A Randomized Double-Blind Control-Comparison Crossover Trial of Oral Glutamine to Suppress Frequently Recurrent Herpes Labialis

Conditions

Herpes Labialis, Herpes Simplex Virus

Keywords

Glutamine, Herpes Labialis, Herpes Simplex Virus, Cold Sore

Brief summary

Background: * A cold sore is usually a blistering rash on or near the lips, caused by infection with herpes simplex virus. After the first infection, the virus goes into a dormant (inactive) state, but it can continue to cause cold sores. * Most people with the herpes simplex virus have a few episodes of cold sores per year. However, some individuals may have many recurrent episodes that are uncomfortable and may cause embarrassment. Researchers are attempting to find treatments that can decrease the number of cold sore episodes for people who have six or more episodes per year. * Glutamine is a molecule called an amino acid and is one of the components that make up proteins in the body. Clinical studies using glutamine have addressed the potential of glutamine to improve immune function and to heal damaged tissue or to help healing. Objectives: \- To find out if the dietary supplement glutamine can help individuals with frequently recurring (more than six episodes per year) cold sores. Eligibility: * Patients between 18 and 65 years of age who have a history of having six or more cold sore episodes per year, and have not received certain kinds of drug treatment for the cold sores within 1 month of beginning the study. * Patients who have two or more episodes of cold sores caused by the herpes simplex virus will be eligible for treatment as part of this study. Design: * Initial clinical visit for a physical examination and medical history, at which blood samples will be drawn for testing. * Eligible participants will undergo a 4-month screening period. Patients who develop sores during this period will visit the NIH to have the sore examined to determine if it is caused by the herpes virus. Patients who have two or more episodes of cold sores caused by the herpes simplex virus will be eligible for treatment. * Patients who are eligible for treatment will provide an initial blood sample and will receive randomized doses of either glutamine or glycine (another amino acid), which must be taken on a regular schedule twice daily, mixed with either liquid or soft food. Patients who develop sores during this period will visit the NIH to have the sore examined to determine if it is caused by the herpes virus. Blood, urine, and saliva specimens will be collected each month during the treatment period. A 2-week washout period will occur between the 2 treatment periods when no doses of glutamine or glycine will be taken. * Patients will then undergo a second 5-month treatment period with either glutamine or glycine (whichever was not given in the first part of the study), taken in the same manner as before. Patients who develop sores during this period will visit the NIH to have the sore examined to determine if it is caused by the herpes virus. * After the second treatment, patients will remain in touch with researchers for 1 month to note any changes.

Detailed description

Frequently recurrent herpes simplex virus type 1 (HSV-1) infection of the lips or perioral area, known as herpes labialis, or commonly as cold sores, can cause discomfort, pain, and embarrassment. Traditional antiviral therapies are moderately effective in suppressing these recurrences. Studies have shown that the amino acid glutamine can affect HSV-1 reactivation in vitro. Glutamine has been studied in various clinical situations and has been found to decrease morbidity in critically ill patients (reducing nosocomial infections), in patients receiving chemotherapy or undergoing bone marrow transplantation (reducing severity of stomatitis, reducing incidence of infection, shortening hospital stay), and in patients with short gut syndrome (decreasing requirement for parenteral nutrition). No significant adverse consequences of glutamine therapy have been reported in these patients. We will conduct a randomized, double-blind, control-comparison crossover trial comparing the efficacy of glutamine versus glycine (control) to suppress recurrences of herpes labialis in patients with frequent episodes (greater than or equal to 6 per year). Based on our in vitro and in vivo data, we hypothesize that oral glutamine will decrease the number of recurrences of herpes labialis during a 5-month treatment period in participants with frequently recurring herpes labialis compared with control.

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Interventions

DRUGGlutamine

Subjects were randomized to take one of the study agents, 15 gm by mouth twice daily for 5 months. After a 2 week washout period, subjects began the other agent at 15 gm by mouth twice daily for 5 months.

DRUGGlycine

Subjects were randomized to take one of the study agents, 15 gm by mouth twice daily for 5 months. After a 2 week washout period, subjects began the other agent at 15 gm by mouth twice daily for 5 months.

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

PREVENTION

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

No

Inclusion criteria

* INCLUSION CRITERIA: 1. Adults, ages 18 to 65, who report a history of 6 or more episodes of herpes labialis per year. 2. Subject agrees to refrain from using over the counter (OTC), prescription or supplemental antiviral medications without obtaining permission from the study team during the course of the study. 3. Women with child-bearing potential are required and willing to practice two effective methods of birth control beginning with the first treatment period and continuing until the end of the study. 4. Women with child-bearing potential are required to have a negative pregnancy test at the time of enrollment and at the time of randomization. 5. To be eligible for randomization in the treatment phase of the study, the participants must experience at least 2 clinically confirmed episodes of herpes labialis, 1 of which must be virologically confirmed, during the 4 month screening period.

Exclusion criteria

1. Oral or intravenous antiviral therapy \< 4 weeks before enrollment or during the study with the following agents is not permitted: acyclovir (intravenous), ganciclovir (intravenous or oral), valganiciclovir (oral), cidofovir (intravenous), or foscarnet (intravenous). 1. Suppressive therapy with oral acyclovir, valacyclovir or famciclovir or with topical antivirals 4 weeks prior to enrollment or during the study is not permitted. 2. Use of oral acyclovir or valacyclovir or famciclovir or topical antiviral ointments or creams for the treatment of herpes labialis outbreaks during the study is permitted AFTER the outbreak has been documented by the study team.. 2. Evidence of active herpes labialis reactivation at the time of enrollment. The volunteer can be enrolled after resolution of herpes labialis and if inclusion and

Design outcomes

Primary

Measure	Time frame	Description
Does Oral Glutamine Reduce the Number of Recurrences of Herpes Labialis, Diagnosed by Clinical and Microbiologic Criteria, in Healthy Participants With Frequently Recurrent Disease.	The screening phase time frame was 4 months. Treatment phase 1 was 5 months. Washout phase was 2 weeks. Treatment phase 2 was 5 months.	During all phases of the study, participants returned to clinic whenever they had a herpes labialis outbreak for staff to assess, obtain a viral swab and document. If unable to return to clinic in the time frame specified in the protocol, participants would take a photo and obtain a swab of the lesion. The number of outbreaks would be measured during each phase.

Secondary

Measure	Time frame	Description
Does Oral Glutamine Reduce the Number of Clinical Recurrences of Herpes Labialis With or Without PCR Confirmation?	The screening phase time frame was 4 months. Treatment phase 1 was 5 months. Washout phase was 2 weeks. Treatment phase 2 was 5 months.	During all phases of the study, participants returned to clinic whenever they had a herpes labialis outbreak for staff to assess, obtain a viral swab and document. If unable to return to clinic in the time frame specified in the protocol, participants would take a photo and obtain a swab of the lesion. The number of recurrences would be documented during each phase of the study.
Does Oral Glutamine Reduce the Time to First Recurrence of Herpes Labialis Diagnosed by Clinical and Microbiologic Criteria or Diagnosed by Clinical Criteria With or Without PCR Confirmation?	The screening phase time frame was 4 months. Treatment phase 1 was 5 months. Washout phase was 2 weeks. Treatment phase 2 was 5 months.	During all phases of the study, participants returned to clinic whenever they had a herpes labialis outbreak for staff to assess, obtain a viral swab and document. If unable to return to clinic in the time frame specified in the protocol, participants would take a photo and obtain a swab of the lesion. The number of recurrences and start and end dates of each recurrence would be documented during each phase of the study.
Does Oral Glutamine Reduce the Duration of Recurrences?	The screening phase time frame was 4 months. Treatment phase 1 was 5 months. Washout phase was 2 weeks. Treatment phase 2 was 5 months.	During all phases of the study, participants returned to clinic whenever they had a herpes labialis outbreak for staff to assess, obtain a viral swab and document. If unable to return to clinic in the time frame specified in the protocol, participants would take a photo and obtain a swab of the lesion. The number of recurrences and start and end dates of each recurrence would be documented.
Does Oral Glutamine Reduce the Area of Recurrent Lesions?	The screening phase time frame was 4 months. Treatment phase 1 was 5 months. Washout phase was 2 weeks. Treatment phase 2 was 5 months.	During all phases of the study, participants returned to clinic whenever they had a herpes labialis outbreak for staff to assess, obtain a viral swab and document. If unable to return to clinic in the time frame specified in the protocol, participants would take a photo and obtain a swab of the lesion. The number of recurrences, start and end dates of each recurrence and measurement of each lesion during each phase of the study would be documented.

Countries

United States

Participant flow

Recruitment details

Recruitment began in November 2009 at the NIH Clinical Center outpatient clinic. Eleven study participants were enrolled and screened from 11/2009 - 11/2010. Two of these participants proceeded to the treatment phase of the study.

Pre-assignment details

Participants were enrolled and randomized to the treatment phase only if they met the eligibility criteria after completing the 4 month screening phase. After completion of phase 1 of treatment, there was a 2 week wash out period before beginning phase 2 of treatment.

Participants by arm

Arm	Count
Glutamine (Study Agent) or Glycine (Placebo) Participants were enrolled and monitored to document presence of 2 clinically confirmed episodes of herpes labialis, 1 of which must be virologically confirmed, during the screening period. Participants took 15 gm of study agent or placebo by mouth twice daily for 5 months followed by a 2 week wash-out. Then participants took the other agent for another 5 months.	11
Total	11

Arm

Count

Glutamine (Study Agent) or Glycine (Placebo)

Participants were enrolled and monitored to document presence of 2 clinically confirmed episodes of herpes labialis, 1 of which must be virologically confirmed, during the screening period. Participants took 15 gm of study agent or placebo by mouth twice daily for 5 months followed by a 2 week wash-out. Then participants took the other agent for another 5 months.

11

Total

11

Withdrawals & dropouts

Period	Reason	FG000
Screening (4 Months)	Not eligible after screening phase.	6
Screening (4 Months)	Physician Decision	3
Treatment Phase 1 (5 Months)	Physician Decision	1

Baseline characteristics

Characteristic	Glutamine (Study Agent) or Glycine (Placebo)
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	11 Participants
Age Continuous	38 years STANDARD_DEVIATION 10.97
Region of Enrollment United States	11 participants
Sex: Female, Male Female	7 Participants
Sex: Female, Male Male	4 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	2 / 2	1 / 1	1 / 1
serious Total, serious adverse events	0 / 2	0 / 1	0 / 1

Outcome results

Primary

Does Oral Glutamine Reduce the Number of Recurrences of Herpes Labialis, Diagnosed by Clinical and Microbiologic Criteria, in Healthy Participants With Frequently Recurrent Disease.

During all phases of the study, participants returned to clinic whenever they had a herpes labialis outbreak for staff to assess, obtain a viral swab and document. If unable to return to clinic in the time frame specified in the protocol, participants would take a photo and obtain a swab of the lesion. The number of outbreaks would be measured during each phase.