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

NCT ID: NCT00031486

Last Updated: 2012-06-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 91 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2000-09-30
• Study Completion Date: 2011-02-28

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.

Conditions

Encephalitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Valacyclovir

Group Type: EXPERIMENTAL

Valacyclovir

Intervention Type: DRUG

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Interventions

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.

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

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].

• Minimum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

St. Joseph's Hospital and Medical Center - Barrow Neurological Institute - Phoenix

Phoenix, Arizona, United States

University of California Davis Medical Center

Sacramento, California, United States

University of Colorado

Denver, Colorado, United States

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Tulane University Health Sciences Center

New Orleans, Louisiana, United States

Johns Hopkins University

Baltimore, Maryland, United States

Mayo Clinic

Rochester, Minnesota, United States

Saint Louis University Hospital - School of Medicine - Department of Neurology & Psychiatry

St Louis, Missouri, United States

University of New Mexico

Albuquerque, New Mexico, United States

University of Toledo

Toledo, Ohio, United States

University of Virginia Health System

Charlottesville, Virginia, United States

University of Manitoba - Medical Microbiology and Infectious Diseases

Winnipeg, Manitoba, Canada

Kingston General Hospital - Internal Medicine - Neurology

Kingston, Ontario, Canada

University of Gothenburg - Sahlgrenska Academy

Gothenberg, , Sweden

niversity of Lund - Infectious Disease

Lund, , Sweden

Karolinska University Hospital, Huddinge

Stockholm, , Sweden

Umea University - Infectious Diseases

Umeå, , Sweden

Uppsala University Hospital

Uppsala, , Sweden

University College London - Royal Free Campus - Virology

London, , United Kingdom

Countries

United States; Canada; Sweden; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 25956891 (View on PubMed)

Other Identifiers

CASG 204

Identifier Type: -

Identifier Source: secondary_id

N01AI30025C

Identifier Type: -

Identifier Source: secondary_id

N01AI30025

Identifier Type: NIH

Identifier Source: secondary_id

View Link

98-022

Identifier Type: -

Identifier Source: org_study_id

NCT00001124

Identifier Type: -

Identifier Source: nct_alias