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Evaluation of the Pharmacokinetics (PK) and Pharmacodymamics (PD) of Ganciclovir (GCV) in Premature Infants Receiving Treatment for Cytomegalorivus (CMV) Infection

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01602614
Recruitment Status : Completed
First Posted : May 21, 2012
Results First Posted : May 19, 2020
Last Update Posted : June 2, 2020
Sponsor:
Information provided by (Responsible Party):
David Kimberlin, MD, University of Alabama at Birmingham

Brief Summary:
This is a clinical sampling study, and no study drugs will be administered under this protocol. Premature infants who receive intravenous ganciclovir as part of clinical care will be eligible for participation in this study. Intravenous ganciclovir will not be provided under this protocol.

Condition or disease
Cytomegalovirus Infections

Detailed Description:

This is an open-label, multi-center, clinical sampling study to assess ganciclovir pharmacokinetics and pharmacodynamics in premature infants. Only those subjects who receive ganciclovir for clinical reasons will be enrolled. The decision to initiate ganciclovir therapy will be made by the attending physician based upon his/her clinical decision to treat virologically-confirmed CMV infection; infants receiving such therapy and meeting entry criteria will then be eligible for this study. Therefore, ganciclovir will not provided under this protocol.

Subjects meeting enrollment criteria will be entered into this clinical trial. Subjects will be stratified by gestational age and by chronologic age as follows: 1) ≤ 27 weeks 6 days gestational age at birth and ≤ 30 days chronologic age at study enrollment; 2) ≤ 27 weeks 6 days gestational age at birth and > 30 days chronologic age at study enrollment; 3) ≥ 28 weeks 0 days gestational age at birth and ≤ 30 days chronologic age at study enrollment; 4) ≥ 28 weeks 0 days gestational age at birth and > 30 days chronologic age at study enrollment. Eight subjects will enroll in each of the four groups, for a total sample size of 32 subjects. Subjects in each cohort with inadequate pharmacokinetic data for analysis (e.g., due to dropping out of the study before PK assessments are performed, or blood sampling obtained but is inadequate for analysis) will be replaced and will not count toward the total of eight subjects in each of the four groups. Additionally, enrollment of an additional 2-3 subjects may be allowed for operational reasons.

A full pharmacokinetic profile will be obtained with one of the ganciclovir doses received after enrollment. PK assessments will be obtained after the subject has received study assessment dose 3, 4, 5, 6, 7, or 8 of intravenous ganciclovir. Specimens will be shipped for processing at that time. The pharmacokinetic data will then be provided to the study site, including the area under curve (AUC) and clearance (CL) values for information purposes.

Duration of intravenous ganciclovir therapy is at the discretion of the treating physician and will not be dictated by the research protocol. Both whole blood for CMV polymerase chain reaction (PCR) and urine for CMV detection will be obtained once in each study period as long as the subject is receiving intravenous ganciclovir therapy. These specimens will be used to determine blood viral load and ganciclovir resistance. Since ganciclovir is a renally excreted drug, serum creatinine will be drawn for the research protocol on the day that the ganciclovir pharmacokinetic specimens are obtained in order to calculate creatinine clearance using a method such as the modified Schwartz formula, and thus correlate ganciclovir clearance with renal function. Otherwise, data from hematology assessments (WBC count and differential, hemoglobin, platelet count) and from chemistry labs (serum creatinine, aspartate aminotransferase (AST) , and alanine aminotransferase (ALT) will be recorded on the study case report forms during each study period if they are being obtained for clinical reasons, but will not be drawn only for the purposes of the study. Ganciclovir dosing information (mg/dose, dosing interval, and patient weight) will be recorded on the day of the pharmacokinetic blood draws, and weekly from Period 1 through Period 7 as long as the subject is receiving intravenous ganciclovir therapy.

If the patient continues to receive intravenous ganciclovir from Study Assessment Day 18 through Study Assessment Day 24 (Period 4), a second PK assessment may be performed at the request of the treating physician if the subject weighs 575 grams or more at the time of specimen collection.

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Study Type : Observational
Actual Enrollment : 18 participants
Observational Model: Other
Time Perspective: Prospective
Official Title: Evaluation of the Pharmacokinetics and Pharmacodynamics of Ganciclovir in Premature Infants Receiving Treatment for Cytomegalovirus Infection
Study Start Date : April 2013
Actual Primary Completion Date : March 2019
Actual Study Completion Date : March 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Ganciclovir

Group/Cohort
Group 1
≤ 27 weeks 6 days gestational age at birth and ≤ 30 days chronologic age at study enrollment. Dose and duration of intravenous ganciclovir therapy is at the discretion of the treating physician and will not be dictated by the research protocol.
Group 2
≤ 27 weeks 6 days gestational age at birth and > 30 days chronologic age at study enrollment. Dose and duration of intravenous ganciclovir therapy is at the discretion of the treating physician and will not be dictated by the research protocol.
Group 3
≥ 28 weeks 0 days gestational age at birth and ≤ 30 days chronologic age at study enrollment. Dose and duration of intravenous ganciclovir therapy is at the discretion of the treating physician and will not be dictated by the research protocol.
Group 4
≥ 28 weeks 0 days gestational age at birth and > 30 days chronologic age at study enrollment. Dose and duration of intravenous ganciclovir therapy is at the discretion of the treating physician and will not be dictated by the research protocol.



Primary Outcome Measures :
  1. Plasma Pharmacokinetics Parameters for Ganciclovir Area Under the Curve at 12 Hours (AUC12mgxh/L) [ Time Frame: within 12 hours after dose administration ]
    A series of blood samples will be collected to assess the ganciclovir levels in the blood at the following time points: 0 hour (immediately prior to intravenous (IV) ganciclovir dose; within 15 min prior to dose), 1 hour (immediately after the end of the IV ganciclovir dose; within 15 min after dose), 2-3 hour, 5-7 hour, and 10-12 hour; required amount of whole blood for plasma ganciclovir determination at each time point is at least 0.2 mL


Secondary Outcome Measures :
  1. Plasma Pharmacokinetics Parameters for Ganciclovir, Including Maximum Serum Concentration (Cmax mg/L). [ Time Frame: within 12 hours after dose administration ]
    Looking at the Pharmacokinetics (PK) parameters for Ganciclovir (GCV). A series of blood samples was collected to assess the ganciclovir levels in the blood at the following time points: 0 hour (immediately prior to intravenous (IV) ganciclovir dose; within 15 min prior to dose), 1 hour (immediately after the end of the IV ganciclovir dose; within 15 min after dose), 2-3 hour, 5-7 hour, and 10-12 hour.

  2. Plasma Pharmacokinetics Parameters for Ganciclovir for Half-life (T1/2 hr). [ Time Frame: within 12 hours after dose administration ]
    Looking at the Pharmacokinetics (PK) parameters for Ganciclovir (GCV). A series of blood samples was collected to assess the ganciclovir levels in the blood at the following time points: 0 hour (immediately prior to intravenous (IV) ganciclovir dose; within 15 min prior to dose), 1 hour (immediately after the end of the IV ganciclovir dose; within 15 min after dose), 2-3 hour, 5-7 hour, and 10-12 hour.

  3. Plasma Pharmacokinetics Parameters for Ganciclovir for Clearance (Cl L/hr/kg). [ Time Frame: within 12 hours after dose administration ]
    Looking at the Pharmacokinetics (PK) parameters for Ganciclovir (GCV). A series of blood samples was collected to assess the ganciclovir levels in the blood at the following time points: 0 hour (immediately prior to intravenous (IV) ganciclovir dose; within 15 min prior to dose), 1 hour (immediately after the end of the IV ganciclovir dose; within 15 min after dose), 2-3 hour, 5-7 hour, and 10-12 hour.

  4. Plasma Pharmacokinetics Parameters for Ganciclovir for Volume of Distribution (Vd L). [ Time Frame: within 12 hours after dose administration ]
    Looking at the Pharmacokinetics (PK) parameters for Ganciclovir (GCV). A series of blood samples was collected to assess the ganciclovir levels in the blood at the following time points: 0 hour (immediately prior to intravenous (IV) ganciclovir dose; within 15 min prior to dose), 1 hour (immediately after the end of the IV ganciclovir dose; within 15 min after dose), 2-3 hour, 5-7 hour, and 10-12 hour.

  5. Correlation of Ganciclovir Plasma Pharmacokinetics (Clearance (CL) With Whole Blood Cytomegalovirus (CMV) Viral Load. [ Time Frame: 6 weeks ]
    Comparing the GCV PK clearance (CL L/hr/kg) results to the whole blood CMV viral load data.

  6. Correlation of Ganciclovir Plasma Pharmacokinetics Maximum Serum Concentration (Cmax) With Whole Blood Cytomegalovirus (CMV) Viral Load. [ Time Frame: 6 weeks ]
    Comparing the GCV PK results maximum serum concentration (Cmax) to the CMV viral load data.

  7. Correlation of Ganciclovir Plasma Pharmacokinetics Area Under the Curve (AUC12) With Whole Blood Cytomegalovirus (CMV) Viral Load. [ Time Frame: 6 weeks ]
    Comparing the GCV PK results area under the curve (AUC12-mgxh/L) to the whole blood CMV viral load data.

  8. Correlation of Ganciclovir Plasma Pharmacokinetics Half-life (T1/2) With Whole Blood Cytomegalovirus (CMV) Viral Load. [ Time Frame: 6 weeks ]
    Comparing the GCV PK results half-life (T1/2 hr) to the whole blood CMV viral load data.

  9. Correlation of Ganciclovir Plasma Pharmacokinetics Volume of Distribution (Vd) With Whole Blood Cytomegalovirus (CMV) Viral Load. [ Time Frame: 6 weeks ]
    Comparing the GCV PK results volume of distribution (Vd L) to the whole blood CMV viral load data.

  10. Correlation of Ganciclovir Plasma Pharmacokinetics Clearance (Cl) With Clearance of CMV in Urine [ Time Frame: 6 weeks ]
    Comparing the GCV PK results clearance (Cl L/hr/kg) to the clearance of CMV in the urine samples

  11. Correlation of Ganciclovir Plasma Pharmacokinetics Maximum Serum Concentration (Cmax) With Clearance of CMV in Urine. [ Time Frame: 6 weeks ]
    Comparing the GCV PK results to the Cmax with clearance of CMV in the urine samples

  12. Correlation of Ganciclovir Plasma Pharmacokinetics Area Under the Curve (AUC) With Clearance of CMV in Urine. [ Time Frame: 6 weeks ]
    Comparing the GCV PK AUC results to the clearance of CMV in the urine samples.

  13. Correlation of Ganciclovir Plasma Pharmacokinetics Maximum Serum Half Life (T1/2) With Clearance of CMV in Urine. [ Time Frame: 6 weeks ]
    Comparing the GCV PK half-life results to the clearance of CMV in the urine samples.

  14. Correlation of Ganciclovir Plasma Pharmacokinetics Volume of Distribution (Vd) With Clearance of CMV in Urine. [ Time Frame: 6 weeks ]
    Comparing the GCV PK Vd results to the clearance of CMV in the urine samples


Biospecimen Retention:   Samples Without DNA
Remnant blood will be retained for future cytomegalovirus (CMV) studies if subjects/subject families consent to future use. Institutional Review Board (IRB) approval for any future studies of remnant specimens will be required.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 180 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Premature infants who receive intravenous ganciclovir as part of clinical care
Criteria

Inclusion Criteria:

  1. Signed informed consent from parent(s) or legal guardian(s)
  2. Confirmation of CMV infection from urine, blood, or saliva by culture, shell vial, or PCR tests (local lab)
  3. Receiving intravenous ganciclovir, prescribed by the patient's physician
  4. < 32 weeks gestational age at birth
  5. ≥ 500 grams at study enrollment

Exclusion Criteria:

  1. Imminent demise
  2. Current receipt of valganciclovir or foscarnet
  3. Receiving breast milk from a mother who is being treated with ganciclovir or valganciclovir
  4. Current receipt of other investigational drugs
  5. Major congenital anomaly that in the site investigator's opinion may impact drug metabolism or the patient's volume of distribution

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01602614


Locations
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United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35233
United States, Arkansas
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States, 72202
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, Florida
University of South Florida School of Medicine
Saint Petersburg, Florida, United States, 33701
United States, Louisiana
Louisiana State University Health Science Center - Shreveport
Shreveport, Louisiana, United States, 71103
United States, Maryland
Johns Hopkins Medical Institutions
Baltimore, Maryland, United States, 21287
United States, Missouri
Washington University in St Louis School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New York
Steven & Alexandra Cohen Children's Medical Center of New York (CCMC)
Manhasset, New York, United States, 11030
University of Rochester
Rochester, New York, United States, 14642
United States, North Carolina
Carolinas Medical Center - Charlotte
Charlotte, North Carolina, United States, 28203
United States, Ohio
MetroHealth Medical Center
Cleveland, Ohio, United States, 44109
Nationwide Childrens Hospital
Columbus, Ohio, United States, 43205
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15224
United States, Rhode Island
Rhode Island Hospital
Providence, Rhode Island, United States, 02903
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
University of Alabama at Birmingham
Investigators
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Principal Investigator: David Kimberlin, MD University of Birmingham at Alabama
Principal Investigator: Richard Whitley, MD University of Alabama at Birmingham
  Study Documents (Full-Text)

Documents provided by David Kimberlin, MD, University of Alabama at Birmingham:
Study Protocol  [PDF] August 14, 2015
Statistical Analysis Plan  [PDF] May 15, 2013

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Responsible Party: David Kimberlin, MD, Protocol Principal and Lead Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT01602614    
Other Study ID Numbers: F21116007
First Posted: May 21, 2012    Key Record Dates
Results First Posted: May 19, 2020
Last Update Posted: June 2, 2020
Last Verified: May 2020
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Cytomegalovirus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases