Second-line and novel TB drugs in children: emerging data ... fileSecond-line and novel TB drugs in...

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

mailto:[email protected]

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



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)



exposures


formulation

MDRPK1,MDRPK2









safety;formulation




Summary: Linezolid

Class Oxazolidinone



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


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




exposures


formulation

MDRPK1,MDRPK2









safety;formulation




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




exposures


formulation

MDRPK1,MDRPK2









safety;formulation




Summary: Delamanid

Class Nitroimidazole

Administration/absorption

Oral, absorption influenced by food (increased 2-4 fold), medsNon-proportional dose-exposure; saturated dissolution


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

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