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

NCT00031486 | Completed Phase 3 Results

• 4 other identifiers: 98-022CASG 204N01AI30025CN01AI30025
• Study Type: interventional
• Target: 91
• Locations: 4 countries
• Sites: 21

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.

Conditions

Encephalitis

Keywords

encephalitis, herpes simplex, valacyclovir

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Effect of Study Medication on Quality of Life Measurements.

  Day 0 and 90, Day 0 and Month 6 and Day 0 and Month 12

• Effect of Antiviral Therapy on Herpes Simplex Virus (HSV) Deoxyribonucleic Acid (DNA) in Cerebral Spinal Fluid (CSF)

  Day 0 and Day 90.

• 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.

  6 months

• 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)

  90 days, 6 and 12 months

• 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).

  90 days, 6 and 12 months

Study Arms (2)

Valacyclovir

EXPERIMENTAL

Drug: Valacyclovir

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Valacyclovir 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.

Valacyclovir

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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 \[e.g. ACV, valacyclovir (VACV), famciclovir\].

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (21)

University of Alabama at Birmingham

Birmingham, Alabama, 35294-2050, United States

Location

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

Phoenix, Arizona, 85013, United States

Location

University of California Davis Medical Center

Sacramento, California, 95817, United States

Location

University of Colorado

Denver, Colorado, 80220, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

Tulane University Health Sciences Center

New Orleans, Louisiana, 70112, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

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

St Louis, Missouri, 63110-0250, United States

Location

University of New Mexico

Albuquerque, New Mexico, 87131, United States

Location

University of Toledo

Toledo, Ohio, 43614, United States

Location

University of Virginia Health System

Charlottesville, Virginia, 22908, United States

Location

University of Manitoba - Medical Microbiology and Infectious Diseases

Winnipeg, Manitoba, R3E 0W3, Canada

Location

Kingston General Hospital - Internal Medicine - Neurology

Kingston, Ontario, K7L 2V7, Canada

Location

University of Gothenburg - Sahlgrenska Academy

Gothenberg, Sweden

Location

niversity of Lund - Infectious Disease

Lund, Sweden

Location

Karolinska University Hospital, Huddinge

Stockholm, Sweden

Location

Umea University - Infectious Diseases

Umeå, Sweden

Location

Uppsala University Hospital

Uppsala, Sweden

Location

University College London - Royal Free Campus - Virology

London, NW3 2PF, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 25956891 DERIVED

MeSH Terms

Conditions

Encephalitis; Herpes Simplex

Interventions

Valacyclovir

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuroinflammatory Diseases; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Skin Diseases, Viral; Skin Diseases, Infectious; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Acyclovir; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Penny Jester
• Organization: University of Alabama at Birmingham

pjester@peds.uab.edu

(877) 975-7280

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 6, 2002
• First Posted: March 7, 2002
• Study Start: September 1, 2000
• Primary Completion: June 1, 2010
• Study Completion: February 1, 2011
• Last Updated: June 12, 2012
• Results First Posted: June 12, 2012

Record last verified: 2011-10

Locations

SE (5); US (13); CA (2); GB (1)