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A Safety and Dose-Determining Study of CMX001 In Infants With Neonatal Herpes Simplex Virus (HSV) Infection Involving the Central Nervous System (CNS Disease)

Primary Purpose

Herpes Simplex Virus

Status
Withdrawn
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Novel Antiviral Drug
Placebo
Sponsored by
University of Alabama at Birmingham
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Herpes Simplex Virus focused on measuring HSV, pharmacokinetics, herpes, neonates

Eligibility Criteria

1 Day - 98 Days (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Signed Informed Consent by parent or legal guardian of study subject
  • Virologically confirmed HSV infection [e.g., positive culture, DNA detection by polymerase chain reaction (PCR), or direct fluorescent antibody stain from any body site or compartment]
  • Evidence of CNS involvement of HSV disease [e.g., CSF pleocytosis, positive CSF PCR testing, clinical or electroencephalogram (EEG) seizure activity, neuroimaging abnormality)
  • Starting parenteral acyclovir therapy at time of initiation of CMX001 study drug or receiving parenteral acyclovir therapy for ≤ 72 hours before start CMX001 study drug
  • ≤ 6 weeks (42 days) of age at time of initial onset of disease symptoms or signs
  • Weight at study enrollment ≥ 2,630 grams
  • Gestational age ≥ 36 weeks at delivery
  • Mother tested negative for HIV during or following pregnancy

Exclusion Criteria:

  • Imminent demise
  • Disseminated or skin/eye/mouth (SEM) neonatal HSV disease classifications
  • Gastrointestinal abnormality which might preclude absorption of an oral medication (e.g., history of necrotizing enterocolitis, gastroschisis, malrotation, etc.)
  • Birth weight < 2,500 grams
  • Birth weight > 4,500 grams
  • Grade 3 or 4 vomiting, utilizing the DAIDS Toxicity Tables (Appendix B)
  • Grade 3 or 4 diarrhea, utilizing the DAIDS Toxicity Tables (Appendix B)
  • Creatinine clearance < 15 mL/min/1.73m2
  • Serum albumin < 2.0 g/dL
  • Alanine aminotransferase (ALT) ≥ 2.6-times upper limit normal (ULN)
  • Aspartate aminotransferase (AST) ≥ 2.6-times upper limit normal (ULN)
  • Direct bilirubin > 2 mg/dL
  • Known immunodeficiency
  • Known congenital infection (e.g., symptomatic congenital cytomegalovirus infection; syphilis; congenital toxoplasmosis)
  • Congenital heart disease (e.g., patent ductus arteriosus, Tetralogy of Fallot, hypoplastic left heart syndrome, AV canal, VSD, ASD, transposition of the great arteries, hypoplastic right ventricle, truncus arteriosus, pulmonic stenosis, Ebstein anomaly, coarctation of the aorta, interrupted aortic arch, double outlet right ventricle, dilated cardiomyopathy)
  • Infants currently receiving or anticipated to need treatment with digoxin that cannot be withheld for the duration of CMX001 therapy
  • Infants currently receiving or anticipated to need treatment with ketaconazole that cannot be withheld for the duration of CMX001 therapy
  • Receipt of investigation drugs within 30 days prior to enrollment
  • Concurrent enrollment or participation in any other interventional research study

Sites / Locations

  • University of Alabama at Birmingham
  • University of Arkansas for Medical Sciences
  • University of Colorado at Denver Health Sciences Center
  • Children's National Medical Center
  • University of South Florida School of Medicine
  • Emory Children's Center
  • Louisiana State University Health Science Center -Shreveport
  • Washington University in St Louis School of Medicine
  • Dartmouth Medical School
  • Steven & Alexandra Cohen Children's Medical Center Of New York (CCMC)
  • University of Rochester Medical Center
  • Carolinas Medical Center - Charlotte
  • MetroHealth Medical Center
  • Children's Hospital of Pittsburgh of UPMC
  • Rhode Island Hospital
  • Vanderbilt University Medical Center
  • University of Texas-Southwestern
  • University of Utah School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Novel Antiviral Drug

Placebo

Arm Description

Subjects will be randomized to receive one of 3 oral doses of a Novel Antiviral Drug: 0.50 mg/kg/dose, 1.0 mg/kg/dose or 2.0 mg/kg/dose twice a week for up to 3 weeks during the time in which the 21 day administration of parenteral acyclovir is being administered

Subjects will be randomized to receive one of 3 oral doses of placebo matched in volume to active drug: 0.50 mg/kg/dose, 1.0 mg/kg/dose or 2.0 mg/kg/dose twice a week for up to 3 weeks during the time in which the 21 day administration of parenteral acyclovir is being administered

Outcomes

Primary Outcome Measures

Evaluate the safety and tolerability of CMX001 oral suspension in infants being treated for neonatal HSV CNS disease.
Determine the plasma pharmacokinetics of the CMX001 and cidofovir following administration of CMX001 oral suspension in infants being treated for neonatal HSV CNS disease.

Secondary Outcome Measures

Explore a plasma drug concentration-response relationship between CMX001 exposure and quantity of HSV DNA in cerebrospinal fluid (CSF) at Day 4 of antiviral therapy
Explore a plasma drug concentration-response relationship between cidofovir exposure and quantity of HSV DNA in cerebrospinal fluid (CSF) at Day 4 of antiviral therapy

Full Information

First Posted
May 30, 2012
Last Updated
June 6, 2016
Sponsor
University of Alabama at Birmingham
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1. Study Identification

Unique Protocol Identification Number
NCT01610765
Brief Title
A Safety and Dose-Determining Study of CMX001 In Infants With Neonatal Herpes Simplex Virus (HSV) Infection Involving the Central Nervous System (CNS Disease)
Official Title
A Safety and Dose-Determining Study of CMX001 In Infants With Neonatal Herpes Simplex Virus (HSV) Infection Involving the Central Nervous System (CNS Disease)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2016
Overall Recruitment Status
Withdrawn
Why Stopped
Study terminated because unable to obtain access to study drug for study population.
Study Start Date
January 2016 (undefined)
Primary Completion Date
June 2017 (Anticipated)
Study Completion Date
June 2017 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Alabama at Birmingham

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study is to identify if a Novel Antiviral Drug could be used to treat babies with Herpes Simplex Virus (HSV) with central nervous system (CNS) disease. In this study the investigators will identify the best dose for young children as well as identify additional safety information about the Novel Antiviral Drug.
Detailed Description
In this study, the pharmacokinetics and safety of a Novel Antiviral Drug will be determined in babies with neonatal HSV CNS disease. The study will be conducted at 18 academic medical centers throughout the United States. Young infants presenting with virologic confirmation of neonatal HSV infection and evidence of CNS involvement will be eligible for study enrollment. Study Day 1 is defined as the day when dose 1 of the Novel Antiviral Drug study medication is administered.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Herpes Simplex Virus
Keywords
HSV, pharmacokinetics, herpes, neonates

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Novel Antiviral Drug
Arm Type
Active Comparator
Arm Description
Subjects will be randomized to receive one of 3 oral doses of a Novel Antiviral Drug: 0.50 mg/kg/dose, 1.0 mg/kg/dose or 2.0 mg/kg/dose twice a week for up to 3 weeks during the time in which the 21 day administration of parenteral acyclovir is being administered
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Subjects will be randomized to receive one of 3 oral doses of placebo matched in volume to active drug: 0.50 mg/kg/dose, 1.0 mg/kg/dose or 2.0 mg/kg/dose twice a week for up to 3 weeks during the time in which the 21 day administration of parenteral acyclovir is being administered
Intervention Type
Drug
Intervention Name(s)
Novel Antiviral Drug
Intervention Description
4 oral doses of a Novel Antiviral Drug: 0.25 mg/kg/dose, 0.50 mg/kg/dose, 1.0 mg/kg/dose or 2.0 mg/kg/dose twice a week for 3 weeks during the time in which the 21 day administration of parenteral acyclovir is being administered. Subjects will be assigned a the higher dose of study drug after the DSMB and sponsor determine that reported adverse events and the PK data show that it is safe to increase dosing to the next higher level.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
4 oral doses of placebo matching the a Novel Antiviral Drug assigned dose: 0.25 mg/kg/dose, 0.50 mg/kg/dose, 1.0 mg/kg/dose or 2.0 mg/kg/dose twice a week for 3 weeks during the time in which the 21 day administration of parenteral acyclovir is being administered. Subjects will be assigned a the higher dose of study drug after the DSMB and sponsor determine that reported adverse events and the PK data show that it is safe to increase dosing to the next higher level.
Primary Outcome Measure Information:
Title
Evaluate the safety and tolerability of CMX001 oral suspension in infants being treated for neonatal HSV CNS disease.
Time Frame
Baseline through day 21
Title
Determine the plasma pharmacokinetics of the CMX001 and cidofovir following administration of CMX001 oral suspension in infants being treated for neonatal HSV CNS disease.
Time Frame
Baseline through day 21
Secondary Outcome Measure Information:
Title
Explore a plasma drug concentration-response relationship between CMX001 exposure and quantity of HSV DNA in cerebrospinal fluid (CSF) at Day 4 of antiviral therapy
Time Frame
Baseline through day 21
Title
Explore a plasma drug concentration-response relationship between cidofovir exposure and quantity of HSV DNA in cerebrospinal fluid (CSF) at Day 4 of antiviral therapy
Time Frame
Baseline through day 56 (end of study)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Day
Maximum Age & Unit of Time
98 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Signed Informed Consent by parent or legal guardian of study subject Virologically confirmed HSV infection [e.g., positive culture, DNA detection by polymerase chain reaction (PCR), or direct fluorescent antibody stain from any body site or compartment] Evidence of CNS involvement of HSV disease [e.g., CSF pleocytosis, positive CSF PCR testing, clinical or electroencephalogram (EEG) seizure activity, neuroimaging abnormality) Starting parenteral acyclovir therapy at time of initiation of CMX001 study drug or receiving parenteral acyclovir therapy for ≤ 72 hours before start CMX001 study drug ≤ 6 weeks (42 days) of age at time of initial onset of disease symptoms or signs Weight at study enrollment ≥ 2,630 grams Gestational age ≥ 36 weeks at delivery Mother tested negative for HIV during or following pregnancy Exclusion Criteria: Imminent demise Disseminated or skin/eye/mouth (SEM) neonatal HSV disease classifications Gastrointestinal abnormality which might preclude absorption of an oral medication (e.g., history of necrotizing enterocolitis, gastroschisis, malrotation, etc.) Birth weight < 2,500 grams Birth weight > 4,500 grams Grade 3 or 4 vomiting, utilizing the DAIDS Toxicity Tables (Appendix B) Grade 3 or 4 diarrhea, utilizing the DAIDS Toxicity Tables (Appendix B) Creatinine clearance < 15 mL/min/1.73m2 Serum albumin < 2.0 g/dL Alanine aminotransferase (ALT) ≥ 2.6-times upper limit normal (ULN) Aspartate aminotransferase (AST) ≥ 2.6-times upper limit normal (ULN) Direct bilirubin > 2 mg/dL Known immunodeficiency Known congenital infection (e.g., symptomatic congenital cytomegalovirus infection; syphilis; congenital toxoplasmosis) Congenital heart disease (e.g., patent ductus arteriosus, Tetralogy of Fallot, hypoplastic left heart syndrome, AV canal, VSD, ASD, transposition of the great arteries, hypoplastic right ventricle, truncus arteriosus, pulmonic stenosis, Ebstein anomaly, coarctation of the aorta, interrupted aortic arch, double outlet right ventricle, dilated cardiomyopathy) Infants currently receiving or anticipated to need treatment with digoxin that cannot be withheld for the duration of CMX001 therapy Infants currently receiving or anticipated to need treatment with ketaconazole that cannot be withheld for the duration of CMX001 therapy Receipt of investigation drugs within 30 days prior to enrollment Concurrent enrollment or participation in any other interventional research study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David W Kimberlin, MD
Organizational Affiliation
University of Alabama at Birmingham
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Richard Whitley, MD
Organizational Affiliation
University of Alabama at Birmingham
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
University of Arkansas for Medical Sciences
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72202
Country
United States
Facility Name
University of Colorado at Denver Health Sciences Center
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
University of South Florida School of Medicine
City
Tampa
State/Province
Florida
ZIP/Postal Code
33606
Country
United States
Facility Name
Emory Children's Center
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Louisiana State University Health Science Center -Shreveport
City
Shreveport
State/Province
Louisiana
ZIP/Postal Code
71103
Country
United States
Facility Name
Washington University in St Louis School of Medicine
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Dartmouth Medical School
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States
Facility Name
Steven & Alexandra Cohen Children's Medical Center Of New York (CCMC)
City
Manhasset
State/Province
New York
ZIP/Postal Code
11030
Country
United States
Facility Name
University of Rochester Medical Center
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
Carolinas Medical Center - Charlotte
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28203
Country
United States
Facility Name
MetroHealth Medical Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44109
Country
United States
Facility Name
Children's Hospital of Pittsburgh of UPMC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
Rhode Island Hospital
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02903
Country
United States
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232-2581
Country
United States
Facility Name
University of Texas-Southwestern
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390-9063
Country
United States
Facility Name
University of Utah School of Medicine
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States

12. IPD Sharing Statement

Learn more about this trial

A Safety and Dose-Determining Study of CMX001 In Infants With Neonatal Herpes Simplex Virus (HSV) Infection Involving the Central Nervous System (CNS Disease)

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