Long Term Treatment of Herpes Simplex Encephalitis (HSE) With Valacyclovir
This study involves patients 12 years and older who have been diagnosed with herpes simplex encephalitis (HSE) by a specific laboratory test and have completed treatment or are being treated with intravenous (given through a needle inserted into a vein) acyclovir. The purpose of the study is to determine if treatment with 4 tablets, 500 milligrams each, of valacyclovir given 3 times daily by mouth for 90 days is both effective and safe after completing intravenous acyclovir treatment and if it can increase survival with or without mild impairment of the brain and mental functions. Participants will be assigned to either drug or placebo (inactive substance) randomly (by chance). Study procedures will include blood samples and lumbar punctures (procedure in which a needle is inserted into the lower back to collect cerebral spinal fluid). Subjects will participate for up to 24 months.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||A Phase III Double-Blind, Placebo-Controlled Trial of Long Term Therapy of Herpes Simplex Encephalitis (HSE): An Evaluation of Valacyclovir (CASG-204)|
- Survival With no or Mild Neuropsychological Impairment at 12 Months After Initiation of Study Medication as Measured by the Mattis Dementia Rating Scale (MDRS) [ Time Frame: One year post therapy. ] [ Designated as safety issue: No ]Number of subjects who were assessed to have no or mild neuropsychological impairment at 12 months using the Mattis Dementia Rating Scale. (A score of 121 or higher refects no or mild neuropsychological impairment.) Scale is: 139-144 normal; 121-139 mild; 114-120 moderate; 87-113 severe; and <=86 very severe.
- Effect of Study Medication on Quality of Life Measurements. [ Time Frame: Day 0 and 90, Day 0 and Month 6 and Day 0 and Month 12 ] [ Designated as safety issue: No ]The SF-36 Questionnaire measures quality of life as reported by the subject. The questionnaire contains 36 questions, each questions can be assigned a maximum score of 100. For each subject, a perfect score would be 3600, hence the higher score is best. The calculated scores reported in the table below reflect the diffence between Day 0 (day study drug started) and Day 90, Day 0 (day study drug started) and Month 6, and Day 0 (day study drug started) and Month 12.
- Effect of Antiviral Therapy on Herpes Simplex Virus (HSV) Deoxyribonucleic Acid (DNA) in Cerebral Spinal Fluid (CSF) [ Time Frame: Day 0 and Day 90. ] [ Designated as safety issue: No ]Few CSF specimens were collected on day 90, hence unable to calculate the difference in PCR at day 0 and day 90.[measured quantitatively by polymerase chain reaction (PCR)].
- Median Number of Reported AEs Describing Safety and Tolerance of Valacyclovir (VACV), Evaluated by the Number Adverse Events, Administered at a Dose of 2.0 Grams Given Orally 3 Times a Day for 90 Days. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]The measure is the number of adverse events per subject. Adverse events were recorded from time of first dose of study drug through 6 months post start of study drug.
- Survival With no or Mild Neuropsychological Impairment at 90 Days and at 6 and 12 Months, as Measured by the Mattis Dementia Rating Scale (MDRS) [ Time Frame: 90 days, 6 and 12 months ] [ Designated as safety issue: No ]The assessment scoring for the Mattis Dementia Rating Scale is as follows: 139 - 144: no neuropsychological impairment; 121- 138: mild neuropsychological impairment; 114 - 120: moderate neuropsychological impairment; 87 - 113: severe neuropsychological impairment; and <=86: very severe neuropsychological impairment.
- Survival With no or Mild Neuropsychological Impairment at 90 Days, and at 6 and 12 Months, as Measured by the Mini-Mental Status Examination (MMSE). [ Time Frame: 90 days, 6 and 12 months ] [ Designated as safety issue: No ]The assessment score for the Mini-Mental Status Examination is as follows: 27 - 30: no neuropsychological impairment; 23 - 26: mild neuropsychological impairment; 16 - 22: moderate neuropsychological impairment; 11 - 15 severe neuropsychological impairment; and <=10: very severe neuropsychological impairment.
- Survival With no or Mild Neuropsychological Impairment at 90 Days and at 6 and 12 Months, as Measured by the Glasgow Coma Scale (GCS). [ Time Frame: 90 days, 6 and 12 months ] [ Designated as safety issue: No ]The assessment scoring for the Glasgow Coma Scale is as follows: 15: no neuropsychological impairment; 12 - 14: mild neuropsychological impairment; 9 - 11: moderate neuropsychological impairment; 6 to 8: severe neuropsychological impairment; and <6: very severe neuropsychological impairment.
|Study Start Date:||September 2000|
|Study Completion Date:||February 2011|
|Primary Completion Date:||June 2010 (Final data collection date for primary outcome measure)|
Valacyclovir is a L-valyl ester of acyclovir. Valacyclovir is provided in 500 mg tablets, 4 tablets (500 mg tablets) 3 times a day (every 8 hours) for 90 days.
|Placebo Comparator: Placebo||
Placebo (identical to active drug in appearance) 500 mg tablets, 4 tablets 3 times daily for 90 days.
Herpes simplex encephalitis (HSE) remains the most common cause of sporadic fatal encephalitis in the world. This study is a phase III, double-blind, placebo controlled study of long term therapy with valacyclovir as a treatment of herpes encephalitis. The primary objective of this study is to assess the impact of valacyclovir (VACV) therapy (following standard intravenous acyclovir therapy) on neuropsychological impairment at one year post therapy, based on the cumulative scores of the Mattis Dementia Rating Scale (MDRS). The secondary objectives of the study are to: assess the effect of therapy on neuropsychological impairment at various time points; assess the effect of therapy on quality of life, based on the SF-36 Quality of Life Assessment; measure the effect of therapy on herpes simplex virus (HSV) deoxyribonucleic acid (DNA) in the cerebral spinal fluid (CSF); and assess the safety and tolerability of long term VACV therapy in patients with HSE. The tertiary objective of the study is to determine the frequency of symptomatic relapse/recurrence of HSE. Study participants will include 120 males and females, 12 years of age and older, diagnosed with HSE; laboratory confirmed CSF positive for HSV DNA by polymerase chain reaction (PCR). Consenting study participants will be randomized (1:1) to either valacyclovir (active drug), 500 mg tablets, four tablets three times daily for 90 days or placebo (identical to active drug in appearance), 500 mg tablets, four tablets three times daily for 90 days. The primary endpoints of the study are to assess the impact of valacyclovir therapy [following standard intravenous acyclovir (ACV) therapy] on neuropsychological impairment at one year post therapy and survival with no or mild neuropsychological impairment at 12 months after initiation of study medication, as measured by the MDRS. The secondary endpoints include: survival with no or mild neuropsychological impairment at 90 days and at 6, 12 and 24 months, as measured by the MDRS, the Mini-Mental Status Examination (MMSE), and the Glasgow Coma Scale; effect of study medication on quality of life measurements; effect of antiviral therapy on HSV DNA in CSF (measured quantitatively by PCR at Day 0 and Day 90); and safety and tolerance of VACV administered at a dose of 2.0 grams given orally three times a day for 90 days. Each study participant will participate for approximately 24 months.
Hide Study Locations
|United States, Alabama|
|University of Alabama at Birmingham|
|Birmingham, Alabama, United States, 35294-2050|
|United States, Arizona|
|St. Joseph's Hospital and Medical Center - Barrow Neurological Institute - Phoenix|
|Phoenix, Arizona, United States, 85013|
|United States, California|
|University of California Davis Medical Center|
|Sacramento, California, United States, 95817|
|United States, Colorado|
|University of Colorado|
|Denver, Colorado, United States, 80220|
|United States, Illinois|
|Northwestern University Feinberg School of Medicine|
|Chicago, Illinois, United States, 60611|
|United States, Kansas|
|University of Kansas Medical Center|
|Kansas City, Kansas, United States, 66160|
|United States, Louisiana|
|Tulane University Health Sciences Center|
|New Orleans, Louisiana, United States, 70112|
|United States, Maryland|
|Johns Hopkins University|
|Baltimore, Maryland, United States, 21287|
|United States, Minnesota|
|Rochester, Minnesota, United States, 55905|
|United States, Missouri|
|Saint Louis University Hospital - School of Medicine - Department of Neurology & Psychiatry|
|St. Louis, Missouri, United States, 63110-0250|
|United States, New Mexico|
|University of New Mexico|
|Albuquerque, New Mexico, United States, 87131|
|United States, Ohio|
|University of Toledo|
|Toledo, Ohio, United States, 43614|
|United States, Virginia|
|University of Virginia Health System|
|Charlottesville, Virginia, United States, 22908|
|University of Manitoba - Medical Microbiology and Infectious Diseases|
|Winnipeg, Manitoba, Canada, R3E 0W3|
|Kingston General Hospital - Internal Medicine - Neurology|
|Kingston, Ontario, Canada, K7L 2V7|
|University of Gothenburg - Sahlgrenska Academy|
|niversity of Lund - Infectious Disease|
|Karolinska University Hospital, Huddinge|
|Umea University - Infectious Diseases|
|Uppsala University Hospital|
|University College London - Royal Free Campus - Virology|
|London, United Kingdom, NW3 2PF|