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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT00031486
Other study ID # 98-022
Secondary ID CASG 204N01AI300
Status Completed
Phase Phase 3
First received March 6, 2002
Last updated May 10, 2012
Start date September 2000
Est. completion date February 2011

Study information

Verified date October 2011
Source National Institute of Allergy and Infectious Diseases (NIAID)
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Other known NCT identifiers
  • NCT00001124

Recruitment information / eligibility

Status Completed
Enrollment 91
Est. completion date February 2011
Est. primary completion date June 2010
Accepts healthy volunteers No
Gender All
Age group 12 Years and older
Eligibility 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].

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Valacyclovir
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
Placebo (identical to active drug in appearance) 500 mg tablets, 4 tablets 3 times daily for 90 days.

Locations

Country Name City State
Canada Kingston General Hospital - Internal Medicine - Neurology Kingston Ontario
Canada University of Manitoba - Medical Microbiology and Infectious Diseases Winnipeg Manitoba
Sweden University of Gothenburg - Sahlgrenska Academy Gothenberg
Sweden niversity of Lund - Infectious Disease Lund
Sweden Karolinska University Hospital, Huddinge Stockholm
Sweden Umea University - Infectious Diseases Umea
Sweden Uppsala University Hospital Uppsala
United Kingdom University College London - Royal Free Campus - Virology London
United States University of New Mexico Albuquerque New Mexico
United States Johns Hopkins University Baltimore Maryland
United States University of Alabama at Birmingham Birmingham Alabama
United States University of Virginia Health System Charlottesville Virginia
United States Northwestern University Feinberg School of Medicine Chicago Illinois
United States University of Colorado Denver Colorado
United States University of Kansas Medical Center Kansas City Kansas
United States Tulane University Health Sciences Center New Orleans Louisiana
United States St. Joseph's Hospital and Medical Center - Barrow Neurological Institute - Phoenix Phoenix Arizona
United States Mayo Clinic Rochester Minnesota
United States University of California Davis Medical Center Sacramento California
United States Saint Louis University Hospital - School of Medicine - Department of Neurology & Psychiatry St. Louis Missouri
United States University of Toledo Toledo Ohio

Sponsors (1)

Lead Sponsor Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Canada,  Sweden,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Survival With no or Mild Neuropsychological Impairment at 12 Months After Initiation of Study Medication as Measured by the Mattis Dementia Rating Scale (MDRS) 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. One year post therapy.
Secondary Effect of Study Medication on Quality of Life Measurements. 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. Day 0 and 90, Day 0 and Month 6 and Day 0 and Month 12
Secondary Effect of Antiviral Therapy on Herpes Simplex Virus (HSV) Deoxyribonucleic Acid (DNA) in Cerebral Spinal Fluid (CSF) 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)]. Day 0 and Day 90.
Secondary 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. 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. 6 months
Secondary 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) 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. 90 days, 6 and 12 months
Secondary 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). 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. 90 days, 6 and 12 months
Secondary Survival With no or Mild Neuropsychological Impairment at 90 Days and at 6 and 12 Months, as Measured by the Glasgow Coma Scale (GCS). 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. 90 days, 6 and 12 months
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