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Updates and Lessons Learned from Pediatric Trials Network (PTN)

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. ”

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Updates and Lessons Learned from Pediatric Trials Network (PTN)

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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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