Acyclovir Herpes Simplex Virus (HSV) Skin, Eye, and Mouth

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00031447
• Collaborator: (none)
• Enrollment: 29
• Locations: 28
• Arms: 2
• Duration (Months): 104
• Patients Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to test whether long-term treatment with oral acyclovir improves the outcome for infants with herpes simplex virus (HSV) disease of the skin, eyes, and mouth (SEM). Study participants will include infants in the United States and Canada who have HSV disease of the skin, eyes, and mouth, with no central nervous system disease present. Initially, all subjects will be treated with acyclovir administered through IV access (through the vein) for 14 days while hospitalized. Participants will then be placed in one of two groups, acyclovir given by mouth or a placebo (substance with no medication present). The participant and the study site will not know to which group the subject is assigned. All children will be followed at 6, 12, 24, 36, 48, and 60 months of age. During the follow up visits, physicals, hearing assessments, eye assessments, and neurological assessments will be completed.

Condition or Disease	Intervention/Treatment	Phase
Herpes Simplex	Drug: Acyclovir; Drug: Placebo	Phase 3

Detailed Description

Neonatal herpes simplex virus (HSV) disease complicates approximately one in every 3,000 births in the United States. This study will be a placebo-controlled Phase III evaluation of suppressive therapy with oral Acyclovir suspension following neonatal HSV infections limited to the skin, eyes, and mouth (SEM). This study will evaluate the efficacy of long-term suppressive therapy with oral acyclovir in infants with SEM disease. It will determine if suppressive oral acyclovir therapy improves neurological outcome in infants following SEM disease. Only infants with SEM disease will qualify for this study. After qualifying for the study and obtaining informed consent, the infant will complete 14 days of intravenous (IV) Acyclovir (20 mg/kg/dose given every 8 hours). Patients will be randomized to receive suppressive oral Acyclovir versus placebo only if they continue to meet all study inclusion criteria at the completion of the IV therapy. This study will be double-blinded and placebo controlled. At the time of randomization, the patient will be placed in 1 of 2 groups (oral suppressive Acyclovir versus placebo). If a patient in either group has a cutaneous HSV recurrence, open-label oral Acyclovir (80 mg/kg/day divided into 4 doses per day) will be provided for 5 days. During the time of administration of open-label oral Acyclovir, study drug will be withheld. All children will be followed at 6, 12, 24, 36, 48, and 60 months of age. Physical examination, hearing assessment, and retinal examination will be performed at each follow up visit. Standardized neurologic evaluation will be performed at 12, 24, 36, 48, and 60 months of age.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Placebo-Controlled Phase III Evaluation of Suppressive Therapy With Oral Acyclovir Suspension Following Neonatal Herpes Simplex Virus Infections Limited to the Skin, Eye, and Mouth
• Study Start Date: Aug 1, 1999
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Apr 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo identical to oral acyclovir suspension in appearance and taste.
Experimental: Acyclovir	Drug: Acyclovir; Oral suspension 300 mg/m^2/dose, 3 times per day (TID), for 6 months.

Outcome Measures

Primary Outcome Measures

1. Participants With Neurologic Impairment at 12 Months as Measured by a Bayley's Neuro-developmental Assessment.(Motor Scores) [At 12 months of life.]

   Motor scores of all participants completing 6 months of blinded therapy as measured by the Bayleys neuro-developmental assessment at 12 months. Scores are classified as the following: greater than or equal to 115 suggests accelerated performance; 85 - 114 suggests development within normal limits; 70 - 84 suggests mildly delayed development and less than or equal to 69 suggests significant delayed development.

2. Participants With Neurologic Impairment at 12 Months as Measured by a Bayley's Neuro-developmental Assessment.(Mental Scores) [At 12 months of life.]

   Mental scores of all participants completing 6 months of blinded therapy as measured by the Bayleys neuro-developmental assessment at 12 months. Scores are classified as the following: less than or equal to 115 suggests accelerated performance; 85 - 114 suggests development within normal limits; 70 - 84 suggests mildly delayed development and less than or equal to 69 suggests significant delayed development.

Secondary Outcome Measures

1. Detection of Herpes Simplex Virus (HSV) DNA in the Cerebrospinal Fluid (CSF) by Polymerase Chain Reaction (PCR) at Anytime During the Initial 12 Months of Life. [post randomization at 12 months]

   Number of participants with positive herpes simplex virus (HSV) DNA by polymerase cahin reaction (PCR) in the cerebrospinal fluid of subjects assessed during the initial 12 months of life.

2. Two or Fewer Episodes of Cutaneous Recurrence of HSV Disease Post-randomization During the Initial 12 Months of Life. [post randomization - 12 months]

   Number of participants experiencing 2 or fewer HSV recurrences during the first 12 months of life as measured by assessments and reports at study visits.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 28 Days
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Isolation by viral culture of herpes simplex virus (HSV)-1or HSV-2 from cutaneous lesions, conjunctivae, or oropharynx. Detection of HSV at any of these sites is sufficient, and the presence of skin lesions is not required for study enrollment.

• Normal cerebrospinal fluid (CSF) indices (<22 white blood cells (WBCs)/mm^{3 and protein <115 mg/dl for term infants; (<25 WBCs/mm}3 and protein <220 mg/dl for preterm infants both at the time of diagnosis of HSV disease and at the time of study randomization.

• No evidence of HSV central nervous system (CNS) disease by computed tomography (CT) with contrast, magnetic resonance imaging (MRI) with gadolinium, or head ultrasound (HUS) [NOTE: CT with contrast is the preferred imaging study].

• Normal electroencephalogram (EEG), if performed [NOTE: EEG is suggested for the evaluation of infants with HSV disease but is not required for this study].

• No evidence of visceral dissemination of HSV infection (normal liver function tests, normal chest x-ray, etc.).

• Negative CSF HSV polymerase chain reaction (PCR) results from specimens obtained both within 72 hours of initiation of intravenous acyclovir therapy and within 48 hours prior to completion of intravenous acyclovir therapy.

• Less than or equal to 28 days of age at the time of initial presentation with skin, eyes, and mouth (SEM) disease.

• Birth weight greater than or equal to equal to 800 grams.

Exclusion Criteria:

• Infants with either grade 3 or grade 4 intraventricular hemorrhage (IVH) prior to study enrollment.

• Breast feeding infants whose mothers are taking acyclovir, valacyclovir, or famciclovir for >120 hours (>5 days). If at any point following enrollment the mother takes these antiviral drugs for >120 hours (>5 days), she will be asked to refrain from breast feeding while taking the drug.

• Infants known to be born to women who are human immunodeficiency virus (HIV) positive (but HIV testing is not required for study entry). These infants are at known risk for acquiring HIV, which would alter their immune response to other infections, including HSV infection. Additionally, they may be receiving antiretroviral and/or antiviral drugs during the time in which the study of suppressive oral acyclovir is being conducted. As such, they will be excluded if the mother's positive HIV status is known at the time of evaluation for study inclusion. If at any point following enrollment it is learned that an infant is HIV positive, he/she will be continued on the study protocol.

• Infants with either central nervous system (CNS) or disseminated HSV infection. Patients with CNS HSV infection will be considered for enrollment and randomization in the ongoing Collaborative Antiviral Study Group (CASG) evaluation of oral suppressive acyclovir therapy following neonatal HSV infections involving the CNS.

• Infants with creatinine >1.5mg/dl at time of study enrollment.

• Infants receiving acyclovir expectantly do not qualify for this study because they never developed HSV disease. Expectant therapy describes infants who are cultured at approximately 24 hours of life because of a risk of HSV infection (i.e. they are born to women with active genital lesions). Oftentimes, if these cultures are positive, the infant will receive a course of intravenous acyclovir to prevent the development of HSV disease. However, since they never actually had HSV disease, their potential outcome cannot be compared with infants with typical skin, eyes, and mouth (SEM) disease, and so they are not included in this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Arkansas Children's Hospital, Department of Infectious Diseases	Little Rock	Arkansas	United States	72202
3	Rady Children's Hospital San Diego	San Diego	California	United States	92123
4	Stanford University School of Medicine	Stanford	California	United States	94305-5208
5	University of Florida - College of Medicine - Jacksonville	Jacksonville	Florida	United States	32209
6	The University of Chicago - Comer Children's Hospital - Infectious Diseases	Chicago	Illinois	United States	60637
7	Kosair Children's Hospital	Louisville	Kentucky	United States	40202
8	Tulane University - Tulane Medical Center - Department of Pediatrics	New Orleans	Louisiana	United States	70112
9	Maine Medical Center - Department of Pediatric Specialty Care - Infectious Disease	Portland	Maine	United States	04101
10	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
11	Children's Hospital of Michigan - Pediatric Infectious Diseases	Detroit	Michigan	United States	48201
12	University of Mississippi	Jackson	Mississippi	United States	39216-4505
13	Washington University School of Medicine in St. Louis - Center for Clinical Studies	St. Louis	Missouri	United States	63110
14	Mount Sinai Hospital	New York	New York	United States	10029
15	UNY Upstate Medical University Hospital - Pediatrics	Syracuse	New York	United States	13210
16	Carolinas Medical Center	Charlotte	North Carolina	United States	28203
17	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45231
18	MetroHealth Medical Center - Pediatric Infectious Disease	Cleveland	Ohio	United States	44109-1998
19	Nationwide Children's Hospital - Infectious Diseases	Columbus	Ohio	United States	43205
20	Oregon Health and Science University	Portland	Oregon	United States	97201-3098
21	Rhode Island Hospital	Providence	Rhode Island	United States	02903
22	Medical University of South Carolina	Charleston	South Carolina	United States	29425
23	Vanderbilt University	Nashville	Tennessee	United States	37232
24	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390-9063
25	Cook Children's Infectious Disease Services	Fort Worth	Texas	United States	76104
26	University of Texas Health Science Center San Antonio - Pediatrics - Immunology & Infectious Disease	San Antonio	Texas	United States	78229
27	Seattle Children's Hospital - Infectious Diseases	Seattle	Washington	United States	98105
28	University of Alberta - Aberhart Centre - Pediatrics	Edmonton	Alberta	Canada	T6R 2C2

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00031447
• Other Study ID Numbers: 97-006; CASG 104; N01AI30025C; NCT00001099
• First Posted: Mar 7, 2002
• Last Update Posted: May 16, 2012
• Last Verified: Nov 1, 2009

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Herpes Simplex, Acyclovir, Infants
• Additional relevant MeSH terms: Herpes Simplex; Acyclovir

Study Results

Participant Flow

Recruitment Details	Neonates diagnosed with HSV-1 or HSV-2 at least than or equal to 28 days of age as evidenced by infections limited to the skin, eye and mouth with normal CNS and treated with intravenous acyclovir therapy.
Pre-assignment Detail	Participants enrolled while on 2 weeks of IV acyclovir therapy who have positive CSF HSV PCR results within 48 hours prior to IV therapy completion, are not randomized.

Arm/Group Title	Placebo	Acyclovir
Arm/Group Description	Identical to oral acyclovir suspension in appearance and taste. Volume is identical to the administration of active drug.	Oral suspension 300 mg/m^2/dose TID for 6 months.
Period Title: Overall Study
STARTED	14	15
COMPLETED	4	8
NOT COMPLETED	10	7

Baseline Characteristics

Arm/Group Title	Placebo	Acyclovir	Total
Arm/Group Description	Identical to oral acyclovir suspension in appearance and taste. Volume is identical to the administration of active drug.	Oral suspension 300 mg/m^2/dose TID for 6 months.	Total of all reporting groups
Overall Participants	14	15	29
Age, Customized (days) [Median (Full Range) ]
Median (Full Range) [days]	15 (3.76)	15 (2.51)	15 (2.23)
Age, Customized (participants) [Number]
< = 28 days	14 100%	15 100%	29 100%
Between 29 days and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	6 42.9%	5 33.3%	11 37.9%
Male	8 57.1%	10 66.7%	18 62.1%
Region of Enrollment (participants) [Number]
United States	14 100%	14 93.3%	28 96.6%
Canada	0 0%	1 6.7%	1 3.4%

Outcome Measures

1. Primary Outcome

Title	Participants With Neurologic Impairment at 12 Months as Measured by a Bayley's Neuro-developmental Assessment.(Motor Scores)
Description	Motor scores of all participants completing 6 months of blinded therapy as measured by the Bayleys neuro-developmental assessment at 12 months. Scores are classified as the following: greater than or equal to 115 suggests accelerated performance; 85 - 114 suggests development within normal limits; 70 - 84 suggests mildly delayed development and less than or equal to 69 suggests significant delayed development.
Time Frame	At 12 months of life.

Outcome Measure Data

Analysis Population Description

Three of 4 subjects receiving placebo and completing 6 months of placebo, and 2 of 8 subjects receiving acyclovir and completing 6 months of acyclovir did not complete the 12 month Bayley's Neuro-developmental Assessment (motor score); therefore, 1 placebo subject and 6 acyclovir subjects are included in the analysis.

Arm/Group Title	Placebo	Acyclovir
Arm/Group Description	Identical to oral acyclovir suspension in appearance and taste. Volume is identical to the administration of active drug.	Oral suspension 300 mg/m^2/dose TID for 6 months.
Measure Participants	1	6
Number of participants with score of > or = 115	0 0%	3 20%
Number of participants with score of 85 - 114	0 0%	0 0%
Number of participants with score of 70 - 84	1 7.1%	2 13.3%
Number of participants with score of < or = 69	0 0%	1 6.7%

2. Secondary Outcome

Title	Detection of Herpes Simplex Virus (HSV) DNA in the Cerebrospinal Fluid (CSF) by Polymerase Chain Reaction (PCR) at Anytime During the Initial 12 Months of Life.
Description	Number of participants with positive herpes simplex virus (HSV) DNA by polymerase cahin reaction (PCR) in the cerebrospinal fluid of subjects assessed during the initial 12 months of life.
Time Frame	post randomization at 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Acyclovir
Arm/Group Description	Identical to oral acyclovir suspension in appearance and taste. Volume is identical to the administration of active drug.	Oral suspension 300 mg/m^2/dose TID for 6 months.
Measure Participants	4	8
Participants with at least 1 positive PCR	0 0%	0 0%
Participants with negative PCR or not done	4 28.6%	8 53.3%

3. Secondary Outcome

Title	Two or Fewer Episodes of Cutaneous Recurrence of HSV Disease Post-randomization During the Initial 12 Months of Life.
Description	Number of participants experiencing 2 or fewer HSV recurrences during the first 12 months of life as measured by assessments and reports at study visits.
Time Frame	post randomization - 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Acyclovir
Arm/Group Description	Identical to oral acyclovir suspension in appearance and taste. Volume is identical to the administration of active drug.	Oral suspension 300 mg/m^2/dose TID for 6 months.
Measure Participants	4	8
with < or = 2 recurrences of HSV	4 28.6%	7 46.7%
with > 2 recurrences of HSV	0 0%	1 6.7%

4. Primary Outcome

Title	Participants With Neurologic Impairment at 12 Months as Measured by a Bayley's Neuro-developmental Assessment.(Mental Scores)
Description	Mental scores of all participants completing 6 months of blinded therapy as measured by the Bayleys neuro-developmental assessment at 12 months. Scores are classified as the following: less than or equal to 115 suggests accelerated performance; 85 - 114 suggests development within normal limits; 70 - 84 suggests mildly delayed development and less than or equal to 69 suggests significant delayed development.
Time Frame	At 12 months of life.

Outcome Measure Data

Analysis Population Description

Two of 4 subjects receiving placebo and completing 6 months of placebo, and 2 of 8 subjects receiving acyclovir and completing 6 months of acyclovir did not complete the 12 month Bayley's Neuro-developmental Assessment(mental); therefore, 2 placebo subject and 6 acyclovir subjects are included in the analysis.

Arm/Group Title	Placebo	Acyclovir
Arm/Group Description	Identical to oral acyclovir suspension in appearance and taste. Volume is identical to the administration of active drug.	Oral suspension 300 mg/m^2/dose TID for 6 months.
Measure Participants	2	6
Number of participants score with > or = to 115	0 0%	1 6.7%
Number of participants with score 85-114	1 7.1%	1 6.7%
Number of participants with score 70-84	1 7.1%	4 26.7%
Number of participants with < or = to 69	0 0%	0 0%

Adverse Events

Arm/Group Title	Placebo		Acyclovir
Arm/Group Description	Identical to oral acyclovir suspension in appearance and taste. Volume is identical to the administration of active drug.		Oral suspension 300 mg/m^2/dose TID for 6 months.
All Cause Mortality
	Placebo		Acyclovir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Acyclovir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/14 (35.7%)		8/15 (53.3%)
Blood and lymphatic system disorders
Neutropenia	2/14 (14.3%)	3	3/15 (20%)	5
Gastrointestinal disorders
Dehydration	0/14 (0%)	0	1/15 (6.7%)	1
Gastroenteritis	0/14 (0%)	0	1/15 (6.7%)	1
Gastroesophageal refux	0/14 (0%)	0	1/15 (6.7%)	1
Vomiting	0/14 (0%)	0	1/15 (6.7%)	1
General disorders
Fever	0/14 (0%)	0	1/15 (6.7%)	1
Hepatobiliary disorders
Langerhans cell histocytosis	1/14 (7.1%)	1	0/15 (0%)	0
Infections and infestations
Adenoiditis	0/14 (0%)	0	1/15 (6.7%)	1
Gastroenteritis	1/14 (7.1%)	1	0/15 (0%)	0
Herpes simplex virus	1/14 (7.1%)	1	2/15 (13.3%)	2
Lesion unspecified	2/14 (14.3%)	5	1/15 (6.7%)	1
Neutropenia	0/14 (0%)	0	0/15 (0%)	0
Otitis media	0/14 (0%)	0	1/15 (6.7%)	1
RSV	0/14 (0%)	0	1/15 (6.7%)	1
Injury, poisoning and procedural complications
Near drowning	0/14 (0%)	0	1/15 (6.7%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Acyclovir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/14 (57.1%)		13/15 (86.7%)
Blood and lymphatic system disorders
Decreased neutrophils	3/14 (21.4%)	6	5/15 (33.3%)	6
Infections and infestations
Herpes simplex virus	2/14 (14.3%)	7	3/15 (20%)	3
Infection ear	3/14 (21.4%)	4	6/15 (40%)	14
Lesion-unspecified	5/14 (35.7%)	12	5/15 (33.3%)	7
Upper respiratory infection	4/14 (28.6%)	4	5/15 (33.3%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.