Clinical trial NCT00031486: Long Term Treatment of Herpes Simplex Encephalitis (HSE) With Valacyclovir
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Encephalitis
Keywords: encephalitis, herpes simplex, valacyclovir
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2002-03-07
Enrollment: 91
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Informed consent and/or assent must be obtained from the patient or legal guardian.
* Patients with encephalopathy consistent with herpes simplex encephalitis (HSE) whose cerebral spinal fluid (or brain biopsy sample) is positive for herpes simplex virus (HSV) deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR).
* Patients who are receiving and will have completed intravenous (IV) acyclovir (ACV) therapy for a minimum duration of 14 days to a maximum of 21 days and a minimum dose of 30 mg/kg/day to a maximum of 60 mg/kg/day, or equivalent dose as adjusted for renal dysfunction.
* Patient is expected to be available for follow-up visits of study drug administration and through the 24 month study visit.
* Patients who are 12 years of age or older.
* Patients who weigh greater than or equal to 45.5kg (100 pounds).
* All female patients with childbearing potential must have a negative pregnancy test within 72 hours prior to initiation of study drug. If the pregnancy test is positive, the patient is ineligible for the study.
* Women must be post-menopausal, surgically sterile or willing to use adequate contraception (barrier method with spermicide, intrauterine device (IUD), oral contraceptives, implant or other licensed hormone method) from time of study enrollment through 1 month after the last dose of study treatment.
* Men must be surgically sterile or willing to use contraception (barrier method with spermicide) from time of study enrollment through 1 month after the last dose of study treatment.

Exclusion Criteria:

* Patients with herpes simplex virus (HSV) meningitis only, without evidence of HSV encephalitis.
* Patients with an anticipated life expectancy \< 90 days.
* Patients with creatinine clearance of less than or equal to 50ml/min./1.73 m\^2.
* Pregnant or breastfeeding females.
* Patients who have received any anti-herpesvirus medication (e.g. ganciclovir) other than intravenous acyclovir (ACV) for acute therapy of the current episode of herpes simplex encephalitis (HSE).
* Patients who are unable to swallow oral medications at the time of study drug randomization (Day 0).
* Patients who are \> 3 days beyond completion of treatment course with intravenous (IV) ACV.
* Patients who are expected to receive long-term (\> 30 days/year) therapy with antiviral medications active against HSV \[e.g. ACV, valacyclovir (VACV), famciclovir\].

Primary outcomes:
measure: Survival With no or Mild Neuropsychological Impairment at 12 Months After Initiation of Study Medication as Measured by the Mattis Dementia Rating Scale (MDRS)
timeFrame: One year post therapy.
Secondary outcomes:
measure: Effect of Study Medication on Quality of Life Measurements.
timeFrame: Day 0 and 90, Day 0 and Month 6 and Day 0 and Month 12
measure: Effect of Antiviral Therapy on Herpes Simplex Virus (HSV) Deoxyribonucleic Acid (DNA) in Cerebral Spinal Fluid (CSF)
timeFrame: Day 0 and Day 90.
measure: 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.
timeFrame: 6 months
measure: 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)
timeFrame: 90 days, 6 and 12 months
measure: 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).
timeFrame: 90 days, 6 and 12 months
measure: Survival With no or Mild Neuropsychological Impairment at 90 Days and at 6 and 12 Months, as Measured by the Glasgow Coma Scale (GCS).
timeFrame: 90 days, 6 and 12 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center - Barrow Neurological Institute - Phoenix
state: Arizona
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: St. Louis
country: United States
facility: Saint Louis University Hospital - School of Medicine - Department of Neurology & Psychiatry
state: Missouri
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Toledo
country: United States
facility: University of Toledo
state: Ohio
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Winnipeg
country: Canada
facility: University of Manitoba - Medical Microbiology and Infectious Diseases
state: Manitoba
city: Kingston
country: Canada
facility: Kingston General Hospital - Internal Medicine - Neurology
state: Ontario
city: Gothenberg
country: Sweden
facility: University of Gothenburg - Sahlgrenska Academy
city: Lund
country: Sweden
facility: niversity of Lund - Infectious Disease
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Huddinge
city: Umea
country: Sweden
facility: Umea University - Infectious Diseases
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: London
country: United Kingdom
facility: University College London - Royal Free Campus - Virology
Study officials:
References:
citation: Gnann JW Jr, Skoldenberg B, Hart J, Aurelius E, Schliamser S, Studahl M, Eriksson BM, Hanley D, Aoki F, Jackson AC, Griffiths P, Miedzinski L, Hanfelt-Goade D, Hinthorn D, Ahlm C, Aksamit A, Cruz-Flores S, Dale I, Cloud G, Jester P, Whitley RJ; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Herpes Simplex Encephalitis: Lack of Clinical Benefit of Long-term Valacyclovir Therapy. Clin Infect Dis. 2015 Sep 1;61(5):683-91. doi: 10.1093/cid/civ369. Epub 2015 May 8.