-6705 Cmax
(ng/mL)81.7 90 114
Median DM-6705 AUC0-24
(ng*h/mL)1780 1870 2411
*Day 10 values from 232 for Groups 1 and 2; Day 14 values from adult trials
Otsuka 233: Comparison of Delamanid Plasma Concentration Time Profile in Pediatric (Trial 233) and Adult (Trial 208) MDR-TB Patients
0
200
400
600
800
1000
1200
1400
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Group 1 (100mg BID)
Trial-208 (100mg BID)
Max (Trial-208)
Min (Trial-208)
Del
aman
idM
edia
nP
lasm
a C
on
cen
trat
ion
s (n
g/m
L)
Time (Weeks)
Presented at Union Meeting 2015 (Cape Town, SA), Jeff Hafkin, Otsuka Pharmaceuticals 45
Otsuka 233: Comparison of DM-6705 Plasma Concentrations Time Profile in Pediatric (Trial 233) and Adult (Trial 208) MDR-TB Patients
0
100
200
300
400
500
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Group 1 (100mg BID)Trial-208(100mg BID)
Min (Trial-208)
DM
-67
05
Med
ian
Pla
sma
Co
nce
ntr
atio
ns
(ng
/mL)
Time (Weeks)
Max (Trial-208)
Presented at Union Meeting 2015 (Cape Town, SA), Jeff Hafkin, Otsuka Pharmaceuticals 46
Otsuka 233: Safety, Group 1 (12-17y)
Table 1. Incidence of QT elevation
Category Cut-off (ms)
Group 1 n (%)
New onset QTcF >450 3 (42.9)
>480 0
>500 0
Change in QTcF from baseline
≥30 and ≤60
5 (71.4)
> 60 1 (14.3)
Table 2. Mean [SD] QTcF by study day
Day Group 1
Baseline 407.0 [19.2]
28 423.4 [11.9]
56 417.1 [16.0]
84 427.9 [17.1]
126 428.6 [13.7]
154 423.6 [15.2]
182 420. 8 [16.8]
210 414.2 [8.0]
Presented at Union Meeting 2015 (Cape Town, SA), Jeff Hafkin, Otsuka Pharmaceuticals
Delamanid: conclusions
• Delamanid exposures in children 6-17y were within adult ranges with proposed dosing; safe
• Dosing:
– 20-35kg – 50mg BD
– >35kg – 100mg BD
• Otsuka 232/233
– Group 3 fully enrolled, 232 data anlyzed
– Group 4 enrolling
– Pediatric dispersible formulation
Novel TB drugs: Delamanid
• IMPAACT 2005
– Sponsor: NIH DAIDS/IMPAACT network
– PK and safety of delamanid in HIV-infected and uninfected children (0-<18y) with DR-TB
– Additional information on PK and safety in children
• Include HIV-infected children – DDIs with EFV, LPV/r
• Model-based optimization of dosing
– To open Q4 2017/Q1 2018
Novel TB drugs in children (3): Summary
• Delamanid– Children 6-17y – same
indications as in adults– Children <6y – case-by-
case basis– Access??
• Bedaquiline– Children >12y – same
indications as in adults– Children <6y – case-by-
case basis
Pretomanid
• Similar class of drug to delamanid
• Component of Nix-TB regimen and NC-006
• Toxicity signals have delayed evaluation in children
– Cataracts, testicular toxicity
• No data in children
• Paediatric trials in early development
Overview
• Ground rules and learning outcomes
• Pharmacokinetics – context in childhood TB treatment
• Key concepts in TB drug PK in children
• Emerging data
• Other issues
– Acceptability and formulation
– Weight-banded dosing
• Conclusion
MFX
LFX
Medication acceptability Acceptability
Overall acceptance or suitability of a dosage formulation
Palatability, dose volume or size, dosing frequency, instructions for use
Palatability Acceptance of taste, smell, texture, aftertaste
Current second-line medications
Future?
Overview
• Approach to TB drug trials in children
• Knowledge gaps and planned drug trials
• Other issues
• Phase 3 trials
• Conclusion
Treatment outcomes (1): Adults with MDR-TB
Treatment outcomes (2): Children with MDR-TB
1 Ettehad D, et al. Lancet ID. 2012;12(6):449-56.2 Harausz E, et al. Children treated for MDR-TB – a systematic review and individual patient data meta-analysis. (Union World Conference on Lung Health, 2015)
• 794 of 1012 (78.5%) children with probable or confirmed MDR-TB had successful outcomes2
Approach to studying TB drugs in children
Dunne J, et al. Extrapolation of Adult Data and Other Data in Pediatric Drug-Development Programs. Pediatrics. 2011;128(5):e1242-e9.
TB-CHAMP, SHINE, SMaRT Kids
????
Tuberculosis disease
Latent TBI or non-severe intrathoracic TB
SMaRT Kids: Background and Rationale (1)
• Children with MDR-TB may suffer disproportionately from existing treatment regimens– Hearing loss, interruption of attachment, school– Critical periods of neurodevelopment
• AND would be expected to respond better than adults to shorter, less intense regimens
• Time is right– More children being diagnosed– New and repurposed treatments becoming available
• Children with probable and confirmed MDR-TB stand to substantially benefit from an efficacy trial of a shortened all-oral regimen
SMaRT Kids: Design (2)• IMPAACT Network• Design: Randomized, open-label two-arm phase III non-
inferiority trial• Population
– Inclusion• Children 0 to <15 years of age; • Probable or confirmed pulmonary or extrapulmonary MDR/RMR-TB,
and MDR-TB with additional resistance to injectables or fluoroquinolones (i.e. pre-XDR and XDR-TB)
• HIV-infected and uninfected
– Exclusion• Stage 2 or 3 TB meningitis, or osteoarticular TB.
• Sample size: 346 (173 per arm) to demonstrate non-inferior efficacy of intervention arm among children with probable or confirmed MDR/RMR-TB with 90% power
SMaRT Kids: Intervention (3)• Children with MDR/RMR randomized 1:1 to control vs intervention
arms• Children with pre-XDR/XDR assigned to treatment arm based on
resistance profile
Proposed treatment regimens by drug-resistance profile and study arm
MDR/RMR TB
Intervention 2 mo DLM (once daily), CFZ, hdLZD, LFX, PZA / 4 mo DLM (once daily), CFZ, sdLZD, LFX, PZA
Control 4-6 mo KAN/AMK, LFX, PTO/ETO, CFZ, PZA, hdINH, EMB / 5-6 mo LFX, CFZ, PZA, EMB
preXDR/XDR-TB
FQN-susc 2 mo DLM (once daily), CFZ, hdLZD, LFX, PZA / 4 mo DLM (once daily), CFZ, sdLZD, LFX, PZA
FQN-susc 6 mo DLM (once daily), CFZ, hdLZD, PZA, PAS
• Question 1: In developing TB drugs for children, the following aspects are critical to study in children themselves (may select more than one):A. Safety (the medicine is safe in children)
B. Pharmacokinetic (the medicine achieves target exposures/concentrations)
C. Efficacy (the medicine kills TB)
D. Acceptability (the medicine is acceptable to children/parents)
• Question 2: Which of the following statements accurately describe ethical considerations for studying novel TB drugs in children (may select more than one)?A. It is unethical to study new medications in children because the risk is too high
B. New medications should be studied in children along with adults from the very beginning of drug development
C. Adolescents can be included in later phase adults studies (Phase 2b/3, after some efficacy/safety demonstrated)
D. Once reasonable efficacy and safety has been demonstrated in adults, well planned paediatric studies should begin
Conclusion
• Rapidly evolving trial landscape
• Advocate for appropriately timely treatment studies in children and adolescents
• Awareness of emerging data that may influence treatment support
• Commments/questions?
ACKNOWLEDGEMENTS
Anneke Hesseling H. Simon SchaafHelen McIlleron Paolo DentiHeather Draper Adelaide CarelseJennifer Norman Lubbe WiesnerPeter Smith Sandra CastellPeter Donald Marianne WillemseAndre Burger Steffi TheeBrooklyn Chest Hospital team Rada SavicKelly Dooley Jeff HafkinDTTC paediatric teamPatients and their parents
Last Update: 10/26/2012 Printer Friendly Email This Page Download Adobe Reader
Spotlights
Diagnosing Gestational Diabetes Mellitus
(GDM)—NIH Consensus Development Conference
GDM is common, affecting about 7% of pregnant women in the United States. There
is current debate in the obstetrical community about the best method for diagnosing
this condition, to optimize pregnancy and later health outcomes for mothers and their
children. To address this issue, the NICHD and the NIH Office of Disease Prevention
are sponsoring a consensus development conference to evaluate available scientific
evidence on the benefits and risks of various screening and diagnostic approaches for
GDM, an important first step toward delivering optimal care to pregnant women who
might be at risk for GDM. Read more about the Diagnosing Gestational Diabetes
Mellitus NIH Consensus Development Conference to be held on October 29–31,
2012.
Preeclampsia Research at the NICHD
Preeclampsia, characterized by a sudden spike in blood pressure after the 20th week
of pregnancy, can affect the health of both mother and baby. Finding ways to detect,
treat, and prevent preeclampsia and its negative health outcomes are priorities for the
NICHD. This spotlight describes some of the Institute's current research activities and
findings related to preeclampsia. Read more about NICHD preeclampsia research.
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