Transcript PTN updates and lessons learned, 2012

Updates and Lessons Learned from
Pediatric Trials Network (PTN)
Michael Cohen-Wolkowiez, MD, PhD
Assistant Professor
Duke University
How Did the PTN Start?
“Create an infrastructure for investigators to
conduct trials that improve pediatric labeling
and child health.”
– Sponsored by the Eunice Kennedy Shriver National Institute of
Child Health and Human Development (NICHD)
– Network for studying drug product formulation, age-appropriate
drug dosing, efficacy, safety, and device validation
– Success: Completed trials that improve dosing, safety
information, labeling, and ultimately child health
PTN Structure
PTN Site Participation
 215 investigators at 120 sites expressed
interest in participating
 Anticipate ~60 sites actively enrolling in
trials conducted in 2012-2013
 Growth of the “rapid start network,” a
pediatric clinical trial consortium affiliated
with PTN to a total of 100 sites
PTN Site Network
Project Update

Metronidazole

Acyclovir

Hydroxyurea

Pediatric Opportunistic PK Study (POPS)

Lisinopril

TAPE

Ampicillin

Obesity database
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Protocol: Metronidazole
Protocol Chair: Cohen-Wolkowiez (Duke)

Protocol: Safety and PK of Metronidazole in Premature Infants

Objective: Evaluate the safety and PK of metronidazole in
premature infants with suspected serious infection

Study Population: 24 participants <32 weeks gestational age

Study Duration: 12 months (original 18); 2-5 days of study drug
administration + 10 days of adverse events monitoring

Number of Sites: 3

October 2011, Enrollment complete

June 2012, Clinical Study Report submitted

Add-on science related to study continuing
–
e.g., genomics and characterization of biotransformation
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Results - Metronidazole
PMA-based regimen
– 15 mg/kg loading
– 7.5 mg/kg
» <34 weeks, q12h
» 34-40 weeks, q8h
Harriet Lane
– 7.5-15 mg/kg
» q12-24 PNA>7
» No loading dose
Neofax
– 15 mg/kg loading
– 7.5 mg/kg
» Q12-48 h
Protocol: Acyclovir
Protocol Chair: Smith (Duke)

Background
– Very limited PK data in premature infants
– Plans for efficacy trial

Objective: Evaluate the safety and PK of IV acyclovir in infants

Study Population: 32 infants

Study Duration: Up to 13 days

Number of Sites: 3

June 2012, Enrollment complete

Q1 2013, Clinical Study Report submission
Results - Acyclovir

>90% of infants had predicted steady-state peak concentrations
≥3 mg/L

Concentrations remained ≥3 mg/L for at least 50% of the dosing
interval

Doses of 20-30 mg/kg q8-12 are appropriate for preterm infants
– Current Neofax dosing 20 mg/kg q8 hours
Data have not been peer reviewed.
Protocol: Hydroxyurea
Protocol Chair: Neville (Children’s
Mercy – Kansas City)

Protocol: PK & Relative Bioavailability of a Liquid Formulation
of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia

Objective: Comparative bioavailability of HU

Study Population: 40 children (2-17 years of age)

Study Duration: Single and multiple dose

Number of Sites: 6

December 2011, First patient enrolled
Results - Hydroxyurea
Hydroxyurea Concentration Profiles
Pt. COU02HUB01001
400 mg dose
Hydroxyurea Conc. (g/mL)
50
Capsule
Liquid
40
30
20
10
0
0
2
4
6
Time (hr)
Interim analysis; data have not been peer reviewed.
8
Protocol: Pediatric Opportunistic PK Study
Protocol Chair: Cohen-Wolkowiez (Duke)

Protocol: Pharmacokinetics of Understudied Drugs
Administered to Children per Standard of Care (POPS)
– Total number of drugs studied = 11

Objectives: Evaluate the PK of understudied drugs currently
being administered to children

Study Population: ~1000 children (birth-20 years)

Study Duration: Up to 90 days per drug

Number of Sites: ~15

November 2011, First patient enrolled
Results - POPS Enrollment
Drug of Interest
Amiodarone
Ampicillin
Clindamycin
Doxycycline
Epinephrine
Griseofulvin
Hydrochlorothiazide
Ketamine
Methadone
Metoclopramide
TMP-SMX
Total
<1 Month
8
75
19
2
7
0
0
5
4
5
1
126
1 Month - 2 Years 2-12 Years 13-16 Years 17-20 Years
5
1
0
0
0
0
0
0
24
19
9
5
0
3
5
1
13
2
0
0
0
1
0
0
7
3
1
1
8
2
1
5
30
16
1
1
7
1
2
4
21
19
3
8
115
67
22
25
Total
14
75
76
11
22
1
12
21
52
19
52
355
Protocol: Lisinopril
Protocol Chair: Trachtman (NYU)

Protocol: Safety and PK of Lisinopril in Pediatric Kidney
Transplant Recipients

Objective: Evaluate PK-PD and safety of lisinopril

Study Population: 24 children (2-18 years of age)

Study Participation: Up to 51 days

Number of Sites: 8

May 2012, First patient enrolled
Protocol: TAPE
Protocol Chair: Abdel-Rahman
(Children’s Mercy – Kansas City)

Protocol: Taking the Guesswork out of Pediatric Weight
Estimation (TAPE): Validation of the Mercy TAPE

Objective: Device validation trial to provide more accurate,
rapid estimation of weight in the acute care setting

Study Population: 624 children (2 months to 16 years of age)
enrolled in the U.S.

Validation studies (funded by WHO) conducted in Africa, India,
and China

January 2012, First patient enrolled
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Results - TAPE

TAPE device is equivalent to measured weight in pediatric
patients of all ages and body habitus
Data have not been peer reviewed.
Protocol: Ampicillin
Protocol Chair: Tremoulet (UCSD)

Protocol: Ampicillin Safety and PK in Infants

Response to written request

Objective: Evaluate the safety and PK of ampicillin in infants
using opportunistic methods

Study Population: 75 for PK, 700,000 for safety
(epidemiological database)

November 2011, First patient enrolled

June 2012, Enrollment complete
18
Clearance (L/kg/h)
Clearance (L/kg/h)
Results - Ampicillin
Postmenstrual age (days)
Data have not been peer reviewed.
Serum creatinine (mg/dL)
Protocol: Obesity PK Review
Protocol Chair: Watt (Duke)

Protocol: Obesity PK Database

Objective: Develop a drug database that provides dosing
information for obese children

Study Population: obese children

November 2012, Literature search completed
20
Results - Obesity

1712 abstracts identified

23 (1%) had PK data for 22 drugs (age 1-21 years)
– 9/23 (39%) included < 8 obese children

9/22 (41%) demonstrated clinically significant PK changes in
obese children

18/22 (81%) were dosed by total body weight or unadjusted body
surface area
– 8/18 (44%) resulted in supra or sub-therapeutic exposures

The knowledge gap in obese child PK and optimal body size
dosing measures is substantial
Data have not been peer reviewed.
Other Clinical Trials in Development

Anti-staph trio (clindamycin, rifampin, ticarcillin)
– Safety and PK of 3 anti-staphylococcal drugs in preterm infants

Sildenafil
– Safety and PK in preterm infants

Clindamycin obesity
– Safety and PK in obese children
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Lessons Learned - Timelines
PTN (average 3 trials) Vs.
Legacy
 First patient 5 months
 First patient 34 months
 Last patient 12 months
 Last infant 48 months
 Clinical study report 17
 Clinical study report 60
months
months
PTN 2013 Tentative

Phase II: dose-ranging study of diuretics to reduce risk of BPD
in premature infants
– Efficacy of diuretics in preterm infants at risk for BPD

Phase II: safety of antibiotics in preterm infants with necrotizing
enterocolitis (NEC)
– Safety and efficacy of ampicllin, clindamycin, piperacillin-tazobactam,
and metronidazole in infants with NEC

Pantoprazole PK in obese children
– Evaluate the safety, PK, and PG of pantoprazole in obese children

Methadone PK in children
– Evaluate the safety and PK or oral methadone in critically ill children
How Do I Participate in the PTN?
 The POPS study
– Children interact with the health care system (e.g.,
admitted to the PICU or seen in the ER)
– On a prioritized off-patent therapeutic that has
insufficient dosing information in their clinical stratum
» Age-based: e.g., premature neonates
» Acuity-based: e.g., resuscitation meds
» Clinical-based: e.g., ethnicity, obesity
– Ask for consent to take blood at pre-specified times
based on dosing interval (Q4 vs. Q24)
PTN and POPS Continued
 15 or more therapeutics bundled into one protocol
 Samples stored locally and sent in batch
 Flexibility to add molecules (e.g., ampicillin)
 Provide preliminary and supportive data for
subsequent trials
 Provide a testing ground for sites—enrollment
 Facilitate contracts and infrastructure—enrollment
in between more traditional trials
Contacting the PTN for the POPS trial
 POPS protocol chair: Micky Cohen-Wolkowiez
[email protected]
 POPS project lead: Barrie Harper
[email protected]
 www.pediatrictrials.org
PTN Collaborations with Other
Networks & Training
 Collaboration with other networks
 Training
– Training grants (NICHD T32 grants in pediatric
pharmacology and pharmacoepidemiology)
– Career development grants (K23, K24)
Limits of the Mechanism
Opportunistic
PK and PK-PD
Safety
Efficacy
PTN Administrative Core
Name
Daniel Benjamin, MD, PhD
Gregory Kearns, Pharm D, PhD
Edmund Capparelli, Pharm D
Andrew Muelenaer, MD
John van den Anker, MD, PhD
Kelly Wade, MD PhD
Jeff Barrett, PhD, FCP
Michael O'Shea, MD
P. Brian Smith, MD
Michael Cohen-Wolkoweiz, MD, PhD
Matthew Laughon, MD
Ian Paul, MD
Anne Zajicek, MD
David Siegel, MD
Perdita Taylor-Zapata, MD
Ravinder Anand, PhD
Traci Clemons, PhD
Role
Network PI
Chair, Clin. Pharmacology Core
Chair, Pharmacometrics Core
Chair, Devices Core
Co-Chair, Mentorship Core
Co-Chair, Safety & Ethics Core
Co-Chair Pharmacometrics Core
Co-Chair Devices Core
Network Co-Investigator
Network Co-Investigator
Administrative Core
Administrative Core
Branch Chief
NICHD COTR
NICHD COTR
DCC PI
DCC Co-PI
Center
Duke University, Durham, NC
Children's Mercy Hospital & Clinics , Kansas City, MO
UC San Diego, San Diego, CA
Virginia Tech Carilion School of Medicine, Roanoke, VA
GWU School of Medicine & Health Science, Washington, DC
Children's Hospital of Philadelphia, Philadelphia, PA
Children's Hospital of Philadelphia, Philadelphia, PA
Wake Forest University Medical Center, Winston-Salem, NC
Duke University, Durham, NC
Duke University, Durham, NC
UNC Memorial Hospital , Chapel Hill, NC
Penn State College of Medicine, Hershey, PA
NIH/NICHD, Bethesda, MD
NIH/NICHD, Bethesda, MD
NIH/NICHD, Bethesda, MD
The Emmes Corporation, Rockville, MD
The Emmes Corporation, Rockville, MD