1. Updates and Lessons Learned from Pediatric Trials Network (PTN) Michael Cohen-Wolkowiez, MD, PhD Assistant Professor Duke University Michael Cohen-Wolkowiez, MD, PhD Assistant Professor Duke University

2. 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

3. PTN Structure

4. 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

5. PTN Site Network

6. Metronidazole Acyclovir Hydroxyurea Pediatric Opportunistic PK Study (POPS) Lisinopril TAPE Ampicillin Obesity database Project Update 6

7. 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 Protocol: Metronidazole Protocol Chair: Cohen-Wolkowiez (Duke) 7

8. 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

9. 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

10. 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.

11. 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

12. Results - Hydroxyurea Interim analysis; data have not been peer reviewed.

13. 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 Protocol: Pediatric Opportunistic PK Study Protocol Chair: Cohen-Wolkowiez (Duke)

14. Results - POPS Enrollment

15. 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

16. Protocol: TAPE Protocol Chair: Abdel-Rahman (Children’s Mercy – Kansas City) 16 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

17. Results - TAPE TAPE device is equivalent to measured weight in pediatric patients of all ages and body habitus Data have not been peer reviewed.

18. Protocol: Ampicillin Protocol Chair: Tremoulet (UCSD) 18 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

19. Results - Ampicillin Data have not been peer reviewed. Clearance (L/kg/h) Postmenstrual age (days) Clearance (L/kg/h) Serum creatinine (mg/dL)

20. Protocol: Obesity PK Review Protocol Chair: Watt (Duke) 20 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

21. 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.

22. Other Clinical Trials in Development 22 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

23. Lessons Learned - Timelines First patient 5 months Last patient 12 months Clinical study report 17 months First patient 34 months Last infant 48 months Clinical study report 60 months PTN (average 3 trials) Legacy Vs.

24. 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

25. 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)

26. 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

27. Contacting the PTN for the POPS trial POPS protocol chair: Micky Cohen-Wolkowiez michael.cohenwolkowiez@duke.edu michael.cohenwolkowiez@duke.edu POPS project lead: Barrie Harper barrie.harper@duke.edu barrie.harper@duke.edu www.pediatrictrials.org

28. 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)

29. Limits of the Mechanism Opportunistic PK and PK-PD Safety Efficacy

30. PTN Administrative Core