Clinical trial NCT00913692: A Randomized Double-Blind Control-Comparison Crossover Trial of Oral Glutamine to Suppress Frequently Recurrent Herpes Labialis
Official title: A Randomized Double-Blind Control-Comparison Crossover Trial of Oral Glutamine to Suppress Frequently Recurrent Herpes Labialis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Herpes Labialis
Herpes Simplex Virus
Keywords: Glutamine
Herpes Labialis
Herpes Simplex Virus
Cold Sore
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2009-06-04
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: PREVENTION

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.

Eligibility 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 exclusion criteria are still met.
3. Subjects with conditions associated with immunodeficiency (e.g., human immunodeficiency virus infection) or conditions requiring either daily systemic corticosteroids exceeding a dose equivalent to10 mg/day of prednisone or other significant immunosuppressant therapy (e.g., organ or stem cell transplantation).
4. Persons with significant liver or kidney disease \[serum glutamic oxaloacetic transaminase \[SGOT\], serum glutamine pyruvic transaminase \[SGPT\], or alkaline phosphatase \> 2.5 times the upper limit of normal (ULN), total bilirubin \> 1.5 times the ULN, or serum creatinine \> 1.5 times the ULN\].
5. Persons with an active seizure disorder. For persons with prior history of seizures, the person should be seizure free for 5 years and not on any anti-seizure medication in order to be enrolled into the study. (Since glutamine is metabolized to glutamate and ammonia, and glutamate is the main excitatory neurotransmitter in the central nervous system (CNS), there is a theoretical increased risk of seizures).
6. Women who are known to be pregnant (pregnancy category C) or breastfeeding (it is not known whether glutamine is excreted in human milk).
7. History of allergic reaction to glutamine or glutamic acid or their derivatives (e.g., monosodium glutamate) or to glycine or sucralose.
8. Subjects cannot take supplemental amino acids (e.g., glutamine, glycine, arginine, other amino acids) or high protein supplements, such as Boost within 30 days of enrollment into the study or during the study (except for study drug amino acid). Subjects can take vitamins.
9. Persons treated with atypical neuroleptics such as clozapine (Clozaril, FazoCIo) or olanzapine (Zyprexa, Zydis).
10. Participation in any study involving investigational drugs within 30 days prior to entry into this trial.
11. Any condition (e.g., schizophrenia, psychosis, major depression, mental deficiency or illness) or major co-morbidity that the study investigator thinks might compromise the person's ability to comply with the requirements of the study.

Primary outcomes:
measure: Does Oral Glutamine Reduce the Number of Recurrences of Herpes Labialis, Diagnosed by Clinical and Microbiologic Criteria, in Healthy Participants With Frequently Recurrent Disease.
timeFrame: 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.
Secondary outcomes:
measure: Does Oral Glutamine Reduce the Number of Clinical Recurrences of Herpes Labialis With or Without PCR Confirmation?
timeFrame: 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.
measure: 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?
timeFrame: 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.
measure: Does Oral Glutamine Reduce the Duration of Recurrences?
timeFrame: 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.
measure: Does Oral Glutamine Reduce the Area of Recurrent Lesions?
timeFrame: 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.
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
References:
citation: Anderson PM, Ramsay NK, Shu XO, Rydholm N, Rogosheske J, Nicklow R, Weisdorf DJ, Skubitz KM. Effect of low-dose oral glutamine on painful stomatitis during bone marrow transplantation. Bone Marrow Transplant. 1998 Aug;22(4):339-44. doi: 10.1038/sj.bmt.1701317.
citation: Aquino VM, Harvey AR, Garvin JH, Godder KT, Nieder ML, Adams RH, Jackson GB, Sandler ES. A double-blind randomized placebo-controlled study of oral glutamine in the prevention of mucositis in children undergoing hematopoietic stem cell transplantation: a pediatric blood and marrow transplant consortium study. Bone Marrow Transplant. 2005 Oct;36(7):611-6. doi: 10.1038/sj.bmt.1705084.
citation: Baker D, Eisen D. Valacyclovir for prevention of recurrent herpes labialis: 2 double-blind, placebo-controlled studies. Cutis. 2003 Mar;71(3):239-42.