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Pediatric Trials Network Updates: Lessons Learned & Current Projects

Learn about the evolution of the Pediatric Trials Network, ongoing trials, and impactful findings in pediatric drug research. The network has successfully conducted trials improving dosing, safety, and labeling for children's health. Updates include studies on metronidazole, acyclovir, lisinopril, and more. Discover the latest advancements and insights from the PTN.

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Pediatric Trials Network Updates: Lessons Learned & Current Projects

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  1. Updates and Lessons Learned from Pediatric Trials Network (PTN) 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. Project Update • Metronidazole • Acyclovir • Hydroxyurea • Pediatric Opportunistic PK Study (POPS) • Lisinopril • TAPE • Ampicillin • Obesity database

  7. 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

  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: HydroxyureaProtocol 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: 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

  14. Results - POPS Enrollment

  15. 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

  16. Protocol: TAPEProtocol 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

  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: 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

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 Results - Ampicillin Data have not been peer reviewed.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

  20. 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

  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 • 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 Legacy PTN (average 3 trials) Vs. • 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

  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 • POPS project lead: Barrie Harper 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

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