NCT02475876

Brief Summary

Developmental changes in physiology during childhood influence drug dosing. Failure to account for these changes leads to improper dosing, which is associated with decreased drug efficacy and safety in children. Population physiologically-based pharmacokinetic (PBPK) modeling offers the opportunity to predict optimal drug dosing based on physiologic parameters adjusted for developmental changes. PBPK models are mathematical constructs that incorporate physiologic processes with drug characteristics and genetic variances to characterize the dose-exposure relationship across the age continuum. These models integrate drug-specific (e.g., metabolism, protein binding) and systems-specific (e.g., organ size, blood flow) information to predict the effect of different factors (e.g., age, genetic variants, disease) on drug exposure. By accounting for these factors and using data from clinical trials to confirm the modeling, PBPK models can reduce the number of children needed for clinical trials while maximizing dose-based efficacy and safety. This trial will evaluate a platform to prospectively validate population PBPK models in children. The study drugs, clindamycin and Bactrim (aka TMP-SMX), are ideal candidates to evaluate population PBPK models in children due to their differing physico-chemical properties and elimination pathways. In addition, a trial of clindamycin and TMP-SMX has broad clinical applicability, as both drugs are among the most commonly used agents to treat gram-positive infections in infants and children.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
51

participants targeted

Target at P50-P75 for phase_1

Timeline
Completed

Started Nov 2015

Longer than P75 for phase_1

Geographic Reach
1 country

3 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

June 12, 2015

Completed
7 days until next milestone

First Posted

Study publicly available on registry

June 19, 2015

Completed
5 months until next milestone

Study Start

First participant enrolled

November 1, 2015

Completed
2.8 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

August 31, 2018

Completed
1.8 years until next milestone

Study Completion

Last participant's last visit for all outcomes

June 30, 2020

Completed
Last Updated

September 21, 2020

Status Verified

September 1, 2020

Enrollment Period

2.8 years

First QC Date

June 12, 2015

Last Update Submit

September 17, 2020

Conditions

Bacterial Infections

Outcome Measures

Primary Outcomes (4)

  • Maximum observed plasma concentration at steady state (Cmaxss) - clindamycin

    We will use the population PBPK models to simulate drug concentration vs. time data for each individual subject using the characteristics and genetic information of the subjects enrolled in the study. We will compare simulated vs. observed plasma concentrations.

    PK sampling taken during 3 continuous days of treatment

  • Area under the plasma concentration versus time curve from the start to the end of one dosing interval at steady state (AUCss) - clindamycin

    We will use the population PBPK models to simulate drug concentration vs. time data for each individual subject using the characteristics and genetic information of the subjects enrolled in the study. We will compare simulated vs. observed plasma concentrations.

    PK sampling taken during 3 continuous days of treatment

  • Maximum observed plasma concentration at steady state (Cmaxss) - Trimethoprim-Sulfamethoxazole

    We will use the population PBPK models to simulate drug concentration vs. time data for each individual subject using the characteristics and genetic information of the subjects enrolled in the study. We will compare simulated vs. observed plasma concentrations.

    PK sampling taken during 3 continuous days of treatment

  • Area under the plasma concentration versus time curve from the start to the end of one dosing interval at steady state (AUCss) - Trimethoprim-Sulfamethoxazole

    We will use the population PBPK models to simulate drug concentration vs. time data for each individual subject using the characteristics and genetic information of the subjects enrolled in the study. We will compare simulated vs. observed plasma concentrations.

    PK sampling taken during 3 continuous days of treatment

Secondary Outcomes (5)

  • Number of reported AEs and SAEs

    33 days

  • Number of Subjects Heterozygous for any CYP3A Family Genotype

    33 days

  • Number of Subjects Heterozygous for any CYP2C9 Genotype

    33 days

  • Number of Subjects Homozygous for any CYP3A Family Genotype

    33 days

  • Number of Subjects Homozygous for any CYP2C9 Genotype

    33 days

Study Arms (2)

clindamycin

OTHER

Each subject will be assigned to study drug (clindamycin or TMP-SMX) at the discretion of the treating clinician. The dose and dosing interval of study drug are dictated by this protocol (see interventions).

Drug: Clindamycin

trimethoprim-sulfamethoxazole

OTHER

Each subject will be assigned to study drug (clindamycin or TMP-SMX) at the discretion of the treating clinician. The dose and dosing interval of study drug are dictated by this protocol (see interventions).

Drug: trimethoprim-sulfamethoxazole

Interventions

ClindamycinDRUG

Route of administration is IV for all Cohorts. Dosing interval is every 8 hrs. for all Cohorts: * Cohort 1; No. Subjects = 5; Age 1-5 months; Dose = 9 mg/kg; * Cohort 2; No. Subjects = 5; Age \>5 months to 1 year; Dose =12 mg/kg; * Cohort 3; No. Subjects = 5; Age \>1-2 years; Dose =12 mg/kg. * Cohort 4; No. Subjects = 4; Age \>2-6 years; Dose =12 mg/kg. * Cohort 5; No. Subjects = 4; Age \>6-12 years; Dose =10 mg/kg. * Cohort 6; No. Subjects = 4; Age \>12-16 years; Dose =10 mg/kg.

Also known as: Cleocin
clindamycin
trimethoprim-sulfamethoxazoleDRUG

Route of administration is PO for all Cohorts. Dosing interval is every 12 hrs. for all Cohorts: * Cohort 1; No. Subjects = 5; Age 1-5 months; Dose = 6 mg/kg. * Cohort 2; No. Subjects = 5; Age \>5 months to 1 year; Dose = 6 mg/kg. * Cohort 3; No. Subjects = 5; Age \>1-2 years; Dose = 6 mg/kg. * Cohort 4; No. Subjects = 4; Age \>2-6 years; Dose = 6 mg/kg. * Cohort 5; No. Subjects = 4; Age \>6-12 years; Dose = 6 mg/kg. * Cohort 6; No. Subjects = 4; Age \>12-16 years; Dose = 4 mg/kg.

Also known as: Bactrim, TMP-SMX
trimethoprim-sulfamethoxazole

Eligibility Criteria

Age1 Month - 16 Years
Sexall
Healthy VolunteersNo
Age GroupsChild (0-17)

You may qualify if:

  • Informed consent from parent or guardian and assent from subject when appropriate
  • Require prevention or treatment of confirmed or suspected infection
  • PMA \>36 weeks
  • Able to take oral drugs (TMP-SMX)
  • Sufficient IV access for study drug administration (for clindamycin) and PK sample collection (both drugs) -

You may not qualify if:

  • History of allergic reactions to study drugs
  • Treatment with the following drugs within 24 hours prior to first dose of clindamycin or expected to receive these drugs during the treatment phase with clindamycin:
  • CYP3A4 inhibitors (nefazodone, fluconazole, ketoconazole, fluvoxamine, conivaptan, diltiazem, verapamil, aprepitant, ticlopidine, crizotinib, and imatinib), or
  • CYP3A4 inducers (rifampin, phenytoin, carbamazepine, phenobarbital, troglitazone, pioglitazone, and St. John's wort).
  • Serum creatinine \>2 mg/dl within 48 hours prior to enrollment
  • Known ALT \>250 U/L or AST \>500 U/L on measurement closest to the time of enrollment
  • Known pregnancy
  • Breastfeeding females
  • On extracorporeal membrane oxygenation support at the time of study drug dosing or PK sampling
  • Any condition that, in the judgment of the investigator, precludes participation because it could affect subject safety -

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (3)

Arkansas Children's Hospital

Little Rock, Arkansas, 72202, United States

Location

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

University of Michigan C.S. Mott Children's Hospital

Ann Arbor, Michigan, 48109, United States

Location

Related Publications (1)

  • Wu YSS, Cohen-Wolkowiez M, Hornik CP, Gerhart JG, Autmizguine J, Cobbaert M, Gonzalez D; Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee. External Evaluation of Two Pediatric Population Pharmacokinetics Models of Oral Trimethoprim and Sulfamethoxazole. Antimicrob Agents Chemother. 2021 Jun 17;65(7):e0214920. doi: 10.1128/AAC.02149-20. Epub 2021 Jun 17.

    PMID: 33903114DERIVED

MeSH Terms

Conditions

Bacterial Infections

Interventions

ClindamycinTrimethoprim, Sulfamethoxazole Drug Combination

Condition Hierarchy (Ancestors)

Bacterial Infections and MycosesInfections

Intervention Hierarchy (Ancestors)

LincomycinLincosamidesPyrrolidinesHeterocyclic Compounds, 1-RingHeterocyclic CompoundsGlycosidesCarbohydratesSulfamethoxazoleBenzenesulfonamidesSulfonamidesAmidesOrganic ChemicalsSulfanilamidesAniline CompoundsAminesBenzene DerivativesHydrocarbons, AromaticHydrocarbons, CyclicHydrocarbonsSulfonesSulfur CompoundsTrimethoprimPyrimidinesDrug CombinationsPharmaceutical Preparations

Study Officials

  • Michael Cohen-Wolkowiez, MD

    Duke Clinical Research Institute

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 1
Allocation
NON RANDOMIZED
Masking
NONE
Purpose
OTHER
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR INVESTIGATOR
PI Title
Associate Professor

Study Record Dates

First Submitted

June 12, 2015

First Posted

June 19, 2015

Study Start

November 1, 2015

Primary Completion

August 31, 2018

Study Completion

June 30, 2020

Last Updated

September 21, 2020

Record last verified: 2020-09

Locations

US(3)