Updates and Lessons Learned from Pediatric Trials Network (PTN)

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Updates and Lessons Learned from Pediatric Trials
Network (PTN)

• Michael Cohen-Wolkowiez, MD, PhD
• Assistant Professor
• Duke University

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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

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PTN Structure
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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

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PTN Site Network
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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 lt32 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
• lt34 weeks, q12h
• 34-40 weeks, q8h
• Harriet Lane
• 7.5-15 mg/kg
• q12-24 PNAgt7
• No loading dose
• Neofax
• 15 mg/kg loading
• 7.5 mg/kg
• Q12-48 h

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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

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Results - Acyclovir

• gt90 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.

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Protocol HydroxyureaProtocol Chair Neville
(Childrens 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

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Results - Hydroxyurea

• Interim analysis data have not been peer
  reviewed.

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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

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Results - POPS Enrollment
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Protocol LisinoprilProtocol 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

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Protocol TAPEProtocol Chair Abdel-Rahman(Child
rens 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.

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Protocol AmpicillinProtocol 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

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Results - Ampicillin

• Data have not been peer reviewed.

Clearance (L/kg/h)
Clearance (L/kg/h)
Postmenstrual age (days)
Serum creatinine (mg/dL)
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Protocol Obesity PK ReviewProtocol 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

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Results - Obesity

• 1712 abstracts identified
• 23 (1) had PK data for 22 drugs (age 1-21 years)
• 9/23 (39) included lt 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.

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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)
Legacy
Vs.

• First patient 34 months
• Last infant 48 months
• Clinical study report 60 months

• First patient 5 months
• Last patient 12 months
• Clinical study report 17 months

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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

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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)

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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 sitesenrollment
• Facilitate contracts and infrastructureenrollment
  in between more traditional trials

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Contacting the PTN for the POPS trial

• POPS protocol chair Micky Cohen-Wolkowiez
  michael.cohenwolkowiez_at_duke.edu
• POPS project lead Barrie Harper
  barrie.harper_at_duke.edu
• www.pediatrictrials.org

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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)

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Limits of the Mechanism
Opportunistic
PK and PK-PD
Safety
Efficacy
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PTN Administrative Core