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

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.

Study Overview

• Status: Withdrawn
• Conditions: Herpes Simplex Virus
• Intervention / Treatment: Drug: Novel Antiviral Drug; Drug: Placebo

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.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • University of Arkansas for Medical Sciences
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado at Denver Health Sciences Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Tampa, Florida, United States, 33606
      • University of South Florida School of Medicine
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Children's Center
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • Louisiana State University Health Science Center -Shreveport
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University in St Louis School of Medicine
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Medical School
  • New York
    • Manhasset, New York, United States, 11030
      • Steven & Alexandra Cohen Children's Medical Center Of New York (CCMC)
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center - Charlotte
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232-2581
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390-9063
      • University of Texas-Southwestern
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 3 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Novel Antiviral Drug; 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	Drug: Novel Antiviral Drug; 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.
PLACEBO_COMPARATOR: Placebo; 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	Drug: Placebo; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Evaluate the safety and tolerability of CMX001 oral suspension in infants being treated for neonatal HSV CNS disease.	Baseline through day 21
Determine the plasma pharmacokinetics of the CMX001 and cidofovir following administration of CMX001 oral suspension in infants being treated for neonatal HSV CNS disease.	Baseline through day 21

Secondary Outcome Measures

Outcome Measure	Time Frame
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	Baseline through day 21
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	Baseline through day 56 (end of study)

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Investigators: Principal Investigator: David W Kimberlin, MD, University of Alabama at Birmingham

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (ANTICIPATED): June 1, 2017
• Study Completion (ANTICIPATED): June 1, 2017

Study Registration Dates

• First Submitted: May 30, 2012
• First Submitted That Met QC Criteria: June 1, 2012
• First Posted (ESTIMATE): June 4, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): June 7, 2016
• Last Update Submitted That Met QC Criteria: June 6, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: pharmacokinetics; neonates; HSV; herpes
• Additional Relevant MeSH Terms: Nervous System Diseases; Skin Diseases; Virus Diseases; Infections; DNA Virus Infections; Skin Diseases, Infectious; Skin Diseases, Viral; Herpesviridae Infections; Herpes Simplex; Central Nervous System Diseases; Anti-Infective Agents; Antiviral Agents
• Other Study ID Numbers: DMID 11-0068