Long Term Treatment of Herpes Simplex Encephalitis (HSE) With Valacyclovir

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00031486
First received: March 6, 2002
Last updated: May 10, 2012
Last verified: October 2011
  Purpose

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.


Condition Intervention Phase
Encephalitis
Drug: Valacyclovir
Drug: Placebo
Phase 3

Study Type: Interventional
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)

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Enrollment: 91
Study Start Date: September 2000
Study Completion Date: February 2011
Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Valacyclovir 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 Comparator: Placebo Drug: Placebo
Placebo (identical to active drug in appearance) 500 mg tablets, 4 tablets 3 times daily for 90 days.

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

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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].
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00031486

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Sponsors and Collaborators
  More Information

No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00031486     History of Changes
Obsolete Identifiers: NCT00001124
Other Study ID Numbers: 98-022, CASG 204, N01AI30025C
Study First Received: March 6, 2002
Results First Received: March 15, 2012
Last Updated: May 10, 2012
Health Authority: Sweden: Regional Ethical Review Board
United States: Institutional Review Board
United States: Food and Drug Administration
United States: Federal Government
United Kingdom: Research Ethics Committee

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
encephalitis, herpes simplex, valacyclovir

Additional relevant MeSH terms:
Encephalitis
Encephalitis, Herpes Simplex
Encephalitis, Viral
Herpes Simplex
Brain Diseases
Central Nervous System Diseases
Central Nervous System Infections
Central Nervous System Viral Diseases
DNA Virus Infections
Herpesviridae Infections
Nervous System Diseases
Skin Diseases
Skin Diseases, Infectious
Skin Diseases, Viral
Virus Diseases
Acyclovir
Valacyclovir
Anti-Infective Agents
Antiviral Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014