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EncephalitisPhase 3NCT00031486

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

A Phase 3 study testing Valacyclovir in people with Encephalitis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 21 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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. Read more about this study

Who is it for?
Ages 12 years and older
Conditions the study is for
Encephalitis
What is being tested?
Valacyclovir
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
91 participants
Where
21 sitesin 4 countries
Study dates
Sep 2000to Feb 2011
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 12 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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).
Show all 9Show fewer
  • 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.

Who cannot join

  • 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].

Trial locations and contacts

21 sites in 4 countries.

21 sites in 4 countries

United States13 sites

  • University of New Mexico

    Albuquerque, New Mexico, 87131

  • Johns Hopkins University

    Baltimore, Maryland, 21287

  • University of Alabama at Birmingham

    Birmingham, Alabama, 35294-2050

  • University of Virginia Health System

    Charlottesville, Virginia, 22908

  • Northwestern University Feinberg School of Medicine

    Chicago, Illinois, 60611

  • University of Colorado

    Denver, Colorado, 80220

  • University of Kansas Medical Center

    Kansas City, Kansas, 66160

  • Tulane University Health Sciences Center

    New Orleans, Louisiana, 70112

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

    Phoenix, Arizona, 85013

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • University of California Davis Medical Center

    Sacramento, California, 95817

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

    St Louis, Missouri, 63110-0250

  • University of Toledo

    Toledo, Ohio, 43614

Other trials in United States

Sweden5 sites

  • University of Gothenburg - Sahlgrenska Academy

    Gothenberg

  • niversity of Lund - Infectious Disease

    Lund

  • Karolinska University Hospital, Huddinge

    Stockholm

  • Umea University - Infectious Diseases

    Umeå

  • Uppsala University Hospital

    Uppsala

Other trials in Sweden

Canada2 sites

  • Kingston General Hospital - Internal Medicine - Neurology

    Kingston, Ontario, K7L 2V7

  • University of Manitoba - Medical Microbiology and Infectious Diseases

    Winnipeg, Manitoba, R3E 0W3

Other trials in Canada

United Kingdom1 site

  • University College London - Royal Free Campus - Virology

    London, NW3 2PF

Other trials in United Kingdom

About this study

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)

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.

Read the 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
Being tested
Valacyclovir, Placebo
Keywords
encephalitis, herpes simplex, valacyclovir
Medical subject headings
Encephalitis, Herpes Simplex

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ValacyclovirDrug

    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.

  • PlaceboDrug

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

Study groups in NCT00031486
Study groupRoleWhat they receive
ValacyclovirExperimentalNot described
Receives: Drug: Valacyclovir
PlaceboPlacebo comparatorNot described
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: One year post therapy.

Secondary outcomes (6)

  1. 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.

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

  2. 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)].

    Measured: Day 0 and Day 90.

  3. 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.

    Measured: 6 months

  4. 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.

    Measured: 90 days, 6 and 12 months

  5. 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.

    Measured: 90 days, 6 and 12 months

  6. 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.

    Measured: 90 days, 6 and 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Mar 2002 (estimated)
  2. Study startSep 2000
  3. Primary completionJun 2010
  4. Study completionFeb 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
91 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00031486
Sponsor's protocol ID
98-022
Other IDs
CASG 204, N01AI30025C, N01AI30025
Status last verified
Oct 2011
First submitted
6 Mar 2002
Last updated
12 Jun 2012

Publications

  • 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.

    PubMed 25956891

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Valacyclovir in people with Encephalitis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 21 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 12 Jun 2012. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 21 sites in United States, Sweden, Canada, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 12 Jun 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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) (time frame: One year post therapy.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00031486, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jun 2012.

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